Gastroenterology Clinical Focus, 3e

Gastroenterology
Clinical Focus
High yield GI and hepatology review
for boards and practice
Third edition
Emad Qayed, M.D., M.P.H.

Gastroenterology Clinical Focus-(Standard Paperback Format, size 8 x 10 inch)
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Gastroenterology Clinical Focus
Preface
"We are drowning in information and starving for knowledge." – Rutherford D. Roger
Gastroenterology is an exciting and enjoyable specialty covering a diverse group of interesting disorders. The specialty
requires that we learn and maintain an up-to-date body of knowledge and a set of endoscopic skills to perform various
procedures. This can prove challenging for the GI trainee and the practicing gastroenterologist.
Most first-time test takers for the GI boards (> 90%) will pass the exam. However, the GI board exam remains an
expensive and certainly stressful experience that requires adequate preparation and a focused review. Preparing for the
boards or recertification exams is an opportunity to shore up our knowledge and reinforce the fundamentals of our daily
practice, rather than just review "board favorite" questions. Many GI books present information in an uninteresting,
digressive format, making it hard to grasp important concepts and gain the intended knowledge. There is a great need for
a comprehensive GI review book that is simple and to the point.
Gastroenterology Clinical Focus, third edition, is a concise, high-yield, up-to-date review book that aims at helping GI trainees
and practicing physicians expand their knowledge and enhance their practice of gastroenterology and general hepatology.
This book focuses on clinically relevant topics and concepts that are important for the daily GI clinical practice as well as
the boards and recertification exams.
The content of this book is presented in a simple format with easy-to-read bullet points. Most tables and figures are
presented in line with the text for a smooth reading experience. This book references the current guidelines at the beginning
of many of its topics. The guidelines can easily be accessed by scanning a QR code using a wireless-enabled smartphone
or tablet. Alternatively, you can search for the documents on the web. Most guidelines are available free of charge for the
public. While practice guidelines (and guidance documents) are not perfect, it is important that we use these documents to
augment our knowledge and ensure that we practice according to the accepted standard of care.
In the "study highlight" section, I have selected specific studies based on their clinical implications and relevance to the
presented topic. A QR code links each topic to the study, should you wish to read the article. There are other studies
referenced in this book that are not highlighted. I advise you to look up the studies that interest you and to read the
introduction, methods and results. Make your own summaries and highlights!
This book offers many GI educational videos covering various topics. These videos can be accessed using the
accompanying QR code, or by typing the link into a web browser. These links are listed at the end of the book.
This book is published on a print-on-demand publishing platform (Kindle Direct Publishing). The major
advantage of such a platform is the ability to continuously update the book to keep up with the constantly changing
clinical practice of gastroenterology. As such, this third edition contains updates relating to trials and guidelines
published up to January 2022.
In summary, this updated third edition of Gastroenterology Clinical Focus is a concise, up-to-date, high-yield review that will
help GI trainees and practicing gastroenterologists strengthen their clinical knowledge and excel on the GI board exams.
A lot of time and effort was put into this book, and I am glad you have decided to use it for your studies.
Happy reading!
Emad Qayed, MD, MPH, FACG, AGAF

Chief of Gastroenterology, Grady Memorial Hospital
Associate Professor of Medicine, Department of Medicine, Division of Digestive Diseases
Emory University School of Medicine, Atlanta, GA
WWW . FACEBOOK . CO M /G ASTROENTEROLO GY C LINI CAL F O CUS @G I C LINI CAL F O CUS EQAYED @E M ORY . EDU
Dedication
To my wife Yara and my children Bassem, Zaina, and Mazen
To all my GI trainees and colleagues
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TABLE OF CONTENTS
Chapter 1- Esophagus ....................................... 1 Small Intestinal Bacterial Overgrowth..........................57

Gastroesophageal Reflux Disease (GERD)..................... 3 Short Bowel Syndrome.................................................59
Endoluminal therapies .............................................. 6 Celiac disease................................................................60
Refractory GERD and functional heartburn.............. 6 Whipple disease ...........................................................64
Extraesophageal GERD.............................................. 8 Small intestinal tumors.................................................64
Barrett's Esophagus........................................................ 9 Small intestinal lymphoma...........................................65
Eosinophilic Esophagitis ............................................... 13 References ....................................................................66
Cricopharyngeal bar ..................................................... 15 Chapter 4-Liver................................................ 65
Tumors of the esophagus ............................................ 16 Liver function tests........................................................69
Caustic ingestions ......................................................... 17 Liver disease in pregnancy............................................70
Motility disorders of the esophagus............................ 19 Hemochromatosis and iron overload syndromes.......72
Esophagitis in HIV ......................................................... 27 Wilson disease ..............................................................75
References .................................................................... 28 Alpha one antitrypsin deficiency..................................77
Chapter 2- Stomach ........................................ 29 Viral hepatitis ................................................................78
Gastroparesis................................................................ 33 Hepatitis A.....................................................................78
Cyclic Vomiting Syndrome ........................................... 35 Hepatitis B.....................................................................79
Rumination syndrome ................................................. 35 Acute hepatitis B ......................................................79
Dyspepsia...................................................................... 36 Chronic Hepatitis B...................................................79
Helicobacter pylori ....................................................... 39 Chronic hepatitis B and pregnancy..........................83
Hypergastrinemia and Zollinger-Ellison syndrome ..... 43 Occupational exposure to hepatitis B .....................83
Gastric polyps ............................................................... 45 HBV prophylaxis in patients receiving
Gastric intestinal metaplasia ........................................ 46 immunosuppressants ..............................................84
Gastric adenocarcinoma .............................................. 48 Hepatitis C .....................................................................86
Hereditary diffuse gastric cancer ................................. 49 Treatment of hepatitis C ..........................................86
Gastric lymphoma........................................................ 50 Occupational exposure to hepatitis C .....................87
References .................................................................... 51 HCV sexual transmission..........................................87
Chapter 3-Small intestine ............................... 51 Hepatitis D.....................................................................88
Malabsorption.............................................................. 55 Hepatitis E .....................................................................88
Diarrhea after ileal resection ................................... 55 Pyogenic liver abscess ..................................................88
Fat malabsorption.................................................... 55 Vascular diseases of the liver........................................89
Protein losing enteropathy...................................... 56 Budd-Chiari Syndrome.............................................89
Carbohydrate malabsorption.................................. 57 Portal vein thrombosis.............................................90

Sinusoidal obstruction syndrome............................92 Gall bladder disease ................................................... 137
Congestive hepatopathy..........................................92 Gallstones .............................................................. 137
Alcoholic liver disease...................................................93 Sphincter of Oddi dysfunction .............................. 138
Nonalcoholic fatty liver disease....................................95 Choledocholithiasis ............................................... 138
Drug Induced Liver Injury .............................................98 Gallbladder polyps................................................. 139
Acetaminophen toxicity........................................ 100 Cholangiocarcinoma.............................................. 139
Autoimmune Hepatitis.............................................. 101 Biliary complications after liver transplantation........ 140
Primary sclerosing cholangitis ................................... 103 Biliary strictures ..................................................... 141
Primary Biliary Cholangitis......................................... 105 Bile leak .................................................................. 142
Acute fulminant liver failure ...................................... 108 References.................................................................. 143
Complications of cirrhosis and portal hypertension. 110 Chapter 6- Pancreas ...................................... 139
Ascites.................................................................... 110 Developmental anomalies......................................... 147
Surgical risk assessment in cirrhosis ..................... 113 Acute pancreatitis ...................................................... 149
Hepatic Encephalopathy....................................... 113 Chronic Pancreatitis ................................................... 153
Hepatorenal syndrome......................................... 115 Etiology .................................................................. 153
Portopulmonary hypertension............................. 115 Diagnosis................................................................ 154
Hepatopulmonary syndrome............................... 116 Treatment .............................................................. 154
Benign Liver tumors................................................... 117 Complications ........................................................ 157
Hemangioma......................................................... 117 Autoimmune pancreatitis.......................................... 160
Hepatocellular adenoma ...................................... 117 Pancreatic cysts .......................................................... 162
Focal nodular hyperplasia ..................................... 118 Intraductal papillary mucinous neoplasm ............ 163
Hepatic cysts.......................................................... 118 Mucinous cystic neoplasm.................................... 163
Nodular regenerative hyperplasia ........................ 119 Serous cystadenoma ............................................. 164
Primary Liver Malignancies ....................................... 119 Solid pseudopapillary neoplasm........................... 164
Hepatocellular carcinoma..................................... 119 Pancreatic adenocarcinoma.................................. 165
Fibrolamellar HCC.................................................. 124 Pancreatic neuroendocrine Neoplasms.................... 168
Intrahepatic cholangiocarcinoma......................... 124 Insulinoma ............................................................. 168
Liver transplantation.................................................. 124 Gastrinoma ............................................................ 169
References.................................................................. 127 Glucagonoma ........................................................ 169
Chapter 5- Biliary tract.................................. 133 VIPoma................................................................... 169
Anatomy and developmental anomalies ................. 135 Somatostatinoma.................................................. 169
Bile duct anatomy ................................................. 135 Familial syndromes associated with pNETs .......... 170
Pancreaticobiliary maljunction.................................. 135 References.................................................................. 171
Choledochal cysts.................................................. 136 Chapter 7 - GI bleeding .................................. 173
Peptic ulcer disease bleeding..................................... 175 Acute colonic pseudo-obstruction (Ogilvie's syndrome)
Gastric Stress ulcers.................................................... 179 .....................................................................................224
UGI bleeding in patients with cirrhosis...................... 179 Colonic polyps.............................................................225
Acute variceal bleeding .............................................. 180 Paris classification of colonic neoplasia......................226
Primary prophylaxis of esophageal variceal bleeding183 Gastrointestinal polyposis syndromes .......................226
Secondary prophylaxis of esophageal variceal bleeding Adenomatous polyposis syndromes .........................227

.................................................................................... 185 Familial adenomatous polyposis ...........................228
Portal hypertensive gastropathy................................ 185 Attenuated FAP ......................................................229
Gastric Antral Vascular Ectasia ................................... 185 MutYH (MYH) associated polyposis. .....................229
Lower GI bleeding ...................................................... 186 Hamartomatous polyposis syndromes......................229
Small bowel and Obscure GI bleeding....................... 187 Peutz-Jeghers syndrome........................................229
References .................................................................. 190 Juvenile polyposis syndrome.................................230
Chapter 8- Large intestine ............................ 193 Cowden syndrome.................................................230
Gastrointestinal infections ......................................... 195 Bannayan-Riley-Ruvalcaba syndrome...................231
Bacterial infections................................................. 195 Serrated polyposis syndrome.....................................231
Viral infections........................................................ 199 Cronkhite-Canada Syndrome.....................................232
Parasitic infections ................................................. 200 Lynch Syndrome and Hereditary Nonpolyposis Colorectal
Trichuris Trichiura (Whipworm)............................. 201 Cancer .........................................................................232
Traveler's diarrhea ................................................. 201 .....................................................................................232
Food poisoning ...................................................... 202 Colorectal cancer ........................................................235
Clostridioides difficile infection................................... 204 Management of advanced and malignant polyps ....239
Chronic diarrhea......................................................... 209 Colon cancer screening ..............................................240
Chronic constipation .................................................. 211 Stool testing............................................................241
Irritable bowel syndrome........................................... 214 Other tests..............................................................242
Non-IBD colitides........................................................ 217 Colonoscopy...........................................................242
Microscopic colitis.................................................. 217 Flexible sigmoidoscopy ..........................................245
Diversion colitis ...................................................... 219 CT colonography ....................................................245
Chronic radiation proctitis ..................................... 219 Polyp surveillance .......................................................245
Immune checkpoint inhibition-induced colitis References ..................................................................247

(Immune-mediated colitis).................................... 220 Chapter 9- Inflammatory bowel disease ....... 253
Segmental Colitis Associated with Diverticulosis (SCAD) Clinical evaluation and basic concepts.......................255
................................................................................ 221 Treatment of ulcerative colitis....................................260
Ischemic colitis ....................................................... 221 5-aminosalicylates..................................................260
Melanosis Coli ............................................................ 223 Corticosteroids .......................................................262
Thiopurines............................................................ 262 Chapter 10- Miscellaneous GI topics.............. 301
Methotrexate ........................................................ 265 Nutrition ..................................................................... 303
Treatment of acute severe ulcerative colitis ............. 266 Gastrointestinal Neuroendocrine Neoplasms .......... 306
Treatment of Crohn’s disease.................................... 268 Gastric neuroendocrine neoplasms ..................... 308
5 aminosalicylates ................................................. 268 Duodenal Neuroendocrine Neoplasms................ 310
Corticosteroids ...................................................... 268 Small Intestine Neuroendocrine Neoplasms........ 310
Methotrexate ........................................................ 269 Appendiceal Neuroendocrine Neoplasms ........... 311
Antibiotics.............................................................. 269 Colonic Neuroendocrine Neoplasms.................... 311
Thiopurines............................................................ 269 Rectal Neuroendocrine Neoplasms...................... 312
Biologic therapy for ulcerative colitis and Crohn’s disease Carcinoid syndrome .............................................. 313
.................................................................................... 269 Carcinoid Heart Disease ........................................ 314
Biosimilars .................................................................. 272 Gastrointestinal stromal tumors................................ 314
Fistulizing and perianal Crohn’s disease.................... 273 References.................................................................. 316
Biologic therapy for Crohn’s disease ......................... 273 Chapter 11-Endoscopy ................................... 317
Therapeutic drug monitoring .................................... 274 Endoscopy in pregnancy............................................ 319
Selected trials of biologics in inflammatory bowel Capsule endoscopy .................................................... 320
disease ................................................................... 276
Endoscopic Retrograde Cholangiopancreatography (ERCP)
IBD and colorectal cancer .......................................... 279 .................................................................................... 321
Extra-intestinal manifestations of IBD....................... 283 ERCP adverse events ............................................. 321
Surgical therapy for ulcerative colitis......................... 284 Techniques for biliary access in difficult cannulation322
Ileal pouch anal anastomosis................................ 284 Techniques without precut papillotomy............... 323
Surgical therapy for Crohn’s disease and post-operative Techniques with precut papillotomy .................... 323
management ............................................................. 286
Sphincteroplasty for extraction of large bile duct stones
Approach to the management of the post-operative ................................................................................ 325
patient with Crohn’s disease................................. 288
Cholangioscopy ..................................................... 326
Endoscopic management of Crohn’s disease strictures
............................................................................... 290 ERCP for hilar strictures ......................................... 326
Fertility and pregnancy issues in IBD......................... 292 Enteral stenting .......................................................... 328
IBD and fertility...................................................... 292 Endoscopic Ultrasound.............................................. 329

Detachable snares (endoloops)................................. 330
General management concepts for IBD before and
during pregnancy .................................................. 292 Endoscopy in the bariatric surgery patient ............... 330
Medication safety and management during pregnancy Endoscopy in the bariatric surgery patient ............... 331
............................................................................... 293 References.................................................................. 334
References.................................................................. 295 Links to the video content ............................. 335
1
1
CHAPTER
Esophagus
Esophageal disorders are common in clinical practice, and they account for 10% of board
questions. The main disorders are GERD, Barrett's esophagus, and achalasia. All of these topics
have recent guidelines with informative summary points. The AGA published a practice update
that outlines the approach to refractory and functional heartburn, and focus on obtaining
objective diagnostic tests of GERD. Eosinophilic esophagitis is relatively uncommon; however,
it is increasing in incidence. Updated diagnostic guidelines were recently published that removed
the need for PPI trial to diagnose EoE, and currently PPIs are considered a treatment option for
EoE. While no medication is FDA approved for EoE, new budesonide and fluticasone
formulations are under development. The Chicago 4.0 classification was published in January
2021 and includes important updates about the performance and interpretation of high
resolution manometry (HRM), especially as it relates to the HRM protocol, and definition of
esophagogastric outflow obstruction and ineffective esophageal motility
New concepts relating to the esophagus include Barrett’s esophagus (non-endoscopic screening,
sample acquisition techniques, ablation techniques, and follow up after endoscopic ablation),
eosinophilic esophagitis (revised definition, and recent budesonide trials), and trials comparing
different achalasia therapies, including per oral endoscopic myotomy (POEM). Functional
luminal imaging probe (FLIP-impedance planimetry) is an emerging technology to examine
esophageal contractions and LES function.
2 Chapter 1: Esophagus
Contents
Chapter 1- Esophagus
Gastroesophageal Reflux Disease (GERD)—3
Endoluminal therapies—6
Refractory GERD and functional heartburn—6
Extraesophageal GERD—8
Barrett's Esophagus—9
Eosinophilic Esophagitis—13
Cricopharyngeal bar—15
Tumors of the esophagus—16
Caustic ingestions—17
Motility disorders of the esophagus—19
Esophagitis in HIV—27
References—28
Chapter 1: Esophagus 3
Gastroesophageal Reflux Disease (GERD)
ACG Clinical Guideline for the Diagnosis and Management Am J Gastroenterol,

of Gastroesophageal Reflux Disease1 2022
Modern diagnosis of GERD: the Lyon Consensus 2 Gut, 2018
AGA Clinical Practice Update on Functional Heartburn:

AGA 2020
Expert Review 3
ACG Clinical Guidelines: Clinical Use of Esophageal Am J Gastroenterol,
Physiologic Testing 4 2020
Surgical endoscopy,
SAGESs guidelines for the surgical treatment of GERD 5
2021
 Pathophysiology
 The most common causes of GERD are a weak lower esophageal sphincter (LES) and increased frequency
of transient lower esophageal sphincter relaxations (TLESR). Other contributing factors: hiatal hernia,
gastric hyperacidity, delayed gastric emptying, increased intra-abdominal pressure.
 Clinical manifestations
 Esophageal symptoms: heartburn, regurgitation, dysphagia, odynophagia, chest pain.
 Extra-esophageal manifestations: asthma, cough, and laryngitis (described on page 8).
 GERD is the most common cause of non-cardiac chest pain.
 Exclude cardiac disease in older patients and those with cardiac risk factors.
 PPI therapy is effective in non-cardiac chest pain.
 In patients with prominent regurgitation symptoms, an important differential diagnosis of GERD is
rumination syndrome (see chapter 2).
 Endoscopic findings:
 Indication for endoscopy in patients with GERD:6 Reflux symptoms unresponsive to medical therapy, dysphagia,
odynophagia, weight loss, GI bleeding, abnormal imaging, persistent vomiting, recurrent symptoms following
endoscopic or surgical therapy. For EGD screening for Barrett’s Esophagus, see page 9.
 Most patients with GERD will have a normal endoscopy (Non-Erosive Reflux Disease-NERD).
 Perform EGD off PPI for 2-4 weeks.1 Document and describe the presence of esophagitis, Barrett’s
esophagus, strictures, hiatal hernia.
 Erosive esophagitis: linear erosions starting at the gastroesophageal (GE) junction, which may progress to
involve larger areas leading to circumferential involvement and stricture formation.
 Los Angeles Classification system of erosive esophagitis :
o LA class A: one or more mucosal breaks < 5 mm in length.

o LA class B: one or more mucosal breaks > 5 mm in length.
o LA class C: mucosal breaks extend between ≥ 1 mucosal folds, involving < 75% esophageal circumference.
o LA class D: mucosal breaks extend between ≥ 1 mucosal folds, involving > 75% esophageal circumference.
 In many cases, describing the exact extent and severity of inflammation is more useful than categorizing
esophagitis into one of the above classes. The presence of erosive esophagitis (class C or D) and/or long
Barrett’s esophagus is specific for GERD, and precludes the need for pH testing.1 LA class B esophagitis
is diagnostic of GERD if there are typical GERD symptoms and PPI response. 1
 Patients with severe erosive esophagitis should undergo a repeat EGD after PPI treatment to evaluate for
the presence of Barrett's esophagus.
 While performing retroflexion, carefully examine the cardia and describe the integrity of the
gastroesophageal flap valve (figure 1).
Figure 1: Hill classification of the gastro-esophageal flap valve. Type 1: Prominent fold of tissue that is
snug around the endoscope. Type 2: The tissue around the scope is less snug and may open intermittently with respiration.
Type 3: The tissue does not close around the endoscope. Type 4: sliding hiatal hernia, no flap valve, and visible squamous
mucosa of the esophagus.
 Manometry
 Manometry has a limited role in the diagnosis of GERD. See page 7 for its role in defining functional
heartburn. It is required prior to surgical fundoplication to rule out motility disorders. Most patients with
GERD will have a normal manometry.
 Role of pH monitoring
 Document abnormal esophageal acid exposure in non-erosive GERD before antireflux surgery.
 Evaluate patients with persistent symptoms after anti-reflux surgery.
 Evaluate patients with reflux symptoms refractory to PPI (see page 6).
 Evaluate patients with non-cardiac chest pain, asthma, or Extraesophageal GERD symptoms (see page 8).
 Wireless pH recording (e.g. BRAVO®)
 The pH-monitoring capsule is placed 6 cm above the GE junction during a sedated upper endoscopy.
 The patient continues a usual diet, and records symptoms over the duration of the study.
 Components of the pH monitoring study are listed in table 1.
 Acid reflux is defined as a decrease in pH to < 4.
 GERD is defined as a total acid exposure time of >6% of the duration of the study.
Table 1: Components of the pH monitoring study
Measures of association between
Measures of reflux duration*
reflux and symptoms
Components  Percent total time pH < 4 (acid exposure time) †  Symptom index (SI)
 Percent upright time pH < 4  Symptom sensitivity index (SSI)
 Percent supine time pH < 4  Symptom association probability
 Number of reflux episodes (SAP)
 Number of reflux episodes ≥ 5 minutes
 Longest reflux episode (minutes)
*The composite pH Score (DeMeester) is calculated based upon these components. It is abnormal if >14.7
† Normal acid exposure time (< 4%), borderline (4-6%), abnormal (> 6% defines GERD)
 Prolonged monitoring up to 96 hours is advised if symptoms are infrequent, if clinical suspicion of GERD is high but
negative prior studies. If there is low clinical suspicion of GERD, prolonged monitoring reliably rules out GERD.7
 Symptom index and symptom sensitivity index (table 2) are used to correlate GERD symptoms
(regurgitation, heartburn, chest pain) with acid exposure events (pH of < 4), and provide an estimate of
the strength of association between symptoms and acid reflux. 8
Table 2: Symptom index and symptom sensitivity index8

Symptom Index (SI) Symptom sensitivity index (SSI)
Definition Percentage of symptom episodes that occur Percentage of reflux episodes associated
at the time of documented pH < 4 with symptoms
Calculation 𝐧𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐫𝐞𝐟𝐥𝐮𝐱 𝐫𝐞𝐥𝐚𝐭𝐞𝐝 𝐬𝐲𝐦𝐩𝐭𝐨𝐦 𝐞𝐩𝐢𝐬𝐨𝐝𝐞𝐬
× 𝟏𝟎𝟎%
𝐧𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐫𝐞𝐟𝐥𝐮𝐱 𝐫𝐞𝐥𝐚𝐭𝐞𝐝 𝐬𝐲𝐦𝐩𝐭𝐨𝐦 𝐞𝐩𝐢𝐬𝐨𝐝𝐞𝐬
× 𝟏𝟎𝟎%
𝐭𝐨𝐭𝐚𝐥 𝐧𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐬𝐲𝐦𝐩𝐭𝐨𝐦 𝐞𝐩𝐢𝐬𝐨𝐝𝐞𝐬 𝐭𝐨𝐭𝐚𝐥 𝐧𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐫𝐞𝐟𝐥𝐮𝐱 𝐞𝐩𝐢𝐬𝐨𝐝𝐞𝐬
Threshold Abnormal if > 50% Abnormal if >10%

 Symptom association probability (SAP)
o SAP expresses the likelihood that the patient's symptoms are related to reflux.
o By using complex computerized statistical methods, SAP is calculated as the probability that the
association between reflux and symptoms did not occur by chance.
● A SAP of > 95% is considered positive, and indicates that the probability that the observed reflux-
symptom association occurred by chance is less than 5%.8, 9
 Transnasal 24-hour pH impedance monitoring measures acidic, non-acidic, alkaline, or gaseous reflux7.
 Esophageal manometry is required for accurate placement of the catheter.
 The test is useful in patients with proven GERD and refractory symptoms despite PPI, patients with
suspected extra-esophageal GERD symptoms (see pages 7 and 8), belching disorders, patients with post
prandial belching, regurgitation and suspicion of rumination syndrome. 7
 Treatment: Consider selective lifestyle modifications for some patients (weight loss, stop smoking, elevate
head of bed, small meals, avoiding alcohol/caffeine)
 Medical therapy
 H2 blockers are reasonable for mild and infrequent GERD.
 PPIs are the mainstay of treatment for more severe GERD.PPIs covalently bind and irreversibly inhibit
active hydrogen potassium (H+, K+)-ATPases. They may need to be given twice daily, and they require
3-5 days to reach maximal efficacy. 10
o PPIs have the greatest efficacy in healing of erosive esophagitis, heartburn relief, and GERD related
chest pain. They are less effective in patients with regurgitation. 11 In patients who do not respond to
one PPI, switching to another PPI is reasonable to try to achieve symptom relief. 1
o Numerous studies found associations between PPI and a myriad of adverse events. However, a
randomized controlled trial found that pantoprazole was not associated with increased risk of any
adverse event (pneumonia, Clostridioides difficile infection, fractures, gastric atrophy, chronic kidney
disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, or cancer), with
the exception of increased risk of other enteric infections (OR 1.33, 95% CI 1.01-1.75).12
 Vonoprazan is a potassium-competitive acid blocker (PCAB) that competitively blocks the availability
of potassium to engage the hydrogen-potassium ATPase. It reversibly blocks active and inactive proton
pumps. It is more potent than traditional PPIs, and results in quicker and steadier inhibition of acid
secretion.13 It is superior to PPI in healing severe erosive esophagitis (LA grade C/D), especially cases
that are resistant to BID PPI. It is not superior to standard PPI in non-erosive reflux disease. It is not yet
available or approved in the United States.
o Other PCABs: Tegoprazan, Fexuprazan, Revaprasan,
 Surgical therapy: Laparoscopic fundoplication is the most common surgical treatment.
o For patients with established GERD (e.g. esophageal mucosal breaks on endoscopy and/or abnormal
24-hour pH monitoring) that is responsive to PPIs, laparoscopic antireflux surgery is an option for
patients who are not willing to stay on PPI, and has similarly high GERD remission rates. A large
prospective randomized trial (LOTUS, n=554) showed that PPIs have a slightly higher remission rate
at 5 years compared to the surgical therapy (92% vs. 85%, log-rank p = .048).14
o Laparoscopic Magnetic Sphincter Augmentation (MSA). The LINX® Reflux Management

System (figure 2) is a small flexible band of magnetized beads that is laparoscopically implanted around
the outside of the lower esophageal sphincter (LES) to augment its pressure and prevent reflux.
o The magnetic attraction between the beads keeps the LES closed. The forces of swallowing
temporarily separate the beads to allow food and liquid to pass into the stomach.
Figure 2: LINX®
Reflux Management
System. (Courtesy of
Torax® Medical, used
with permission)
Endoluminal therapies
 Endoscopic radiofrequency procedure of the lower esophageal sphincter (LES) (Stretta procedure)
 This procedure delivers radiofrequency energy to the LES. It operates at low frequencies and power
settings, and it is considered non-ablative. The radiofrequency catheter is advanced to the distal
esophagus, small probes protrude from the catheter into the muscular layer of the LES and deliver and
deliver the radiofrequency “burns” to the LES.
 The mechanism by which this procedure reduces GERD is unclear. Potential mechanisms of action are
increased LES muscle thickness, decreased transient lower esophageal sphincter relaxation (TLESR),
and reduced gastro-esophageal junction compliance without causing fibrosis.15
 Stretta is an FDA approved outpatient procedure that is performed in less than an hour.
 Some studies showed that the procedure improves symptoms of GERD and quality of life, with durable
results after 4-8 years of follow up. 16 However, a meta-analysis of 4 RCTs showed no difference
between Stretta and control group for the outcomes of mean (%) time the pH was less than 4 over a 24-
hour time course, lower esophageal sphincter pressure, ability to stop PPIs, or health-related quality of
life.17 A more recent (and favorable) meta-analysis of 4 RCTs, 23 cohort studies, and 1 registry study
showed that Stretta improves GERD symptoms and quality of life.18 It is not recommended by ACG.1
 EsophyXTM Transoral incisionless fundoplication (TIF): A completely per oral procedure performed
under general anesthesia that creates a full thickness partial circumferential fundoplication (~270o). 19
 A randomized, sham-controlled trial (RESPECT) found this procedure more effective than PPI in
treatment of regurgitation at the end of 6 months of follow up (67% in TIF + placebo vs 45% in sham
+ PPI; p = 0.02). 20 TIF is FDA approved. It is also emerging as a treatment of GERD after per oral
endoscopic myotomy (POEM) for achalasia (see page 25). It is best suited for patients without severe
reflux esophagitis, with small hiatal hernia, and hill type 2 gastroesophageal flap valve (see page 4).
Refractory GERD and functional heartburn
 Definition of refractory GERD: persistent bothersome heartburn (>2 times/week for 3 months) despite
BID PPI therapy.
 Etiology: True GERD with Inadequate acid suppression, GERD with non-acid reflux, or symptoms due to
an etiology other than GERD.
 Diagnosis:
 The following diagnostic strategy is based on AGA guidelines 3 and Lyon consensus2.
 PPI dose optimization: Make sure the patient is taking PPI 30-60 minutes prior to meals.21
 Consider adjunctive H2 receptor blocker therapies added at nighttime (e.g. famotidine)-controversial.
 The goal of further investigations in patients with refractory GERD is to make an accurate diagnosis,
suggest effective therapy, and discontinue ineffective medications such as PPI. 3
 Consider gastric emptying study in patients with refractory GERD symptoms.
 Perform EGD (off PPI for 2-4 weeks) to exclude other etiologies and evaluate for erosive esophagitis
and Barrett's esophagus..
 Biopsy the esophageal mucosa to rule out eosinophilic esophagitis (present in 1-8%).3
 If the patient has a normal endoscopy (or mild LA class A esophagitis), proceed with pH testing.3
 In patients with previously unproven GERD (no previous positive pH study or significant esophagitis
or Barrett’s): perform pH testing OFF PPI for 7 days.
 In patients with previously proven GERD: perform pH + impedance ON BID PPI.
 The acid exposure time refers to the percent of time the pH is below 4 (calculated as total time the
pH is < 4 divided by the total monitoring time of the study).
o Pathologic acid exposure time (>6%): This is consistent with GERD.
o Physiologic acid exposure time (<4%) with positive reflux-symptom association: This is
consistent with reflux hypersensitivity. This results in perception of non-painful esophageal
stimuli as being painful (allodynia) or perception of painful stimulus as more painful than usual
(hyperalgesia).22
o Borderline acid exposure time (4-6%): Diagnosis of GERD suggested if there is adjunctive evidence
of GERD (abnormal esophageal biopsy, abnormal impedance, positive reflux-symptom association,
frequent reflux episodes >40). Absence of these features suggests functional heartburn.
 If the patient has no prior diagnosis of GERD, the current pH study has normal acid exposure with
negative reflux-symptom association, and esophageal manometry does not show major motility
disorders, then the diagnosis is functional heartburn.
 If the patient previously had a proven diagnosis of GERD and the current pH impedance (ON PPI)
shows normal acid exposure and negative symptom association with acid and weakly acidic reflux,
and esophageal manometry does not show major motility disorders, then the diagnosis is functional
heartburn overlapping with GERD.2
 The etiology of functional heartburn is unknown; it is possibly related to esophageal hypersensitivity.
 Management
 Truly refractory GERD and reflux related heartburn: Surgical therapy with Nissen
fundoplication appears to be more effective than medical therapy.
o A recent trial evaluated the efficacy of medical versus surgical treatment in patients with proven
reflux related heartburn (acid exposure > 4.2% and positive reflux-symptom association),
unresponsive to PPI BID. These patients (n=78) were selected after careful workup using
endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal
impedance-pH monitoring.
● Patients were randomized to ●Nissen fundoplication, or ●medical treatment (PPI plus
baclofen, +/- desipramine as needed), or ●PPI +placebo.
● Treatment success (≥ 50% improvement in GERD related quality of life) occurred in 67% of
the surgical group, 28% in the medical treatment group and 12% in the PPI alone group. 23
 Functional heartburn
o Discontinue PPI in purely functional heartburn. PPI can be continued in patients with functional
heartburn overlapping with GERD.
o Consider a trial of TCAs (imipramine 25 mg/day) or SSRI (fluoxetine 20 mg/day).
o Avoid anti-reflux surgery and endoscopic treatment.
o Other treatments: tegaserod, melatonin, acupuncture, hypnotherapy.
 Non-acid reflux
o Diagnosis: Non-acid reflux is diagnosed by the detection of reflux episodes on impedance testing
during which the pH is > 4, and in association with GERD symptoms.
o Management
● Lifestyle modifications including weight loss, smaller meals.
● Baclofen is a GABA-b receptor agonist. It decreases transient lower esophageal sphincter
relaxations. It should be considered in patients with intact esophagogastric junction barrier
(intact LES and no Hiatal hernia) who have non-acid reflux especially if regurgitation is the
predominant symptom.
 The dose used in clinical studies is 20 mg t.i.d. However, it is recommended to start at a
lower dose (10 mg t.i.d.) and to increase gradually to 20 mg t.i.d.
 Side effects are mainly neurological including nausea, drowsiness, dizziness, fatigue.
● Alginic acid derivatives (Alginate antacids): These medications create a mechanical barrier
between the esophagus and the stomach and prevent GERD. 24, 25 Consider their use in GERD
patients not responding to PPI, or those with weak LES or hiatal hernia.
 Example: Gaviscon ®-Double action (DA)
● Laparoscopic fundoplication is controversial in non-acid reflux, but should be considered in
patients with severe symptoms refractory to medical therapy.
Extraesophageal GERD
 Established extraesophageal reflux syndromes include asthma, cough, laryngitis, and dental erosions.
 Other possible GERD related syndromes include pharyngitis, sinusitis, pulmonary fibrosis, and otitis.
 Laryngitis is also called "laryngopharyngeal reflux".
 Symptoms are nonspecific and include hoarseness, throat pain, sensation of a lump in the throat,
repetitive throat clearing, and excessive phlegm production.
 Laryngoscopy may show nonspecific edema and erythema of the larynx.
 Many healthy asymptomatic individuals will have abnormal laryngeal findings. Therefore, the
diagnosis of reflux laryngitis should not be based solely on laryngoscopic findings.
 Treatment of extra-esophageal GERD
 If the patient has GERD symptoms, give a therapeutic trial of PPI for at least 3 months.
 In patients without GERD symptoms, reflux monitoring is recommended prior to PPI.4
 EGD without reflux monitoring is not recommended as a means of diagnosis of extraesophageal GERD.1
 Asymptomatic GERD does not appear to be a contributing factor in uncontrolled asthma.
 In a prospective randomized double blind trial of 412 patients with inadequately controlled asthma,
esomeprazole b.i.d. did not improve asthma control in patients without symptoms of GERD.26
 The presence of GERD was documented by pH monitoring in 40% of patients. However, even in
those patients, asthma control did not improve on PPI.
Barrett's Esophagus
ASGE guideline on screening and surveillance of Barrett’s Gastrointestinal

esophagus27 Endoscopy, 2019
Am J
ACG Clinical Guideline: Diagnosis and Management of Barrett’s
Gastroenterol,
Esophagus28
2016
Endoscopic eradication therapy for patients with Barrett’ s esophagus Gastrointestinal
–associated dysplasia and intramucosal cancer 29 Endoscopy, 2018
AGA Clinical Practice Update on Endoscopic Treatment of Barrett's Gastroenterology,

Esophagus With Dysplasia and/or Early Cancer: Expert Review 30 2020
 Definition
 Barrett's esophagus (BE) is defined as the presence of intestinal metaplasia of ≥ 1cm that replaces the normal
stratified squamous epithelium.
 This change is recognized endoscopically by its salmon colored mucosa and histologically by
demonstrating intestinal metaplasia and goblet cells.
 Irregular Z-line or segments less than 1 cm should be referred to as specialized intestinal
metaplasia of the GE junction, and are not associated with increased risk of malignancy or
dysplasia. 28 Biopsy of a slightly irregular z line is not recommended.
 Risk of malignancy
 BE is a significant risk factor for esophageal adenocarcinoma. The risk varies among studies, and is higher
in studies conducted in referral centers.
 A population based study showed that the absolute annual risk of adenocarcinoma is 0.12% (incidence
rate of 1.2 cases per 1000 person-years).31 A recent meta-analysis of 57 trials showed the risk to be
~0.33% (3.3 cases per 1000 person.years).
o This was lower than the previous commonly cited rate of 0.5% / year.
 Incidence rate is higher in patients with long segment BE (> 3 cm), and in patients with low-grade
dysplasia (~0.7%/year) and high-grade dysplasia (7%/year).
o The progression from LGD to HGD and/or adenocarcinoma is higher in patients with
confirmed LGD (second pathologist) compared to those without confirmed LGD, and it is highest in
those with confirmed and persistent LGD at follow up endoscopy. 32
o This progression is also higher in those with long segment BE compared to short segment. 33
 A meta-analysis of 24 studies showed that in patients with BE and low grade dysplasia, the
annual incidence rate of adenocarcinoma was 0.54%, while the incidence rate for both
adenocarcinoma and high grade dysplasia was 1.73%. 34
 Endoscopic screening for BE is recommended in the following groups of patients: 28
 Male patients with >5 years symptoms of GERD (heartburn or acid regurgitation) and two or more of the following
risk factors: age >50 years, Caucasian race, central obesity, current or past history of smoking, and first degree
relative with esophageal adenocarcinoma.
 Screening is not recommended in women with chronic reflux (ACG), but it could be considered if multiple risk
factors are present.
 Endoscopic examination in BE:

 Perform a thorough and careful examination.
 Document important measurements of the following
landmarks (figure 3): Diaphragmatic pinch, Lower
esophageal sphincter (LES), Circumferential extent of BE
(C), Maximum extent of BE (M), +/- hiatal hernia.
 Prague classification of BE: report the length of BE as
C/M as shown in figure 3. Isolated islands of BE should
be reported separately.
 Carefully examine the BE mucosa for any nodularities or
ulcerations. Any suspicious area is biopsied separately.
 Obtain good quality biopsies and place each distance level
in a separate jar.
 Non-dysplastic BE: four quadrant biopsies every 2 cm.
 Dysplastic BE (low or high grade): four quadrant Figure 3: Endoscopic landmarks in BE.
biopsies every 1 cm. Consider using a large biopsy In this example, there is a 3 cm hiatal hernia.
BE is reported as C2/M4.
forceps.
 Wide-area transepithelial sampling with computer-assisted 3-dimensional analysis (WATS-3D) is a novel
technique of sample acquisition in BE. It can sample a larger surface area of the esophagus, obtaining cells
from deeper tissue layers. The sample is analyzed using a computer scan, and suspicious areas are flagged
for analysis by a pathologist. The ASGE suggests the use of this technology as an adjunctive sampling
method in addition to regular white light endoscopy and biopsy 27. There are no studies to evaluate the cost-
effectiveness of implementing WATS-3D in routine surveillance.
 CytospongeTM (Medtronic) is an emerging non-endoscopic screening modality for BE35. This device consists of
a polyester sponge compressed into a capsule, and attached to a polyester string. The subject swallows the capsule,
which disintegrates in the stomach within 3 to 5 minutes. The string remains outside the patient's mouth, and is
then pulled to retrieve the sponge. The sponge collects cells from the gastroesophageal junction and the
esophagus. The collected cells are examined by immunohistochemistry testing for Trefoil factor 3 (TFF3). This
protein is secreted from mucin-producing cells, and it is associated with the presence of BE.
 Management of BE with or without dysplasia and T1 adenocarcinoma (table 3)
Table 3: Management of BE
Dysplasia or cancer Diagnosis Management options
No dysplasia One EGD with adequate sampling  EGD every 3 -5 years
with biopsy q 2 cm  Ablation is not recommended
Indefinite for dysplasia mucosal changes that are abnormal  Optimize PPI therapy
but insufficient to call dysplasia  Repeat EGD in 3-6 months,
Low grade dysplasia Confirm with another EGD and  Surveillance EGD every 1 year until no
(Confirmed by 2 pathologists) biopsy within 3-6 month dysplasia on 2 exams or
 Endoscopic ablation *
 EMR if nodular dysplasia
High grade dysplasia Confirm with another EGD and  EMR if nodular dysplasia
(Confirmed by 2 pathologists) biopsy within 3 months  Endoscopic ablation
Mucosal esophageal Tumor invades lamina propria or  EMR and ablation preferred over
adenocarcinoma (T1a) muscularis mucosa esophagectomy30
Submucosal esophageal Tumor invades submucosa  EMR and ablation is an alternative to
adenocarcinoma (T1b) esophagectomy if low risk features†
especially if poor surgical candidate.30
* Endoscopic therapy is the preferred approach (ACG). † (<500 μm invasion in the submucosa [sm1], good to moderate
differentiation, and absence of lymphatic invasion). EMR: Endoscopic Mucosal Resection.
 Treatment should be individualized according to the patient's age, co-morbidities, availability of endoscopic
and surgical treatments, and local expertise.
 All patients (regardless of GERD symptoms) should receive acid suppression with once-daily PPI to treat
the underlying GERD. Refractory GERD may be given twice-daily PPI if needed.
 Post-endoscopy esophageal neoplasia (PEEN) is used to describe esophageal high-grade dysplasia or
adenocarcinoma detected prior to the next recommended surveillance EGD in a patient with non-dysplastic
Barrett’s esophagus.36 This may occur due to missed high-grade dysplasia or rapidly progressing
adenocarcinoma.
 Endoscopic eradication therapy
 The goal of endoscopic therapy is removal of all neoplasia and BE mucosa.
 Nodular BE should be resected using endoscopic mucosal resection (EMR) to get an accurate pathologic
examination and staging. This should be followed by complete eradication of flat BE using
radiofrequency ablation or cryotherapy.
 Radiofrequency ablation (RFA)
o RFA is FDA approved for the treatment of BE with dysplasia.
Study Highlight
Radiofrequency Ablation in Barrett’s Esophagus with
Dysplasia37
● This is a large randomized multicenter trial of RFA versus sham
in the treatment of dysplastic, non-nodular BE.
● Patients with a history of esophageal cancer, esophageal varices or life
expectancy of less than 2 years were excluded from the trial.
● 64 patients had low-grade dysplasia, while 62 had high-grade
dysplasia.
● Length of BE varied from 0.5 to 8 cm.
● Patients were randomly assigned in 2:1 ratio to RFA or sham.
 All patients received esomeprazole 40 mg b.i.d.
● At 12 months, RFA was associated with a high rate of complete
eradication of both dysplasia and intestinal metaplasia (figure 4).
 There was less disease progression (3.6% vs. 16.3%, p=0.03)
and fewer cancers (1.2% vs. 9.3%, p=0.045) in the ablation Figure 4: Primary Outcome of RFA
group compared to controls. versus sham at 12 months
 Strictures occurred in 6% of patients (most required one or two dilation sessions).
o Recurrence of BE after RFA
● One retrospective study showed that the recurrence rate is 20% after 1 year and 33% after 2 years.38
Another large study of the US RFA registry showed that BE recurs in ~20% of patients who achieved
complete eradication after a mean follow up of 2.4 years. Most recurrences were non dysplastic or
indefinite for dysplasia (86%), and short segment (average length of 6 mm). 39
o Following complete eradication of BE, endoscopic surveillance with EGD should be performed at
the following intervals:30
● If baseline diagnosis of HGD/esophageal adenocarcinoma: at 3 , 6 , 12 months then annually
● If baseline diagnosis of LGD: at 1 year then 3 years
● Surveillance technique:
 EGD with high definition white light and optical (electronic) chromoendoscopy.
 Treat visible recurrent BE with ablation and with EMR for nodular lesions.
 If no visible BE, obtain random four quadrant biopsies of the neosquamous mucosa and the
gastric cardia.
 If BE or dysplasia is present: repeat EGD and ablation.

 If no recurrent BE: continue surveillance.
 Isolated intestinal metaplasia in the cardia does not require ablation.
 Endoscopic spray cryotherapy
o Cryotherapy is used to ablate dysplastic BE.
o Liquid nitrogen is sprayed endoscopically under direct visualization.
● Similar to RFA, the depth of treatment is very superficial (~2 mm).
o Small non randomized prospective studies showed that cryotherapy was effective in the treatment of
BE with high grade dysplasia or intramucosal carcinoma. 40
o Complications include chest pain, dysphagia, and mild esophageal strictures.
 Photodynamic therapy (PDT)
o A photosensitizing agent is injected intravenously. The esophageal mucosa is exposed 48 hours later
to a laser light of a specific wavelength that results in mucosal ablation.
o In a randomized controlled trial, PDT with omeprazole was shown to be superior to omeprazole alone
in complete ablation of HGD (77% vs. 39%). 41
● There was less progression to cancer in PDT group (13%) compared to omeprazole only group (28%).
● Complications: photosensitivity reactions occurred in 69% of patients. Esophageal strictures were
common and developed in 36% of patients.
o This treatment has been largely replaced by RFA and cryotherapy.
 Endoscopic mucosal resection (EMR)
o Band assisted EMR (video 1-1): rubber band ligation followed by snare resection. A
special banding kit is used that allows a small snare to be passed through the channel while
the banding device is applied to the tip of the scope.
● In a large multicenter retrospective study of band-assisted EMR (n=3827 procedures),
the rate of perforation was 0.4% (17 perforations, 15 closed endoscopically). The rate Video 1-1
of post procedural bleeding was 0.9% (n=35 cases). 42
o Cap assisted EMR: a cap is affixed to the tip of the EGD scope. A special snare is opened and
positioned at the internal margin of the cap. Suction of the lesion into the cap is
followed by snare entrapment and resection.
o The main indication for EMR in BE is resection of nodular dysplasia or early esophageal
adenocarcinoma extending to the superficial submucosa.
o EMR should be followed by ablation of the rest of BE mucosa.
● The risk of recurrent malignancy after EMR without complete BE ablation is estimated at 11 to
30% after a mean follow up of 3 years.43
o EMR is important for accurate staging. It will often show intramucosal carcinoma
or superficial submucosal carcinoma in lesions initially diagnosed as high-grade dysplasia.
o Risk of esophageal strictures following EMR is high if extensive EMR is performed during the same session.
● The risk of esophageal strictures is estimated at 50% if more than 3 cm of esophageal mucosal
length is resected. The risk is also increased if two thirds of the circumference of the esophagus is
resected. Therefore, avoid EMR for large areas of BE and use other superficial mucosal ablation
techniques.
Eosinophilic Esophagitis
Guidelines on eosinophilic esophagitis: evidence-based United European

statements and recommendations for diagnosis and Gastroenterology Journal,
management in children and adults 44 2017
Updated International Consensus Diagnostic Criteria for
Eosinophilic Esophagitis: Proceedings of the AGREE Gastroenterology, 2018
Conference 45
AGA Institute and the Joint Task Force on Allergy-
Immunology Practice Parameters Clinical Guidelines for Gastroenterology, 2020
the Management of Eosinophilic Esophagitis 46
ACG Clinical Guideline: Evidenced Based Approach to

the Diagnosis and Management of Esophageal Am J Gastroenterol, 2013
Eosinophilia and Eosinophilic Esophagitis 47
 Definition: eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus characterized
clinically by dysphagia and food impaction (with or without esophageal strictures), and histologically by an
eosinophilic infiltrate, in the absence of other causes of esophageal eosinophilia.
 Criteria for diagnosis45
 (1) Presence of esophageal symptoms.
 (2) Eosinophilic infiltration limited to the esophagus (>15 eosinophils per high power field in esophageal
biopsies).
 (3) Absence of other causes of esophageal eosinophilia, most importantly GERD.
 Other causes of esophageal eosinophilia include eosinophilic GI disease, Crohn's disease, achalasia, graft
versus host disease, vasculitis, drug hypersensitivity response, esophageal leiomyomatosis,
Hypereosinophilic syndrome, parasitic infection, and Bullous pemphigoid.48
 EOE and GERD can occur in the same patient.
 Note: Until recently, the diagnosis of EoE required a treatment trial with PPI to rule out an entity called
“PPI responsive esophageal eosinophilia” (PPI-REE). The updated EoE guidelines realize that PPI-REE
and EoE are the same disease, and removed this diagnostic step from the algorithm of EoE diagnosis.
Currently a patient can be diagnosed with EoE if the three
criteria above are fulfilled. PPI are considered first line
treatment for EoE.
 Solid food dysphagia is the most common symptom in adults.
Other clinical features include food impaction, chest
pain, heartburn, and upper abdominal pain.
 EOE is associated with atopic conditions such as food
allergies, asthma, allergic rhinitis, atopic dermatitis, allergic
conjunctivitis, urticaria, angioedema 49
 Endoscopic findings are suggestive but not diagnostic of EoE. Figure 5: Eosinophilic esophagitis
 Esophageal rings (trachealization or feline esophagus), with longitudinal furrows and
longitudinal furrows and fragile esophageal mucosa (crêpe- splitting of the mucosa (crêpe-
paper esophagus)
paper) - (figure 5), white patches or specks (often mistaken for
candida), esophageal strictures, and narrowed esophagus.
 Endoscopy will be normal in ~15% of cases.50
Biopsy technique: obtain biopsies in all patients with suspected eosinophilic esophagitis (2-4 biopsies from
the distal and 2-4 biopsies from the proximal esophagus; place in the same jar).
 The disease may be patchy, and biopsies from the same esophageal level may yield different eosinophil counts.
 In patients with suspected eosinophilic esophagitis, obtain biopsies from the stomach and duodenum to
rule out eosinophilic gastroenteritis.
 Histologic findings: eosinophilic infiltration (≥15 eosinophils / HPF, or ≥ 60 eosinophils/mm3), eosinophilic
microabscesses or superficial “crusts”, extracellular eosinophilic granules, intracellular edema “spongiosis”,
basal cell hyperplasia, subepithelial fibrosis. 51
 Treatment
 The goal of treatment is to achieve symptom resolution, histology remission (<15 eosinophils/HPF) and
improvement in endoscopic appearance (lumen diameter>15mm).52
 None of the EoE medications are FDA approved.
 PPIs have anti-inflammatory properties in addition to acid anti-secretory effects. They may induce clinical and
histologic remission in up to 50% of patients.53 BID dosing appears to be better than once daily dosing. After a 6-8
week trial, patients who respond to treatment should be continued on PPI long term to maintain remission. 44
 Topical steroids
 Swallowed fluticasone: 880-1760 mcg/day (e.g. 220 mcg 2-4 puffs b.i.d.).
o The patient is instructed to take a deep breath then puff the medication into the mouth using a metered
dose inhaler without a spacer. The patient should then swallow the medicine and avoid eating or
drinking for 30 minutes.
 Swallowed budesonide: given at 1-2 mg b.i.d.
o Oral viscous budesonide (OVB): is compounded for adults by mixing the budesonide suspension
for nebulization (Pulmicort Respules®) of either 0.5 mg/2 ml or 1 mg/2 ml concentration with
sucralose (Splenda®) - 10 packets of sucralose per 1 gram of budesonide. 54
o Budesonide orodispersible tablets (BOT): This new formulation was shown in a placebo-controlled
trial (n=88) to induce clinical (57%) and endoscopic (93%) remission in patients with EoE at 6
weeks.55 None of the patients in the placebo arm achieved clinical or endoscopic remission.
 An 8-week randomized trial showed that both swallowed fluticasone (880 mcg BID) and OVB (1 mg
BID) are effective treatments for EoE in patients who have not responded to proton pump inhibitors. 56
 Patients should be cautioned to avoid PO intake for 60 minutes after administration of oral topical
corticosteroids, and that esophageal candidiasis can occur in 20% of patients. 57
 Consider maintenance therapy in patients with severe symptoms, such as those with prior stricture or
food impaction or those who relapse after treatment. AGA suggests continuation of topical
glucocorticoids. 46
o Maintenance therapy options are OVB at 1 mg/day or fluticasone 880 mcg/day.
o A small RCT showed that OVB (0.25 mg BID) maintains histologic remission in 35.7% (5 of 14
patients) at 1-year compared to zero patients in the placebo arm. 58 Patients treated with OVB were
more likely to be in clinical remission (64% vs 36%) and had longer time to relapse (125 days vs 95
days) compared to placebo, though this was not statistically significant (p>0.05). This was likely
related to the small dose of OVB.
o A larger randomized control trial (n=93) of OVB (higher dose of 2 mg BID) compared to placebo
showed that OVB leads to significant improvement in symptoms, endoscopic and histologic
parameters compared to placebo.59
o An extension of the induction trial of BOT vs placebo in EOE found that BOT at either 0.5 mg BID
or 1 mg BID maintained clinical remission in 75% of patients at 48 weeks, compared to 4.4%
maintained on placebo.60 Histologic and clinical relapse rates were higher in the placebo group
compared to the budesonide ODT groups. The rate of candidiasis was 12-16%.
 Other preparation under study: Budesonide Oral suspension and Fluticasone oral tablets
 PO steroids (1-2 mg/kg): give prednisone if topical preparations are not effective, or in patients with severe
weight loss and/or dysphagia. 51
 There are limited data to support leukotriene antagonists, mast cell stabilizers, or biologics to treat EOE. 47
 Dietary elimination
 Six-food elimination diet (SFED): this diet removes the most common food allergens including milk,
wheat, soy, eggs, nuts, seafood, sesame. It can be considered for children and adults. However,
compliance with this strict diet is challenging.
 Endoscopic dilation for EoE strictures
 Highly Effective and results in 90% symptom improvement.
o It does not improve eosinophils count.
 Use balloon dilators or over the wire bougie dilators. Start at a low dilation diameter and dilate gradually
over multiple sessions (up to 15-18mm), and avoid over aggressive dilation.
 Inspect the mucosa after each dilation. Stop if there is a mucosal tear, moderate resistance to dilation, or
blood on the dilator. Experts also recommend limiting the progression of dilation per session to
≤ 3 mm after resistance is felt.61
 Complications include chest pain (2%), esophageal tears and perforations (0.3%).62
 A retrospective cohort study showed no major bleeds, perforations or deaths in 164 patients who
underwent 486 dilations for EoE. Most patients (58%) required multiple dilations, 75% had repeat
dilation within 1 year of the first dilation. 63
Cricopharyngeal bar
 Definition: cricopharyngeal bar (CPB) describes the radiologic abnormality that

appears as a posterior indentation at the level of the cricoid cartilage on barium
swallow (figure 6).64
 A CPB can be an incidental finding and does not always correlate with an
upper esophageal sphincter abnormality.
 It usually results from increased upper esophageal sphincter pressure and
decreased compliance, possibly secondary to sphincter fibrosis.
 The same pathophysiology can lead to the formation of Zenker's
diverticulum. This is a herniation of the mucosa and submucosa of the
hypopharynx through a weak area of the posterior hypopharyngeal wall
(Killian's triangle). Figure 6: Cricopharyngeal bar
seen on barium swallow.
 Symptomatic patients are usually elderly with symptoms of oropharyngeal
dysphagia to solids and/or liquids, cough, choking, and throat pain with swallowing.
 Manometric findings: increased intrapharyngeal bolus pressure and failure of the upper esophageal sphincter to relax
normally. These manometric findings are predictors of response following dilation.
 Manometry is not always required for diagnosis.
 Management: in a patient with dysphagia and a negative workup, the finding of a CPB on barium swallow is significant,
and the patient should be considered for endoscopic dilation.
 Dilation technique: Use a wire-guided bougie dilator to try to disrupt the tight upper esophageal sphincter.
o Start at 48 French, and then increase the dilator diameter to 54 and 60 French.
 If the narrowing is too tight, start at lower dilation diameter, and perform gradual dilations over multiple sessions.
 Response to dilation is usually immediate. Recurrent dysphagia after initial improvement can be treated with repeated
dilations. Treatment of Zenker's diverticulum is by surgical or endoscopic cricopharyngeal myotomy.
Tumors of the esophagus
 Esophageal adenocarcinoma
 Esophageal adenocarcinoma is the most common esophageal cancer in the United States.
 It is more common in whites compared to blacks, and more common in men compared to women.
 Risk factors: Barrett's esophagus, GERD, smoking, obesity.
 Alcohol and achalasia are not risk factors for esophageal adenocarcinoma.
 95% of patients with a new diagnosis of adenocarcinoma do not have a previous diagnosis of
Barrett's esophagus, and 40% deny having any previous GERD symptoms.65
 Esophageal squamous cell carcinoma
 More common in blacks compared to whites.
 It has a similar incidence in men and women.
 Risk factors: history of esophageal caustic injury, smoking, alcohol, achalasia (due to chronic
stasis), radiation esophagitis, vitamin C deficiency, Plummer-Vinson syndrome, HPV infection.
 Tylosis is a rare autosomal dominant disease that is associated with hyperkeratosis of the palms
and feet and esophageal squamous cell carcinoma.
 The most common symptoms are dysphagia, odynophagia, hematemesis, and weight loss.
 Diagnosis: endoscopy and biopsy.
 Staging: PET/CT scan, EUS +/- FNA
 TNM staging of esophageal cancer is shown in table 4.
Table 4: TNM staging of esophageal cancer

Tumor (T) Regional lymph nodes (N)
● Tx: Primary tumor cannot be assessed  Nx: LN cannot be assessed
● T0: No evidence of primary tumor  N0: No regional lymph node metastasis
● Tis: High-grade dysplasia  N1: Metastasis in 1-2 regional lymph
● T1: nodes
 T1a: Tumor invades lamina propria or  N2: Metastasis in 3-6 regional lymph
muscularis mucosa nodes
 T1b: Tumor invades submucosa*  N3: Metastasis in ≥ 7 regional lymph
● T2: Tumor invades muscularis propria nodes
● T3: Tumor invades adventitia
● T4: Tumor invades adjacent structures
Distant metastasis (M)
 M0: No distant metastasis
 M1: Distant metastasis
*T1b tumors are further divided into superficial submucosal (sm1), middle (sm2) or deep (sm3) tumors
 Treatment for esophageal cancer (squamous cell carcinoma and adenocarcinoma)

 In general, small and early tumors (T1a or T1b) can be treated with EMR if there are
no regional lymph nodes involved and no distant metastasis (T1N0M0) (Video 1-2)
 A meta-analysis of 7 retrospective and prospective studies showed that endoscopic Video 1-2
therapy for HGD and T1a cancers is associated with similar survival rates at 1, 3,
and 5 years compared to esophagectomy. Endoscopic therapy is associated with similar cancer-
related deaths, but lower adverse events compared to esophagectomy.66
 AGA recommends EMR and ablation as a preferred therapy over esophagectomy in T1a tumors.30
 A small retrospective study (n=66) showed that endoscopic therapy for T1b-sm1 tumors was
associated with complete endoluminal remission in 87% of patients, with a higher rate of 97%
in those with small focal neoplasia ≤ 2 cm.65
 Therefore, AGA states that EMR and ablation is an alternative to esophagectomy in T1b tumors
with low risk features (<500- μm invasion in the submucosa [sm1] for adenocarcinoma, good to
moderate differentiation, and absence of lymphatic invasion). 30
 Esophagectomy is indicated in patients with T2, T3 cancers without lymph node involvement.
 Chemoradiotherapy is indicated in patients with locally advanced or metastatic cancers.
 Restaging is performed after chemoradiotherapy, and esophagectomy is considered depending
on response to therapy.
 Endoscopic stenting for obstructing esophageal tumors is discussed in chapter 11-endoscopy.
 Screening is recommended in high-risk groups.
 Screening is recommended in patients with tylosis beginning at age 30, to be repeated every 1-3 years.67
 Screening in patients with a caustic esophageal injury is recommended 15-20 years after ingestion,
to be repeated every 1-3 years.
 Screening in achalasia is not recommended.68
Caustic ingestions
 Most caustic ingestion cases in adults are intentional rather than accidental.
 Types of caustic ingestions (table 5)
Table 5: Types of caustic ingestions

Alkaline ingestions Acidic ingestions
Mechanism Liquefactive necrosis: cell wall Coagulative necrosis: denaturation of
of tissue destruction, solubilization of protein proteins with eschar formation that limits
injury and liquefaction of tissue resulting in substance penetration and deep injury 69
deep injury
Severity Usually severe Less severe
Prevalence Common in western countries Common in developing countries
 Clinical manifestations: Chest pain, sore throat, odynophagia, dysphagia, stridor, hoarseness, respiratory
distress, epigastric pain, hematemesis.
 Symptom and signs do not predict the severity of esophageal or gastric injury.
 Physical examination should focus on the overall condition of the patient (vital signs, mental status). Look
for signs of severe complications such as subcutaneous emphysema (esophageal perforation) and rebound
abdominal tenderness and guarding (gastric perforation).
 Management
 NPO, supportive care. Avoid emetics and gastric lavage.
 EGD should be performed within 24-48 hours in all patients with caustic ingestion.
 Contraindications to EGD include respiratory distress, severe chest pain, and suspicion of esophageal perforation.
 Avoid EGD within 5-15 days of corrosive ingestion due to tissue softening and increased risk of perforation.70
 Carefully examine the esophagus, stomach, and duodenum. Document the extent of injury to each area.
 The Zargar's endoscopic grading of caustic esophageal injury and corresponding management
recommendations are summarized in table 6.
 Examples of endoscopic findings are shown in figure 7.
Table 6: Zargar's endoscopic grading of caustic esophageal injury and suggested management
Grade Description Management
0 Normal Discharge home, normal diet
1 Edema, mucosal erythema Start liquid diet and advance within 1-2 days to
Friable mucosa , erosions/superficial ulcers, full diet
2a
exudates
2b 2a+ deep localized or circumferential ulcers NPO, start liquids in 48 hours and advance
3a Small, scattered areas of necrosis (brown/black slowly
discoloration)
3b Extensive necrosis
Figure 7: Endoscopic findings in a patient with caustic ingestion. This patient swallowed sodium
hydroxide powder (alkaline). Endoscopy showed proximal esophageal edema and erythema (A), distal
esophageal deep ulcerations and severe inflammation (B), and severe erosive gastritis (C)
 Other treatments
 Sucralfate
 PPI.
 Steroids are not recommended.
 Prophylactic esophageal stenting is not recommended.
 Give antibiotics for suspected or confirmed perforations.
 Late complications
 Strictures can be multiple and tortuous. Therefore, consider obtaining a barium swallow prior to
endoscopy to characterize the strictures and plan the procedure.
 Wire-guided bougie dilation is preferred for multi-level or tortuous strictures.
 The risk of squamous cell carcinoma is increased in patients with history of lye or caustic esophageal injury.
 Screening is recommended 15-20 years after caustic esophageal injury, to be repeated every 1-3 years.
Motility disorders of the esophagus
ACG Clinical Guideline: Diagnosis and

Am J Gastroenterol, 2020
Management of Achalasia71
ASGE guideline on the management of

GIE, 2020
achalasia 72
Esophageal motility disorders on high-
Neurogastroenterology and
resolution manometry: Chicago classification
motility 2021
version 4.0©73
 High resolution manometry (HRM) and pressure topography

 The HRM catheter has multiple sensors spaced one cm apart along the length of the catheter. The pressure data
from the manometry tracing is converted into color (pressure topography).
 The Chicago classification v4.0 recommends recording 10 supine wet swallows followed by 5 upright wet swallows.
 A normal pressure topography is shown in figure 8-A. Notice the upper and lower lines that correspond to the upper and
lower esophageal sphincters (UES and LES), with normal progression of the swallow.
Figure 8: High-resolution manometry with esophageal pressure topography.

A-normal swallow (see text); B-Type 2 achalasia with panesophageal pressurization.
C-Esophagogastric Junction Outlet Obstruction with elevated IRP (22 mmHg), elevated intrabolus
pressure (intrabolus pressurization-IBP), and normal peristalsis. D- Jackhammer esophagus
(DCI=11,572 mmHg-cm-s, IRP=14 mmHg)
 Basic HRM parameters

 Integrated relaxation pressure (IRP): This value measures LES pressure by evaluating a continuous
or interrupted 4-second relaxation in a 10-second window, and measuring the median IRP value.
o The cutoffs for abnormal values vary per type of catheter and patient position (table 7)73.
 Distal contractile integral (DCI) measures the vigor Table 7: abnormal IRP values (in mmHG)
(power) of the distal esophageal contraction. The normal Company
Supine Upright
range is 450-8000. name
o DCI values below 100 indicate failed peristalsis; values Medtronic ≥ 15 ≥ 12
between 100-450 indicate weak peristalsis. Failed or Diversatek, ≥ 22 ≥ 15
weak peristaltic contractions are labelled as ineffective Laborie
swallows. DCI ≥ 8000 indicates hypercontractile pattern.
 Contractive wave integrity (not shown) measures the contiguity of peristalsis using 20 mmHg isobaric
contour. Peristaltic break (discontinuity of peristalsis) of > 5 seconds is considered a large break and
signifies ineffective swallows (previously called fragmented contraction in Chicago 3.0).
 Distal Latency (DL) is measured from the onset of swallow to the contractile deceleration point (CDP).
This point is located within 3 cm of the LES at the 30mmHg contour. A distal latency less than 4.5
seconds (with DCI>450) is indicative of premature/spastic contraction.
 Pressurization is examined using the isobaric contour (IC). Panesophageal pressurization occurs when
the esophageal content is trapped between two simultaneously contracting esophageal segments, seen as
a vertical isobaric pressure band at IC ≥ 30mmhg.(figure 8-B).74 Intrabolus pressurization is seen as
compartmentalization of intrabolus pressure (at IC ≥ 20mmhg) that precedes the esophageal contraction
above the esophagogastric junction (figure 8-C).75
 Supportive HRM data
 The HRM protocol may include other supportive manometric measurements such as solid test meal, multiple
rapid swallows, rapid drink challenge, and pharmacologic provocation.73
 Motility disorders of the esophagus are shown in table 8.
Table 8: Manometry findings esophageal motility disorders based on Chicago classification 4.0©
Median IRP Other findings Diagnosis
Elevated ▪ 100% Failed peristalsis Type 1 Achalasia (classic)
▪ No panesophageal pressurization
Disorders of EGJ
Elevated ▪ 100% Failed peristalsis Type 2 Achalasia

▪ ≥ 20% with panesophageal pressurization
outflow
Elevated ▪ No evidence of peristalsis Type 3 Achalasia (spastic

▪ ≥ 20% swallows with premature/spastic achalasia)
contractions (DL< 4.5 sec and DCI > 450)
Elevated ▪ ≥ 20% swallows with increased intrabolus Esophagogastric junction
(supine & pressure in supine position outflow obstruction
upright) ▪ Not meeting criteria for achalasia
Normal ▪ 100% failed peristalsis (DCI<100) Absent contractility
Normal ▪ ≥ 20% swallows with premature/spastic Distal esophageal spasm*
Disorders of
peristalsis
contractions
Normal ▪ ≥ 20% swallows with hypercontractile pattern Hypercontractile esophagus
(DCI ≥ 8000) *
Normal ▪ > 70% ineffective swallows (failed swallows Ineffective esophageal
[DCI<100] or weak [DCI 100-450] or break >5 motility
sec) or ▪ ≥ 50% failed peristalsis (DCI<100)
IRP: Integrated relaxation pressure (4 second); DCI: Distal contractile integral; DL: distal latency
*These disorders were labeled as “manometric patterns of unclear relevance” in Chicago 4.0 classification,
and they require additional features (clinical symptoms, abnormal esophagogram) to establish a clinically
relevant diagnosis.
 Achalasia
 Presents at any age, usually 20-65 years.
 Symptoms include dysphagia to solids and liquids, chest pain, regurgitation, heartburn, weight loss, aspiration.
 Pathophysiology: Achalasia results from the selective loss of post-ganglionic inhibitory neurons containing nitric
oxide and substance P. This leads to continuous cholinergic stimulation and high LES pressure. Pathology from
surgical specimens may show inflammatory infiltrate around the ganglion cells in the myenteric plexus of the LES.
 Normal peristalsis requires normal progression of a series of contractions and relaxations. Therefore, loss of
relaxation results in aperistalsis and abnormal contractions. The esophageal dysmotility is confined to the mid
and distal esophagus where smooth muscles form the muscular layer of the esophagus.
 Infection with the parasite Trypanosoma Cruzi (Chagas' disease) can lead to achalasia.
A clinical presentation similar to achalasia (pseudoachalasia) can occur due to any of the following causes:
o Infiltrating tumor at the GE junction or cardia. The tumor can involve the myenteric plexus of the
lower esophagus resulting in symptoms similar to achalasia. If this is suspected, obtain cross sectional
imaging of the chest and abdomen +/- EUS of the distal esophagus and gastric cardia.
o Paraneoplastic achalasia from extraintestinal malignancy (e.g. lung cancer). These patients will have
positive antineuronal antibodies (also called anti-Hu antibodies).
o Pseudoachalasia should be suspected in older patients with a short duration of symptoms (<6 months),
and rapid weight loss.76 Perform additional testing such cross sectional imaging +/-EUS.
 Workup:
 EGD is needed to rule out mechanical obstruction, with close attention to the GE junction to rule out a tumor.
Findings in achalasia may include dilated esophagus, residual secretions, candidal plaques, and a tight LES.
 Barium swallow may show a dilated esophagus and tight LES (bird's beak appearance).
o The timed barium swallow is a simple adjunctive test with low radiation exposure. In the upright
position, the patient ingests 200 ml of low-density barium sulfate. Frontal radiographs are obtained
at 1, 2 and 5 minutes. In a retrospective study, barium column height of 2 cm at 5 min showed a
sensitivity of 85% and specificity of 86% in differentiating untreated achalasia from EGJOO and non-
achalasia.77
 Esophageal manometry: Manometric features of achalasia include both of the following:
 Absent esophageal peristalsis: All swallows are either failed or premature.73
 EGJ outflow abnormality: all cases have absent or incomplete deglutitive relaxation of the LES, with
integrated relaxation pressure (IRP) (see table 7 on page 20)
o False negative manometry for achalasia can be encountered with conventional manometry without
pressure topography. This is due to significant esophageal shortening during swallowing results in
the distal sensor recording the low pressure in the gastric cardia instead of the LES. This is
misinterpreted as LES relaxation.
● High-resolution manometry with pressure topography corrects for esophageal shortening and
gives accurate measurements of LES pressure.
 Classification of achalasia based on pressure topography (see table 8)
o Type 1: classic achalasia. No pressurization in the esophagus + 100% failed peristalsis.
o Type 2: achalasia with esophageal compression (figure 8-B)
● In this type there is compartmentalized pressurization (>30 mmHg) spanning the entire length
of the esophagus in at least 20% of swallows + 100% failed peristalsis.
o Type 3: spastic achalasia. In this type, there are spastic premature esophageal contractions (DL<4.5 sec)
in at least 20% of swallows. These contractions are severe and obliterate the lumen of the esophagus.
 Classifying achalasia allows us to evaluate different methods of treatment for different subtypes in an
effort to customize treatment.
o Type 2 achalasia has better overall response to treatment compared to the other types, and responds
better to treatment with pneumatic dilation compared to laparoscopic Heller’s myotomy.78
o Per Oral Endoscopic Myotomy (POEM) is more effective in patients with type 3 achalasia due to the
ability to perform an extended myotomy that treats the entire contracted segment of the LES in the
distal esophagus (see page 24). 79
 Endoscopic Functional Luminal Imaging Probe (EndoFLIPTM) utilizes impedance planimetry to
measure the luminal geometry and mechanical characteristics of the esophagus, including opening dynamics
of the LES. It is composed of a catheter with a balloon that has voltage and pressure sensors. The voltage
allows for measurement of the cross sectional area. The balloon is inflated across the GE junction and the
distensibility of the GE junction can be assessed using the distensibility index (DI), which is measured by
calculating the ratio of the cross sectional area to the pressure. 80
 Early studies found that patients with untreated achalasia have lower DI (mean 0.7 ± 0.9 mm2/mmHg)
compared to healthy controls (mean 6.3 ± 0.7 mm2/mmHg).81 Lower DI values also correlate with better
symptom response following LES directed therapy in achalasia. 82 Patients with persistent symptoms post
Heller myotomy have lower DI compared to those whose symptoms resolved. Some patients with low DI
values and persistent symptoms have normal esophageal manometry findings, suggesting that EndoFLIP
may better characterize the mechanical characteristics of the LES that lead to symptoms in achalasia.
 It is important to look at the entire clinical picture and all the previous studies to make the diagnosis of
esophageal dysmotility. For example, consider a patient with chronic dysphagia, dilated esophagus, bird beak
appearance on barium, delayed barium emptying, tight LES perceived during endoscopy, 100% failed
swallows, and IRP of 10 mmHg. This patient very likely has achalasia, even if the IRP is “normal”. In this case,
you can treat as achalasia, or perform additional testing if available (such as EndoFLIP).
 Management of achalasia (figure 9)
Figure 9: Suggested approach for the management of achalasia.

POEM is the preferred treatment in patients with type 3 achalasia due to the ability to perform an extended
myotomy that treats the entire contracted segment of LES in the distal esophagus.71, 79
Treatment with botulinum toxin injections does not affect success rates of future myotomy.71
 Assess symptoms of achalasia using an objective assessment score (e.g., Eckardt score see figure 9).
 Medical management may provide temporary, mild relief of dysphagia, but it is reserved for patients who
cannot tolerate other types of therapy. Options include nifedipine 10-30 mg given 30-45 minutes before meals,
sublingual isosorbide dinitrate 5-10 mg 15 minutes before meals, sildenafil 25-50 mg with each meal83.
 Pneumatic dilation
o A special balloon dilator (Rigiflex®, Boston scientific) is used to break the muscular fibers of the
lower esophageal sphincter. The balloons come in 30, 35, and 40 mm diameters.
o The balloon is passed over the wire and positioned across the GE junction (confirmed with fluoroscopy).
It is then inflated for 30 to 60 seconds, reaching a pressure of 7-15 p.s.i of air (figure 10).
● Experts recommend starting at 30 mm for the majority of patients.
● In young healthy men or those with prior Heller’s myotomy, dilation to 35 mm is performed. 84
o In cases of persistent symptoms, dilation can be repeated with a larger balloon size up to 40 mm.
o Efficacy of pneumatic dilation
● 70-90% immediate response rate.85, 86
● One study showed that one-third of the patients treated by dilation would relapse during a 4-year
follow up period.86 Repeated dilations after relapse are effective.
● Response rate for dilation after prior myotomy is ~50%. 87
o Predictors of therapeutic failure
● Patient related: age younger than 40 years, male, pre-dilation LES pressure > 20 mmHg, type 3 achalasia
● Procedure related: single dilation, small balloon (< 30 mm), post dilation LES pressure > 10 mmHg.
o Side effects of pneumatic dilation: perforation (2%), GERD (15-35%), reflux esophagitis (2%).
Figure 10: Pneumatic dilation for achalasia.

A: Tight gastro-esophageal junction in a patient with type 2 achalasia and failed Heller’s myotomy. B: Pneumatic dilation
balloon inflated to 35 mm under fluoroscopic guidance across the GE junction (arrows).
C: Post dilation appearance reveals large tears at the LES without perforation. (Images courtesy of Melvin Simien, MD)
 Botulinum toxin injection
o Mechanism of action: botulinum toxin inhibits the excitatory acetylcholine-releasing neurons,
resulting in decreased LES pressure.
o Technique: botulinum toxin is injected in 1 ml aliquots (25 units/ml) into four quadrants of the
esophagus at the level of the LES (1 cm above the normal Z line).
o Efficacy of botulinum toxin injection
● 70-90% initial response rate. Relapse occurs in 50% of patients within 6-12 months.
 Laparoscopic Heller myotomy
o Efficacy: immediate response is achieved in more than 85% of patients.
o Partial fundoplication (Dor or Toupet) should be performed post myotomy to decrease the risk of GERD.71
o Long-term response varies among studies, but it is estimated at 85% in 10 years and 70% at 20 years.
 Per Oral Endoscopic Myotomy (POEM)

o This procedure represents a natural orifice transluminal alternative approach to Heller’s myotomy.
It utilizes submucosal tunneling to access the lower esophageal sphincter and perform a myotomy of
the circular muscle bundle at the LES. Steps of the procedure are shown in figure 11.
o Contraindications to POEM include history of esophageal or mediastinal radiotherapy, coagulopathy,
low platelet, severe pulmonary disease, prior esophageal mucosal ablative therapies, cirrhosis with
portal hypertension.
o POEM is the preferred treatment in patients with type 3 achalasia due to the ability to perform an
extended myotomy that treats the entire contracted segment of LES in the distal esophagus.
A. Esophageal wall B. Mucosal injection C. Mucosal incision D. Scope entry

layers
E. Submucosal F. Antegrade myotomy G. Myotomy extended H. Closure of mucosal

dissection for of the circular 2-3 cm into the entry site using
tunnel creation muscle starting cardia endoclips
above the GEJ
Figure 11: Steps of POEM for achalasia
o Studies have shown very good immediate and long-term response to POEM.
o One prospective study of 70 patients who underwent POEM showed that 82% of patients were in
symptom remission at 12 months after the procedure. 88
o A larger multicenter, retrospective study followed 564 patients after they underwent POEM, with a
median follow-up of 49 months, and showed overall favorable long term results. 89
● Clinical success was defined by a decrease in Eckardt score (symptom scores for dysphagia,
regurgitation/chest pain, and weight loss) to 3 or lower. Clinical success rates at 1, 2, 3, 4, and 5
years were 94.2%, 92.2%, 91.1%, 88.6%, and 87.1%, respectively.
● Adverse events (6.4%): Delayed mucosal barrier failure (0.5%), delayed bleeding requiring
interventions and/or transfusion (0.5%), hydrothorax-requiring drainage (1.1%), pneumothorax
requiring drainage (3.7%). GERD occurred in 37.3% of patients (155/ 416).
 Transoral Incisionless fundoplication (TIF) performed after POEM is feasible to control GERD and esophagitis
based on small case series.90 Others have described TIF immediately after POEM during the same session91
Study Highlights: Clinical trials comparing different achalasia treatment modalities

 Heller versus pneumatic dilation: A prospective randomized study (n=201) showed that there
was no difference in response between Heller myotomy (84%) and pneumatic dilation [PD]
(82%) after a mean follow up of 5 years (p=0.92).92 In the PD group, 25% of patients required
repeat dilation. There was a 5% overall perforation rate in the PD group.
 POEM versus pneumatic dilation: A multicenter multinational clinical trial randomized patients
with achalasia to receive POEM (n = 67) or pneumatic dilation (PD) with 30-mm and 35-mm
balloon (n = 66). Treatment success occurred in 92% in the POEM group vs 54% in the
pneumatic dilation group.93 POEM was associated with higher rate of esophagitis (41%)
compared to PD (7%). The investigators used a lower dilation pressure in PD and considered
retreatment with PD as treatment failure, which led to a lower response rate in the PD group.
 POEM versus Heller myotomy: A randomized multicenter multinational clinical trial
randomized patients with achalasia to POEM (n=112) or laparoscopic Heller’s myotomy plus
Dor’s fundoplication (n=109).94 Clinical success at the 2-year follow-up was similar in the
POEM group (83%) vs LHM group (81.7%), P=0.007 for non-inferiority. POEM group had
higher incidence of esophagitis compared to LHM at 3 months (57% vs. 20%) and at 2 years
(44% vs. 29%).
 All three treatment modalities remain valid options for treating achalasia (see figure 9)
 In patients who do not respond to treatment, evaluate their symptoms using Eckardt score (page 22), and examine
LES using time barium esophagogram (page 21), high-resolution manometry, or FLIP (page 22).
 Distal esophageal spasm (DES)
 Clinical presentation: dysphagia and chest pain, Barium may show the classic "corkscrew" esophagus.
 Manometry shows normal median IRP
 ≥ 20% of swallows have premature contraction (DL < 4.5 seconds) and DCI >450. These contractions
are intermixed with normal peristalsis in other swallows.
 Type 3 achalasia can be misdiagnosed as DES. In achalasia, the IRP is high. Other investigations such
as FLIP (see page 22) could further elucidate the diagnosis if the IRP is borderline.
 Hypercontractile (jackhammer) esophagus
 Clinical presentation is similar to distal esophageal spasm.
 Nutcracker esophagus (DCI > 5000) is no longer a distinct entity in the Chicago classification 3.0 or 4.0.
 Hypercontractile (jackhammer) esophagus: manometry shows DCI > 8000 in at least two swallows and
normal LES relaxation (normal median IRP) (see figure 8-D).
 Rule out esophageal mechanical obstruction that can give manometric findings of jackhammer esophagus.
 Treatment of DES and hypercontractile esophagus:
 Control symptoms of GERD with PPI.
 Trial of tricyclic antidepressant, calcium channel blockers (diltiazem), nitrates, sildenafil. Botulinum
toxin injection may improves dysphagia and chest pain in patients with DES95, 96
 POEM may improve symptoms but its use in hypercontractile disorders is not well established.
 Functional Esophagogastric Junction Outflow Obstruction (EGJOO)

 Symptomatic patients present mainly with dysphagia and/or chest pain.
 EGD usually shows normal esophagus and LES appearance. Other findings: tight LES (similar to achalasia),
epiphrenic diverticulum (just above LES). In patients with history of Nissen fundoplication, a tight wrap
can be appreciated in some cases.
 It is important to assess carefully the esophagogastric junction during endoscopy for any visible lesions or
abnormalities on both forward and retroflexed views. Obstruction due to strictures and external compression
can present with features similar to functional EGJOO. However, these patients have mechanical EGJOO. The
yield of cross sectional imaging in patients with functional EGJOO appears to be low. 97
 Manometric diagnosis was revised in Chicago 4.0 classification as follows:
 Elevated median IRP in both supine and upright positions, and increased intrabolus pressure in ≥20% of
swallows, with normal peristalsis (see Figure 8-C)
 EGJOO may have additional features of dysmotility:
o EGJOO with spastic features (≥ 20% premature swallows).
o EGJOO with hypercontractile features (DCI >8000).
o EGJOO with ineffective motility (>70% ineffective swallows or ≥ 50% failed peristalsis)
o EGJOO with no evidence of disordered peristalsis (peristalsis is normal)
 Possible underlying etiologies of EGJOO include post fundoplication (tight wrap), paraesophageal hernia,
eosinophilic esophagitis, infiltrative esophageal process (malignancy, fibrosis), chronic opiate use, or
variant/early achalasia with preserved peristalsis.98, 99
 In patients with mechanical EGJOO, treat the underlying etiology (PPI for esophagitis, PPI+/- topical
steroids for EOE, redo operations for tight Nissen fundoplication, endoscopic dilation for esophageal
stricture, surgery and other treatments of obstructing malignancy).
 In patients with manometric findings of EGJOO, further investigation using either timed barium swallow (see
page 21) or EndoFLIP (see page 22) to assess for a clinically relevant conclusive diagnosis of EGJOO. 73.
 Patients with truly functional EGJOO have an overall good prognosis, and symptoms may subside without
treatment during follow up.100 Targeted therapy of the lower esophageal sphincter, similar to achalasia, can
be attempted to relieve symptoms (botulinum toxin injection, dilation, surgery, POEM). However, more
data is needed to evaluate the role of these therapies in functional EGJOO.
 Scleroderma
 Esophageal symptoms develop in more than 50% of patients with scleroderma.
 Patients present with dysphagia and severe GERD. EGD is performed to rule out peptic stricture.
 Manometry shows weak or absent esophageal contractions in the distal two thirds of the esophagus (smooth
muscle), low LES pressure (< 10 mmHg).
 Surgical treatment options include fundoplication, modified Roux-en-Y gastric bypass, or esophagectomy. 101
Esophagitis in HIV
 Candida esophagitis
 Patients present with oral thrush, dysphagia, and mild odynophagia.
 Endoscopy reveals white mucosal plaques and esophagitis of variable severity.
 Histology: Candida in elongated pseudohyphae and round forms
 Treatment: Empiric treatment with fluconazole is indicated patients with oral thrush and esophageal
symptoms. If symptoms do not improve in 5-7 days, perform an EGD for further workup.
 CMV esophagitis
 Presents with severe odynophagia and substernal chest pain. Dysphagia is less common.
 Endoscopy typically reveals large and deep esophageal ulcers.
 CMV affects the endothelial cells in the granulation tissue of the ulcer base. Therefore, biopsy from the
center of the ulcer will have a higher yield for CMV.
 Histology shows large cytomegalic cells with (1) granular cytoplasmic inclusions and (2) basophilic
intranuclear inclusions surrounded by eosinophilic halos (owl’s eye appearance). Special CMV staining is
required in many cases to establish the diagnosis.
 Treatment: ganciclovir, foscarnet.
 HSV esophagitis
 Less common than candida and CMV.
 Symptoms include dysphagia, odynophagia, and chest pain.
 Endoscopy shows multiple ulcers less than 2 cm in size,
erythema, and exudates.
 HSV affects the epithelial cells at the periphery of the
ulcer. Therefore, biopsy from the edge of the ulcer will
have a higher yield for HSV.
 Histology (figure 12) Figure 12: HSV esophagitis.
 Multinucleated giant cells, nuclear moulding, and Esophageal biopsy shows multinucleated
margination of the nuclear chromatin (3 Ms). giant cells, with nuclear moulding and
margination of nuclear chromatin (arrows)
 Cowdry type A bodies: Intranuclear eosinophilic
(pinkish) droplet-like bodies, which are pathognomonic.
 Cowdry type B bodies: Basophilic intranuclear bodies.
 Treatment options include acyclovir, famciclovir, and valacyclovir.
 Idiopathic HIV esophageal ulcers

 Presents with odynophagia and dysphagia
 Endoscopy reveals large, deep ulcers, with no evidence of viral infection on esophageal
biopsy and staining (video 1-3).
 Treatment: Confirm the absence of viral infection on previous biopsies.
 Consider repeat EGD to obtain multiple biopsies from the center and edge of the ulcer.
Video 1-3
 Medical therapy: IV/PO steroids. Thalidomide (200 mg/day) is effective in healing HIV
idiopathic ulcers.102
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2
29
CHAPTER
Stomach
Chapter 2- Stomach
Gastroduodenal disorders account for 15% of the GI board questions. Gastroparesis is common
in clinical practice. It is important to know the limitations and possible side effects of treatment.
Rumination syndrome is an important consideration in patients with “refractory” GERD and
regurgitation. The new ACG and CAG guidelines (2017) for dyspepsia recommend EGD for
patients older than 60 (not 55). For those younger than 60, EGD is not recommended for the
workup of dyspeptic symptoms, regardless of alarm features. It is unclear if these newer
recommendations will be adhered to in practice. It would be difficult to treat a patient as
functional dyspepsia without an initial negative EGD. However, once you have a negative EGD,
It is important to accept the diagnosis of functional dyspepsia, provide reassurance to the
patient, and avoid an extensive workup in typical cases. The functional dyspepsia treatment trial
was fully published in 2015, and summarized here. H. pylori treatment is updated in three major
society guidelines (ACG, Toronto, and European guidelines). All agree that clarithromycin-based
triple therapy is less effective today than it used to be in the past, due to worldwide rise in
clarithromycin resistance. Exposure to prior macrolide antibiotics is an important predictor of
clarithromycin resistance, and this should prompt the treating physician to avoid clarithromycin-
based triple therapy (ACG). Gastric intestinal metaplasia is a commonly encountered clinical
problem, with three recently published guidelines addressing this topic (AGA, British, European).
This is summarized in this chapter based on these three documents. The benefit of surveillance
is not established, but it is suggested for some patients. Topics that are less common in practice,
but appear on the boards are gastric lymphoma, gastric neuroendocrine tumors, and
gastrinoma. Peptic ulcer disease bleeding is covered in chapter 7. Gastric neuroendocrine
tumors and GISTs are important for the boards, and are discussed in chapter 10.
32 Chapter 2: Stomach
Contents
Chapter 2- Stomach
Gastroparesis—33
Cyclic Vomiting Syndrome—35
Rumination syndrome—35
Dyspepsia—36
Helicobacter pylori—39
Hypergastrinemia and Zollinger-Ellison syndrome—43
Gastric polyps—45
Gastric intestinal metaplasia—46
Gastric adenocarcinoma—48
Hereditary diffuse gastric cancer—49
Gastric lymphoma—50
References—51
Chapter 2: Stomach 33
Gastroparesis
Clinical Guideline: Management of Gastroparesis 1 Am J Gastroenterol, 2013
AGA Clinical Practice Update on Management of Clin Gastroenterol Hepatol,

Medically Refractory Gastroparesis: Expert Review 2 2021
 Etiology
 Gastroparesis is most commonly idiopathic, diabetic, or post-surgical.
o Diabetic gastroparesis: the risk of developing diabetic gastroparesis over a 10 year period was
estimated at 5.2% in type 1 DM, 1% in type 2 DM, compared to 0.2% in controls. 3
o Idiopathic gastroparesis
● 90% of patients are women. Depression and anxiety are common in these patients.
● Ask about a viral prodrome preceding the onset of symptoms of gastroparesis. This suggests post
viral gastroparesis, which resolves in 80% of patients after 1 year.
o Post-surgical gastroparesis can result from gastrojejunostomy, vagotomy for peptic ulcer disease,
pancreaticoduodenectomy (Whipple procedure), and laparoscopic fundoplication.
● Upper gastrointestinal symptoms following fundoplication resolve in more than 90% of patients
within 1 year. 1
o Other etiologies
● Medication induced gastroparesis
 Glucagon-like peptide-1 (GLP-1) agonists: exenatide (Byetta®).
 Amylin agonists: pramlintide (Symlin®).
 Other: Opioids, tramadol, marijuana, anticholinergics, TCAs, dopamine agonists.
● Other associated disorders: hypothyroidism, hyperparathyroidism, Addison's disease, scleroderma,
Parkinson's disease, multiple sclerosis, muscular dystrophy.
 Symptoms of gastroparesis include nausea, vomiting, abdominal pain, early satiety, bloating.
 Diagnosis
 Scintigraphic gastric emptying of solids (low fat, egg white meal) is the recommended test for diagnosis.
The percentage of meal retained at 4 hours is used to diagnose and grade the severity of gastroparesis:
o Mild (11-20%), moderate (21-35%), severe (36-50%), and very severe (> 50%). 4
 The wireless motility capsule is FDA approved for evaluation of suspected gastric emptying.
However, this technology is not widely available and not recommended by the ACG.
 Differential diagnosis: gastric outlet obstruction, functional dyspepsia, constipation associated with nausea and
vomiting, narcotic bowel, cyclic vomiting syndrome (see page 35), and rumination syndrome (see page 35).5
 Treatment
 Treat coexisting constipation, as it can exacerbate gastroparesis symptoms.
 Correct fluid and electrolyte imbalances. Optimize glycemic control in diabetic gastroparesis.
 Stop offending medications.
 Diet: small, low fat, low residue meals. Consider liquid caloric supplementations in severe cases.
 Metoclopramide
o Central and peripheral dopamine antagonist and serotonin 5-HT3 antagonist with promotility and
antiemetic actions. It is FDA approved for treatment of gastroparesis for less than 12 weeks.
o A black box warning was added to the label due to neurologic side effects, mainly tardive dyskinesia
and dystonia.
● Tardive dyskinesia is an important side effect of metoclopramide. It occurs more commonly in

elderly (>70 years old) female patients, and is associated with treatment duration of more than 3
months, and higher medication doses.
● The absolute risk of tardive dyskinesia related to metoclopramide was previously estimated to be
high (1-10%), but more recent estimates are much lower (<1%, as low as 0.1/1000 patient years).
o General guidelines for using metoclopramide in gastroparesis:
● Use the minimal effective dose. Start at 5 mg before meals, up to 20 mg four times per day.
● Stop treatment if there is no response in 3 months.
● If treatment is beneficial and the duration needs to be extended beyond 3 months, discuss the risks
and benefits of treatment thoroughly with the patient.
● Metoclopramide Nasal Spray (Gimoti ®) was FDA approved in 2020 for diabetic gastroparesis.
 Domperidone
o Domperidone is a peripheral dopamine antagonist with promotility and antiemetic actions.
o It does not cross the blood-brain barrier. Neurologic side effects are minimal.
o It can lead to QT interval prolongation. Therefore, obtain a baseline EKG and a repeat EKG while
on treatment. Dose: PO 10 mg TID to 20 mg q.i.d. It is not available in the USA. It can only be
prescribed through an investigational new drug clearance from the FDA.
 Erythromycin
o Mechanism of action: motilin receptor agonist that stimulates antral contractions.
o It can be given as IV or PO. Dose is 40 - 250 mg every 8 hours.
o Limit to 2 weeks per treatment course, after which treatment becomes less effective due to the
development of tachyphylaxis.
 Tricyclic antidepressants (TCAs) are not effective in gastroparesis. A large randomized trial
(NORIG) showed that nortriptyline is not effective in patients with idiopathic gastroparesis.6 Results
from the functional dyspepsia treatment trial (see page 38) suggest that patients with functional
dyspepsia and delayed gastric emptying do not benefit from TCAs. 7
 Antiemetics: consider ondansetron, meclizine, scopolamine for nausea and vomiting.
 Intrapyloric injection of botulinum toxin is not recommended, as randomized controlled trials
showed that it was not superior to placebo.
 Enteral feeding with a nasoduodenal tube is preferable to TPN.
o Other options include venting gastrostomy, jejunostomy, or PEG-J placement.
 Surgery for extreme cases include gastrojejunostomy, pyloroplasty or gastrectomy. 1
o Gastric electrical stimulation (GES)
● GES mainly improves symptoms of nausea and vomiting in patients with refractory diabetic
gastroparesis.8 It does not improve abdominal pain.
● Most studies on GES are open label with small number of patients.
● The GES device Enterra™ is FDA approved (humanitarian use device status) for patients with
refractory idiopathic or diabetic gastroparesis.
● The mechanism by which GES improves symptoms in gastroparesis is unclear, but it is likely a
result of neuromodulation of sensory gastric nerves. It does not improve gastric emptying. The
device does not pace the stomach nor does it change the gastric electrical rhythm.
o Gastric per-oral endoscopic myotomy (G-POEM): This endoscopic technique creates a
submucosal tunnel in the antrum, followed by scope insertion and endoscopic myotomy of the
pylorus. Small studies found that it is effective in improving symptoms in patients with gastroparesis
refractory to medical therapy.9 However, larger prospective, sham-controlled studies with longer
follow up are required to confirm the effectiveness of this technique.
Cyclic Vomiting Syndrome

 Cyclic vomiting syndrome (CVS) is an idiopathic disorder characterized by recurrent, self-limited episodes of
nausea and vomiting alternating with symptom-free intervals.
 It usually affects children and young adults.
 Rome IV diagnostic criteria 10
 Must include all of the following:
 Stereotypical episodes of vomiting regarding onset (acute) and duration (< 1 week).
 Three or more discrete episodes in the prior year occurring 1 week apart.
 Absence of vomiting between episodes, other milder symptoms can be present.
 These criteria should be fulfilled for the last three months with symptom onset at least six months prior to diagnosis.
 Supportive criterion: personal or family history of migraine headaches.
 Phases of CVS
 Prodromal phase: most patients are able to sense the approach of an episode. They may develop nausea,
but are still able to eat
 Emetic phase: persistent nausea and vomiting, with or without abdominal pain.
 Recovery phase: resolution of symptoms and improved appetite.
 Associated conditions
 Migraine headaches, psychiatric conditions such as anxiety and depression.
 Cannabinoid hyperemesis syndrome is characterized by chronic excessive marijuana use, cyclic episodes
of nausea, vomiting, and abdominal pain (similar to CVS), and relief of these vomiting episodes with
cessation of cannabis use. Patients may exhibits pathologic bathing behavior to relieve their symptoms11
 Differential diagnosis includes gastrointestinal disorders (gastroparesis, peptic ulcer disease, gallbladder
disease, small bowel obstruction or Pseudoobstruction) and extra-intestinal disorders (increased intracranial
pressure due to mass lesion, nephrolithiasis, adrenal insufficiency, acute intermittent porphyria). 12
 Management
 Treatment during the acute episode: Supportive care, hydration. Give antiemetics (ondansetron,
Promethazine). Consider anxiolytics (benzodiazepines).
 Inter-episode treatment
 Prophylactic therapy: consider propranolol, amitriptyline (25-50 mg/day), Zonisamide (100-600 mg
daily) or levetiracetam (500-1000 BID).
 Avoid cannabis use. Avoid stress, avoid fasting, and maintain good sleep hygiene.
Rumination syndrome
Clinical Practice Update: Expert Review: Diagnosis Clin Gastroenterol

And Treatment Of Rumination Syndrome 13 Hepatol, 2018
 In this disorder, there is effortless regurgitation of undigested food within 10-15 minutes after eating.
 Usually there is no retching or nausea.
 The regurgitation of stomach content is facilitated by a coordinated abdomino-pelvic maneuver in which there
is contraction of the intercostal muscles and abdominal wall muscles, and relaxation of the diaphragm. 14
 Most commonly affects adolescents, with a strong female preponderance. Postprandial regurgitation in
these patients can be mislabeled as refractory GERD or vomiting. 13
 Associated with stress and anxiety.
 Differential diagnosis: GERD, achalasia, peptic ulcer disease, eating disorders.

 Rome IV diagnostic criteria:
 Must include both of the following 10
 (1) Persistent or recurrent regurgitation of recently ingested food into the mouth with subsequent spitting
or re-mastication and swallowing
 (2) Regurgitation is not preceded by retching.
 Supportive criteria:
 (1) Regurgitation events are usually not preceded by nausea.
 (2) Regurgitant contains recognizable food that might have a pleasant taste (regurgitation of acidic
content does not exclude the diagnosis of rumination).
 The presence of nighttime symptoms and nausea does not rule out the diagnosis. 13
 Treatment is with behavioral therapy (with or without biofeedback). Behavioral therapy focuses on postprandial
diaphragmatic breathing for 5 minutes before and after meals to compete with the urge to regurgitate.
 Diaphragmatic breathing instructions: breathe in slowly by taking air through the nose into the abdomen
(belly expands), and breathe out slowly through the mouth to allow the air to exit the abdomen (belly retracts).
 Diaphragmatic breathing can be taught by speech therapists, psychologists, or gastroenterologists and then
practiced by the patients. Smartphone apps are available to help teach patients diaphragmatic breathing.
 Baclofen 10 mg three times daily can be used in refractory patients.
Dyspepsia
Am J
ACG and CAG Clinical Guideline: Management of
Gastroenterol,
Dyspepsia 15
2017
AGA Guideline on the Role of Upper GI Biopsy to Evaluate Gastroenterology,

Dyspepsia in the Absence of Visible Mucosal Lesions16 2015
 Definition: pain or discomfort in the central upper abdomen, which originates in the upper gastrointestinal tract.
 Other symptoms include early satiation, anorexia, belching, nausea, vomiting, bloating.
 Dyspepsia can be caused by an organic disease (e.g. peptic ulcer disease, gastritis, esophagitis, malignancy)
or a functional disorder (functional dyspepsia).
 Examples of medication-induced dyspepsia: NSAIDS, iron, narcotics, colchicine, acarbose.
 Rome IV criteria for functional dyspepsia (FD)10: Must include both of the following criteria for the last 3
months with symptom onset ≥ 6 months prior to diagnosis.
 One or more of the following symptoms: bothersome postprandial fullness, early satiation, epigastric
pain, or epigastric burning.
 No evidence of structural disease that is likely to explain the symptoms (normal EGD).
 FD is further divided into two subtypes (The two subtypes can coexist)
 Post prandial distress syndrome (PDS): Postprandial fullness, Early satiation)
 Epigastric pain syndrome
 Moderate intermittent epigastric pain that is not generalized & not localized to other abdominal or chest regions.
 It is not relieved by defecation, and not related to gallbladder or sphincter of Oddi disease.
 The pain can be burning in character, but without a retrosternal component.
 The pain is meal unrelated or fasting.
 Workup and initial management of uninvestigated dyspepsia
 The American College of Gastroenterology (ACG) and the Canadian Association of Gastroenterology (CAG)
updated their guidelines on the management of dyspepsia in 2017 in a joint publication.
 In the previous guidelines (2005):
 EGD was recommended in patients with dyspepsia who are older than 55 years of age, or who present with one or
more alarm features (bleeding, anemia, early satiety, weight loss, dysphagia, recurrent vomiting, family history of
GI malignancy, prior GI malignancy, or peptic ulcer disease).17
 In patients who are younger than 55 years of age, and do not have alarm features, a trial of PPI treatment
or H. pylori test and treat strategy was recommended.
 EGD was indicated for those who do not respond to these interventions.
 The updated ACG and CAG guidelines of 2017 recommend:
 EGD in patients with dyspepsia who are ≥ 60 years of age.
 If EGD is normal, then treat as FD (H. pylori eradication, PPI trial, TCA, prokinetics, psychotherapy).
Avoid performing multiple EGDs and imaging studies in patients with typical features of FD.
 In those younger than 60, EGD is not recommended, regardless of the presence of an alarm feature. The
role of alarm features was de-emphasized. Alarm features increase the likelihood of malignancy, however,
the overall risk of malignancy in those with an alarm feature is low (<1%).15
 Patients who may benefit from endoscopy: Progressive dysphagia, severe weight loss, abnormal
imaging, iron deficiency anemia, or those with a combination of alarm features.
 Patients with pancreaticobiliary presentations (biliary pain pattern, jaundice) should undergo
appropriate workup with ultrasound and/or cross sectional imaging studies.
 Management in those younger than 60 years of age includes the following interventions in this order:
 Test and treat for H. pylori.
 If the patient does not respond to H. pylori eradication, or H. pylori negative, treat with empiric PPI
therapy with PPI once daily for four weeks.
o If the patient responds to PPI, stop treatment after 4-8 weeks. If symptoms recur, give another course
e of PPI or consider long-term treatment.
o If no response to PPI once daily, there is no role of increasing PPI to twice daily
 If PPI treatment and H. pylori eradication fail to improve symptoms, treat as functional dyspepsia (TCA,
prokinetics, or psychotherapy).
 It is unclear if these newer guidelines will be adhered to in practice. It is difficult for the gastroenterologist
to avoid EGD in patients with persistent dyspepsia, and to treat those with “uninvestigated dyspepsia” as
“functional dyspepsia” without having one negative EGD.
 Patients should be managed on a case-by-case basis and those who do not undergo EGD should be informed
that their risk of malignancy is small. Consider EGD in those with > 1 alarm features who do not respond to
treatment with H. pylori eradication and PPI. Consider adding an EGD to a screening colonoscopy in patients
with dyspepsia who need colon cancer screening.
 In patients undergoing EGD for dyspepsia as the sole indication:18
 Do not routinely biopsy the esophagus.
 Obtain biopsies from the normal appearing stomach.
 Do not routinely biopsy the duodenum in immunocompetent patients.
 In immunocompromised patients, obtain biopsies from the stomach and from the duodenum (to rule out
graft versus host disease) in immunocompromised patients
 There is no need to perform routine histologic stains.
 Treatment options for FD
 PPI treatment for 4 weeks is more effective in patients with reflux-like symptoms compared to those with
dysmotility-like symptoms such as nausea and bloating.
 Give PPI once daily. There is no added benefit of twice-daily PPI for FD.
 The number of patients needed to treat to improve symptoms in one patient is 10.
 There is a small but statistically significant benefit from testing and treating H. pylori in FD. The number
needed to treat is 14.
 Diet recommendations for functional dyspepsia consist of smaller meals and a low fat diet.
 Herbal medications for functional dyspepsia
 STW-5 (Iberogast ®) is a combination of nine herbs. A placebo controlled trial showed benefit in FD. 19
Follow up in this trial was up to 8 weeks. Other herbal preparations with variable efficacy in FD include
artichoke leaf extract, peppermint and caraway oils.
 Selective serotonin reuptake inhibitors (SSRIs)
 A randomized controlled trial of Venlafaxine in 160 patients with FD showed that it was not superior to
placebo in treating FD symptoms. 20
 Tricyclic antidepressants (TCAs)
 TCAs are more effective in patients with functional abdominal pain and IBS.
 The functional dyspepsia treatment trial (FDTT) showed that amitriptyline is beneficial in FD,
particularly in those with ulcer-like FD.7
Study highlight Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A

Multicenter, Randomized Controlled Study
 The FDDT is a randomized, double-blind, placebo-controlled multi-center trial of 292
patients given placebo, 50 mg amitriptyline, or 10 mg escitalopram for 10 weeks. The
primary endpoint was adequate relief of FD symptoms for 5 weeks of the last 10 weeks.
o An adequate relief response was achieved in 40% of placebo, 53% of amitriptyline, and 38% of
escitalopram (p=0.05)
o Patients with ulcer-like dyspepsia (epigastric pain) were more likely to respond to amitriptyline compared
to dysmotility-like dyspepsia (epigastric discomfort, fullness, early satiety, bloating, and nausea).
o Patients with delayed gastric emptying were less likely to report adequate relief than those with
normal gastric emptying (OR = 0.4; 95% CI: 0.2-0.8).
 Acotiamide is a new gastroprokinetic agent works as an acetylcholine esterase inhibitor and enhances
acetylcholine release from enteric neurons.
 Al large phase 3 study from Japan showed that acotiamide significantly improved symptom severity and
eliminated meal-related symptoms in patients with FD (15% in treated patients vs. 9% in placebo, p=0.004,
number needed to treated = 16). 21 Acotiamide is not available in the United States.
 Buspirone is a 5-hydroxytryptamine 1A receptor agonist that relaxes the proximal stomach and improves
gastric accommodation. A small randomized, double-blind, placebo-controlled, crossover study of 17 patients
showed that in patients with FD, administration of buspirone (10 mg t.i.d. for 4 weeks) significantly improved
symptoms (post prandial fullness, early satiation and bloating) and gastric accommodation, compared with
placebo. 22 Buspirone did not improve gastric emptying.
 Mirtazapine is a tetracyclic antidepressant that can improve symptoms of dyspepsia and induce weight gain in
patients with functional dyspepsia. 23, 24 Dose is 15 – 30 mg per day for at least 4 weeks.
 Acupuncture may have a role in treating symptoms in postprandial distress syndrome. In a randomized trial from
China, 278 patients with PDS were randomized to acupuncture or sham acupuncture conducted at 3 sessions /week
for 4 weeks.25 83% of the acupuncture group had improvement compared to 52% in the sham group; corresponding
numbers for complete resolution of symptoms were 28% and 17%, respectively. The effects were sustained at 3
months follow up.
Helicobacter pylori
AGA Clinical Practice Update on the

Gastroenterology,
Management of Refractory Helicobacter pylori
2021
Infection: Expert Review26
ACG Clinical Guideline: Treatment of Am J Gastroenterol,
Helicobacter pylori Infection 27 2017
Management of Helicobacter pylori infection—

Gut 2017
the Maastricht V/ Florence Consensus Report 28
The Toronto Consensus for the Treatment of Gastroenterology,

Helicobacter pylori Infection in Adults 29 2016
 H. pylori is a gram-negative spiral shaped bacterium that lives in the gastric mucous layer.
 It is recognized by the World Health Organization as a class 1 carcinogen.
 Eradication of H. pylori decreases the risk of developing gastric cancer.
 A meta-analysis of 24 studies showed that gastric cancer developed in 253 of 20,484 individuals with
H. pylori who received eradication therapy and 462 of 27,580 untreated patients. The incidence rate
ratio was 0.54 (95% CI 0.46-0.65).30
 A recent single-center, double-blind, placebo-controlled trial (n=1676, South Korea) showed that
treatment of H. pylori in patients with a first degree relative with gastric cancer reduces the risk of
gastric cancer (1.2% in the treatment group and 2.7% in the placebo group, hazard ratio [HR] 0.45,
p=0.03).31 The reduction was even lower (HR 0.27) in those who successfully eradiated H. pylori.
 The main indications for H. pylori testing are listed in table 1.27
 All patients who test positive should be offered eradication therapy, regardless of the reason of H. pylori testing.
 H. pylori screening is recommended prior to bariatric surgery in high prevalence areas. 32
 Recommendations by other international societies include:
 Unexplained B12 deficiency, idiopathic thrombocytopenic purpura, first degree relative with gastric
cancer, screening in communities with high risk for gastric cancer, chronic PPI use >1 year,
environmental risk factors for gastric cancer (e.g. heavy smoking). 28, 33
Table 1: Indications for testing for H. pylori

Established indications (recommended) Controversial indications (conditional
recommendation)
 Active peptic ulcer disease  Patients on low dose aspirin
 Confirmed history of peptic ulcer disease  Unexplained iron deficiency anemia
(without prior therapy)  Idiopathic thrombocytopenic purpura
 Low grade gastric MALT lymphoma
Testing is Not indicated
 After endoscopic resection of early gastric
cancer  GERD without dyspepsia or PUD
 Uninvestigated dyspepsia (non-endoscopic Insufficient evidence to recommend for or
testing in patients without indication for EGD) against testing
 Functional dyspepsia (collect biopsies during  Lymphocytic gastritis
EGD if not already tested)  Asymptomatic persons with family history of
 Long term NSAIDS users gastric cancer (evidence emerging, see study above)
 Gastric hyperplastic polyps
 Hyperemesis gravidarum
 H. pylori testing modalities are listed in table 2.

 Steps of the urea breath test (figure 1)
 Patients must be off PPI for at least 2 weeks and must be
fasting for 1 hour prior to the test.
 The patient provides a baseline breath sample, and then
drinks a solution containing carbon labeled urea (13C-Urea
or 14C-Urea).
 Post ingestion breath samples are collected 15 minutes
later.
 If H. pylori is present, carbon labeled urea is converted by
H. pylori urease into tagged CO2. This circulates in the
blood, and is excreted through the lungs and detected in breath. Figure 1: Urea breath test.
 Gastric biopsy protocols for H. pylori are shown in figure 2.34 (See text)
Table 2: H. pylori testing modalities*

Sensitivity Specificity Comments
Tests to detect current
infection (preferred)
Biopsy urease test: 90-95% 95-100%  Sensitivity is decreased with recent GI bleeding, PPI,
(CLO test, Pyloritek) antibiotics, bismuth
 In the setting of acute bleeding, a negative test should
Histology 90-95% 95-100% be confirmed with repeat testing at a later time34
Urea breath test † 95% 90-95 %  C13: non-radioactive.
 C14: low radiation, contraindicated in pregnancy
Stool antigen † 93% 93%  Sensitivity is decreased with PPI, bismuth and
antibiotics
 GI bleeding can cause false positive results and
decreases specificity
 Monoclonal test are more reliable than polyclonal
Tests to detect current
or prior infection
Serology (serum IgG 85% 80%  If the test is negative in a patient with ulcer bleeding,
antibody) then it is recommended to repeat H. pylori testing
with an active test after the acute bleeding episode
resolves
Other H. pylori tests that are not routinely available include culture and sensitivity, and PCR.
*For confirmation of eradication of H. pylori, it should be performed at least 4 weeks after completion of therapy.
Figure 2: Gastric biopsy

protocols for H. pylori in
patients with normal
mucosa. Obtain mucosal
biopsies from all these sites
(one jar). The AGA
recommends using the
5-biopsy system, rather than
the 3-biopsy system.
 All patients who receive treatment for H. Pylori should be offered testing to prove successful H. pylori
eradication. This is particularly important for patients with PUD, persistent dyspeptic symptoms, H. pylori-
associated MALT lymphoma, and those who have undergone resection of early gastric cancer.
 Testing is recommended 4 weeks after completion of treatment, while off PPI for 2 weeks, and using a test
to detect current (active) infection –see table 2. Do not use the serum antibody in this setting.
 The recommended regimens are summarized in table 3.
 Bismuth quadruple therapy (14 days) is the recommended first line treatment, rather than triple therapy.29
 Decisions about the choice of initial therapy should be based on local antibiotic resistance patterns, if available.
 The use of clarithromycin is an option only in areas with low clarithromycin resistance <15% or proven high
eradication rates >85%.
 The routine use of probiotics to reduce the rate of adverse events is not recommended.
 Sequential regimens are not recommended by the Toronto guidelines and they were eliminated.
 The 2017 ACG guidelines provide more options for first line treatment and include sequential therapies. 27
 The use of clarithromycin containing regimens is generally discouraged, but remains an option if the patient
does not give a history of prior macrolide exposure. However, in regions with documented high macrolide
resistance (>15%), use non-macrolide regimens.
 Sequential and hybrid therapies are listed as first line options; however, their efficacy is inferior to
clarithromycin triple and bismuth quadruple therapies.
 Talicia® delayed-release capsules (omeprazole, amoxicillin and rifabutin) (10 mg/250 mg/12.5 mg) is approved for
the treatment H. pylori infection in adults as first line or second line treatment.
 Dose: patient should take (4) capsules every 8 hours with food for 14 days.35
 Unsuccessful treatment of H. pylori infection indicates a refractory infection. This is most commonly related
to antibiotics resistance, medication non-adherence, and inadequate acid suppression. 26
 In patients who are labelled to have penicillin allergy, consider referral for allergy testing to confirm the
presence of a significant allergy. 26
 In cases of refractory infection, antibiotic sensitivity testing (e.g. culture-based testing or molecular-based
sensitivity testing) should be considered, based on availability, to help further guide treatment regimens.
 The benefits of H. pylori eradication with multiple rounds of antibiotics should be weighed against risks of repeated
antibiotic exposure (e.g. C. difficile infection). 36 In elderly, frail patients with multiple comorbidities, and without
history of peptic ulcer, gastric atrophy, or intestinal metaplasia, stopping further treatment is appropriate. .
Ménétrier’s disease
 This is a rare disorder characterized by giant hypertrophic gastric folds. There is an increased risk of
developing gastric adenocarcinoma. Patients present with abdominal pain, nausea, vomiting, anemia,
peripheral edema. Presents in adults with an insidious onset and a progressive clinical course. 37
 The childhood type of Ménétrier's disease usually presents with a sudden onset. It is possibly related to
CMV or H. pylori infection, and resolves spontaneously.37
 Molecular pathogenesis: enhanced signaling through the receptor tyrosine kinase-epidermal growth factor
receptor (RTK-EGFR) through overexpression of TGF-α.38
 Endoscopy: this reveals thick gastric folds and increased mucous production.
 The disease predominantly affects the fundus and body, with relative sparing of the antrum. Superficial biopsies
are usually not diagnostic. Deeper biopsies or snare resections of gastric mucosa are essential for diagnosis.
 Histology shows a preserved mucosal architecture, foveolar hyperplasia, tortuosity, and dilatation of the
glands, forming a "corkscrew" appearance. In addition, there is smooth muscle hyperplasia and decreased
numbers of parietal cells.37
 Treatment: supportive care. Consider octreotide. Gastric resection in severe cases.
Table 3: Treatment regimens for H. pylori 29
Regimen Comments
First line therapy
Bismuth quadruple therapy Appropriate for all patients; preferred
PPI + bismuth + metronidazole (QID)+ tetracycline regimen if penicillin allergy and/or prior
x14 days clarithromycin exposure
Concomitant non-Bismuth quadruple therapy Appropriate in patients without prior
PPI + Amoxicillin + Clarithromycin +metronidazole exposure to macrolide and no penicillin
(BID) x14 days allergy
Levofloxacin triple therapy Note: Sequential regimens are not
PPI + amoxicillin +levofloxacin x14 days recommended by the Toronto guidelines.
PPI triple
PPI +amoxicillin +clarithromycin x14 days
Hybrid therapy:
PPI and amoxicillin for 5-7 days followed by PPI,
clarithromycin and metronidazole BID
Sequential clarithromycin therapy
PPI + amoxicillin x 5-7 days, followed by PPI,
clarithromycin and metronidazole BID x 5-7 days
Sequential levofloxacin therapy

PPI +amoxicillin x 5-7 days, followed by PPI,
levofloxacin and metronidazole BID x 5-7 days
PPI triple without amoxicillin Appropriate if penicillin allergy and no

PPI+ metronidazole (TID)+ clarithromycin x14 days prior clarithromycin exposure
Other PPI triple Listed by Toronto H. pylori guidelines, not
PPI + amoxicillin + metronidazole (BID) x14 days ACG
Prior treatment failure (salvage treatment)
Bismuth quadruple therapy Appropriate if not previously given and
PPI + bismuth + metronidazole (QID)+ tetracycline failed
Levofloxacin triple therapy Appropriate if no prior quinolone exposure
PPI + amoxicillin +levofloxacin and no penicillin allergy
Rifabutin containing regimen Appropriate if no penicillin allergy
PPI+ amoxicillin + Rifabutin
Concomitant non-Bismuth quadruple therapy Appropriate if first regimen did not contain
PPI + Amoxicillin + metronidazole QID- clarithromycin
Clarithromycin
High dose dual Appropriate if no penicillin allergy
PPI (TID or QID) + amoxicillin (1 g TID or 750 QID)
Drug doses:
PPI: esomeprazole 40 mg BID, lansoprazole 30 mg, omeprazole 20 mg BID, pantoprazole 40 mg BID,
rabeprazole 20 mg BID.
Bismuth 525 mg QID, tetracycline 500 mg QID, metronidazole 500 mg BID, TID or QID, as above (can be
replaced with tinidazole), clarithromycin 500 mg BID, amoxicillin 1000 mg BID, levofloxacin 500 mg QD or
250 BID, rifabutin 300 qday.
Talicia® (omeprazole magnesium, amoxicillin and rifabutin) delayed-release capsules (10 mg/250 mg/12.5 mg) is
approved for the treatment H. pylori infection in adults. Dose: take (4) capsules every 8 hours with food for 14 days.35
Hypergastrinemia and Zollinger-Ellison syndrome
ENETS Consensus Guidelines for the Management of

Patients with Digestive Neuroendocrine Neoplasms: Neuroendocrinology. 2012
Functional Pancreatic Endocrine Tumor Syndromes 39
 Hypergastrinemia is defined as fasting serum gastrin level greater than 200 pg/mL.
 Etiology (table 4)
 Hypergastrinemia can be classified as appropriate hypergastrinemia (due to decreased gastric acid
production) or inappropriate hypergastrinemia (with normal or increased gastric acid production).
Table 4: Etiology of hypergastrinemia
Appropriate (decreased acid production) Inappropriate (normal or increased acid production)
 Acid suppression: H2 blockers, PPI  Zollinger Ellison syndrome (ZES)
 Chronic metaplastic atrophic gastritis  Retained antrum syndrome
-Type A: autoimmune gastritis, pernicious anemia  Antral predominant H. pylori infection
-Type B: H. pylori pangastritis (G-cell hyperplasia)
 Chronic renal failure  Gastric outlet obstruction
 Vagotomy without antrectomy  Small bowel resection
 Retained antrum syndrome is a rare complication
after Billroth 2 surgery. A small segment of the antrum
is retained in the duodenal stump.
 The retained gastric mucosa is only exposed to the
alkaline duodenal contents. Without the negative
feedback of an acidic environment, it continuously
secretes gastrin, leading to recurrent peptic ulcers.
 The level of gastrin elevation by itself has limited use in
distinguishing the various etiologies of hypergastrinemia.
However, gastrin levels >1000 pg/mL are mostly associated
with ZES or chronic atrophic gastritis.
 Clinical manifestations of ZES: abdominal pain, severe
heartburn, severe esophagitis, diarrhea, and multiple,
recurrent peptic ulcers (most ulcers occur in the duodenal
bulb, other sites are distal duodenum and jejunum.)
 Diagnostic approach to suspected ZES (figure 3)
 ZES should be suspected in the following conditions:39
 Recurrent PUD, H. pylori and NSAID negative
PUD, PUD in association with thick gastric folds,
and patients with hypergastrinemia.
 The diagnosis of ZES requires the demonstration of
elevated level of gastrin and low gastric pH
(inappropriate hypergastrinemia).
 In cases where serum gastrin is >10 times the upper limit
of normal (ULN), demonstration of low gastric pH is Figure 3. General approach to the patient
with elevated serum gastrin and
sufficient to diagnose ZES.
suspected ZES *Gastric pH and secretin
 In cases where the elevation of gastrin is less stimulation test should be performed off PPI (see
pronounced, the diagnosis of ZES requires the text). Serum gastrin is a good initial screening test
demonstration of abnormal secretin stimulation test. and is elevated in > 98% of ZES cases.
 Secretin stimulation test

 This test differentiates ZES from other etiologies.
 Secretin dose: 2 units/kg infused over 30 seconds.
 An increase in gastrin by at least 120 pg/ml within 5-10 minutes is considered a positive test.
 The cutoff level of > 120 pg/ml was found to be more sensitive compared to the older cutoff of
> 200 pg/ml (94% vs. 83%), with the same specificity (100%).40, 41
 Performance of secretin stimulation test on PPI appears to be non-inferior to performance of the test off
PPI. Therefore, PPI withdrawal may not be necessary prior to this test. 42
 Basal acid output in ZES is greater than 15 meq/hr. However, this test is generally unavailable.
 Patients with features of ZES and normal gastric level may have elevation of cholecystokinin (CCK) due to a
rare pancreatic neuroendocrine tumor secreting CCK (CCKoma). 43
 Hypergastrinemia and PPI
 PPIs can lead to elevation of serum gastrin, usually to less than 3 times ULN. In addition, PPI therapy
results in a high gastric pH (achlorhydria) and interferes with the results of the secretin stimulation
test.
 Therefore, in order to obtain accurate gastrin levels, gastric pH measurements and secretin stimulation
test, these tests should be performed off PPI. However, it is important to consider the dangers of
abruptly stopping PPI.
 In patients with gastrinoma, stopping PPI can cause an exaggerated rebound gastric acid
hypersecretion. This leads to severe upper gastrointestinal symptoms such as nausea, vomiting,
abdominal pain, and even perforation.44
 The reason for this phenomenon is that during initial gastrinoma growth and gastrin production,
pancreatic secretion of bicarbonate increases gradually to buffer the increased gastric acid output. PPI
therapy will decrease acid output, eliminating the stimulus for bicarbonate secretion, resulting in
decreased pancreatic bicarbonate secretion while on PPI. 45
 Acute withdrawal of PPI will result in a sudden increase in acid output without the buffering action of
pancreatic bicarbonate, leading to severe symptoms.
 Steps to safely withdraw PPI prior to ZES testing: 46
 Perform an EGD and document healing of PUD and esophagitis.
 Explain to the patient the need to stop PPI and the associated risks.
 Wean PPI gradually instead of a sudden withdrawal.
 Switch to high dose H2 blockers for 3-5 days.
 Stop H2 blockers and give only antacids 24 hours prior to the day of the test.
● If ZES is confirmed, the next step is to search for the primary tumor using different imaging modalities
such as CT, MRI, EUS, Octreoscan, or other somatostatin imaging studies such as 68Gallium- positron
emission tomography [PET].
 Most gastrinomas arise within the "gastrinoma triangle" (figure
4). This is bound superiorly by the junction of the CBD and
cystic duct, inferiorly by the junction of the second and third
portions of duodenum, and medially by the junction of the head
and neck of the pancreas
 30-60% of patients with gastrinoma have multiple endocrine
neoplasia (MEN) type 1.
 Test for pituitary gland tumors and hyperparathyroidism.
 A patient with hyperparathyroidism should undergo Figure 4: The gastrinoma triangle.
(See text)
parathyroidectomy prior to gastrinoma resection surgery.
"
Gastric polyps
The role of endoscopy in the management of premalignant

ASGE, 2015
and malignant conditions of the stomach 47
British Society of Gastroenterology guidelines on the

diagnosis and management of patients at risk of Gut, 2019
gastric adenocarcinoma 48
 Fundic Gland polyp (FGP)
 Sporadic FGPs are usually small, 1-5 mm in size, and located in the body and fundus.
 FGPs are associated with chronic PPI therapy. They are unrelated to H. Pylori infection.
 Histology shows dilated fundic glands lined by normal gastric body type epithelium.
 Management: always biopsy or resect gastric polyps to rule out adenomatous histology.
 Perform a screening colonoscopy in patients with multiple and diffuse FGPs.
 Malignant transformation is rare, with a reported rate of less than 1% in polyps larger than
1 cm in size. Therefore, routine surveillance is not recommended.
 ASGE recommends that sporadic fundic gland polyps ≥ 1 cm in size should be resected.34
 Multiple FGPs arise in patients with familial adenomatous polyposis and MUTYH associated polyposis.
 Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) is a recently described,
rare autosomal dominant cancer predisposition syndrome associated with gastric fundic gland
polyposis.49 It is caused by a germline mutation in the YY1 binding site of the APC promotor 1B. It is
associated with fundic gland polyps (with and without dysplasia, usually >100 polyps) restricted to the
fundus and body of the stomach (with sparing of the antrum), and without colonic or duodenal
polyposis. The risk of gastric adenocarcinoma is increased, but not colon adenocarcinoma.
 Hyperplastic polyps
 Hyperplastic polyps develop due to chronic inflammation, including H. pylori infection and autoimmune
gastritis. They are commonly located in the antrum.
 ACG did not recommend for or against H. pylori testing due to insufficient evidence of association. 27
 Other societies recommend testing for H. pylori and intestinal metaplasia in the surrounding mucosa. 48
 Histology shows dilated, elongated, tortuous foveolar epithelium surrounded with an edematous, reactive,
and inflammatory stroma.
 The risk of malignant transformation is increased in hyperplastic polyps larger than 2 cm.
 ASGE recommends that hyperplastic gastric polyps larger than 5 mm should be resected, while the
British guidelines recommend resection for hyperplastic polyps that are pedunculated, size > 1 cm, or
symptomatic polyps (anemia, obstruction). 34
 Gastric adenomas
 Gastric adenomas are histologically similar to colonic adenomas.
 They are considered premalignant, and they require resection in all cases.
 Surveillance EGD is recommended one year following resection.
Gastric intestinal metaplasia
British Society of Gastroenterology guidelines on the

diagnosis and management of patients at risk of Gut, 2019
gastric adenocarcinoma 48
Management of epithelial precancerous conditions and Endoscopy,

lesions in the stomach (MAPS II) (European Guideline) 50 2019
AGA Clinical Practice Guidelines on Management of

AGA, 2020
Gastric Intestinal Metaplasia 51
 Gastric intestinal metaplasia (IM) refers to the replacement of normal gastric epithelium with intestinal type
epithelium, as a response to chronic injury. 52 Histologically, they can be classified as:
 Complete IM: the crypts are organized, straight; goblet cells are round and well developed; and columnar
cells have well-developed brush border.
 Incomplete IM: The crypts are distorted and branched; goblet cells vary in size, with some columnar cells
present as immature “intermediate” cells that contain mucous.
 The Correa precancerous cascade describes the progression of pre-cancerous lesions to gastric
adenocarcinoma through the following steps:51, 53
Normal gastric mucosa  Non-atrophic gastritis (H. pylori)  Multifocal atrophic gastritis 
Gastric IM of complete type  Gastric IM of incomplete type  Low grade dysplasia 
High grade dysplasia  Adenocarcinoma
 H. pylori infection (especially CagA strain) is the main cause and driver of progression in the Correa cascade.
 H. pylori should be tested, treated, and eradicated in patients with chronic atrophic gastritis and IM to
reduce the risk of progression to adenocarcinoma.
 Autoimmune gastritis is also associated with these conditions.48 Patients with pernicious anemia should
undergo baseline endoscopy and biopsy of the proximal and distal gastric mucosa (see below).
 Endoscopic evaluation of intestinal metaplasia and other precursor lesions
 For accurate diagnosis of intestinal metaplasia and other precursor lesions, a careful, high quality upper
endoscopy should be performed. Careful examination and photo documentation of all regions of the
stomach is recommended using a systematic screening protocol: 48
 On anterograde view, examine the antrum, lower, mid, and upper gastric body.
 On retroflexion, examine the incisura, middle to upper gastric body, and fundus/cardia regions.
 The suggested minimal examination time is 7 minutes. 48
 The use of high-resolution endoscopy with image enhancement (e.g. narrow band imaging) in addition to
standard white light is recommended.
 If abnormal mucosa is encountered, the area should be accurately described and biopsied separately.
 At least five biopsies should be taken to detect and map the location of IM. The biopsy protocol is similar
to the Sydney protocol for the diagnosis of H. pylori (see page 40). However, for mapping of IM, the
samples should be separated into two jars:
 Two biopsies from the antrum (lesser and greater curvature), one biopsy from the incisura  Jar A
 Two biopsies from the body (lesser and greater curvature) Jar B
 Based on histologic diagnosis, the location of gastric atrophy and IM should be documented as involving
the antrum/incisura, or proximal body. This determines the extent of involvement (focal vs.
multifocal/extensive gastric atrophy and IM).
 Biomarkers: low pepsinogen I levels and/or low pepsinogen I/pepsinogen II ratio is associated with advanced
atrophic gastritis, and such patients should undergo endoscopy. However, the use of these biomarkers to screen
for gastric atrophy and IM in areas with low incidence of gastric cancer is not recommended. 48
 Risk factors for progression of intestinal metaplasia to dysplasia and cancer
 Family history of gastric cancer (first degree relative confers more risk than second degree relative)
 Gastric histology shows IM of incomplete type (vs. complete type IM)
 Multifocal IM in the gastric body and antrum (vs. unifocal IM).
 Persistent H. pylori infection
 Patients with overall increased risk of gastric cancer: Racial/ethnic minorities (Hispanics, Asians, African
Americans, and Native Americans/Alaska Natives) and immigrants from high incidence regions 51
 Endoscopic surveillance
 There is clear uncertainty about the benefit of surveillance. The British and European guidelines explicitly
recommend surveillance, while the AGA recommends against routine surveillance in gastric IM. However,
the option of surveillance is mentioned in patients with higher risk of gastric cancer who “put a high value
on potential but uncertain reduction in gastric cancer mortality”.51 In the discussion below, the word
(consider) is added to reflect this decision making process with the patient.
 The AGA recommends a surveillance interval of 3-5 years, while other societies recommend a 3-year interval.
 The British and European guidelines also recommend surveillance in cases of severe gastric atrophy in
addition to IM. The AGA does not include gastric atrophy in the surveillance recommendations.
 If IM is noted in gastric biopsy during routine endoscopy, and the patient has risk factors for IM progression
(see above), and the quality of the initial exam was adequate, then (consider) repeat endoscopy in 3-5 years
for surveillance. This is based on the presence of intestinal metaplasia, combined with patient risk factors,
regardless of extent or type of intestinal metaplasia.
 In clinical practice, the quality of the initial upper endoscopy, performed for various indications, may
not be adequate. Therefore, a repeat endoscopy within 1 year should be considered.
 If IM is noted in gastric biopsy during routine endoscopy and the patient does not have risk factors for IM
progression, or if the quality of the initial endoscopy was inadequate to fully examine the gastric mucosa,
then (consider) repeat endoscopy within 1 year. The goal of this repeat endoscopy is to determine the extent
and type of IM, for further risk stratification.
 Focal IM increases the risk of gastric cancer, but it does not by itself justify surveillance. 50
 If there is focal intestinal metaplasia (antrum only), and there are no risk factors for progression (family
history, incomplete IM, or persistent H. pylori), then there is no need for further endoscopic surveillance.
o In patients with limited IM and any risk factor, consider surveillance every 3 years.
 If there is multifocal/extensive IM (gastric body+/- antrum), then (consider) repeat endoscopy in 3-5 years.
 The European guidelines suggest surveillance every 1-2 years in those with extensive gastric atrophy/IM
with a family history of gastric cancer.
 The European guidelines suggest surveillance every 3-5 years in patients with autoimmune gastritis. 50
 The use of NSAIDS, COX-2 inhibitors, or antioxidants is not recommended to prevent the progression of
gastric atrophy or IM to malignancy.
Gastric adenocarcinoma
 In the United States, gastric cancer is the fourth most common GI malignancy (after colorectal cancer,
pancreas and liver).54 There were 27,600 estimated new cases of gastric cancer in 2020 (16,980 in males).
 Globally, gastric cancer is the fifth most common malignancy and third most common cause of cancer death.
 Risk factors: obesity, smoking, high salt and nitrite containing diet, H. pylori infection, EBV infection, prior
gastric surgery (Billroth 2), Ménétrier's disease.
 Adenocarcinoma can also arise from gastric adenomas and large hyperplastic polyps.
 Clinical features: Abdominal pain, nausea, vomiting, anemia, early satiety. Dysphagia develops in patients
with proximal gastroesophageal junction tumors.
 Physical examination may reveal cachexia, abdominal mass, hepatomegaly, left supraclavicular lymph
node enlargement (Virchow's node).
 Rare signs not specific for gastric cancer:
 The sign of Leser-Trélat: sudden onset of multiple seborrheic keratosis on the trunk.
 Acanthosis nigricans: dark velvety discoloration in body folds and creases.
 Trousseau syndrome: hypercoagulable state and deep vein thrombosis.
 Diagnosis: EGD and biopsy.
 Describe the location, size, and appearance of the tumor. Obtain multiple biopsies.
 Histologic subtypes
 The Lauren classification classifies gastric adenocarcinoma into two main histologic subtypes: intestinal
(well-differentiated) and diffuse (poorly differentiated). 55
 These histologic subtypes have distinct clinical, morphological, and molecular characteristics (table 5)
Table 5: Comparison between the intestinal and diffuse subtypes of gastric adenocarcinoma
Intestinal type Diffuse type
 Older patient  Younger patient
 Lower socioeconomic status  Higher socioeconomic status
 Decreasing in incidence  Increasing in incidence
 Usually polypoid or fungating mass  Diffuse gastric thickening (linitis plastica)
 Distal stomach  Proximal stomach
 Associated with atrophic gastritis, intestinal  Occurs due to loss of E-cadherin gene (CDH1)
metaplasia and dysplasia related to H. pylori
 Well differentiated histology (neoplastic gland  Poorly differentiated signet ring cell histology
infiltrating into desmoplastic mucosa)
Figure 5: Intestinal type gastric adenocarcinoma Figure 6: Poorly differentiated gastric adenocarcinoma
with mucin vacuoles displacing the nucleus forming
"signet ring" appearing malignant cells
 Staging: CT, EUS, PET, laparoscopy.

 Treatment
 Early tumors: Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) can be
considered for the curative resection of early gastric cancer that is < 1.5 cm in size, well or moderately
differentiated in histology, without penetration beyond the superficial submucosa or lymphovascular
invasion. All other tumors require surgery and lymph node resection. 56
 Adjuvant chemoradiotherapy is given for lymph node positive disease.
 Eradication of H. pylori.
 A randomized controlled trial showed that H. pylori eradication reduces the rate of metachronous gastric
carcinoma after endoscopic resection of early gastric cancer. 57
 Locally advanced tumors: neoadjuvant chemotherapy (+/-radiotherapy) followed by restaging.
 Advanced tumors (locally advanced, recurrent or metastatic) are treated with chemotherapy or palliative
care, depending on the patient's performance status. 56
 Prognosis depends on the stage of the disease. The overall 5-year survival is 10%.
Hereditary diffuse gastric cancer
 Defined by any of the following criteria: 58
 Two or more documented cases of diffuse gastric cancer in first or second degree
relatives, with at least one diagnosed before the age of 50.
 Three or more cases of documented diffuse gastric cancer in first or second-degree relatives,
independent of age of onset.
 The median age of cancer diagnosis is 38 years. It has an autosomal dominant inheritance.
 30% have germline mutation in E-cadherin gene (CDH1) on chromosome 16. Patients who are CDH1
negative may have a mutation in alpha-E-catenin gene (CTNNA1) on chromosome 5.
 CDH1 mutation has a high penetrance. The estimated cumulative incidence of gastric cancer for
CDH1 mutation carriers by age 80 is 67% for men and 83% for women.59
 Prophylactic total gastrectomy is recommended in patients with the CDH1 mutation.
 Endoscopic surveillance with annual EGD should be performed in young patients
(< 20 years old) and those who decline prophylactic surgery.
 There is an increased risk of lobular breast cancer in females.
 Annual mammography and breast MRI starting at the age of 35 years is recommended.58
Gastric lymphoma
 The gastrointestinal tract is the most common location for extra nodal non-Hodgkin’s lymphoma.
 The stomach is the most common location of GI lymphoma in the western world.
 Gastric lymphoma accounts for less than 5 % of primary gastric neoplasms.
 The main histologic feature is the "lymphoepithelial lesion". This describes the finding of neoplastic
atypical lymphocytes infiltrating the epithelium (figure 7).
Figure 7: Diffuse large B cell lymphoma of the stomach.

A: Neoplastic B cells replacing the entire gastric mucosa (lymphoepithelial lesion). B: High power view of large
neoplastic B cells. C: Positive CD20 stain (B cell marker-brown color).
 Gastric lymphoma arises from the mucosa-associated lymphoid tissue (MALT).

 Clinical manifestations
 Abdominal pain, nausea, vomiting, early satiation, anorexia, weight loss, GI bleeding.
 Diagnosis is mainly with EGD and biopsy. There are three main endoscopic patterns: 60
 Exophytic type presenting as a polypoid-like mass.
 Ulcerative types with ulcerations or multiple small erosions.
 Hypertrophic type with large gastric folds.
 Obtain large biopsies with jumbo forceps, snare resection, or bite on bite technique.
 Lugano staging of GI lymphomas:61 (there is no stage III in this system)
 Stage I: tumor confined to the gastrointestinal wall.
 I1: infiltration of mucosa and submucosa.
 I2: infiltration into muscularis propria and/or serosa.
 Stage II: tumor extends into the abdomen.
 II1: local nodal involvement (e.g. perigastric lymph nodes for gastric lymphoma,
mesenteric nodes in small intestinal lymphoma).
 II2: distant nodal involvement (e.g., mesenteric nodes in gastric lymphoma, other lymph nodes
include para-aortic, para-caval, pelvic, inguinal).
 IIE: Penetrates serosa into adjacent organs.
 Stage IV: Disseminated extranodal involvement, e.g. bone marrow, liver etc.; or a gastric lesion with
supradiaphragmatic nodal involvement.
 Histological classification: gastric lymphoma has two subtypes:
 Marginal B cell lymphoma (MALToma)
 Endoscopically appears ulcerative or hypertrophic rather than a nodular lesion.
 More likely to respond to H. pylori eradication compared to the diffuse large B cell types.
 Treatment
o Stage I1 disease with positive H. Pylori.
● Eradication of H. pylori. Repeat EGD in 6-8 weeks with biopsy.

● Repeat treatment if persistent H. pylori infection.
o Perform a follow up EGD every 6 months for 2 years then every 1 year.
o 75% of patients will achieve complete remission with H. pylori eradication.
o 25% will not respond treatment. These patients have a more extensive and aggressive disease
with a positive t (11; 18) translocation.
o Stage I disease with negative H. pylori, or disease is non-responsive to H. pylori treatment, or
advanced disease
● No clear consensus for treatment. Most patients receive radiation therapy ± chemotherapy.
o Stage IV: this is treated as advanced low-grade non-Hodgkin’s lymphoma.
● Most patients are given R-CHOP chemotherapy (Rituximab, Cyclophosphamide,
Hydroxydaunorubicin, Oncovin, and Prednisone).
 Diffuse large B cell lymphoma
 Endoscopically nodular in appearance. Less likely to respond to H. pylori eradication alone.
 Treatment options include surgery for early disease, radiotherapy, and chemotherapy.
 Most patients receive chemotherapy with or without radiotherapy.
Gastric neuroendocrine tumors and gastrointestinal stromal tumors (GISTs) are discussed separately in Chapter 10-Miscellaneous
GI topics.
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Guidelines Update for the Management of Patients with
3
51
CHAPTER
Small
Intestine
Chapter 3-Small intestine

Small intestinal disorders are generally less common in clinical practice compared to gastric and
colonic disorders. They account for 10% of board questions. Important disorders are celiac
disease and other diarrheal diseases such as small intestinal bacterial overgrowth and
malabsorptive disorders. Small intestinal tumors are relatively uncommon. However, they are
important to keep in mind in cases of obscure GI bleeding.
54 Chapter 3: Small intestine
Contents
Chapter 3-Small intestine

Malabsorption—55
Diarrhea after ileal resection—55
Fat malabsorption—55
Protein losing enteropathy—56
Carbohydrate malabsorption—57
Small Intestinal Bacterial Overgrowth—57
Short Bowel Syndrome—59
Celiac disease—60
Whipple disease—64
Small intestinal tumors—64
Small intestinal lymphoma—65
References—66
Chapter 3: Small Intestine 55
Malabsorption
Diarrhea after ileal resection

 In normal conditions, the terminal ileum absorbs 95% of
bile acids through active bile acid transport into the
portal circulation. Bile acids circulate back to the liver
(enterohepatic circulation). Only ~5% of bile acids are
excreted in stool (figure 1).
 The etiology of diarrhea after ileal resection depends on
the length of the resected ileum.
 If less than 100 cm of the ileum is resected, this results
in bile acid malabsorption. The unabsorbed bile acids
irritate the colonic mucosa resulting in secretory diarrhea
(cholerheic diarrhea). Figure 1: Enterohepatic circulation of bile
 The liver can compensate for the lost bile acids, and the acids in normal conditions
total bile acid content in the enterohepatic circulation remains constant, therefore steatorrhea does not develop.
 Bile acid sequestrants such as cholestyramine are beneficial in this type of diarrhea.
 If more than 100 cm of the ileum is resected, this results in severe bile acid malabsorption.
 The liver in this case is unable to compensate adequately for the significant bile acid loss. This results in a
decreased total bile acid content leading to fat malabsorption and steatorrhea.
 Cholestyramine will worsen symptoms of steatorrhea.
 Treat with low fat diet and antidiarrheals. Consider medium chain fatty acids.
 The ileum secretes peptide YY in response to fat and other luminal nutrients. Peptide YY acts to slow upper
gastrointestinal motility. This negative feedback mechanism is referred to as the ileal "break".
 Loss of the ileal break can contribute to diarrhea in patients with ileal resection.
Fat malabsorption
 Clinical features: greasy, foul smelling diarrhea, weight loss, vitamins A, D, E, and K deficiencies.
 Main etiologies are exocrine pancreatic insufficiency, small intestinal disease, and bile acid deficiency.
 Tests to prove fat malabsorption
 Stool Sudan stain is abnormal if there are > 5 fat globules / HPF.
 Fecal fat excretion is abnormal if > 7 grams of fat / 24 hours (patients are instructed to consume around
100 grams of fat per day for three days prior to the test).
 Tests to investigate the etiology of fat malabsorption
 Chemistry panel to rule out biliary obstruction and look for hepatic disease (PBC, PSC).
 Tissue Transglutaminase Antibodies (tTG-IgA) for celiac disease.
 Fecal elastase to test for pancreatic insufficiency.
 D-Xylose test (see also page 57)
 An abnormal D-Xylose test suggests small intestinal mucosal disease.
 Normal results suggest pancreatic or other non-small bowel etiologies of steatorrhea.
 Cross sectional abdominal imaging (CT, MRI) to look for pancreatic or small intestinal disease such as
Crohn’s disease and lymphoma.
 Endoscopic workup: EGD or enteroscopy and biopsy, ileocolonoscopy, or capsule endoscopy.
 Treatment: treat the underlying etiology. Consider pancreatic enzymes replacement.
 Supplementation with medium chain fatty acids, which do not require bile acids for absorption.
Protein losing enteropathy

 Protein losing enteropathy is a rare condition characterized by excessive loss of protein from the GI tract
resulting in hypoproteinemia and edema.
 Clinical presentation: edema, ascites, pericardial or pleural effusion, anasarca.
 Etiology (table 1)
 Gastrointestinal mucosal disease: erosive or non-erosive mucosal disease can result in protein loss from
the surface epithelium.1
 Increased mucosal interstitial pressure because of lymphatic or venous outflow obstruction leading to
protein leakage from the mucosa.
Table 1: Etiology of protein losing enteropathy

GI mucosal disease Increased interstitial pressure
 Erosive  Intestinal lymphangiectasias
o Severe gastritis (e.g. H. pylori)  Heart disease
o Ulcerative jejuno-ileitis o Constrictive pericarditis, congestive heart
o Infectious colitis/enteritis failure, congenital heart disease
o Inflammatory bowel disease o Post Fontan procedure for single ventricle
o Gastrointestinal ischemia  Severe portal hypertension
o Acute graft versus host disease  Mesenteric venous thrombosis
 Non- erosive  Neoplastic involvement of mesenteric lymph
o Hypertrophic gastropathies (e.g. nodes
Ménétrier's disease)  Mesenteric tuberculosis
o Celiac disease  Retroperitoneal fibrosis
o Whipple disease
o Eosinophilic gastroenteritis
o GI sarcoidosis, amyloidosis
 Diagnosis
 Alpha-1 antitrypsin (A1-AT) clearance: This is the best method to evaluate enteric protein loss.
 It requires a 24-hour stool collection. Spot stool measurements are not reliable.
o A1-AT clearance is abnormal if > 27 ml/day in patients without diarrhea, and if >56 ml/day in
patients with diarrhea.2
 Pepsin can degrade A1-AT that is lost from the gastric mucosa, resulting in a false negative test result.
Therefore, PPIs are recommended prior to conducting the A1-AT clearance test, especially if a gastric
source of protein loss is suspected.
 This does not distinguish between intestinal and gastric sources of protein loss.
 Technetium-99m-labeled albumin scintigraphy
 Technetium 99m-labeled albumin is injected and serial images of the abdomen are
obtained to identify the site of protein loss.
 Treatment
 Supportive care. Treat underlying etiology.
 Nutritional support. Give a low fat, high protein diet
Carbohydrate malabsorption
 Tests for carbohydrate malabsorption

 Fecal pH < 5.5 suggests carbohydrate malabsorption (normal fecal pH is 6.5 - 7.5).
 Stool osmotic gap > 100. This is calculated as 290- [(stool Na + stool K) x 2].
 The D-Xylose test examines the ability of the small intestine to absorb the monosaccharide D-Xylose,
which does not require bile acids or pancreatic enzymes for absorption.
 Steps of the D-Xylose test
o The patient ingests 25 grams of D-Xylose.
o A blood sample is collected one hour after ingestion. Levels < 20 mg/dL are abnormal.
o Urine samples are collected over the next 5 hours. Urine levels < 4 grams are abnormal.
 Abnormal results suggest impaired small intestinal absorptive capacity.
 False positive results are seen in renal dysfunction.
 Hydrogen breath test
 The patient ingests a substrate (e.g. lactose, fructose) and hydrogen is measured in the breath.
 The test is abnormal if there is a rise of > 20 parts per million after ingestion of the substrate.
 Hydrogen breath tests require bacterial fermentation of the unabsorbed substrate.
o False positive results can occur in small intestinal bacterial overgrowth (SIBO).
o False negative results can occur in patients receiving antibiotics.
 Lactose tolerance test
 The patient ingests 50 grams of lactose.
 A blood glucose increase of < 20 mg /dL within 2 hours of ingestion, combined with the development
of symptoms, is diagnostic of lactose intolerance.
Small Intestinal Bacterial Overgrowth
ACG Clinical Guideline Am J Gastroenterol,

Small Intestinal Bacterial Overgrowth 3 2020
AGA Clinical Practice Update on Small Intestinal

Gastroenterology, 2020
Bacterial Overgrowth: Expert Review 4
 Definition and background
 Small intestinal bacterial overgrowth (SIBO) is caused by an increase in the number or change in the type
of bacteria in the small intestine resulting in symptoms of excessive gas formation and malabsorption.
 Bacterial density in the GI tract ranges from 103 (per gram of content) in the stomach and duodenum, to
104 and 107 in the small intestine and 1010 and 1013 in the colon. 5
 Streptococcus and lactobacillus form most of the proximal intestinal bacteria, while the colon contains
mainly anaerobes such as Bacteroid, Clostridium and Bifidobacterium species.
 Etiologies and risk factors
 Anatomical: blind small intestinal loop (e.g. post Billroth 2 surgery), absence of ileocecal valve, small
intestinal diverticula, entero-enteric fistula.
 Motility disturbances: diabetic autonomic neuropathy, scleroderma, amyloidosis, hypothyroidism, opiates
 Acid suppression: vagotomy, atrophic gastritis and achlorhydria, PPI (controversial)
 Other etiologies include celiac disease, cystic fibrosis, chronic renal failure, radiation enteritis, Crohn's
disease, chronic pancreatitis and pancreatic insufficiency, chronic liver disease, and cirrhosis.
 Clinical manifestations: bloating (most common), diarrhea, abdominal pain, steatorrhea, weight loss.
 Labs:
 ↑ Folate levels due to increased bacterial synthesis. ↓ B12 levels due to increased bacterial usage of B12.
 Diagnosis
 Gold standard: proximal jejunal aspirate of ≥ 103 colony forming units/mL.
 Hydrogen breath test
 General concept: anaerobic bacteria ferment a test substrate (glucose 75 gram or lactulose 10 grams),
producing hydrogen that is detected in breath samples.
 The test is abnormal if there is a rise in hydrogen concentration: (PPM: parts per million)
o > 20 PPM within 2 hours after ingestion of lactulose.
o > 12 PPM within 3 hours after ingestion of glucose.
 Late peaks in hydrogen are due to colonic bacterial fermentation of the substrate.
 Test limitations
o Rapid absorption of glucose in the proximal small intestine may result in a false negative result.
o Rapid intestinal transit results in a false positive early peak of hydrogen due from colonic
fermentation rather than SIBO. A retrospective study found that 48% of patients with a positive test
result (early peak) were due to colonic fermentation. 6
o Therefore, it is recommended that in patients with a positive test, are considered for repeat testing
with scintigraphy. This involves labelling the ingested meal with 99m Tc-sulfur colloid.
This radiolabeled meal is detected by nuclear scanning in the cecum to confirm the time the test meal
arrives to the colon.
● If the hydrogen peak occurs after the meal reaches the cecum, then this is due to colonic
fermentation rather than SIBO.
● This technique is also used to measure intestinal transit.
 Intestinal Methonogenic overgrowth (IMO) is a proposed term for excessive methane production by
methanogenic Archaea (organisms that are not bacteria). In the intestine, the main methanogen is
Methanobrevibacter smithii 3.
 SIBO and irritable bowel syndrome
 The interaction between SIBO and IBS is difficult to ascertain because of lack of standardized diagnostic
tests and good quality studies.
 In general, it does not appear that patients with IBS have a higher incidence of SIBO compared to the
general population.
 Treatment: Treat underlying etiologies.
 Diet: high fat, low carbohydrate and low fiber diet. Avoid sorbitol and artificial sweeteners.
 If SIBO is considered based on symptoms and risk factors, and if diagnostic tests are not available, it is
reasonable to give a treatment trial for 7-10 days. Antibiotic choices include:
 Amoxicillin-clavulanic acid 500/125 t.i.d. ,
Doxycycline 100 mg b.i.d., metronidazole 250-500 mg t.i.d., ciprofloxacin 500 mg b.i.d., trimethoprim-
sulfamethoxazole 160/800 mg b.i.d.
 Rifaximin (400 or 550 mg t.i.d.) is probably the safest due to its low intestinal absorption, but it is
significantly more expensive than other antibiotics
 Probiotics have not been found to consistently improve SIBO and are not recommended. 3
 Recurrence after treatment is common.
o Patients can be given repeated courses of antibiotics as needed for symptom control.
o Change the antibiotic type to decrease the rate of bacterial resistance.
Short Bowel Syndrome
 Definition and background

 Short bowel syndrome (SBS) is defined as malabsorption and intestinal failure resulting from the decrease
in the normal intestinal length (or surface area) to < 30%, or 200 cm in adults.
 The presence of the colon partially compensates for malabsorption by increasing its absorption of water
and electrolytes.
 Etiology
 Common etiologies include mesenteric vascular events (SMA or SMV thrombosis), midgut volvulus,
Crohn's disease, trauma, and radiation enteritis.
 Post-operative short bowel syndrome is increasing in prevalence, and results from intestinal resection due
to postoperative intestinal obstruction, volvulus and strangulated bowel. 7, 8
 Predictors of TPN dependency
 Small bowel length < 50-100 cm.
 Low plasma citrullin levels. Citrullin is an amino acid produced by enterocytes.
 Absence of ileocecal valve.
 Absence of an intact and functional colon.
 Residual small bowel mucosal disease.
 Complications
 D-lactic acidosis
 Rare neurologic syndrome that results from the accumulation of D-lactate in the serum of patients with
short bowel syndrome.
 The accumulation of D-lactate results from the increased delivery of carbohydrates to the colon, where
they are metabolized by colonic bacteria to produce D-lactate.
 Neurologic signs and symptoms: altered mentation, hallucinations, nystagmus, dysarthria, ataxia,
weakness.9
 Diagnosis
o The diagnosis is based on the clinical presentation, mainly the development of neurologic symptoms
following ingestion of carbohydrate in a patient with SBS.
o D-lactate concentration can be measured using a specialized assay.
● Levels above 3 mmol/L are abnormal.
 Treatment: withhold carbohydrate intake, give IVF and oral antibiotics (metronidazole, vancomycin).
 Prevention: limit simple sugars; provide complex carbohydrates in tube feeds.
 Hyperoxaluria results from the effect of steatorrhea on oxalate absorption.
 Normally calcium binds oxalate in the intestinal lumen and is excreted in stool.
 In patients with steatorrhea, calcium binds the unabsorbed fat, and oxalate binds sodium and is absorbed
in the colon in higher amounts. Oxalate is excreted in the urine resulting in oxalate stones.
 In the absence of a functional colonic epithelium, oxalate is not absorbed and hyperoxaluria does not
develop.
 Management
 Diet: encourage hyperphagia. Give elemental and low fat diet. Add medium chain fatty acids.
 Parenteral IVF and TPN. Micronutrient, vitamin, and mineral supplementation.
 Pharmacotherapy
o Loperamide (2-4 mg every 8 hours).
o Diphenoxylate with atropine (2.5-5 mg every 8 hours).
o Tincture of opium (5-10 drops every 8 hours).
o Clonidine (0.2 mg PO b.i.d. or transdermal patch).

o Octreotide (50-100 mcg subq or IV b.i.d. or t.i.d.).
o PPIs are given to inhibit excess gastric secretion.
 Medications to enhance bowel adaptation (trophic agents)
 Somatropin (Zorbtive®) is recombinant growth hormone that is FDA approved for treatment of SBS. It
has significant side effects (peripheral edema, arthralgia, carpal tunnel syndrome) and may lead to acute
pancreatitis and impaired glucose tolerance. It is not widely used in clinical practice.
 Teduglutide (Gattex®)
o FDA approved for the treatment of SBS.
o Glucagon like peptide 2 (GLP-2) is normally secreted from the L cells in the ileum and colon and
improves intestinal adaptation and proliferation.
o Teduglutide is a long acting GLP-2 analogue given as a subcutaneous injection that enhances the
structural and functional integrity of the remaining intestine in SBS.10
o There is a risk of acceleration of neoplastic growth. Active GI neoplasia is a contraindication for
Teduglutide.
● The drug's package insert recommends performing a colonoscopy with removal of polyps before
initiating treatment with teduglutide.
 Intestinal transplantation
 SBS is the most common indication for intestinal transplant.
 The 1-year patient survival after intestinal transplant is 90%. The 1-year graft survival is 75%.11
Celiac disease
Am J
ACG Clinical guidelines: Diagnosis and
Gastroenterol,
Management of Celiac Disease 12
2013
AGA Clinical Practice Update on Diagnosis and
Gastroenterology,
Monitoring of Celiac Disease-Changing Utility of
Serology and Histologic Measures: Expert Review.13
2019
 Celiac disease is an immune mediated enteropathy that results from hypersensitivity to gluten.
 The prevalence of celiac disease in the United States is 0.71% (1 in 141).14
 An estimated 3 million people in the United States have celiac disease.
 Most cases are undiagnosed.
 Gastrointestinal manifestations
 Malabsorption, steatorrhea, abdominal pain, bloating, intussusception.
 Non Gastroenterological manifestations
 Iron deficiency anemia (IDA)
o Up to 15% of patients presenting for endoscopy for iron deficiency anemia have celiac disease. This
association is only present in Caucasian patients.
● One study showed that in patients with IDA, celiac disease occurred in 2.5% of Caucasian
patients and in zero% of non-Caucasian patients.15 Another study showed that the prevalence
of celiac disease is low (0.33%) in an urban, predominately male, black population with IDA.16
 Other nutritional deficiencies include vitamins A, D, E, K, B12 and folate deficiency.
 Metabolic bone disease (osteopenia, osteoporosis), hyposplenism, spontaneous abortion, infertility,
chronic fatigue.
o Abnormal liver function tests: Patients may have a mild elevation of liver enzymes.
o Liver biopsy, if performed, shows non-specific hepatitis.

● Test for celiac disease in patients with idiopathic mild elevation of liver enzymes.
 “Celiac crisis” is a rare clinical presentation of celiac disease, which refers to life threatening diarrhea,
malabsorption, and severe metabolic derangements caused severe edema in the small bowel.17
 Most patients with this condition do not have a pre-existing diagnosis of celiac disease.
 Conditions associated with celiac disease
 Autoimmune and connective tissue diseases: Type 1 DM, thyroiditis, Addison disease, Rheumatoid
arthritis, Sjögren's syndrome.
 Liver: Autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis
 Down syndrome patients have a six fold increased risk of celiac disease.
 Dermatitis herpetiformis presents as grouped pruritic papules and vesicles on extensor surfaces. It is
seen in up to 25% of patients with celiac disease. Nearly 100% of patients with dermatitis herpetiformis
have celiac disease. Skin biopsy with immunofluorescence shows granular IgA deposition at the
dermoepidermal junction.
 Diagnosis
 The patient has to be on gluten containing diet while performing the serologic testing and biopsies,
otherwise the sensitivity of these tests will decrease.
 Serologic testing should be performed in patients on gluten containing diet.
 IgA-tissue transglutaminase antibody (IgA TTG)
o Sensitivity ~95%, specificity > 95%.
o This test is recommended as the first line test for celiac disease.
o If there is a high suspicion for celiac disease in a patient with a negative IgA TTG, test for total IgA levels.
If IgA levels are low, test for celiac disease using IgG-TTG, or IgG deamidated gliadin peptides.
o If antibodies are positive, then perform duodenal biopsies to confirm the diagnosis.
 Anti-endomysial antibody: sensitivity 85-95%, specificity 95-97%.
 Antigliadin antibodies have low sensitivity and specificity (<80%), and are not recommended.
 Celiac disease is strongly related to HLA-DQ2 and HLA-DQ8 on chromosome 6.
 90% to 95% of patients with celiac disease have the HLA-DQ2 allele, and the other 5% to 10% have
the HLA-DQ8 allele.
 Absence of both alleles rules out the diagnosis of celiac disease (i.e. negative predictive value is ~100%)
 Small bowel biopsies should be obtained in all adult patients with suspicion of celiac disease to confirm
the diagnosis and allow for a baseline before starting gluten free diet.
 Endoscopic findings in celiac disease: mucosal fissuring, scalloping, nodularity, and loss of villi.
 These findings have low sensitivity (50-60%).
 Always obtain mucosal biopsies, even if the duodenal mucosa appears normal.
o Take four biopsies from the distal second portion, and 1-2 biopsies from the bulb.
o Most patients with celiac disease have duodenal involvement +/- jejunal patchy enteropathy,
however, few patients (<5%) may have patchy jejunal enteropathy alone. 18
 Histology: the Marsh classification system describes the whole spectrum of histologic changes in celiac disease
(table 2).
Table 2: Modified Marsh classification of histologic spectrum in celiac disease
Marsh I Marsh II Marsh IIIa Marsh IIIB Marsh IIIC
Increased IELs Increased IELs + Subtotal villous Partial villous Total villous
(≥25/100 epithelial cells) crypt hyperplasia atrophy atrophy atrophy
IELs: Intraepithelial lymphocytes
 Table 3 shows possible dilemmas encountered in the workup of celiac disease.

Table 3: Dilemmas in the diagnosis and workup of celiac disease.
Dilemma Management options
 Positive TTG antibody  Review the biopsy
and negative biopsy  Repeat biopsy after gluten challenge for 6 weeks, consider getting
more distal biopsies (enteroscopy).
 Test HLA DQ2,DQ8
 Negative TTG  Review clinical scenario and overall suspicion for celiac disease
antibody and positive  Consider IgA deficiency, check total IgA level or IgG TTG
biopsy with villous  Check IgG deamidated gliadin peptides
atrophy or increased  Review biopsy. Consider other causes of villous atrophy* or
IEL alone. increased IELs
 Test HLA DQ2 ,DQ8
 Consider Gluten free diet if patient has either HLA DQ2 or DQ8
 Patient with possible  Test HLA DQ2 , DQ8
celiac disease who is  If negative for both haplotypes:
already on gluten free  The patient does not have celiac disease
diet without biopsy  Consider continuing gluten free diet if the patient reports
symptom control (non-celiac gluten sensitivity)
 If positive HLA DQ2 and/or DQ8:
 Gluten challenge (start with 3 g of gluten daily for 2 weeks) and
test for TTG antibodies every 2-3 months
 Perform an EGD and biopsy when the patient develops
symptoms, antibodies turns positive, or at 6 months
*Other causes of villous atrophy include peptic duodenitis, Whipple disease, gastrinoma, eosinophilic
gastroenteritis, HIV enteropathy, lymphoma, Crohn's disease, radiation enteritis, common variable
immunodeficiency, giardiasis, tropical sprue, drug induced (olmesartan, colchicine, mycophenolate)19. Other causes
of increased IELs are NSAIDS, H. pylori, SIBO
 Treatment
 Refer to a dietician to start a gluten free diet (GFD).
 Patients should avoid all wheat, barley, and rye.
 In August of 2013, the FDA published new regulations to define the term "gluten-free".
o This food should not contain any ingredient that is any type of wheat, rye, barley, or crossbreeds of
these grains. It should contain less than 20 parts per million of gluten.
 Check for nutritional deficiencies (A, D, E, B12, folate, iron, copper, zinc) and supplement as necessary.
 Celiac crisis (see page 61) is treated with IV hydration, supportive care, corticosteroids, and gluten free diet.
 Larazotide acetate is a novel oral peptide that modulates intestinal permeability through its effects on tight
junctions. It is thought to inhibit the expression of zonulin, a tight junction protein that regulates epithelial
permeability20. This leads to decreased paracellular permeability and decreased passage of active gluten peptides.
 In a randomized, double blind, placebo controlled, phase 2b trial, 342 adults with celiac disease who
had been on a GFD for 12 months or longer and had ongoing symptoms were assigned to larazotide 0.5,
1, or 2 mg or placebo three times daily for 12 weeks. 21 Patients continued their GFD during the study.
Larazotide 0.5 mg (but not higher doses) reduced signs and symptoms of celiac disease better than GFD
alone. Larazotide had similar safety profile compared to placebo. Further studies are underway, and it
is not available in the US.
 Latiglutenase is a mixture of two gluten-specific recombinant proteases that degrades gluten proteins before
reaching the small intestine. Early phase 2a and 2b studies showed mixed results on histologic and symptom
improvement when added to gluten free diet. 22, 23
 Non-responsive celiac disease

 Definition: persistent symptoms, signs or laboratory abnormalities typical of celiac disease despite 6 to12
months of dietary gluten avoidance.12 This is further divided into primary non response (no initial response
to gluten free diet) or secondary response (recurrence after initial response).
 Management
 Confirm the diagnosis. Review the results of prior serology and biopsy.
 Check for noncompliance with gluten free diet, which is the most common cause of non-responsive
celiac disease.
o Ask about intentional intake of gluten.
o Refer to a dietician experienced in celiac disease to assess for inadvertent gluten intake.
o A negative TTG-IgA does not confirm strict adherence to a gluten free diet, as antibodies can revert
to negative even with minimal diet adherence.
 Repeat endoscopy and biopsy.
o If the duodenal biopsy is normal, consider alternative or co-existing disease such as lactase
deficiency, microscopic colitis, SIBO, irritable bowel syndrome or pancreatic insufficiency.
o Perform a colonoscopy and biopsy if diarrhea is present.
o Consider capsule endoscopy to assess for complications 24
 Refractory (truly non-responsive) celiac disease
 This accounts for 10% of cases of non-responsive celiac disease.
 Definition: symptomatic severe villous atrophy despite a confirmed gluten free diet of at least 6 months.
Refractory celiac disease is divided into two types:
 Type 1 refractory celiac disease
o This is less severe than type 2, with a five-year survival is ~90%.
o Small intestinal biopsy shows normal (polyclonal) intraepithelial lymphocytes (IELs).
 Type 2 refractory celiac disease
o This is a more severe disease with a five-year survival is less than 50%.
o Characterized by the presence of an abnormal clonal population of IELs. These can demonstrate loss
of normal CD3 or CD8 expression. 25
o This type can progress to enteropathy-associated T-cell lymphoma (see page 65),
ulcerative jejunoileitis, or rarely to mesenteric lymph node cavitations.
o Evaluate for lymphoma using enteroscopy, capsule endoscopy, CT, MRI, or PET scan.
 Treatment options include glucocorticoids (prednisone, budesonide) and thiopurines.
 Other gluten related disorders
 Wheat allergy: This is an allergy to wheat associated with the production of specific IgE antibodies.
 Non celiac gluten sensitivity (NCGS): A condition in which ingestion of gluten leads to symptoms similar
to celiac disease, but without celiac-specific antibodies and histologic features of villous atrophy. 26
 50% of patients with NCGS have celiac disease-predisposing HLA-DQ2 and DQ8 genotypes and 56%%
have positive anti-gliadin antibodies.
 Patients present with IBS-like symptoms such as diarrhea, constipation, abdominal pain. Weight loss
and bloating. They may also have arthralgias, myalgias, headaches, skin rash, and depression.
 Symptoms improve or disappear with cessation of gluten intake, and reappear after gluten challenge.
 The pathophysiology of NCGS is unclear, and there are no guidelines for management or
followup. Many patients choose to gluten-free diet. Consider reintroduction of gluten every 6-12 months
if the patients agrees in an attempt to switch to less strict gluten free diet.
Whipple disease
 Whipple disease is caused by Tropheryma whipplei, a gram-positive rod shaped bacterium.
 It is a rare disease that predominantly affects middle-aged white men.
 Clinical features: Abdominal pain, fever, arthralgias, diarrhea, weight loss, occult GI bleeding.
 Neurologic manifestations27
 Cognitive dysfunction is the most common symptom.
 Pathognomonic findings are present in less than 20% of patients with neurologic disease.
o Oculomasticatory myorhythmia (eye and jaw movement).
o Oculo-facial-skeletal myorhythmia (slow nystagmus with rhythmic jaw and skeletal movement).
 Other findings: dementia, supranuclear ophthalmoplegia, seizures, ataxia, cranial nerve palsies.
 Cardiac manifestations: endocarditis, myocarditis, pericarditis.
 Upper endoscopy shows proximal intestinal edema and white patches that represent lipid collections. Take
multiple biopsies from the distal second or third portion of the duodenum.
 Histology: the diagnosis is confirmed by demonstrating foamy macrophages in the lamina propria that are
periodic acid-Schiff stain (PAS) positive. The positive PAS stain represents the large amount of glycoprotein
in the cell wall of the T. whipplei organisms filling the macrophages.
 In common variable immunodeficiency, foamy macrophages can be seen in small bowel biopsies, but these
are PAS negative.
 Whipple disease can also cause villous atrophy.
 PCR of saliva, stool and cerebrospinal fluid is not routinely available and lacks adequate specificity.
 Treatment
 Ceftriaxone for 10-14 days followed by oral TMP/SMX for 1 year.
 Alternative regimen: penicillin G for 10-14 days followed by oral TMP/SMX for 1 year
 Sulfa-allergic patients should receive ampicillin instead of TMP/SMX.
 Treatment with tetracycline has a high relapse rate and it is not recommended.
Small intestinal tumors
 The most common small intestinal tumors are listed in table 4.
Table 4: Small intestinal tumors
Tumor Most common Location
Adenocarcinoma Proximal small intestine
Carcinoid Distal Ileum
Lymphoma Throughout small intestine
Sarcoma including GIST
Metastatic Disease
 The most common benign lesion in the small bowel is tubular adenoma.
 Other lesions include leiomyoma, fibroma, Brunner's gland hyperplasia (hamartoma), and lipoma.
 Risk factors for small intestinal adenocarcinoma
 Inherited genetic syndromes such as Peutz-Jeghers syndrome, familial adenomatous polyposis, Lynch
syndrome. Other risk factors include celiac disease and Crohn's disease.
 Risk factors for small intestinal lymphoma
 Prolonged immunosuppression, celiac disease, Crohn's disease, radiation enteropathy.
 Patients with neurofibromatosis type 1 (von Recklinghausen disease) develop multiple small intestinal GISTs.
Small intestinal GISTs are discussed in chapter 10.
Small intestinal lymphoma
 B cell lymphomas
 Diffuse large B cell lymphoma
 Marginal B cell lymphoma
 Immunoproliferative small intestinal disease (IPSID)
 IPSID is the most common type of GI lymphoma in the
Middle East. It is also called Mediterranean lymphoma,
or α-heavy chain disease. It arises from the mucosal
associated lymphoid tissue (MALT). Figure 2: Diffuse large B cell
 IPSID is characterized by overproduction of a lymphoma arising in the 4th portion
of the duodenum with large
monoclonal immunoglobulin α-heavy chain. ulcerations and friability
 The etiology is likely infectious. Many reports showed an association with Campylobacter jejuni
infection. 28
o Similar to H. pylori and gastric lymphoma, Campylobacter jejuni can stimulate MALT of the small
intestine and result in lymphomatous transformation.
 It has a male predominance and presents at a young age.
 It presents with abdominal pain, diarrhea, and weight loss.
 Treatment is with antibiotics and chemotherapy.
 Mantle cell lymphoma (MCL)
 Most common site of GI tract involvement is the ileocecal region.
 MCL is characterized by the chromosomal translocation t(11:14), resulting in overexpression of cyclin D1.
Cyclin D1 is a cell cycle regulatory nuclear protein that promotes cell proliferation. 29
 Presents as multiple lymphomatous polypoid lesions (lymphomatous polyposis).
 Positive immunohistochemical staining for cyclin D1 is diagnostic for MCL.
 The main treatment is chemotherapy.
 Follicular lymphoma
 Rare, affects the terminal ileum.
 It is associated with chromosomal translocation t (14:18).
 The main treatment is chemotherapy.
 Burkitt's lymphoma
 Most commonly arises in terminal ileum and cecum.
 It is highly aggressive. The main treatment is chemotherapy.
 T cell lymphoma
 Enteropathy-associated T-cell lymphoma (EATL)
 Rare, associated with type 2 refractory celiac disease.
 Occurs in ~10 % of celiac disease patients who are non-compliant with gluten free diet.
 The most common site of involvement is the small intestine, followed by the mesenteric and abdominal
lymph nodes. 30
o Presents with abdominal pain, fatigue, anorexia, jejunal obstruction, and bleeding. It is most
commonly diagnosed in resected specimens after surgery for perforation or bleeding.
 Prognosis
o EATL has a poor prognosis, with a median overall survival of 10 months. 30
o Many patients die from acute intestinal complications such as perforation and bleeding.
o Treatment: Chemotherapy, surgery, stem cell transplantation, Gluten free diet.
 Post-transplant lymphoproliferative disease (PTLD)

 Etiology: B cell proliferation induced by Epstein-Barr virus (EBV) infection in the setting of chronic
immunosuppression.
 Chronic immunosuppression and decreased T-cell function prevents the normal elimination of EBV
infected B cells from the circulation. This allows for unchecked B cell proliferation leading to PTLD.
 The risk of PTLD depends on the intensity of immunosuppression and the type of organ transplantation.
 The risk is highest after small bowel transplant (5-20%), followed by lung and heart transplant (2-10%),
followed by renal and liver transplants (1-5%).31
 The median time to disease onset is 6 months, but it can vary between 1 week and 9 years. 31
 PTLD presents with non-specific symptoms of malaise, fever, and weight loss.
 Sites of involvement include the transplanted allograft, liver, GI tract, skin, and CNS.
 Management
 Withdraw immunosuppression.
 Treatment options include rituximab, chemotherapy, and radiotherapy.
References
1. Umar SB, DiBaise JK. Protein-Losing Enteropathy: Case Illustrations 17. Soldera J, Coelho GP, Heinrich CF. Life-Threatening Diarrhea in an
and Clinical Review. Am J Gastroenterol 2009;105(1):43-49. Elderly Patient. Gastroenterology 2021;160(1):26-28.
2. Strygler B, Nicar MJ, Santangelo WC, Porter JL, Fordtran JS. Alpha 18. Murray JA, Rubio-Tapia A, Van Dyke CT, et al. Mucosal atrophy in
1-antitrypsin excretion in stool in normal subjects and in patients with celiac disease: extent of involvement, correlation with clinical
gastrointestinal disorders. Gastroenterology 1990;99(5):1380-7. presentation, and response to treatment. Clin Gastroenterol Hepatol
3. Pimentel M, Saad RJ, Long MD, Rao SSC. ACG Clinical Guideline: 2008;6(2):186-93; quiz 25.
Small Intestinal Bacterial Overgrowth. 2020;115(2):165-78. 19. DeGaetani M, Tennyson CA, Lebwohl B, et al. Villous Atrophy and
4. Quigley EMM, Murray JA, Pimentel M. AGA Clinical Practice Negative Celiac Serology: A Diagnostic and Therapeutic Dilemma.
Update on Small Intestinal Bacterial Overgrowth: Expert Review. 2013;108(5):647-53.
Gastroenterology 2020;159(4):1526-32. 20. Freeman HJ. Emerging drugs for celiac disease. Expert Opin Emerg
5. Simren M, Barbara G, Flint HJ, et al. Intestinal microbiota in Drugs 2015;20(1):129-35.
functional bowel disorders: a Rome foundation report. Gut 21. Leffler DA, Kelly CP, Green PHR, et al. Larazotide Acetate for
2013;62(1):159-76. Persistent Symptoms of Celiac Disease Despite a Gluten-Free Diet: A
6. Lin EC, Massey BT. Scintigraphy Demonstrates High Rate of False- Randomized Controlled Trial. Gastroenterology 2015;148(7):1311-
positive Results From Glucose Breath Tests for Small Bowel Bacterial 19.e6.
Overgrowth. Clin Gastroenterol Hepatol 2016;14(2):203-8. 22. Murray JA, Kelly CP, Green PHR, et al. No Difference Between
7. Thompson JS, Weseman RA, Mercer DF, et al. Risk of Intestinal Latiglutenase and Placebo in Reducing Villous Atrophy or Improving
Malignancy in Patients With Short Bowel Syndrome. 2017;41(4):562- Symptoms in Patients With Symptomatic Celiac Disease.
65. Gastroenterology 2017;152(4):787-98.e2.
8. Thompson JS, DiBaise JK, Iyer KR, Yeats M, Sudan DL. 23. Syage JA, Murray JA, Green PHR, Khosla C. Latiglutenase Improves
Postoperative short bowel syndrome. J Am Coll Surg 2005;201(1):85- Symptoms in Seropositive Celiac Disease Patients While on a Gluten-
9. Free Diet. Dig Dis Sci 2017;62(9):2428-32.
9. Uribarri J, Oh MS, Carroll HJ. D-lactic acidosis. A review of clinical 24. Gerson LB. Use and misuse of small bowel video capsule endoscopy
presentation, biochemical features, and pathophysiologic mechanisms. in clinical practice. Clin Gastroenterol Hepatol 2013;11(10):1224-31.
Medicine (Baltimore) 1998;77(2):73-82. 25. Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac
10. Jeppesen PB, Pertkiewicz M, Messing B, et al. Teduglutide Reduces disease, and enteropathy-associated T-cell lymphoma. French Coeliac
Need for Parenteral Support Among Patients With Short Bowel Disease Study Group. Lancet 2000;356(9225):203-8.
Syndrome With Intestinal Failure. Gastroenterology 26. Catassi C, Bai JC, Bonaz B, et al. Non-Celiac Gluten sensitivity: the
2012;143(6):1473-81.e3. new frontier of gluten related disorders. Nutrients 2013;5(10):3839-
11. Fishbein TM. Intestinal Transplantation. New England Journal of 53.
Medicine 2009;361(10):998-1008. 27. Louis ED, Lynch T, Kaufmann P, Fahn S, Odel J. Diagnostic
12. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG guidelines in central nervous system Whipple's disease. Ann Neurol
Clinical Guidelines: Diagnosis and Management of Celiac Disease. 1996;40(4):561-8.
Am J Gastroenterol 2013;108(5):656-76. 28. Mesnard B, De Vroey B, Maunoury V, Lecuit M. Immunoproliferative
13. Husby S, Murray JA, Katzka DA. AGA Clinical Practice Update on small intestinal disease associated with Campylobacter jejuni.
Diagnosis and Monitoring of Celiac Disease-Changing Utility of Digestive and Liver Disease 2012;44(9):799-800.
Serology and Histologic Measures: Expert Review. Gastroenterology 29. Nguyen VX, Nguyen BD, Petris GD, Nguyen CC. Gastrointestinal:
2019;156(4):885-89. Gastrointestinal involvement of mantle cell lymphoma. Journal of
14. Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE. Gastroenterology and Hepatology 2012;27(3):617-17.
The prevalence of celiac disease in the United States. Am J 30. Delabie J, Holte H, Vose JM, et al. Enteropathy-associated T-cell
Gastroenterol 2012;107(10):1538-44; quiz 37, 45. lymphoma: clinical and histological findings from the international
15. Murray JA, McLachlan S, Adams PC, et al. Association Between peripheral T-cell lymphoma project. Blood 2011;118(1):148-55.
Celiac Disease and Iron Deficiency in Caucasians, but not Non- 31. Nourse JP, Jones K, Gandhi MK. Epstein–Barr Virus-Related Post-
Caucasians. Clin Gastroenterol Hepatol 2013. Transplant Lymphoproliferative Disorders: Pathogenetic Insights for
16. Abbass R, Hopkins M, Dufour DR, et al. Celiac disease in an urban Targeted Therapy. American Journal of Transplantation
VA population with iron deficiency: the case against routine duodenal 2011;11(5):888-95.
biopsy. Dig Dis Sci 2011;56(7):2037-41.
4
65
CHAPTER
LIVER
Chapter 4-Liver
Around 25% of the GI boards' questions are liver related. Favorite topics for the boards are liver
diseases of pregnancy, hepatitis B, metabolic and cholestatic disorders, and complications of
cirrhosis and portal hypertension. Primary biliary cirrhosis was renamed as primary biliary
cholangitis, and new guidance was published by AASLD in 2018. New drugs are approved
(obeticholic acid) and several are being studied (fibrates). Hepatitis B therapy with tenofovir and
entecavir has high efficacy and minimal resistance rates. Guidelines on HBV prophylaxis in
patients receiving immunosuppression are important to review because they address common
clinical scenarios. A new table was added in this chapter to summarize management.
Hepatitis C treatment has been revolutionized with the introduction of the newer oral antiviral
agents. This chapter contains basic information about simplified treatment regimens for
patients with and without compensated cirrhosis. The reader is advised to check frequently for
updates about HCV treatment. A good website for such updates is hcvguidelines.org.
Noninvasive methods to assess liver fibrosis in NASH and other disorders and emerged over the
past several years (liver scores, MRE, transient elastography) and are presented in the section
on NAFLD. Hepatocellular carcinoma treatment continues to evolve, with several advancements
in local ablative therapy (microwave ablation) and new chemotherapeutic agents. Liver
transplantation is mentioned in brief at the end of this chapter.
68 Chapter 4: Liver
Contents Alcoholic liver disease—93

Nonalcoholic fatty liver disease—95
Chapter 4-Liver
Drug Induced Liver Injury—98
Liver function tests—69
Acetaminophen toxicity—100
Liver disease in pregnancy—70
Autoimmune Hepatitis—101
Hemochromatosis and iron overload syndromes—
72 Primary sclerosing cholangitis—103
Wilson disease—75 Primary Biliary Cholangitis—105
Alpha one antitrypsin deficiency—77 Acute fulminant liver failure—108
Viral hepatitis—78 Complications of cirrhosis and portal

hypertension—110
Hepatitis A—78
Ascites—110
Hepatitis B—79
Surgical risk assessment in cirrhosis—113
Acute hepatitis B—79
Hepatic Encephalopathy—113
Chronic Hepatitis B—79
Hepatorenal syndrome—115
Chronic hepatitis B and pregnancy—83
Portopulmonary hypertension—115
Occupational exposure to hepatitis B—83
Hepatopulmonary syndrome—116
HBV prophylaxis in patients receiving
immunosuppressants—84 Benign Liver tumors—117
Hepatitis C—86 Hemangioma—117
Treatment of hepatitis C—86 Hepatocellular adenoma—117
Occupational exposure to hepatitis C—87 Focal nodular hyperplasia—118
HCV sexual transmission—87 Hepatic cysts—118
Hepatitis D—88 Nodular regenerative hyperplasia—119
Hepatitis E—88 Primary Liver Malignancies—119
Pyogenic liver abscess—88 Hepatocellular carcinoma—119
Vascular diseases of the liver—89 Fibrolamellar HCC—124
Budd-Chiari Syndrome—89 Intrahepatic cholangiocarcinoma—124
Portal vein thrombosis—90 Liver transplantation—124
Sinusoidal obstruction syndrome—92 References—127
Congestive hepatopathy—92
Chapter 4: Liver 69
Liver function tests
ACG Clinical Guideline: Evaluation of Abnormal

ACG 2017
Liver Chemistries 1
 General concepts in patients with abnormal liver enzymes
 Obtain a thorough clinical history including risk factors for liver disease and complete medication history.
Consider calling the patient’s pharmacy to ask about previous and current prescriptions.
 Patterns of liver enzyme elevation based on the R value (see also page 98)
 R value = (ALT/ULN) ÷ (ALKP/ULN) [ULN: Upper Limit of Normal]
 Hepatocellular: elevation of ALT and AST more than ALKP (R > 5)
 Cholestatic: elevation of ALKP more than ALT/AST (R < 5)
 Mixed pattern: elevation of both ALT/AST and ALKP (R = 2 to 5)
 High ALT and AST levels >1000 IU/L: Drug induced liver injury, acute viral hepatitis, ischemic hepatitis,
and mushroom poisoning. LDH is elevated in ischemic hepatopathy.
o The degree of elevation of liver enzymes does not correlate with hepatocellular necrosis.
 Important point: Occasionally choledocholithiasis can cause severe elevation of liver enzymes with normal
bilirubin and ALKP levels. The clinical history of biliary pain in patients with risk factors for gallstones
will aid in establishing the diagnosis.2 Avoid an extensive liver workup.
 Elevated AST/ALT ratio is suggestive of advanced alcoholic liver disease, rather than heavy alcohol
drinking without liver disease.3 Other causes of this pattern are cirrhosis, ischemic hepatitis, congestive
hepatopathy, Budd Chiari syndrome and TPN. 1
 Celiac disease can present with mild elevation of liver enzymes.
o Test for celiac disease in patients with elevated liver enzymes of unclear etiology.
 Gilbert syndrome is the most common cause of mild unconjugated hyperbilirubinemia.
o It is caused by reduced activity of uridine diphosphatase glucuronyl transferase.
o It has an autosomal dominant inheritance.
o Fasting and stress can lead to unconjugated hyperbilirubinemia (usually < 3 mg/dL, up to 6-8 mg/dL).
 Approach to post-operative jaundice
 Investigate the presence of previous chronic liver disease.
 Consider drug induced liver injury.
 Rule out intra- or extra-hepatic obstruction with an ultrasound, CT or MRI.
 Other etiologies to consider: TPN, resorption of a large hematoma, multiple blood transfusions (unconjugated
hyperbilirubinemia) and congestive hepatopathy (see page 92).
 Sepsis induced cholestasis
 Sepsis due to any cause can lead to conjugated hyperbilirubinemia.
 Sepsis results in changes in bile transport such as decreased clearance of conjugated bilirubin, decreased
basolateral and canalicular transport of bile acids. These changes can lead to hyperbilirubinemia.
 One study showed that among 23 patients with sepsis-induced cholestasis, most patients had a bilirubin of
3-8 mg/dL. Few patients had bilirubin > 15 mg/dL, and could reach up to 60mg/dL. 4
 Most associated with gram-negative bacteremia and intraabdominal infection.
 Search for and treat underlying infection (liver infection, UTI, pneumonia and other infections).
 Avoid ERCPs if there are no clues for cholangitis (no abdominal pain, normal bile ducts).
 "Benign post-operative jaundice" is multifactorial in etiology and has a benign course.
 This is characterized by a progressive increase in conjugated bilirubin that starts within the first 2 to 10
days after surgery.
70 Chapter 4: Liver
 Bilirubin levels range between 10 to 40 mg/dl, while AST, ALT and ALKP are < 5 times ULN.5
 Treatment is supportive: treat sepsis, adjust the TPN, and stop any offending medications.
 Liver biopsy is rarely required.
Liver disease in pregnancy
Reproductive Health and Liver Disease: Practice

Guidance by the American Association for the Study of AASLD, 2020
Liver Diseases6
ACG Clinical Guideline: Liver Disease and Pregnancy 7 ACG 2016
 Liver disease in pregnancy is commonly due to etiologies not specific to pregnancy.

 Viral hepatitis (A, B, C, D, and E) is the most common cause of liver disease in pregnancy.
 Acute hepatitis E has a high mortality in pregnancy (up to 20%).
 HSV hepatitis
o More commonly due to HSV-2 (~60% of cases) than HSV-1 (~40%).8
o Presents with a viral prodrome followed by elevation of liver enzymes with a relatively normal bilirubin
(anicteric hepatitis). Rash is present in less than 50% of cases. 8
o Other lab abnormalities include leukopenia, coagulopathy, and thrombocytopenia.
o HSV hepatitis can progress to fulminant hepatic failure.
o Consider empiric treatment in patients with fulminant hepatic failure while awaiting the results of HSV serologies.
o Treatment of choice is with acyclovir.
 Gallstones are a common cause of liver enzyme elevation in pregnancy.
 Pregnant women are at an increased risk of developing gallstones due to decreased gallbladder contractility
combined with increased cholesterol saturation in the bile.
 Most patients with gallstones remain asymptomatic, and they should be managed conservatively.
 Symptomatic patients (biliary pain, choledocholithiasis, cholecystitis, and pancreatitis) should be strongly
considered for cholecystectomy (+/- ERCP) during pregnancy to decrease the rate of recurrent symptoms
and hospitalizations.9, 10 The ACG recommends that symptomatic cholecystitis should be managed with
early surgical intervention with laparoscopic cholecystectomy. 7 The guidelines do not specifically
comment on other gallstone complications.
o Laparoscopic cholecystectomy is safest in the second trimester. Patients who develop gallstone
complications in the third trimester should undergo cholecystectomy in the early postpartum period.
o ERCP in pregnancy is discussed in chapter 11- endoscopy.
 Other diseases relevant to pregnancy include hepatitis B (see page 83), autoimmune hepatitis (see page
103), and hepatocellular adenoma (see page 117).
 Liver diseases specific to pregnancy (table 1)
 Hyperemesis gravidarum
 Persistent nausea and vomiting with weight loss of > 5% of pre-pregnancy body weight.11
 It occurs in ~0.5% of pregnancies, and is more common in nulliparous women and twin pregnancy. It
presents early in the first trimester. Patients may have a mild elevation of liver enzymes.
 Treatment: supportive care, IVF, electrolyte replacement, vitamin supplementations, promethazine,
metoclopramide, ondansetron, cyclizine, doxylamine, dimenhydrinate.11
Chapter 4: Liver 71
Table 1: Liver diseases specific to pregnancy

Intrahepatic cholestasis of HELLP (hemolysis, Acute fatty liver of
pregnancy (ICP) elevated liver enzymes, low pregnancy (AFLP)
platelets)
Onset  Second or third trimester  Second or third trimester or  Third trimester or
postpartum postpartum
Risk  Multiple gestations (e.g.  HTN, DM, Multiparity  Deficiency of LCHAD
factors twin pregnancy),  Age > 35  Primiparity (first gestation)
multiparity, metabolic  Caucasian  Male fetus
syndrome, HCV infection,  Multiple gestations
personal or family history
of ICP6
Family  Usually present  None  None
history
Clinical  Itching  Abdominal pain, nausea,  Swansea criteria:
features  Elevated liver enzymes vomiting Vomiting, abdominal pain,
and lab  Mild jaundice (bilirubin  Pre-eclampsia encephalopathy, polydipsia/
findings < 5 mg/dL)  Shock with hepatic rupture polyuria, leukocytosis,
 Elevated serum bile acids and infarction coagulopathy, transaminitis,
>10 μmol/L  Hemolysis (↑ LDH, ↑ammonia, ↑bilirubin, ↑urate,
↑indirect bilirubin) hypoglycemia, ↑creatinine,
 Low platelets (< 100 k) ascites, microvesicular fat on
biopsy
Liver  Normal  Rare hepatic infarction and  Fatty infiltration
imaging rupture, hematoma
Liver  Normal or mild cholestasis  Necrosis  Pericentral microvesicular
histology  No inflammation  Periportal hemorrhage steatosis (mainly zone 3),
confirmed with oil red O
staining of microvesicular fat
 Minimal or absent
inflammation
Maternal  0%  1% 12  10%
mortality
Fetal risk  Increased prematurity and  Increased prematurity and  Perinatal
IUFD (1%) especially if IUGR mortality 10-20%
serum bile acid>100  Perinatal
μmol/L13 mortality 7-20% 14
Treatment  Ursodiol (10–15 mg/kg,  Delivery  Delivery
1st line)  Consider platelet  Consider molecular testing
 Cholestyramine (less transfusion to 40,000– for LCHAD in women with
effective)15 50,000 cells/μ l AFLP and their offspring
 Delivery At week 37 EXPL6, 7
(ACG strong
recommendation)7
Recurrence  Frequent (45-70%)  Less common (5-15%)  Recurs in patients with
in future LCHAD mutations
pregnancies
Abbreviations: LCHAD: long-chain 3-hydroxyacyl-CoA dehydrogenase; IUFD: Intrauterine fetal death;
IUGR: Intrauterine growth retardation.
*Swansea criteria: Six of these criteria in the absence of other etiologies is suggestive of AFLP
 Intrahepatic cholestasis of pregnancy (ICP) is characterized by new onset pruritus in the second or third
trimester, and elevated bile acid levels >10 μmol/mL6
 ICP is the most common liver disease specific to pregnancy
72 Chapter 4: Liver
oOne study showed that there is an association between ICP and several liver and biliary disorders including
hepatitis C and nonalcoholic fatty liver disease.16 Therefore, it is recommended to test for viral serologies
and monitor for normalization of liver enzymes post-partum.
 Acute fatty liver of pregnancy (AFLP)-see table 1.
 Hypertensive disorders of pregnancy: Pre-eclampsia, eclampsia, HELLP (hemolysis, elevated liver enzymes,
low platelets)-see table 1.
 Pre-eclampsia Affects 5-10% of pregnancies.
o Risk factors include nulliparity, age > 40 years, chronic hypertension, and diabetes.
o Clinical features include hypertension, proteinuria, edema, abdominal pain, and jaundice.
o Labs may reveal elevated ALT and AST, and bilirubin (< 5 mg/dL).
o Pre-eclampsia can progress to eclampsia (pre-eclampsia + seizures6), AFLP, HELLP, hepatic rupture
and infarction.
o Treatment:
● Low dose aspirin, blood pressure management.
● Delivery at 34 weeks in pre-eclampsia with severe features (extreme elevation of blood pressure,
end organ damage).
● Pre-eclampsia without severe features: delivery at 37 weeks.
Hemochromatosis and iron overload syndromes
Diagnosis and management of

AASLD, 2011
hemochromatosis: 2011 Practice Guideline 17
ACG Clinical Guideline

ACG, 2019
Hereditary Hemochromatosis 18
 Intestinal iron absorption (figure 1).
 Iron is mainly absorbed in the proximal small intestine.
 Ferric iron (Fe+3) is reduced to ferrous iron (Fe+2) by duodenal cytochrome B (DcytB). It is then absorbed by
the mucosal transmembrane protein DMT1 into the enterocyte. 19
 Ferroportin (FPN) exports iron across the basolateral membrane into the circulation.
 This also requires the iron oxidase hephaestin (Hp) that converts Fe+2 to Fe+3 (requires copper). Fe+3 then
binds to transferrin (Tf).
o Loss of function mutation in ferroportin gene SLC40A1 leads to "ferroportin disease" (type 4a HH). This
is an autosomal dominant form of iron overload. Reduced iron export leads to its characteristic
accumulation in the reticuloendothelial macrophages and liver Kupffer cells.
● There is a characteristic increase in ferritin level with normal or low transferrin saturation.
o Gain of function mutation in ferroportin gene SLC40A1 leads to "non-classical ferroportin disease" (type
4b HH), and leads to hepcidin resistance. This has similar presentation as type 1 hemochromatosis.
 Hepcidin is a negative regulator of iron absorption.
o It is synthesized in the liver in response to excess iron.
o It downregulates ferroportin, which leads to decreased iron absorption.
 Hemojuvelin (HJV) is an important protein involved in the molecular pathway leading to the expression of
hepcidin. A defect preventing HJV expression leads to very low hepcidin levels and increased iron absorption.
Chapter 4: Liver 73
Figure 1: Intestinal iron absorption.

(See text)
DMT1: Ferrous iron transporter divalent

metal ion; DcytB: Duodenal cytochrome B;
FPN: Ferroportin; Tf: Transferrin;
Hp: Hephaestin
 The classification of iron overload syndromes is shown in table 2

Table 2: Iron overload syndromes
Primary iron overload
Secondary iron overload
[Hereditary hemochromatosis (HH) classification]
 Type 1: HFE related HH  Dyserythropoiesis (thalassemia, chronic
 Type 1A: C282Y homozygote hemolytic anemia)
 Type 1B: C282Y/H63D (compound heterozygote)  Chronic blood transfusions
 Type 1C: S65C mutation  Chronic liver disease
 Non-HFE related HH (rare)  Chronic viral hepatitis
 Type 2: Juvenile hemochromatosis  Alcoholic liver disease
 Type 2A: Hemojuvelin (gene: HJV)  Nonalcoholic steatohepatitis
 Type 2B: Hepcidin (gene: HAMP)
 Type 3: Transferrin receptor-2 (gene:TfR2)
 Type 4A: loss of function mutation (gene: SLC40A1)
- Ferroportin disease
 Type 4B: gain of function mutation (gene: SLC40A1)
– non-classical Ferroportin disease18
 African iron overload

 This disease is described in Sub Saharan Africa.
 It is most likely related to drinking beer with high iron concentrations (brewed in large iron containers), possibly
with a genetic predisposition due to mutations in non-HFE genes (possibly ferroportin). 17
 Iron deposition is seen in hepatic parenchymal cells in addition to Kupffer cells.
 Secondary iron overload results from dyserythropoiesis, chronic blood transfusions, and chronic liver disease.
Iron deposition is present in both the hepatocytes and Kupffer cells.
 The membrane protein transferrin receptor 2 (TFR2) is involved in sensing transferrin saturation. Mutation of
can lead to a reduction in hepcidin production and increased iron absorption (very rate)
 HFE associated hereditary hemochromatosis (Type 1 HH)
 The HFE gene on chromosome 6p encodes HFE protein, which is a non-classical major histocompatibility
complex (MHC) protein.20 This protein modulates the formation of hepcidin.
 HH is an autosomal recessive disease that most commonly results from a Cysteine to Tyrosine mutation on
location 282 of the HFE gene (C282Y mutation). Other less important mutations: H63D, S65C
 The C282Y mutation impairs the formation of a disulfide bond, which affects binding of HFE protein with
β2microglobulin, impairing its ability to reach the cell surface. This leads the intracellular aggregation of
74 Chapter 4: Liver
HFE, impairment of cell signaling, reduced hepcidin expression, and increased intestinal iron absorption and
parenchymal iron deposition in multiple organs.20
 Genotypes that lead to HFE-related HH:
 C282Y/C282Y (C282Y homozygote)
o This is the main disease genotype and is present in 90% of patients with HH.
 C282Y/H63D (compound heterozygote)
o Most patients with this genotype have elevated iron indices; however, significant iron overload is
uncommon.21
 The following genotypes do not lead to clinical iron overload (but may present with elevated ferritin and
transferrin saturation):
 C282Y heterozygotes (C282Y/wild type), H63D homozygotes (H63D/H63D), and H63D heterozygotes
(H63D/wild type), S65C mutation
 HH is common.
 The prevalence of C282Y homozygotes in the USA is 1:200 to 1:500.
 The prevalence of C282Y heterozygotes is 1:10.
 Clinical presentation
 Most C282Y homozygotes are asymptomatic and present with abnormal iron indices.
o Serum ferritin and transferrin saturation are elevated in 40-60% of female patients and
75-100% of male patients who are C282Y homozygotes. 22
 Iron overload related disease is much less common.
o A prospective cohort study of 203 subjects who were C282Y homozygotes showed that iron overload
related disease was present in 28.4% of men and only 1.2% of women. 22
 Symptomatic patients present with fatigue, abdominal pain, weight loss, arthralgia, impotence, amenorrhea,
diabetes, cirrhosis, and congestive heart failure symptoms.
 Physical exam may reveal hepatomegaly, skin pigmentation (due to increased synthesis of melanin by
melanocytes, which is accelerated by iron deposition), arthritis of the second and third
metacarpophalangeal joints, diabetes, testicular atrophy, and splenomegaly.
 Diagnosis
 Iron parameters suggestive of HHC are shown in table 3.
 The typical findings are elevated ferritin level associated with elevated transferrin saturation.
o Elevated serum ferritin with normal or low transferrin saturation can occur in secondary iron overload
and ferroportin disease (HH type 4a). In addition, some patients with metabolic syndrome can have a
condition referred to as “dysmetabolic iron overload syndrome”, possibly related to hepatic
inflammation and hepcidin dysfunction.23
Table 3: Iron parameters in HHC.
Serum iron Transferrin Ferritin Total iron binding
(mcg/dL) saturation (%) (ng/mL) capacity (mcg/dL)
Normal 50-150 20-50 30-250 230-380
Hemochromatosis > 150 > 50 > 300 < 300
 HFE mutation analysis is recommended in patients with any of the following:

o Elevated ferritin (> 200 ng/mL in women or > 300 ng/mL in men) with no signs of inflammatory disease.24
o Transferrin saturation > 45%.17
 Liver biopsy in HHC 17
o Indicated if ferritin is more than 1000 mcg/L or liver enzymes are elevated in a patient with confirmed
hemochromatosis. Liver biopsy is mainly performed to determine the degree of fibrosis or cirrhosis. It
Chapter 4: Liver 75
can also differentiate between classic HH (iron deposition is seen in parenchymal cells), and ferroportin
disease (iron deposition in Kupffer cells)
o Hepatic iron stores measurement: Hepatic iron concentration (HIC) is > 4,000 mcg/gm dry weight.
Hepatic iron index > 1.9
 MRI can also be used to estimate the hepatic iron content and diagnose iron overload. 18
 Treatment
 Phlebotomy is performed if ferritin is >1000 ng/ml and/or elevated liver enzymes. 18
 Phlebotomy of one unit of blood per week, until hematocrit is < 35%, ferritin is 20-50 ng/ml, and transferrin
saturation is < 50%. Patients with ferroportin disease have higher risk of phlebotomy-induced anemia.
 Maintenance phlebotomy of one unit every 2-3 months.
 Each unit of blood has around 250 mg iron, and drops the serum ferritin by ~30 ng/ml.
 Effects of phlebotomy
 No reversal in cirrhosis, arthropathy, diabetes, or testicular atrophy.
 Improvement of portal hypertension and reversal of hepatic fibrosis.
 Improved skin pigmentation, fatigue, cardiac function, and liver enzymes.
 Improved survival if the disease is diagnosed before the development of cirrhosis.
 Avoid vitamin C supplements, which increase iron absorption (no need for such restriction in ferroportin disease).
 Chelating agents can be used in selected patients who do not tolerate phlebotomy (anemia, congestive heart
failure)18 or in secondary iron overload. Examples: Deferoxamine (SQ), Deferiprone (PO), Deferasirox (PO).
 Other treatment: Erythrocytapheresis (selective removal of red blood cells).
 Low gastric acidity inhibits iron release from food. PPIs have been shown to decrease the needed frequency of
phlebotomy.25 However, prescribing PPI solely for this purpose is controversial and phlebotomy/voluntary
blood donation remains the mainstay of treatment. 26 The ACG recommends against using PPI for the treatment
of hemochromatosis.18
 Genetic counseling
 Screen first-degree family members of patients with hemochromatosis for the HFE mutation.18
 To avoid testing the patient's children, test the spouse.
o If the spouse has no HFE mutation, then the children are not at risk of developing the disease. However,
they may be heterozygote for the mutation.
Wilson disease
Diagnosis and treatment of Wilson disease:

AASLD, 2008
An update 27
European association for the study of the liver Journal of hepatology,

Clinical Practice Guidelines: Wilson’s disease 28 2012
 Wilson disease is a rare autosomal recessive disorder that results in copper accumulation in various organs,
mainly the liver, brain, and cornea.
 It is caused by mutation of the copper transport protein ATP7B on chromosome 13.
 More than 300 mutations have been described, and most patients are compound heterozygotes (two different
mutations, one on each chromosome).
 Therefore, mutation testing is not routinely performed for diagnosis. It could be considered to screen family
members of patients with known mutations.
76 Chapter 4: Liver
 Clinical presentation
 Neuropsychiatric manifestations
 More common in adolescents and young adults (mean age is ~20 years old).
 Hypophonia (a weak voice), clumsiness, psychiatric disturbances, movement disorders (tremor, dystonia,
Parkinson-like features).
 Patients with Wilson disease have normal IQ.
 Ophthalmologic manifestations
 Kayser-Fleischer rings are copper deposits in descemet's membrane of the cornea.
o These rings are present in more than 95% of patients with neurologic abnormalities and in ~50% of patients
with liver disease. They disappear in the majority of patients after treatment.
o They can also be seen in cholestatic liver disease such as primary biliary cholangitis.
 Sunflower cataracts result from copper deposits in the lens.
 Hepatic manifestations
 More common in younger patients.
 Liver involvement can present with asymptomatic elevation of liver enzymes, acute hepatitis, fulminant
hepatic failure, or it may have a more insidious onset leading to cirrhosis and portal hypertension.
 Hepatic presentation can resemble autoimmune hepatitis, and may lead to fatty liver similar to NASH.
 Liver biochemistry
 Acute fulminant Wilson disease is associated with elevation of AST/ALT ratio > 2, ALKP to bilirubin ratio
< 4, and Coombs negative hemolytic anemia.
 Wilson disease should be considered in any individual between the ages of 3 and 55 years with liver
abnormalities of unclear etiology.27
 Liver histology
 Liver histology is non-specific, can resemble other liver diseases such as autoimmune hepatitis, NASH.
 The earliest abnormality is fatty infiltration.
 Liver hepatic copper concentration is > 250 mcg/gm dry weight.
 Electron microscopy shows a characteristic finding of abnormal mitochondrial cristae with widened
membranes and electron dense granules.
 Wilson disease is also associated with renal tubular acidosis (both type 1 and 2), Fanconi syndrome,
congestive heart failure, arrhythmias and glucose intolerance.
 Copper measurements
 Decreased serum ceruloplasmin < 20 mg/dL.
 Increased urine copper >100 mcg/24 hrs (> 40 mcg/24 hrs in patients with Kayser-Fleischer rings)
 Treatment
 Treatment with any chelating agent can initially lead to worsening of neurologic symptoms.
 Discontinuation of therapy is not recommended, as most patients will recover.
 Dose reduction is recommended for penicillamine and trientine prior to surgery and during pregnancy to
promote wound healing.
 Food decreases absorption of penicillamine and trientine (give one hour before or after a meal).
 Penicillamine
 Increases urinary copper excretion. Dose: 500 mg PO q.i.d.
 Early sensitivity reactions include fever, rash, and proteinuria. Stop treatment immediately.
o Other side effects: elastosis perforans serpingosa (extrusion of abnormal elastic fibers through the
epidermis), thrombocytopenia, and aplastic anemia.
 Trientine: Inhibits intestinal copper absorption, and increases urinary excretion.
 Dose 27: Initial treatment: 750-1500 mg/day divided b.i.d. or t.i.d. Maintenance:750-1000 mg/day.
Chapter 4: Liver 77
Side effects: gastritis, aplastic anemia. Avoid coadministration of trientine with iron, which can form a
toxic complex. Space out the two medications by at least 2 hours.
 A large retrospective study showed that trientine and penicillamine had similar efficacy in treating Wilson disease.29
 Zinc: Inhibits absorption of copper from the GI tract, and increases stool excretion.
 Used mainly for maintenance therapy following treatment with other copper chelators. Dose: 50 mg t.i.d.
 Liver transplantation in patients with fulminant or advanced Wilson disease is curative.
Alpha one antitrypsin deficiency
 Alpha one antitrypsin (α1-AT) is a serine protease inhibitor produced primarily in the liver.
 It functions to inhibit multiple proteases including neutrophil elastase, which degrades elastin and other
connective tissue proteins.
 α1-AT deficiency has an autosomal codominant inheritance.
 The gene encoding α1-AT is SERPINA1, located on chromosome 14.
 More than 100 alleles of this gene have been identified. These alleles are designated by alphabetical letters.
The normal allele is M.
 The most common mutation leading to α1-AT deficiency is Glu342Lys that results in the
Z allele of the SERPINA1 gene.
 α1-AT phenotype is expressed as Pi (protease inhibitor) followed by the two letters representing both alleles
of the gene. Common phenotypes are:
 PiMM: normal phenotype.
 PiMZ: intermediate deficiency of α1-AT.
 PiZZ: this is the most common disease phenotype, which results in severe deficiency of
α1-AT. Patients develop lung and liver disease.
 Null phenotype: this is a rare phenotype (PiQOQO) that leads to complete absence of α1-AT protein. This
causes severe emphysema without liver disease.30
 Clinical manifestations are mainly related to emphysema and liver disease
 Pathophysiology of liver disease: accumulation of the mutant protein in the endoplasmic reticulum of
hepatocytes leading to hepatocyte damage. Liver disease does not develop in the rare null phenotype, as there
is complete absence of the protein.
 Pathophysiology of lung disease: increased destruction of elastin in the lungs by the uninhibited action of
neutrophil elastase, leading to emphysema.
 Diagnosis
 Serum α1-AT level: serum levels of < 11 micromole/L are associated with a clinically significant deficiency. 30
 Genotype testing.
 Liver histology
 Liver biopsy is not used for diagnosis, but rather for staging the severity of liver involvement in patients with
advanced liver disease.30
 Histology shows PAS positive, diastase resistant granules in the cytoplasm of periportal hepatocytes. These
represent accumulated abnormal protein in the endoplasmic reticulum, and are most commonly associated
with the PiZZ phenotype.
 Treatment of liver disease
 Supportive care, avoid alcohol and smoking. Liver transplantation is curative for liver disease.
78 Chapter 4: Liver
Viral hepatitis
Hepatitis A
Update: Recommendations of the Advisory Committee on
MMWR Morb
Immunization Practices for Use of Hepatitis A Vaccine for
Mortal Wkly Rep
Postexposure Prophylaxis and for Preexposure Prophylaxis for
2018
International Travel31
 Hepatitis A is a non-enveloped, RNA virus of the Picornaviridae family.
 Acute hepatitis A is decreasing in incidence due to widespread vaccination.
 It is transmitted by the feco-oral route. Risk factors include international travel, household or daycare contact,
and men who have sex with men.
 The incubation period is ~30 days (range 15-50 days).
 Fever, fatigue, nausea, vomiting, diarrhea, jaundice, and right upper quadrant pain.
 Physical findings: jaundice and hepatomegaly.
 Diagnosis: positive IgM anti-HAV antibody.
 Treatment: supportive care. Ursodiol can be given for itching.
 Prognosis: Most patients develop acute, self-limited illness.
 Fulminant hepatitis is uncommon, but can develop in patients with pre-existing liver disease.
 There is no chronic stage of hepatitis A infection.
 Rare presentations
 Prolonged cholestatic hepatitis: following the acute hepatitis episode, patients develop a prolonged period of
cholestasis lasting more than three months.
 Relapsing hepatitis: patients will relapse and present with another episode of acute hepatitis after complete
resolution of the infection.
 Treatment in both cases is supportive, as all patients will recover completely.
 Prevention
 Vaccination: hepatitis A vaccine (2 doses at least 6 months apart).
 Pre-exposure prophylaxis with HAV vaccine is recommended for unvaccinated persons traveling to endemic
countries. If travel is planned within the following 2 weeks, then HAV immunoglobulin (HAVIG) should be
administered in addition to HAV vaccine.
 Post exposure prophylaxis
 If the exposed is a healthy person between 12 months and 40 years, give HAV vaccine within 2 weeks of
exposure. HAVIG is as an alternative, but vaccination is preferred.
 If the exposed person is older than 40 years, give both HAV vaccine and HAVIG.
 If the exposed person is immunocompromised, or with chronic liver disease and they are >12 months of
age, give both HAV vaccine and HAVIG.
 If the exposed is a child < 12 months old, give HAVIG only (HepA vaccine is not licensed for children <1 year old).
Chapter 4: Liver 79
Hepatitis B
Update on prevention, diagnosis, and treatment of chronic AASLD,

hepatitis B: AASLD 2018 hepatitis B guidance 32 2018
AASLD,
AASLD Guidelines for Treatment of Chronic Hepatitis B 33
2016
American Gastroenterological Association Institute Guideline on

AGA.
the Prevention and Treatment of Hepatitis B Virus Reactivation
2015
During Immunosuppressive Drug Therapy 34, 35
World Health Organization Guidelines for the prevention, care
WHO,
and treatment of persons with chronic hepatitis b infection 36
2015
 Hepatitis B is a double stranded DNA virus of the hepadnaviridae family of viruses.

 Screening for hepatitis B is indicated for all those with high risk of hepatitis B (pregnancy, men who have sex
with men, HIV, chronic liver disease, IV drug users, and healthcare workers at risk for occupational exposure-
refer to guidelines for full list).
 Screening should be performed with HBsAg and HBsAb. Vaccinate those who are HBsAb negative and do
not have chronic hepatitis B.
 Interpretation of hepatitis B serologies:
 HBsAg (+), Anti-HBc Ab (+), Anti-HBs Ab (-/+)Current HBV infection
 HBsAg (-), Anti-HBc Ab (+), Anti-HBs Ab (+)Prior resolved infection
 HBsAg (- ), Anti-HBc Ab (+ ), Anti-HBs Ab (- )Prior infection, or occult infection (associated with
detectable HBV DNA), or false positive anti-HBc. 37
 HBsAg (-), Anti-HBc Ab (- ), Anti-HBs Ab (+)Prior vaccination to HBV
Acute hepatitis B
 The incubation period is 1-4 months.
 70% of patients infected with hepatitis B develop mild subclinical anicteric hepatitis.
 Most of these patients have asymptomatic elevations of liver ALT and AST (>1000 IU/L).
 Some patients have non-specific symptoms of fatigue, malaise, and nausea.
 30% of patients develop acute icteric hepatitis. Less than 1% of these patients develop acute fulminant hepatitis.
 More than 95% of patients will recover completely. Less than 5% of adults infected with HBV will develop
chronic infection (compared to > 90% of children).
 Treatment
 Supportive care is sufficient in the majority of patients.
 Indications for antiviral therapy in acute HBV infection: fulminant hepatitis, hepatic encephalopathy, INR
> 1.6, protracted course (elevated bilirubin > 10 mg/dL for > 4 weeks), immunocompromised patients,
coexisting hepatitis C or other chronic liver disease. 38
 Interferons should be avoided. Treatment with any of the oral antivirals is appropriate (page 81).
Chronic Hepatitis B
 Chronic hepatitis B infection (acquired at birth) passes through several stages (table 4).
80 Chapter 4: Liver
Table 4: Stages of chronic hepatitis B infection.

Stage 2: Immune active HBeAg positive
Stage 1: Immune tolerant
chronic hepatitis B
 Most patients are younger than 40 and  Elevated liver enzymes
asymptomatic  Active inflammation on liver biopsy
 Normal liver enzymes  (+) HBeAg, (-) HBeAb
 No inflammation or fibrosis on liver biopsy  High HBV DNA levels >20,000 IU/ml
 (+) HBeAg, (-) HBeAb  Treatment is indicated
 High HBV DNA levels >20,000 IU/ml
 Monitor every 3-6 months for progression
Stage 4: Immune active HBeAg negative
Stage 3: Inactive chronic hepatitis B
chronic hepatitis B
 Liver enzymes normalize  Most patients are younger than 40 and
 No inflammation on liver biopsy, variable asymptomatic
fibrosis level  Variable liver enzymes levels
 (-) HBeAg, (+) HBeAb  Chronic hepatitis on liver biopsy and
 Low HBV DNA levels <2,000 IU/mL Advanced fibrosis on liver biopsy (30% of
 Good prognosis patients already have cirrhosis)
 Monitor liver enzymes every 3-6 months.  (-) HBeAg , (+) HBeAb,
 Lower HBV DNA compared to stage 2
 Treatment is indicated
 Treatment (figure 2)
Figure 2: AASLD algorithm for the management and follow up of chronic hepatitis B infection.
*Treat if there is evidence of inflammation and/or fibrosis on liver biopsy. HBV DNA is measured in IU/mL.
(Adapted from Lok AS, et al. Chronic hepatitis B: update 2009. Hepatology 2009;50(3):661-2, with permission)
 The decision to treat or not is based on the stage of viral infection. Hepatitis B infection responds to treatment
in the immune reactive and HBeAg negative reactivation stages.
 Treatment is not indicated in the immune tolerant and low replicative stages.
 In general, treatment is indicated when there is evidence of inflammation (elevated ALT > 2 ULN or active
inflammation and/or advanced fibrosis on biopsy) combined with elevated HBV DNA level.
 ULN for ALT is 25 U/L for women and 35 U/L for men.
Chapter 4: Liver 81
The AASLD management approach to HBV treatment is shown in figure 2 on the next page.
 Other societies’ recommendations (e.g. EASL) differ in the cutoff for HBV DNA level and ALT.
 For compensated cirrhosis, AASLD recommends treatment regardless of HBV DNA level to prevent
decompensation. Those patients with cirrhosis on HBV therapy should continue hepatocellular carcinoma
(HCC) surveillance.
 Entecavir and tenofovir are preferred; however, Peg interferon alfa is not contraindicated.
 For decompensated cirrhosis or acute liver failure due to hepatitis B (see page 79), treatment is always indicated.
 The risk of lactic acidosis is higher in patients with decompensated cirrhosis treated with nucleos(t)ide
analogues (table 5). Close monitoring of these treated patients is recommended.
 Consider treatment in high-risk pregnant females (page 83) and patients receiving immunosuppression (page 84).
 Patients who are not treated should have liver enzymes checked every 3-6 months.
 Medications
 FDA approved hepatitis B therapies are shown in table 5.
Table 5: Hepatitis B therapy

Medication Type Dose* Pregnancy class
Peg interferon alfa-2a† - 180 mcg/week subq X
Peg interferon alfa-2b† - 1.5 mcg/kg/week subq X
Tenofovir disoproxil fumarate (TDF) Nucleotide analog 300 mg/day PO B
Tenofovir Alafenamide Prodrug of TDF 25 mg /day PO unclear
Adefovir Nucleoside analogue 10 mg /day PO C
Lamivudine Nucleoside analogue 100 mg/day PO C‡
Entecavir Nucleoside analogue 0.5 mg/day PO in nucleoside naive C
1 mg/day in lamivudine resistance
Telbivudine Nucleoside analog 600 mg /day PO B
* All medication doses should be adjusted in renal impairment.
† Interferons are given for a treatment duration of 48 weeks
‡ Lamivudine has extensive pregnancy data and appears to be safe
 First line medications are those with a high resistance barrier (entecavir or tenofovir).
 Lamivudine is cheaper but has a high rate of resistance.
o Consider lamivudine if the patient cannot afford entecavir or tenofovir, or if the treatment is planned
for a limited period (e.g. preventing HBV flare during chemotherapy).
 Tenofovir disoproxil fumarate (TDF) is associated with Fanconi syndrome; renal insufficiency in patients
treated for HIV/HBV co-infection (rare).It has been associated with osteomalacia and lactic acidosis (rare).
o A retrospective analysis evaluated renal function in patients treated with TDF and entecavir for a
median of 43-46 months. In those with normal baseline renal function, TDF was not associated with
higher frequency of worsening renal function compared to entecavir. In patients with abnormal
baseline renal function (GFR<60), more significant renal decline was seen with TDF.39
 Tenofovir Alafenamide is a newer formulation of Tenofovir. It is a prodrug of Tenofovir. It results in
lower plasma concentrations in the plasma, but higher concentration in cells. This results in less drug
exposure to the kidneys and bones, and potentially less pronounced adverse effects.
o Test patients for HIV before starting Tenofovir. Assess renal function, serum phosphorus, urine
glucose and protein before treatment and during treatment if there is a suspicion of renal impairment.
 HIV/HBV coinfection:40 (HAART: Highly Active Anti-Retroviral Treatment)
 If the patient is not on HAART and is not anticipated to be started on HAART:
o Treat with peg interferon-alpha (if CD4 > 500 and HBeAg+) or adefovir (this has no anti-HIV effect).
82 Chapter 4: Liver
 If the patient is starting HAART and HBV treatment:

o Treat with lamivudine + tenofovir or emtricitabine + tenofovir.
 If the patient is already on HAART:
o Add peg interferon-alpha or adefovir.
 Follow up after initiation of oral antiviral treatment
 Labs: Monitor HBV DNA every 3 months until undetectable, then every 6 months. Liver function tests
every 3 months. HBeAg and anti-HBeAb every 6 months (in HBeAg (+) patients).
 At week 24
o If HBV DNA > 2000 IU/mL, switch or add alternative drug.
o If HBV DNA > 60 and < 2000 IU/mL (partial response) 41
● If the patient is on entecavir or tenofovir, continue therapy, as most patients will continue to drop
their HBV DNA. Monitor more frequently. In the rare event of persistent HBV DNA at 96 weeks,
switch or add alternative drug.
● If the patient is on other antiviral medications, switch to entecavir or tenofovir.
o If HBV DNA is negative, continue therapy.
 The main goal of treatment is to achieve a negative HBV DNA at week 48.
 Treatment endpoints
o In patients with HBeAg (-) disease, treat until HBsAg clearance.
o In patients with cirrhosis, stop treatment if HBsAg clearance. Otherwise, treat indefinitely.
o In patients with HBeAg (+) disease without cirrhosis, consider stopping treatment if HBeAg
seroconversion is achieved and maintained for > 12 months, and HBV DNA undetectable
 Antiviral resistance 40
 Resistance rates to antiviral therapy are shown in table 6.
o The first manifestation of resistance is virologic breakthrough (>10-fold increase in serum HBV DNA
during treatment in a patient who had initial virologic response). 40 This is followed by the biochemical
breakthrough (increase in serum ALT).
 Management
o Confirm that the patient is compliant with therapy.
o Confirm antiviral resistance with genotypic testing.
o Switch or add medications as outlined in table 6.
 Screening for HCC: see page 120
Table 6: Rate of viral resistance to hepatitis B therapy and corresponding management

Medication Resistance rate Management40
Lamivudine  15-30% after 1 year of treatment  Add adefovir or tenofovir*
 60-70% at 5 years  Stop lamivudine, switch to Truvada®†
Adefovir  HBeAg(+): 42% at 5 year  Add lamivudine
 HBeAg(-) : 29% at 5 years  Stop adefovir, switch to Truvada®
 Switch to or add entecavir
Entecavir  Nucleoside naive  Switch to tenofovir or Truvada®
● 1.2% at 5 years
 Lamivudine refractory patients
● 7% at 1 year, 16% at 2 years
Telbivudine  HBeAg(+): 5% at 1 year, 25% at 2 years  Add adefovir or tenofovir
 HBeAg (-): 2.3% at 1 year, 11% at 2 years  Stop telbivudine, switch to Truvada®
Tenofovir  Rare  Switch to another agent
*Avoid entecavir in lamivudine resistance. †Truvada® is combination emtricitabine + tenofovir
Chapter 4: Liver 83
Chronic hepatitis B and pregnancy

 Indications for treatment of HBV in pregnancy
 Advanced fibrosis and cirrhosis.
 Active HBV infection with high viral load and elevated liver enzymes.
o Discuss risks and benefits of treatment.
o Consider tenofovir if treatment is planned long term.
 Chronic hepatitis B and perinatal transmission
 Most neonatal HBV transmission (> 95%) occurs during delivery.
 The risk of HBV transmission without neonatal vaccination in HBeAg (+) mothers with high viral load is ~ 90%.
 With immunoprophylaxis (HBIG and vaccination), the overall rate of transmission is 3-9%.
 Most immunoprophylaxis failures leading to HBV transmission to the newborn occur in patients with very
high viral load.
 Many studies have shown that suppressing HBV starting in the second or third trimester in addition to
immunoprophylaxis will reduce the risk of perinatal transmission (to a rate close to zero).
o The medications used in these studies were lamivudine, telbivudine, and tenofovir.42-45
 Management approach
 Measure HBV DNA at the end of the second trimester (week 26-28).46
o If the mother has a prior child with HBV(+) due to immunoprophylaxis failure (regardless of her DNA
level), or if HBV DNA >200,000 IU/mL, treat with antivirals (tenofovir is recommended6) starting in
the third trimester to decrease the risk of transmission.
o If HBV DNA <200,000 IU/mL, antivirals are not recommended. However, they should be considered in
patients with threatened premature labor, threatened abortion, and if there are indications for invasive
procedures. 47
 At delivery: Cesarean section is not recommended. There is no consistent evidence that it reduces the risk
of neonatal transmission.
o Give 100 IU of HBIG and the first dose of hepatitis B vaccination to the newborn, the other two doses of the
vaccine are given at 1 month and 6 months. For preterm and low birth weight infants who weight <2000 grams,
give the HBIG at birth, followed by the hepatitis B vaccine at 1 month, 3 months, and 7 months. 47
 Postpartum
o If antivirals were started during pregnancy, consider continuing treatment after delivery. This depends
on the mother's plans for future pregnancy and breastfeeding.
o Breastfeeding is safe in patients with chronic hepatitis B, and it is not prohibited in patients on HBV
antiviral therapy.6, 32
o Lamivudine is not recommended for long-term use due to the high rate of viral resistance.
o If treatment is discontinued after delivery, monitor the patient for the development of a flare for at least
6 months. Long-term follow up is needed to assess the need for future treatment.
Occupational exposure to hepatitis B
 Risk of transmission of HBV after needle stick injuries is shown in table 7.
Table 7: Risk of occupational transmission of HBV after needle stick injuries 48

Source's hepatitis B status Rate of clinical hepatitis in Rate of serologic
exposed conversion in exposed
HBsAg (+) and HBeAg (+) 22-30% 37-62%
HBsAg (+) and HBeAg (-) 1-6% 23-37%
84 Chapter 4: Liver
 Management of needle stick injuries depends on the HBsAg status of the infection source and the hepatitis B
vaccination and vaccine-response status of the exposed person (table 8). 48
Table 8: recommended post exposure prophylaxis for exposure to HBV (CDC 48)
Vaccination and Treatment
antibody response of Source HBsAg(+) Source HBsAg(-) Source unknown or
the exposed worker unavailable
Unvaccinated HBIG x 1 and initiate HBV Initiate HBV Initiate HBV vaccine series
vaccine series vaccine series
Previously vaccinated
Known responder No treatment No treatment No treatment
(HBsAb ≥ 10 mIU/mL)
Known non-responder -If the exposed person has No treatment If source is known high
(HBsAb ≤ 10 mIU/mL) not previously completed a risk, treat as if source is
second vaccination: HBIG HBsAg+
x 1 and initiate HBV
revaccination
-If previously completed
revaccination but without
success: HBIG x 2*
Antibody response Test exposed person for No treatment Test exposed person for
unknown anti-HBsAb anti-HBsAb
-Adequate: no treatment -Adequate: no treatment
-Inadequate: HBIG x 1 and -Inadequate: vaccine
vaccine booster booster and recheck titer in
1-2 months
HBIG: Hepatitis B immunoglobulin (dose is 0.06 ml/kg IM). *Second dose of HBIG given 1 month later.
HBV prophylaxis in patients receiving immunosuppressants
 All patients receiving immunosuppressive medications (prolonged steroids, thiopurines, anti-TNF agents, chemotherapy)
should be tested for chronic HBV infection (HBsAg, Anti HBc, Anti HBs).
 The risk of reactivation and subsequent management depends on the results of the hepatitis b serologies and the type of the
planned immunosuppressive medication (table 9). In some situations, either antiviral treatment OR monitoring is appropriate.
 Consider the ease of monitoring and the patient’s compliance when you choose an approach. For HBV prophylaxis in
patients undergoing HCV treatment, see page 87.
 General points
 The strength of evidence for antiviral prophylaxis is variable. It is strongest for patients with high risk of
reactivation.
 If HBsAg (+), this indicates active HBV infection. If HBsAg (-), HBcAb (+), HBsAb (+/-), this indicates
prior exposure to HBV. The risk of reactivation is higher if HBsAg (+), but there is a real risk of reactivation
in HBsAg (-) depending on immunosuppressive therapy
 If only HBsAb is (+), this indicates immunity to HBV. Antiviral prophylaxis is not indicated.
 HBV prophylaxis should be given using antivirals with high resistance barrier (entecavir or tenofovir).
 If these drugs are expensive and resources are limited, consider other antivirals (e.g. lamivudine, adefovir,
telbivudine).
 Treatment should be given for at least 2 weeks before start of immunosuppression, and up to 12 months post
treatment completion.
Chapter 4: Liver 85
Table 9: Antiviral prophylaxis in patients with positive markers for HBV undergoing
immunosuppressive treatment.32, 35
Immunosuppressive
Medication or HBsAg(+)/anti HBc(+) HBsAg(-)/anti HBc(+)*
immunosuppressive status
B cell depleting agents
(rituximab, ofatumumab, High risk
alemtuzumab, ibritumomab, Give antiviral prophylaxis (12 month post TC)
ocrelizumab)
Anthracycline derivative
(doxorubicin, epirubicin, Moderate risk
High risk
Daunorubicin, etc...) -Give antiviral prophylaxis
Give antiviral prophylaxis
Moderate (10-20mg) or high (6 month post TC) OR
(6 month post TC)
dose (>20) steroids dose -Monitor HBV-DNA, HBsAg, ALT
steroids (prednisone q1-3mo
equivalent) for ≥4weeks
Potent Anti TNF agents †
(Infliximab, Adalimumab,
certolizumab, golimumab)
Low to Moderate risk
Cytokine or Integrin inhibitors Moderate to high risk
-Give antiviral prophylaxis
(Natalizumab, Vedolizumab, -Give antiviral prophylaxis
(6 month post TC) OR
etc...) (6 month post TC)
-Monitor HBV-DNA, HBsAg, ALT
Tyrosine kinase inhibitors
q1-3mo
(Imatinib, Sunitinib, etc…)
Immunophilin inhibitors
(cyclosporin)
Moderate risk
Low dose steroids (<10mg
-Give antiviral prophylaxis
prednisone equivalent) for Low risk, no prophylaxis
(6 month post TC) OR
≥4weeks
-Monitor HBV-DNA, ALT q1-3mo
Azathioprine, 6-MP,
Methotrexate Low risk,
Low risk, no prophylaxis
Acitretin Monitor HBV-DNA, ALT q1-3mo
ampremilast (Otezla®)
Intra-articular steroids
Low risk, no prophylaxis
Any oral dose steroids≤1 week
Monitor HBV-DNA, HBsAg, ALT
q1-3mo post-transplant x 1 year.
Recipients of non-liver solid
-Lifelong antiviral therapy OR
organ transplant32
Consider treatment with antivirals
for 6-12 months
Hepatocellular carcinoma
High risk. Give antiviral prophylaxis Moderate risk ~9%50 management
receiving local therapy 49
(6 month post TC) unclear but could treat or monitor
including TACE and RFA
TC: treatment completion. TACE: Transarterial chemoembolization. RFA: Radiofrequency Ablation
*With or without anti HBsAb. † Etanercept is a less potent anti-TNF with lower reactivation risk
86 Chapter 4: Liver
Hepatitis C
Hepatitis C Guidance 2019 Update: American Association for the

Study of Liver Diseases-Infectious Diseases Society of America AASLD, IDSA
Recommendations for Testing, Managing, and Treating Hepatitis 2019
C Virus Infection. (http://www.hcvguidelines.org) website Document
 Hepatitis C is an RNA virus of the Flaviviridae family of viruses.

 Around 3.2 million people are infected with hepatitis C in the USA. Three out of 4 people with HCV are unaware
of their infection. HCV is the most common cause of chronic hepatitis and cirrhosis in the USA.
 Most hepatitis C acute infections progress to chronic infection.
 The opioid epidemic has led to an increase in the incidence of HCV in the United States. The majority of new
HCV cases (70%) are in people who inject drugs (PWID). HCV treatment in PWID is effective and associated
with low rates of reinfection.
 Universal screening for HCV is recommended.
 The U.S. Preventive Services Task Force (USPSTF) recommend one-time testing for HCV-Ab of all adults
aged 18-79 years regardless of their risk factors for hepatitis C.51
 CDC recommends HCV screening ”at least once in a lifetime for all adults aged 18 years and older, except in
settings where the prevalence of HCV infection (HCV RNA‑positivity) is less than 0.1%”52
 CDC also recommends HCV screening for all pregnant women done during each pregnancy.
 There has been remarkable progress in drug regimens and treatment success over the past decade.
 Several direct acting combination antivirals (2 or 3 drugs per pill) have been approved and new oral-only
regimens have evolved.
 Treatment duration has become shorter, with less side effects to therapy, and higher success rates.
 Several clinical conditions (cardiopulmonary disease, psychiatric conditions, autoimmune disease, HIV
coinfection, older age, obese, thrombocytopenia anemia) are no longer a challenge to treat. Patients with many of
these conditions are eligible for treatment.
Treatment of hepatitis C
 All patients with HCV should receive standard adult vaccinations, including HAV and HBV if not immune.
 Baseline labs: HCV RNA, CBC, INR, liver function panel, creatinine, HBsAg, HIV Ab.
 The goal of HCV therapy is to achieve sustained virologic response (SVR), defined by an undetectable HCV
RNA at 12 weeks after the completion of therapy. SVR indicates HCV cure.
 There are several treatment options and regimens available. Treatment type and duration (generally 8-24 weeks)
can vary according to the viral genotype, the presence of cirrhosis, status of cirrhosis (compensated vs
decompensated), and previous HCV treatment.
 Table 10 shows the recommended simplified treatment regimens for treatment naïve patients with or without
compensated cirrhosis. Other treatment regimens for decompensated cirrhosis may include ribavirin and vary in
duration (12-24 weeks).
Chapter 4: Liver 87
Table 10: Simplified HCV treatment regimens based on the HCV guidance by AASLD/IDSA53
Link to guidance
Regimen Duration summary (1 page)
Treatment Naïve patients without cirrhosis
Any genotype: glecaprevir (300 mg)/pibrentasvir (120 mg) [Mavyret®] 8 weeks
Dose: Three pills once a day with food.
Any genotype: sofosbuvir (400 mg)/velpatasvir (100 mg) [Epclusa®] 12 weeks
Dose: one tablet once a day with or without food.
Treatment Naïve patients with compensated cirrhosis
Genotypes 1-6: glecaprevir (300 mg)/pibrentasvir (120 mg) [Mavyret®] 8 weeks
Dose: Three pills once a day with food.
Genotypes 1,2,4,5,or 6: sofosbuvir (400 mg)/velpatasvir (100 mg) [Epclusa®] 12 weeks
Dose: one tablet once a day with or without food.
 During HCV treatment with direct acting antivirals (DAA), HBV reactivation can occur in patients who are co-
infected with HBV (HBsAg positive).54
 Management of HCV/HBV coinfected patients who are planned for DAA treatment is as follows:
 If the patient is on HBV therapy, continue treatment.
 If the patient meets HBV treatment criteria (see page 80), start HBV therapy before DAA treatment, and
continue HBV treatment indefinitely.
 HBsAg positive with low (<1000 or undetectable HBV DNA): options include:
 Preemptive HBV therapy: start HBV therapy before DAA treatment, and continue for 12 weeks post DAA
treatment completion (SVR12)
 Monitor HBV DNA Q 4 weeks (not more frequently than every 4 weeks), start treatment if HBV DNA level
increases >10-fold or is >1000 IU/mL53
 HBsAg negative, HBcAb positive (+/- HBsAb): these patients have very low risk of reactivation. Monitor with
ALT +/- HBsAg during treatment and up to SVR12.
Occupational exposure to hepatitis C
 The average incidence of anti-HCV seroconversion after accidental percutaneous exposure from an HCV
positive source is 1.8% (range 0%-7%). 48
 Management 55
 Test the exposed individual for baseline anti-HCV Ab and liver enzymes.
 Test the exposed individual for HCV RNA in 3-6 weeks post exposure. If negative, repeat testing 4-6 months
post exposure.
 There is no role for post exposure immunoglobulin or other antiviral treatments.
 If the patient develops + HCV RNA or seroconverts to positive HCV Antibody, then treatment should be initiated
without waiting for spontaneous resolution. 56
HCV sexual transmission
 HCV transmission among monogamous couples is extremely low.
 A recently published cross sectional study estimated the risk of HCV sexual transmission at 0.07%/year, or
approximately one per 190,000 sexual contacts. 57 This study supports the current CDC recommendations stating
that couples in a long-term monogamous relationship do not need to alter their sexual practices.
 The HCV positive patient should discuss with their partner the need for counseling and testing. The couple
should be counseled about the very low risk of transmission of HCV.
88 Chapter 4: Liver
Hepatitis D
 Hepatitis D virus (HDV) is a defective RNA virus that requires HBV for its replication.
 HDV is acquired by co-infection with HBV or by superinfection of a patient with chronic HBV.
 Co-infection of HDV with HBV leads to chronic HDV infection in only 2% of cases.
 Clinical presentation is similar to acute HBV.
 Superinfection leads to chronic hepatitis in > 90% of cases. It presents clinically as acute decompensation
of chronic HBV infection, or as acute hepatitis in a previously asymptomatic chronic HBV carrier.
 Chronic hepatitis D can lead to a rapidly progressive liver disease and cirrhosis.
Hepatitis E
EASL Clinical Practice Guidelines on hepatitis E virus infection 58 EASL 2018
 Nonenveloped RNA virus of the hepeviridae family of viruses. It has a wide host range: swine, cats, rats.
 It is mainly spread by feco-oral route through contaminated water.
 Most patients develop a self-limited infection that resolves spontaneously.
 Acute hepatitis E in pregnancy can lead to fulminant hepatic failure with high mortality (up to 20%).
Pyogenic liver abscess

Etiology: Bacterial: infection is usually polymicrobial. Most common organisms are E. coli, Streptococcus,
Staphylococcus aureus, and Klebsiella pneumoniae. Anaerobes include Bacteroides and Fusobacterium species.
 Non-bacterial: candida and Entamoeba histolytica.
 Risk factors: DM, biliary infections, and intra-abdominal infections (e.g. appendicitis, diverticulitis).
 Clinical features: fevers, abdominal pain, jaundice, and hepatomegaly.
 Diagnosis: ultrasound, CT scan, MRI.
 Management
 Blood cultures, supportive care.
 IV antibiotics: piperacillin/tazobactam, ciprofloxacin + metronidazole, or meropenem are acceptable regimens.
o Antibiotics should be given for at least 6 weeks.
 Treat the underlying source of infection.
o ERCP or PTC should be performed in patients with cholangitis and biliary obstruction.
 Percutaneous drainage is recommended in addition to antibiotics in most cases.
 Small abscesses < 5 cm in a stable patient can be treated with antibiotics alone. Aspiration should be
performed if the abscess is not responding to treatment or the clinical status deteriorates.
o All other abscesses require percutaneous drainage (needle aspiration or catheter drainage).
 Surgical drainage is indicated in patients with continued infection not responding to percutaneous drainage and in
complicated infections (e.g. ruptured abscess or intra-abdominal infection).
Chapter 4: Liver 89
Vascular diseases of the liver
Vascular Disorders of the Liver 59 AASLD, 2021
ACG Clinical Guideline: Disorders of the Hepatic

ACG 2020
and Mesenteric Circulation 60
Budd-Chiari Syndrome
 Budd-Chiari syndrome (BCS) is a clinical syndrome caused by obstruction of the hepatic venous outflow.
 The most common cause of obstruction is hepatic venous thrombosis (classic BCS).
 Venous obstruction can involve any part of the posthepatic venous circulation, including the inferior vena
cava and the smaller hepatic venules.
 Etiology (table 11):
 Multiple risk factors can coexist and result in a hypercoagulable state and thrombosis.
 Fulminant (acute) BCS
 This is an uncommon presentation. Patients present with sudden onset of right upper quadrant pain, severe
ascites, and jaundice.
 There is severe elevation of liver enzymes. This can progress into fulminant hepatic failure.
 Subacute presentation
 Symptoms develop over the course of several weeks to months.
 Patients develop gradual hepatic dysfunction.
 Liver enzymes are mildly elevated. Mild hyperbilirubinemia (< 5 mg/dL) is common.
 Ascites.
Table 11: Risk factors for Budd-Chiari syndrome

Hypercoagulable states Other etiologies
Inherited thrombophilia Malignancy
 Factor V Leiden mutation  Hepatocellular carcinoma
 Protein C, S deficiency  Leukemia
 Prothrombin gene mutation  Renal cell carcinoma
 Antithrombin gene mutation Liver infections
 Lupus anticoagulant  Liver abscess
Acquired thrombophilia  Hydatid cyst disease
 Myeloproliferative disorders Membranous obstruction of the vena cava
 Antiphospholipid syndrome Sarcoidosis
 Paroxysmal nocturnal hemoglobinuria Trauma
Other hypercoagulable states Celiac disease (rare association) 61
 Oral contraceptive pills
 Pregnancy
 Malignancy
 IBD
 Chronic presentation
 Patients present with chronic symptoms and develop portal hypertension and cirrhosis.
90 Chapter 4: Liver
 Diagnosis
 Doppler ultrasound, CT, MRI.
 The caudate lobe drains directly into the inferior vena cava, and is not affected by hepatic venous
thrombosis. Caudate lobe hypertrophy is seen in 75% of cases.
 Diagnostic paracentesis: SAAG > 1.1 g/dL, total protein > 2.5 g/dL.
 Management
 Treat the underlying disorder.
 Anticoagulation.
 Ascites management with diuretics and paracentesis.
 Other treatment options
o Angioplasty with or without stent placement: this aims to relieve the obstruction of the inferior vena
cava or hepatic veins.
o Thrombolysis: direct injection of thrombolytics into the thrombosed vein should be considered in
acute Budd-Chiari syndrome.
o Portosystemic shunting with TIPS or surgical portosystemic shunt.
● A large retrospective study of TIPS in 133 patients with severe BCS showed that TIPS was
successful in 93% of patients. Transplant-free survival was 88% at one year and 69% at 10-years,
which was better than the predicted outcome using the BCS Rotterdam prognostic score.62 Therefore,
TIPS is recommended in patients who do not improve on anticoagulation. 63
 Direct intrahepatic portosystemic shunt (DIPS), also called “percutaneous TIPS” maybe
required because of the hepatic vein occlusion.
● Surgical portosystemic shunts have high rates of perioperative complications in patients with
advanced liver disease.
o Liver transplantation is indicated in patients with fulminant hepatic failure or chronic BCS with
decompensated cirrhosis.
 Screen for hepatocellular carcinoma in patients with chronic BCS (ultrasound +AFP q 6 months)60.
Portal vein thrombosis
 Risk factors for portal vein thrombosis (PVT) are shown in table 12.
 PVT should be described according to its onset, location, and clot burden59 (see box below).
Table 12: Risk factors for portal vein thrombosis.
Liver cirrhosis Hypercoagulable states
(refer to table 11) Important descriptors of PVT
Timing
Intra-abdominal infections Malignancy
-Recent PVT: present < 6 months
 Diverticulitis  Hepatocellular -Chronic PVT: present >6 months
 Appendicitis carcinoma Involved veins
 Cholecystitis  Cholangiocarcinoma -Portal vein
 Pancreatic -Portal vein and splenic / mesenteric veins
adenocarcinoma Percent occlusion
Intra-abdominal Abdominal surgery -Completely occlusive (100%)
inflammation  Splenectomy -Partially occlusive (>50% lumen)
 Pancreatitis  Biliary surgery -Minimally occlusive (<50% lumen)
 Duodenal ulcer  Liver transplantation -Cavernous transformation (collateral
 Inflammatory bowel  TIPS formation, original portal vein not visualized)
disease  Peritoneal dialysis
Chapter 4: Liver 91
 PVT can be asymptomatic or present with abdominal pain, nausea, vomiting.
 In addition, PVT can lead to portal hypertension, esophageal, gastric, and ectopic varices.
 Diagnosis
 Doppler ultrasound, CT scan, MRI. In patients with cirrhosis, it is important to rule out malignant PVT
(thrombus enhancement, neovascularization, liver mass, elevated AFP). 64
 Chronic portal vein thrombosis leads to cavernous transformation of the portal vein. The portal vein is replaced
with multiple vascular channels, associated with surrounding collateral venous circulation.
 Complications
 GI bleeding results from gastric and esophageal varices.
 Extension of the portal thrombosis into the mesenteric veins can lead to mesenteric venous thrombosis,
intestinal ischemia, and infarction.
 In extreme cases, congestion of the portal venous system and severe collateral formation can result in external
biliary compression (portal biliopathy).
 Management
 Acute (recent) portal vein thrombosis: anticoagulation is indicated in all non-cirrhotic patients to induce
recanalization of the portal vein and prevent further extension of the thrombosis.
o Treat for at least six months. Consider repeat imaging in 3 months to assess for thrombus resolution.
Indefinite anticoagulation is recommended in patients with thrombophilia. 60
o Consider imaging every 6 months after discontinuing anticoagulation to assess for recurrence.
 Chronic portal vein thrombosis:
o Screen for esophageal and gastric varices. If esophageal varices are present, then treat with nonselective
beta-blockers (preferred) or endoscopic band ligation for primary prevention.
o Anticoagulation is recommended in patients with permanent prothrombotic states, extension of the clot
into the mesenteric veins, and if current or previous evidence of bowel ischemia.60
 Portal vein thrombosis in patients with cirrhosis:
 The benefits of anticoagulation should be weighed against the risk of bleeding, especially in those with low
platelets and with encephalopathy and risk of falls. 60 In cirrhosis, portal hypertension already exists, and the
goal of anticoagulation in cirrhosis is to avoid progression of thrombosis that may affect a future liver
transplant. 59
 Acute (recent) venous thrombosis:
o Screen for esophageal and gastric varices. If esophageal varices are present, then treat with
nonselective beta-blockers (preferred) or endoscopic band ligation for primary prevention.
● Anticoagulation can be initiated and not delayed until after variceal eradication. 59
o Anticoagulation for 6 months is recommended in patients with cirrhosis and acute complete main PVT,
mesenteric venous thrombosis, or extension of the thrombus to the mesenteric veins.60
Give anticoagulation beyond 6 months in those awaiting liver transplant.
 Chronic portal vein thrombosis
 Anticoagulation is recommended in permanent prothrombotic states, extension of the clot into the
mesenteric veins, and if current or previous evidence of bowel ischemia. Consider anticoagulation in
those awaiting liver transplant.
 In patients with adequate renal function, consider low molecular weight heparin for anticoagulation
instead of warfarin.
92 Chapter 4: Liver
Sinusoidal obstruction syndrome

 Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease, is a distinct liver
disease that occurs most commonly following high dose chemotherapy and stem cell transplant.
 Ingestion of herbal teas containing pyrrolizidine (e.g. bush tea) has been linked to the development of SOS
in developing countries.65
 SOS results from injury to the sinusoidal endothelial cells and subsequent obstruction at the level of the
hepatic sinusoids.
 Clinical features: Usually presents within 10-20 days following stem cell transplant.
 Symptoms include RUQ pain, jaundice, hepatomegaly, ascites, weight gain, peripheral edema.
 Diagnosis: The diagnosis is suspected in patients with SOS risk factors and typical clinical features, and is
established by the following clinical criteria (table 13)
Table 13: Criteria for the diagnosis of sinusoidal obstruction syndrome after stem cell transplant
Modified Seattle Criteria 66 Baltimore Criteria 67
Presence of two of the following criteria Bilirubin > 2 mg/dL within 21 days of SCT
within 20 days of SCT: plus two of the following criteria:
 Bilirubin > 2 mg/dL  Hepatomegaly
 Hepatomegaly or RUQ pain  Ascites
 Weight gain (> 2% from baseline)  Weight gain (> 5% from baseline)
 Other supportive tests.
o Doppler ultrasound shows reversal of portal venous flow, abnormal hepatic venous flow pattern, and
gallbladder wall edema.
o Liver biopsy is reserved for cases in which the diagnosis is unclear, or to exclude other etiologies of
liver disease. The transjugular approach is recommended for liver biopsy.
o Measurement of the hepatic venous pressure gradient: a value of > 10 mmHg is highly specific for SOS.68
 Treatment
 Supportive care, diuretics are given to treat volume overload.
 Liver transplantation can be considered in patients with advanced liver failure.
 Defibrotide is an antiplatelet/thrombolytic agent that has been shown in small studies to be an effective
treatment for SOS. It is currently not FDA approved for this indication, and larger studies are awaited.
 TIPS has unproven benefit, and it is not recommended.
 Prophylaxis: the most recent AASLD guidance statement support using ursodiol as prophylaxis against SOS
in patients undergoing allogenic SCT (dose is 12 mg/kg divided B.I.D starting the day before chemotherapy
and continued for 3 months after SCT. 59
Congestive hepatopathy
 Congestive hepatopathy refers to liver disease due to passive congestion and elevated central venous pressure.
 Etiology: right sided heart failure (most common cause), constrictive pericarditis, severe pulmonary hypertension.69
 Clinical manifestations: Patients are usually asymptomatic.
 Symptomatic patients have right upper quadrant pain, lower extremity edema, hepatomegaly, ascites (SAAG
> 1.1, protein > 2.5 mg/dL), and signs of right ventricular dysfunction.
 Varices do not develop in patients with congestive hepatopathy. Both the central venous and the portal
pressures are elevated; therefore, there is no gradient between the portal and the central venous systems.
 Labs usually show mild elevation in ALT, AST and bilirubin. However, bilirubin elevation can be severe.
 Prothrombin time can be prolonged in severe cases.
Chapter 4: Liver 93
 Imaging:
 Cardiac echocardiogram is performed to evaluate the right and left ventricular function.
 Abdominal imaging (CT/MRI) can show liver congestion (hepatomegaly and IVC distension).
 The abnormal perfusion of the liver in the setting of passive congestion results in a mosaic, mottled pattern of
contrast enhancement. 69
 "Nutmeg liver" is a term used to describe the gross appearance of the congested liver. 69
 Liver biopsy: Histology shows atrophy, sinusoidal distention, fibrosis extending between the central veins,
forming a "reversed lobulation" pattern. 70
 Treatment:
 Treat underlying cardiac disease, diuretics, and paracentesis as needed.
Alcoholic liver disease
Diagnosis and Treatment of Alcohol‐Related Liver AASLD,

Diseases: 2019 Practice Guidance from the AASLD 71 2019
ACG Clinical Guideline: Alcoholic Liver Disease 72 ACG, 2018
 Alcoholic liver disease includes fatty liver, acute alcoholic hepatitis, and alcoholic cirrhosis.
 Acute alcoholic hepatitis
 Clinical presentation: jaundice, fever, ascites, encephalopathy, and coagulopathy.
 Obtain detailed history of alcohol use, drug use, previous alcohol-related admissions
 Physical examination: assess for signs of malnutrition, chronic liver disease, portal hypertension, and alcohol
withdrawal.72
 Lab findings: leukocytosis, elevated ALT and AST (usually 300-500 IU/L), AST/ALT ratio > 2, elevated
bilirubin and worsening creatinine.
 Maddrey's discriminant function (DF) (PT= prothrombin time)
o 4.6 x [patient's PT-control PT (seconds) ] + serum bilirubin (mg/dL)
 Liver biopsy is rarely required for diagnosis Link
 Features of alcoholic liver disease include macrovesicular steatosis, neutrophil infiltrate (lobular inflammation),
Mallory bodies (eosinophilic material within the cytoplasm of hepatocytes), fibrosis, or overt cirrhosis. These findings are not
specific, and can be seen in non-alcoholic steatohepatitis and cirrhosis.
 Treatment:
 Complete Alcohol abstinence.
 Nutritional support using NG tube in those with severe disease (protein 1.2-1.5g/kg and total calories of 35Kcal/kg).
 Corticosteroid therapy
o Indications for corticosteroids include DF > 32 or hepatic encephalopathy.
o Contraindications to corticosteroids include acute hepatitis B, active TB.
o Relative contraindications are sepsis, hepatorenal syndrome, uncontrolled diabetes, and GI bleeding.
Many of these patients were excluded from the studies of corticosteroids in alcoholic hepatitis.
Corticosteroids can be given once these disease conditions are corrected.
o Treatment regimen: prednisolone 40 mg daily for 30 days, then dose taper over 2-3 weeks.
o The Lille score is calculated on day 7 to determine if there is a response to corticosteroids.73
● A Lille score ≥ 0.45 indicates no treatment response with a 6-month survival rate of < 25%.
Discontinue steroids. Link
● A Lille score < 0.45 indicates a good response with a 6-month survival rate of 85%. Continue steroids.
o A recent study found that Lille score calculated on day 4 is equally indicative of response as day 7. 74
 Pentoxifylline
94 Chapter 4: Liver
o Consider pentoxifylline if corticosteroids are contraindicated.

o Some studies found that pentoxifylline improves in-hospital mortality in severe alcoholic hepatitis and reduces
the risk of developing hepatorenal syndrome. 75
o A randomized controlled trial showed that patients who were treated with a combination of prednisolone and
pentoxifylline had similar survival at 6 months compared to those treated with prednisolone and placebo (70% vs.
69%, p=0.91). 76 There was a trend towards a lower incidence of hepatorenal syndrome at 6 months in the
prednisolone-pentoxifylline group compared to the prednisolone-placebo group (8.4 % vs. 15.3%). However, this
did not reach statistical significance (p=0.07).
o Due to mixed efficacy in clinical trials, the use of pentoxifylline in alcoholic hepatitis remains controversial. Dose:
400 mg t.i.d. for 28 days.
Study highlight
(STOPAH) Trial: Prednisolone or Pentoxifylline for Alcoholic Hepatitis. 77
 Multicenter RCT of Pentoxifylline, Prednisolone, (Pentoxifylline+ Prednisolone) or placebo for the
treatment of severe alcoholic hepatitis.
 1103 patients were randomized, and data for 1053 patients were analyzed.
 Primary endpoint: mortality at 28 days
 Secondary endpoints: death or liver transplantation at 90 days and at 1 year.
 Results:
Table 14: Primary and secondary endpoints of STOPAH trial

No No Prednisolone Pentoxifylline
Prednisolone Pentoxifylline
Prednisolone Pentoxifylline OR (95%CI) OR(95%CI)
28-day 14% 18% 16% 16% 0.72(0.52-1.01), 1.07 (0.77-
mortality p=0.06 1.49), p=0.69
90 day 30% 29% 29% 30% 1.02 (0.77- 0.97 (0.73-1.28)
mortality or 1.35), p=0.87 ,p=0.81
liver
transplant
1-year 57% 56% 56% 57% 1.01(0.76-1.35), 0.99(0.74-1.33),
mortality or p=0.94 p=0.97
liver
transplant
 Prednisolone lowered 28-day mortality but did not reach statistical significance.
 Pentoxifylline did not affect short term mortality, and neither drug affected 90-day and 1-year mortality
 A recent meta-analysis (that included STOPAH study) showed that corticosteroids lower 28-day mortality
compared to controls (hazard ratio [HR] 0.64, 95%CI [0.48-0.85]), and compared to pentoxifylline (HR 0.64
[0.43-0.95])78. None of the medical treatments improved 6-month mortality.
Chapter 4: Liver 95
Nonalcoholic fatty liver disease
The Diagnosis and Management of Non-Alcoholic Fatty Liver

AASLD,2018
Disease 79
National
Non-alcoholic fatty liver disease (NAFLD): assessment and Institute for
management. NICE guideline 80 Health and Care
AGA Clinical Practice Update on Screening and Surveillance Excellence, 2016
Gastroenterology
for Hepatocellular Carcinoma in Patients with Nonalcoholic
2020
Fatty Liver Disease: Expert Review 81
 Non-alcoholic fatty liver disease (NAFLD) includes non-alcoholic fatty liver (NAFL) and non-alcoholic
steatohepatitis (NASH).
 NAFL: hepatic steatosis (Excess fat accumulation in the liver >5%) without inflammation, in the absence of
known causes of liver steatosis such as:
 Alcohol: threshold for alcohol intake is defined as consumption of > 21
drinks/week in men and > 14 drinks/week in women. One standard drink Table 15:
contains 14 grams of pure alcohol. Metabolic syndrome
 Hepatitis C, TPN, abetalipoproteinemia, short bowel syndrome, rapid Adult treatment panel
weight loss. III criteria for metabolic
 Prevalence: NAFL affects ~30% of US adults. NASH affects ~ (1.5%-6.5%) syndrome
(diagnosis requires ≥3
of US adults79.
criteria)
 Risk factors: older age, DM, dyslipidemia, obesity, Hispanic/Latinx  Waist circumference
ethnicity, metabolic syndrome (table 15), polycystic ovary.  Men > 102 cm (>
 Pathophysiology (two hit hypothesis) 40 inches)
 First hit: insulin resistance results in increased liver gluconeogenesis,  Women > 88 cm (>
35 inches)
increased adipose tissue lipolysis and decreased fatty acid oxidation.  Triglycerides
 The released fatty acids are taken up by the liver leading to increased  ≥ 150 mg/dL
lipogenesis. This results in increased fat storage and macrovesicular steatosis.  HDL cholesterol
 Second hit: once steatosis develops, oxidation of fatty acids in the  Men < 40 mg/dL
hepatocyte leads to the formation of reactive oxygen species, which  Women < 50 mg/dL
induce inflammatory  Blood pressure
cytokines and trigger inflammation.82 The end result is steatohepatitis,  ≥ 130/≥ 85 mmHg
fibrosis, and cirrhosis.  Fasting glucose
 Prognosis: Fatty liver is generally benign. The long-term risk of cirrhosis is  ≥ 110 mg/dL
low (< 5%). In contrast, the 10-year risk of cirrhosis in NASH is ~20%.
 The presence of liver fibrosis and its severity is predictive of the development of liver specific morbidity
(complications of cirrhosis), liver specific mortality and the need for Liver transplant, and all-cause mortality. 83, 84
 Diagnosis and workup
 Fatty liver can be seen on ultrasound (bright liver), CT, and MRI.
 Exclude other causes of liver diseases (viral, autoimmune, hemochromatosis, etc.)
 NAFLD patients may have positive ANA in up to 17% of patients. 85
 Test for risk factors for NASH such as diabetes and dyslipidemia. Measure BMI.
 Screening for NASH and NASH-related fibrosis: The AGA clinical care pathway
recommends screening for NASH in those with type 2 diabetes, 2 or more metabolic
risk factors, and those with hepatic steatosis and elevated liver enzymes . 86
96 Chapter 4: Liver
 Methods to assess fibrosis

 Laboratory tests and scores:
 Fibrosis scoring: These non-invasive scoring systems are based on several lab values, and predict
the level of fibrosis in patients with NAFLD.
o NAFLD fibrosis score (NFS).
o NAFLD Fibrosis-4 score (FIB-4).
 Enhanced liver fibrosis (ELFTM) test: Measures plasma levels of three biomarkers (Hyaluronic acid,
Procollagen III amino terminal peptide, and Tissue inhibitor of metalloproteinase) and combines them
into a single score using a specific algorithm. A score ≥ 10.51 in a patient with NAFLD suggests
advanced fibrosis80. This test is not approved in the USA, but it is
available in Europe.
 Fibrosure® test measures several biomarkers (ALT, Bilirubin, total
GGT, α2-macroglobulin,Apolipoprotein A1, Haptoglobin) to provide an
Link Link
estimate of fibrosis stage

Vibration Controlled Transient Elastography (Fibroscan®):
 This device uses a small transducer and an ultrasound probe positioned in an intercostal space near the
right hepatic lobe to send ultrasound waves through the liver. The shear wave velocity is measured
and converted into a liver stiffness measurement (in kilopascals).87
o The higher the shear wave speed, the higher the stiffness of the liver (and higher fibrosis).
o A value more than 9.9 kilopascals predicts advanced fibrosis with 95% sensitivity.79
o Falsely elevated values can occur in non-fasting states, ascites, acute hepatitis, congestive
hepatopathy, cholestasis and iron overload.
 It was approved by the U.S. FDA in 2013 for noninvasive diagnosis of liver fibrosis.
 The other parameter obtained from the Fibroscan® machine is the CAPTM score (Controlled
Attenuation Parameter). This measures how fast ultrasound waves attenuate as they pass through the
liver. Low CAP scores correlate with no steatosis, high CAP value correlates with significant steatosis.
 Fibroscan AST (FASTTM) score incorporates elastography score, CAP score, and AST, that predicts the
likelihood of fibrotic NASH (defined as elevated NAFLD activity score (NAS≥4), and advanced
fibrosis (stage 2 or higher)88.
 Magnetic resonance elastography (MRE): This is an MRI technique that uses a mechanical driver
(source of vibration) to generate mechanical shear waves (range, 20–200 Hz) through the liver tissue.
This is followed by imaging of these waves using a special MRI sequence. The software processes the
wave information and produces an elastogram that represent tissue stiffness.89
 MRE is superior to elastography is assessing liver fatty change and fibrosis.
 MR-Proton density fat fraction for steatosis (MR -PDFF): used to quantify the liver fat content.
 Liver biopsy is the gold standard for diagnosis.
 Findings include steatosis, necroinflammation, ballooning hepatocytes, Mallory bodies, and fibrosis.
 Indications for liver biopsy 79
 Patients with increased risk of steatohepatitis and advanced fibrosis:
o Patients with the metabolic syndrome.
o Patients with high NAFLD fibrosis score (NFS or FIB-4).
o Patients with high liver stiffness measured by transient elastography or MRE
 Patients in whom liver biopsy is needed to exclude other etiologies of liver disease.
Chapter 4: Liver 97
 Management
 Treatment of metabolic syndrome. Treat cardiovascular risk factors.
o The most common cause of death in NAFLD is cardiovascular disease.
o Statins are safe to use to treat dyslipidemia. Avoid statins in decompensated cirrhosis.79
 Low salt, hypocaloric diet. Smoking cessation. Regular exercise (150 minutes per week; or ≥5 exercise
sessions per week, with each session of ≥10 minutes in duration)
 Weight loss: A weight loss of 5% can improve steatosis, steatohepatitis, while 10% weight loss can
reverse fibrosis.90 Bariatric surgery should not be performed specifically for NASH.
 A multicenter prospective uncontrolled study showed that life style interventions (diet and physical
activity) could decrease portal pressure in overweight/obese patients with compensated cirrhosis. 91
 Insulin sensitizers
 Metformin did not show a major benefit on liver histology in randomized controlled trials.
o It is not recommended for the treatment of NASH.
 Pioglitazone
o Most studies of pioglitazone in NASH were conducted in non-diabetic patients.
o Pioglitazone can be used to treat biopsy proven steatohepatitis. However, it is not FDA approved for
non-diabetics in the USA.
Study highlight
(PIVENS) Trial: Pioglitazone versus Vitamin E versus Placebo for the Treatment of
Nondiabetic Patients with NASH 92
 This is a multicenter, randomized controlled trial.
 247 non-diabetic patients with biopsy proven NASH were randomly assigned to receive placebo, vitamin E 800
IU/day, or pioglitazone 30 mg/day. Treatment duration was 96 weeks.
 Primary endpoint
o Improvement in the histologic features of NASH, based on multiple histologic activity scores including
steatosis, inflammation, and hepatocellular ballooning.
 Secondary endpoints included changes in individual histologic activity scores.
o The significance level was set at p value < 0.025.
 Results: The primary endpoint was achieved in 43% of vitamin E patients compared to 19% of placebo
(p < 0.01).The primary endpoint was achieved in 34% of pioglitazone patients. This did not reach statistical
significance compared to placebo (p=0.04).
● Pioglitazone achieved secondary endpoints such as improvement in inflammation, and steatosis, and
resolution of steatohepatitis.
 Neither vitamin E nor pioglitazone was associated with improvement in fibrosis or inflammation scores
 Conclusion: vitamin E improved liver histology in non-diabetic patients with NASH. Pioglitazone had no benefit
compared to placebo for the primary endpoint. Nevertheless, it did improve important secondary endpoints.
 Vitamin E (α-tocopherol)
 Based on the results of the PIVENS trial above, vitamin E at 800 IU/day is recommended for non-
diabetic, biopsy proven NASH.93 Discuss the risks and benefits of treatment, including reports of
increased risk of prostate cancer.
 There is no evidence to support its use in patients with diabetic NASH or NASH cirrhosis.
98 Chapter 4: Liver
Drug Induced Liver Injury
ACG Clinical Guideline: Diagnosis and

ACG, 2021
Management of Idiosyncratic Drug-Induced Liver Injury (DILI)94
 Drug induced liver injury (DILI) is the most common cause of acute liver failure
 Intrinsic DILI causes predictable liver injury caused by a drug given at sufficient doses (e.g. acetaminophen).
 DILI is most commonly related to acetaminophen overdose.
 Idiosyncratic DILI causes rare hepatotoxicity in susceptible persons only.
 Chronic DILI refers to chronic elevation of liver enzymes with manifestations of chronic liver disease.
 Patterns of liver enzyme elevation: Hepatocellular, cholestatic, or mixed pattern.
 R value = (ALT/ULN) ÷ (ALKP/ULN)
 Hepatocellular: elevation of ALT and AST more than ALKP (R > 5)
 Differential diagnosis: acute viral hepatitis (A,B, less commonly C, E, HSV, CMV, EBV) autoimmune and
ischemic liver disease, Budd Chiari, Wilson disease, choledocholithiasis(see page 69)
o ACG recommends ruling out acute HCV infection with HCV RNA in cases of suspected DILI.94
 The level of enzyme elevation does not correlate with the severity of liver injury.
 Hy's Law: Liver enzyme elevation (>3 upper limit of normal)+rising bilirubin to>2 ULN (without initial
cholestasis) is associated with a poor prognosis. The explanation of this observation is that even in severe
hepatocellular injury, the bilirubin excreting ability of the liver is usually preserved. Jaundice indicates that
liver injury is substantial and affects the liver excretory function, hence the poor prognosis.95, 96
 Cholestatic: elevation of ALKP more than ALT/AST (R < 5). Focus on imaging studies to rule out biliary obstruction.
 Other considerations: Primary biliary cholangitis.
 Drug induced cholestasis per se does not indicate a poor prognosis.
 Mixed pattern: elevation of both ALT/AST and ALKP (R = 2 to 5). Differential diagnosis similar to hepatocellular.
 See also table 16 on the next page for histological patterns of liver injury.
 An analysis performed by the United States Drug Induced Liver Injury Network on 899 DILI patients found
that the top ten medications related to DILI are (in descending frequency): 97
 Amoxicillin-clavulanate, Isoniazid, Nitrofurantoin, Sulfamethoxazole/trimethoprim, Minocycline,
Cefazolin, Azithromycin, Ciprofloxacin, Levofloxacin, and Diclofenac.
 The most common drug classes: antimicrobials, herbal/dietary supplements, cardiovascular, and CNS agents.
 Mechanism of DILI
 Immune mediated: characterized by fever, rash, and eosinophilia.
 Non-immune mediated: this is most commonly related to a metabolite of the drug causing direct toxicity
(e.g. isoniazid, acetaminophen).
 General Risk factors
 Age: Isoniazid toxicity is more common in adults older than 60 years.
 Valproic acid and salicylate toxicities are more common in children.
 Chronic alcohol intake predisposes to isoniazid and acetaminophen toxicity.
 HIV predisposes to isoniazid and sulfonamide toxicities.
 History of DILI increases the risk of future DILI.
 Risk factors for isoniazid (INH) induced hepatotoxicity
 Age > 35 years (2% incidence of toxicity if older than 50 years), females > males, chronic alcohol
consumption, acetaminophen, rifampin, chronic hepatitis B or C.
Chapter 4: Liver 99
 Risk factors for methotrexate induced liver injury

 Age > 60 years, total incremental dose, chronic alcohol consumption, obesity, diabetes mellitus, chronic liver
disease (viral hepatitis and other liver disease), psoriasis, renal failure.
 Indications for liver biopsy:94
 If autoimmune hepatitis is being considered as an etiology.
 If the liver enzymes continue to rise after stopping the suspected offending agent.
 If the peak ALT level has not decreased by >50% at 30-60 days or peak ALKP has not decreased by >50% at 180 days.
 If DILI is unclear and continued exposure and use of the suspected drug is expected.
 If liver enzyme elevation persists beyond 180 days to evaluate for chronic DILI.
Table 16: Patterns of liver injury
Type of injury Associated medications
 Microvesicular steatosis HAART drugs, valproate, salicylates, tetracycline
 Macrovesicular steatosis Amiodarone, diltiazem, corticosteroids, methotrexate, tamoxifen,
OCP
 Cholestatic hepatitis Amoxicillin-clavulanic acid, TCA, erythromycin, anabolic
steroids, methimazole, chlorpromazine,
 Vanishing bile duct syndrome* Amoxicillin, Ciprofloxacin, Azithromycin, Allopurinol, and
Carbamazepine
 Steatohepatitis Amiodarone, estrogens, tamoxifen, methotrexate
 Fibrosis and cirrhosis Methotrexate, vitamin A, amiodarone

 Granulomatous hepatitis Allopurinol, hydralazine, carbamazepine, methyldopa
 Autoimmune hepatitis** Minocycline, nitrofurantoin, infliximab, adalimumab, halothane,
diclofenac, propylthiouracil, atorvastatin, methyldopa, isoniazid,
etanercept, atorvastatin, rosuvastatin, clometacine, immune
checkpoint inhibitors (possible association)
 Vascular liver disease
o Budd-Chiari syndrome OCP
o Sinusoidal obstruction syndrome Busulfan, dactinomycin, azathioprine, mitomycin,
cyclophosphamide
o Peliosis hepatis† Anabolic steroids, tamoxifen, azathioprine, 6-thioguanine, OCP
 Neoplastic lesions
o Hepatocellular adenoma OCP
o Hepatocellular carcinoma Aflatoxin‡
o Angiosarcoma Exposure to vinyl chloride monomer (VCM)-rare
HAART: highly active antiretroviral therapy; OCP: Oral contraceptive pills; TCA: tricyclic antidepressants
* Vanishing bile duct syndrome is characterized by progressive loss of intrahepatic bile ducts, cholestasis, and
eventually hepatic failure. This condition could be related to congenital, immune, infectious, or drug induced etiology.
** The listed drugs have definite or probable association with drug-induced autoimmune hepatitis.98
†
Peliosis hepatis is a rare condition in which the liver develops multiple blood-filled cavities
‡ Aflatoxin is a fungal toxin that contaminates crops such as corn, wheat and peanuts
 Treatment :
 Consider checking LiverTox® website, which provides up-to-date information on the diagnosis,
frequency, and clinical patterns of DILI.
 Stop the offending agent.
 Re-challenge with a suspected drug should be avoided.
 N -Acetyl cysteine (NAC) should be given in acetaminophen toxicity (see next section). NAC can be considered in
patients with non –acetaminophen DILI and acute liver failure, especially in early stage ALF during early stages of
hepatic encephalopathy (Grade1-2).99-101 The dose used in the study was 150 mg/kg/hr of NAC over one hour, followed
by 12.5 mg/kg/hour for 4 hours, then continuous infusions of 6.25 mg/kg NAC for the remaining 67 hours.
100 Chapter 4: Liver
Acetaminophen toxicity
 Acetaminophen (APAP) toxicity is the most common cause of acute fulminant liver failure. It can result from a
single acute overdose or after multiple supratherapeutic doses (chronic ingestion of > 4 gm/day).
 Metabolism (figure 3)
 More than 90% of APAP is conjugated to glucuronide and sulfate and excreted in the urine.
 Only ~2% is metabolized by cytochrome p450 to N-acetyl-p-benzoquinone imine (NAPQI).
 With therapeutic doses of APAP, the small amount of NAPQI is conjugated with glutathione forming non-
toxic metabolites.
In APAP overdose, a larger amount of NAPQI is produced. Glutathione stores are not sufficient to
conjugate all NAPQI. Therefore, NAPQI
covalently binds to the sulfhydryl groups
of cellular proteins and causes
hepatocellular necrosis. Liver injury
consists mainly of centrilobular (zone III)
liver necrosis.
 Conditions that lower threshold for APAP
toxicity:
 Drugs that induce cytochrome p450:
Isoniazid, phenytoin, carbamazepine,
phenobarbital.
 Drugs that compete with glucuronidation:
Figure 3: APAP metabolism and toxicity
zidovudine, trimethoprim/sulfamethoxazole. (see text) NAC: N-acetyl cysteine
 Conditions with reduced glutathione stores: NAPQI: N-acetyl-p-benzoquinone imine
chronic alcohol abuse, prolonged fasting.
 Presentation after a single acute ingestion
 Early manifestations: Nausea, vomiting, abdominal pain, severe elevation of aminotransferases.
 Late manifestations: Progressive encephalopathy, liver failure, high INR, bilirubin and creatinine.
 Management
 Obtain a good history. Try to establish the time of ingestion in single acute ingestions.
 Labs: Serum chemistry, liver panel, glucose level, serum APAP level.
 If the patient presents within the first 4 hours, give activated charcoal.
 In cases of a single acute ingestion: if the patient presents between 4 and 24 hours of
ingestion, obtain serum APAP level and plot it on the Rumack-Matthew nomogram to
decide if acetylcysteine (NAC) is indicated. Link
o Administer NAC in patients who are at possible or probable risk of toxicity.
 The Rumack-Matthew nomogram cannot be used in the following cases:
 Time at presentation beyond 24 hours of ingestion.
 Patients with altered metabolism (e.g. chronic alcoholics).
 Cases of chronic supratherapeutic ingestions.
 NAC is indicated in all these cases. It improves outcome even if given beyond 24 hours of ingestion.102
 Dose of NAC
o Oral: 140 mg/kg loading dose, followed by 17 doses of 70 mg/kg every 4 hours
o IV: 21-hour IV protocol: Loading dose: 150 mg/kg over 1 hour. Dose 2: 50 mg/kg over 4 hours.
Dose 3: 100 mg/kg over 16 hours. If the patient has evidence of liver failure, continue NAC infusion
at 6.25 mg/kg per hour until liver function improves.
Chapter 4: Liver 101
Autoimmune Hepatitis
Diagnosis and management of autoimmune hepatitis in adults

AASLD,
and children: 2019 practice guidance and guidelines from the
2019
American Association for the study of liver diseases 98
 Definition: Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver characterized by circulating
antibodies and characteristic histopathologic findings (lymphoplasmacytic interface hepatitis) on liver histology.
 There is a significant female preponderance. Female: male ratio is 5:1.
 Main genetic susceptibility is linked to HLA-DR3 and DR4. Classification of AIH is shown in table 17.
Table 17: Classification of AIH

Type 1 Type 2
Antibodies* ASMA >1:80 , ANA >1:80 Anti-LKM1 >1:80
ANCA, AAA, Anti-SLA/LP Anti-LC1
Distribution Worldwide Rare in the US
Age of presentation Any age Children and young adults
Associated Autoimmune thyroid disease Autoimmune polyendocrinopathy-
disorders Graves’ disease candidiasis-ectodermal dystrophy
Ulcerative colitis (APECED)
Celiac disease
Diabetes mellitus type 1
Abbreviations: ASMA: anti-smooth muscle antibody; ANA: anti-nuclear antibodies; ANCA: anti-
cytoplasmic cell antibodies; AAA: anti-actin antibodies; anti-SLA/LP: Anti-soluble liver/liver pancreas
antigen; anti-LKM1: anti-liver-kidney microsomal-1; anti-LC1: anti-liver cytosol.
*Antibody titers are not predictive of disease severity or prognosis
 Presentations
 Asymptomatic patients with AIH present with elevated liver enzymes.
 Symptomatic patients can present with acute hepatitis, acute liver failure, or chronic hepatitis and cirrhosis.
 African American patients have a higher frequency of cirrhosis at presentation.
 Drug induced AIH is associated with several drugs (see page 99). Patients are mainly women, have acute
onset symptoms, and may present with fevers, rash, and eosinophilia. 98 Treatment is by stopping the
offending agent with or without glucocorticoids.
 Immune checkpoint inhibitors (ipilimumab, Nivolumab, cemiplimab, pembrolizumab, atezolizumab,
avelumab, durvalumab) have been associated with immune-mediated liver injury and are steroid
responsive. The pattern of hepatocellular injury is often mixed cholestatic and hepatocellular injury, and
patients do not have typical clinical, serologic and histologic features(ANA is positive in 50% of cases,
few have positive autoantibodies, and there is no female predominance). 103
o Monitor patients with ALT elevation <3 x ULN, hold medications in those with ALT elevation 3-5 times
ULN, resume if Enzymes return to normal, consider steroids. If ALT> 5 x ULN: stop medication, give
steroids, if no improvement of if ALT> 10x ULN permanently stop therapy.
 Diagnosis is made by a constellation of clinical, laboratory and histologic findings.
 Positive autoantibodies, elevated γ-globulin levels (>1.5 ULN).
 Characteristic histologic findings
 Interface hepatitis: portal mononuclear and plasma cell infiltrate spilling across the limiting plate of the
portal tract (non-specific for AIH), +/- lobular inflammation, +/- bridging fibrosis. Bile ducts are intact.
o The presence of ductopenia or ductular inflammation may suggest the presence of an AIH-primary
biliary cholangitis overlap syndrome
 Exclude other causes of chronic hepatitis (hereditary, viral, NASH, drug induced, etc.).
 A scoring system can be used to aid in diagnosis in cases that have atypical clinical, laboratory or histologic
findings (this can be found in the AASLD guidelines).
 Screen all patients with AIH for celiac and thyroid diseases. Consider drug induced AIH.98
 Indications for treatment (table 18)
 Patients with evidence of cirrhosis on biopsy but without active inflammation (inactive cirrhosis) do not
benefit from treatment.
Table 18: Absolute and relative indications for treatment in AIH.

Absolute Relative
 Acute liver failure  Symptoms of fatigue, arthralgia,
 Incapacitating symptoms jaundice
 serum AST or ALT > 10 upper limit of normal (ULN)  Elevated serum AST or ALT,
 Serum AST or ALT > 5 ULN and γ-globulin > 2 ULN γ-globulin less than absolute criteria
 Bridging or multilobular necrosis on biopsy  Interface hepatitis
 Treatment of AIH (without cirrhosis or acute severe symptoms):

 Prednisone monotherapy (consider in pregnant patients): 60 mg/day for 1 week, then 40 mg/day for 1 week,
then 30 mg/day for 2 weeks, then maintenance therapy (≤ 20 mg/day)
 Combination prednisone + azathioprine (preferred regimen)
 Prednisone 20-40 mg/day + Azathioprine 50 mg/day (or use a weight-based dose of 1-2 mg/kg).
 Test for TPMT activity prior to AZP therapy
 Combination therapy Budesonide + azathioprine: Budesonide 3mg TID + Azathioprine 1-2 mg/kg/d
 Budesonide should not be given in patients with acute severe hepatitis or cirrhosis.
 Monitor treatment response every 2-4 weeks.
 Once biochemical response is achieved, taper prednisone to 5-10 mg/day or budesonide to 3mg/day over the
next 6 months.98
 Maintenance: check labs q3-4 months; consider withdrawing steroids.
 Remission is defined as disappearance of clinical symptoms, normal liver enzymes, normal γ-globulin levels,
and normal histology (or inactive cirrhosis).
 If remission is achieved for at least 24 months, consider withdrawing treatment over a 6-week period with
close observation of liver enzymes
o Do not attempt to withdraw treatment in patients who initially presented with acute severe hepatitis.
 Relapse after withdrawing treatment occurs in up to 60% of patients
o Restart AZP and prednisone. Taper off prednisone and increase AZP to 2 mg/kg.
o Continue AZP indefinitely (do not re-attempt treatment withdrawal)
 Treatment failure (~10% of patients)
 Give prednisone 60 mg/day (or prednisone 30 mg/day + AZP 150/day) for at least 1 month.
 Once response is achieved, decrease prednisone and azathioprine doses over 2-3 months until standard doses
are reached.
 Mycophenolate mofetil or tacrolimus are second line options for treatment in patients who fail steroids and AZP. 98
 Other immunosuppressive therapies: cyclosporine, sirolimus, everolimus, rituximab, infliximab,
plasmapheresis.
 Treatment of AIH with cirrhosis: do not use budesonide, and do not use AZP in decompensated cirrhosis.
 Treatment of severe acute AIH: give prednisone or prednisolone alone. Patients who do not respond to treatment
and those with liver failure should be evaluated for liver transplant.
 Liver transplantation is highly successful in AIH

 A large European registry showed that the 5-, 10-, 15-year patient survival is 79%, 71%, 60%, and for graft
survival is 73%, 63%, 61%, respectively.
 (5-year graft survival 80-90%, 5-year graft survival 74%).
 Recurrence varies from 12-50% after 8-10 years, with median time to recurrence of 2 years.
 Steroids should be gradually withdrawn after liver transplant.
 In patients with AIH-primary biliary cholangitis overlap syndrome, start the appropriate treatment based on the
prominent histologic pattern of liver involvement, rather than serology.
 If the pattern is more consistent with AIH (markedly elevated AST and ALT, prominent lobular inflammation
on biopsy): treat with corticosteroids/AZP.
 If the pattern is more consistent with PBC (normal or mild elevation of ALT and AST, cholestasis with
minimal lobular inflammation on liver biopsy): treat with ursodiol.
 If the pattern is mixed, treat with steroids/AZP + ursodiol.
 Pregnancy and AIH
 Most AIH cases improve with pregnancy. However, up to 50% of patients may have a flare postpartum.
 Pregnancy outcomes in patients with AIH are comparable to the general population.
 The goal of treatment of AIH in pregnancy is to maintain biochemical response using the lowest effective
dose of medications.
 It is considered safe to continue AZP in pregnancy.
 Treatment discontinuation is generally not recommended if the patient is in remission on AZP.
 Use the lowest effective dose and consider minor dose reductions to AZP and prednisone.
 Mycophenolate mofetil is contraindicated in pregnancy6
 Monitor patients closely in the peripartum and postpartum period.
 If the treatment was stopped or the medication doses were reduced earlier in pregnancy, then the full
treatment regimen should be restarted 2 weeks before delivery and maintained throughout the postpartum
period. 104 AZP is considered compatible with breastfeeding.
 Other issues related to diagnosis and treatment
 Screen for bone disease (DEXA scan) in patients with risk factors for osteoporosis (prolonged steroids,
postmenopausal, history of low trauma fractures, and age > 65 for females and >70 for males).
 Check 25-OH-vitamin D level at baseline and annually. 98
 Supplement with calcium and vitamin D.
Primary sclerosing cholangitis
ACG Clinical Guideline: Primary Sclerosing Cholangitis 105 ACG, 2015
British Society of Gastroenterology and UK-PSC guidelines for

Gut, 2019
the diagnosis and management of primary sclerosing cholangitis 106
Role of endoscopy in primary sclerosing cholangitis: European

ESGE, EASL,
Society of Gastrointestinal Endoscopy (ESGE) and European
2017
Association for the Study of the Liver (EASL) Clinical
107
Guideline
AGA Clinical Practice Update on Surveillance for
Clin gastro hep,
Hepatobiliary Cancers in Patients With Primary Sclerosing
2019
Cholangitis: Expert Review 108
 Introduction
 Definition: primary sclerosing cholangitis (PSC) is a chronic progressive cholestatic liver disease characterized by
inflammation of the medium and large bile ducts leading to intra- and extrahepatic bile duct strictures.
 PSC is a diagnosis of exclusion. PSC strictures are not secondary to another condition such as AIDS
cholangiopathy, IGG4 associated cholangitis, and cholangiocarcinoma.
 75% of patients are males. Mean age of diagnosis is ~40 years.
 Clinical manifestations:
 Majority of patients are asymptomatic at diagnosis, and many patients present with abnormal LFTs.
 Fatigue, pruritus, signs and symptoms of cholangitis (fevers, chills, RUQ pain, hypotension).
 PSC association with IBD
 ~75% of PSC patients have UC, and ~5-10% have Crohn's disease.
 5% of UC patients and 2% of Crohn's disease patients have PSC.
 Lab findings
 Elevated ALKP, normal or elevated AST, ALT.
 Elevated PT and INR in advanced cirrhosis.
 Autoantibodies: p-ANCA is positive in 80% of patients; ANA is positive in 30%. Both are non-specific for PSC.
 Imaging: MRCP can provide diagnostic images and preclude the need for a diagnostic ERCP.
 Findings include stricturing and beading in the intra- and extrahepatic biliary tree.
 ERCP is helpful in cases of progressive jaundice/cholangitis (rule out stone, stricture, or cholangioca)
 Liver biopsy
 Liver biopsy is not required for all cases. It can confirm the diagnosis and rule out other etiologies.
 Histology shows concentric (onion skin-type) periductal fibrosis of the medium-sized and/or large bile ducts.
This finding is characteristic of PSC but is uncommon.
 Risk of malignancy 109
 Cholangiocarcinoma
 Cumulative lifetime incidence in PSC is 10-15%.
 CA19-9: In patients with PSC, a CA19-9 value of 503 U/ml was found to be the best cutoff for the diagnosis
of cholangiocarcinoma.110
 The AGA recommends screening for cholangiocarcinoma (and gallbladder cancer) using either ultrasound
or MRI every 6-12 months, combined with CA19-9 levels. 108
 Gallbladder cancer
 Lifetime cumulative risk is 2%. Yearly ultrasound is recommended by the ACG and AASLD.
 Cholecystectomy is recommended for any gallbladder polyp >8 mm in PSC (ACG)105, while AASLD
recommends it in PSC patients with a gallbladder lesion of any size (if reasonable liver function). 111
 PSC is a significant risk factor for colorectal cancer in IBD patients.
 Yearly colonoscopy is recommended in IBD-PSC patients.
 Continue yearly surveillance even after liver transplantation for IBD-PSC patients, and continue yearly
evaluation of the ileal pouch (pouchoscopy) in those who receive ileal pouch surgery. 112
 Small duct PSC
 Characterized by cholestatic liver enzymes elevation, normal cholangiography, and classic PSC findings on biopsy.
 Small duct PSC has a better prognosis than classic PSC.
 One study showed that 23% of patients will progress to large duct PSC over a median follow up of 7.4 years. 113
 The risk of cholangiocarcinoma is increased only after development of large duct PSC.
 Treatment: Ursodiol is not recommended, as it is not effective in improving important outcomes such as
mortality or the need for liver transplantation. One study found increased mortality in patients with PSC treated
with high dose ursodiol. 114
 Endoscopic therapy: stricture balloon dilation (+/- plastic stent) in patients with a dominant stricture.
 Brush cytology, biopsy under fluoroscopy or with cholangiography, and FISH testing should be obtained
as well as other workup for cholangiocarcinoma (see chapter 6, section on cholangiocarcinoma).
 PTC can be performed for difficult or proximal strictures, Roux-en-Y hepaticojejunostomy for refractory
strictures in non-cirrhotic PSC. 112
 Continuous prophylactic antibiotics are given to patients with recurrent cholangitis
 PSC patients undergoing ERCP should be given prophylactic antibiotics (give a 5-day course of quinolone
or cephalosporin-ACG conditional recommendation, low quality of evidence) 105.
 Treatment of pruritus: Cholestyramine, antihistamines, rifampin, naltrexone, SSRI, gabapentin, liver transplant.
 PSC patients are at increased risk of osteoporosis and osteopenia.
 Check bone mineral density (DEXA scan) at the time of diagnosis and q2-4 years.
 Give calcium and vitamin D for osteopenia, and bisphosphonate for osteoporosis.
 Check for fat-soluble vitamin deficiency (A, D, E, K).
 Liver transplantation is indicated in patients with PSC and advanced liver disease (high MELD score),
patients with severe uncontrolled pruritus, or those with recurrent cholangitis.
 Patient survival at 1, 5, and 10 years is estimated at 94%, 86% and 70%, respectively.115
 Recurrence of PSC is ~20% at 5 years.
Primary Biliary Cholangitis
Primary Biliary Cholangitis: 2021 Practice Guidance from

AASLD 2021
the American Association for the Study of Liver Diseases116
 Introduction
 Definition: primary biliary cholangitis (PBC, previously called primary biliary cirrhosis) is a chronic
progressive cholestatic liver disease that results from autoimmune inflammation of the small and medium
sized intrahepatic bile ducts.
 95% of patients are women. Most cases are diagnosed between ages 40-50 years.
 The most common symptom is fatigue, followed by pruritus and jaundice.
 Skin manifestations: xanthelasmas occur in 10% of patients and xanthomas in 5%.
 Associated disorders
 65% of patients have Sjögren's syndrome, 10% have rheumatoid arthritis.
 10% have one or more features of CREST syndrome (Calcinosis cutis, Raynaud's phenomenon, Esophageal
dysmotility, Sclerodactyly and Telangiectasia)
 Celiac disease (3-7%), thyroiditis, interstitial nephritis and renal tubular acidosis (rare)
 Lab findings
 Elevated ALKP, the level of elevation correlates with severity of ductopenia in those without cirrhosis
 Normal or mild elevation of ALT and AST.
 Hyperlipidemia: 50% of patients have an increase in both LDL and HDL.
 Hyperlipidemia in PBC is not associated with an increased risk of cardiovascular disease. 117, 118
 Antimitochondrial antibodies (AMA) are present in 95% of patients with PBC.
 AMAs are antibodies against the E2 component of pyruvate dehydrogenase on the inner mitochondrial
membranes. They are not cytotoxic, and not related to disease activity, and persist with treatment.
 Other antibodies: PBC-specific antinuclear antibodies (sp100 and gp210), anti-kelch-like 12 and anti-
hexokinase 1. These antibodies are present in around 30% of AMA-negative cases.
 Liver biopsy
 Ductopenia: absence of interlobular bile ducts in >50% of portal tracts.
 "Florid duct lesion" describes the finding of inflammation in the portal tract, with destruction of the
interlobular bile ducts. This finding is pathognomonic but uncommon.
 Late stages of PBC are characterized by bridging fibrosis and cirrhosis.
 Liver biopsy is not required for diagnosis in AMA positive patients with the typical biochemical profile of PBC.
 Liver biopsy is indicated in atypical cases, or if concomitant AIH is suspected.
 The combination of a positive AMA, elevated ALKP > 1.5 times the ULN, and ALT, AST levels less than
5 times the ULN, has a 98.2% positive predictive value for PBC. 119
 The diagnosis of PBC requires 2 of the following 3 criteria: (1) biochemical evidence of cholestasis (elevated
ALKP), (2) positive AMA or PBC specific ANA (sp100 or gp210), and (3) positive histology (nonsuppurative
destructive cholangitis and injury to the interlobular bile ducts).
 Autoimmune hepatitis-PBC overlap is diagnosed when 2 of the following 3 criteria are present (Paris criteria):
(1) ALT >5 ULN, (2) IgG ≥2 ULN and/or +ASMA, (3) histology with moderate or severe interface hepatitis
 Treatment
 Ursodiol (URSO®) - Ursodeoxycholic acid (epimer of chenodeoxycholic acid).
 Mechanism of action
o One of the proposed mechanisms of liver damage in PBC is the retention of bile acids inside the
hepatocytes due to bile duct inflammation and destruction.
o Ursodiol increases the export of intracellular bile acids into the canaliculus, therefore protecting the
hepatocytes from the harmful effects of bile acids. 120
 Ursodiol is the first line FDA approved treatment for PBC.
 Dose: 13-15 mg/kg/day, given once daily or divided b.i.d. It should be continued indefinitely.
 Effects of ursodiol
o Relieves fatigue and pruritus, improves liver enzymes, decreases histologic severity,
delays progression to cirrhosis, and improves survival (controversial).
 Ursodiol is more effective in patients in the early stages of PBC.
 Follow up after initiating ursodiol therapy:
o Follow ALKP level. AMA remains positive.
 In patients who do not respond to ursodiol after 6-12 months of treatment, consider inadequate dose,
autoimmune hepatitis overlap, or occult celiac disease.
 Obeticholic acid is a ligand (agonist) of the farnesoid X receptor, which plays a role in bile acid homeostasis.
It is FDA approved for the treatment of PBC in patients who do not respond to ursodiol (who took an
appropriate dose for 1 year) or in those intolerant to ursodiol.
Study highlight
A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis 121
 The PBC OCA International Study of Efficacy (POISE) was a randomized, double-blind, placebo-
controlled, 12-month phase 3 trial.
 This study enrolled 217 patients who did not have adequate response to ursodiol or who had side effects
 Patients were randomized to obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose
of 5 mg with adjustment to 10 mg as needed (the 5–10-mg group), or placebo.
 The primary endpoint was a decrease of ALKP level to less than 1.67 times the ULN, and a reduction of at least
15% from baseline, and a total bilirubin level ≤ULN at 12 months.
 Results: More patients achieved the primary end point in the 5–10-mg group (46%) and in the 10-mg group
(47%) compared to placebo group (10%) at month 12 (P<0.001).
 Pruritus was more common with obeticholic acid (56% and 68%, respectively) compared to placebo (38%), and
was commonly treated with bile acid sequestrants and antihistamine.
 Of note, obeticholic acid has not been demonstrated to improve survival, and this will be further studied during
the open label extension of the trial.
 Note: the dose of obeticholic acid in decompensated cirrhosis (Child-Pugh B and C) is 5 mg per week. Incorrect
dosing in decompensated cirrhosis (e.g. giving 5 mg daily) has been linked to increased risk of serious liver injury
and death. For this reason, AASLD discourages the use of obeticholic acid in decompensated cirrhosis. 116
 Fibrates: Bezafibrate and Fenofibrate are agonists of peroxisome proliferator–activated receptors. They can
reduce bile acid synthesis and bile acid induced inflammation.
 Bezafibrate was shown to be effective in inducing complete biochemical response in patients with PBC who
do not respond to Ursodiol. It is not available in the US. 122
 Fenofibrate is a similar medication that is available in the US but prospective data is lacking. In a retrospective
study of 120 patients, Fenofibrate (145 mg daily) was associated with biochemical response, and with
improved decompensation free and transplant free survival. 123
 A meta-analysis of multiple small studies also showed added benefit of fibrate added to ursodiol in PBC124
 Fibrates can be considered as off-label treatment for PBC.
Study highlight A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis 122

 A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis
 BEZURSO trial was a 24-month, double-blind, placebo-controlled, phase 3 trial.
 100 patients who had had an inadequate response to ursodiol were randomized to receive
bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), added to ursodiol.
 Primary outcome: complete biochemical response (normal ALKP, normal total bilirubin, AST, ALT, Albumin,
and prothrombin index) at 24 months.
 Results: The primary outcome occurred in 31% in Bezafibrate group and 0% of placebo (p<0.001).
 The itch intensity score was consistently lower in Bezafibrate group throughout the 24 months.
 Adverse events included elevated liver enzymes, CPK elevation, increase in serum creatinine levels
 Other treatment options for pruritus:

 Cholestyramine (first line for pruritus, give UDCA and other meds 1 hour before or 4 hours after cholestyramine)
 Consider rifampicin (150-300mg BID), naltrexone (up to 50 mg /day), and sertraline (75-100 mg/day)
 Patients with PBC have an increased risk of osteoporosis and bone fractures. Therefore, check bone density
scan every 2 years, and give calcium (1-1.5 gm daily) and vitamin D (1000 IU daily) supplementation.
 In patients with jaundice, monitor levels of vitamins A, D, E and prothrombin time (vitamin K) annually.
 Liver transplantation is highly successful in patients with PBC. 10-year graft survival is 71.9%. Disease
recurrence is ~30% at 10 years and 50% at 20 years.
Acute fulminant liver failure
AASLD Position Paper: The Management of

Hepatology, 2011
Acute Liver Failure 125
Intensive care of patients with acute liver failure:

Critical Care Medicine,
recommendations of the U.S. Acute Liver Failure
2007
Study Group.126
EASL Clinical Practical Guidelines on the

J Hepatol, 2017
management of acute (fulminant) liver failure 127
 Definition: the development of severe liver injury with evidence of coagulopathy (INR > 1.5) and
encephalopathy in a patient without preexisting cirrhosis and a disease duration of less than 26 weeks. 125
 Etiologies of acute liver failure (ALF)
 Drugs: acetaminophen and other drug induced liver injuries.
 Viral hepatitis: hepatitis A, B and HSV.
 Autoimmune hepatitis.
 Vascular: ischemic hepatitis, Budd-Chiari syndrome.
 Acute fatty liver of pregnancy and HELLP syndrome.
 Mushroom poisoning (Amanita phalloides)
 Phallotoxins lead to enterocyte injury and gastroenteritis.
 Amatoxins (mainly α-Amanitin) are thermostable toxins with a very low lethal dose. They inhibit RNA
polymerase resulting in necrosis of intestinal mucosa, hepatocytes, and proximal tubules of the kidney.
 Clinical features
 History of substance abuse and drug overdose. Ask about recent initiation of immunosuppressive drugs,
which could lead to a flare of underlying HBV or to an opportunistic liver infection.
 Symptoms: malaise, nausea, jaundice, abdominal pain, pruritus.
 Physical: fever, hepatomegaly, jaundice, rash. Examine for stigmata of chronic liver disease.
 Assess the mental status and the need for intubation. Encephalopathy develops due to cerebral edema and
increased intracranial pressure, rather than porto-systemic shunting.
 Labs 125
 Obtain a CBC, renal and hepatic panels, INR, Arterial blood gas, serum lactate.
 APAP level, toxicology screen, ETOH level.
 Viral serologies: HAV-IgM Ab, HBsAg, HBc-IgM Ab, HBsAb, HCV Ab, HSV-IgM Ab, CMV IgM Ab, HSV
PCR, CMV PCR, EBV serology, RPR, HIV antibody, RPR, ceruloplasmin, alpha-1 antitrypsin level.
 Autoimmune antibodies (ASMA, ANA).
 Consider Wilson's disease if age<40 yrs, with low AKLP and high bilirubin (order 24 hour -urine copper).
 Urine analysis/ drug screen. Screen for infection by blood culture, urine culture. Paracentesis if ascites present.
 Note: nonspecific CMV/HSV positive IgM is common in acute severe hepatitis, always confirm results with PCR
 Imaging
 Ultrasound with doppler or MRI/CT to rule out Budd-Chiari syndrome and check for underlying chronic
liver disease and cirrhosis.
 Consider head CT to rule out an intracranial event and for any evidence of cerebral edema.
 Absence of cerebral edema on CT scan does not rule out pathological intracranial hypertension. 128
 General Management
 Admit to the ICU for close monitoring. Monitor mental status.
 Consider elective intubation if there is advanced encephalopathy.
 Contact a transplant center and discuss possible transfer.
 Search for the underlying etiology with focus on treatable causes of ALF (table 19).
Table 19: Treatment of specific etiologies of ALF
Etiology Treatment
Tylenol toxicity N-acetylcysteine (NAC)-see page 100
Mushroom poisoning Penicillin G, silibinin IV (both inhibit toxin
(Amanita phalloides) uptake by hepatocytes) and NAC (antioxidant)
Autoimmune hepatitis IV methylprednisolone 60 mg/day
Hepatitis B Nucleotide or nucleoside analogues- see page 80
HSV or VZV hepatitis IV acyclovir
Acute fatty liver of pregnancy and HELLP Delivery
 Consider placement of an intracranial pressure (ICP) monitoring device.

 Placement of these monitoring devices is controversial and is not associated with improved survival.
Placement requires significant expertise, and there is a risk of causing intracranial hemorrhage. 128
 Management of elevated ICP (> 25 mmHg) and cerebral edema
o Quiet room. Head of bed elevation.
o Mannitol is the first line treatment of cerebral edema.
o Hypertonic saline with a goal serum sodium 145-155 meq/L can be given to high-risk patients to prevent
cerebral edema.
o Other treatment options include hypothermia, barbiturate coma.
o Goal ICP < 25 mmHg, cerebral perfusion pressure of ≥60mmHg.
o Consider EEG monitoring.
 Treatment of coagulopathy and thrombocytopenia is not recommended unless bleeding is present, or prior to
invasive procedures.
 Consider recombinant factor 7 for quick correction of INR.
 Treat coagulopathy in pregnant patients to avoid placental bleeding.
 Prophylactic antibiotics and antifungals do not improve survival, and they are not recommended.
 Give empiric antibiotics if there are signs of infection (SIRS, refractory hypotension), or progression to
severe encephalopathy. 127
 Give PPI for prophylaxis of GI bleeding.
 Vasopressors are recommended in patients with refractory hypotension (norepinephrine is preferred).
 Goal MAP ≥ 75 mmHg to achieve cerebral perfusion pressure (CPP) of 60-80 mmHg (CPP = MAP - ICP).
 Extracorporeal liver support is still experimental.
 Initial studies did not show survival benefit. Other studies with better design are underway.
 Molecular Absorbent and Recirculating System (MARS)-[albumin dialysis]:
o Uses an albumin impregnated dialysis membrane for extraction and clearance of toxins from the circulation.
 Extracorporeal Liver Assist Device (ELAD®)-[bioartificial liver]:
o Uses artificial cells (hepatoblastoma cell lines) to improve clearance and metabolism of toxins.
 High volume Plasma exchange
 Replaces the patient’s plasma with a replacement fluid.
 A prospective multicenter RCT in patients with ALF (N=182) showed that high volume plasma exchange
with fresh frozen plasma improves transplant free survival compared to standard treatment (58.7%,
47.8%, p = 0.0083).129
 Liver transplantation
 Indications for liver transplantation in ALF are shown in table 20.
o Etiologies associated with poor prognosis are idiosyncratic drug reaction, acute hepatitis B, autoimmune
hepatitis, mushroom poisoning, Budd Chiari syndrome, Wilson disease. 125
 Most patients with mushroom poisoning will require liver transplantation.
Table 20: King's College criteria for liver transplantation in ALF

Acetaminophen induced Non acetaminophen induced
 Arterial lactate > 3 mmol/L after fluid  INR > 6.5 + any grade of encephalopathy
resuscitation or
or  Any three of the following
 pH < 7.3  Age < 10 or > 40 years
or  Jaundice > 7 days before encephalopathy
 Grade 3 and 4 encephalopathy +  INR ≥ 3.5
INR > 6.5 +  Serum bilirubin ≥ 17 mg/dL
Creatinine > 3.4 mg/dL  Wilson disease or idiosyncratic drug reaction
Complications of cirrhosis and portal hypertension
Expanding consensus in portal hypertension

Report of the Baveno VI Consensus Workshop: Stratifying EASL, 2015
risk and individualizing care for portal hypertension130
Ascites
Diagnosis, Evaluation, and Management of Ascites, Spontaneous

AASLD
Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice
Guidance by the AASLD131
2021
 Paracentesis and ascites workup

 Routine tests include ascitic fluid cell count, protein, and albumin levels.
 Calculate the serum ascites albumin gradient (SAAG).
(Albumin concentration of serum minus Albumin concentration of ascitic fluid)
o SAAG ≥ 1.1 indicates portal hypertension related ascites.
● Total protein of < 2.5 g/dL: cirrhotic ascites.
● Total protein of ≥ 2.5 g/dL: post sinusoidal etiologies: cardiac ascites (congestive heart failure,
constrictive pericarditis) or Budd-Chiari syndrome.
o SAAG < 1.1 indicates non-portal hypertension related ascites.
● Total protein of < 2.5 g/dL: nephrotic ascites.
● Total protein of ≥ 2.5 g/dL: peritoneal carcinomatosis, tuberculous ascites.
 Polymorphonuclear (PMN) leukocyte count of ≥ 250 cells/mm3 is indicative of infection, which is most
commonly secondary to spontaneous bacterial peritonitis (SBP).
o Secondary peritonitis occurs in cases of bowel perforation or intra-abdominal abscess.
● In these cases, gram stain and culture of the ascitic fluid will grow multiple organisms. The ascitic
fluid will also have low glucose, high protein, and high LDH.
 Obtain ascitic fluid culture if infection is suspected. Place 5-10 ml of the ascitic fluid in blood culture
bottles (aerobic and anaerobic) at the bedside to increase the diagnostic yield of fluid culture.
 Other tests include glucose, LDH (secondary bacterial peritonitis), amylase, triglyceride levels, cytology.
 Fluid CA-125 is not helpful, and should not be ordered for any indication.
 Complementary tests based on suspected etiology of ascites: liver ultrasound and doppler, cardiac echo,
abdominal imaging (CT/MRI), laparoscopy and biopsy.131
 Treatment of cirrhotic ascites
 Limit dietary sodium to 90 mmol (2 grams) per day. For severe ascites, perform large volume paracentesis.
 Diuretics: spironolactone +/- furosemide.
 Avoid NSAIDS, ACE inhibitors, and Angiotensin receptor blockers. 131
 Measuring the 24-hour urine collection for sodium excretion can be helpful in differentiating between
diuretic resistance ascites or dietary non-compliance.
 A patient who is not on diuretics will lose weight only if the dietary sodium is limited to
< 88 meq/day, and the urinary sodium excretion is > 78 meq/24 hour (10 meq non-urinary losses). This
will create a negative sodium and fluid balance.
o Only 10% of patients can achieve diuresis without diuretics even with a low sodium diet.
 A patient who is on diuretics with a urinary sodium excretion > 78 meq/24 hours should be losing weight.
If there is no weight loss, the patient should be counseled about compliance with dietary salt restriction.
 A patient who is on diuretics and excreting < 78 meq of sodium /24 hours with no weight loss is considered
diuretic resistant.
 Some studies showed that 90% of patients with urine electrolytes analysis showing
Na/K ratio >1 have sodium excretion of > 78 meq /24 hour urine collection. 132 This can be an alternative
to performing a 24-hour urine collection. If Na/k ratio is > 1, the patient should be losing weight, unless
he/she is not compliant with sodium restriction.
 Limit or avoid NSAIDS, ACE inhibitors, or angiotensin receptor blockers as they may worsen renal function
 Diuretic resistant (refractory) ascites131
 Defined as the inability to treat ascites despite compliance with dietary sodium restriction
(< 88 meq sodium/day, confirmed by 24 hr urine sodium < 78 meq) and maximal diuretic therapy ([400
mg of spironolactone or amiloride 30 mg/day] and 160 mg of furosemide x 1 week), or development of
treatment related complications (renal failure, electrolyte imbalance (↓K, ↓Na, encephalopathy).
 Treatment
o In patients with refractory ascites, nonselective betablockers for variceal prophylaxis are not
contraindicated. However, avoid high doses (>160 mg/day propranolol and >80 mg/day nadolol). Hold
medications if there is circulatory dysfunction (systolic BP<90) or hepatorenal syndrome. 133
o Serial large volume therapeutic paracentesis (>5 L) with albumin (6-8 g of albumin for every litre of
fluid removed) are required for resistant or refractory ascites.
o Fluid restriction (<1 L) if hyponatremia is present.
o Consider other treatment options such as midodrine (7.5 mg t.i.d.)
o Consider TIPS using small diameter coated stent (<10mm) if MELD <18, no cardiac or pulmonary
disease, no encephalopathy. Sarcopenia also increases the risk of post IPS complications. 131
o Other treatments of unclear safety and benefit include indwelling peritoneal catheters, and automated
low-flow ascites pump (alfapump®) which is implanted subcutaneously and pumps ascitic fluid from
the peritoneal cavity into the urinary bladder. 134
o Refer refractory cases that are difficult to treat for liver transplantation.
 Spontaneous bacterial peritonitis (SBP)

 Ascitic fluid polymorphonuclear leukocyte (PMN) count ≥ 250 cells/mm3 in the absence of an intra-
abdominal infection secondary to a treatable surgical cause (e.g. abscess or perforation).
 It is important to sample the ascitic fluid before giving antibiotics.
 SBP can be community acquired (occurs <48 hours after admission), nosocomial (occurs >48 hours after
admission), or healthcare associated (recent hospitalization in the past 90 days).
 Treatment of active SBP
 Intravenous ceftriaxone or twice-daily PO norfloxacin for 7 days (for community acquired infection who do
not have recent exposure to antibiotics and not in septic shock)
 If nosocomial infection, recent antibiotics, or septic shock: give broad-spectrum antibiotics with
piperacillin/tazobactam.
 Give albumin on day 1 (1.5 gm/kg) and day 3 (1 gm/kg). Alternatively regimen: albumin 1gm/kg on day 1 and 2. 131
 Albumin was shown to decrease the risk of renal failure and increase survival. 135
 Guidelines recommend restricting the use of albumin to patients with SBP and any of the following:
creatinine > 1 mg/dL, BUN > 30 mg/dL, or bilirubin > 4 mg/dL. This is based on the results of a more
recent study showing benefit only in these high risk patients. 136
 Performing a repeat paracentesis to document response to treatment (↓IPMN by 25% from baseline)
 Indications for primary prophylaxis against SBP
 Patients at high risk of SBP:
 Ascitic fluid protein < 1.5 g/dL and at least one of the following:
o Serum creatinine ≥ 1.2 mg/dL , Blood urea nitrogen ≥ 25 mg/dL, serum sodium ≤ 130 meq/L
o Child-Pugh ≥ 9 points with bilirubin ≥ 3 mg/dL
 A randomized controlled trial showed that patients with the above risk factors who were treated with
norfloxacin once daily, had less SBP compared to placebo (7% vs. 61%), and less hepatorenal syndrome
(7% vs. 28%) during a 1 year follow up. 137
 Patients with a prior history of documented SBP.
 Patients with cirrhosis and gastrointestinal bleeding.
 Recommended prophylactic regimen
 Norfloxacin 400 mg once daily or trimethoprim-sulfamethoxazole one double-strength tablet once daily.
 IV ceftriaxone given in GI bleeding. Intermittent dosing is not recommended to avoid bacterial resistance.
 Hepatic hydrothorax
 Hepatic hydrothorax occurs in 5-10% of patients with cirrhosis.
 It results from translocation of ascitic fluid through congenital defects in the diaphragms.
 The diaphragm is thicker on the left side; therefore, most effusions are right sided (60-80% of cases).138
 Treatment: Sodium restriction, diuretics, thoracentesis ± paracentesis. Consider TIPS in refractory cases.
 Eligible patients should be referred for liver transplant.
 Other treatment: Surgical pleurodesis, repair of diaphragmatic defects, terlipressin, octreotide. 138
 Chest tube insertion is contraindicated, as it has been associated with complications of electrolyte
abnormalities, renal failure, and inability to remove the tube. Consider indwelling pleural catheter in those
who are not transplant candidates (associated with 10% infection risk and 2.5 risk of mortality).139
 Pleural fluid analysis with PMN ≥ 250 cells/mm3 is consistent with infected fluid (spontaneous bacterial
pleuritis) and could be present in the absence of SBP. Treat with antibiotics for 7-10 days.
 Thrombocytopenia. Avatrombopag and lusutrombopag are FDA approved to treat thrombocytopenia in adult
patients with chronic liver disease who are scheduled to undergo a procedure. Despite achieving a platelet count
> 50,000/μL, these agents did not show a reduction in bleeding episodes compared to placebo.
Portal hypertension-related bleeding (Refer to chapter 7-GI bleeding, section on GI bleeding in patients with cirrhosis)
Surgical risk assessment in cirrhosis
AGA Clinical Practice Update on Surgical Risk Assessment and

AGA, 2018
Perioperative Management in Cirrhosis: Expert Review 140
 Patients with chronic liver disease are at increased risk of surgical complications due to portal hypertension,
impaired protein synthesis, thrombocytopenia, co-existing renal dysfunction, impaired coagulation, and
impaired immune function. 140, 141
 Several factors are taken into consideration when assessing the surgical risk in patients with cirrhosis 141
 Age
 Severity of liver disease (Child-Turcotte-Pugh (CTP) score, MELD score)
 Patients with CTP class A may undergo surgery if there is no thrombocytopenia or portal hypertension.
 Patients with CTP class C should not undergo elective surgery
 Patients with MELD> 20 have a high risk of postoperative decompensation and death140
 Type of planned surgery
 Acuity of surgery (elective or emergent surgery)
 Presence of other comorbidities (renal disease, heart disease, etc...)
 American Society of Anesthesiologists (ASA) Physical Status classification (i.e. ASA score)
 Using age, ASA score, and MELD score, the Mayo Postoperative Mortality Risk Score estimates
the probability of mortality at 7 days, 30 days, 90 days, 1 year, and 5 Years.
Hepatic Encephalopathy
AASLD,
Hepatic encephalopathy in chronic liver disease practice guideline 142
EASL 2014
 Hepatic encephalopathy (HE) is brain dysfunction caused by hepatic insufficiency or portosystemic shunting,
leading to a wide spectrum of neurologic and psychiatric abnormalities 142 (table 21).
Table 21: Stages of hepatic encephalopathy
Stage Clinical manifestations
Minimal HE  Difficulty driving, abnormal psychometric testing*
 Language and verbal skills are intact
Stage 1  Trivial lack of awareness, shortened attention span, sleep abnormalities,
euphoria or depression, asterixis, tremor and incoordination
Stage 2  Lethargy or apathy, disorientation, inappropriate behavior, slurred speech,
asterixis, ataxia
Stage 3  Gross disorientation and confusion, arousable
 Asterixis is generally absent
Stage 4  Stupor and coma
*An example of a psychometric test is the trail-making test, which tests the ability of the patient to connect different circles
with numbers or letters as fast and accurate as possible.
 Management
 Obtain a detailed history and perform a thorough physical and neurologic exam.
 In patients with altered mental status in whom the diagnosis of hepatic encephalopathy is unclear, rule out
an intracranial event with a brain CT or MRI.
 Other differential diagnosis includes hypoglycemia, lactic acidosis, side effects of medications, severe
hyponatremia and other electrolyte disturbances)
 Admit for close monitoring. Consider elective intubation for advanced HE.
 Look for and treat precipitating factors:
 Hypovolemia possibly related to diarrhea and overtreatment with diuretics.
 Renal failure, GI bleeding, infections (SBP, urinary tract infection, pneumonia).
 Metabolic abnormalities: hypokalemic alkalosis, hypoglycemia.
 Medications: sedatives, narcotics, non-compliance with lactulose.
 In patients with altered mental status, a normal level of ammonia calls in question the diagnosis of hepatic
encephalopathy, however, a high ammonia by itself does not add any prognostic and diagnostic value in
patients with chronic disease. 142
 Medical treatment
 Primary prophylaxis of HE is not recommended. Prophylaxis is not recommended routinely after TIPS.
 Lactulose: Lactulose is not digested in the small intestine. It enters the colon where it is metabolized by
intestinal bacteria to short chain fatty acids. This lowers colonic pH, and favors the formation of the
nonabsorbable form of ammonia (NH4+) instead of NH3. This lowers plasma ammonia level.
o Lactulose is recommended for prevention of recurrence of HE after the first episode of HE.
 Rifaximin is a Semisynthetic analog of rifampin, minimally absorbed (oral bioavailability is < 0.4%).
o It inhibits the beta-subunit of bacterial RNA polymerase.
o A randomized, double-blind controlled trial showed that lactulose and rifaximin was more effective than
lactulose alone for the treatment of overt hepatic encephalopathy. 143
● Complete reversal of HE was achieved in 76% in the combination treatment group compared to
50% in the lactulose alone group (76% vs 50.8%, p<0.004). There was a shorter hospital stay and
lower mortality in the combination group compared to the lactulose alone group.
o Rifaximin is FDA approved for the prevention of recurrent HE. AASLD recommend adding rifaximin
to lactulose for the prevention of recurrent HE after the second episode of HE.
Study highlight
Rifaximin Treatment in Hepatic Encephalopathy 144
o Multicenter, multinational, double-blind, placebo controlled trial of rifaximin used
concomitantly with lactulose for the maintenance of remission from episodes of HE in outpatients with
a recent history of recurrent overt HE.
o Inclusion criteria: two episodes of overt HE, MELD < 25.
o Exclusion criteria: HE precipitated by GI bleeding, medications, and renal failure,
● Other exclusion criteria: anemia (Hgb < 8 gm/dL), active SBP, creatinine > 2 mg/dL,
Na < 125 mmol/L, K < 2.5 mmol/L, Ca > 10 mg/dL.
o Intervention: rifaximin 550 mg b.i.d. versus placebo.
● Lactulose was administered to ~90% of patients in both groups at baseline.
o Primary endpoint: the time to the first breakthrough episode of HE. Duration of study: 6 months.
o Results: breakthrough episodes of HE were reported in 22.1% in the rifaximin group compared to 45.9%
in the placebo group.
● The hazard ratio of recurrent HE in rifaximin group compared to placebo group was 0.42 (p < 0.001).
● Conclusion: combination rifaximin and lactulose is superior to lactulose alone for the prevention
of recurrent encephalopathy. It is important to note the strict inclusion criteria and diverse exclusion
criteria of this study. Results may not be applicable to many of our patients with HE.
Hepatorenal syndrome
 Hepatorenal syndrome (HRS) is a functional renal failure that occurs in the setting of acute or chronic liver
disease and advanced hepatic failure and portal hypertension.
 Pathophysiology: Advanced liver disease leads to circulatory dysfunction and splanchnic vasodilation. This
results in a circulatory state of perceived hypovolemia, which triggers the renin angiotensin system leading to
intrarenal vasoconstriction and renal dysfunction.
 The main precipitants of HRS are bacterial infections, most commonly SBP.
 Acute kidney injury (AKI) in cirrhosis:
 Stage 1: increase creatinine ≥ 0.3mg/dL up to 2 the baseline creatinine.
 Stage 2: increase creatinine 2 to 3 times the baseline
 Stage 3: increase creatinine > 3 times the baseline, creatinine > 4 mg/dL, or renal replacement therapy.
 Diagnostic criteria for HRS-AKI
 Cirrhosis with ascites.
 Elevated serum creatinine meeting acute kidney injury criteria
 Lack of improvement in serum creatinine after at least 2 days of holding diuretics and volume expansion
with albumin of 1 g/kg per day up to 100 g/day.
 Absence of nephrotoxic drugs, shock
 Absence of parenchymal kidney disease (urine protein < 500 mg/dL, urine RBC excretion
< 50 cells/HPF, with absence of intrinsic kidney disease on renal ultrasound).
 Etiology of acute kidney injury in patients with cirrhosis
 Two thirds of cases are due to prerenal azotemia. One third of these cases are due to hepatorenal syndrome.
 One third of cases are due to acute tubular necrosis.
 < 1% of cases are due to post-renal azotemia (obstructive uropathy).
 Treatment of AKI-HRS145
 Reduce or stop diuretics, volume replacement, stop nephrotoxic drugs (antibiotics, NSAIDs, angiotensin-
converting enzyme inhibitors,), treat underlying infections.
 Albumin (1 gram/kg/day followed by 20-40 mg/day)
 Vasoconstrictors
 Terlipressin is preferred but is not available in the US.
 Midodrine (5-12.5 mg PO every 8 hours) combined with octreotide (100-200 mcg subq every 8 hours).
 Norepinephrine infusion (0.1–1 mg/hour).
 There is limited data on TIPS use in HRS. Small studies suggest that TIPS can improve renal function in
patients who do not respond to vasoconstrictors and albumin.
 Referral for liver transplantation.
Portopulmonary hypertension
 Portopulmonary hypertension (PPH) is defined as the presence of pulmonary arterial hypertension in association
with portal hypertension, with or without liver disease. 146
 PPH is present in 2-4% of patients with cirrhosis. Incidence in males = females.
 Diagnostic criteria 146
 Mean pulmonary artery (PA) pressure > 25 mmHg at rest (or > 30 mmHg with exercise).
 Pulmonary capillary wedge pressure < 15 mmHg (indicates no left ventricular dysfunction).
 Supportive findings include increased pulmonary vascular resistance > 240 dyn·s/cm5.
 Pathogenesis
 Increased pulmonary arteriolar vasoconstriction due to decreased clearance of vasoactive substances.
 Hyperdynamic circulation in cirrhosis leads to increased pulmonary blood flow and increased shear stress
on the vascular wall. This results in vessel hypertrophy and increased pulmonary vascular resistance.
 Shortness of breath (exertional or at rest), chest discomfort.
 Physical findings: elevated JVP, tricuspid regurgitation murmur, lower extremity edema.
 Diagnosis
 Echocardiogram is the screening test of choice, with a sensitivity of 97%.
 Findings suggestive of PPH: right ventricular systolic pressure > 50 mmHg, signs of right ventricular
dysfunction (tricuspid regurgitation, right ventricular hypertrophy).
 If these findings are present, a right heart catheterization should be performed to confirm the diagnosis
using the diagnostic criteria mentioned above.
 Pulmonary function tests are normal.
 Treatment: The goal of treatment is to decrease PA pressure to < 35 mmHg.
 Nonspecific therapy includes oxygen and diuretics.
 Vasodilators (nitrates, prostacyclin analogues) need further study in patients with PPH.
 TIPS may increase PA pressure and worsen symptoms of PPH.
 Beta-blockers worsen symptoms in patients with portopulmonary hypertension.
 PA pressure > 50 mmHg is considered a contraindication to liver transplantation.
Hepatopulmonary syndrome
 Definition of hepatopulmonary syndrome (HPS): hypoxemia in a patient with liver disease and portal
hypertension resulting from increased alveolar-arterial (A-a) oxygen gradient due to intrapulmonary vascular
dilatations (IPVDs).
 HPS independently worsens prognosis in chronic liver disease patients.
 The presence or severity of HPS does not correlate with the severity of the underlying liver disease.
 Diagnostic criteria 146
 Presence of liver disease. HPS most commonly occurs in cirrhosis, but can occur at any stage of liver disease.
 Increased (A-a) oxygen gradient
 > 15 mmHg in patients < 65 years old; > 20 mmHg in patient’s ≥ 65 years old.
 Positive contrast enhanced echocardiography suggestive of IPVD (see below).
 Shortness of breath is the main symptom.
 Platypnea: shortness of breath in the upright position.
 Orthodeoxia (decrease in PaO2 > 4 mmHg or decrease in O2 saturation > 5% upon sitting upright compared
to the supine position).
 Platypnea and orthodeoxia can also occur in patients post pneumonectomy, patients with recurrent
pulmonary embolisms, atrial septal defects, and chronic lung disease.
 Physical exam may reveal spider naevi and digital clubbing.
 Diagnosis
 Arterial blood gas shows a PaO2 < 70 mmHg. Chest xray and pulmonary function tests are normal.
 Tests to demonstrate IPVDs:
 Contrast-enhanced echocardiography (microbubble study).
o A contrast agent, usually agitated saline, is injected intravenously.
o The appearance of bubbles in the left heart within 3-6 heartbeats after they appear in the right heart
indicates the presence of IPVDs.
o If bubbles appear in the left heart within three beats of injection, this suggests intra-cardiac shunting.

Nuclear scanning: technetium-labeled macroaggregated albumin study.
o This study cannot distinguish intra-cardiac from pulmonary shunt.
 Angiography can also demonstrate IPVDs. However, it is invasive and less commonly used.
 Treatment
 Oxygen therapy; liver transplantation reverses HPS.
 Patients with a PaO2 of ≤ 50 and a shunt fraction of ≥ 20% are at increased risk of postoperative mortality. 147
 Patients should have an expedited referral and evaluation for liver transplantation. 148
Benign Liver tumors
Diagnosis and Management of Focal Liver Lesions 149 ACG, 2014
Hemangioma
 Hemangiomas are the most common benign liver lesion.
 They are found in all age groups, but are more common between the third and fifth decades of life. 150
 More common in females than males.
 The size of the lesions does not correlate with the presence of symptoms. Hemangiomas are not related
to oral contraceptive pills (OCP). OCPs and pregnancy are not contraindicated. 149
 Imaging: CT scan shows peripheral arterial enhancement with gradual centripetal (towards the center)
filling of contrast. The lesion may have areas of calcification.
 Hemangiomas have no malignancy or rupture risk.
 Treatment
 Asymptomatic patients are managed conservatively and they require no specific follow up.
 Symptomatic patients are treated with surgical resection, radiofrequency ablation, or cryotherapy.
Hepatocellular adenoma
 Hepatocellular adenomas (HCA) most commonly occur in women older than 30 years old.
 Multiple hepatic adenomas (>5-10) is referred to as hepatic adenomatosis. 151
 Risk factors
 HCAs are strongly associated with OCP, especially prolonged OCP use of > 5 years.
 Other associations: anabolic steroids, hormone-containing intrauterine devices.
 HCAs may decrease in size after discontinuation of OCP.
 Obesity, DM, fatty liver.
 Pregnancy is associated with an increase in HCA size and risk of rupture.
 Glycogen storage disease type Ia, III, and Klinefelter syndrome are associated with hepatic adenomatosis.
 In patients with glycogen storage disease, HCAs show a strong male predominance.
 Genetic subtypes of HCA 152
 HCA with hepatocyte nuclear factor 1 alpha (HNF1 alpha) mutation.
 HCA with beta catenin mutation. This subtype is associated with high risk of malignancy.
 Inflammatory HCA (telangiectatic subtype).
 Risk of malignant transformation increases with size > 5 cm, glycogen storage disease, and HCAs with
beta catenin mutation.
 Risk of rupture increases with size > 5 cm, prolonged OCP, pregnancy, and subcapsular location.
 Treatment
 Discontinue OCP and remove hormone containing intrauterine devices.
 Surgical resection if the patient is symptomatic or lesion size > 5 cm.
 Women with HCA > 5 cm should avoid pregnancy.
 Women with HCA>5 who are planning to become pregnant should consider prophylactic
embolization os surgery. 6
 If such large lesions are found during pregnancy, resection should be strongly
considered due to the increased risk of rupture ,which is associated with a high maternal and fetal
mortality (44% and 38%, respectively). 153
 Pregnant women with HCA < 5 cm should be monitored with serial ultrasounds every 3 months
during pregnancy and at 3 months post-partum.
Focal nodular hyperplasia
 Focal nodular hyperplasia (FHN) is the second most common benign tumor of the liver.
 It presents as a well-circumscribed (non- encapsulated) mass with central scar in one third of patients.
 FNH is usually solitary, but can be multiple in 20% of cases.
 Characterized by nodular hyperplasia of the hepatic parenchyma around a central stellate area of
fibrosis. 154 The incomplete nodules are separated by fibrous tissue with abnormal thick walled
vessels, bile duct proliferation, and chronic inflammation. 151
 More common in females in their third and fourth decades of life
 The lesion is possibly estrogen sensitive, and patients on OCP tend to have larger lesions.
 OCPs and pregnancy are not contraindicated.
 FNH has no malignancy or rupture risk.
 FNH is usually isodense on non-contrast sequences, and becomes hyperdense in the arterial phase. The
central scar is seen in one third of patients. The lesion can also be isointense on MRI.
 The term 'stealth lesion' has been used to describe FNH because the lesions can be undetectable on
unenhanced images and only seen in the arterial phase and enhances with Gadolinium contrast.
 Biopsy is usually not required. If performed biopsy of the central scar shows abnormal thick walled
vessels, bile ductular proliferation, and normal surrounding hepatocytes.
 FNH may coexist with hemangiomas, HCA and other liver lesions in up to 20% of cases.
 Treatment
 Asymptomatic patients are managed conservatively, and require no specific follow up.
 If the patient is on OCP, monitor lesion with annual ultrasound over 2-3 years for any progression in size. 150
 Symptomatic patients are treated with surgical resection.
Hepatic cysts
 Simple hepatic cysts: usually asymptomatic, present in young adults (females > males) as a well-
defined homogenous lesion without enhancement. Treatment for symptomatic patients may include
laparoscopic de-roofing, aspiration, or sclerotherapy 155
 Hydatid cysts: caused by infection with the tapeworm Echinococcus granulosus. Human infection
results from close exposure to dogs, or consuming food contaminated by dog feces. Dogs acquire
the infection by eating infected, home-slaughtered sheep and livestock.
 Patients develop fever, pain and eosinophilia.
 Simple Xray may show cyst calcifications in the right upper quadrant. CT shows a hypodense
lesion with ring enhancement and/or calcification. Multiloculations can be present if daughter
cysts develop within the mother cyst.
 Treatment depends on the size and extent of the cyst and includes antihelmintics (albendazole or
mebendazole), aspiration and injection of a scolicidal agent, and surgery.
Nodular regenerative hyperplasia
 Nodular regenerative hyperplasia (NRH) is an uncommon condition in which the liver is grossly
transformed into nodules of 1-3 mm in size.
 Imaging studies may or may not show these nodules and it is difficult to distinguish these from the
regenerating nodules of cirrhosis. 149
 NRH has equal gender predominance. It usually affects middle-aged patients.
 Liver biopsy is usually required for diagnosis to distinguish NRH from cirrhosis.
 A special reticulin stain demonstrates nodules of hepatocytes compressed with surrounding reticulin
fibers and atrophic parenchyma. In contrast to cirrhosis, there is no fibrosis in NRH. 156
 It is thought to be the result of an adaptive hyperplastic reaction of hepatocytes with altered arterial
blood flow. NRH can lead to non-cirrhotic portal hypertension.
Primary Liver Malignancies
Hepatocellular carcinoma
Diagnosis, Staging, and Management of

AASLD, 2018
Hepatocellular Carcinoma 157
AASLD guidelines for the treatment of

AASLD, 2018
hepatocellular carcinoma 158
Liver Imaging Reporting and Data System

(LIRADS) 2018 Diagnostic Categories ACR, 2018
[for hepatocellular carcinoma]
 Hepatocellular carcinoma (HCC) accounts for 85-90% of primary liver malignancies. It is the third most
common cause of cancer death worldwide. HCC affects males > females, and Asians > Blacks > Whites.
 Risk factors: most HCCs are due to underlying HCV (45%) or HBV (15%) or both (5%).
 Hepatitis B: 10-30% of HCC cases develop in chronic hepatitis B without underlying cirrhosis.
 The risk of developing HCC increases with increasing HBV DNA level.
Study highlight Risk of hepatocellular carcinoma across a biological gradient of serum
hepatitis B virus DNA level (REVEAL study) 159
● This is a prospective cohort study of 3653 Taiwanese patients (aged 30-65 years), with a
positive HBsAg and a negative HCV Ab. Two thirds of patients were male, two thirds were > 40
years old, and 85% of patients were HBeAg (-).
● Most patients likely acquired HBV perinatally. Mean follow up of 11 years.
● The cumulative incidence rate of hepatocellular carcinoma was 1.3% among patients with HBV DNA < 300
copies/ml, and 14.9% among patients with HBV DNA > 1 million.
 There was a stepwise increase in the cumulative incidence of HCC with increasing HBV DNA level. This remained
true after adjusting for sex, age, cigarette smoking, alcohol consumption, HBeAg status, serum ALT, and liver
cirrhosis at study entry.
Despite the findings of the REVEAL study, it is not recommended to treat patients in the immunotolerant
stage of hepatitis B infection, even with a high viral load (see page 80). This is especially true for young
patients without inflammation who have a low risk of HCC.
 Patients who clear HBsAg are still at a higher risk of developing HCC compared to the general population,
but the risk is lower than those who do not clear the HBsAg. 160
 Results of another analysis from the REVEAL-HBV Study Group found that that a family history of HCC
(first-degree relative ) and HBsAg positive had a synergistic interaction with the risk of HCC (hazard ration
of 32.33, 95%CI 20.8–50.3; P < .001) compared to HBsAg positive without a family history of HCC. 161
 Other risk factors for HCC: cirrhosis of any etiology, aflatoxin exposure in food, smoking, alcohol, diabetes,
obesity, hemochromatosis.
 Possible protective factors include coffee consumption and statins.
 Clinical manifestation
 Jaundice, abdominal pain, worsening ascites or encephalopathy.
● Hypoglycemia
 Type A: This is the most common type and is generally mild. It occurs late in the disease course due to
extensive liver infiltration with malignancy and impaired gluconeogenesis.
 Type B: This is less common (< 5% of cases) but usually severe. It occurs early in the disease course
due to defective production of insulin-like growth factor (IGF) type 2.
● Cutaneous manifestation
 Pityriasis rotunda: presents as discrete, round, scaly and pigmented patches.
 Sign of Leser-Trélat: sudden onset of seborrheic keratosis associated with internal malignancy.
 Surveillance
● There are no randomized controlled trials of HCC surveillance in patients with cirrhosis.
● The only large RCT of HCC surveillance versus no surveillance was performed in China. 162
 This study included 18816 patients who had markers of current or prior HBV infection.
 Surveillance was performed with alpha-fetoprotein (AFP) and ultrasound.
 Adherence to surveillance was 58%. There was a higher detection of HCC in the surveillance group,
with 37% reduction in cancer mortality.
● HCC surveillance is recommended in the following patients: 163
 All patients with cirrhosis, regardless of etiology. AASLD suggests that patients with advanced cirrhosis
(Child Pugh C) only receive screening if they are on the transplant list due to their low anticipated
survival.
 Patients with hepatitis B without cirrhosis who meet any of the following criteria:
o Asian male hepatitis B carriers over age 40.
o Asian female hepatitis B carriers over age 50.
o Hepatitis B carrier with family history of HCC.
o African/North American Blacks with hepatitis B.
 Patients on the liver transplant list.
 Patients with chronic Budd Chiari syndrome
● In patients with hepatitis B, continue surveillance after successful treatment of HBV.
● Surveillance methods
 Ultrasound (US) every 6 months (optimal interval q4-8 months)
o Sensitivity is 65%, specificity > 90%.
 The AASLD guidelines in 2011 removed AFP as a surveillance method due to its low sensitivity and
specificity. The most recent guidelines (2018) comment that it is not possible to determine if US + AFP
is superior to US alone.157 Therefore, AFP is optional as an additional measure of screening.
 Other novel biomarkers such as AFP L3, des-gamma carboxy prothrombin (DES) are recommended by other
countries (e.g. Japan), but are not yet recommended by AASLD due to insufficient evidence for their use.
 Cross sectional imaging: MRI, triple phase CT scans. These are especially useful in obese patients in
whom ultrasound is limited
● Management of liver lesions found on surveillance ultrasound is shown in figure 4.
 Diagnosis
 Cross sectional imaging (figure 5)
 The Liver Reporting & Data System (LI-RADS) standardizes the interpretation and reporting of
multiphasic contrast enhanced CT and MR imaging findings.
 Major features of HCC: Non rim-like arterial enhancement, enhancing capsule, non peripheral washout,
growth of ≥50% increase in size in ≤6 months, and size ≥ 20mm
o Intrahepatic cholangiocarcinoma may have arterial enhancement but lacks delayed washout.
o Dysplastic nodules do not show arterial enhancement.
 Based on the radiologic appearance, Liver lesions are reported using several categories. AASLD
recommends specific management depending on the LIRAD classification (in italics)157 :
o LR-1 (definitely benign-repeat surveillance in 6 months)
o LR-2 (probably benign-repeat surveillance in 6 months or earlier)
o LR-3 (intermediate probability of malignancy-repeat imaging in 3-6 months)
o LR-4 (probably HCC, consider biopsy or repeat imaging in ≤3 months)
o LR-5 (definitely HCC-HCC confirmed, manage as HCC).
o LR-NC (non categorizable- repeat imaging in ≤3 months)
o LR-M (probably or definitely malignant but not HCC specific- consider biopsy or repeat imaging in ≤3 months)
o LR-TIV (definite tumor in vein),
 Contrast enhanced ultrasound appears to be highly sensitive and specific for HCC, but is not widely available. 164
 Alpha fetoprotein (AFP)
 AFP should not be used to diagnose HCC as it lacks specificity. 163
 Mild elevations in AFP can be seen in some cases of intrahepatic cholangiocarcinoma.165
 Staging
 The Barcelona-Clinic Liver Cancer (BCLC) staging system and management is shown in figure 6.
 All patients should be discussed in a multidisciplinary tumor board.
Figure 6: The BCLC staging system for HCC and treatment options.
CTP: Child-Turcotte-Pugh; PST: Performance status; OLT: Orthotopic liver transplantation; RFA: Radiofrequency
ablation; MWA: microwave ablation; TACE: Transarterial chemoembolization; N1: Regional lymph node involvement;
M1: Distant metastasis; TARE: Transarterial Radioembolization (AKA selective internal radiation therapy-SIRT)
(Adapted in part from Bruix, J. et al, Hepatology, 2011. 53(3): p. 1020-1022, with permission)
 Treatment
 Surgical resection is the treatment of choice in patients with HCC without cirrhosis, or patients with
compensated cirrhosis without portal hypertension and with normal bilirubin.
 Pre- and post-treatment adjuvant therapy is not recommended.
 Orthotopic liver transplantation (OLT)
Study Highlight
Liver transplantation for the treatment of small hepatocellular carcinomas in
patients with cirrhosis 166
o This pivotal study enrolled 48 patients with cirrhosis and HCC.
o All patients had either a single tumor (5 cm or less in diameter) or multiple tumors (up to three tumor
nodules, each 3 cm or less in diameter).
● These tumor criteria are referred to as the "Milan" criteria.
o All patients underwent OLT.
o After pathologic review of the explanted liver, 35 patients met the predetermined criteria.
o Results four years post OLT are shown in table 22.
o The authors concluded that OLT is an effective treatment for small unresectable HCC.
Table 22: Results four years post OLT
Overall Survival Recurrence-free survival
All patients 75% 83%
Patients who met predetermined criteria 85% 92%
Patients who exceeded predetermined criteria 50% 59%
 Other studies have confirmed that patients with HCC within the Milan criteria have an overall survival of
>70 % at 5 years post OLT.
 Patients with HCC between 2 to 5 cm or 3 nodules < 3 cm receive a MELD exception score of 22. Patients
with an HCC < 2 cm are not given exception points.
 In patients with hepatic lesions that are beyond the Milan criteria, liver transplantation should be considered
after successful downstaging into the Milan criteria. 157
 The most important predictor of recurrence of HCC is macro or microvascular invasion in the surgical specimen.
 If OLT waiting time is > 6 months, then percutaneous treatment of HCC is recommended prior to OLT.
 Percutaneous ablation is performed in patients with small tumors who are not candidates for liver
transplantation or surgical resection.
 Percutaneous ethanol injection (PEI) 163
 Ethanol is injected directly into the tumor. Efficacy depends on tumor size: Tumors < 2 cm: 90-100% necrosis
rate, Tumors 2-3 cm: 70% necrosis rate. Tumors > 3 cm: 50% necrosis rate.
 Patients who achieve successful necrosis of the lesion have a 5-year survival of 50%.
 Thermal ablation utilizes heat to destroy cancer tissue. It is preferred over PEI, especially for lesions >2 cm.
 Radiofrequency ablation (RFA): In this method, heat is generated by passing electrical current through the
tumor and surrounding tissues. The technique is limited in large lesions because of difficulty passing
electrical current through desiccated tissue that has high impedance.
 Efficacy is similar to PEI in lesions < 2 cm. However, it requires less treatment sessions. RFA is superior
to PEI in patients with lesions > 2 cm.
 The 5-year survival is 70%.
 RFA is generally avoided in subcapsular lesions, as there is an increased risk of peritoneal seeding.
 Outcomes in patients with solitary HCC < 2 cm treated with RFA are similar to surgical resection.
 Microwave ablation (MWA): Induces thermal destruction of the lesion using alternating electromagnetic
field that propagates through the tumor tissue. It is not limited by the impedance of the desiccated tissue. 167
 MWA requires shorter ablation time, and achieves higher ablation temperature, and larger ablation zone
compared to RFA. A Prospective study comparing MWA to RFA in HCC< 4 cm showed similar efficacy
and 2-year progression for both techniques.168
 Transarterial chemoembolization (TACE)
 Selective arterial embolization combined with selective injection of a chemotherapeutic agent
(doxorubicin, cisplatin, mitomycin) mixed with a contrast agent.
 Improves survival in patients with intermediate stage HCC.1-year survival: 80%; 2-year survival: 60%.
 Contraindications: portal vein thrombosis, extrahepatic spread.
 Complications: Nausea, vomiting, abdominal pain.
o Post-embolization syndrome: Patients present with fever, abdominal pain, and ileus.
o Treatment is supportive. It resolves in most patients within 48 hours.
 Other forms of embolotherapy for HCC:169
 Arterial embolization: disruption of blood supply leading to tumor ischemia.
 Drug eluting bead chemoembolization: administration of drug loaded microspheres leading to sustained
tumor drug delivery and tumor ischemia.
 Transarterial radioembolization (TARE): delivery of microspheres impregnated with a radioisotope (e.g.
yttrium-90- y90) leading to high dose and targeted tumor radiation.
 Also called selective internal radiation therapy (SIRT)
 Chemotherapeutic medications for advanced stage (C) disease:
 FDA approved first line treatments are atezolizumab plus bevacizumab, Sorafenib, Lenvatinib.
 FDA approved second line treatments: Regorafenib, Nivolumab, Nivolumab plus ipilimumab,
pembrolizumab¸ cabozantinib, ramucirumab
 Palliative care is appropriate in cases with advanced disease, CTP class C or performance status > 2.
Fibrolamellar HCC
 Fibrolamellar HCC is an uncommon malignant tumor of the liver, with distinct epidemiologic and clinical
features compared to classic HCC.
● It occurs in younger patients compared to classic HCC, with equal gender predominance.
● Most patients do not have chronic hepatitis or cirrhosis.
● AFP is normal. Plasma neurotensin and serum vitamin B12 binding globulin are frequently increased in
fibrolamellar HCC.
 CT shows a hypodense, well-circumscribed mass.
● Up to 70% of tumors have a central scar that enhances on delayed imaging.
● Most tumors are large (>10 cm).
 Histology shows malignant hepatocytes with abundant eosinophilic cytoplasm, separated by a lamellar pattern
of fibrosis.
 Fibrolamellar HCC has a better prognosis compared to classic HCC.
● 5-year survival after partial hepatectomy is ~70%. 170
Intrahepatic cholangiocarcinoma
 Intrahepatic cholangiocarcinoma (ICC) is the second most common liver malignancy, comprising ~10% of
primary liver cancers, and 20% of all cholangiocarcinomas.
 The incidence of ICC is increasing. The age adjusted incidence increased from 0.32 per 100,000 in 1975–1979
to 0.85 per 100,000 in 1995–1999 time periods.171
 ICC arises from the cholangiocytes of small intrahepatic bile ducts or bile ductules.
 Risk factors include PSC, liver cirrhosis, HBV, HCV (stronger risk factor than HBV), choledochal cysts,
hepatolithiasis, and recurrent pyogenic cholangitis.
 Presents with dull right upper quadrant pain, weight loss, abnormal liver enzymes, or liver mass.
 Diagnosis: CT/MRI, biopsy of the liver mass. AFP can be elevated in ICC.
 Treatment options
 Surgical resection in patients with small, resectable tumors.
 Advanced tumors: chemoradiation, locoregional therapy (TACE or RFA).
 Advanced or metastatic tumors: systemic chemotherapy with gemcitabine and cisplatin. 172
 Liver transplantation is performed in some expert centers but remains experimental at this time.
Liver transplantation
Evaluation for Liver Transplantation in Adults: 2013 Practice

Guideline by the AASLD and the American Society of AASLD, 2013
Transplantation 173
Long-Term Management of the Successful Adult Liver Transplant:
2012 Practice Guideline by the American Association for the Study AASLD, 2012
of Liver Diseases and the American Society of Transplantation 174
 The most common indications for liver transplantation in patients with cirrhosis are alcoholic liver disease
(40%), non-alcoholic steatohepatitis (30%), and hepatitis C cirrhosis (20%).175 Overall survival post orthotopic
liver transplantation (OLT): 90% at 1 year, 80% at 3 years, and 75% at 5 years.
 In patients with hepatocellular carcinoma, HCV is the most common indication for liver transplantation,
 Immunosuppressive drugs used post OLT are shown in table 23 (the first five are the most important).
Table 23: Immunosuppressive drugs

Medication Mechanism of action Side effects and toxicity
Prednisone Cytokine inhibitor (↓IL-2, ↓IL-6, HTN, DM, osteoporosis,
↓INF-γ) psychiatric side effects,
dyslipidemia, cataracts
Cyclosporin Cyclic peptide that binds cyclophilin→ Renal toxicity, hirsutism,
(Neoral®) inhibits calcineurin→ reduces gingival hyperplasia, neurologic
transcription of IL-2, TNF-α, INF-γ side effects (headache,
genes→ inhibits lymphocyte paraesthesia)
proliferation176
Tacrolimus Macrolide antibiotic, binds Hypertension, renal toxicity,
(Prograf®) FK-binding protein→ inhibits neurotoxicity
calcineurin similar to cyclosporin
Sirolimus Macrolide antibiotic, binds Neutropenia, thrombocytopenia,
(Rapamune®) FK-binding protein →inhibits mTOR* impaired wound healing,
Everolimus (Zortress®) (a kinase involved in signal possible prothrombotic effect
transduction pathways for IL-2 (hepatic artery thrombosis) 177
receptor)→ inhibits T and B cell
proliferation177
Mycophenolate mofetil Inhibits purine synthesis (by inhibiting Bone marrow suppression,
(CellCept®) & inosine monophosphate GI side effects (nausea,
Mycophenolate sodium dehydrogenase) → inhibits T and B abdominal pain, diarrhea)
(Myfortic®) cell proliferation
Antithymocyte globulin Polyclonal animal derived antibodies Fever, chills, anemia, serum
(ATG)(Genzyme®, to multiple T cell antigens (CD2, CD3, sickness
Atgam®) CD4, CD8)
Antilymphocyte globulin
(ALG)(Lymphoglobulin)
Muromonab-CD3 Monoclonal anti-CD3 antibody Cytokine-release syndrome
(Orthoclone OKT3®) (pulmonary edema, fever,
rigors) and GI toxicity 177
Basiliximab (Simulect®) Monoclonal anti-IL2 receptor antibody Anaphylaxis and
& Daclizumab (anti-CD25) hypersensitivity, cytokine
(Zenapax®)† release syndrome less common
* mTOR: mammalian Target of Rapamycin † Withdrawn from the market in 2009
 Drug-drug interactions (tables 24 and 25)
 Cardiovascular risk factors are very prevalent in LT recipients (hypertension, diabetes, hyperlipidemia,
obesity, dyslipidemia, and smoking) and can lead to coronary artery disease and chronic kidney disease. 174
 Hypertension post liver transplant is common.
 It could be related to treatment with steroids and calcineurin inhibitors.
 First line treatment is with the newer generation calcium channel blockers (amlodipine, felodipine, and
nicardipine), which do not alter calcineurin inhibitor levels.
 The differential diagnosis if elevated liver enzymes is broad and include graft rejection, recurrent hepatic
disease, drug toxicities, alcohol, malignancy, NAFLD, viral/bacterial infections, vascular disease (hepatic
artery thrombosis, splanchnic venous thrombosis).
 Assess for metabolic bone disease by measuring bone mineral density (DEXA scan), calcium, vitamin D, PTH
and Thyroid hormone levels
 Screen for skin cancer: dermatology screening annually starting 5 years after LT
 Other malignancies: colon, breast, prostate, post-transplant lymphoproliferative disease (PTLD).
 Avoid live vaccinations; give annual influenza vaccine, and pneumococcal vaccine (repeated every 3-5 years).
Table 24: Important drug interactions with cyclosporin and tacrolimus

Drugs that increase blood levels Drugs that decrease blood levels
 Antifungals  Antiepileptics
 Fluconazole, ketoconazole, voriconazole, itraconazole,  Phenytoin, carbamazepine,
posaconazole phenobarbital
 Antibacterials  Antacids
 Erythromycin, clarithromycin, azithromycin, levofloxacin  Magnesium hydroxide, sodium
 First generation calcium channel blockers bicarbonate
 Verapamil, diltiazem, nifedipine  Antibacterials
 Food: Grapefruit juice  INH, rifampin, nafcillin
 Protease inhibitors  Others
 Nelfinavir, saquinavir, lopinavir/ritonavir  Cinacalcet, sevelamer
 Others: Bromocriptine, allopurinol, metoclopramide  Herbal preparations
 St John's wort
Table 25: Clinically relevant drug interactions with mycophenolate mofetil

Drugs that increase blood levels Drugs that decrease blood levels
 Antivirals  Antacids: Magnesium hydroxide, sodium
 Acyclovir, ganciclovir, valacyclovir bicarbonate
 Others  Antibacterial: Norfloxacin, metronidazole,
 Rosiglitazone rifampin
 Supplements: Iron sulfate
 Others: Cholestyramine, sevelamer
 Biliary complications after liver transplantation are discussed in chapter 5-biliary tract.
17. Bacon BR, Adams PC, Kowdley KV, Powell LW,

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Clinical gastroenterology and hepatology : the official
133
CHAPTER
5
Biliary Tract
Chapter 5- Biliary tract
Biliary tract disorders account for 10% of the GI boards' questions. Choledochal cysts are
occasionally encountered in young patients with right upper quadrant pain, or found incidentally
on imaging studies. It is important to be aware of the malignant potential of some of these
congenital anomalies. If you perform ERCPs, it is important to know the different anatomic
variants of the biliary tree. In patients with suspected choledocholithiasis, use the scoring system
suggested by ASGE to predict the likelihood of common bile duct stones (updated in 2019), and
order non-invasive imaging studies (e.g.MRCP) in the appropriate patients.
Cholangiocarcinomas remain a challenge to diagnose, especially in early stages. Combining

different modalities to maximize tissue acquisition increases the diagnostic yield. Biliary
complications of liver transplantation are discussed in this chapter. This is an important topic
for the boards. ERCP in pregnancy, complications of ERCP, and advanced techniques of biliary
cannulation are discussed separately in chapter 11-endoscopy.
134 Chapter 5: Biliary Tract
Contents
Chapter 5- Biliary tract

Anatomy and developmental anomalies—135
Bile duct anatomy—135
Pancreaticobiliary maljunction—135
Choledochal cysts—136
Gall bladder disease—137
Gallstones—137
Sphincter of Oddi dysfunction—138
Choledocholithiasis—138
Gallbladder polyps—139
Cholangiocarcinoma—139
Biliary complications after liver transplantation—140
Biliary strictures—141
Bile leak—142
References—143
Chapter 5: Biliary Tract 135
Anatomy and developmental anomalies
Bile duct anatomy

 Figure 1 shows the anatomical variations of the intrahepatic bile ducts.
 Knowledge of the different configurations is important for accurate interpretation of cholangiograms and
planning intervention during ERCP.
Figure 1: Anatomic variations of the

intrahepatic ducts. CHD: common hepatic
duct; RHD: right hepatic duct; LHD: left hepatic
duct; RPSD: right posterior segmental duct;
RASD: right anterior segmental duct; CD: cystic
duct.
Pancreaticobiliary maljunction
 Pancreaticobiliary maljunction (PBM) is also called abnormal pancreaticobiliary junction, pancreatic-biliary
malunion.
 In this malformation, the common bile duct (CBD) and pancreatic duct (PD) join each other outside the
duodenal wall forming a long common channel (CC), which is usually > 6 mm in length. 1
 In 75%, this is associated with biliary ductal dilation and choledochal cysts.
 Komi classification of the PBM is shown in figure 2.
● Type 1: The CBD and PD join each other at a right angle
 1A: without CC dilation; 1B: with CC dilation
● Type 2: The CBD and PD join each other at an acute angle
 2A: without CC dilation; 2B: with CC dilation
● Type 3: Complex pattern with patent accessory pancreatic duct.
 3A: Pancreas divisum with CBD dilation
 3B: Pancreas divisum with absent ventral PD (Wirsung)
 3C-1: Pancreas divisum with small duct connecting main and
accessory pancreatic ducts.
 3C-2: Common channel of main and accessory PD of equal size
 3C-3: Complete or partial dilation of the pancreatic ductal system
 PBM is associated with reflux of pancreatic secretions into the bile
duct leading to chronic inflammation and increase risk of biliary
malignancy.
 The dilated common channel and reflux of bile into the pancreatic
duct may increase the risk of pancreatitis. Figure 2: Komi classification of
 In patients with PBM, there is an increased risk of gallbladder pancreaticobiliary maljunction
cancer; therefore, prophylactic cholecystectomy should be strongly
considered. 1
Choledochal cysts
 Figure 2 shows the classification of choledochal cysts.
 Table 1 summarizes the appearance of different types
of choledochal cysts and their management.
 Clinical manifestations: Abdominal pain, recurrent
cholangitis, obstructive jaundice.
 Think of choledochal cysts in patients with CBD dilation
without evidence of an obstructing stone or mass.
 There is an increased risk of malignancy in
choledochal cysts type 1, 4, and 5.
 The most common cancer is cholangiocarcinoma.
Other associated malignancies include anaplastic,
undifferentiated, and squamous cell carcinoma.2 Figure 3: Types of choledochal cysts.
 The overall lifetime risk of malignancy is 10-15%,
which represents a 20-30 fold increase compared to the general population. The risk increases with
increasing age.
 Choledochal cysts are often associated with an abnormal Pancreaticobiliary junction (see page 135).
 The pancreatic duct drains into the bile duct, leading to pancreatic reflux and chronic inflammation, which
increases the risk of malignancy of the bile duct and gallbladder.
Table 1: Choledochal cysts

Type Description Frequency Management
IA*  Cystic dilation of the entire extrahepatic 50-85%  Complete excision and
biliary tree, sparing the intrahepatic bile hepaticojejunostomy
ducts
 The cystic duct arises from the dilated CBD
IB  Focal, segmental dilation of the extrahepatic
bile duct
 The cystic duct arises from a normal CBD
1C  Fusiform dilation of the entire extrahepatic
biliary tree, extending to the intrahepatic
bile ducts
 The cystic duct arises from the dilated CBD
II  True diverticulum of the extrahepatic bile 2%  Simple cyst excision
duct  Risk of malignancy is low
III  Also called "choledochocele" 1-5%  Sphincterotomy
 Dilation of the distal CBD limited to the  Risk of malignancy is low
intraduodenal portion of the CBD
IVa  Multiple intra- and extrahepatic bile duct 15-35%  Cyst excision and
dilations (cystic or fusiform) hepaticojejunostomy
IVb  Multiple dilations of the extrahepatic biliary  Segmental hepatectomy of
tree localized intrahepatic liver
involvement
V  Multiple dilations of the intrahepatic bile 20%  Consider segmental
ducts (Caroli disease†) hepatectomy if localized
 Liver transplantation
*Type 1a is the most common type
†Caroli syndrome is Caroli disease combined with congenital hepatic fibrosis. It is a rare congenital syndrome
usually associated with polycystic kidney disease.3
Gall bladder disease
Gallstones
 Cholesterol stones are the most common type in adults (composed of cholesterol monohydrate crystals)
 Pigment stones are composed of calcium bilirubinate crystals. Black stones are associated with chronic
hemolytic anemia. Brown stones are associated with biliary stasis and infection.
 Risk factors: older age, female gender, pregnancy and postpartum, obesity, rapid weight loss, TPN, DM,
cirrhosis, Crohn's disease. Drugs: estrogen, OCP, somatostatin analogues, ceftriaxone, clofibrate.
 Clinical presentation and complications
● Asymptomatic: the risk of developing biliary pain in asymptomatic patients is 2% per year.
● Biliary pain has a rapid onset and is typically located in the epigastrium or the right upper quadrant. The pain is
constant and lasts for several hours. The term "biliary colic" is a misnomer, as the pain is not colicky in nature.
● Other complications: Cholecystitis, choledocholithiasis and cholangitis, gallstone pancreatitis.
● Rare presentations
 Mirizzi's syndrome refers to an impacted cystic duct stone obstructing the common hepatic duct.
 Gallstone ileus results from a large gallstone obstructing the terminal ileum. The gallstone enters the
small bowel through a gallbladder-enteric fistula associated with cholecystitis.
 Bouveret's syndrome: gastric outlet obstruction due to impaction of a gallstone in the pylorus or duodenum.
● Diagnosis: Gallbladder (GB) ultrasound is highly sensitive and specific for gallstones, but only 50%
sensitive for choledocholithiasis. Other tests include CT, MRI/MRCP, EUS, ERCP, HIDA.
 Treatment: Prophylactic cholecystectomy is not recommended for asymptomatic gallstones in the general
population, nor in patients with diabetes or chronic hemolytic anemia.
● Prophylactic cholecystectomy is recommended for the following groups of patients:
 Patients with GB wall calcifications also referred to as "porcelain gallbladder".
o The risk of coexisting GB malignancy is ~ 20%. 4
 Patients with an abnormal pancreatobiliary junction (due to increased risk of gallbladder cancer, see page 135)
 Patients with GB polyps > 10 mm.
 Astronauts with gallstones before long duration space missions (controversial). 5
 American Indians (high risk of gallbladder cancer).
 For morbidly obese patients undergoing bariatric surgery, cholecystectomy is usually performed at the
time of surgery. Ursodiol was shown to decrease the risk of formation of gallstones post bariatric surgery
in patients who did not undergo cholecystectomy.
 Patients who undergo resection of small intestinal neuroendocrine tumors who are planned to undergo treatment
with somatostatin analogues (due to the increased risk of cholelithiasis and complications in patients on these
medications.
● In patients with cholecystitis who are too sick to undergo cholecystectomy, options for gallbladder drainage
include percutaneous cholecystectomy, endoscopic ultrasound-guided gallbladder drainage, or endoscopic
transpapillary drainage.6
● Bile leak following cholecystectomy
 Bile leak complicates ~0.5-2.5% of laparoscopic cholecystectomies.
 The most common site of leakage is the cystic duct stump or the ducts of Luschka.
 Diagnosis: US, CT, HIDA, or increased bilirubin level in the peritoneal drain fluid.
 Treatment: ERCP with stent placement, with or without a sphincterotomy.
Sphincter of Oddi dysfunction

 Sphincter of Oddi dysfunction (SOD) is suspected in patients with
biliary type pain after cholecystectomy, and less commonly in
those with intact gallbladder and no stones, idiopathic recurrent
pancreatitis, and AIDS cholangiopathy
 Historically it has been classified as types 1, 2, 3 (see figure 4).
 New terms have been proposed for these subtypes.
● Type 1 SOD is now referred to as “sphincter of Oddi stenosis”
because there is likely mechanical obstruction at the biliary
sphincter. The treatment of choice is sphincterotomy.
● Type 2 SOD have less clear obstruction, and may have spasm at
the sphincter. This is referred to as “suspected functional biliary
Figure 4: Old and new
sphincter disorder”. Rome IV criteria for this disorder are: Biliary pain, classification and terminology for
dilated CBD or elevated liver enzymes, absence of choledocholithiasis Sphincter of Oddi dysfunction.
or structural abnormalities. Supportive criteria are normal LE: liver enzymes. CBD: Common Bile
amylase/lipase and abnormal sphincter of Oddi manometry.7 Duct.
 In these patients, rule out organic disease with endoscopy and imaging (CT/MRI/EUS).7 Other workup
may include ERCP and manometry ± sphincterotomy, HIDA (assess bile excretion to the duodenum).
 Empiric sphincterotomy should be considered. Medical treatment with uncertain benefits: TCA,
duloxetine.
● The EPISOD trial found no benefit of sphincterotomy for SOD type III (biliary pain with no duct dilation
and no liver enzymes elevation) compared to sham intervention.8 Therefore, type 3 SOD has been abandoned
and these patients are considered to have functional pain.
Choledocholithiasis
ASGE guideline on the role of endoscopy in the evaluation and Gastrointestinal

management of choledocholithiasis9 endoscopy, 2019
Updated guideline on the management of common bile duct

GUT 2017
stones 10
● Abdominal ultrasound and liver function tests should be ordered for basic workup. Consider cross
sectional imaging in older patients with obstructive jaundice to rule out biliary malignancy.
● In suspected choledocholithiasis (biliary pain, elevated liver enzymes, gallstone pancreatitis), use the following
scoring system (table 2) to decide on further biliary workup prior to cholecystectomy.
Table 2: Predictors of choledocholithiasis and corresponding management (ASGE, 2019)9
Predictors of choledocholithiasis in patients Probability of
Management
with symptomatic gallstones choledocholithiasis
 CBD stone on abdominal imaging High Proceed with preoperative
 Clinical diagnosis of cholangitis ERCP
 Both: Bilirubin > 4 mg/dL and dilated CBD
 Abnormal liver enzymes Intermediate Preoperative EUS, MRCP, or
 Age > 55 intraoperative laparoscopic
 Dilated CBD (>6 mm if intact GB, cholangiogram
>8 mm if history of cholecystectomy)
 No predictors Low Proceed with
cholecystectomy
Gallbladder polyps
 Etiology: Non-neoplastic growths are the most common type.
 Cholesterolosis: villous hyperplasia of the gallbladder mucosa associated with infiltration of the lamina
propria with lipid laden foamy macrophages.
 Adenomyomatosis: thickened mucosa with invaginations into the muscularis propria.
 Inflammatory polyps
 Neoplastic growths such as adenomas are uncommon.
 The risk of malignancy is significantly increased in patients with polyps > 10 mm in size.11 Cholecystectomy
should be performed in these patients.
 Follow up ultrasound every 6-12 months is recommended in poor surgical candidates and for polyps smaller
than 10 mm.
Cholangiocarcinoma
 Risk factors of cholangiocarcinoma: Primary sclerosing cholangitis (cumulative incidence of ~9% after 10
years),12 Lynch syndrome, choledochal cysts, Caroli disease, hepatolithiasis, hepatobiliary infections with liver
flukes such as Opisthorchis viverrini and Clonorchis sinensis, hepatitis C.
 Location:
 Extrahepatic cholangiocarcinoma (80%)
 Distal: accounts for 30% of extrahepatic tumors.
 Perihilar: accounts for 70% of extrahepatic tumors.
 Intrahepatic cholangiocarcinoma (20%):
 Refer to chapter 4-liver, section on intrahepatic cholangiocarcinoma.
 Clinical manifestations: jaundice, abdominal pain, itching, weight loss, fever.
 Imaging: CT, MRI, EUS can show a mass or a biliary stricture and ductal dilation.
 Differential diagnosis of the indeterminate biliary stricture (with or without a mass):
 Malignant disease: cholangiocarcinoma, hepatocellular carcinoma, gallbladder carcinoma, metastatic
disease, lymphoma.
 Benign disease: Primary sclerosing cholangitis, IgG4 cholangiopathy, Mirizzi syndrome, radiation induced
strictures, ischemic stricture, post-operative stricture).
 Diagnosis
 CA19-9 has a moderate specificity as a tumor marker for cholangiocarcinoma.
 The presence of cholestasis and cholangitis lowers specificity.
 At a serum cutoff level of ≥ 180 U/mL: sensitivity 53-79%, specificity 83-98%.
 At a serum cutoff level of ≥ 37 U/mL: 13
o In the absence of cholangitis: sensitivity 78%, specificity 83%.
o In the presence of cholangitis: specificity 42%.
 In patients with PSC, one study found that a CA19-9 value of 503 U/ml was the best cutoff value for
the diagnosis of cholangiocarcinoma.14
 Tissue acquisition in suspected malignant biliary strictures remains suboptimal (table 3).
 Combining different techniques increases the diagnostic yield.
 A recent prospective randomized, multicenter trial (n=60) compared (A) digital single operator
cholangioscopy (DSOC) and targeted biopsy, with (B) standard group of ERCP and brush cytology in
patients with indeterminate hilar biliary strictures (i.e. Excluding distal CBD strictures). 15
o The sensitivity for malignancy was higher in the DSOC group 68.6% compared to 21.4% in the standard
group. There was no statistically significant difference in specificity, positive or negative predictive value,
and overall accuracy.
 Treatment
 Biliary drainage with ERCP with stenting is the treatment of choice.
 Refer to chapter 11-endoscopy for the Bismuth-Corlette classification of perihilar tumors.
 Percutaneous transhepatic cholangiography can be performed if ERCP is unsuccessful.
 Surgical treatment
 Pancreaticoduodenectomy (Whipple) for distal cholangiocarcinoma.
 Local bile duct resection and segmental hepatectomy for proximal or perihilar tumors.
 Adjuvant chemoradiation is given for patients with positive margins or lymph node metastasis.
 Patients who are not surgical candidates receive systemic chemotherapy with gemcitabine and cisplatin.16
o Neoadjuvant chemoradiation followed by transplantation for hilar cholangiocarcinoma is being
performed in selected patients at few transplant centers. This was shown to have a 5-year recurrence
free survival of 65%.17
Table 3: Tissue acquisition modalities in cholangiocarcinoma

Modality Performance characteristics*
Retrieved stent cytology Sensitivity 7-30%
Brush cytology Sensitivity 42%, specificity 98%, PPV 98%)18
Improved by digital image analysis (DIA) and
fluorescence in-situ hybridization (FISH) †
Forceps biopsy (under fluoroscopy) Sensitivity 56%, specificity 100%, PPV 100%18
Cholangioscopy and targeted biopsy Sensitivity 68-100%, specificity of 87-96%19
EUS-FNA ‡ Sensitivity varies between 43%- 89% for indeterminate
biliary strictures 20
Lower sensitivity in proximal tumors and patients with
stents
Multimodal tissue acquisition
Brush cytology and biopsy Sensitivity 86% 21
Brush cytology, FNA, and forceps biopsy Sensitivity 77% 22
PPV: positive predictive value.
*Numbers are reported from multiple studies.
†Both techniques assess the nuclear DNA content and aneuploidy to diagnose malignancy
23
‡EUS-FNA of the primary hilar tumor should be avoided as it can result in disease dissemination
Biliary complications after liver transplantation

 Types of biliary anastomosis: Duct to duct anastomosis and Roux-en-Y choledochojejunostomy.
 There is a similar rate of complications in patients with a duct-to-duct anastomosis compared to
choledochojejunostomy.
 In PSC patients, choledochojejunostomy is the preferred anastomosis.
 The most common biliary complications include biliary strictures (anastomotic and non-anastomotic), bile
leaks, biliary stones, and casts.
 Biliary complications can develop after living donor liver transplantation (LDLT) or deceased donor liver
transplant (DDLT)
 The small diameter of the anastomosed bile ducts leads to a higher rate of anastomotic strictures.
 Bile leakage can result from the cut surface of the liver.
 Bile leaks occur in up to 10% of donors.
 Right liver graft recipients have higher rates of complications compared to left liver graft recipients.
Biliary strictures
● Obtain a good clinical history. Determine the type of biliary anastomosis.
● Most strictures present in an asymptomatic patient with elevated liver enzymes.
● Non-specific symptoms include pruritus and jaundice.
 Workup
● Doppler ultrasound to rule out hepatic artery thrombosis.
● MRCP, ERCP, or PTC (for choledochojejunostomy strictures).
 Anastomotic strictures account for 80% of all strictures.
● Occur in 5-15% of patients. These strictures are short and limited to the anastomosis.
● Most strictures present in the first year after transplant.
● Bile leaks are a risk factor for anastomotic strictures.
● Treatment
 ERCP with balloon dilation to 6-8 mm followed by stenting is the treatment of choice for duct-to-duct
anastomotic strictures. Repeat ERCP every 6-8 weeks maximum 3 months).
 Most patients require 3-5 ERCP sessions.
 Other therapeutic options during ERCP: placement of multiple plastic stents (two or more stents side
by side through the stricture), placement of a fully covered metal stent (off-label use, not proven to
improve outcomes compared to plastic stents, high risk of migration ~16%)24.
● Prognosis
 Long-term success rate is 70-100%.
● Choledochojejunostomy strictures are treated with percutaneous dilation and stent placement.
 In specialized centers, ERCP for choledochojejunostomy strictures can be performed using the
pediatric colonoscope or balloon-assisted enteroscopy. However, this is technically challenging and
requires special ERCP instruments.
 Non-anastomotic strictures account for 20% of all strictures.
● Occur in 1-10% of patients. These strictures affect the hilum, intrahepatic and extrahepatic bile ducts
proximal to the anastomosis.
● Risk factors25
 Ischemic strictures develop secondary to hepatic artery thrombosis.
o These present within 1 year after transplantation.
 Immunogenic: ABO incompatibility, autoimmune hepatitis, PSC.
o These usually present after 1-year post transplantation.
 Other risk factors: prolonged cold and/or warm ischemia time, donation after cardiac death.
● Treatment:
 ERCP with balloon dilation and stenting is the treatment of choice. Due to the diffuse nature of these
strictures, multiple plastic stents are usually required.
 PTC can be used for refractory intrahepatic strictures
 Prognosis
● Non anastomotic strictures are more complex and more difficult to treat compared to anastomotic
strictures. Most strictures persist despite treatment.
● Patients may develop repeated episodes of cholangitis and biliary cirrhosis or atrophy of the involved lobe.
● Up to 46% of patients eventually develop graft loss and 30% require re-transplantation.26
● Patient survival is not affected.
Bile leak
 Incidence ranges from 2%-25% after liver transplantation.
 Potential sites of biliary leakage include the anastomosis, cystic duct remnant or the cut surface of the liver in LDLT.
 Clinical manifestations: fevers, chills, abdominal pain, elevated liver enzymes.
 Diagnosis
 HIDA scan is a non-invasive test that has good accuracy in detecting bile leaks.
 Cross sectional imaging with CT and MRI may reveal a bile collection (biloma).
 In patients with equivocal findings, ERCP is indicated for diagnosis and treatment.
 Treatment
 ERCP with sphincterotomy and stent placement is indicated in all cases of bile leaks.
 Repeat ERCP for stent removal or exchange in 2-3 months. 27
o Due to slower healing in liver transplant patients, stents are kept for a longer duration compared to
those placed for bile leaks following cholecystectomy.
o More than 90% of bile leaks will resolve on repeat ERCP.
 For large biliary collections, percutaneous drainage is required.
 Surgery is reserved for refractory cases.
References
1. Le Roy B, Gagnière J, Filaire L, et al. analysis using a receiver operating characteristic

Pancreaticobiliary maljunction and choledochal curve. Am J Gastroenterol 1999;94(7):1941-6.
cysts: from embryogenesis to therapeutics 14. Sinakos E, Saenger AK, Keach J, Kim WR,
aspects. Surg Radiol Anat 2016;38(9):1053-60. Lindor KD. Many Patients With Primary
2. Singham J, Yoshida EM, Scudamore CH. Sclerosing Cholangitis and Increased Serum
Choledochal cysts: part 1 of 3: classification and Levels of Carbohydrate Antigen 19-9 Do Not
pathogenesis. Can J Surg 2009;52(5):434-40. Have Cholangiocarcinoma. Clin Gastroenterol
3. Bawany MZ, Alaradi O, Nawras A. Caroli's Hepatol 2011;9(5):434-39.e1.
syndrome in a post renal transplant patient: case 15. Gerges C, Beyna T, Tang RSY, et al. Digital
report and review of the literature. Saudi J single-operator peroral cholangioscopy-guided
Gastroenterol 2012;18(1):59-61. biopsy sampling versus ERCP-guided brushing
4. Schnelldorfer T. Porcelain Gallbladder: A for indeterminate biliary strictures: a prospective,
Benign Process or Concern for Malignancy? randomized, multicenter trial (with video).
Journal of Gastrointestinal Surgery Gastrointest Endosc 2020;91(5):1105-13.
2013;17(6):1161-68. 16. Valle J, Wasan H, Palmer DH, et al. Cisplatin
5. Ball CG, Kirkpatrick AW, Williams DR, et al. plus Gemcitabine versus Gemcitabine for Biliary
Prophylactic surgery prior to extended-duration Tract Cancer. New England Journal of Medicine
space flight: is the benefit worth the risk? Can J 2010;362(14):1273-81.
Surg 2012;55(2):125-31. 17. Darwish Murad S, Kim WR, Harnois DM, et al.
6. Podboy A, Yuan J, Stave CD, et al. Comparison Efficacy of Neoadjuvant Chemoradiation,
of EUS-guided endoscopic transpapillary and Followed by Liver Transplantation, for Perihilar
percutaneous gallbladder drainage for acute Cholangiocarcinoma at 12 US Centers.
cholecystitis: a systematic review with network Gastroenterology 2012;143(1):88-98.e3.
meta-analysis. Gastrointest Endosc 18. de Bellis M, Sherman S, Fogel EL, et al. Tissue
2021;93(4):797-804.e1. sampling at ERCP in suspected malignant biliary
7. Cotton PB, Elta GH, Carter CR, Pasricha PJ, strictures (Part 2). Gastrointestinal Endoscopy
Corazziari ES. Rome IV. Gallbladder and 2002;56(5):720-30.
Sphincter of Oddi Disorders. Gastroenterology 19. Rerknimitr R, Angsuwatcharakon P, Ratanachu-
2016. Ek T, et al. Asia-Pacific consensus
8. Cotton PB, Durkalski V, Romagnuolo J, et al. recommendations for endoscopic and
Effect of Endoscopic Sphincterotomy for interventional management of hilar
Suspected Sphincter of Oddi Dysfunction on cholangiocarcinoma. J Gastroenterol Hepatol
Pain-Related Disability Following 2013.
Cholecystectomy: The EPISOD Randomized 20. Khashab MA, Fockens P, Al-Haddad MA. Utility
Clinical Trial. JAMA 2014;311(20):2101-09. of EUS in patients with indeterminate biliary
9. Buxbaum JL, Abbas Fehmi SM, Sultan S, et al. strictures and suspected extrahepatic
ASGE guideline on the role of endoscopy in the cholangiocarcinoma (with videos).
evaluation and management of Gastrointestinal Endoscopy 2012;76(5):1024-33.
choledocholithiasis. Gastrointestinal Endoscopy 21. Ponchon T, Gagnon P, Berger F, et al. Value of
2019. endobiliary brush cytology and biopsies for the
10. Williams E, Beckingham I, El Sayed G, et al. diagnosis of malignant bile duct stenosis: results
Updated guideline on the management of of a prospective study. Gastrointest Endosc
common bile duct stones (CBDS). Gut 1995;42(6):565-72.
2017;66(5):765-82. 22. Jailwala J, Fogel EL, Sherman S, et al. Triple-
11. Jeong Youp P, Sung Pil H, Yoon Jae K, et al. tissue sampling at ERCP in malignant biliary
Long-term follow up of gallbladder polyps. obstruction. Gastrointestinal Endoscopy
Journal of Gastroenterology & Hepatology 2000;51(4):383-90.
2009;24(2):219-22. 23. Heimbach JK, Sanchez W, Rosen CB, Gores GJ.
12. Claessen MMH, Vleggaar FP, Tytgat KMAJ, Trans-peritoneal fine needle aspiration biopsy of
Siersema PD, van Buuren HR. High lifetime risk hilar cholangiocarcinoma is associated with
of cancer in primary sclerosing cholangitis. disease dissemination. HPB 2011;13(5):356-60.
Journal of Hepatology 2009;50(1):158-64. 24. Kao D, Zepeda-Gomez S, Tandon P, Bain VG.
13. Kim HJ, Kim MH, Myung SJ, et al. A new Managing the post-liver transplantation
strategy for the application of CA19-9 in the anastomotic biliary stricture: multiple plastic
differentiation of pancreaticobiliary cancer: versus metal stents: a systematic review.
Gastrointest Endosc 2013;77(5):679-91.
25. Ayoub W, Esquivel C, Martin P. Biliary transplantation. Am J Transplant 2003;3(7):885-

Complications Following Liver Transplantation. 90.
Dig Dis Sci 2010;55(6):1540-46. 27. Thuluvath PJ, Pfau PR, Kimmey MB, Ginsberg
26. Guichelaar MM, Benson JT, Malinchoc M, et al. GG. Biliary Complications after Liver
Risk factors for and clinical course of non- Transplantation: the Role of Endoscopy.
anastomotic biliary strictures after liver Endoscopy 2005;37(09):857-63.
139
6
CHAPTER
Pancreas
Chapter 6- Pancreas
Pancreatic disorders account for 10% of the GI boards' questions. Acute pancreatitis is common
in clinical practice. It is important to identify the etiology and assess the severity of the acute
episode. Goal-directed fluid resuscitation is important to prevent the development of pancreatic
necrosis. It is imperative to be knowledgeable of the different types of pancreatic fluid
collections, as they differ in their management approach. The ACG published new guidelines for
chronic pancreatitis in 2020. Treatment of pain in chronic pancreatitis remains generally
disappointing. Randomized trials of surgical versus endoscopic therapy are important to review.
All GI physicians should be familiar with the typical features of autoimmune pancreatitis, which
falls in the differential diagnosis of patients with a pancreatic mass and suspected
adenocarcinoma. There is an overall shift towards conservative management and surveillance
of pancreatic cystic lesions, but the management strategies remain mostly based on expert
opinion due to lack of good quality data. Several guidelines have been updated (AGA, ACG,
Fukuoka). These guidelines focus on high quality pancreatic imaging to identify the type of cyst
and presence of high risk and worrisome features. This information is used to determine the
need for EUS/FNA and further management with surgery, surveillance, or no follow up.
146 Chapter 6: Pancreas
Contents
Chapter 6- Pancreas
Developmental anomalies—147
Acute pancreatitis—149
Chronic Pancreatitis—153
Etiology—153
Diagnosis—154
Treatment—154
Complications—157
Autoimmune pancreatitis—160
Pancreatic cysts—162
Intraductal papillary mucinous neoplasm—163
Mucinous cystic neoplasm—163
Serous cystadenoma—164
Solid pseudopapillary neoplasm—164
Pancreatic adenocarcinoma—165
Pancreatic neuroendocrine Neoplasms—168
Insulinoma—168
Gastrinoma—169
Glucagonoma—169
VIPoma—169
Somatostatinoma—169
Familial syndromes associated with pNETs—170
References—171
Chapter 6: Pancreas 147
Developmental anomalies
 Embryology
 The pancreas develops from the formation and rotation of the ventral and dorsal pancreatic buds during the
7th to 8th week of gestation.
 The dorsal bud forms the body and tail of the pancreas.
 The ventral bud forms the pancreatic head and uncinate process.
 Normal Anatomy
 The main pancreatic duct is formed from the fusion of the dorsal and ventral ducts.
 This duct drains the majority of the pancreatic parenchyma and empties through the major papilla.
 The accessory pancreatic duct connects to the dorsal duct and empties through the minor papilla. This
accessory duct could be very small (figure 1-A) or completely absent (figure 1-B) in the normal pancreas.
 Pancreas divisum
 Pancreas divisum is the most common pancreatic congenital anomaly.
 It is present in 8-10% of the population.
 Subtypes
 Complete pancreas divisum (85%)
o The dorsal pancreatic duct empties through the minor papilla, and the ventral pancreatic duct empties
through the major papilla (figure 1-C).
 Partial pancreas divisum (15%)
o The dorsal pancreatic duct empties mainly through the minor papilla. There is a small connection
between the dorsal and ventral pancreatic duct that empties through the major papilla (figure 1-D).
 Reversed pancreas divisum (uncommon)
o The accessory pancreatic duct is separated from the dorsal duct. The dorsal pancreatic duct connects
to the ventral duct and empties through the major papilla (figure 1-E).
 Most patients with pancreas divisum are asymptomatic.
 Patients with recurrent pancreatitis and pancreas divisum can benefit from minor papilla sphincterotomy,
dilation, and stenting.
 Annular Pancreas
 Annular pancreas is a rare anomaly (1:20,000).
 It is the most common congenital pancreatic anomaly presenting in children.
 It is associated with Down syndrome, intestinal malrotation and duodenal atresia. 1
 A ring of pancreatic tissue surrounds the second portion of the duodenum (figure 1-F)
 A proposed mechanism of formation of annular pancreas is failure of the tip of the ventral pancreatic bud
to rotate with the rest of the pancreatic tissue to its final position, and thus stretches around the second
portion of the duodenum with its draining ducts.
 Clinical manifestations: the patient can be asymptomatic or may complain of intermittent abdominal pain,
vomiting, and symptoms of gastric outlet obstruction. Annular pancreas is a rare cause of acute pancreatitis.2
 Abdominal Xray in neonates can show the “double bubble sign”, due to duodenal obstruction.
 Other conditions that can cause the same sign are duodenal atresia and intestinal malrotation.
 Treatment
 Duodenoduodenostomy or gastroduodenostomy to bypass the annular pancreas.
 Division of the annular part of the pancreas should be avoided. 1
Figure 1: Normal anatomy and congenital anomalies of the pancreas (see text).
Acute pancreatitis
ACG Guideline: Management of Acute

Pancreatitis 3
AGA Institute Guideline on Initial Management of

Gastroenterology 2018
Acute Pancreatitis 4
Acute Pancreatitis Task Force on Quality: Development

of Quality Indicators for Acute Pancreatitis Am J Gastroenterol, 2019
Management 5
American Gastroenterological Association Clinical

Practice Update: Management of Pancreatic Necrosis 6
 Definition: Acute pancreatitis requires two of the following criteria:3

 Abdominal pain that is typical of acute pancreatitis.
 Elevation of amylase and/or lipase ≥ 3 times the upper limit of normal.
 Characteristic findings of acute pancreatitis on abdominal imaging.
 Etiology of acute pancreatitis
 Most common etiologies are gallstones and alcohol.
 Other causes: post-ERCP pancreatitis (see chapter 11 -endoscopy), hypertriglyceridemia, hypercalcemia,
and abdominal trauma.
 Genetic mutations can lead to recurrent acute pancreatitis and chronic pancreatitis (see page 153 ).
 Drug-induced pancreatitis: azathioprine, 6-mercaptopurine, valproate, ACE inhibitors, aminosalicylates,
furosemide, and many other medications.
 Anatomic abnormalities of the pancreaticobiliary system: anomalous pancreaticobiliary junction, biliary
cysts, annular pancreas, and pancreas divisum.
 Classification
 Mild acute pancreatitis: no organ failure and no local or systemic complications.
 Moderately severe acute pancreatitis: Local complications and/or transient organ failure <48 hours.
 Severe acute pancreatitis: persistent organ failure >48 hours.
 Imaging
 Contrast enhanced CT or MRI show diffuse or focal pancreatic edema, peripancreatic stranding with or
without pancreatic fibrosis. MRI/MRCP is more sensitive for choledocholithiasis than CT scan.
 Right upper quadrant ultrasound is more sensitive for gallstones than CT scan, and should be performed in
all patients with suspected cholelithiasis.
 Management
 Assess the severity of the acute episode.
 Risk factors for severe pancreatitis: age > 55, BMI > 30, altered mental status,
organ failure, systemic inflammatory response syndrome (SIRS), rising BUN
and hematocrit.3
 The acute physiologic and chronic health evaluation (APACHE II) score
o A score ≥ 8 indicates severe pancreatitis.
Link Link
 Bedside Index for Severity in Acute Pancreatitis (BISAP) score
o BUN>25mg/dL, Impaired mental status, SIRS, Age>60, Pleural effusion. Score>2 predicts higher mortality
 Supportive care
 IV fluids: 1-2 L IVF bolus followed by maintenance IVF at a rate of 250-500 ml / hour.
 Inadequate resuscitation leads to decreased pancreatic perfusion. This increases the risk of necrotizing
pancreatitis and end organ failure (e.g. renal failure from acute tubular necrosis).
 Goal directed IVF therapy (to maintain target mean arterial pressure, central venous pressure, BUN,
hematocrit) is recommended by the AGA.
 Signs of inadequate resuscitation include increasing hematocrit levels, tachycardia, hypotension, and
decreased urine output. Maintain a urine output of > 0.5 ml/kg/hour. Avoid overly aggressive fluid
resuscitation that can lead to pulmonary edema and increased intra-abdominal pressure. 7
 IV Analgesia, O2, NG tube if significant nausea and vomiting.*
 Nutrition
 Early oral feeding within 24 hours is recommended. Routine NPO orders are not necessary. 8
 Enteral feeding (nasogastric or nasojejunal tube) is the preferred method of providing nutrition in
patients with acute pancreatitis who are unable to tolerate PO within 72 hours. 5
o Enteral feeding is associated with fewer complications compared to parenteral nutrition.
o Limitations to enteral feeding include severe ileus and difficulty inserting a nasojejunal tube.
Randomized trials showed that in severe AP, nasogastric tube feeding has similar safety and efficacy
compared to nasojejunal feeding.3, 9 Therefore, nasogastric feeding is an acceptable alternative if a
nasojejunal tube cannot be placed.
 In the PYTHON multicenter trial, 208 patients with acute pancreatitis were randomized to the early
nutrition group (nasojejunal tube feeding within 24 hours- early group) or to oral diet initiated 72 hours
after presentation followed by NJ tube feeding if oral diet was not tolerated (on-demand group). Both
groups had similar rates of infection or death during 6 months of follow up. 10
 Subsequent abdominal imaging
 An abdominal CT scan with contrast to assess for pancreatic necrosis is indicated in patients with acute severe
pancreatitis, worsening abdominal pain or patients with organ failure within 72 hours of admission.
 Antibiotics
 Prophylactic antibiotics are not recommended in patients with acute pancreatitis (with or without necrosis).3, 8
 If the patient appears sick with systemic inflammatory response syndrome (tachycardia, leukocytosis,
fevers), it is reasonable to start empiric antibiotics while awaiting the results of blood cultures.
 Recommended antibiotics are imipenem-cilastatin, meropenem, or a combination of a quinolone and
metronidazole. If cultures are negative and no source of infection is identified, then antibiotics should be
discontinued.
 ERCP in acute pancreatitis
 The goal of ERCP is to perform sphincterotomy with stone extraction.
 Emergent ERCP (performed within 24 hours) is indicated in cases of cholangitis.
 Early ERCP (within 24-72 hours) is indicated in patients with severe acute pancreatitis with elevated
bilirubin and biliary obstruction.
 Elective ERCP is performed in cases of suspected retained CBD stone in a stable patient.
o A rising bilirubin or liver enzymes with persistent dilation of the CBD are strong predictors of
choledocholithiasis. An ERCP is clearly indicated in these cases.
o In cases when there is a lower level of suspicion of choledocholithiasis, noninvasive tests such as
EUS or MRCP can be performed for further workup (see chapter 5-biliary tract).
o ERCP and sphincterotomy do not improve outcomes in predicted severe pancreatitis without
cholangitis. 11
 Cholecystectomy is indicated in all patients with acute biliary pancreatitis to prevent recurrence.
 Inpatient cholecystectomy before hospital discharge is recommended rather than after discharge.8
o Defer cholecystectomy in patients with necrosis or fluid collection until pancreatitis subsides and
these complications stabilize.5
 ERCP and sphincterotomy is associated with lower rates of recurrent biliary pancreatitis in patients who
do not undergo cholecystectomy.12
 Peripancreatic fluid collections in the setting of acute pancreatitis (table 1)
 Peripancreatic fluid collections are classified according to the time they develop in relation to the acute pancreatitis
episode.
 Fluid collections develop following acute interstitial or acute necrotic pancreatitis.
 Fluid collections can be sterile or infected.
 Most acute peripancreatic fluid collections resolve spontaneously.
 Observation and repeat imaging in 8-12 weeks is reasonable in most patients without infection.
Table 1: Revised Atlanta classification of peripancreatic fluid collections in acute pancreatitis 13

< 4 weeks after acute pancreatitis > 4 weeks after acute pancreatitis
Acute peripancreatic fluid collection Pancreatic pseudocyst
 Homogenous fluid collection without a  Homogeneous collection with fluid density
definable wall without any non-liquid component and with a
 Located in the peripancreatic area well-defined wall without calcifications
 Associated with interstitial edematous  Located in the peripancreatic area
pancreatitis without peripancreatic necrosis  Develops following interstitial edematous
pancreatitis*
Acute necrotic collection Walled off pancreatic necrosis
 A collection containing variable amounts of  A collection of heterogeneous (liquid and non-
fluid, necrotic debris, and loculations without liquid density) pancreatic necrosis and loculations
a definable wall with a well-defined inflammatory and fibrotic wall
 Located in the peripancreatic and/or  Located in the pancreatic and/or peripancreatic
intrapancreatic areas areas
 Associated with necrotizing pancreatitis  Develops following necrotizing pancreatitis
*Pancreatic pseudocysts can also develop in chronic pancreatitis (see page 157)
 Pancreatic necrosis
 Initiate enteral feeding early to decrease the risk of infected necrosis. 6
 Sterile necrosis: most patients will improve with supportive care. If there are persistent symptoms (nausea,
vomiting, abdominal pain, and inability to tolerate oral diet) then surgical or endoscopic debridement is indicated.
 Routine use of prophylactic antibiotics to prevent the development of infected necrosis is not recommended.6
 Infected necrosis: patients with infected necrosis require drainage and/or debridement. In a clinically
stable patient, supportive care with intravenous antibiotics for several weeks (≥ 4 weeks) is required before
attempting definitive management. During this time the necrotic collection will mature, liquefy, and
become walled off, allowing for easier debridement.14 Routine use of antifungals is not recommended. 6
 Debridement and drainage options for walled off pancreatic necrosis with or without infection include:
 Minimally invasive surgical approach: laparoscopic drainage and necrosectomy, video assisted
retroperitoneal debridement –VARD, percutaneous drainage.
 Endoscopic approach: transgastric or transduodenal drainage using self-expanding metal stents (lumen-
apposing metal stents) +/- plastic stents +/- direct endoscopic necrosectomy.
 Transcutaneous drainage approach
 The open surgical approach is the least preferred approach due to higher complications than the
minimally invasive approaches (see below).
 The AGA recommends endoscopic drainage or transcutaneous drainage as first line treatment for
infected necrosis.6 Endoscopic drainage is preferred because it avoids the potential complication of
pancreatico-cutaneous fistula, while transcutaneous drainage is appropriate in those with early necrosis
(< 2 weeks) or if the patient is too ill to undergo endoscopy.
 Selected studies addressing endoscopic and surgical necrosectomy
 A randomized trial showed that in patients with infected necrosis, a step up therapy with antibiotics,
percutaneous catheter drainage, and minimally invasive surgery through (VARD) was as effective as
the open surgical approach.15 However, patients in the step up approach had lower mortality and less
complications after a mean follow up of 86 months.16
 Several trials compared endoscopic transluminal drainage +/- necrosectomy with the minimally
invasive surgical approach (e.g. percutaneous drainage, VARD, laparoscopic cystogastrostomy and
necrosectomy) in patients with infected necrosis. In the MISER 17 and TENSION18 trials, the two
approaches were overall similar in terms of effectiveness, mortality, development of organ failure,
bleeding, and perforation.
 However, there was a higher incidence of pancreatic fistulae in the minimally invasive surgical approach
(MISER: 28%, TENSION 32%) compared to the endoscopic approach (MISER 0; TENSION 5%).
 Other complications
 Splanchnic vein thrombosis (splenic vein, portal vein, and mesenteric veins) occurs in up to 20% of patients
with acute necrotizing pancreatitis. The overall course is benign and complications are uncommon. 19
 Treatment is aimed at the underlying pancreatitis. However, short-term anticoagulation can be given in
patients with portal or mesenteric vein thrombosis.
Chronic Pancreatitis
ACG Clinical Guideline Chronic Pancreatitis 20 AJG , 2020
Endoscopic treatment of chronic pancreatitis: European Society

Endoscopy,
of Gastrointestinal Endoscopy (ESGE) Guideline + update 2012 & 2018
August 2018 21, 22
United European
United European Gastroenterology evidence based guidelines for the
Gastroenterol J.
diagnosis and therapy of chronic pancreatitis (HaPanEU) 23
2017
American Pancreatic Association Practice Guidelines in Chronic

Pancreas, 2014
Pancreatitis: Evidence-Based Report on Diagnostic Guidelines 24
The role of endoscopy in benign pancreatic disease 25 GIE, 2015
Etiology
 Etiologies and risk factors for chronic pancreatitis (CP) are summarized in table 2.
 Alcohol Accounts for 70%-90% of all causes of CP.
 At least 5 years of alcohol intake of more than 150 g/day is required to develop the disease.
 Only 10-20% of heavy drinkers develop CP.
 Smoking is an important cofactor for the development of CP in heavy alcohol drinkers.
 Less than 10% of patients with alcoholic CP present without pain (primary painless chronic pancreatitis).
 Genetic mutations that are linked to the development of CP are shown in table 3.
Table 2: Classification of etiologies of chronic pancreatitis according to the TIGAR-O system26
Category Etiology
Toxic / Metabolic Alcohol, smoking, hypercalcemia, hyperlipidemia
Idiopathic Classified as early onset (<35 years) or late onset (>35)chronic
pancreatitis
Tropical pancreatitis
Genetic (see table 3)
Autoimmune Autoimmune chronic pancreatitis
Recurrent and severe pancreatitis Post-necrotic, recurrent acute pancreatitis, post-irradiation
Obstructive Duct obstruction secondary to tumor, trauma, or anatomic
abnormalities (abnormal pancreatico-biliary junction, pancreas
divisum, annular pancreas, ampullary stenosis)
Table 3: Genetic mutations linked to the development of CP
Mechanism of chronic
Mutation Inheritance pattern
pancreatitis
PRSS1 (serine protease 1 gene Complex low penetrance Increased trypsin activation
encoding cationic trypsinogen)*
CFTR Autosomal recessive Decreased pancreatic secretion and
increased trypsin activation
SPINK-1 Autosomal recessive Decreased trypsin degradation
Chymotrypsinogen C (CTRC) Autosomal dominant Decreased elimination of
prematurely activated trypsin
*This mutation results in autosomal dominant hereditary pancreatitis
Diagnosis
 Functional tests
 72-hour fecal fat collection: this test is abnormal if there is excretion of > 7 gm of fat per 24 hours.
 Spot fecal fat (Sudan staining): this test is insensitive for steatorrhea, and detects fat only if there is
excretion of ≥ 25 gm of fat / 24 hours.
 Fecal elastase: abnormal if < 100 mcg/gm of stool.
 Serum trypsin: abnormal if < 20 ng/ml.
 Secretin stimulation test (double tube test)
 In CP, the pancreas produces less bicarbonate in response to secretin stimulation.
 Technique: gastric and duodenal secretions are collected through nasogastric and nasoduodenal tubes. Secretin
is given IV and peak bicarbonate concentration is measured in the duodenal fluid. A concentration of < 80
meq/L is abnormal. Sensitivity is 75% for early CP, and 97% for late CP. Specificity is 90%
 This test is more sensitive than imaging studies for early CP. However, it is unpleasant, time consuming,
invasive, and available only in few referral centers.
 Structural tests
 All structural tests are more sensitive for late CP than for early CP.
 CT or MRI are the first line tests for diagnosis.
 EUS can be used to examine for features of CP if cross sectional imaging is equivocal (table 4).27
Table 4: EUS criteria for the diagnosis of chronic pancreatitis (Rosemont classification)
Criteria Diagnosis
Major criteria Consistent with chronic pancreatitis
 Major A  1 major A feature + ≥ 3 minor features
 Hyperechoic foci with shadowing  1 major A feature + major B feature
 Main pancreatic duct (PD) calculi  2 major A features
 Major B Suggestive of chronic pancreatitis
 Lobularity with honeycombing  1 major A feature + < 3 minor features
Minor criteria  1 major B feature + ≥ 3 minor features
 Cysts  ≥ 5 minor features (any)
 Dilated ducts ≥ 3.5 mm, Indeterminate for chronic pancreatitis
 Irregular PD contour  3 to 4 minor features, no major features
 Dilated side branches ≥ 1 mm  Major B feature alone or with < 3 minor
 Hyperechoic duct wall features
 Hyperechoic strands Normal
 Nonshadowing hyperechoic foci  ≤ 2 minor features, no major features
 Lobularity with noncontiguous lobules
 Consider Secretin enhanced MRCP if suspicion for CP is high and other tests do no establish the diagnosis. 20
 ERCP features of CP include dilated main pancreatic duct, dilated side branches, strictures, and stones.
Treatment
 Confirm the diagnosis of CP by carefully reviewing the patient's history and diagnostic tests.
 Review risk factors for CP (Table 2) to identify potentially modifiable risk factors.
 Rule out treatable complications of CP such as pancreatic pseudocyst, duodenal obstruction, bile duct obstruction, and
malignancy.
 Consider other causes of pain such as peptic ulcer disease and gastroparesis.
 Encourage alcohol abstinence and smoking cessation.
 Consider testing levels of fat soluble vitamins (A, E, D, K).

 Genetic testing is recommended in CP of unknown etiology, especially if <35 years old (table 3). 20
 Medical therapy of pain in CP
 Consider referral to a specialized pain clinic. Treat coexisting depression.
 Analgesics include acetaminophen, NSAIDS, and tramadol. Narcotics carry a high risk of addiction.
 Non-enteric coated pancreatic enzyme therapy
 One of the proposed mechanisms of pain in CP
is increased intrapancreatic pressure. It is
postulated that ingestion of food induces the
production of cholecystokinin releasing factor
(CCK-RF) in the duodenum, which stimulates
the release of CCK. CCK stimulates the
secretion of pancreatic enzymes into the
pancreatic parenchyma. This leads to
increased pancreatic pressure and pain
(figure 2-a). Figure 2: Proposed mechanism of action of
 Exogenous pancreatic enzymes denature pancreatic enzymes relieving pain of CP.
CCK-RF, which limits CCK release and CCK-RF: cholecystokinin releasing factor
therefore decreases the sensation of pain (figure 2-b).
 Since CCK-RF is produced in the proximal small intestine, exogenous enzymes should be provided in
the uncoated form (in combination with acid suppression). Uncoated enzymes are released in the
proximal small intestine to denature CCK-RF.
 The ACG 2020 guidelines do not suggest using pancreatic enzyme supplementation for the treatment
of pain in CP due to their overall expense and lack of efficacy.
 Endoscopic therapy
 The goal of endoscopic therapy is to improve pancreatic drainage and thus decrease intrapancreatic pressure.
 The ideal candidate for endoscopic therapy is the patient with pancreatic duct stone or stricture in the head
of the pancreas with upstream ductal dilation.
 Endoscopic techniques include pancreatic sphincterotomy, stricture dilation, and stone extraction with or
without stent placement (7-10 French) in the PD.
 External shock wave lithotripsy (ESWL) is helpful in cases with large pancreatic stones (> 5 mm), prior to
endoscopic therapy. One randomized trial showed that in patients with painful CP and calcifications obstructing
the main PD, ESWL alone had similar efficacy compared to a combined approach of ESWL and endoscopic
therapy. 28
 Celiac plexus block
 This is performed by injecting a local anaesthetic with or without steroids around the celiac plexus.
 It can be done percutaneously or endoscopically through EUS, and provides short-term pain relief (2-4 months).
 Surgical therapy
 Lateral pancreaticojejunostomy (Puestow procedure) is considered in patients with dilated PD (> 5 mm).
 Other surgeries include pancreaticoduodenectomy (Whipple procedure), pancreatic head resection combined
with drainage (Berger and Frey procedures), or total pancreatectomy with islet autotransplantation.
 Studies comparing endoscopic and surgical therapy:
Study highlights
Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis 29
o This is a randomized trial of 39 patients with severe advanced CP and distal obstruction of the
PD without an inflammatory mass.
o Patients were randomised to either endoscopic therapy (n=19) with sphincterotomy, lithotripsy, PD stenting
or pancreaticojejunostomy (n=20).
o Results at 2 years showed that 75% of patients who underwent surgery had complete or partial relief of pain
compared to 32% in the endoscopic group. Pain scores were lower in the surgical group during follow up.
o The study was terminated early due to the superior outcomes in the surgical group.
o Results of the five-year follow up of this study were published separately and showed that 68% of patients
treated with endoscopic therapy required additional procedures compared to only 5% in the surgery group.30
● 47% of the patients in the endoscopy group eventually underwent surgery.
● Pain relief was superior in the surgical group compared to the endoscopic group.
A Prospective, Randomized Trial Comparing Endoscopic and Surgical Therapy for Chronic
Pancreatitis 31
o 72 patients with CP and PD obstruction were randomized to either endoscopic drainage (n=36) with
sphincterotomy, stenting, stone removal (no ESWL) or surgery (n=36). Of patients randomized to surgery,
80% had pancreatic resection and 20% had a drainage procedure.
o The initial success rates were similar in both groups. Around 90% of patients had partial or complete pain
relief. After 5 years, patients in the surgery group maintained higher complete pain relief compared to
patients in the endoscopic therapy group (37% vs. 14%, p=0.002).30
o Summary: Endoscopic and surgical treatments of CP have comparable initial success rates. However, surgical
treatment seems to provide better long-term pain relief with a lower rate of reintervention. Patients included
in the studies above had severe CP and dilated PD. Therefore, these results may not be applicable to patients
with less severe disease.
Effect of Early Surgery vs Endoscopy-First Approach on Pain in Patients With Chronic
Pancreatitis The ESCAPE Randomized Clinical Trial 32
o Design and patient population: prospective multicenter trial of adult patients with severe pain due
to obstructive chronic pancreatitis with a dilated pancreatic duct, who recently started weak or strong opioids
for severe pain. Weak opioids included codeine, tramadol, hydrocodone, and were started less than 6 months
prior to enrolment. Strong opioids included morphine, oxycodone, fentanyl, and other formulations, started
less than 2 months prior to enrolment.
o Patients were randomized to two treatment groups
● Early Surgery (n=44): Surgical drainage with pancreaticojejunostomy, or Frey procedure if the pancreatic
head was enlarged (duodenal-preserving resection of the head of the pancreas combined with longitudinal
pancreaticojejunostomy)
● Endoscopy-First Approach (n=44): medical therapy (escalation of analgesia, referral to pain specialist,
treatment of neuropathic pain with pregabalin, gabapentin or amitriptyline, and dietary advice). In non-
responders, this is followed by endoscopic therapy (ESWL for large stones ≥7 mm, ERCP,
sphincterotomy, pancreatic stone extraction, stricture dilation, stenting, repeat ERCP up to 1 year)
● Primary outcome: The primary outcome was pain, measured on the validated Izbicki pain score and
integrated over a follow-up period of 18 months.
● Results: During 18 months of follow-up, the Izbicki pain score was lower in the early surgery group
compared to endoscopy first approach (37 vs. 49; P=0.02). However, when pain was measured as a
percentage, there was no difference in the percentage of complete or partial pain relief at end of follow-
up (58% in the early surgery vs. 39% in the endoscopy-first approach group, P = .10)
● The total number of interventions was lower in the early surgery group. Mortality was zero% in both groups.
Hospital admissions, pancreatic function, and quality of life were not significantly different between both
groups.
 Summary: Endoscopic and surgical treatments of CP have similar initial success rates. However, surgical
treatment seems to provide better long-term pain relief with a lower rate of reintervention, especially in
patients in later phase of chronic pancreatitis who suffer from refractory pain and long-term opioid use
(first two studies above). In patients in the early phase of treatment with short-term opioid use, early
surgical intervention results in lower pain scores when integrated over 18 months.
 In clinical practice, endoscopic therapy is usually offered as a first line treatment approach, but surgery
should be considered early in patients who do not respond to endoscopic therapy within 6-8 weeks. Multiple
ERCPs and prolonged years of stenting should be avoided.
Complications
 Pancreatic pseudocyst
 Definition: peripancreatic fluid collection that develops more than 4 weeks after acute pancreatitis and has
a well-defined wall. It develops because of PD disruption and pancreatic inflammation.
 Most pseudocysts communicate with the PD.
 Patients present with constant abdominal pain, nausea, and vomiting.
 Complications: gastric outlet obstruction, infection, pancreatic ascites, and pleural effusion.
 Treatment: In the past, it was recommended to drain all pseudocysts larger than 6 cm or those that persisted
more than 6 weeks. However, large asymptomatic pseudocysts (up to 12 cm) can be followed safely without
complications. Therefore, the main indication for pseudocyst drainage is a symptomatic or complicated
pseudocyst.
 If the cyst is asymptomatic or with minimal symptoms, consider watchful waiting and repeat imaging
q3-6 months.
 Cyst drainage options
o Endoscopic drainage
● Transpapillary pancreatic stenting: consider this option if the cyst is small <50 mm) and if there
is clear communication with the PD. Bridging the site of leakage increases the chances of cyst
resolution.
● Transmural cyst gastrostomy or cyst duodenostomy using double pigtail plastic stents or Lumen
Apposing Metal Stents (LAMS).
o Percutaneous drainage
o Surgical drainage: Open or laparoscopic cyst-gastrostomy, cyst duodenostomy, or resection. Other
surgeries: Roux-en-Y cyst jejunostomy, distal pancreatic resection if the pseudocyst is close to
pancreatic tail.
 Duodenal obstruction
 This results from inflammation in the pancreatic head or due to a large pseudocyst.
 Management options include pseudocyst drainage and gastrojejunostomy.
 Common bile duct strictures
 CBD strictures most commonly occur secondary to inflammation and fibrosis around the intrapancreatic portion
of the CBD. Other causes include compression from a pseudocyst, choledocholithiasis, or malignancy.
 They appear as smooth tapering in the distal CBD, usually of 2-6 cm in length.
 Clinical manifestations: the patient can be asymptomatic, or have jaundice, pain, pruritus, or recurrent cholangitis.
 Treatment is indicated in symptomatic patients. The ESGE recommends treatment of asymptomatic strictures if
there is choledocholithiasis, biliary stricture progression, elevated alkaline phosphatase > 3 times ULN or
bilirubin for >1 month. 22
 Endoscopic therapy with ERCP with balloon dilation and stenting is the treatment of choice.
 Multiple plastic stents are probably better than a single stent. The goal is to induce tissue remodeling at the
site of the stricture to achieve long-term patency and stricture resolution.
 Some of the fully covered metal stents are FDA approved for treating benign CBD strictures in CP (e.g.
WallFlex® stent-Boston Scientific).
 A recent open-label, randomized clinical trial of evaluated the treatment approaches in 164 patients with CP
induced CBD strictures. 33
 ERCP with placement of a fully covered metal stents (with a 12-month stent indwell time) led to similar
rates of stricture resolution and adverse events compared to multiple plastic stents at 2 year follow up
(75.8% vs. 77.1%).
 There were fewer numbers of ERCPs over the 24-month study period in the metal stent study group
(2.6±1.3) compared to the multiple plastic stent group (3.9±1.3).
 Surgical treatment
 Choledochoduodenostomy is a surgical option in refractory strictures. The distal CBD below the CBD-
duodenal anastomosis can rarely become obstructed with stones and debris, so-called "sump syndrome".
 Roux-en-Y choledochojejunostomy is a more complex operation. The jejunal Roux limb can be used to
drain the PD or a pseudocyst if necessary.
 Differentiating CP strictures from malignant strictures can be difficult.
 In CP strictures, the patient is generally younger and has a lower bilirubin level that waxes and wanes.
The stricture appears smooth and tapered.
 In malignant strictures, the patient is generally older and has a higher, persistent elevation in bilirubin
level. The stricture can appear as an abrupt cutoff of the CBD.
 Always rule out an associated mass. Check Ca 19-9. Obtain biliary brushings ± biopsy under
fluoroscopy ± cholangioscopy and targeted biopsy.
 Pancreatic leak and fistula formation
 Leakage of pancreatic fluid can lead to pancreatic ascites, pleural effusion (pancreatico-pleural fistula) ,
and rarely pericardial effusion (pancreatico-pericardial fistula)34, 35
 The fluid has a characteristically high amylase level (>1000 IU/mL).
 Evaluate for pancreatic leakage with CT/MRCP/ERCP.
 Treat with conservative management if there is a small volume ascites or pleural effusion. TPN, octreotide.
 ERCP with PD stent is indicated if there is documented PD leakage.
 Surgical resection and drainage are used for refractory cases.
 Splenic vein thrombosis
 In CP, splenic vein thrombosis develops secondary to local inflammation or extrinsic compression from a
pseudocyst. It can lead to portal hypertension and gastric varices.
 Treatment of gastric variceal bleeding in this setting is with splenectomy.
 Pseudoaneurysm
 Aneurysms develop secondary to inflammation and partial digestion of an arterial wall leading to aneurysmal
dilation. The dilated artery can rupture and bleed into an adjacent pseudocyst, leading to the formation of a
pseudoaneurysm. GI bleeding results from bleeding into the pancreatic duct (hemosuccus pancreaticus).
 Pseudoaneurysms most commonly arise from the splenic artery. Other arteries include the gastroduodenal,
pancreaticoduodenal, and left gastric artery.
 Treatment is with angiography and embolization. Surgical resection is needed in refractory cases.
 Pancreatic exocrine insufficiency
 Steatorrhea develops when there is less than 10% of functioning pancreatic exocrine glands.
 It usually develops more than 10 years after the onset of abdominal pain.
 In cases of PD obstruction, steatorrhea can develop early in the course of CP.
 Treatment is with pancreatic enzyme replacement therapy

 Consider the type of enzyme preparation (coated vs. uncoated). With uncoated preparations, give acid
suppression (H2 blockers or PPI) to prevent acid induced deactivation of pancreatic enzymes.
 Starting dose is 500 units of lipase/kg/meal (25,000-40,000 units/meal).
o Start with a formulation containing 16,000-20,000 units per pill.
o Give 2-3 pills per meal. Titrate up to 2500 units/kg/meal.
o Higher doses have been associated with fibrosing colonopathy (rare).
o Supplement with 50% of the meal dose with snacks. 36
 Monitor body weight, improvement of steatorrhea, fat-soluble vitamin levels.
 Endocrine dysfunction
 Diabetes is a late manifestation of CP. Screening for diabetes is recommended annually in patients with CP.
 Since pancreatic alpha cells that produce glucagon are also destroyed, there is a higher incidence of
hypoglycemia in these patients.
 Metformin is a reasonable first-line option in patients with mild hyperglycemia, and insulin can be given
for more severe cases.36 Most patients will require insulin.
 Metabolic bone disease (chronic pancreatitis -associated osteopathy)
 Osteopenia and osteoporosis are common in patients with CP
 One study found that osteopenia is present in 42% of patients with CP, and osteoporosis in 22%.37
 Consider baseline screening (DEXA scan), especially there is exocrine insufficiency and/or vitamin D deficiency.
 Give vitamin D and calcium. Encourage smoking and ETOH cessation, and weight bearing exercises.
 Pancreatic cancer
 The risk of pancreatic adenocarcinoma is increased in CP.
 The cumulative risk is around 1.8% after 10 years and 4% after 20 years of follow up. 38
 The risk is increased with smoking. In hereditary pancreatitis (PRSS1 mutation encoding cationic
trypsinogen), the risk of pancreatic cancer is estimated at 40% by age 70. 39
Autoimmune pancreatitis
International consensus for the treatment of

Pancreatology, 2017
autoimmune pancreatitis 40
International consensus diagnostic criteria for

autoimmune pancreatitis: guidelines of the Pancreas, 2011
International Association of Pancreatology 41
 Definition: autoimmune pancreatitis (AIP) is a distinctive form of pancreatitis that results from autoimmune
inflammation of the pancreas characterized by a prominent lymphoplasmacytic infiltrate and fibrosis.
 Subtypes of autoimmune pancreatitis are described in table 5 on the next page.
 Diagnosis: the diagnosis of AIP is based on multiple criteria (HISORt-Mayo clinic). The certainty of diagnosis
depends on the presence of typical features, or atypical features combined with other criteria.
 Histopathology of the pancreas
 Histology is the gold standard for diagnosis, but it is not routinely performed.
 EUS-FNA can rule out malignancy, but generally provides insufficient tissue to diagnose AIP. An EUS-
core biopsy is required to demonstrate all the pathologic features of AIP.
 Imaging features
 Typical features: diffusely enlarged (sausage shaped) pancreas with surrounding capsule-like rim hypo-
enhancement, and absence of pancreatic ductal dilation (figure 3).
 Atypical features: focal pancreatic enlargement.
o Abrupt cutoff of the PD with upstream pancreatic atrophy is suggestive of malignancy.
 Serology: elevated serum IgG4 ≥ 2 folds the upper limit of normal (ULN). However, lower levels of
elevations do not rule out AIP. IgG4 can be elevated in 10% of patients with pancreatic cancer, and 1% of
pancreatic cancer patients will have elevation to ≥ 2 folds ULN.42 Ca 19-9 can be elevated in AIP
 Other organ involvement (see table 5)
 Response to steroids therapy
 Treat with steroids and repeat pancreatic imaging and IgG4 level in 4 weeks.
 Objective improvement of abnormal imaging and a decreasing IgG4 is suggestive of AIP.
o Improvement of clinical symptoms is not specific to AIP.
o A decrease in IgG4 levels should not be considered diagnostic of AIP. Falsely elevated IgG4 due to
malignancy can also decreases with steroid therapy.43
 Treatment
 In patients with severe jaundice and/or cholangitis, ERCP with stenting, brushing, and biopsy is indicated.
 Initial treatment: prednisone 40 mg (or 0.6-1.0 mg/kg/day) for 4 weeks. Assess response at 4 weeks
(clinical, liver enzymes, IgG4 level, radiologic). If response is achieved, taper steroids by 5 mg/week.
 Rituximab is a B cell-depleting monoclonal anti-CD20 antibody. It is effective in inducing remission in AIP
(two doses of 1000 mg, given 2 weeks apart). Consider using Rituximab as a first line therapy in patients who
have contraindications or intolerance to steroids, or who have high risk of relapse (see below).40
 Relapse occurs in up to 60% of patients with type 1 AIP.42
 Maintenance treatment with low dose steroids (5-7.5 mg/day), immunomodulators (AZP or mycophenolate
mofetil), or Rituximab should be considered in patients who have predictors of relapse: (1) diffuse
enlargement of the pancreas (2) delayed radiological response (3) persistent elevation of IgG4 (>2xUNL)
post treatment (4) involvement of ≥2 organs with IgG4 disease (5) proximal biliary IgG4-SC strictures.
 Treat relapse with steroids. Consider maintenance low dose steroids or thiopurines. In a randomized
controlled trial, low dose corticosteroids lowered the 3-year relapse rate from 57.9% to 23.3%. 44
 Patients who relapse while on steroids or those who do not respond to steroids should be treated with rituximab.
 Relapse is uncommon in patients with type 2 AIP. If this occurs, treat with repeat steroids. 42
Table 5: Autoimmune pancreatitis subtypes.
Type 1 AIP Type 2 AIP
Main features  Pancreatic manifestation of a  Also called Idiopathic duct-centric pancreatitis
systemic, multi-focal disease (IgG4 (IDCP), or AIP with granulocyte epithelial
related disease) lesion (GEL)
 Characterized by elevated serum  Pancreas specific disorder with normal IgG4
IgG4 levels and tissue infiltration level and absence of tissue infiltration with
with IgG4 positive cells IgG4 positive cells
Age Mean age of diagnosis ~61 years Mean age of diagnosis ~40 years
Sex 3:1 male predominance Affects males and females equally

predominance
Pancreatic  Both subtypes present with obstructive jaundice, pancreatic mass, acute or chronic
presentation pancreatitis. Patients rarely have severe pain and cachexia. Malignancy should be strongly
and imaging suspected in these patients. Both subtypes have similar radiologic appearance (diffusely
enlarged pancreas or mass like enlargement)
Extra-  IgG4-SC (most common) † None
pancreatic  Enlarged salivary/lacrimal gland
presentation*  Retroperitoneal fibrosis
 Lymphadenopathy
 Interstitial nephritis
 Thyroid enlargement
IBD association Less commonly associated with IBD Strongly associated with IBD (up to 30%)
Histology41, 45 “Lymphoplasmacytic sclerosing  Periductal lymphoplasmacytic infiltrate
pancreatitis”  Infrequent storiform fibrosis and obliterative
 Periductal lymphoplasmacytic phlebitis
infiltrate  None or few IgG4 positive cells (< 10/ HPF)
 Storiform fibrosis‡  GEL: intraluminal and intraepithelial neutrophils in
 Obliterative phlebitis medium/small ducts leading to the destruction and
 >10 IgG4 positive cells /HPF obliteration of the duct lumen.
Steroid response ~100% ~100%
Relapse rate 30-60% Uncommon (<10%)
*Isolated pancreatic involvement occurs in 50% of patients with type 1 AIP. †IgG4 sclerosing cholangitis (IgG4-SC) refers to
the biliary manifestation of AIP type 1‡Fibroblasts arranged in an irregular "swirling" fashion around pancreatic ducts.
Figure 3: CT scan
findings in
autoimmune
pancreatitis type 1.
(A) Diffuse enlargement
of the pancreas. The
pancreatic duct measured
3 mm in diameter. IgG4
levels were elevated.
Panel (B) shows mass-
like enlargement of the
pancreatic head.
Pancreatic cysts
American gastroenterological association institute

Gastroenterology,
guideline on the diagnosis and management of 2015
asymptomatic neoplastic pancreatic cysts 46
ACG Clinical Guideline: Diagnosis and Management of Am J Gastroenterol,
Pancreatic Cysts 47 2018
Revisions of international consensus Fukuoka guidelines Pancreatology, 2017

for the management of IPMN of the pancreas 49
 General principles to the diagnosis, workup, and surveillance of pancreatic cysts

 Pancreatic cysts are a common incidental finding due to the widespread use of abdominal imaging.
 Differentiating between the different types of pancreatic cysts requires careful review of the clinical history,
cross sectional imaging, EUS/FNA, and cyst fluid characteristics.
 However, the decision to proceed with workup or surveillance of a pancreatic cyst should consider the
patient’s overall condition, including age, comorbidities and readiness to undergo surgery if malignancy is
detected. Workup should be offered to patients in whom the diagnosis of the cyst will alter their overall
management. Patients should understand the risks and benefits of repeated imaging tests for surveillance. 47
 In general, EUS and FNA is indicated in patients with a pancreatic cyst of unclear etiology on imaging, or
those with suspicious features (dilated pancreatic duct, abrupt change in duct diameter, size ≥ 3cm).47
 EUS helps to differentiate the types of cyst (mucinous versus non-mucinous), and obtain cytology
specimens to examine for cellular atypia, malignancy, and DNA mutations.
 A cyst with a CEA level above a cutoff of 192-200 ng/mL is considered mucinous with 80% accuracy.49, 50
 The “string sign” can be performed during EUS by placing drop of cystic fluid between fingers and
measuring maximum length of stretch before the string breaks. If the string persists ≥1 cm for ≥1 sec,
this is indicative of mucinous cyst with 95% specificity and 94% positive predictive value. 51 The string
sign test can be added to cyst fluid analysis to improve overall accuracy of diagnosing mucinous cysts.
 DNA mutation analysis (KRAS, GNAS, RNF43) remain mostly investigational.
 MRI/MRCP is preferred over CT scan for surveillance of pancreatic cysts. EUS is an alternative in patients
who cannot undergo MRI. The types of pancreatic cystic neoplasms are listed in table 6.
Table 6: Characteristics of pancreatic cystic neoplasms

Cyst type Gender Peak Location Malignan Fluid Fluid
predominance incidence t potential CEA amylase
Pseudocysts Male Any age Anywhere No Low High
Simple cyst Equal Any age Anywhere No low low
Serous cystadenoma Female 7th decade Anywhere Very rare Low Low
Mucinous cystic Female 5th decade Body and tail > Yes High Low
neoplasm* head
Intraductal papillary Male 7th decade Head > Yes High High
mucinous neoplasm body/tail
(IPMN)
Solid pseudopapillary Female 3rd decade Anywhere Yes Low Low
neoplasm
Cystic pancreatic Equal 5th decade Anywhere Yes Low low
neuroendocrine tumor
Intraductal papillary mucinous neoplasm

 Intraductal papillary mucinous tumors (IPMNs) are intraductal papillary epithelial growths that overproduce mucous.
Ductal obstruction and dilation can result from papillary growth or mucin blockage, which can lead to acute pancreatitis.
 IPMNs are located in the main PD in 60% of cases (main duct IPMN), in side branches in 30% (branch duct
IPMN), and in both locations in 10% of cases (mixed type).
 Histologic subtypes52
 Gastric type (~70%) associated mostly with branch duct IPMN, with low risk of cancer progression.
 Intestinal type (~30%) associated mostly with main duct IPMN, with a higher risk of cancer progression.
 Fluid characteristics: Small volume, viscous, mucoid fluid with high amylase, high CEA. The string sign is
usually positive due to the high viscosity of fluid (see page 162 ).
 Cytology shows mucin containing cuboidal cells, with or without malignant features.
 Features associated with increased risk of malignancy
 Main duct IPMN are more likely to harbor malignancy compared to branch duct IPMN.
 Other features: size ≥ 3 cm, presence of mural nodules or parenchymal mass, main pancreatic duct diameter
≥ 5 mm, presence of lymphadenopathy, atypical FNA cytology.
 A meta-analysis found estimated the risk of High grade dysplasia or pancreatic adenocarcinoma in low risk
IPMN (absence of main pancreatic duct involvement (i.e. PD <5mm) or mural nodule): the cumulative
incidence was 0.02% at 1 year, 1.4% at 3 years, 3.12% at 5 years, and 7.77% at 10 years.53
 Management approach
 Main duct IPMN: Surgical resection is indicated in all cases due to the high risk of malignancy.
 Branch duct IPMN: The following management strategy is mainly based on the revised Fukuoka guidelines
(2017).49 Variation in these criteria and surveillance are found in the ACG and AGA guidelines. 46, 47
ACG recommends referring patients with worrisome and high-risk features to an expert interdisciplinary panel.
 Patients with high-risk stigmata should be referred to surgery:
 Symptomatic lesions (pancreatitis, obstructive jaundice), enhancing mural nodule ≥ 5mm, and
pancreatic duct dilation to ≥ 10 mm.
 Patients with any worrisome features should undergo EUS/FNA:
 Cyst ≥ 3 cm, enhancing mural nodule < 5 mm (consider surgery if ≥ 5 mm), pancreatic duct dilation to
5-9 mm, abrupt narrowing of the pancreatic duct and upstream pancreatic atrophy, lymphadenopathy,
high CA 19-9, cyst growth ≥ 5 mm / 2 year (or 3 mm/year).
 Patients with the following findings on EUS/FNA should be referred for surgical resection:
 Mural nodule ≥ 5 mm, features of main duct involvement (thickened wall, intraductal mucin), or
positive/suspicious cytology.
 Post resection surveillance is required after resecting IPMN. If there are no pancreatic cysts in the remnant
pancreas MRI q 2 years. If there are remnant cysts repeat MRI based on size of largest cyst47
 Patients without these findings should undergo surveillance as in Figure 4.
 If surgical resection is performed and there was no associated pancreatic cancer no need for surveillance
Mucinous cystic neoplasm
 This was formerly called "cystadenoma".
 Imaging features: Usually large and monolocular, and may have calcification in their wall (eggshell calcification).
 Fluid characteristics: Large volume, mucoid fluid, high viscosity, high CEA, low amylase, + string sign (see above).
 Cytology reveals mucin secreting epithelial cells with or without dysplasia or malignant features.
 Overall, surgical resection is recommended due to the high malignant potential of these cysts.
 A multi-center retrospective study of 349 patients with mucinous cystic neoplasms who underwent surgical
resection found the overall rate of HGD or adenocarcinoma was 14.9%. 54 Male sex, pancreatic head and
neck location, increased radiographic size of the MCN, presence of a solid component or mural nodule,
and pancreatic duct dilation were associated with adenocarcinoma or HGD.
 If surgical resection is performed and there was no associated pancreatic cancer no need for surveillance
Figure 4: Surveillance of Branch-duct IPMN, based on the revised Fukuoka guidelines (2017)
Patients with cyst growth rate ≥ 5 mm / 2 years

(or ≥ 3 mm / year) should be considered for surgery, repeat EUS/FNA, and more intensive surveillance.
Serous cystadenoma
 Imaging characteristics: usually small (< 5 cm), with multiple microcysts, thin septation (honeycomb /sponge like
appearance). They are lined by cuboidal cells that secrete glycogen.
 In some cases, a central stellate scar with calcifications can be seen (sunburst appearance).
 Less commonly, serous cystadenoma may appear oligocystic similar to MCNs.
 Fluid characteristics: Small volume, low viscosity (absent mucin), usually bloody, low CEA, low amylase.
 Cytology reveals a glycogen rich cellular aspirate (PAS positive).
 Malignant transformation is rare (~0.1%)55, therefore surgery is recommended only in symptomatic patients.
Surveillance post resection is not necessary.
Solid pseudopapillary neoplasm
 Present mostly in young women. 88% of cases occur in women with a mean age of 28 years
 Imaging characteristics: large, solid tumor with a well-demarcated fibrous capsule.
 In most cases, it has both solid and cystic components. It is purely cystic in 10% of patients.
 Fluid characteristics: Low amylase, low viscosity, low CEA.
 Cytology is characterized by the presence of pseudopapillary structures that are lined by cytologically bland cells.56
 Immunostaining is positive for vimentin, CD10, and beta-catenin.57
 Malignant transformation is uncommon but has been described.
 Surgical resection should be attempted in patients who are fit for surgery. Outcomes are excellent with a 3-year
disease-free survival of 96%.55 ACG recommend surveillance MRI q1 year post resection for a total of 5 years.
Pancreatic adenocarcinoma
National Comprehensive Cancer Network Clinical

Practice Guidelines in Oncology: Pancreatic NCCN, 2020
Adenocarcinoma 58
Management of patients with increased risk for familial pancreatic
cancer: updated recommendations from the International Cancer of Gut, 2020
the Pancreas Screening (CAP S) Consortium 59
 Epidemiology 60
 In the United States, the estimated incidence of pancreatic cancer in 2020 is ~ 57,600 new cases.
 The estimated lifetime risk of pancreatic cancer is 1.7%
 It is the f leading cause of cancer death, with 47,050 deaths in 2020. The overall 5-year survival is only 9% (for all
stages). At diagnosis, 52% of patients have distant metastatic disease, and only 10% have localized disease.
 Risk factors
 Males, increasing age, obesity, smoking, cystic fibrosis, chronic pancreatitis, hereditary pancreatitis, long-
standing diabetes, pancreatic cancer in a first-degree relative.
 Pancreatic adenocarcinoma may arise from precursor lesions of the pancreas: pancreatic intraepithelial
neoplasia, intraductal papillary mucinous neoplasm (IPMN), and mucinous pancreatic cysts.
 Patients with IPMN may develop pancreatic adenocarcinoma in areas away from the pancreatic cyst.
 Other syndromes that predispose to pancreatic cancer are shown in table 7. Screening for pancreatic cancer
is recommended as shown in the table.
 The NCCN and American Society of Clinical Oncology recommends germline testing for all patients with
confirmed pancreatic adenocarcinoma using comprehensive gene panels for hereditary cancer syndromes. 58
Table 7: Syndromes that predispose to pancreatic cancer. Screening recommendations based on the
recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium 59
Lifetime risk of
Syndrome and mutation Mutation pancreatic Screening for pancreatic cancer*
cancer
Hereditary pancreatitis PRSS1 40%39 All patients regardless of familyHx
Start screening at age 40 or 20 years
after the first pancreatitis attack.
Peutz-Jeghers syndrome LKB1/STK11 10-3061 All patients regardless of familyHx
Start screening at age 40
Familial atypical multiple CDKN2A p16 10-3061 All patients regardless of familyHx
mole melanoma (FAMMM) Start screening at age 50-55 or 10
Syndrome- years younger than the youngest
affected blood relative
Familial pancreatic cancer No specific 10% Start screening at age 50
kindred** mutation
Ataxia-telangiectasia ATM 1-5%61 If there is one FDR with pancreatic
Lynch syndrome MLH1,MSH2,MSH6 4%62 cancer:
BRCA1, BRCA2, 1.2-3% 63, 64 Start screening at age 45-50 or 10
Hereditary breast/ovarian
cancer syndrome PALB2 years younger than the youngest
affected blood relative
PRSS1: serine protease 1 gene encoding cationic trypsinogen; FDR: First degree relative. FamilyHx: Family History
*Screening should start with a baseline MRI (MRCP) + EUS + blood glucose (fasting level and A1C). Repeat every
year (alternate MRI/EUS) if there are no concerning findings. 59 EUS-FNA should be performed to investigate
worrisome findings.
**Individuals who have≥1 FDR with pancreatic cancer who are also FDR of a person with pancreatic cancer
 Weight loss, anorexia, abdominal pain, back pain, jaundice, itching, nausea, vomiting.
 Physical findings include cachexia, jaundice, and hepatomegaly. Other nonspecific signs include:
 Courvoisier’s sign: enlarged palpable gallbladder. Trousseau sign: superficial venous thrombosis.
 Acute pancreatitis is an uncommon presentation of pancreatic cancer (~1%). 65
 Pancreatic cancer is found in up to 6% of patients with non-alcoholic, non-gallstone related acute pancreatitis.65
 Pancreatic cancer should be considered in older patients with acute pancreatitis of unclear etiology.
Good quality imaging of the pancreas should be obtained to rule out cancer.
 Diabetes is common in pancreatic adenocarcinoma, with a prevalence of ~ 40%.
 New onset diabetes in adults can be a manifestation of pancreatic cancer.
 Pancreatic cancer-associated diabetes manifests up to 2 years prior to the cancer diagnosis.
 Pancreatic adenocarcinoma should be suspected in elderly, non-obese patients without a family history
of diabetes who present with weight loss and diabetes.
 The biomarkers Vanin-1 and matrix metalloproteinase 9 are associated with pancreatic cancer-associated diabetes. 66
 Diagnosis:
 Imaging: high quality CT with IV contrast), MRI, ERCP, EUS-FNA,
 CT-guided biopsy of the pancreas or of a metastatic lesion.
 Tumor markers: CA 19-9.
 Sensitivity and specificity varies among different studies and by the different cutoff levels that are used.
One study showed that at a cutoff level of 37 U/mL, CA19-9 had a sensitivity of 81% and specificity of
89%. CA 19-9 can be elevated in patients with obstructive jaundice and cholangitis without cancer.
 Treatment
 Surgical resection is the only chance for cure in pancreatic adenocarcinoma.
 The NCCN defines “resectable tumors” as tumors with no arterial contact (celiac, superior mesenteric
or common hepatic artery), and no contact with the superior mesenteric vein, or portal vein. 58 Lesions
with less than 180-degree contact with these veins without contour irregularity are also considered
resectable. Other criteria to define “borderline resectable” and “unresectable” are mentioned in the
NCCN guidelines.58 Only 10-15% of patients are resectable at presentation.
 Whipple pancreaticoduodenectomy is the most common surgery.
 Adjuvant chemotherapy or chemoradiotherapy is given to all patients following resection.
 For patients who have an unresectable tumor, treatment options include chemotherapy and radiotherapy.
 For patients with metastatic disease and a good performance status, single or combination chemotherapy is offered.
 Preoperative biliary drainage
 ERCP should not be performed routinely in every patient with jaundice prior to surgery for pancreatic
head malignancy. ERCP is indicated to relieve severe jaundice, itching, and cholangitis.
 If ERCP is performed pre-operatively, consider a fully covered self-expandable metal stent instead of a
plastic stent to prevent stent related complications such as occlusion and the need for stent exchange.
Study Highlight
Preoperative Biliary Drainage for Cancer of the Head of the Pancreas 67
o This is a multicenter randomized trial of 202 patients with obstructive jaundice and a
bilirubin level of 2.3 to 14.6 mg/dL. Patients with cholangitis were excluded.
o Patients were randomized to (1) Preoperative biliary drainage for 4 to 6 weeks (two attempts of
ERCP and plastic stent placement, PTC was done if ERCP fails) followed by surgery, or (2) Surgery
alone within 1 week after diagnosis. 67% of patients underwent pancreatic resection (Whipple
procedure), while 30% underwent a palliative bypass procedure.
o Results: The rate of serious complications was higher in the biliary drainage group compared to the
early surgery group (74% vs. 39%. p < 0.001).
● Complications related to preoperative biliary drainage were pancreatitis (7%), cholangitis (26%),
perforation (2%), stent occlusion (15%), and the need to exchange stent (30%).
● There was a trend towards higher rates of surgery-related complications in the biliary-drainage
group compared to the early surgery group (47% vs. 37%, p=0.14).
● Mortality and the length of hospital stay were similar between the two groups.
o The authors concluded that routine preoperative biliary drainage in patients undergoing surgery for
pancreatic head cancer increases the rate of complications.
● Study limitations include overall low success rate of ERCP (75%) and higher ERCP complication
rate compared to usual practice. Plastic stents are known to be more prone to occlusion.
Placement of a fully covered metal stents could have decreased the complication rates in the
drainage group.
● Surgery was delayed up to 6 weeks (mean time to surgery was 5.2 weeks) in the drainage group.
Performing the surgery at an earlier time would have likely decreased the rate of stent occlusion
prior to surgery.
 A meta-analysis of preoperative endoscopic plastic stent placement prior to pancreaticoduodenectomy
analyzed results from 10 heterogeneous studies (8 retrospective and 2 randomized controlled trials). 68
o 337 patients had endoscopic stent placement and 412 patients did not have a stent.
o There was no difference between the two groups in post-operative mortality and morbidity.
 Endoscopic and surgical palliation of

malignant gastric outlet obstruction:
 Duodenal stent placement (figure 5-A)
and surgical gastrojejunostomy (Figure
5-C) should both be considered in
patients with pancreatic cancer and
gastric outlet obstruction.
 One randomized controlled trial
showed that surgical
gastrojejunostomy has better long-term
symptom relief compared to duodenal
stent placement.69 There were more Figure 5: Treatment of malignant gastric outlet
major complications and recurrent obstruction (see text)
obstructive symptoms requiring
reintervention in the stent group compared to surgical gastrojejunostomy.
 In general, duodenal stent placement should be considered in patients with expected survival of less than
three months and in those who are not surgical candidates. In patients with impending biliary obstruction,
biliary drainage should be secured (preferably with ERCP and metal stent) prior to placement of
gastroduodenal stent.
 EUS-guided gastroenterostomy (Figure 5-B) is an emerging endoscopic technique that bypasses the
gastroduodenal obstruction by inserting a lumen apposing metal stent (LAMS) through the gastric wall into
the small bowel.
 This procedure has high technical success rate (>90%) in centers with expertise in therapeutic EUS.70
 It should be considered if duodenal stenting is unsuccessful, or in patients with recurrent obstruction
following enteral stenting (e.g. due to tumor ingrowth).
 EUS-guided celiac plexus neurolysis should be considered for palliation of cancer pain, if available. 58
Pancreatic neuroendocrine Neoplasms
ENETS Consensus Guidelines Update for the Management of Neuroendocrinology,

Patients with Functional Pancreatic Neuroendocrine Tumors and
Non-Functional Pancreatic Neuroendocrine Tumors71
2018
 Pancreatic Neuroendocrine Neoplasms (NEN) account for 3% of pancreatic tumors. They are subdivided into
pancreatic neuroendocrine tumors (NETs) and pancreatic neuroendocrine carcinoma (pNEC) based on their
histologic features and degree of differentiation (table 8).
 pNETs have a well-differentiated histology and are graded G1 to G3 based on the proliferation markers
ki-67 and mitotic index.
 pNEC have poorly differentiated histology and are divided into small and large cell types.
 Functional tumors secrete different hormones leading to symptoms of hormonal excess. Around 50% of
pNETs are functional.
Table 8: Classification of Pancreatic neuroendocrine tumors based on histology and proliferation

markers (WHO 2019)
Category Grade* Ki-67 Mitotic Index Histology
NET G1 Low <3% <2/mm2 Well differentiated
NET G2 Intermediate 3-20% 2-20/mm2 Well differentiated
NET G3 High > 20% >20/mm2 Well differentiated
Neuroendocrine carcinoma Considered > 20% >20/mm2 Poorly differentiated
(NEC) High grade
-Small cell and Large cell types by definition
MiNEN † variable As above As above Well or poorly
Mixed neuroendocrine-non- differentiated
neuroendocrine neoplasm
*If the levels of Ki-67 and mitotic index are discordant, then the higher grade is used to assign the grade
classification.
†
MiNEN refers to a neoplasms with mixed neuroendocrine and non-neuroendocrine components (adeno or
squamous), each neuroendocrine and non-neuroendocrine component should account for ≥30% of the
tumor.
 Tumor markers: Chromogranin A, Chromogranin B, Pancreatic polypeptide, urinary 5-HIAA, serotonin,
neuron-specific enolase, synaptophysin.
 Diagnosis depends on detecting an elevated hormonal level combined with a mass on imaging studies, such
as CT, MRI, and EUS for tumor localization.
 Octreoscan uses indium-111 labelled octreotide to detect somatostatin receptors that are present on most
neuroendocrine tumors. Newer, more sensitive scans are gallium-68 DOTATATE PET scans and similar scans
that use other compounds (DOTANOC, DOTATOC).
 Most pNETs are sporadic, non-inherited tumors. However, some of these tumors are associated with an
inherited syndrome (see page 170 ).
Insulinoma
 Insulinomas are the most common functional NET of the pancreas.
 They are usually solitary and small. 90% of tumors are benign.
 Present with hypoglycemic symptoms, which can be precipitated by fasting or exercise.
 Diagnosis: 72-hour fast with measurement of blood glucose, insulin, and c-peptide levels.
Patients develop hypoglycemia (glucose <55 mg/dl ) with elevated serum insulin ( ≥ 3.0 μU/ml) and c-
peptide levels (≥ 0.6 ng/ml)
 The plasma insulin to glucose ratio is > 0.3.
 Octreoscan and gallium-68 DOTATATE PET scans are positive in only 50% of patients.
 Treatment
 Surgical removal of the tumor by enucleation or limited surgical resection.
 For patients who are not surgical candidates, ablative therapy with EUS-guided ethanol ablation or CT-
guided radiofrequency ablation is an alternative
 Medical therapy includes diazoxide and somatostatin analogues (octreotide).
 Several reports have described the effective use of everolimus in controlling hypoglycemia I patients with
insulinoma who are not candidates for resection.
Gastrinoma
 Pancreatic gastrinomas are the most common malignant functional NET of the pancreas.
 Most sporadic gastrinomas (> 50%) are located in the duodenum, and most are in the duodenal bulb. 72
 Most gastrinomas are small in size and multiple.
 Pancreatic gastrinomas tend to have a larger size compared to duodenal gastrinomas.
 Gastrinomas are malignant in ~60% of cases.
 Present with abdominal pain, diarrhea, multiple upper GI ulcerations (Zollinger-Ellison syndrome).
 Diagnosis (refer to chapter 2-stomach, section on hypergastrinemia)
 Serum gastrin, gastric pH, secretin stimulation test.
 Treatment: surgical resection, PPI.
Glucagonoma
 Usually large (> 5 cm), located in the body and tail region, and metastatic at diagnosis.
 Present with rash, anemia, glucose intolerance, dermatitis, deep vein thrombosis.
 Necrolytic migratory erythema is a characteristic pruritic maculopapular rash that develops into bullae and
later erodes and becomes crusted.
 This rash is most commonly related to glucagonoma. However, it can also be seen in patients with
nutritional deficiencies (zinc), and autoimmune disorders such as lupus.
 Diagnosis: serum glucagon levels > 500 pg/ml.
 Treatment: surgical resection, octreotide.
VIPoma
 These rare tumors secrete vasoactive intestinal peptide (VIP).
 They are usually large in size (> 3 cm) and metastatic at diagnosis.
 They presents with chronic large volume watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome).
This presentation is also called pancreatic cholera or Verner-Morrison syndrome.
 Diagnosis: elevated serum VIP levels.
 Treatment: correction of fluid and electrolyte imbalances, surgical resection, octreotide.
Somatostatinoma
 These tumors are usually large (> 5 cm) and metastatic at diagnosis.
 They present with abdominal pain, weight loss, diabetes, diarrhea, and cholelithiasis.
 Somatostatinomas are extrapancreatic in 40% of cases, and most of these tumors are located in the proximal
small intestine.
 Diagnosis: elevated somatostatin level.
 Treatment: correction of fluid and electrolyte imbalances, surgical resection, octreotide.
Familial syndromes associated with pNETs

 Multiple Endocrine Neoplasia (MEN) type 1
 This is an autosomal dominant disorder caused by a mutation in MEN 1 gene on chromosome 11.
 The gene product is a tumor suppressor protein called menin, which is a tumor suppressor protein.
 Components of MEN 1
 Parathyroid tumors (95% of cases)
 Pancreatic and duodenal NETs (60%-80% of cases)
o Patients characteristically develop multiple NETs.
o Gastrinomas (duodenal, gastric or pancreatic) are the most common, followed by insulinomas
(pancreas). Most gastrinomas (> 70%) are located in the duodenum.72
 Pituitary tumors (50% of cases )
 Gastric type 2 neuroendocrine tumors are associated with hypergastrinemia, and arise in 13-37% of patients
with MEN1-associataed gastrinoma (refer to chapter 10-Gastric neuroendocrine neoplasms).73
 Rarely, patients do not have a mutation of MEN 1, but rather a mutation in CDKN1B gene-also referred to
as MEN type 4
 In MEN type 2 syndrome, patients develop medullary carcinoma of the thyroid, pheochromocytoma (more
commonly bilateral, extra-adrenal, and malignant compared to sporadic pheochromocytoma) and
hyperparathyroidism. They do not develop pancreatic NET.
 Von Hippel–Lindau (VHL) disease
 Autosomal dominant disorder caused by a mutation in the VHL tumor suppressor gene on chromosome 3. 74
 Patients develop a variety of tumors.
 The most common tumors are retinal and central nervous system hemangioblastoma, clear cell renal
cell carcinoma and pheochromocytoma.
 In addition, patients develop pancreatic cysts and non-functional pNET in 10-17% of cases.
 Neurofibromatosis type 1
 Up to 10% of patients develop pancreatic and duodenal somatostatinoma. Other features: GI tract
gastrointestinal stromal tumors (GISTS), neurofibromas, café au lait spots, optic nerve gliomas.
 Tuberous sclerosis
 This is a rare autosomal dominant syndrome caused by mutation of Tuberous Sclerosis Complex 1 and 2
on chromosomes 9 and 16, respectively. It is associated with pancreatic insulinoma and somatostatinoma,
and with GI tract hamartomas. 75, 76
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173
7
CHAPTER
GI bleeding
Chapter 7 - GI bleeding
GI bleeding is the bread and butter of gastroenterology. GI physicians should be comfortable

dealing with all kinds of GI bleeding cases regardless of severity. Competence should be achieved
in assessing the patient, deciding on the optimal time for endoscopy, and delivering effective
endoscopic therapy to achieve hemostasis. If the bleeding source is not found, it is important to
follow an algorithmic approach in management, keeping in mind the differential diagnosis of
small bowel bleeding. Here are some recommendations related to the study and practice of GI
bleeding:
 Read and understand the guidelines. It is important to know the science and evidence
behind PPIs and other pharmacologic treatments of GI bleeding.
 Resuscitate aggressively but do not over transfuse patients.
 Identify high-risk patients, and perform early endoscopy <24 hours
 Do not delay endoscopy due to minor coagulation abnormalities.
 Treat high risk lesions (e.g. visible vessel aggressively with effective coaptive
coagulation or endoclips. Familiarize yourself with newer modalities of hemostasis.
 Do not forget to test and treat H. pylori in patients with peptic ulcer disease.
 Develop confidence in managing variceal by mastering the banding technique.
 Familiarize yourself with the insertion technique and handling of the Blakemore tube.
 In patients with GI bleeding and normal EGD/colonoscopy who present with recurrent
bleeding, consider a repeat upper endoscopy with a careful examination focusing on
possible missed lesions (e.g. duodenal ulcers, Cameron lesions, and gastric antral
vascular ectasia).
174 Chapter 7: GI bleeding
Contents
Chapter 7 - GI bleeding
Peptic ulcer disease bleeding—175
Gastric Stress ulcers—179
UGI bleeding in patients with cirrhosis—179
Acute variceal bleeding—180
Primary prophylaxis of esophageal variceal bleeding—183
Secondary prophylaxis of esophageal variceal bleeding—185
Portal hypertensive gastropathy—185
Gastric Antral Vascular Ectasia—185
Lower GI bleeding—186
Small bowel and Obscure GI bleeding—187
References—190
Chapter 7: GI bleeding 175
Peptic ulcer disease bleeding
Management of Nonvariceal Upper Gastrointestinal

Bleeding: Guideline Recommendations From the Ann Intern Med 2019
International Consensus Group1
ACG Clinical Guideline: Upper Gastrointestinal and Am J Gastroenterol,
Ulcer Bleeding2 2021
Asia-Pacific working group consensus on non-variceal

Gut, 2018
upper gastrointestinal bleeding: an update 2018 3
 Melena develops after a blood loss of about 50-100 ml. Bleeding most commonly originates from the upper
GI tract. Less common sources are the small bowel and the right colon.
 Hematochezia resulting from an upper GI source requires loss of around a 1000 ml of blood.
 A negative nasogastric tube aspirate does not rule out an upper GI source of bleeding.
 Up to 15% of patients will still have a high risk lesion on endoscopy.
 Clues of rare but important etiologies:
 A critically ill patient with a history of forceful vomiting and subcutaneous emphysema on physical
examination should raise the suspicion of Boerhaave syndrome.
 In patients with a history of abdominal aortic aneurysm repair, think of aorto-enteric fistula. Consider
abdominal CT scan with IV contrast (without PO contrast).
o The most common location of an aorto-enteric fistula is the third part of the duodenum.
 Clinical predictors of poor outcomes in upper GI bleeding
 Age > 60, comorbid diseases, red blood hematemesis or NG aspirate, hypotension, transfusion of ≥ 6 units
packed red blood cells, inpatient status at the time of bleeding, coagulopathy.
 Management
 Resuscitation: Maintain adequate IV access.
 Transfusion threshold for PRBC should be at Hgb of 7 gm/dL and a threshold of 8 gm/dL is suggested if
there is pre-existing cardiovascular disease. In cases of hypotension and exsanguination, transfusion should
be given prior to reaching the threshold of 7 gm/dL.
Study highlight
Transfusion strategies for acute upper GI bleeding 4
o This randomized controlled trial enrolled 921 patients with severe acute upper GI bleeding.
o Inclusion criteria: confirmed melena or bloody nasogastric tube output.
o Exclusion criteria: low risk upper GI bleeding (Rockall score of 0), massive hemorrhage, acute coronary
syndrome, transient ischemic attacks, Hgb >12 gm/dL
o 921 patients were randomized to one of two transfusion strategies:
● Restrictive strategy: Hgb threshold of 7 for transfusion, target Hgb of 7-9 gm/dL.
● Liberal strategy: Hgb threshold of 9 for transfusion, target Hgb of 9 to 11 gm/dL.
o Randomization was performed according to the presence or absence of cirrhosis.
o Transfusion was given one unit at a time and Hgb was checked following each unit.
o All patients had an upper endoscopy within 6 hours of presentation. Standard of care was followed in terms of
medical and endoscopic therapy.
o Results
● 31% of patients had cirrhosis. Bleeding was due to PUD in 49% and esophageal varices in 21%.
● Most outcomes were significantly improved with a restrictive transfusion strategy.

Important outcomes are shown in table 1.
Table 1: Primary and secondary outcomes

Outcomes Restrictive Liberal p value
strategy strategy
N=444 N=445
Death from any cause within 45 days
 All patient (primary outcome) 5% 9% 0.02
 All patients with cirrhosis 11% 18% 0.08
 Child Pugh class A or B cirrhosis 4% 12% 0.03
 Bleeding from varices 11% 18% 0.18
 Bleeding from peptic ulcer 3% 5% 0.26
Further bleeding
 All patients 10% 16% 0.01
 Patients with cirrhosis 12% 22% 0.02
 Patients with PUD bleeding 10% 16% 0.09
Adverse events 40% 48% 0.02
 Transfusion reactions 3% 9% 0.02
Number of days in hospital 9.6±8.7 11.5±12.8 0.01
o This study showed that among patients with cirrhosis, patients in the liberal strategy group had an
increase in their portal pressure from 20.5±3.1 mmHg to 21.4±4.3 mmHg, p = 0.03.
● However, this small change in portal pressure is not clinically significant.
● There was no change in the portal pressure in patients in the restrictive strategy group.
o Since the study excluded patients with transient ischemic attacks, stroke and ischemic heart disease, a
restrictive transfusion strategy cannot be recommended in these patients based on the results of this study.
 Coagulopathy should be corrected; however, this should not delay endoscopy.
 Studies have shown that mild to moderate elevations of INR (1.3 to 2.5) do not increase the risk of
rebleeding following endoscopic therapy.5
 Platelet transfusions are not beneficial and not recommended in patients with GI bleeding (upper or lower)
on antiplatelet agents with normal platelet count.3, 6 One case control study (n=204 with this intervention)
found that this intervention was not associated with lower risk of rebleeding compared to controls, and was
associated with increased mortality.6
 Medical management before endoscopy
 The most recent ACG guideline could not reach a recommendation for or against pre-endoscopic PPI.2
 Pre-endoscopic PPI therapy does not decrease re-bleeding rates or mortality.
o Patients who receive pre-endoscopic PPI are more likely to have non-bleeding ulcers during endoscopy,
and are less likely to need endoscopic therapy. 7
 IV PPI : Dose example: omeprazole 80 mg IV bolus followed by 8 mg/hour IV drip.
 While the IV drip is the most reliable way to administer PPIs, they can also be given IV every 12 hours.
 IV erythromycin
 IV erythromycin improves mucosal visualization during endoscopy, increases the diagnostic yield, and
decreases the need for a second look endoscopy.2, 8
 It is recommended in patients who are likely to have large amounts of blood in the stomach.
 Dose: 3 mg/kg (or 250 mg) IV given 30 to 90 minutes prior to endoscopy.
 Endotracheal intubation for airway protection is indicated in those with active hematemesis or altered mental status.
 CT angiography and other bleeding scans should NOT be ordered routinely in upper GI bleeding.
 Endoscopy: EGD is recommended within 24 hours of an upper GI bleeding episode. More urgent endoscopy
does not improve outcomes, although this can benefit patients with active bleeding.
Study highlight
Timing of Endoscopy for Acute Upper Gastrointestinal Bleeding9
 This trial (n=516) randomized patients with acute upper GI bleeding to urgent upper
endoscopy within 6 hours of GI consult (n=258) and early upper endoscopy performed 6-24 hours after GI
consult (n=258).
 Patients with hypotensive shock and those who did not stabilize after resuscitation were excluded.
 Primary endpoint was all-cause mortality at 30 days.
 Majority of patients had peptic ulcer disease (~60%), ~10% had esophageal or gastric varices.
 There were no differences between the urgent and early groups in the 30-day mortality (8.9% vs. 6.6%, p >
0.05), and in the rate of persistent or recurrent bleeding (10.9% vs. 7.8%, p > 0.05)
 Endoscopic treatment was performed more frequently in the urgent group compared to the early group.
There were no differences in need for embolization or surgery, length of stay, or need for transfusion.
 The Forrest classification and management of peptic ulcer bleeding is shown in table 2.
Table 2: Forrest classification and management of peptic ulcer bleeding

Forrest
Stigmata Management
classification
Active bleeding
 Arterial , spurting Ia Dual endoscopic therapy* + IV PPI for 72 hours
hemorrhage
 Oozing hemorrhage Ib
Recent hemorrhage
 Visible vessel IIa Dual Endoscopic therapy* + IV PPI for 72 hours
 Adherent clot IIb  Aggressive irrigation or suction to expose and treat the
underlying lesion (video 7-1)
● Consider removing the clot with a snare.
 If the clot cannot be removed, consider epinephrine injection
in high risk patients
 Give intensive PPI therapy post EGD (IV drip or b.i.d. PPI)
Video 7-1
 Flat pigmented spot IIC No endoscopic therapy. PO PPI
Lesions without active bleeding
 Clean base III No endoscopic therapy. PO PPI
*Dual endoscopic therapy: epinephrine injection plus thermocoagulation or endoclips
 Traditional endoscopic hemostasis techniques include epinephrin injection, thermocoagulation, and endoclips.
Newer endoscopic devices include the hemostatic powder and over-the-scope clips.
 Hemostatic powder- Hemospray (Cook® medical)
 Hemostatic powder that can achieve hemostasis by creating a mechanical barrier and activating the
clotting cascade, thereby reducing clot formation time. 10 In order for the powder to work, it requires an
actively bleeding lesion (e.g. ulcer or bleeding malignancy).
 A large series of 202 patients treated with Hemospray for upper GI bleeding for various indications: ulcers,
tumors, and postendoscopic bleeding. The immediate efficacy rate is 96.5%. the rate of rebleeding was
26.7% at day 8 and 33.5% at day 30.10
The device was FDA approved in 2018 for non-

variceal GI bleeding.
 The Asia pacific working group and the
international consensus group recommend
endoscopic hemostatics powder spray for
temporary control of bleeding when definitive
hemostasis cannot be achieved using traditional
techniques3.
 OTSC (example: Ovesco® OTSC-Figure 1) are
applied to the tip of the scope and deployed by Figure 1: Ovesco® over -the-scope clip.
rotating a wheel. They grasp more tissue and Image courtesy of Ovesco ®
deeper layers compared to conventional endoclips.

 A randomized controlled trial (n=66) showed
that OTSC was more effective than standard treatment (endoclips, epinephrine, thermocoagulation) in cases
of severe recurrent upper gastrointestinal bleeding.11 The rate of persistent bleeding was higher in the
standard treatment group (42.4% vs 6%, p=0.001).
 Doppler endoscopic probe (DEP)
 This disposable probe is inserted into the working channel of the scope to examine the bleeding lesion
for arterial flow before and after endoscopic therapy. If arterial flow is detected after endoscopic therapy,
further treatment with clips or electrocoagulation is applied until disappearance of signal.
 In a randomized controlled trial, DEP guided hemostasis led to lower rates of recurrent bleeding (11.1%)
compared to the standard hemostatic approach (26.3%).12 A cost-effectiveness analysis found DEP to
be less costly and more effective than traditional hemostatic approach. 13 This technique requires
considerable skills and is not currently endorsed for routine use by major society guidelines. 3, 13
 Medical management after endoscopy
 PPI therapy: Patients who receive endoscopic therapy for high risk lesions should be given high dose
IV PPI (continuous or intermittent infusion) for 72 hours after successful endoscopic hemostasis.2 This
was shown to decrease the risk of rebleeding and mortality. 14 Continuous infusion example: 80mg IV
followed by 8mg/hour infusion. Intermittent infusion: 40 mg q6-12 hours.
 PPI IV once or twice daily appears to have similar efficacy to the high dose IV drip. 15, 16 High dose oral
PPI (e.g., esomeprazole 40 mg BID) also appears to be as effective as IV PPi to prevent rebleeding
following endoscopic hemostasis.17
 For low risk lesions (flat pigmented spot or white base), give PPI PO once or twice daily.
 Test for H. pylori and stop NSAIDS.
 Routine second look endoscopy is not recommended.
 Restart low dose aspirin following endoscopic hemostasis in patients with a history of cardiovascular disease.
o A randomized controlled study showed that in patients with a history of cardiovascular disease who
restarted aspirin following ulcer hemostasis, there was a lower 30-day all-cause mortality compared to
patients who continued to withhold aspirin (1.3% vs. 9%). 18
● There was a higher rate of rebleeding in patients who continued aspirin (10.3% vs. 5.4%).
 Rebleeding
 60-75% of re-bleeding occurs in the first 72 hours.
 Repeat endoscopy is recommended, which can control bleeding in 70% of cases. 19
o The presence of ulcers larger than 2 cm or hypotension at the time of rebleeding is associated with failure
to control bleeding at repeat endoscopy.19
o Over-the-scope clip is an alternative to traditional hemostatic techniques in severe rebleeding.
 Salvage therapies
o Angiographic embolization and surgery are considered in patients with severe hemorrhage not
controlled or localized by endoscopy. It is also considered in patients with recurrent bleeding where
endoscopic therapy was unsuccessful. These salvage therapies are required in < 4% of cases. 20
o Consider endoscopic marking of the bleeding ulcer with a metallic clip to guide embolization during
angiography. Embolization is successful in 52% to 98% of cases. Bleeding recurs in 10-20%.
o The type of emergency surgery depends on the location of the ulcer and other anatomical factors. These
include simple ulcer excision, oversewing, or partial gastrectomy.
 Other causes of upper GI bleeding (see also page 187):
 Mucosal disease: Esophagitis, gastritis, stress ulcers.
 Dieulafoy’s lesion, Mallory-Weiss Tears (MWT) (see video 7-2 of MWT treated by clips).
 Cameron’s Lesions (linear erosions or ulcerations in the proximal stomach at the
diaphragmatic impression of a hiatal hernia). Video 7-2
 Other: Malignancy, Gastric antral vascular ectasia, arteriovenous malformations.
Gastric Stress ulcers
 Gastric stress ulcerations (also known as “stress-related mucosal injury”) occur in the setting of multi-organ
failure in critically ill patients.
 They result from gastric mucosal hypoperfusion. Acid injury has a minor role.
 Most important risk factors are mechanical ventilation, coagulopathy, CNS injury, extensive burns, sepsis, and
multiorgan failure. They can present with overt or occult bleeding.
 Endoscopy shows multiple shallow erosions in the proximal stomach. These can progress to deeper ulcers in
severe cases.
 Treatment: Supportive care. Blood transfusion. IV PPI.
 Bleeding is usually diffuse, and not amenable to endoscopic therapy.
 Prophylaxis
 IV H2 blockers or IV PPI. Most studies showed that IV H2 blockers are equally effective compared to IV PPI.
 A meta-analysis showed that PPIs are superior to IV H2 blockers. 21 However, the magnitude and cost
effectiveness of this effect is unclear. In most patients, IV H2 blockers are sufficient and effective in preventing
stress ulcerations.
UGI bleeding in patients with cirrhosis
Portal hypertensive bleeding in cirrhosis: Risk stratification,

AASLD 2016
diagnosis, and management: 2016 Practice Guidance 22
Expanding consensus in portal hypertension

Report of the Baveno VI Consensus Workshop: Stratifying EASL, 2015
risk and individualizing care for portal hypertension 23
 Acute variceal bleeding is the most common cause of UGI bleeding in patients with cirrhosis.
 Other etiologies: peptic ulcer disease, portal hypertensive gastropathy, angiodysplasia, and Mallory-Weiss tears.
 A large cross-sectional study showed that peptic ulcer bleeding is associated with higher mortality in
patients with cirrhosis compared to those without cirrhosis. 24 Another study found that 90-day mortality
after peptic ulcer disease bleeding is higher in patients with chronic liver disease (20.7%) and those with
cirrhosis (25%) compared to patients without chronic liver disease (18.3%). 25
Acute variceal bleeding
 Clinical significance
 The mortality of acute variceal bleeding remains high (5-8% in 1 week, 20-30% in 6 weeks after the first
episode of bleeding).
 Accounts for about one-third of all deaths related to cirrhosis.
 50% of bleeding events stop spontaneously, and 30% rebleed.
 40% of rebleeding episodes occur within 5 days.
 Management
 Admit to the ICU for close monitoring.
 Intubation is required in cases of encephalopathy or massive hematemesis.
 PRBC transfusion with a goal Hgb level of 7 to 9 g/dL. Transfusion threshold is 7 g/Dl.
 Consider fresh frozen plasma in patients with coagulopathy, and platelet transfusion in patients with severe
thrombocytopenia. However, the optimal use of these products in the setting of cirrhosis is still unclear.
 Medical therapy
 IV octreotide (50 mcg IV bolus followed by 50 mcg/hour IV drip for 5 days).
 Alternatives to octreotide: vasopressin, somatostatin, or terlipressin
 Antibiotics should be administered to all patients with cirrhosis and upper GI bleeding, regardless of the etiology.
 Antibiotics decrease the risk of infection (mainly spontaneous bacterial peritonitis), rebleeding, and mortality. 26
 IV ceftriaxone or IV/PO quinolone for 7 days are the most commonly used antibiotics.
 Recombinant activated factor VIIa has no benefit in controlling variceal hemorrhage or decreasing
rebleeding rates and mortality.27, 28
 Non-selective beta blockers (NSBB) should be started prior to discharge (see page 184).
 Endoscopic therapy
 EGD should be performed as soon as the patient is hemodynamically stable. Guidelines recommend EGD
within 12 hours of presentation.
 Endoscopic variceal ligation (EVL) is the recommended treatment for esophageal varices.
 Start at the GE junction and proceed proximally in a spiral fashion.
 Hepatic venous pressure gradient (HVPG) > 20 mmHg is associated with treatment failure and early rebleeding.
 Endoscopic variceal sclerotherapy is an alternative to EVL.
 This involves injecting a sclerosing agent (e.g. sodium morrhuate) into the varices to control bleeding.
Sclerotherapy has been largely replaced by EVL.
 Balloon tamponade
 Balloon tamponade with the Sengstaken-Blakemore tube or the Minnesota tube temporarily controls
bleeding in up to 80% of patients. This is a temporary stabilizing measure that is used for 24-48 hours.
 Insertion technique
 The patient should be intubated. The orogastric route is preferred as it allows for easier insertion.
Lubricate the tube and insert it to at least 55-60 cm.
 During insertion, coiling of the tube in the oropharynx or esophagus is common. In this
case, remove the tube and reattempt insertion. Consider passing a biopsy forceps through
the central gastric suction port to stiffen the tube and prevent coiling.
o Make sure the forceps does not exit from the side holes at the tip of the tube. Video 7-3
 Confirm correct placement with an abdominal Xray.
o Alternatively, endoscopy can be performed immediately after placement to confirm the presence of the
gastric balloon in the gastric lumen (video 7-3).
 Once correct placement is confirmed, the gastric balloon is inflated with 300-400 ml of air and clamped.
 The tube is then pulled until resistance is felt, to allow the gastric balloon to tamponade the GE junction.
o This will decompress the esophageal varices and control bleeding in most patients.
 Continuous traction can be achieved using different devices. The simplest is a pulley system, with the
tube connected to a rope attached to a weight of 1-2 pounds.
 The gastric balloon should be deflated every 12 hours to check for rebleeding.
 If bleeding continues despite inflating the gastric balloon, then the esophageal balloon should be inflated
to a pressure of 35 mmHg using the included pressure gauge.
 The esophageal balloon should not be inflated for longer than 12 hours to prevent the development of
esophageal necrosis.
 Esophageal stents: Placement of a temporary fully covered metal stent is another option for temporary
control of refractory variceal bleeding.
 One small randomized trial (n=28) compared the fully covered metal stent with balloon tamponade in
refractory esophageal bleeding. Retrieval of the esophageal stent was scheduled at 7 days.
 Control of bleeding was more successful in the stent group compared to the balloon tamponade. . There
was higher control of bleeding (85% vs 47%) at day 15, and less adverse events (16% vs 47%) in the stent
group versus balloon tamponade group.
 Survival was similar between both groups at day 15 (69% vs 47%) and 6 weeks (54% vs 40%).
 Stent migration occurred in 7 (53%) of stent cases.
 Transjugular intrahepatic portosystemic shunt (TIPS)
 TIPS is used in patients who fail endoscopic therapy.
 Polytetrafluoroethylene covered stents have less stent dysfunction compared to bare stents.
 The main complication of TIPS is encephalopathy because of portosystemic shunting.
 TIPS has been evaluated in high-risk patients with variceal bleeding as a preemptive adjunct to endoscopic
therapy (p-TIPS), rather than salvage therapy (see example of such study next).
Study highlight
Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding 29
 Study population: 63 patients with acute variceal bleeding and Child Pugh cirrhosis class C
(CP-C;score of 10-13) or class B with active bleeding on endoscopy (CP-B+AB)
 Exclusions: age >75 years, hepatocellular carcinoma that did not meet the Milan criteria, cr > 3 mg/Dl, Child–
Pugh score > 13 points, previous medical and endoscopic therapy to prevent rebleeding, previous TIPS, total
portal-vein thrombosis, and heart failure.
 Study design: prospective randomized clinical trial.
 Treatment groups
o Standard therapy (31 patients): EVL and vasoactive-drug therapy, followed after 3 to 5 days by treatment
with propranolol or nadolol and long-term EVL. These patients received TIPS if needed as a rescue therapy.
o Early TIPS following EVL (32 patients). TIPS was performed within 72 hours of endoscopy.
 Results: Patients in the early TIPS group were more likely to remain free of rebleeding events compared to
the standard therapy group (97% versus 50%, p < 0.001).
o The 1-year survival was higher in early TIPS group compared to standard therapy group (86% versus 61%, p
< 0.001). 29
 A recent meta-analysis of published studies evaluated the approach of early p-TIPS (within 72 hours) in high
risk patients (CP-C <14 points) and CP-B+AB. Results showed that p-TIPS improves survival at 1-year
compared to drugs and endoscopy (hazard ratio 0.443; 95% CI 0.323–0.607; P < 0.001).30 p-TIPS also
improved control of bleeding and ascites, and there was no increased risk of encephalopathy.
 In high-risk patients with acute variceal bleeding (Child-Pugh class C, or class B with active bleeding),
consider early TIPS after initial pharmacologic and endoscopic therapy, even if this therapy was successful
in achieving hemostasis.22, 31
 Gastric varices
 Types of gastro-esophageal varices (GEV) and
isolated gastric varices (IGV) (figure 2):
 GEV1 appear as a continuation of esophageal varices,
and extend 3-5 cm below the GEJ into the lesser
curvature of the stomach.
 GEV2 appear as a continuation of esophageal
varices, and extend into the fundus.
 IGV1 are isolated gastric varices in the fundus.
 IGV2 are isolated gastric varices outside the fundus.
 Management of gastric varices with acute bleeding
 Management is similar to esophageal varices
(resuscitation, antibiotics, vasoactive medications). Figure 2: Sarin classification of
 GEV1 are generally managed like esophageal varices. gastric varices.
 Cyanoacrylate injection therapy can be attempted if available (see below).
 IGV1 are usually seen in splenic vein thrombosis without cirrhosis. In these patients, treatment is with
splenectomy.
 The Linton-Nachlas tube has a large gastric balloon (600 ml). It can be used as a temporary method to
control fundal variceal bleeding.
 Endoscopic treatment
 EVL can be attempted in patients with GEV1.
 TIPS is the treatment of choice to control bleeding from GEV2 and IGV1 varices 22
o Endoscopic variceal obturation therapy with cyanoacrylate tissue glue can be attempted if TIPS is not
available. This is not FDA approved in the United States.
o Endoscopic variceal obturation can be performed through the direct endoscopic approach or EUS
guided approach.
● Uncommon but serious complications include systemic glue migration and thromboembolism,
sepsis, and death. 32
● In the EUS approach, coil embolization immediately prior to injection of glue can be performed
and may reduce the rate of adverse events.
● A meta-analysis found that treatment efficacy is similar in both approaches (94% EUS approach
vs 91% direct endoscopic approach), however EUS approach was associated with higher rate of
obliteration of gastric varices (84% vs 63%) and lower rate of recurrence (9% vs 18%) compared
to the direct endoscopic approach 33
● EUS coil embolization plus glue injection is associated with lower rate of recurrence of gastric
varices and lower rate of late rebleeding compared to EUS-glue injection alone. 33 It is also linked
to lower rate of systemic migration and thromboembolism. 34, 35
 Interventional radiologic procedures are used to decompress the portal system, or to access the porto-systemic
circulation through venous structures, and inject sclerosing agents into the varices. (Figure 3-a)
 TIPS is the management of choice for IGV1 and GEV2. It creates a shunt between the hepatic vein and
the portal vein (figure 3-b).
 Balloon-occluded retrograde transvenous obliteration (BRTO) (figure 3-c): The gastric varices are
accessed "retrograde" through the femoral vein, inferior vena-cava, left renal vein and through a
gastrorenal shunt. Other connections such as gastrocaval shunts can be used to access the gastric varices.
 Balloon-occluded anterograde transvenous obliteration (BATO) (figure 3-d): The gastric varices are
accessed “anterograde” through the portal vein, splenic vein, and the short or posterior gastric veins.
o The access to the portal vein could be transjugular through the hepatic veins and existing TIPS.
Alternatively, the portal vein can be accessed percutaneously through the liver.
 The balloon is then inflated to occlude the vein, and the varices are injected with a sclerosing agent.
BRTO has a high success rate (> 70%). 36
Figure 3: Porto-systemic venous anatomy and interventional radiologic interventions for

gastric varices. (A) Common porto-systemic venous anatomy in patients with gastric varices. Note
arrow depicting the direction of venous flow into and out of the gastric varices. The gastric varices are
fed by many venous structures including the posterior gastric veins (afferent vessels). Other veins are
short gastric veins and left gastric veins (not shown). The gastrorenal shunt drains the gastric varices into
the left renal vein. (B) Transjugular Intrahepatic porto-Systemic Shunt (TIPS); (C) Balloon-occluded
Retrograde Transvenous Obliteration (BRTO); (D) Balloon-occluded Anterograde Transvenous
Obliteration (BATO)
Primary prophylaxis of esophageal variceal bleeding
 The aim of primary prophylaxis is to prevent the first occurrence of variceal bleeding. This is indicated in all patient
with cirrhosis (figure 4).
 EGD is indicated in all patients with decompensated cirrhosis (ascites, encephalopathy) to screen for esophageal
and gastric varices. If no varices or small varices are seen, EGD should be repeated in 1 year. 37 If varices are seen,
follow algorithm as in compensated cirrhosis.
Figure 4:
Esophageal
variceal
screening
algorithm in
cirrhosis.
(see text)
 In patients with clinically compensated cirrhosis, EGD is indicated for variceal screening. Alternatively, non-
invasive assessment of liver stiffness (transient elastography) and platelet count can guide the need for EGD.
Patients with liver stiffness measurement of <20 kPa and platelet count >150k/mm3 have a low risk of having
clinically significant varices requiring treatment on EGD (<5%). These patients can safely avoid EGD (AASLD
and Baveno VI recommendation).22, 23
 Repeat transient elastography and platelet count q 1 year and perform EGD if these measurements change
outside of these parameters. 23
If no varices are seen on EGD:
 Repeat EGD in 3 years in patients who do not have ongoing liver injury, or every 2 years if there is ongoing
liver injury (e.g. alcohol, obesity in NASH, untreated hepatitis C)
 If small varices are seen without high risk features such as red wale signs or in patients with advanced cirrhosis
(Child Pugh C), start Non selective beta blockers (NSBB).22
 If small varices are seen without high risk features, repeat EGD in 1 year if there is ongoing liver injury, or in 2
years in those without ongoing liver injury. 22
 In patients with medium or large varices that have not bled, give NSBB or perform EVL for primary prophylaxis.
Combination NSBB and EVL is not recommended for primary prevention of bleeding (studies have shown no added
benefit of combination therapy compared to monotherapy in this setting)
 If NSBB are chosen, titrate the dose for a resting heart rate of 55-60.No need for follow up EGD.
 If the patient cannot tolerate NSBB, then EVL should be performed.
 If variceal banding is performed, repeat banding every 2-4 weeks until varices obliterated, then at 6 months,
then every 6-12 months for surveillance.
 Non-selective beta blockers (NSBB)

 NSBB decrease cardiac output (β1 blockade) and cause splanchnic vasoconstriction (β2 blockadeunopposed
α adrenergic stimulation); both these effects decrease portal pressure.22
 One meta-analysis showed that NSBB decrease the risk of bleeding by 44% and the risk of death from
bleeding by 42%. 38 The number needed to treat to prevent one bleeding episode is 6.
 Medications: propranolol (starting dose of 20 - 40 mg twice daily, max dose 320 mg/day) and nadolol (starting dose
of 20-40 mg once daily, max dose 160 mg/day), carvedilol (6.25 once daily).
 Patients with refractory ascites can receive NSBB, but avoid high doses (the maximum dose of propranolol is
160 mg daily and nadolol 80 mg daily). Monitor BP, and decrease dose/ suspend the medication if systolic
BP<90 mmHg, and in patients with hepatorenal syndrome.22
 EVL
 Perform EVL every 2-4 weeks until obliteration of esophageal varices.
 A randomized trial of EVL q1week versus q2weeks showed that EVL q1week achieves eradication more rapidly
(18.1 vs. 30.8 days), but there were no differences in the rebleeding rate or mortality.39
 Recurrence of varices is common, surveillance every 6-12 months is recommended after variceal eradication.
 TIPS is not recommended for the primary prophylaxis of esophageal variceal bleeding.
Secondary prophylaxis of esophageal variceal bleeding

 Secondary prophylaxis of variceal bleeding (in patients who recovered from acute variceal bleeding) is performed
using combination NSBB (nadolol or propranolol, not carvedilol) and EVL.
 If the patient received successful TIPS, there is no need for EVL or NSBB.
Portal hypertensive gastropathy
 Endoscopic appearance
 In mild gastropathy, the mucosa has a mosaic, polygonal pattern.
 In severe gastropathy, the mucosa has a mosaic pattern in addition to petechial erythema.
 Spontaneous bleeding may be present. However, severe bleeding is uncommon.
 Mucosal involvement is more pronounced in the proximal stomach (body > antrum).
 This is in contrast to GAVE which mainly affects the antrum (see below).
 Bleeding risk correlates with the severity of portal hypertension.
 NSBB can be given for secondary prophylaxis following an episode of bleeding.
 TIPS can be used for recurrent or refractory bleeding.
Gastric Antral Vascular Ectasia
 Gastric antral vascular ectasia (GAVE) consists of multiple ectasias scattered in the gastric antrum.
 When they are arranged in a linear pattern, the appearance is often referred to as "watermelon stomach".
 It may also have a diffuse nodular appearance that resembles hyperplastic polyps.
 GAVE can cause severe recurrent bleeding leading to iron deficiency.
 It is associated with cirrhosis; however, most cases occur in patients without cirrhosis.
 Mucosal biopsy can differentiate between portal HTN gastropathy and GAVE.
 Biopsy in GAVE shows dilated mucosal capillaries, fibrin thrombi, and spindle cell proliferation.
 Endoscopic treatment with argon plasma coagulation (APC) is effective (video 7-4)
 Other treatments include radiofrequency ablation40, band ligation for nodular GAVE 41,
tranexamic acid (antifibrinolytic), and gastric antral resection in refractory bleeding.
 Bleeding from GAVE is not related to portal hypertension. Therefore, TIPS and
beta blockers are not helpful. GAVE reverses with liver transplantation. Video 7-4
Lower GI bleeding
ASGE Guideline: the role of endoscopy in the patient with lower-

ASGE, 2014
GI bleeding 42
Management of Patients With Acute Lower Gastrointestinal

ACG 2016
Bleeding 43
Diagnosis and management of acute lower gastrointestinal

Gut, 2019
bleeding: guidelines from the British Society of Gastroenterology 44
 The classic definition of lower GI bleeding is GI bleeding from a source distal to the ligament of Treitz.
 The practical definition is GI bleeding from a distal ileal or colonic source (accessible with a regular colonoscope).
 Etiologies: The most common etiologies of LGIB are diverticulosis and angiodysplasia.
 Diverticular bleeding ceases spontaneously in 90% of cases.
 Other etiologies of LGI bleeding include ischemic colitis, Dieulafoy's lesion, hemorrhoids, rectal ulcer,
rectal varices and post polypectomy bleeding.
 Management
 Adequate resuscitation and blood transfusions.
 Consider an upper GI source of bleeding in patients with severe hematochezia and hemodynamic instability.
 Perform EGD in patients with a bloody NG tube aspirate, cirrhosis, or risk factors for UGI bleeding.
 Colonoscopy: ASGE recommends colonoscopy for the "early" management of severe acute LGI bleeding.
 Consider a rapid purge (polyethylene glycol given via NG tube over 1-1.5 hours) followed by early colonoscopy.
 Earlier studies suggested that early colonoscopy for acute lower GI bleeding might increase early control of
bleeding and reduces rebleeding.45, 46 These improved outcomes were not reproduced in later studies. Small,
single center, randomized trials showed that urgent colonoscopy in patients with serious lower GI bleeding
does not improve clinical outcomes nor lowers costs compared to elective colonoscopy. 47, 48
 A recent meta-analysis of randomized trials found that early colonoscopy within 24 hours does not reduce
further bleeding or mortality in patients admitted with acute LGIB.49
 An open label multicenter randomized trial of 170 patients in japan showed no difference in identification of
stigmata of recent hemorrhage and rebleeding rates early between early colonoscopy (within 24 hours of
hospital visit) and elective colonoscopy (24-96 hours).50
 Examples of therapeutic endoscopic therapy: APC treatment of AVMs; epinephrine injection and endoclip
placement for active diverticular bleeding (video 7-5).
 In cases of massive GI bleeding, angiography is indicated for localization and therapy.
 In post-polypectomy bleeding, minimize workup; treat with colonoscopy and endoscopic
hemostasis.
Video 7-5
Small bowel and Obscure GI bleeding
AGA Institute technical review on obscure Gastroenterology

gastrointestinal bleeding 51 2007
The role of endoscopy in the management of suspected Gastrointestinal
small-bowel bleeding 52 Endoscopy 2017
Diagnosis and Management of Small Bowel Bleeding 53 ACG, 2015
 In patients with GI bleeding and negative workup with EGD and

colonoscopy, the term “potential small bowel bleeding” should
be used to describe these bleeding cases (figure 5).
 Small bowel GI bleeding (or mid GI bleeding) is defined as
bleeding from a source that is not reachable with an upper
endoscope or a colonoscope (from the ampulla of Vater to the
terminal ileum).
 The term “Obscure GI bleeding (OGIB)” should be used only
after negative small bowel evaluation, usually with capsule
endoscopy as the first line investigation of the small bowel.
 Overt bleeding refers to visible bleeding with hematochezia
or melena, and occult bleeding refers to iron deficiency
anemia, with or without hemoccult positive stool.
 Possible causes of small bowel bleeding are shown in table 3.
 OGIB can be caused by missed lesions on EGD or colonoscopy
(table 4), or missed lesion in the small bowel. Figure 5: Workup and nomenclature
used in patients with GI bleeding
Table 3: Etiology of small bowel bleeding. after negative EGD and colonoscopy
Age < 45 years Age ≥ 45 years Rare causes
 Small intestinal tumors*  Angiodysplasia  Hemobilia‡
 Meckel's diverticulum†  NSAID enteropathy  Hemosuccus Pancreaticus
 Crohn's disease  Tumors  Aorto-enteric fistula
 Polyposis syndromes  Dieulafoy’s lesions
 Dieulafoy’s lesions  Celiac disease
 Angiodysplasia
 Celiac disease
*GIST, neuroendocrine tumors, lymphoma, adenocarcinoma
†Meckel’s diverticulum is a true diverticulum that contains gastric mucosa and can lead to bleeding in the adjacent
ileal mucosa. It is usually 2 inches long, and located 2 feet from the ileocecal valve.
‡Hemobilia most commonly results from hepatobiliary instrumentation (TIPS, PTC, liver biopsy) or hepatobiliary tumors.
Table 4: Missed lesions on EGD and colonoscopy
Missed lesions on
Missed lesions on EGD
Colonoscopy
 Peptic ulcer disease*  Angiodysplasia
 Fundal varices  Malignancy
 Angiodysplasia or Dieulafoy’s lesions (especially periampullary location)  Dieulafoy’s
 Gastric antral vascular ectasia (GAVE): misdiagnosed as gastritis lesions
 Cameron erosions: appear as small longitudinal ulcerations at the diaphragmatic  Hemorrhoids
impression of a hiatal hernia (video 7-6), and can lead to chronic occult blood loss.
*Commonly overlooked areas are the pyloric channel, the duodenal sweep and the medial wall of the duodenal bulb
 If the patient with OGIB has a rebleeding episode with a suspicion of an upper GI bleeding source (e.g.
melena), it is reasonable to repeat an upper endoscopy (EGD or push enteroscopy).
 The diagnostic yield of repeat EGD is 15-25%. Consider using a side viewing scope to examine
the periampullary area and the medial wall of the duodenum.
 The yield of repeat colonoscopy is generally low, unless the initial colonoscopy was incomplete
or the prep was inadequate.
 Small bowel endoscopy Video 7-6
 Push enteroscopy (PE): PE can examine the proximal 90-150 cm of the small bowel.
 The yield of PE in obscure GI bleeding varies between 24-56%.
 Capsule endoscopy (CE)
 CE has higher yield compared to push enteroscopy in patients with OGIB (50% vs. 24%). 54
 Following a negative EGD, colonoscopy and push enteroscopy, the diagnostic yield of capsule
endoscopy in obscure GI bleeding is ~ 30%.
 Diagnostic yield is higher if CE is performed during the acute bleeding episode.
 Rebleeding rate after a negative capsule endoscopy is 5-10%.
 Miss rate of CE
o A meta-analysis of 32 studies including 691 patients showed that the overall CE miss rate was 10.8%.
The miss rate was 5.9% for vascular lesions, 0.5% for ulcers, and 19% for small bowel neoplasms.55
o In patients with overt OGIB and a negative CE, other small bowel studies such as deep enteroscopy
and CT enterography should be obtained for further workup. This is especially important in young
patients who are more likely to have small bowel neoplasms.
o Consider repeat CE in patients with persistent overt OGIB, especially if there is a significant drop in
HGB, or if the previous CE study was incomplete.
 Deep enteroscopy
 Deep enteroscopy is performed using special overtubes that "pleat" the bowel over the endoscope,
allowing for deeper insertion into the small bowel.
 Options of deep enteroscopy include single balloon, double balloon, or spiral enteroscopy.
 Deep enteroscopy can be performed anterograde (to examine the proximal small intestine), or retrograde
(to examine the distal small intestine).
 The decision to perform anterograde vs. retrograde deep enteroscopy is based on the results of capsule endoscopy.
If the lesion is reached within the first two thirds of the small bowel time, perform anterograde deep enteroscopy.
If the lesion is reached within the last third of the small bowel time, perform a retrograde deep enteroscopy.
 Double balloon enteroscopy (DBE)
o DBE can examine 240 -300 cm of the small bowel (100-140 cm of the ileum).
o It has a higher yield compared to PE (73% vs. 44%), and a comparable diagnostic yield compared to CE. In a
meta-analysis of 11 studies, the pooled overall yield was 60% for CE and 57% for DBE. 56
 Deep enteroscopy has the advantage of being both a diagnostic and therapeutic procedure, compared to
CE, which is purely diagnostic.
o However, since CE is non-invasive, it is reasonable to start with CE. This is followed by deep
enteroscopy if a lesion is identified.
 Small bowel imaging
 Small bowel follow through (small bowel radiography) has a low yield for small bowel lesions, and it is
not recommended in the workup of small bowel bleeding. 53
 A prospective randomized study showed that in obscure GI bleeding (including negative push enteroscopy),
the diagnostic yield for capsule endoscopy was 30% compared to 7% in small bowel follow through. 57
 Radionuclide scan: Scans for overt OGIB (detect bleeding at a rate of ≥ 0.1 ml/min)
 Technetium sulfur colloid.

 Technetium pertechnetate-labeled autologous red blood cells.
o A positive scan is followed by angiography for further localization and treatment.
 Scans for Meckel's diverticulum
o 99m technetium pertechnetate scan detects ectopic gastric mucosa in the diverticulum.
 Angiography
 Indicated in acute massive GI bleeding. Detects bleeding at a rate of ≥ 0.5-1 ml/min.
 A prospective randomized study showed that in patients with acute overt OGIB (negative upper and
lower endoscopy), capsule endoscopy had a higher diagnostic yield compared to angiography
(53.3% vs. 20%), with similar rates of rebleeding and mortality. 58
 CT Enterography (CTE) has variable quality and diagnostic yield among different centers.
 It has a higher yield for overt OGIB compared to occult OGIB.
 Studies have shown that CTE can detect small bowel tumors missed on capsule. 59, 60 Consider CTE in
OGIB in patients with negative CE or in suspected small bowel bleeding and contraindications to
capsule endoscopy.53
 Intraoperative enteroscopy (IOE)
 IOE is an invasive procedure in which a laparotomy and enterotomy is performed. An endoscope is
inserted through the enterotomy to examine the small bowel (Figure 6).
 IOE is reserved for patients with continued overt OGIB in which other techniques (CE, deep
enteroscopy, angiography) are unsuccessful or unavailable.
Figure 6: Intraoperative enteroscopy.

The scope is inserted through an enterotomy while another operator pleats the small intestine over the scope.
The scope dials are controlled separately.
 Pharmacologic provocation
 Patients with refractory OGIB, or bleeding from a known segment of the GI tract without a clear lesion, can be
considered for careful pharmacologic provocation using IV heparin and clopidogrel (150-300mg po).
 If there is a known area of bleeding identified on prior workup without a clear lesion, pharmacologic
provocation should be followed by targeted endoscopy of that area.
 If the source of bleeding is completely unknown, pharmacologic provocation should be followed by capsule
endoscopy (preferred) or deep enteroscopy to first identify the source of bleeding.
 One retrospective study of 27 patients who underwent pharmacologic provocation followed by

endoscopic workup found that this intervention was revealing in 15 patients (56%). 61
 Lesions that were found in these patients were typical lesions associated with obscure bleeding:
Dieulafoy lesions, angiodysplasia, neuroendocrine tumor, Hemosuccus Pancreaticus, aorto-enteric
fistula, and gastric antral vascular ectasia.61
 Patients with refractory OGIB in whom previous studies were unrevealing can be considered for
provocative angiography (pharmacologic provocation followed by angiography). 53
 One small retrospective study (n=34 patients) showed that this intervention was successful in finding
and treating the bleeding source in 11 of 36 studies (31%). 62
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Gastroenterology 2021;160(1):193-205.e10. gastrointestinal bleeding. Routine outcomes and cost
31. de Franchis R. Revising consensus in portal analysis. Gastrointest Endosc Clin N Am
hypertension: report of the Baveno V consensus 1997;7(3):477-98.
workshop on methodology of diagnosis and therapy in 46. Jensen DM, Machicado GA, Jutabha R, Kovacs TO.
portal hypertension. Journal of Hepatology Urgent colonoscopy for the diagnosis and treatment of
2010;53(4):762-8. severe diverticular hemorrhage. N Engl J Med
32. Cheng LF, Wang ZQ, Li CZ, et al. Low Incidence of 2000;342(2):78-82.
Complications From Endoscopic Gastric Variceal 47. Laine L, Shah A. Randomized Trial of Urgent vs.
Obturation With Butyl Cyanoacrylate. Clinical Elective Colonoscopy in Patients Hospitalized With
gastroenterology and hepatology : the official clinical Lower GI Bleeding. Am J Gastroenterol 2010.
practice journal of the American Gastroenterological 48. Green BT, Rockey DC, Portwood G, et al. Urgent
Association 2010;8(9):760-66. colonoscopy for evaluation and management of acute
33. Mohan BP, Chandan S, Khan SR, et al. Efficacy and lower gastrointestinal hemorrhage: a randomized
safety of endoscopic ultrasound-guided therapy versus controlled trial. Am J Gastroenterol
direct endoscopic glue injection therapy for gastric 2005;100(11):2395-402.
varices: systematic review and meta-analysis. 49. Tsay C, Shung D, Frumento KS, Laine L. Early
Endoscopy 2020;52(4):259-67. Colonoscopy Does Not Improve Outcomes of Patients
34. Romero-Castro R, Ellrichmann M, Ortiz-Moyano C, et With Lower Gastrointestinal Bleeding: Systematic
al. EUS-guided coil versus cyanoacrylate therapy for Review of Randomized Trials. Clinical
the treatment of gastric varices: a multicenter study Gastroenterology and Hepatology.
(with videos). Gastrointestinal Endoscopy 50. Niikura R, Nagata N, Yamada A, et al. Efficacy and
2013;78(5):711-21. Safety of Early vs Elective Colonoscopy for Acute
35. Bhat YM, Weilert F, Fredrick RT, et al. EUS-guided Lower Gastrointestinal Bleeding. Gastroenterology
treatment of gastric fundal varices with combined 2020;158(1):168-75.e6.
injection of coils and cyanoacrylate glue: a large U.S. 51. Raju GS, Gerson L, Das A, Lewis B. American
experience over 6 years (with video). Gastrointest Gastroenterological Association (AGA) Institute
Endosc 2016;83(6):1164-72. Technical Review on Obscure Gastrointestinal
36. Patel A, Fischman AM, Saad WE. Balloon-Occluded Bleeding. Gastroenterology 2007;133(5):1697-717.
Retrograde Transvenous Obliteration of Gastric 52. Gurudu SR, Bruining DH, Acosta RD, et al. The role
Varices. American Journal of Roentgenology of endoscopy in the management of suspected small-
2012;199(4):721-29. bowel bleeding. Gastrointest Endosc 2017;85(1):22-
37. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. 31.
Prevention and management of gastroesophageal 53. Gerson LB, Fidler JL, Cave DR, Leighton JA. ACG
varices and variceal hemorrhage in cirrhosis. Clinical Guideline: Diagnosis and Management of
Hepatology 2007;46(3):922-38. Small Bowel Bleeding. Am J Gastroenterol
2015;110(9):1265-87; quiz 88.
54. de Leusse A, Vahedi K, Edery J, et al. Capsule study with long-term follow-up. Am J Gastroenterol
endoscopy or push enteroscopy for first-line 2012;107(9):1370-6.
exploration of obscure gastrointestinal bleeding? 59. Hara AK, Leighton JA, Sharma VK, Fleischer DE.
Gastroenterology 2007;132(3):855-62; quiz 1164-5. Small bowel: preliminary comparison of capsule
55. Lewis BS, Eisen GM, Friedman S. A pooled analysis endoscopy with barium study and CT. Radiology
to evaluate results of capsule endoscopy trials. 2004;230(1):260-5.
Endoscopy 2005;37(10):960-5. 60. Huprich JE, Fletcher JG, Alexander JA, et al. Obscure
56. Pasha SF, Leighton JA, Das A, et al. Double-balloon gastrointestinal bleeding: evaluation with 64-section
enteroscopy and capsule endoscopy have comparable multiphase CT enterography--initial experience.
diagnostic yield in small-bowel disease: a meta- Radiology 2008;246(2):562-71.
analysis. Clin Gastroenterol Hepatol 2008;6(6):671-6. 61. Raines DL, Jex KT, Nicaud MJ, Adler DG.
57. Laine L, Sahota A, Shah A. Does capsule endoscopy Pharmacologic provocation combined with endoscopy
improve outcomes in obscure gastrointestinal in refractory cases of GI bleeding. Gastrointest Endosc
bleeding? Randomized trial versus dedicated small 2017;85(1):112-20.
bowel radiography. Gastroenterology 62. Kim CY, Suhocki PV, Miller MJ, Jr., et al. Provocative
2010;138(5):1673-80 mesenteric angiography for lower gastrointestinal
58. Leung WK, Ho SS, Suen BY, et al. Capsule endoscopy hemorrhage: results from a single-institution study. J
or angiography in patients with acute overt obscure Vasc Interv Radiol 2010;21(4):477-83.
gastrointestinal bleeding: a prospective randomized
8
193
CHAPTER
Large Intestine
Chapter 8- Large intestine
Around 20% of the GI boards' questions cover the large intestine (including IBD - chapter 9).
Infectious diarrhea is an all-time favorite exam topic. Clostridioides difficile infection is an
important nosocomial disease. Fecal microbiota transplantation is rapidly gaining acceptance
as an effective treatment for recurrent C. difficile. New IDSA guidelines recommend
Vancomycin for all cases as first line treatment. Fidaxomicin and Bezlotoxumab are newly
approved treatments. A summary of chronic diarrhea is presented with a focus on differential
diagnosis and workup. Chronic constipation and IBS are common in our practice. Several new
drugs were recently FDA approved, and are described in this chapter. Immune checkpoint
inhibitor associated colitis is a relatively new entity associated with new cancer drugs, and
has a specific treatment approach. Lynch syndrome seems to be underdiagnosed in clinical
practice, and it is imperative to test for this syndrome in patients with suggestive clinical
features and family history. Other polyposis syndromes (FAP, Peutz-Jeghers, etc.) are
uncommon in practice, but are a favorite exam topic. Colon cancer screening is one of the
most important services we provide to our patients, and is presented in some detail in this
chapter. There is evidence that colonoscopy quality is related to important outcomes (post
colonoscopy colon cancer). Therefore, there is a strong focus on colonoscopy quality metrics
and interventions for quality improvement. New ACG, USPSTF, US multi society (ACG, AGA,
ASGE), American Cancer Society (ACS), and American College of Physicians (ACP) guidelines
were recently published. While CRC incidence and mortality have been decreasing overall, the
incidence in young persons (<50) has been steadily increasing. This has prompted several
societies and groups to lower the recommended age to start screening for CRC in all individuals
to 45 years. There are also new guidelines on follow-up post colonoscopy and polypectomy by
the USMSTF (2020) which are summarized in a table at the end of this chapter. The reader
should also review a new USMSTF consensus statement on Endoscopic Removal of Colorectal
Lesions, which is not summarized in this book.
194 Chapter 8: Large Intestine
Contents
Chapter 8- Large intestine Hamartomatous polyposis syndromes—229

Gastrointestinal infections—195 Peutz-Jeghers syndrome—229
Bacterial infections—195 Juvenile polyposis syndrome—230
Viral infections—199 Cowden syndrome—230
Parasitic infections—200 Bannayan-Riley-Ruvalcaba syndrome—231
Trichuris Trichiura (Whipworm)—201 Serrated polyposis syndrome—231
Traveler's diarrhea—201 Cronkhite-Canada Syndrome—232
Food poisoning—202 Lynch Syndrome and Hereditary Nonpolyposis
Clostridioides difficile infection—204 Colorectal Cancer—232
Chronic diarrhea—209 —232
Chronic constipation—211 Colorectal cancer—235
Irritable bowel syndrome—214 Management of advanced and malignant

polyps—239
Non-IBD colitides—217
Colon cancer screening—240
Microscopic colitis—217
Stool testing—241
Diversion colitis—219
Other tests—242
Chronic radiation proctitis—219
Colonoscopy—242
Immune checkpoint inhibition-induced colitis
(Immune-mediated colitis)—220 Flexible sigmoidoscopy—245
Segmental Colitis Associated with CT colonography—245

Diverticulosis (SCAD)—221 Polyp surveillance—245
Ischemic colitis—221 References—247
Melanosis Coli—223
Acute colonic pseudo-obstruction (Ogilvie's
syndrome)—224
Colonic polyps—225
Paris classification of colonic neoplasia—226
Gastrointestinal polyposis syndromes—226
Adenomatous polyposis syndromes—227
Familial adenomatous polyposis—228
Attenuated FAP—229
MutYH (MYH) associated polyposis.—229
Chapter 8: Large Intestine 195
Gastrointestinal infections
Bacterial infections
Vibrio cholerae
 Vibrios are gram-negative, curved, comma shaped bacteria.
 The pathogenicity of Vibrio cholera is related to its enterotoxin production.
 The cholera toxin is composed of two subunits: A (active) subunit and B (binding) subunit.
 Subunit B binds enterocyte receptors, while subunit A activates adenylate cyclase, which increases cAMP
levels. This leads to increased small intestinal electrolyte and fluid loss, and severe watery diarrhea.
 V. cholera does not invade the epithelium.
 Infection results from oral ingestion of the bacteria through contaminated food and water.
 A large infective dose is required (≥ 108). The bacteria are easily killed by gastric acid.
 Infection is more common in patients with hypochlorhydria due to PPI.
 Incubation period is 2 to 5 days.
 Symptoms include large volume watery diarrhea, nausea, and vomiting. Severe dehydration leads to
hypotension, tachycardia, and renal failure.
 Treatment is mainly supportive with correction of fluid and electrolyte imbalances.
 Antibiotics shorten the duration of disease and bacterial fecal shedding. Treatment options include
tetracycline, doxycycline, azithromycin, or fluoroquinolones.
Vibrio parahaemolyticus
 V. parahaemolyticus causes acute gastroenteritis resulting from consumption of raw or undercooked seafood,
particularly oysters.
 Infection is common in Japan. It is much less common in the United States, where most infections are reported
in the coastal states.
 Moderate to severe watery diarrhea, abdominal cramps, nausea, and vomiting.
 Less commonly, V. parahaemolyticus can lead to skin and soft tissue infections.
 The disease is self-limited and lasts 3-5 days.
 Treatment is supportive. Antibiotics are not necessary.
Vibrio vulnificus
 V. vulnificus is the leading cause of seafood-related deaths in the USA.
 Most common vehicles for V. vulnificus infections are oysters and shellfish.
 Patients with cirrhosis are particularly susceptible to this infection due to immune system dysfunction related
to decreased complement levels and reduced phagocytic activity.
 V. vulnificus causes three main clinical syndromes:
 Wound infections occur in 45% of cases. They can progress rapidly and lead to severe bullous skin lesions,
cellulitis, and myositis. The case fatality rate is ~ 15%.
 Primary septicemia occurs in 45% of cases, with a case fatality rate of ~50%.
 Gastroenteritis occurs in 10% of cases and has low mortality.
 Fevers, chills, diarrhea, nausea, vomiting, lower extremity cellulitis, bullae, and ecchymosis.
 Diagnosis: V. vulnificus infection is suspected based on the clinical presentation, and confirmed by blood and
wound cultures.
 Treatment
 IV doxycycline combined with IV third generation cephalosporin (ceftriaxone or ceftazidime).
 An alternative regimen is fluoroquinolone combined with cefotaxime.
 Surgical consultation is needed in cases of necrotizing fasciitis.
 Prevention: patients who are immunocompromised (including those with chronic liver disease and cirrhosis)
should avoid eating raw seafood, especially oysters.
Escherichia coli
 Enterotoxigenic E. coli (ETEC)
 ETEC is the most common cause of traveler's diarrhea (see page 201), and is a major cause of acute diarrhea
in children in developing countries.
 It produces two kinds of toxins:
 Heat-labile toxin (LT) stimulates adenylate cyclase resulting increase fluid secretion and severe watery
diarrhea (similar to the cholera toxin described earlier).
 Heat stable toxin (ST) stimulates guanylyl cyclase, which also increases fluid secretion.
 ETEC does not cause an invasive intestinal infection.
 Most cases are caused by contaminated food or water.
 Clinical manifestations include watery diarrhea, abdominal pain, nausea, and vomiting.
 Most infections last for 3-5 days.
 Treatment for mild cases is supportive. Antibiotics are given for patients with more severe symptoms (page 201)
 Enteroinvasive E. coli (EIEC)
 EIEC is an uncommon cause of gastroenteritis. It can lead to an invasive diarrhea and dysentery similar to
shigellosis. It produces a toxin similar to Shigella toxin.
 Clinical manifestations include watery or bloody diarrhea, abdominal cramps, and fever.
 Treatment is supportive. Antibiotics are given to patients with severe symptoms.
 Enteropathogenic E. coli (EPEC)
 EPEC is an important cause of diarrhea in infants in developing countries. 1
 EPEC tightly adheres to the small intestinal epithelium, leading to effacement of the microvilli. This
characteristic feature of EPEC is called "attachment and effacement", and is seen on electron micrographs
of small intestinal biopsies. 1
 Clinical manifestations include watery diarrhea, fever, and dehydration.
 Treatment is supportive.
 Enterohemorrhagic E. coli (EHEC)
 EHEC is also called Shiga toxin-producing E. coli (STEC) due to its ability to produce two types of toxins
similar to Shigella: Shiga-like toxin 1 and Shiga-like toxin 2. 1
 EHEC is a common cause of bloody diarrhea in the United States.
 It is associated with hemorrhagic colitis, hemolytic uremic syndrome (HUS), and thrombotic
thrombocytopenic purpura.
 E. coli serotype O157:H7 is the most common strain associated with hemorrhagic colitis.
 HUS consists of microangiopathic anemia, renal failure, and thrombocytopenia.
 It develops due to direct toxicity of the Shiga-like toxin on the endothelial cells of the kidney and small
blood vessels. This leads to microthrombi formation (thrombotic microangiopathy), renal failure, and
hemolytic anemia.
 Treatment with antibiotics increases the amount of Shiga-like toxin release and increases the risk of
developing HUS. 2
 E. coli O157:H7 colitis can resemble ischemic colitis. This is likely due to fibrin thrombi formation and
ischemic-like colonic injury.3
 Clinical features
 Infection is most commonly acquired by ingesting undercooked hamburger meat.
 Incubation period is 3-5 days.
 The patient develops fever, chills, abdominal cramps, nausea, vomiting and bloody diarrhea.
 Diagnosis
 E. coli O157:H7 differs from other E. coli bacteria by its inability to ferment sorbitol. It is detected by
performing bacterial culture on a special medium (sorbitol MacConkey agar).
 Shiga-like toxin can be detected using enzyme immunoassays (EIAs) or PCR. 1
 Treatment
 Supportive care. Place patients on contact isolation.
 Antibiotics and anti-motility agents are not recommended due to the possible increased risk of HUS.
 Enteroaggregative E. coli (EAEC)
 EAEC causes acute and chronic watery diarrhea in children in developing countries and in HIV patients. It
is also a cause of traveler's diarrhea.
 Diffusely adherent E. coli (DAEC)
 DAEC is associated with diarrhea in children.
Salmonella
 Salmonella is a gram-negative, rod shaped bacterium. It is divided into two main categories:
 Typhoidal salmonella (S. typhi and S. paratyphi) causes typhoid fever.
 Non typhoidal salmonella
 S. enteritidis, S. typhimurium and S. newport are the most common serotypes in the United States.4 The
following discussion is related to non-typhoidal salmonella.
 Non-typhoidal Salmonella is most commonly acquired after ingestion of contaminated raw or undercooked
eggs. Poultry, pork, beef, peanut butter, dairy products, and many other types of food have been implicated
in the transmission of salmonellosis.
 Persons with the highest risk of infection are the elderly, infants, immunocompromised and cancer patients.
 Incubation period is 12-72 hours.
 Most patients develop gastroenteritis of variable severity.
 Symptoms include nausea, vomiting, abdominal pain, and diarrhea (watery or bloody).
 Symptoms usually resolve in 4-7 days. Bacterial shedding in stool lasts for an average of 2-4 weeks.
Chronic fecal carriage (> 1 year) is rare.
 Uncommon complications: Bacteremia (< 10% of patients), severe enterocolitis and toxic megacolon,
endocarditis, osteomyelitis, cholecystitis.
 Treatment
 Antibiotics are not necessary in most patients with salmonella gastroenteritis, as they do not shorten the
disease duration. In addition, antibiotics can prolong the duration of fecal carriage.
 Indications for antibiotic treatment include extremes of age (< 1 year old and the elderly),
immunocompromised patients, patients with prosthetic valves, vascular grafts, hemolytic anemia and those
with severe disease.
 Antibiotic options include fluoroquinolones, trimethoprim-sulfamethoxazole, ampicillin, amoxicillin, or third-

generation cephalosporins (ceftriaxone, cefotaxime).
 Chronic carrier states should be treated with ampicillin or ciprofloxacin. In resistant cases, cholecystectomy
should be considered to remove the bacterial reservoir.
Shigella
 Shigella is a gram-negative, rod shaped bacterium.
 The most common pathogenic Shigella species are Shigella dysenteriae, Shigella flexneri, Shigella boydii, and
Shigella sonnei.1
 Shigella sonnei is the most common species in the United States.
 ~15,000 cases of shigellosis occur annually in the United States.
 Most infections occur in young children who are 2 to 4 years old.
 Shigella has a very low infective dose (100 organisms can cause disease).
 Pathogenesis
 The most important pathogenic mechanism in shigellosis is the direct invasion of the bacteria into the
colonic epithelium. This is followed by bacterial cell-to-cell transmission, resulting in severe mucosal
ulcerations and abscesses.
 Shigella dysenteriae produces an enterotoxin (shigatoxin) that contributes to the colonic inflammation seen
in shigellosis. EHEC produces a similar toxin (see page 196).
 Shigellosis is spread by the feco-oral route. Incubation period is 1-3 days.
 Patients present initially with watery diarrhea. This is followed by the development of fever, abdominal
pain, and bloody diarrhea (dysentery).
 The disease usually resolves in 5 to 7 days.
 Complications: Bacteremia (< 5%), reactive arthritis 2-3 weeks post infection (~2%), hemolytic uremic
syndrome, toxic megacolon.
 Treatment
 Antibiotic treatment is indicated in all confirmed cases of shigellosis to decrease the duration of the disease
and limit person-to-person spread.
 Ciprofloxacin is the drug of choice. Other options include azithromycin, trimethoprim-
sulfamethoxazole, and ceftriaxone.
 Antidiarrheal agents are contraindicated as they can worsen symptoms and prolong the infection.
Yersinia
 Yersinia is a gram-negative coccobacillus.
 Yersinia infection (yersiniosis) is uncommon in the United States. Yersinia enterocolitica accounts for the
majority of cases. Most infections are reported in children.
 The disease is acquired by eating contaminated foods (especially pork), milk, or water.
 Yersiniosis most commonly affects the terminal ileum, and can mimic Crohn's ileitis.
 Patients present with fever, nausea, vomiting, diarrhea, and abdominal pain.
 Severe systemic yersiniosis is associated with iron overload and deferoxamine therapy.
 Treatment is indicated in patients with severe disease or prolonged symptoms. Antibiotic options include
tetracyclines, trimethoprim-sulfamethoxazole, fluoroquinolones, or ceftriaxone.
Campylobacter
 Campylobacters are gram-negative curved rods.
 Campylobacter jejuni and Campylobacter coli are the most common cause of bacterial diarrhea in the United States.
 Infection is acquired by eating contaminated foods (especially chicken), milk, or water.
 The mean incubation period is 3 days.
 One third of patients develop a prodrome of fever, headaches, and myalgias. Most patients present with watery
diarrhea followed by bloody stools and abdominal pain.
 Symptoms usually resolve within 1 week.
 Uncommon complications include bacteremia, severe enterocolitis, toxic megacolon, cholecystitis, Guillain-
Barré syndrome, and HUS.
 Antibiotics are indicated in severe cases and in immunocompromised patients. Treatment with
fluoroquinolones or erythromycin is effective.
Viral infections
Rotavirus
 Rotavirus is an important cause of diarrhea in children.
 It is spread by the feco-oral route. Incubation period is 1-3 days.
 Symptoms include fever, vomiting, abdominal pain, and watery diarrhea. Adult patients are usually
asymptomatic or have mild symptoms.
 Diagnosis: stool rotavirus antigen, or stool PCR.
 Treatment: supportive care, correction of fluid and electrolyte imbalances.
Norovirus
 Norovirus was previously known as Norwalk or Norwalk-like virus. It belongs to the Caliciviridae family of
viruses.
 Norovirus is the most common cause of acute gastroenteritis in the United States. It is responsible for 570–
800 deaths, 56,000–71,000 hospitalizations, and an ~20 million total illnesses per year.5
 Norovirus causes epidemics of gastroenteritis affecting all age groups.
 Outbreaks commonly occur in nursing homes, schools, airplanes, and cruise ships.
 Foods that are commonly related to infection include raw shellfish, especially oysters that are grown in
contaminated water.
 The infection is spread from person to person by the feco-oral route.
 The incubation period is 1-2 days. Patients develop nausea, vomiting abdominal pain, and diarrhea. Some
patients develop fevers, headaches and muscle aches.
 Symptoms usually resolve in 1-3 days.
 Diagnosis: diagnostic tests are not recommended for sporadic cases.
 Tests include stool antigen immunoassay, and stool PCR.
Parasitic infections
Entamoeba histolytica
 E. histolytica is endemic in Africa, Asia and central and South America. 6
 Risk groups for amebiasis include travelers to tropical areas with poor sanitation, immigrants from tropical
countries, and homosexual men.
 The parasite exists in two forms: trophozoites (motile, active form) and cysts (non-motile, responsible for
transmission of the parasite).
 Life cycle
 Ingestion of mature E. histolytica cysts in contaminated food or water is followed by the release of
trophozoites in the small intestine.
 Trophozoites migrate to the colon where they continue to multiply. The parasite is then excreted in both
forms (trophozoites and cysts) in stool.
 Colonization of the colon can lead to chronic asymptomatic intestinal amebiasis, or to invasive infection
(colitis and less commonly ileitis).
 Symptoms develop 1-3 weeks following ingestion of the cysts. Patients present with bloody diarrhea,
abdominal pain, fever, and tenesmus.
 Amebic colitis varies in severity and can lead to perforation in fulminant cases. The mucosa develops
erythema, edema, and deep flask-shaped ulcers.
 Extraintestinal infection most commonly results in amoebic liver abscess.
 Diagnosis
 Stool microscopy shows amebic cysts or trophozoites in the stool.
 Demonstration of these cysts or trophozoites is not pathognomonic for E. histolytica.
 Other non-pathogenic amoebas, such as E. dispar, are morphologically similar to E. histolytica.
 The demonstration of red blood cells inside trophozoites (erythrophagocytosis) is considered diagnostic
of invasive E. histolytica. 7
 Colonoscopy and biopsy of colonic ulcers reveals active inflammation, as well as amoebic trophozoites or
cysts on the surface of the mucosa.
 Serology: serum anti-amebic antibodies are present in the majority of patients with E. histolytica colitis
(>80%), and in 95-100% of patients with E. histolytica liver abscess.6 However, positive serology does not
distinguish between active or past infection.
 Stool antigen and PCR.
 Treatment
 Amebic colitis or liver abscess is treated with metronidazole, tinidazole or the newer agent nitazoxanide.
Treatment of active disease should be followed by treatment with luminal agents to eradicate amebic cysts.
 Asymptomatic intestinal amebiasis (intraluminal infection) is treated by luminal agents to eradicate the amebic
cysts.
 Luminal agents include paromomycin, diiodohydroxyquin, or diloxanide furoate.
Giardia lamblia
● Giardia lamblia is also referred to as Giardia duodenalis or Giardia intestinalis.
● Giardiasis is the most common cause of human parasitic disease in the United States.8
● The parasite is spread from person to person by the feco-oral route.
● Giardia causes infection in nursing homes, daycare centers, travelers, and hikers who drink untreated
water from lakes or rivers.
● It exists in two forms: trophozoites (motile, active form) and cysts (non-motile).
● Life cycle
 Ingestion of Giardia cysts in contaminated food or water is followed by the release of trophozoites in
the small intestine (excystation).
 Trophozoites attach to the mucosa of the duodenum and jejunum, resulting in epithelial damage,
inflammation, crypt hypertrophy and villous atrophy. 1
o The trophozoites do not invade the mucosa.
 Trophozoites pass to the large intestine, where they encyst and pass in stool. 1
● Clinical manifestations
 Incubation period is 1-2 weeks.
 Most patients are asymptomatic. Symptomatic patients develop abdominal cramps, weakness, bloating,
and acute or chronic diarrhea. The diarrhea is usually fatty and foul smelling.
● Diagnosis
 Stool Giardia antigen is preferred over stool microscopy as it has higher sensitivity.
 Duodenal aspirate or biopsy can be helpful in cases where less invasive tests are inconclusive.
o Giardia trophozoites are seen on the surface of the mucosa.
● Treatment
 Metronidazole and tinidazole are both effective therapies for Giardiasis.
 Alternative medications include nitazoxanide, albendazole, or mebendazole.
Trichuris Trichiura (Whipworm)
● Also referred to as Whipworm

● Most commonly acquired through ingestion of the parasite
egg the hatch in the intestine and migrate to the cecum. 9
● The worm has a thin anterior end that attach to the mucosa and
may cause inflammation and bleeding. However, most infected
persons are asymptomatic
● Children with heavy infestation may develop dysentery and
rectal prolapse.
● Diagnosis is by detecting T. trichiura eggs in stool.
● Treatment: mebendazole or albendazole. Figure 1: Trichuris trichiura in the
cecum
Traveler's diarrhea
 Traveler's diarrhea is the most common travel-associated disease.

 Areas with the highest risk of traveler's diarrhea are the Middle East, central and south America, and Africa.
 Definition
 Passage of 3 or more unformed stools in addition to a symptom of enteric infection, such as abdominal pain or
cramps.10
 Etiology
 The most common pathogen is Enterotoxigenic E. coli (ETEC). Other bacterial pathogens are
Enteroaggregative E. coli, diffuse adherent E. coli, Campylobacter, Shigella.
 The most common viral pathogen is Norovirus.
 Parasitic etiologies include Giardia, Entamoeba histolytica, and Cryptosporidium.
 Symptoms start 4-7 days after arrival. These include abdominal cramping, nausea, vomiting, watery
diarrhea, myalgia, and headache. Most cases resolve in 3-5 days.
 Treatment 11
 Mild disease is defined as diarrhea not affecting the patient's daily activities.
 Increase oral fluid and salt intake.
 Antidiarrheals: loperamide, bismuth subsalicylate, or diphenoxylate with atropine.
 Moderate disease is defined as diarrhea severe enough to cause alteration in the patient's daily schedule.
Any of the following medication regimens is reasonable:
 Azithromycin in a single 1000 mg dose.
 Fluoroquinolone (ciprofloxacin 750 mg, levofloxacin 500 mg, or norfloxacin 400 mg) given as a one-time
dose. The dose can be repeated on day 2 and 3 if needed.
 Rifaximin (200 mg t.i.d. for 3 days) is FDA approved for traveler's diarrhea.
 Rifamycin (two 194 mg tablets BID for 3 days) is FDA approved for traveler's diarrhea.
o Rifaximin and rifamycin should not be given to patients with signs of dysentery (fever, bloody stool).
o Loperamide can be given to accelerate initial response to treatment.
 Severe disease is characterized by fever or bloody stools.
 Azithromycin in a single 1000 mg dose is the recommended therapy for adults.
Food poisoning
 Etiology
 Norovirus is the most common pathogen that leads to food poisoning. 12
 Salmonella is the most common cause of bacterial food poisoning, followed by Clostridium perfringens,
Campylobacter and Staph aureus.12 Salmonella is the most common pathogen that leads to hospitalization
due to food poisoning.
 Staphylococcus aureus and Bacillus cereus

 S. aureus is a gram-positive coccus, while B. cereus is a gram-positive rod.
 Food poisoning results from ingestion of food contaminated with preformed bacterial enterotoxins.
 Common foods linked to S. aureus poisoning include ham, pork, and pastries.
 B. cereus is linked to reheated rice, sauces, and soups.
 Symptoms start within 1- 6 hours, and include nausea, vomiting, abdominal pain, and diarrhea.
 Symptoms resolve within 48 hours.
 Patients with B. cereus can also develop a diarrheal illness characterized by watery diarrhea that starts
6-18 hours after ingestion and lasts for 24-48 hours.
 Clostridium perfringens
 C. perfringens is a spore-forming, gram-positive obligate anaerobic rod.
 Food poisoning results from ingestion of food contaminated with the bacteria. This is followed by
production of an enterotoxin leading to symptoms of gastroenteritis.
 Common foods linked to C. perfringens are beef, fish, poultry, gravies, pasta, salads, and dairy products.
 Symptoms start 6 to 24 hours post ingestion. Patients develop abdominal pain and diarrhea.
 Fever and vomiting are uncommon. Symptoms resolve in 24 hours.
 Treatment is supportive. Antibiotics are not recommended.
 Listeria monocytogenes
 L. monocytogenes is a gram-positive bacillus that causes gastroenteritis and septicemia by ingesting food
contaminated with the bacteria.
 Foods linked to listeriosis are uncooked meats and vegetables, unpasteurized milk, soft cheeses and cole
slaw.
 Immunocompetent hosts develop symptoms of gastroenteritis and fever that resolve spontaneously within 48
hours.
 Immunocompromised and pregnant patients are particularly susceptible to listeriosis. Patients develop
bacteremia, meningitis, endocarditis, and disseminated infection. Infection in pregnancy can lead to fetal
death, premature delivery, and severe infection in the newborn.
 Treatment: ampicillin combined with an aminoglycoside.
 Clostridium botulinum
 C. botulinum is an anaerobic spore forming, gram-positive rod.
 Botulism is rare in the United States, with an annual incidence of ~150 cases. 13
 Foodborne botulism is caused by eating foods that contain botulinum toxin. This neurotoxin blocks
acetylcholine release. Foods that have been related to foodborne botulism include home canned vegetables and
fermented fish.13
 Other types of infection include wound and infant botulism.
 Symptoms start within 12-24 hours after ingestion. Patients present with nausea, vomiting, abdominal pain,
and diarrhea. Neurologic symptoms include diplopia, dysarthria, dry mouth, dysphagia, weakness,
descending paralysis and respiratory muscle paralysis.
 Treatment consists of supportive care, in addition to administering a specific antitoxin.
Clostridioides difficile infection
ACG Guidelines for Diagnosis, Treatment, and Prevention of Am J Gastroenterol,

Clostridium difficile infections 14 2021
European consensus conference on fecal microbiota

Gut, 2017
transplantation in clinical practice 15
Clinical Practice Guidelines for Clostridium difficile

Infection in Adults and Children: 2017 Update by the Clinical Infectious
Infectious Diseases Society of America (IDSA) and Society Diseases, 2018
for Healthcare Epidemiology of America (SHEA) 16
 Background
 Clostridium difficile has been reclassified and given a new name: Clostridioides difficile.17
 Clostridioides difficile (C. difficile) is a gram positive, anaerobic, spore-forming rod.
 C. difficile infection (CDI) is implicated in 10–25% of cases of antibiotic-associated diarrhea.
 C. difficile colonization refers to the detection of the bacteria in an asymptomatic person. 14
 Risk factors
 Old age (> 65 years), prolonged hospital stay, immunosuppression (HIV, steroids, chemotherapy), colonic
disease (IBD), antibiotics, possibly PPI.
 The most common antibiotics associated with C. difficile are clindamycin, second and third generation
cephalosporins, and fluoroquinolones.
 Over the past several years, there has been an increasing incidence in community acquired CDI among
young patients without any known risk factors for CDI.
 Pathophysiology
 C. difficile spores germinate under favorable conditions.
 The bacteria adhere to the colonic wall, and produce toxins A and B.
 Toxin A and B are cytotoxic and lead to cell damage by disrupting the cytoskeletal structure of the cell and
increasing the release of cytokines, leading to severe inflammation.
 Toxin B is more potent than toxin A.
 Some strains produce only toxin B (toxin A-/B+).
 A hypervirulent strain (C. difficile NAP1/BI/027- also called "epidemic strain") is associated with more
severe disease, lower cure rates, and higher recurrence rates.
 This strain has a mutation in a bacterial gene (txcD), which leads to the production of larger quantities
of toxins A and B. It produces an additional toxin called "binary toxin". The role of this toxin in
C. difficile induced colonic injury is still unclear.
 Watery diarrhea, abdominal pain, fever, leukocytosis.
 Severe cases may develop colonic ileus and dilation (toxic megacolon).
 Diagnosis
 Stool studies: Only stools from patients with unexplained, new onset diarrhea (≥3 unformed bowel
movements) should be tested for C. difficile. Repeat testing or testing for cure should not be performed.
 The most commonly used tests for C. difficile are shown in table 1.
 Possible testing strategies using these tests are shown in figure 2.
o Testing for toxin A & B should not be performed as the only test for CDI because it lacks
adequate sensitivity and specificity.
Table 1: Stool tests for C. difficile infection

Test Characteristics
Polymerase chain reaction (PCR)  High sensitivity and specificity
for C. difficile toxins A and B
Enzyme immunoassay (EIA) for  High sensitivity (> 90%)
C. difficile glutamate  More sensitive than EIA for toxin A/B
dehydrogenase (GDH)  High negative predictive value (95-100%)
 Useful as an initial screening test
 Low specificity
Enzyme immunoassay (EIA) for  Lower sensitivity (75-95%) and specificity (83-93%)
C. difficile toxins A and B compared to PCR
 Not recommended as the only test for C. difficile
Figure 2: Testing strategies for CDI.

Some testing kits combine both the EIA
for GDH and EIA for toxin A&B in one
step (strategy A). If these tests are
discordant, PCR is performed to confirm
the presence or absence of C. difficile.
Alternatively, PCR can be performed as
the first and only test (strategy B). This
strategy (B) is recommended in
institutions where clinicians agree to
restrict testing for C. difficile to patients
with unexplained new onset diarrhea (≥3
unformed bowel movements, not on
laxatives). If there is no such
institutional strategy, then strategy A is
recommended.
 Endoscopy
 Endoscopy is useful in cases in which the clinical presentation is atypical or if the
patient does not respond to antibiotic therapy.
 Sigmoidoscopy with biopsy is usually sufficient to make the diagnosis.
 Avoid a prolonged procedure and minimize air insufflation in cases of severe colitis to
avoid perforation. Video 8-1
 The classic appearance of pseudomembranous colitis is diagnostic of CDI (video 8-1).

 Histology shows varying degrees of mucosal inflammation.
o It may also show the classic "summit" or "volcano" lesion, which describes ulceration of the colonic
mucosa with "eruption" of pseudomembranes containing inflammatory cells, fibrin and debris. 18
 CDI in the setting of IBD
o It is difficult to differentiate CDI from an IBD flare based on the endoscopic appearance.
o The most common endoscopic findings of CDI in a patient with IBD are nonspecific edema and
friability. Pseudomembranes are uncommon19.
 Abdominal Xray may show a dilated colon (>7 cm), suggestive of toxic megacolon.
 CT scan can be helpful in evaluating the extent of colonic mucosal inflammation and detecting
complications such as an abscess or a perforation.
 Management
 Stop the offending antibiotic as soon as possible. Place the patient on contact precautions.
 If the patient is receiving PPI therapy, reassess the indication for PPI. Consider stopping PPI during
treatment for C. difficile if the indication for PPI therapy is weak.
 PPI may allow C. difficile to remain in the vegetative state. One retrospective study found that PPI use during
treatment for C. difficile was associated with a 42% increased risk of recurrence.20
 The effect of PPI on C. difficile is still unclear. Therefore, do not stop PPI in patients with clear indications
for therapy (severe esophagitis, history of PUD, severe GERD, etc.).
 If test results for C. difficile cannot be obtained on the same day of testing, then empiric contact isolation is
recommended while awaiting for the results.16
 For patients with confirmed C. difficile infection, patients should be placed in a dedicated room with isolated
toilet and contact precautions to decrease the risk of transmission to other patients.16
 Treatment according to severity of infection (per the updated IDSA guidelines 2017 and ACG 2021) 14, 16
 First episode, mild to moderate infection
 Give Vancomycin PO 125 mg QID x 10 days or Fidaxomicin 200 mg BID x 10 days
 Alternative if above not available: Metronidazole 500 mg PO TID for 10 days.
 First episode, severe infection
 Criteria: WBC >15,000/mm3 or creatinine >1.5 mg/dL.
 Give Vancomycin PO 125 mg QID x 10 days or Fidaxomicin 200 mg BID x 10 days
 Two large phase 3 studies have shown that fidaxomicin has comparable efficacy to vancomycin in the treatment
of CDI, with a lower rate of recurrence of CDI in non-NAP1/ BI/027 strains. 21, 22 There is no difference in the
recurrence rate between the two treatments in patients infected with the NAP1/ BI/027 strain.
Study highlight:
Fidaxomicin versus Vancomycin for Clostridium difficile Infection 21
o This is a phase 3 prospective, multicenter, double blind, randomized trial comparing
fidaxomicin with vancomycin for the treatment of CDI.
o 629 patients with confirmed CDI were randomized to receive fidaxomicin (200 mg twice daily) or vancomycin
(125 mg four times daily) orally for 10 days.
o Results (table 2)
● The rate of clinical cure was similar in both treatment groups.
● Fidaxomicin treatment was associated with lower rates of recurrence within 4 weeks after treatment. The lower rate
of recurrence was limited to patients with CDI not caused by the NAP1/ BI/027 strain.
Table 2 : Primary and secondary endpoints
Analysis method fidaxomicin vancomycin p value
o
1 endpoint: mITT 88.2 85.8 ns
clinical cure the day after
treatment PP 92.1 89.8 ns
2o endpoint: recurrence mITT 15.4 25.3 0.005
of CDI within 4 weeks
after treatment PP 13.3 24 0.004
o
2 endpoint: global cure mITT 74.6 64.1 0.006
(clinical cure with no
PP 77.7 67.1 0.006
recurrence)
Abbreviations: mITT: modified intention-to-treat: all patients randomized to that arm and
received at least one dose of the medication; PP: per-protocol; ns: non-significant.
o Follow up was limited to 4 weeks after treatment completion, which could have missed later recurrences in
both groups.
o Conclusion: fidaxomicin is an alternative to vancomycin in the treatment of severe CDI that seems to lower rates of
recurrent infection in non-NAP1/ BI/027 strains. However, it is significantly more expensive than vancomycin.
 First episode, severe and fulminant disease:

 Defined as hypotension, shock, ileus, or megacolon (IDSA)16 or altered mental status, WBC ≥ 35,000/mm3 or
< 2,000/mm3, lactate > 2.2 mmol/L, end organ failure, admission to the intensive care unit (ACG)
 Vancomycin 500 mg PO QID and metronidazole 500 mg IV every 8 hours.
 If there is significant ileus or abdominal distension, add vancomycin enema 500 mg in 100 ml of normal
saline given via Foley catheter. Repeat every 6 hours.
 For severe and fulminant disease not responding to antibiotics, fecal microbiota transplantation (FMT)
should be considered especially if the patient is not a candidate for surgery.
 If there is severe infection with hemodynamic instability, elevated lactate ≥ 5 mmol/L, or
WBC >50,000/mm3, obtain surgical consult for consideration of total colectomy.
o If surgery is performed, then subtotal colectomy with preservation of the rectum is recommended.
o An alternative surgical approach is performance of a loop ileostomy, colonic lavage, and vancomycin
flushed through the ileostomy into the colon. 16
 C. difficile and IBD
 If the patient is on immunosuppressive medications, continue these medications while on antibiotics.
 Do not increase the dose or initiate new immunosuppressive regimens until the infection is treated and
the patient is stable. Vancomycin PO 125 mg QID is the recommended Treatment.14 BMT should be
considered in recurrent CDI in IBD.
 Recurrent CDI
 Defined as recurrent symptoms of CDI within 8 weeks after the onset of symptoms of the previous CDI
episode, and provided that the patient’s symptoms resolve after treatment of the first episode. 15
 Recurrence more commonly results from relapse of CDI with the same strain, rather than re-infection
with a different C. difficile strain.
 Treatment of recurrent CDI
o First recurrence16
● If previously treated with metronidazole, treat with Vancomycin PO 125 mg QID x 10 days or
Fidaxomicin 200 mg BID x 10 days
● If previously treated with fidaxomicin, treat with Vancomycin PO 125 mg QID
● If previously treated with oral vancomycin, consider:
 Fidaxomicin 200 mg BID x 10 days or
 Vancomycin pulse then tapered therapy (125 mg PO q.i.d. for 10-14 days, then 125 mg PO b.i.d. for
1 week, then 125 mg PO qday for 1 week, then 125 mg PO once every 2 to 3 days for 2 to 8 weeks.)
o Second recurrence: treatment options include: 16, 23, 24
● Vancomycin pulse then tapered therapy (see above)
● Vancomycin PO 125 mg QID x 10 days
● Rifaximin "chaser" regimen:
o Vancomycin125 mg PO q.i.d. for 14 days, followed by rifaximin 400 mg b.i.d. for 14 days.
● Fecal microbiota transplantation should be offered as treatment for the second recurrence.
 Bezlotoxumab is a monoclonal antibody against toxin B. It was shown to lower the recurrence of CDI. It is
FDA approved as adjunctive therapy for patients on antibiotics for CDI, and who are at high risk for recurrence.
 ACG recommends against the use of probiotics for the prevention of CDI or prevention of CDI recurrence. 14
 Fecal microbiota transplantation (FMT)
 FMT can be considered for the treatment of recurrent or severe refractory CDI.
 FMT for other indications requires submission of an investigational new drug (IND) application to the FDA
 FMT can be administered by oral capsules, nasogastric (NG)/Nasojejunal (NJ) tubes, colonoscopy, or retention enema.
 ACG recommends oral capsules or colonoscopy as the preferred methods of FMT, and enema if these
methods are unavailable.
Study highlight
Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile 25
 This small open label trial randomized patients with recurrent CDI to one of three treatment
regimens (1) Standard regimen of vancomycin (500 mg PO q.i.d. For 14 days). (2) Standard regimen of
vancomycin with bowel lavage. (3) Initial vancomycin regimen (500 mg PO q.i.d. for 4 days), followed
by bowel lavage and infusion of a donor feces suspension through a nasoduodenal tube.
 The primary endpoint was cure without relapse after 10 weeks. Table 3 shows the main study results.
 The study was stopped early due to clear efficacy in the donor infusion group.
 Stool samples analysis of some patients showed restoration of microbiota diversity 2 weeks after fecal infusion.
Table 3: Results - cure and relapse rates per treatment group
Treatment group Cure Relapse at week 5
Vancomycin (n=16) 31% 62%
Vancomycin and bowel lavage (n=13) 23% 54%
Fecal infusion (n=13) 94% 6%
o A large (n=232) randomized, double blind, non-inferiority trial compared clinical resolution of diarrhea
without relapse between frozen (n = 114) versus fresh (n = 118) FMT via enema among 232 adults with
recurrent or refractory C. difficile infection. 26 Clinical resolution was 75% for the frozen FMT group and
70.3% for the fresh FMT group (P < .001 for non-inferiority).
o A meta-analysis of seven randomized controlled trials and thirty case series evaluated the efficacy
of FMT in treating recurrent and refractory CDI. 27 Clinical resolution across all studies was 92%
● Clinical resolution was higher among FMT administered via colonoscopy or enema (lower GI route)
compared to upper GI route via EGD, NG or NJ tube, (95% vs 88%,respectively ,P=.02)
● There was no difference between fresh and frozen FMT (92% vs 93%, respectively, p=0.84).
 The results also suggested that consecutive courses of FMT after a previously failed FMT had an
incremental beneficial effect.
 A retrospective study of 328 patients who received FMT for CDI found that severe infection, severe
complicated infection, and inpatients status were associated with early failure of FMT for CDI. 28
 A randomized trial assessed the efficacy of FMTV(FMT preceded by 4 days of vancomycin), vancomycin x 10days,
and fidaxomicin x 10 days, in patients with recurrent CDI (n=64). FMTV was superior to superior to fidaxomicin
or vancomycin in achieving end points of clinical and microbiological resolution or clinical resolution alone. 29
 In June 2019, the FDA raised concerns about the safety of FMT after two immunocompromised adults who
received investigational FMT developed invasive infections caused by extended-spectrum beta-lactamase
(ESBL)-producing Escherichia coli (E.coli). One of these patients died. This highlights the need for adequate
donor screening for multi-drug resistant organisms, and adequate consent about the risk of these infections.
Chronic diarrhea
Clinical Gastro
Chronic Diarrhea: Diagnosis and Management 30 Hepatol, 2017
AGA Clinical Practice Guidelines on the Laboratory
Gastroenterology,
Evaluation of Functional Diarrhea and Diarrhea- 2019
Predominant Irritable Bowel Syndrome in Adults (IBS-D)
31
Clin
Canadian Association of Gastroenterology Clinical Practice
Gastroenterol
Guideline on the Management of Bile Acid Diarrhea32 Hepatol, 2020
 Definition: Decrease in stool consistency or increased frequency of defecation (> 3/day) for > 4 weeks.
 Etiology: The differential diagnosis is broad. Below is a categorized listing of all possible etiologies (common
and/or frequently overlooked etiologies are listed in bold).
 Watery diarrhea
 Osmotic: laxatives, sorbitol/mannitol ingestion (sugar free gum), carbohydrate malabsorption.
 Secretory
o Bile acid malabsorption and colonic irritation (limited ileal resection <100cm,
post cholecystectomy, radiotherapy, SIBO). Bile acid deficiency leads to steatorrhea
o Dysmotility: diabetic autonomic neuropathy, post-vagotomy diarrhea, IBS.
● Endocrine disorders can lead to dysmotility: hyperthyroidism, Addison's disease (adrenal
insufficiency), pheochromocytoma, other tumors (see below).
o Chronic infections: Giardiasis, cryptosporidium, cyclosporiasis.
o Neoplastic disease
● Colon cancer, villous adenoma (in the distal colon), intestinal lymphoma.
● Functional pancreatic endocrine tumors (gastrinoma, VIPoma, somatostatinoma).
● Medullary thyroid carcinoma: paraneoplastic diarrhea secondary to calcitonin production.
● Carcinoid syndrome.
 Inflammatory diarrhea
 Inflammatory bowel disease, microscopic colitis, radiation colitis, intestinal ischemia.
 Infectious enteritis or colitis: Clostridioides difficile, CMV, parasitic infections (Entamoeba histolytica,
Giardia lamblia, Cryptosporidium, Strongyloides), Whipple disease, Tuberculosis.
 Fatty diarrhea (steatorrhea)
 Pancreatic exocrine insufficiency: Chronic pancreatitis, cystic fibrosis, pancreatic duct obstruction.
 Bile acid deficiency: cirrhosis, bile duct obstruction, abnormal enterohepatic circulation (extensive ileal
resection >100 cm ).33
 Small intestinal disease: SIBO, short bowel syndrome, celiac disease, celiac sprue
 Medication-induced diarrhea: Important medications to remember are metformin, NSAIDS, PPI,
antibiotics, magnesium supplements, and colchicine.
 Other: Factitious diarrhea, fecal incontinence, true food allergies, idiopathic (chronic idiopathic secretory diarrhea).
 Workup:
 Detailed history and physical examination. .
 Ask about stool frequency, consistency, volume of diarrhea, nocturnal symptoms, relation to defecation,
relation to certain foods, stress and anxiety, associated abdominal pain, weight loss, GI bleeding, fever,
travel water source, restaurant food), medication, sick contacts, alcohol use, extraintestinal
manifestations of IBD and other diseases. Dietary history (e.g. excess caffeine, sugar free gum).
 Rule out fecal incontinence as a cause of chronic diarrhea, especially in elderly patients.
 Past medical history: Diabetes, thyroid disorders, HIV, other immune disorders.
 Surgical history: cholecystectomy, intestinal resection, radiation therapy.
 Medication history (e.g. metformin, Beta Blockers, h2blockers, PPI, NSAIDS, antibiotics, SSRI)
 Ask about family history of IBD or celiac disease.
 Physical examination
o Hemodynamic status, lymphadenopathy, abdominal tenderness, thyroid mass, oral ulcers, anal
sphincter weakness, skin rash, joint swelling, muscle wasting, edema.
o Rectal exam: perianal ulcers, fistulas, examine the anal sphincter tone.
 Labs:
 CBC, chemistry, HIV test, Celiac serologies (IgA-TTG, total IgA), thyroid function testing. Do not use
CRP and ESR to screen for IBD.31
 Stool studies
o The stool osmotic gap (in mOsm/kg) = 290 - [ (stool Na + stool K) x2 ]
● If > 100 mOsm/kg → osmotic diarrhea, if < 50 mOsm/kg → secretory diarrhea.
o Stool pH < 5 is suggestive of carbohydrate malabsorption.
o Stool fat staining/quantification. Fecal elastase < 200 mcg/g suggests pancreatic insufficiency
o Stool ova and parasites (Giardia in all patients, others such as Amoeba, Cyclospora, and
Cryptosporidium in patients with travel history).31
o Stool calprotectin can differentiate between inflammatory from noninflammatory causes of chronic
diarrhea (IBS versus IBD) with a sensitivity of 93% and specificity of 96%. 34
o The AGA recommends testing for fecal calprotectin (threshold 50 μg/g) or fecal lactoferrin
(threshold range 4.0-7.25 μg/g) to screen for IBD (low quality evidence).35 However, patients with
persistent diarrhea require a colonoscopy for further workup, and fecal markers are not needed.
o In refractory watery diarrhea of unclear etiology, test for paraneoplastic diarrhea by checking serum
gastrin, vasoactive intestinal peptide (VIP), calcitonin, and somatostatin levels.
o Check a 24-hour urine collection for 5-hydroxyindoleacetic acid (5-HIAA) in suspected carcinoid syndrome.
 Imaging
 Consider cross sectional imaging with CT/MRI to evaluate diseases of the pancreas, small and large
intestine, and work through the differential diagnosis above.
 Bile acid malabsorption tests
 SeHCAT test: radiodiagnostic measurement of bile acid pool using the 75selenium homocholic acid
taurine (SeHCAT) test can identify patients with bile acid diarrhea (BAD).32
 The patient is given this radiolabeled synthetic bile acid, and the amount of SeHCAT is measured by
whole-body scans at baseline and repeated in 7 days. Bile acid retention of < 15% is considered
abnormal (<5%: severe BAD; 5-10%: moderate BAD; 10-15%: mild BAD).
 Other tests for BAD (investigational):
o Serum C4 (7α-hydroxy-4-cholesten-3-one) assay: increased levels are associated with BAD
o Serum Fibroblast Growth Factor 19 (FGF19) assay: decreased levels are associated with BAD
 Colonoscopy with TI intubation and biopsy is useful in most patients, with a diagnostic yield of 2-15%.36
 If the mucosa is normal, obtain random colonic biopsies (right and left colon) to rule out microscopic colitis.
Other diseases that may show on biopsy are quiescent IBD, eosinophilic colitis, amyloidosis.37
o Avoid biopsies of the normal cecum which can show nonspecific inflammation.38 Start obtaining
biopsies from the ascending colon.
o Examine the terminal ileum. Findings may include Crohn's disease, neuroendocrine tumor,
tuberculosis, lymphoma, adenocarcinoma, or NSAIDs induced ulcers.
o Biopsy of the normal TI has a low yield (0-4%), and is not routinely recommended. 37
 Upper endoscopy (EGD or enteroscopy) with small intestinal biopsy has a very low yield for non-celiac etiologies
of chronic diarrhea.39 Celiac disease serologies preclude the need for EGD in most cases.
 Consider EGD and biopsy in patients with unexplained steatorrhea. 30
 Capsule endoscopy: Consider capsule endoscopy if there is a suspicion of small bowel disease. Etiologies
that can be detected on capsule endoscopy are small bowel Crohn’s disease, NSAIDS enteropathy, celiac
disease, enteritis (e.g. radiation, infectious), and small bowel tumors. 40
 Breath tests for suspected carbohydrate malabsorption and SIBO, and tests for fat malabsorption are
discussed in chapter 3-small intestine.
 Other: Consider anorectal manometry and rectal EUS for the workup of anorectal incontinence.
 Treatment is focused on treating the underlying etiology.
 Consider symptomatic treatment with diphenoxylate with atropine, loperamide, fiber.
 Consider bile acid binders (cholestyramine, colestipol, colesevelam) trial for suspected bile acid diarrhea.
 Consider a trial of pancreatic enzymes for suspected or confirmed pancreatic exocrine insufficiency.
Chronic constipation
AGA Medical Position

Statement on Constipation 41
AGA Institute Guideline on the Medical

Management of Opioid-Induced Constipation 42
 Rome IV criteria for the diagnosis of chronic functional constipation: 43

 Two or more of the following during at least 25% of defecations:
 Straining, lumpy or hard stool, sensation of incomplete evacuation or anorectal obstruction, manual
maneuvers to facilitate evacuation, less than 3 defecations per week, rare loose stools without laxatives.
 Patients do not meet IBS criteria (page 215). Pain is not a predominant symptom in chronic constipation.
 Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis
 Secondary constipation
 Medication induced constipation: opioids, calcium channel blockers, anticholinergics, TCAs, oral iron.
 Diabetes mellitus, Parkinson's disease, multiple sclerosis, scleroderma, hypothyroidism, hypokalemia, hypercalcemia.
 Irritable bowel syndrome with constipation
 Colon obstruction is an uncommon cause of chronic
constipation, and usually apparent from the clinical
history. Anorectal anatomic abnormalities (rectocele,
rectal prolapse or intussusception) may lead to
constipation.
 Pathophysiology and classification of chronic functional
constipation.
 Based on the underlying pathophysiology, functional
constipation can be classified as slow transit
constipation, functional defecatory disorder, or
normal transit constipation (figure 3). It is difficult to
determine the underlying pathophysiology based on Figure 3: Classification of chronic functional
clinical features. However, the clinical presentation constipation based on the underlying
pathophysiology
can provide some useful clues (see below).
 Slow transit constipation

 Decreased colonic motility leading to infrequent defecation and constipation.
 History of < 2 defecations/week and laxative dependence is suggestive of slow transit constipation. 44
 Functional defecatory disorder
 Dyssynergic defecation (pelvic floor dysfunction or dyssynergia): characterized by paradoxical
contraction or inadequate relaxation of the pelvic floor muscles during attempted defecation.45
 Inadequate defecatory propulsion: inadequate propulsive forces during attempted defecation.
 Clinical features
o Use of digital maneuvers to induce defecation suggests dyssynergia.
o Other symptoms include fecal urgency and straining during defecation.
 The digital rectal examination (DRE) is an important part of the clinical evaluation.
o DRE evaluates the resting and squeeze anal tone, abdominal wall contraction, and the ability to relax
the anal sphincter and to push the examiner's finger out of the rectum.
o Abnormalities in the DRE suggest a functional defecatory disorder as the cause of chronic constipation.
 General management and basic workup
 Check a CBC in older patients. Perform a colonoscopy if the patient is older than 45 years, or if there are
any alarm features for colon cancer (rectal bleeding, anemia, weight loss).
 First line treatment is a trial of stool softeners (docusate), high fiber diet (20-30 gram/day) and laxatives.
 Osmotic laxatives: polyethylene glycol, magnesium citrate, lactulose, sorbitol
 Stimulant laxatives: bisacodyl, senna.
 If there is no response to treatment, further diagnostic testing should be considered to evaluate the
underlying pathophysiology of chronic constipation. Consider secretagogues and other novel drugs as
second line treatment options (see page 214 ).
 Anorectal manometry
 Manometry assesses the internal and external sphincters, rectal pressure, and the rectoanal reflex.
 The rectoanal inhibitory reflex refers to the transient internal anal sphincter relaxation in response to
rectal distension (figure 4A).
o The presence of this reflex excludes Hirschsprung disease, which is an important cause of chronic
constipation in children; however, the disease can remain undiagnosed until adulthood. Rectal biopsy
in Hirschsprung disease shows hypertrophied nerve fibers and absence of ganglion cells. 46
 The main abnormality in patients with dyssynergic defecation is the demonstration of less than 20%
relaxation of basal resting sphincter pressure during attempted defecation, with adequate rectal
propulsive forces (figure 4B).
o Some patients have paradoxical anal contraction with attempted defecation (figure 4C).45
 The main abnormality in patients with inadequate defecatory propulsion is the demonstration of inadequate
propulsive forces with or without dyssynergia during attempted defecation. 45
Figure 4: Anorectal manometry in dyssynergic defecation. A: Normal manometry showing a normal

decrease in anal pressure with attempted defecation. B: Dyssynergic defecation showing a minimal decrease (< 20%) in
anal pressure. C: Dyssynergic defecation showing a paradoxical increase in anal pressure with attempted defecation.
 Balloon expulsion test

 Measures the time it takes for the patient to expel a 50 ml balloon from the rectum.
 The normal time to expel the balloon is less than one minute.
 An abnormal balloon expulsion test suggests abnormal defecation but does not provide other information
about the underlying pathophysiology. Nevertheless, it is a good screening test for defecatory dysfunction.
 Colonic transit testing
 Radiopaque marker study (e.g. Sitzmarks®): The patient ingests one capsule containing 24 radiopaque
markers. Avoid laxatives during the study period.
 An abdominal xray is obtained at day 5.
 The study is abnormal if there are more than five markers at day 5. The distribution of the markers can
distinguish between slow transit and dyssynergic defecation (figure 5):
Figure 5 : Sitz marker

study for chronic
constipation.
A: Normal study (< 5 markers); B:
Slow transit constipation. The
markers are distributed throughout
the colon; C: Dyssynergic
defecation. The markers collect in
the distal colon and rectum.
 Wireless motility capsule

 This small orally ingested device records pH, pressure, and temperature. It measures gastric emptying
time as well as small and large bowel transit times.
 It is comparable to the radiopaque marker study in assessing slow transit constipation, and is FDA
approved for this indication. It can also be helpful in ruling out gastroparesis and small bowel
dysmotility prior to elective colectomy in patients with severe constipation. 47
 However, the wireless motility capsule is not yet standardized, and is significantly more expensive than
traditional tests.48 Further research is needed to evaluate its role in chronic constipation.
 Other tests
 Barium defecography can identify anatomic abnormalities (rectocele, enterocele, mucosal prolapse or
intussusception).49 MRI defecography evaluates pelvic floor anatomy.
 Other treatment options
 Biofeedback therapy is recommended as the first line treatment for patients with dyssynergic defecation
o The aim of this therapy is to teach the patient to relax the pelvic floor muscles while increasing intra-
abdominal pressure, in order to produce a propulsive force to empty the rectum.
 Several secretagogues are FDA approved for chronic idiopathic constipation and IBS (table 4).
 Prucalopride (Motegrity®) is a 5-HT4 agonist that is FDA approved for the treatment of chronic
constipation (dose 2 mg once daily, patients with Cr clearance <30 ml/min: 1 mg once daily).
● In a randomized, placebo controlled trial, prucalopride was shown to improve bowel function and
decrease symptoms in patients with severe chronic constipation. 50
● Most common side effects are headache, abdominal pain, nausea and diarrhea.
 Elobixibat is an ileal bile acid transporter (IBAT) inhibitor that inhibits bile acid absorption, increasing
bile acid passage into the colon. This increases the frequency of bowel movements and improves
constipation.51 Dose: 0mg PO qday. Elobixibat is not FDA approved yet.
 Opioid induced constipation (OIC) is defined as new or worsening symptoms of constipation (reduced
frequency of bowel movements, hard stool, straining, incomplete rectal evacuation) when initiating, changing, or
increasing opioid therapy.43
 It occurs due to opioid activation of the mu-receptors in the GI tract.
Table 4: Secretagogues for the treatment of chronic constipation.

Lubiprostone Linaclotide Plecanatide
Trade name Amitiza® Linzess® Trulance®
Mechanism of  Increases intestinal fluid  Increases intestinal fluid secretion by acting as a
action secretion and intestinal guanylate cyclase-C receptor agonist that increases
motility by activating the cGMP, leading to the opening of CFTR chloride
chloride C2 channels at channels at the enterocyte apical membrane,
the apical membrane of increasing chloride and bicarb content, increasing
enterocytes intestinal fluid and transit
Side effects Nausea ~30% (dose Diarrhea ~15% Diarrhea 4% to 5%
dependent)
Diarrhea 10%, Headache 7%
Dose for 24 mcg b.i.d. 145 mcg once daily 3 mg once daily
chronic
constipation
Dose for IBS-C 8 mcg b.i.d. 290 mg once daily 3 mg once daily
42
 The AGA recommends traditional laxatives as the first line treatment.
 In patients who do not respond to laxatives, other options for treatment include:
o Peripherally acting mu-opioid receptor antagonists: These drugs block the constipating effects of opioids
without affecting the CNS mediated effects (analgesia).
● They are preferred in patients with OIC without a prior history of constipation.52
● FDA approved agents in non-cancer patients: Naloxegol (Movantik®), Naldemedine (Symporic®),
or Methylnaltrexone (Relistor®).
o Secretagogues: preferred in patients with prior history of constipation (opioid exacerbated constipation).52
● Lubiprostone (FDA approved). Prucalopride and linaclotide are in trials for OIC.
 Surgical therapy
 Sacral neuromodulation (sacral nerve stimulation) may improve symptoms in patients with chronic
constipation due to colonic inertia or dyssynergia who remain refractory to treatment with other modalities.49
A temporary lead is placed to stimulate the third sacral nerves (S3). Patients with successful nerve stimulation
are candidates for implantation of sacral nerve stimulation device. This treatment modality is not FDA
approved and further well-designed studies are needed to evaluate its role in chronic constipation.
 Subtotal colectomy with ileorectal anastomosis and fecal diversion with an ileostomy or colostomy can
be considered in patients with slow transit constipation that is refractory to all other therapies.49
Irritable bowel syndrome
American Gastroenterological Association Institute
Gastroenterology,
Guideline on the Pharmacological Management of
2014
Irritable Bowel Syndrome 53
American College of Gastroenterology Monograph on Am J Gastroenterol,

Management of Irritable Bowel Syndrome 54 2018
ACG Clinical Guideline: Management of Irritable Am J Gastroenterol,

Bowel Syndrome55 2021
 Definition: irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by recurrent
abdominal pain or discomfort associated with abnormal stool frequency or consistency, and not related to
structural abnormalities of the GI tract.
 Prevalence: 10-15% of people in the United States have IBS.
 Updated Rome IV diagnostic criteria for IBS43

 Recurrent abdominal pain, on average at least 1 day per week in the last 3 months associated with two or
more of the following:
 Abdominal pain is related to defecation (improvement or worsening of pain with defecation)
 Abdominal pain is associated with a change in frequency of stool.
 Abdominal pain is associated with a change in the consistency of stool.
 Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.
 Classification: IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed IBS, or IBS-unclassified (IBS-U).
 Risk factors for post-infectious IBS include female gender, severe and prolonged gastroenteritis, pre-existing
psychiatric illness such as anxiety and depression.
 Diagnosis (see page 210 for workup of chronic diarrhea)
 Careful history (abdominal pain, stool form, consistency, association with pain, straining, urgency,
tenesmus, mucous). Alarm features: rectal bleeding, weight loss, anemia, nocturnal symptoms.
 Obtain dietary history.
 Physical examination including a rectal exam.
 Perform a limited workup. Consider the following tests in some patients:
 Labs: CBC, chemistry. Stool ova and parasites for selected patients but not routinely. 55
 Fecal calprotectin/lactoferrin are recommended for those without alarm features. 55
 Colonoscopy in patients older than 50 (or 45 in African Americans), or those with alarm features.
Colonoscopy is not recommended in patients younger than 45, with typical IBS symptoms without alarm
features. If colonoscopy is performed, obtain colonic biopsies in patients with diarrhea.
 Test for celiac disease in patients with diarrhea or mixed-IBS. 56
 Consider tests for carbohydrate malabsorption.
 Routine testing for small bowel bacterial overgrowth is not recommended.
 Anorectal manometry is recommended in patients with symptoms of dyssynergic defecation or refractory
constipation.55
 Treatment
 Reassure the patient, explain the functional nature of pain, and establish realistic treatment goals. Effective
communication with the patient is essential for successful treatment.
 Consider asking the patients to use a stool and symptom diary to monitor treatment. Recommend lifestyle
modifications such as good sleep hygiene and exercise. Treat associated depression and anxiety.
 Medications: the treatment should be based on the most predominant symptom(s).
 Diarrhea predominant IBS
o Loperamide can improve diarrhea, but does not improve abdominal pain.
o Bile acid sequestrants: Cholestyramine (9 gm BID-TID), colestipol (2 gm 1-2 times/day)
o Rifaximin is FDA approved for IBS-D. Dose: 550 mg TID for 10-14 days.
 Eluxadoline (Viberzi®) 100 mg BID
o Eluxadoline is a mixed opioid receptor modulator (mu- and kappa- opioid receptor agonist and delta-
opioid receptor antagonist).57 It is FDA approved for the treatment of IBS-D.
o It is contraindicated in patients with previous cholecystectomy due to the small but significant risk of
severe acute pancreatitis (0.4%), possibly related to sphincter of Oddi spasm.
o Other contraindications: history of sphincter of Oddi dysfunction, history of pancreatitis, alcohol abuse
and alcohol addiction (> three alcoholic drinks a day). Consider alternatives in these patients.
 Alosetron (Lotronex®) - 5HT-3 receptor antagonist that was used to treat women with IBS-D.
o It was withdrawn from the market due rare but life threatening ischemic colitis and severe constipation.
o Currently available only through a special prescribing program for women with severe IBS-D.
 Constipation predominant IBS

o Polyethylene glycol improves symptoms of constipation and straining in IBS, but not abdominal pain.
o Soluble fiber supplements (e.g. psyllium/ispaghula husk).
o Secretagogues (refer also to table 4 on page 214)
● A meta-analysis found these novel agents effective for the treatment of IBS-C, with similar
efficacy at 12 weeks. 58 There are three FDA approved secretagogues in the United States:
 Lubiprostone (Chloride channel activators- Amitiza®): 8 μg twice daily.
 Linaclotide (Guanylate Cyclase C agonists- Linzess®): 290 μg once daily.
 Plecanatide (Guanylate Cyclase C agonists- Trulance®): 3 mg once daily.
 TCAs, SSRIs, and antispasmodics are used to treat IBS with variable efficacy for IBS related
abdominal pain (table 5).
 SNRI (serotonin-norepinephrine reuptake Inhibitor (such as duloxetine, venlafaxine, desvenlafaxine
have not been well studied in IBS, but they have been used to treat functional abdominal pain.
Table 5: Medications used to treat abdominal pain in IBS
Class Medication Starting dose Maximum dose
TCA Amitriptyline 10-25 mg /day at bedtime 150 mg /day
Imipramine 10-25 mg/ day at bedtime 150 mg /day
Desipramine 10-25 mg /day at bedtime 200 mg /day
Nortriptyline 10-25 mg /day at bedtime 150 mg /day
SSRI Escitalopram 10 mg /day 20 mg /day
Citalopram 20 mg /day 60 mg /day
Fluoxetine 20 mg /day 80 mg /day
Sertraline 25-50 mg /day 200 mg /day
Paroxetine 10 mg/day 60 mg/day
Antispasmodics Hyoscyamine 0.125-0.25 mg every 4-6 hours 1.5 mg /day
Dicyclomine 10 mg t.i.d. 160 mg /day
Peppermint oil 250 b.i.d. or t.i.d. 750 mg TID
 Tegaserod (Zelnorm®) - 5-HT4 receptor agonist. It improves abdominal pain and constipation. It was
withdrawn from the market in 2007 due to increased risk of serious cardiovascular events. It was reintroduced in
2019 following an FDA review that concluded that there was no clear cardiovascular risk.
o It is currently approved for the treatment of adult women with IBS-C who are younger than 65 years of age,
without a history of ischemic heart disease, and have no more than one risk factor for cardiovascular disease.
o Dose 6 mg PO twice daily, 30 minutes before meals
 Tenapanor (Ibsrela ®) – is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (NHE3), this
inhibits absorption of sodium from the small intestine and colon, increasing water secretion and accelerating
intestinal transit. Two randomized controlled trials showed that it increases bowel movements and decreases
abdominal pain compared to placebo.59, 60 The most common side effect was diarrhea (15%), and severe
diarrhea occurred in 2.5% of patients.
o It is FDA approved for IBS-C in adults (50 mg PO BID).
 Dietary changes
 Restriction of gluten for symptoms improvement in IBS is not recommended, as this does not seem to be
beneficial based on two randomized trials with 111 participants. 61
 Consider a trial of lactose avoidance in selected patients who report symptom worsening with milk ingestion. 62
 A low FODMAP diet is recommended for overall symptom improvement in IBS.
o FODMAP stands for Fermentable Oligo-, Di- and Mono-saccharides, and Polyols.
o These indigestible carbohydrates are easily fermented by the gut flora leading to gas
formation. This is thought to trigger some of the symptoms in IBS.
● Examples of high FODMAP food sources: broccoli, cabbage, wheat, rye, lentils, chickpeas, apples,
nectarines, peaches, watermelon, mushrooms, artificial sweeteners and many others.
o A randomized, controlled, single-blind, cross-over trial of 30 patients with IBS have shown that a diet
low in FODMAPs improves functional symptoms in patients with IBS. 63
o Several other studies were conducted; the overall evidence suggests short-term efficacy and safety of low
FODMAP diet in patients with IBS. 54, 64
o Consider referral to a trained dietician, and a trial of low FODMAP diet for 6-8 weeks.
 Probiotics: the summary of evidence suggests that probiotics are beneficial for IBS54. However, the overall
benefit seems to be minimal, and it is not clear which probiotic is beneficial. ACG recommends against their
use to treat global symptoms of IBS. 55
 Psychotherapy: Hypnosis, cognitive behavioral therapy, and relaxation therapy appear to be effective in IBS,
but with variable results.
Non-IBD colitides
Microscopic colitis
American Gastroenterological Association Institute Guideline on Gastroenterology,

the Medical Management of Microscopic Colitis 65 2016
 Definition: microscopic colitis (MC) is a disease of the colon characterized by chronic watery diarrhea,
normal or near-normal colonoscopy, and evidence of epithelial lymphocytosis on biopsy.
 MC is divided into two main subtypes: lymphocytic colitis (LC) and collagenous colitis (CC).
 It is found in up to 10% of patients with chronic diarrhea in referral centers.
 LC is three times more common than CC.
 MC is associated with autoimmune diseases (thyroid disease, celiac disease, IBD, type 1 DM, rheumatoid arthritis).
 Risk factors: Smoking. Medications: PPI (lansoprazole), ranitidine, statins, NSAIDS, SSRI, aspirin,
acarbose, ticlopidine.
 Age and gender
 Peak incidence 55-70 years. 15-25% of patients with microscopic colitis are younger than 40.
 Female: male ratio is 7:1 in LC, and 2:1 in CC.
 Chronic watery diarrhea, abdominal pain in 50% of patients.
 Presentation may mimic IBS-D
 Autoimmune diseases may co-exist in up to one third of patients: celiac disease (12.9%) and autoimmune thyroid
disease (10.3%), Sjögren's syndrome (3.4%), diabetes mellitus (1.7%), and skin/ joints disease (6.0%).66
 Colonoscopy reveals normal colonic mucosa. Occasionally it shows minor mucosal changes (erythema, subtle
irregularities, and erosions). Obtain multiple biopsies from the right and left colon.
 Biopsies obtained only from the left colon may miss the diagnosis.
 Histology
 Lymphocytic colitis
 Increased intraepithelial lymphocytes (IEL) of the surface and crypt epithelium (>20 per 100 epithelial cells)
 Other features: Normal crypt architecture, surface epithelial injury, and chronic inflammation in the lamina
propria.
 Collagenous colitis
 Characterized by the presence of a subepithelial pink collagen band (>10 microns in thickness).
 More pronounced surface epithelial injury compared to lymphocytic colitis. 67+
 Less pronounced intraepithelial lymphocytosis compared to lymphocytic colitis.
 Normal crypt architecture.
 Differential diagnosis of diarrhea and increased colonic intraepithelial lymphocytes:
 Brainerd diarrhea refers to an acute outbreak of severe watery diarrhea that can last from months to years.
Named after the city of Brainerd, Minnesota where the first reported outbreak took place in 1983.68 It is likely

caused by an unidentified infectious agent. It can cause colonic inflammation on biopsy with increased IELs.
 Celiac disease is present in 15% of patients with lymphocytic colitis. Mild colonic epithelial
lymphocytosis without surface epithelial injury or inflammation can be present in celiac disease. 69
 LC is strongly associated with refractory celiac disease.
 Other conditions: resolving acute infectious colitis, Crohn's disease.
 A population based study from Sweden found an increase in the risk of IBD in patients who were diagnosed with
microscopic colitis. The adjusted Hazard Ratio for Crohn’s disease was 12.6, and for ulcerative colitis was 17.3.70
 Treatment
 Stop medications that could be related to MC. Recommend smoking cessation in all patients.
 First line treatment: Budesonide (9 mg/day x 8 weeks then taper as 6 mg/day x 2 weeks and 3 mg/day x 2 weeks).
 Budesonide is highly effective for induction of clinical remission (86% success at 6 weeks). 71
 If patients relapse after cessation of budesonide (60-80% relapse rate), give budesonide 9 mg/day for eight
weeks, then continue low dose maintenance (6 mg daily over 6 months, or 3 mg daily alternating with 6 mg
daily over 12 months).65 The long-term benefit and safety of budesonide for MC is still unclear.
 Mesalamine was recommended as second line treatment (AGA), before the publication of the
following study, which showed that mesalamine was not superior to placebo.
 Other treatment options (with very limited data) include bismuth subsalicylate, loperamide, prednisolone
(or prednisone), bile acid binders (cholestyramine or colestipol), thiopurines (6-MP and azathioprine), anti-
TNF agents, and methotrexate
Study highlight
Efficacy and Safety of Budesonide, vs Mesalazine or Placebo, as Induction Therapy for
Lymphocytic Colitis 72
 Multicenter, randomized, Placebo controlled trial comparing the efficacy of Budesonide (9 mg/day), mesalazine
(3gm/day-same as mesalamine), and placebo in patients with lymphocytic colitis. Patients with collagenous
colitis, drug induced lymphocytic colitis, and other colitides were excluded.
 Primary endpoint: clinical remission
(≤ 21 stools and ≤ 6 watery stools), in the 7 days prior to week 8.
 Results (Figure 6): At 8 weeks, clinical response and histologic response were higher in Budesonide
compared to placebo. Mesalazine was not superior to placebo.
Figure 6: Efficacy of
budesonide, vs
mesalazine or
placebo, as induction
therapy for
lymphocytic colitis.
N=19 in each study
group. Proportions
represent clinical (A)
and histologic (B)
response at 8 weeks
Diversion colitis
 Definition: Inflammatory colitis in colonic segments that are diverted away
from the fecal stream.
 It typically affects the colonic segment distal to an ileostomy or colostomy.
 Pathophysiology: In the normal colon, bacterial flora ferment non-
absorbable carbohydrates and fibre that are present in stool into short chain
fatty acids (acetate, propionate, and butyrate). These luminal fermentation
metabolites provide a direct energy source to colonic epithelial cells. The
absence of stool and bacterial flora in isolated colonic segments deprives
the colonic epithelium from this energy source, leading to inflammation.
 Clinical manifestations: Most patients are asymptomatic, some patients may Figure 7: Diversion colitis
complain of abdominal pain, tenesmus, rectal bleeding, or mucous discharge.
 Diagnosis
 Endoscopic findings include friability, erythema, and superficial ulcerations. These are non-specific
and can occur in infectious colitis or inflammatory bowel disease (figure 7 and video 8-2).
 Histology shows prominent mucosal lymphoid hyperplasia associated with a chronic inflammatory
infiltrate.73 The presence of crypt architectural distortion favors the diagnosis of IBD.
 Treatment: The most effective treatment is surgical restoration of colonic continuity. Video 8-2
 Short chain fatty acids enemas can be tried in patients who are not surgical candidates.
Chronic radiation proctitis
The American Society of Colon and Rectal Surgeons

Clinical Practice Guidelines for the Treatment of Dis Colon Rectum, 2018
Chronic Radiation Proctitis 74
ASGE guideline on the role of endoscopy for bleeding

GIE, 2019
from chronic radiation proctopathy75
 Rectal injury after radiation can lead to acute radiation proctitis, with
clinical symptoms related to inflammation (diarrhea, mucous discharge,
tenesmus, rectal bleeding).
 This can progress to chronic radiation proctitis, or “chronic radiation
proctopathy”. Endoscopy reveals mucosal pallor, ulcerations, and friability.
 The term Radiation Associated Vascular Ectasia (RAVE) is suggested to
describe the formation of multiple ectasias in the rectum, leading to chronic
bleeding and anemia.76 Endoscopy reveals multiple telangiectasia with or
without spontaneous bleeding (figure 8).
 Endoscopic therapy includes argon plasma coagulation, heater probe, bipolar Figure 8: Radiation
associated vascular ectasia
electrocoagulation, and radiofrequency ablation of the affected areas.75
(RAVE) with spontaneous
Patients may require several sessions of treatment. bleeding
 RAVE can coexist with chronic radiation proctopathy. The term chronic
radiation proctitis, albeit a misnomer, remains the most commonly used term to describe these conditions.
 Other treatment options: formalin application; sucralfate retention enemas, (2 g in 20ml of water, twice daily);
hyperbaric oxygen therapy.
Immune checkpoint inhibition-induced colitis (Immune-mediated colitis)
AGA Clinical Practice Update on Diagnosis and

Management of Immune Checkpoint Inhibitor Gastroenterology, 2020
(ICI) Colitis and Hepatitis: Expert Review 77
 Cancer cells evade the host immune response by inducing upregulation of several immunosuppressive pathways,
inhibiting lymphocyte activation and proliferation, and promoting tumor escape. 78
 Immune checkpoint inhibitors (ICPi) are antibodies that modulate the immune system and inhibit these upregulated
immunosuppressive pathways. They are used to treat several advanced malignancies (melanoma, lung, bladder cancer,
and hodgkin’s lymphoma) .79 Examples include:
 Ipilimumab: blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) on T cells.
 Nivolumab, cemiplimab, pembrolizumab: block programmed cell death receptor-1 (PD-1).
 Atezolizumab, avelumab, durvalumab: block programmed cell death ligand 1 (PD-L1).
 Diarrhea and colitis are common side effects of ICPi. Ask about the frequency of bowel movements (number of
stools increase over baseline, incontinence) and about symptoms of colitis (pain, mucous, blood in stool).
 Management is based on severity of symptoms:80
 Patients with mild grade 1 diarrhea (↑ in stool output of < 4 stools/d over baseline) can be monitored and given
supportive care. Consider loperamide, hydration, and dietary modifications81
 ICPi can be continued, or temporarily withheld.
 Patient with grade 2 diarrhea (↑ of ≥ 4 stools per day over baseline) or higher grades:
 ICPi therapy should be withheld, and basic workup performed (CBC, CMP, TSH, ESR, CRP, stool culture and
Clostridioides difficile testing).
 Consider other tests (HIV, hepatitis A and B, and serum quantiFERON for TB) to prepare for the possibility of
giving infliximab for persistent and/or severe symptoms.
 Consider cross sectional imaging if you suspect toxic megacolon, perforation, abscess formation or intestinal
obstruction.81
 Early ileocolonoscopy is encouraged to assess the presence and severity of inflammation, and decide on further
treatment with infliximab in severe colitis, and the safety of restarting ICPi.80, 81
 Any part of the GI tract can be involved. Consider an upper endoscopy (EGD or enteroscopy) in addition to colonoscopy.
 Endoscopic findings range from mild colitis to severe erythema, edema, friability, ulcerations, and
exudates.82 In most cases (80%) the pattern of inflammation is continuous, but 20% of cases show skip
pattern and segmental involvement similar to Crohn’s disease.79
 Histology shows epithelial erosions, chronic inflammatory cell infiltrates, intraepithelial lymphocytosis,
cryptitis, crypt abscess, crypt architectural distortion, crypt apoptosis. 82, 83
 Patients with severe colitis and ulcerations are more likely to be resistant to steroid therapy.
 Prednisone 1-2 mg/kg/day should be given to those with persistent diarrhea. If response achieved: Slow taper
over 4-6 weeks. Consider repeat colonoscopy in 8-10 weeks to confirm mucosal healing.
 In patients with severe diarrhea (e.g. increase in stool output by ≥7 stools per day over baseline, hospitalization
due to diarrhea), or severe colitis on endoscopy, ICPi should be permanently stopped.80
 Consider infliximab (5-10mg/kg) in patients who do not respond to steroids. Usually a single dose is given,
with subsequent doses considered after 2 weeks. Long term maintenance therapy is not required. 84
 Vedolizumab can be considered in patients who do not respond or cannot receive infliximab.
Segmental Colitis Associated with Diverticulosis (SCAD)

 This refers to chronic inflammation of the colonic segments
in areas of diverticulosis, in patients with otherwise
uncomplicated diverticulosis. The disease characteristically
affect the left colon (sigmoid and descending colon) with
sparing of the rectum.
 Endoscopy most commonly reveals patchy erythema
typically in areas where diverticular disease is present85
(crescentic fold pattern-Figure 9). Other patterns of
involvement mimic Crohn’s disease (aphthous ulcers) or
ulcerative colitis (continuous friability and inflammation).
Figure 9: SCAD in the sigmoid colon
 Histologic findings vary and can reveal mild, chronic active
inflammatory pattern, severe acute inflammation, crypt
abscess formation, and cry pt architectural distortion that mimic inflammatory bowel disease.
 Differential diagnosis: diverticulitis, inflammatory bowel disease, and radiation colitis are important considerations
in patients with suspected SCAD.
 In most patients, the disease is self-limited and discovered incidentally during screening colonoscopy.
 Symptomatic patients can be treated with antibiotics (ciprofloxacin and metronidazole) or 5-aminosalicylates
products. Patients with severe colitis can be treated with prednisone. Surgery is rarely required.
Ischemic colitis
ACG clinical guideline: epidemiology, risk factors,

patterns of presentation, diagnosis, and management Am J Gastroenterol, 2015
of colon ischemia 86
 Vascular supply of the colon (figure 10)

 The superior mesenteric artery (SMA) supplies the cecum,
ascending colon and proximal two thirds of the transverse colon.
 The inferior mesenteric artery (IMA) supplies the distal
transverse colon, descending and sigmoid colon, and the rectum.
 The rectum receives additional blood supply from the internal
iliac arteries via the middle and inferior rectal arteries.
Therefore, isolated rectal ischemia is rare.
 The marginal artery of Drummond runs along the entire
length of the colon and gives rise to the vasa recta. It
provides collateral circulation to the colon and distal small
intestine in cases of isolated arterial occlusion.
 Acute colonic ischemia can be precipitated by an occlusive or
non-occlusive event (table 6). Figure 10: Colonic blood supply.
(see text).
 Patients with ischemic colitis commonly have multiple cardiac risk factors, acute congestive heart failure, or
hypovolemic or septic shock. Symptoms include abdominal pain, hematochezia, nausea, vomiting, and diarrhea.
 Labs: Elevated serum lactate level. Stool culture and C. difficile testing should be ordered to rule out
infectious colitis.
Table 6: Etiology of acute colonic ischemia

Occlusive disease External compression
 Arterial thrombosis or embolus  Volvulus
 Post-surgical (aortoiliac surgery,  Strangulated hernia
cardiopulmonary bypass)  Intussusception
 Vasculitis
 Venous thrombosis (hypercoagulable
state, pancreatitis)
Non occlusive disease Medications
 Cardiogenic, septic or hypovolemic shock  Digoxin, alosetron (5HT3 antagonist),
 Severe burns sumatriptan (5HT1 agonist), cocaine, oral
 Severe pancreatitis contraceptives, amphetamines, NSAIDS,
 Long distance running antibiotics, danazol
 Figure 11 shows the distribution of colonic ischemia in a study of

313 patients with biopsy proven or compatible ischemic colitis.87
 Diagnosis
 Abdominal Xray
 This may reveal a "thumbprinting" pattern of the
colonic mucosa. It also assesses for perforation in
severe cases. Otherwise, radiographs have limited
utility in ischemic colitis.
 Barium enema should be avoided in severe cases where
gangrene or perforation is suspected.
 CT scan is the imaging modality of choice in patients Figure 11: Distribution of colonic
suspected to have colon ischemia ischemia. Distribution of disease is defined
by the most proximal extent of involvement. 44
 Findings include mucosal edema, transmural
thickening, intestinal pneumatosis, portal venous gas, decreased bowel enhancement, mesenteric stranding,
megacolon, and perforation.88
 Angiography
 Angiography is not required in most cases of colonic ischemia.
 It could be useful in cases of suspected mesenteric ischemia such as isolated right sided colonic
involvement that suggests superior mesenteric thrombosis. 89
 CT angiography or MRA are alternative non-invasive studies to assess the colonic vascular supply.
 Colonoscopy should be performed within 2-3 days of onset of symptoms to have the highest diagnostic yield.
 Endoscopic findings are less frequent after 3 days of symptom onset.
 Colonoscopy should be avoided in patients with peritoneal signs. 86
 Colonoscopy provides direct assessment of the colonic mucosal appearance and distribution of colitis,
with the ability to obtain mucosal biopsies to rule out other etiologies.
 Endoscopic findings include mucosal pallor, areas of erythema, thickening, submucosal edema, and
hemorrhage.
 The “single stripe sign” refers to a single mucosal linear ulceration or erythema along the longitudinal
axis of the colon. 86 This finding is very suggestive of ischemic colitis (figure 12).
 In advanced cases, the mucosa appears black and gangrenous.
o Gangrene is diagnostic of ischemic colitis. Segmental distribution of colitis and rectal sparing are
suggestive of the diagnosis, but are not specific.
 Strictures and ulcerated masses may form in areas of ischemic colitis, and these changes can mimic
malignancy.90

Care should be taken not to over-distend the
colon. The procedure should not be continued if
there are severe or gangrenous changes in the left
colon.
 Histology
o Findings on mucosal biopsy are usually non-
specific and include loss of epithelial cells,
mucosal and submucosal edema, hemorrhage or
necrosis, inflammatory cell infiltrates, capillary
thrombi, crypt atrophy and destruction.
o The only pathognomonic findings of ischemic
colitis are mucosal infarction and the presence
of "ghost cells" (preserved cell outline without
Figure 12: Single stripe sign in the
cellular content). 87
sigmoid colon in a patient with
 Prognosis ischemic colitis
 Most cases resolve spontaneously. Endoscopic findings
resolve within 2 weeks. More severe cases of colitis may take up to 6 months to heal.
 Some patients will develop a form of chronic colitis due to chronic colonic ischemia.
 Isolated right colonic involvement has worse prognosis compared to left sided disease. 91
 Treatment
 Supportive care. Stop any offending medications. Consider IV antibiotics in severe cases.
 Laparotomy is indicated in cases of perforation or gangrene.
Melanosis Coli
 Melanosis coli (also known as pseudomelanosis coli) describes the dark black or brown discoloration of the colon.
 It is associated with the chronic use of anthraquinone laxatives (e.g. senna, rhubarb, cascara).
 These laxatives lead to apoptosis of colonic epithelial cells, followed by phagocytosis of these cells by macrophages,
conversion of apoptotic bodies to lipofuscin pigment (not melanin), which accumulates in macrophages within the
lamina propria, producing the discoloration in the mucosa.92
 Melanosis coli is a harmless condition that is reversible within 6-12 months of stoppage of the causing laxative.92
 Since neoplastic and adenomatous tissues do not contain the pigment-laden macrophages, these lesions appear pale in
contrast to the rest of the mucosa. Any pale area should be examined carefully and resected appropriately.
Figure 13: Melanosis coli. A: Black pigmentation in the colonic mucosa in a patient with long standing laxative
use. B: Adenomatous polyp on white light endoscopy. C: Adenomatous polyp on Narrow-Band Imaging (NBI).
Acute colonic pseudo-obstruction (Ogilvie's syndrome)
The role of endoscopy in the management of patients with known

and suspected colonic obstruction and pseudo-obstruction 93 GIE 2010
 Definition: severe colonic dilation that leads to symptoms and signs of colonic obstruction without mechanical blockage.
 Autonomic innervation of the colon
 Parasympathetic innervation is excitatory through the vagus and sacral nerves (S2, S3, S4).
 Sympathetic innervation is inhibitory through the celiac and mesenteric plexuses.
 The majority of patients have one or more predisposing factors:
 Infection, cardiac disease, trauma, neurologic disease, organ failure, pancreatitis, electrolyte imbalance,
post-operative (e.g. cardiac and orthopedic surgery).
 Medications: narcotics, anticholinergics, anesthetics, TCAs, chemotherapeutic agents.
 Clinical manifestations include abdominal pain, distension, constipation, nausea, vomiting.
 Management
 Exclude mechanical obstruction.
 Consider C. difficile testing if the clinical presentation is suggestive of infectious megacolon.
 Assess for colonic ischemia and perforation by clinical exam, labs, and radiologic studies.
 The reported spontaneous perforation rate is 3-15%.
 Initial management is supportive. NPO, correct underlying predisposing factors, nasogastric and rectal tube
decompression, frequent position changes. This conservative management is successful in 77-96% of
patients. If there is no response, consider neostigmine.
 Neostigmine
 Neostigmine inhibits acetylcholine esterase, which increases acetylcholine levels. Acetylcholine
stimulates colonic muscarinic receptors and enhances colonic motility.
 Contraindications to neostigmine include mechanical obstruction, ischemia, pregnancy, arrhythmia,
severe bronchospasm, creatinine > 3 mg/dL.
 Dose: 2 mg IV over 3-5 minutes. Monitor for 30
minutes.
 Atropine should be ready at the bedside in case
symptomatic bradycardia develops.
 The mean time until onset of action is 4 minutes.
Duration of action is 1-2 hours.
 Neostigmine has a high response rate (~94%).94
 Consider polyethylene glycol solution (17 grams b.i.d.)
after initial decompression to increase stool output and
decrease colonic distension recurrence rate.95
 Colonoscopic decompression (figure 14)
 Indications: Cecal diameter is more than 10 cm,
prolonged pseudo-obstruction (> 5 days), No
response to conservative management, the patient
fails or cannot receive neostigmine. Figure 14: colonic pseudo-obstruction.
 Contraindications to colonoscopy include peritonitis Severe colonic distension (12 cm).
or perforation.
 Colonoscopy in this setting is technically difficult and associated with a higher rate of perforation (~3%).
 Technique
o Use a regular colonoscope and minimize air insufflation.
o Advance the scope at least to the hepatic flexure.
o Aspirate air during withdrawal.
o Studies show that placing a decompression tube may decrease recurrence rate.
 The success rate of colonoscopic decompression is 70%. The recurrence rate of colon distension is
~40% if a decompression tube is not placed.
 Consider percutaneous cecostomy in patients who do not respond to colonoscopic decompression or those
who are poor surgical candidates. Surgical cecostomy should be considered in refractory cases. Colectomy
is performed in cases of perforation or severe ischemia.
Colonic polyps
Adenomatous polyps
 Adenomatous polyps are the main type of neoplastic polyps.
 Histologic subtypes include tubular, villous, and tubulovillous adenomas.
 All adenomas have some degrees of dysplasia.
 Mild or moderate dysplasia is classified as low-grade dysplasia.
 Severe dysplasia or carcinoma in situ is classified as high-grade dysplasia.
 Advanced adenomas include those with a size of ≥10 mm, villous or tubulovillous histology, or those with
high-grade dysplasia.
Serrated polyps
 Hyperplastic polyps (HP)

 HPs are present in 20-30% of average risk patients, and account for 70-95% of all serrated polyps.
 Most polyps are small and located in the distal colon (80%). They have no malignant potential.
 They have two histologic subtypes: microvesicular HP and goblet cell rich HP. 96
 Histology shows straight crypts, wide at the top and narrow at the base. Serration is more pronounced in
the upper half of the crypt.
 Sessile serrated lesions (SSLs)
 These were formerly called sessile serrated adenoma/polyp (SSA/P).
 They are present in 5-15% of average risk patients and account
for 5-25% of serrated polyps.
 75-90% of SSLs are present in the proximal colon.
 The mean diameter of 5-7 mm96. They can grow to a large size.
 These polyps are indistinct and can easily be missed.
 A mucous cap often covers the surface of the polyp (figure
15), or they may have a ring of debris.
Figure 15: Subtle SSL with
 The diagnosis of SSL requires the unequivocal presence of at least
a yellow mucous cap
one feature of crypt distortion: horizontal crypt growth pattern,
dilated crypt base, crypt serration extending to the crypt base, and asymmetric proliferation.97 Branching
crypts are no longer considered diagnostic of SSLs.96
 SSLs can progress to SSLs with dysplasia (SSLD).
 SSLs have a significant malignant potential, and are the main precursors of hypermethylated colorectal
cancer (CpG island hypermethylation phenotype), which develops through the serrated neoplasia pathway
(see page 235).
 Traditional serrated adenoma

 Uncommon, they are present in <1% of average risk patients and account for < 2% of serrated lesions.
 Usually pedunculated and located in the rectosigmoid colon.
 They have a significant malignant potential.
 Histology shows filiform projections lined with tall eosinophilic cells. There is a characteristic growth pattern
with ectopic crypts perpendicular to the long axis of the villi.98
Juvenile polyps
 Juvenile polyps occur most commonly in children. 10% of cases are diagnosed in adults.
 The most common location is in the rectosigmoid area.
 Histology: the polyp appears as a hamartomatous malformation of the mucosa that consists of lamina propria
encircling dilated cystic glands, with associated inflammation and superficial congestion.99 In contrast to
hamartomatous polyps in Peutz-Jeghers syndrome, there is no smooth muscle hypertrophy in juvenile polyps.
 Juvenile polyps and cancer risk
 A single isolated juvenile polyp is not associated with an increased cancer risk.
 Multiple juvenile polyps are seen in juvenile polyposis syndrome. This syndrome is associated with an
increased risk of colon cancer (see page 230).
Paris classification of colonic neoplasia
 This is a useful morphologic classification of superficial colonic neoplastic lesions (figure 16).100
 The same classification is used for superficial neoplasia of the esophagus and stomach.
Figure 16: Paris

classification of superficial
colonic neoplasia
Lesions are classified as
polypoid and non-polypoid
(flat). Type Is and IIa polyps
are differentiated according to
their protrusion above the
mucosa compared to the height
of the closed biopsy forceps
(2.5 mm).
Gastrointestinal polyposis syndromes

 GI polyposis syndromes include inherited and non-inherited syndromes:
 Inherited polyposis syndromes:
 Adenomatous: Familial adenomatous polyposis (FAP), Gardener syndrome, Turcot syndrome,
Attenuated FAP, MutYH associated polyposis, Polymerase proofreading-associated polyposis.
 Hamartomatous: Peutz-Jeghers syndrome, Juvenile polyposis, Cowden's syndrome.
 Non-inherited polyposis syndromes: Cronkhite-Canada syndrome, Serrated polyposis syndrome (SPS).
Adenomatous polyposis syndromes

Table 7: Adenomatous polyposis syndromes
Syndrome Main features Genetics features / comments
FAP
-GI manifestations  Mutation in APC gene on
 Colonic adenomas (>1000 polyps) chromosome 5
(figure 16,  Duodenal adenomas, periampullary  Autosomal dominant
video 8-3) adenocarcinoma inheritance
 Gastric fundic gland polyps  30% of cases are sporadic
● Gastric adenomas and gastric cancer
are less common*
 Small intestinal adenomas
-Extraintestinal manifestations
 Mandibular osteomas
 Dental anomalies
Gardner -GI manifestations: same as FAP  Mutation in APC gene
syndrome -Extraintestinal manifestations  Autosomal dominant
 Osteomas  Prominent extra colonic
 Congenital hypertrophy of the retinal manifestations
pigment epithelium
 Desmoid tumors
 Epidermal and sebaceous cysts
 Lipomas, fibromas
 Dental anomalies
 Adrenal adenomas
Turcot -GI manifestations: same as FAP  Mutation in APC gene
syndrome** -Extraintestinal manifestations  Autosomal dominant
 Medulloblastoma 
 Glioblastoma multiforme
Attenuated FAP -GI manifestations  Mutation at the 5' and 3'
 Less colonic adenomas (10-100 polyps) ends of the APC gene
 Duodenal adenomas/periampullary  Autosomal dominant
adenocarcinoma
 Gastric fundic gland polyps
MutYH -GI manifestations  Biallelic mutation of the
associated  Colonic adenomas (15-100 polyps) base excision repair gene
polyposis  Duodenal adenomas MutYH
 Gastric fundic gland polyps  Autosomal recessive
Polymerase GI manifestations  Mutations in POLE and
proofreading-  Colonic adenomas (10-100 polyps) POLD1
associated  Duodenal adenomas  Autosomal dominant
polyposis Extraintestinal manifestations
(PPAP)  Endometrial cancer (POLD1 mutation
carriers)
*Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) is a rare autosomal dominant cancer
predisposition syndrome associated with germline mutation in the YY1 binding site of the APC promotor 1B. It is
associated with fundic gland polyps located mainly in the fundus and body of the stomach, without colonic or duodenal
polyposis. The risk of gastric adenocarcinoma is increased (but not colon adenocarcinoma).
**Turcot syndrome was originally used to describe the association of brain tumors and colonic polyposis. It can also
refer to cases of colorectal cancer associated with Lynch syndrome and brain tumors (glioblastoma) 101
APC: Adenomatous polyposis coli; POLE: polymerase epsilon; POLD1: polymerase delta 1.
Familial adenomatous polyposis
The role of endoscopy in familial adenomatous

GIE, 2020
polyposis syndromes 102
ACG Clinical Guideline: Genetic Testing and
Management of Hereditary Gastrointestinal AJG, 2015
Cancer Syndromes103
Endoscopic management of polyposis syndromes:
European Society of Gastrointestinal Endoscopy Endoscopy, 2019
(ESGE) guideline 104
 Colonic adenomas: patients with the APC mutation start developing adenomas at a young age. The colon
eventually develops thousands of adenomas (figure 17).
 The risk of colon cancer is 100% by age 45, with an average age of onset of 35 years.
 Start annual screening sigmoidoscopy at age 10-12 years. Perform colonoscopy if distal polyps are
detected. Proctocolectomy is performed in patients with numerous large polyps. Other social and
educational factors are considered when deciding on the time of surgery. The goal is to minimize the impact
on the patient's development during early teenage years.105
 If subtotal colectomy is performed, surveillance of the rectal pouch every 1-2 years is recommended. 104
Video 8-3
Figure 17: Familial adenomatous polyposis . This adult patient had a history of FAP and ileo-rectal anastomosis.
A: Multiple duodenal adenomas. B: Innumerous rectal adenomas.
 Duodenal adenocarcinoma
 Duodenal adenocarcinoma in the periampullary region is the most common cause of death after
prophylactic colectomy. Lifetime risk of duodenal and periampullary cancer is 5-10%.
 In patients with FAP, start endoscopic duodenal surveillance at the age of 25 years.104 Perform EGD with careful
inspection using a forward viewing gastroscope and a side viewing duodenoscope.
 The risk of malignancy is related to polyp burden, size, and histology. The polyposis score is calculated
based on the number, size, and histology of the duodenal polyps (table 8).
 Surveillance is performed according to the polyposis stage (table 9).
 Consider polypectomy for polyps larger than 1 cm in size or those that show high-grade dysplasia on biopsy.
Argon plasma coagulation can be used to ablate small flat polyps.
 Sulindac combined with erlotinib (Epidermal Growth Factor Receptor Inhibitor) was shown to lower
duodenal polyp burden compared to placebo in patients with FAP. 106
 Patients with high polyp burden and advanced polyposis stage should be considered for preventive surgery.
Surgical options include pancreas preserving duodenectomy or pylorus preserving Whipple surgery.
Table 8: Spigelman scoring of duodenal polyposis.107

1 point 2 points 3 points
Number of polyps 1-4 5-20 >20
Polyp size (mm) 1-4 5-10 >10
Histology tubular TVA Villous
Dysplasia mild Moderate Severe
Table 9: Risk of malignancy and recommended surveillance method and interval
Spigelman stage 10-year risk of stage 10-year Screening (start at age 20)
108 108
Points Stage progression cancer risk Interval Method Comments
1-4 1 20% 0% 5 years EGD
5-6 2 16% 2.3% 3 years EGD
7-8 3 12% 2.4% 1-2 year EGD Consider celecoxib
3 years Capsule or sulindac to
decrease duodenal
polyposis
9-12 4 36% 36% 3-6 months EGD Preventive surgery
3 years capsule is the best option
 Desmoid tumors
 Soft tissue fibrous tumors that develop in 10-20% of FAP patients (Gardener syndrome).
 Most desmoid tumors in FAP are intra-abdominal, and their surgical resection is difficult.
 Treatment options include NSAIDS (sulindac), tamoxifen, imatinib, sorafenib.
Attenuated FAP
 Attenuated FAP is caused by a mutation in the FAP gene in the 3' or 5' end of the gene.
 It results in a fewer number of adenomas, and presents later compared to classic FAP.
 Average age of onset for polyps is 45 years, and for colon cancer is 55 years.
 The lifetime cumulative risk of colon cancer is 70%.
 Surveillance: colonoscopy every 2-3 years, and EGD every 1-3 years starting at age 20.
MutYH (MYH) associated polyposis.

 This is an autosomal recessive disease caused by biallelic mutation of MutY-homologue (MutYH) gene.
 It is associated with colonic and duodenal adenomas, as well as gastric fundic gland polyps.
 There is an increased risk of several extracolonic tumors such as ovarian, bladder and skin cancer. 109
 Surveillance: colonoscopy every 2-3 years starting at age 20. EGD at age 25-30.
Hamartomatous polyposis syndromes
Peutz-Jeghers syndrome
 This autosomal dominant syndrome is caused by a mutation in STK11/LKB1 gene on chromosome 19.
 Patients develop mucocutaneous pigmentations and diffuse GI hamartomatous polyps.
 Polyp histology: proliferations of smooth muscle in the lamina propria in the shape of tree branches -“arborization”.
 There is an increased risk of gastrointestinal and extra-intestinal cancer (table 10).
Table 10: Cancer risks and screening recommendations in Peutz-Jeghers syndrome.

Cancer associations Screening recommendations
 Increased risk of colon, gastric and small  EGD at age 8 every 2-3 years
bowel cancer  Colonoscopy late teenage years every 2-3 years
 Screening small bowel follow through or capsule endoscopy at
age 10†
 Ovarian sex cord tumors  Annual ultrasound starting at age 20

 Sertoli cell tumors of the testis*  Yearly testicular examination starting at age 10
 Pancreatic cancer (risk is 5% at 55 years,  Consider CA 19-9 or EUS/MRI every 1-2 years starting at age 30
25% at 70 years)110
 Breast cancer (risk is 8% at 40 years, 40%  Monthly breast self-examinations at age 18
at 60 years)  Screening breast MRIs starting at age 25 and annual
mammograms at age 50
* Sertoli cell tumors can secrete estrogen, leading to feminizing features
† Capsule endoscopy appears to be effective and safe even in patients with prior small bowel surgery. However,
consider a patency study prior to capsule endoscopy. 111, 112
Juvenile polyposis syndrome
 This is a rare autosomal dominant disease associated with multiple (>10) colonic and gastric juvenile polyps.
 It is associated with mutations in SMAD4, bone morphogenetic protein receptor type 1A (BMPR1) and ENG gene.
 There is an increased risk of colorectal cancer that arises from dysplastic changes in the polyp epithelium. In
addition, there is an increased risk of gastric and duodenal cancer.
 Screening colonoscopy is recommended in early teenage years every 3 years. Screening EGD is every 3 years.
Cowden syndrome
 Cowden syndrome is an autosomal dominant disease that presents in adulthood.

 It is caused by a mutation in the PTEN gene. Other possible genetic alterations include SDH gene mutation,
and hypermethylation of the promoter of the "Killin" gene.
 Table 11 summarizes the clinical features and screening recommendations.
Table 11: Cowden syndrome: clinical features and screening recommendations

Clinical features and cancer associations Screening recommendations
 Multiple trichilemmomas*  Annual skin exam
 GI polyposis: hamartomas, adenomas, hyperplastic polyps  Baseline colonoscopy at diagnosis
 Increased risk of colon cancer Repeat every 5 years
 EGD at age 15, repeat every 2 years
 Esophageal glycogenic acanthosis  None
 Benign thyroid conditions§  Baseline and annual thyroid ultrasound
 Non medullary thyroid cancer
 Benign breast conditions†  Monthly self breast exam
 Breast cancer‡  Annual mammogram in females
 Endometrial cancer  Consider endometrial biopsies
 Renal cell carcinoma  Annual urinalysis
 Dysplastic gangliocytoma of the cerebellum, macrocephaly  Baseline brain MRI
*Tumors of the hair follicle § Goiter, hashimoto thyroiditis
†
Ductal hyperplasia, papillomatosis ‡ Lifetime risk is 25-50%
Bannayan-Riley-Ruvalcaba syndrome
 This autosomal dominant disease presents in childhood. It is caused by a mutation in the PTEN gene.
 Characterized by intestinal hamartomatous polyps, pigmented maculae of the glans penis, vascular
abnormalities, developmental delay, and mental retardation.113
Serrated polyposis syndrome
 Serrated polyposis syndrome (SPS) was formerly known as hyperplastic polyposis syndrome.
 World health organization's (WHO) 2019 SPS definition requires one of the following two criteria:
1. ≥ 5 sessile serrated lesions (SSLs) or serrated polyps (includes HP, TSA) proximal to the rectum, all of
which are > 5 mm, of which at least two are ≥ 10 mm in size.
2. ≥ 20 cumulative (SSLs) or serrated polyps (includes HP, TSA) distributed throughout the colon, with at
least 5 proximal to the rectum.
Note: the previous WHO definition included a third criterion (any number of serrated polyps proximal to the
sigmoid colon, in a patient with a first-degree relative with SPS), which was removed in the 2019 definition.
 SPS is associated with a higher risk of CRC. One study of 296 patients with SPS found that 47(15.8%)
developed CRC.114 The majority of patients with CRC had colon cancer before (17%) or at the time of
diagnosis of SPS (74.5%).
 Among those without a diagnosis of cancer at the time of SPS diagnosis, the cumulative incidence of CRC was
1.9% at 5 years. Therefore, the risk of CRC appears to be low in patients undergoing surveillance (see study below).
 CRC risk is increased if ≥1 serrated polyp+dysplasia, ≥1 advanced adenoma, or multiple proximal serrated polyps.115
Study highlight
Personalized surveillance for serrated polyposis syndrome: results from a prospective
5-year international cohort study 116
 This prospective study evaluated the risk of CRC and advanced neoplasia (AN) in 271 SPS patients
followed for a median of 3.6 years.
 SPS was defined based on older, slightly different, WHO SPS criteria #1 and #3 as follows:
 SPS type 1: At least 5 serrated polyps proximal to the sigmoid of which at least two are ≥ 1 cm in size
 SPS type 3: 20 or more serrated polyps throughout the colon.
 All patients underwent baseline colonoscopy and clearance of polyps, and they were followed with
colonoscopy at 1- or 2- year intervals, based on baseline polyp burden and histology. Patients were
recommended a surveillance interval of 1 year if any one of the following criteria is met:
 One or more advanced SSL or adenomas were removed.
 Cumulatively ≥ 5 relevant polyps were removed (any size SSL, any size adenomas, HPs ≥ 5 mm)
 Surgery was needed during the last surveillance.
o In all other cases, a 2-year surveillance interval was recommended.
 Results:
 The cumulative 5-year incidence of CRC was 1.3%, and of AN was 44%.
 AN was lower in those with SPS type 3 (26%) than those with SPS type 1 (53%).
 The incidence of AN in patients initially followed every 2 years was 15.6% compared with 24.4% in
those initially followed every 1 year (OR 0.57, p=0.08).
 This study suggests that a more personalized surveillance approach is feasible and lengthening surveillance intervals
to q2 years should be considered, especially in those with lower risk SPS (~criterion #2 per the new WHO definition).
 The management of SPS includes colonoscopic polypectomy and surveillance in two phases: 117
 Clearance phase: in which the colon is cleared from polyps ≥3 mm in size (may require a repeat
colonoscopy in 3-6 months).
 Surveillance phase: Surveillance colonoscopy every 1 year 118
 First-degree relatives of patients with SPS should be screened starting at age 40.
 The risk of CRC after subtotal colectomy in patients with SPS appears to be low.
 One cohort study of 48 patients with SPS followed for a median of 4.7 years after subtotal colectomy
found that none of the patients developed CRC.119 Five patients developed AN (cumulative 5-year
incidence of AN of 13%).
Cronkhite-Canada Syndrome
 This is a rare, non-familial syndrome of gastrointestinal hamartomatous polyposis, skin pigmentation, alopecia,
and nail dystrophy. Other clinical features include diarrhea, weight loss, and abdominal pain.
 The etiology of Cronkhite-Canada Syndrome is unclear but could be immune-mediated.
 It is associated with a high mortality rate due to malnutrition and gastrointestinal complications.
 There is an increased risk of gastric and colon cancer.
 Treatment: nutritional support (TPN). Steroids and azathioprine can improve symptoms.
Lynch Syndrome and Hereditary Nonpolyposis Colorectal Cancer
Guidelines on Genetic Evaluation and Management of

Lynch Syndrome: A Consensus Statement by the US Am J Gastroenterol, 2014
Multi-Society Task Force on Colorectal Cancer 101
American Gastroenterological Association Institute

Guideline on the Diagnosis and Management of Gastroenterology, 2015
Lynch Syndrome 120
 Terminology: Amsterdam I criteria for HNPCC

 Lynch syndrome refers to families and patients who have a -Three or more relatives with
germline mutation in any DNA mismatch repair (MMR) genes: colorectal cancer (one must be a
first-degree relative of the other two).
(hMSH2, hMLH1, hMSH6, hPMS1, hPMS2) or have loss of
-CRC involving at least two
expression of MSH2 gene due to deletion of EPCAM gene. 101
generations.
 Hereditary nonpolyposis colorectal cancer (HNPCC) refers to
-One or more CRC cases diagnosed
patients and families who fulfill the Amsterdam I and II criteria in a patient younger than 50 years.
 If they also have a germline mutation in MMR or EPCAM,
they are referred to as having Lynch syndrome. Amsterdam II criteria for HNPCC
 Lynch syndrome is the most common hereditary colon cancer syndrome. -Three or more relatives with
 Accounts for approximately 3% of cases of CRC. histologically proven HNPCC
 Mean age at diagnosis of CRC in Lynch syndrome is 44 years. associated cancer (colon,
 Right-sided tumors occur in 70% of patients. Synchronous endometrium, small bowel, ureter,
renal pelvis), one of these patients is
tumors occur in 20% of patients, while metachronous tumors
a first degree relative of the other two
occur in 25%.
(excluding FAP)
 In general, loss of MMR can be caused by either a germline mutation
-CRC involving at least two
of MMR genes (as in Lynch syndrome), or by epigenetic silencing of
generations.
MMR expression which occurs in sporadic colon cancer. -One or more CRC cases diagnosed
 Microsatellite instability in a patient younger than 50 years.
 Microsatellite instability (MSI) is the molecular feature that
results from loss of MMR. Microsatellites are areas of short repetitive DNA sequences that normally have
a stable length in each individual.
 Loss of MMR function leads to a higher DNA mutation rate. This causes variability in the size of
microsatellites, i.e. microsatellite instability.
 Tumor specimens can be tested for the presence of MSI using polymerase chain reaction (PCR).
 Tumors that are microsatellite unstable are divided into MSI-high and MSI-low tumors.121
 Tumors that do not have MSI are called microsatellite stable (MSS) or non-MSI tumors.
 10-15% of sporadic colon cancers are MSI-high. Patients with those tumors have better long term
survival compared to patients with MSI-low tumors.121
 Familial colorectal cancer type X refers to patients/families who fulfill the Amsterdam I criteria, but lack MSI 101
 Muir Torre syndrome
 This is a variant of Lynch syndrome. Patients have features of Lynch syndrome in addition to sebaceous gland
tumors, skin basal cell and squamous cell carcinomas, and keratoacanthomas.
 Prediction of Lynch syndrome
 Several clinical criteria and risk prediction models are available to help predict the presence of Lynch
syndrome and decide which patients should be tested.
 Revised Bethesda guidelines: testing for Lynch syndrome should be performed if any of the following criteria is met:
 Colorectal cancer diagnosed in a patient younger than 50 years.
 Presence of synchronous or metachronous CRC, or other Lynch syndrome related cancers regardless of age.
o Other HNPCC tumors: endometrial, ovarian, ureter, renal pelvis, stomach, pancreas, biliary tract, brain
tumors (glioblastoma), sebaceous gland adenomas, keratoacanthomas, and small bowel carcinoma.
 CRC with histologic features suggestive of MSI-high tumor diagnosed in a patient younger than 60
years old. MSI-high histology includes any of the following: tumor infiltrating lymphocytes,
mucinous/signet-ring histology, medullary growth pattern, Crohn's-like reaction 101
 CRC diagnosed in a patient with one or more first degree relatives with an HNPCC-related tumor, with
one of the cancers diagnosed under age 50 years.
 CRC diagnosed in a patient with two or more first or second degree relatives with HNPCC-related
tumors, regardless of age.
 PREMM® model:
 This model is used to predict the presence of Lynch syndrome in patients with or without
a personal history of colon cancer. http://premm.dfci.harvard.edu/
 Patients with a predicted risk of ≥2.5% should undergo germline testing for Lynch syndrome.
 Diagnosis
 Universal testing of all colon cancer specimens for lynch syndrome is now recommended by many
societies. Preferably, testing should be performed on preoperative cancer biopsies, if available. 101
 The most specific test for Lynch syndrome is gene sequencing of the MMR genes. However, workup
usually starts by performing immunohistochemistry for the MMR proteins (figure 18-A).
 If MLH1 staining is absent, then it is recommended to test for BRAF mutation.
o If BRAF mutation is present, this rules out Lynch syndrome and confirms sporadic colon cancer.
● BRAF mutation is present in 70% of colon cancer cases with absent MLH1 staining.
o If BRAF mutation is absent, proceed with MLH1 gene sequencing to test for Lynch syndrome.
 In cases of absent MSH2 staining without a genetic mutation of MSH2, this could be secondary to a
germline mutation of EPCAM (epithelial cell adhesion molecule) resulting in MSH2 inactivation.122
 An alternative testing strategy is to start by testing the tumor for microsatellite instability. If the tumors is
MSI-high, then immunohistochemistry is performed (figure 18-B).
 Lynch syndrome should be suspected in patients or families fulfilling the clinical criteria (Amsterdam I and
II, revised Bethesda), or other prediction tool (e.g. PREMM®). In addition, patients with endometrial
cancer diagnosed at age <50, and individuals with first degree relative with known MMR/EPCAM mutation
are also at a high risk of having Lynch syndrome
 If these patients have a CRC specimen, it should be tested for Lynch syndrome (figure 18).
 If these patients do not have CRC or a specimen, they should be referred to genetic counselling and
genetic testing.
 If the patient tests positive for Lynch (Lynch confirmed) or the patient is not tested (Lynch not excluded),
or testing is inconclusive, start surveillance for all Lynch syndrome associated tumors (table 12).
Figure 18: Suggested algorithm for testing for Lynch syndrome.

Both testing strategies A and B are acceptable (see text).
IHC: Immunohistochemistry; MSI: Microsatellite instability.
 Management
● Patients with Lynch syndrome and CRC that is not endoscopically resectable should undergo total
colectomy and ileorectal anastomosis.101 Patients > 60 years may consider less extensive surgery.
● Table 12 summarizes the main cancer risks and screening recommendations in Lynch syndrome.
Table 12: Cancer risks and screening recommendations in Lynch syndrome.
Cancer risks* Screening / chemoprevention recommendation
 CRC  Colonoscopy every 1-2 years starting age 20-25 or 10 years
o 25% by age 50, 80% by age 70 younger than the youngest diagnosis of CRC in family
 Annual colonoscopy after the age of 40
 Offer aspirin to patients for CRC prevention 120
 Endometrial cancer  Annual endometrial biopsy, transvaginal ultrasound, and CA
o 20% by age 50, 70% by age 70 125 levels starting at age 30-35
 Ovarian: 10% lifetime risk  Prophylactic hysterectomy/salpingo-oophorectomy is
recommended after childbearing or age 40
 Gastric cancer: 9% lifetime risk  EGD every 2-3 years starting at age 30-35
 Check for H. pylori and eradicate if present
 Small bowel cancer: 7% lifetime risk  Screening not recommended
 Urinary tract cancers: 4-12% lifetime risk  Annual renal ultrasound, urinalysis with urine cytology starting
at age 30
 Pancreatic adenocarcinoma: (~4% risk by age 70)  Screening not recommended
*Other associated cancers include hepatobiliary tumors and glioblastoma multiforme
Colorectal cancer
ASGE guideline: Role of endoscopy in the staging and Gastrointestinal

management of colorectal cancer 123 endoscopy, 2013
Colonoscopy Surveillance After Colorectal Cancer Am J

Resection: Recommendations of the US Multi- Gastroenterol,
Society Task Force on Colorectal Cancer 124 2016
 Epidemiology
 Colorectal cancer (CRC) is the third most common cancer in males and females and the fourth most
common cause of cancer death in the United States.
 Estimated number of new CRC cases in the USA in 2018 is 147,950 (8% of all new cancer cases), with ~
53,200 deaths (9% of all cancer deaths).125
 The lifetime risk of CRC is ~6%. Around 90% of cases occur in patients older than 50.
 Since 1975, the incidence of CRC has decreased by ~30%, and mortality has decreased by ~50%.
 However, the incidence in younger adults (ages 20–49 years) is increasing.
 Since 1990s, CRC incidence have increased by 26% in younger adults (from 8.5 per 100,000 in 1992
to 10.7 per 100,000 in 2013).126 CRC mortality rates have remained stable in young adults.
 Younger adults are usually diagnosed at a later stage of CRC and with more advanced histology. 127, 128
 Despite this significant relative increase, the absolute rate of CRC in younger adults remains low.
 Risk factors
 Age, gender (males > females), race (black > white).
 Smoking, alcohol, lack of physical activity.
 Diet (high fat, low fiber).
 Prior surgery: ureterosigmoidostomy, cholecystectomy (controversial).
 Other risk factors include hereditary colon cancer syndromes, first-degree relative with colon cancer, and
inflammatory bowel disease.
 Constipation was found to be associated with colon cancer in case control studies. However, cross sectional
surveys and cohort studies do not support constipation as a risk factor for CRC.129
 Protective factors
 There is strong evidence that aspirin decreases the risk of colon cancer and prevents the recurrence of
adenomas. Patients should take aspirin for at least 5-10 years to gain the protective effect of aspirin.130
 Other possible protective factors include calcium and vitamin D, high fiber, low fat diet.
 Colon cancer genetic pathways are complex, but are simplified in figure 19.97, 131
 Chromosomal instability pathway accounts for 80% of cases.
 Hereditary: caused by FAP and MutYH associated polyposis.
 Acquired: caused by mutations in APC, KRAS, DCC, SMAD, and TP53 genes. (TP53 is the same as p53)
 Mutator phenotype (hereditary) pathway
 This is the cancer pathway in Lynch syndrome. It starts with a germline mutation in one of the mismatch
repair genes. Mutations in BAX, caspase 5, insulin growth factor 1 (IGF-1) and TGF-β II receptor may
also contribute to the accelerated carcinogenesis in these patients.132-134
● BRAF mutations are not present in Lynch syndrome.
 Serrated neoplasia pathway
 This is also called "serrated" pathway which includes the sessile serrated lesions (SSL) and traditional
serrated adenoma (see page 225 )
o The sessile serrated lesions develop through BRAF mutation, followed by either one of the following routes:
● CpG Island hypermethylation Phenotype (CIMP) in which DNA hypermethylation leads to

MLH1 methylation that progresses to mismatch repair gene (MMR) deficient CRC.
● TP53 mutation that progresses to MMR proficient CRC
o The traditional serrated adenoma develop by either BRAF or KRAS mutation to progress to MMR
proficient CRC
Figure 19: Colon cancer genetic pathways (see text)

 Clinical presentation
 Bleeding, weight loss, anemia, altered bowel habits, bowel obstruction.
 Diagnosis: colonoscopy, CT scan.
 Patients who cannot undergo a complete colonoscopy due to malignant colonic obstruction should have a
complete colonoscopy within 3-6 months post operatively to rule out synchronous CRC and resect
precancerous polyps. 124 In these patients, preoperative CT colonography should be obtained, if available,
to exclude proximal malignancy.
 Staging and prognosis
 The TNM classification is the most common staging system (table 13 and 14).
 Rectal endoscopic ultrasound (EUS) is an important test for staging for rectal cancer.
 It is performed in patients without distant metastasis to determine the depth of tumor invasion, and the
presence of perirectal lymphadenopathy.
 It is essential to differentiate T2 from T3/T4 cancers and N0 from N1/N2 cancers, as this will affect
management. Advanced cases are given neoadjuvant chemoradiotherapy prior to resection.
Table 13: TNM staging of colorectal cancer.

T: primary tumor depth of penetration N: nodal metastasis
 Tis: Carcinoma in situ: intraepithelial or invasion  N0: No regional lymph node metastasis
of lamina propria above the muscularis mucosa  N1: Metastasis in 1-3 regional lymph nodes
 T1: Tumor invades submucosa o N1a: 1 regional lymph node
 T2: Tumor invades muscularis propria o N1b: 2-3 regional lymph nodes
 T3: Tumor invades through the muscularis  N2: Metastasis in four or more regional lymph
propria into pericolorectal tissues nodes
 T4a: Tumor penetrates to the surface of the o N2a: Metastasis in 4-6 regional lymph nodes
visceral peritoneum o N2b: Metastasis in seven or more regional
 T4b: Tumor directly invades other organs lymph nodes
M: distant metastasis
 M0: No distant metastasis

 M1: Distant metastasis
 M1a: Metastasis confined to one organ or site
 M1b: Metastases in more than one organ or site, or the distal peritoneum
Table 14: Colon cancer stage and five-year survival

Stage T N M 5-year survival 135
I T1 N0 M0 74%
T2 N0 M0
IIA T3 N0 M0 67%
IIB T4a N0 M0 59%
IIC T4b N0 M0 37%
IIIA T1-2 N1 M0 73%
T1 N2a M0
IIIB T3-T4a N1 M0 46%
T2-T3 N2a M0
T1-T2 N2b M0
IIIC T4a N2a M0 28%
T3-T4a N2b M0
T4b N1-N2 M0
IVA Any T Any N M1a 6%
IVB Any T Any N M1b
 Treatment
 Surgery: colonic segmental resection and lymph node removal is the treatment of choice.
 Rectal cancer involving the upper rectum is treated with low anterior resection.
 Rectal cancer involving the lower 5 cm of the rectum is treated with abdominoperineal resection and
permanent colostomy.
 Chemotherapy: adjuvant chemotherapy is aimed at treatment of micrometastasis to decrease cancer
recurrence and increase cure rates.
 It is indicated in patients who underwent primary cancer resection for curative intent with either stage
III cancers (lymph node involvement) or stage II cancers with high-risk features (e.g. T4 cancer, poorly
differentiated, lymphovascular and perineural involvement).
 Adjuvant chemotherapy was shown to improve survival in patients with non-MSI or
MSI-low tumors, but not in patients with MSI-high tumors.136, 137
 Patients who undergo complete resection of metastasis are also candidates for chemotherapy.
o The most commonly used regimen is 5-fluorouracil, leucovorin, and oxaliplatin.
 Locally advanced colon cancers and stage IV cancers are treated with 5-FU, leucovorin, and irinotecan.
 Radiotherapy
 Neoadjuvant chemoradiotherapy is indicated in patients with T3 or T4 rectal cancer, and patients with
lymph node involvement (N1).
 Other treatment
 Bevacizumab (Avastin®) is recombinant antibody against vascular endothelial growth factor-A (VEGF-A).
It inhibits angiogenesis. It is approved for metastatic colorectal cancer.
 Cetuximab (Erbitux®) is a recombinant antibody against epidermal growth factor receptor (EGFR). It
induces apoptosis and inhibits angiogenesis. It is approved for the treatment metastatic colorectal
cancers that do not have KRAS activating mutations.
 Surveillance after CRC resection
 Colonoscopy at 1 year, then after three years (4 years after surgery), then every 5 years.
 CEA levels every 3 months for 2 years, then every 6 months.
 An alternative to CEA is CT chest, abdomen, and pelvis every 6 months for 2 years then every 1 year.
 A prospective randomized study showed that performing either CT or CEA surveillance as above results in a
higher rate of surgery for curative intent, compared to a minimum follow up strategy (single CT in 12-18
months). Combining both CT and CEA did not provide any additional benefit.138
 Prognosis: the prognosis of colon cancer is directly related to the TNM stage (5-year survival is shown in table 15).
Management of advanced and malignant polyps
Endoscopic Recognition and Management Strategies for

Malignant Colorectal Polyps: Recommendations of the US Gastroenterology, 2020
Optimal Management of Malignant Polyps, From Endoscopic Clin Gastroenterol
Assessment and Resection to Decisions About Surgery 140 Hepatol, 2019 (Review)
 Advanced polyps are polyps with carcinoma in situ,
intraepithelial or intramucosal carcinoma (figure 20-A)
 In this kind of polyps, there is no invasion beyond
the muscularis mucosa.
 Polypectomy with a negative margin is
sufficient for treatment.
 Surgery is not indicated, because the risk of
lymph node metastasis is zero %.
 Malignant polyps are those with invasive
carcinoma beyond into the submucosa without
extension to the muscularis propria (T1
lesions-figure 20-B) Figure 20: Colon wall layers and depth of
invasion of advanced and malignant polyps.
 If the polyp has not been tattooed, repeat the A: Intramucosal carcinoma. B: T1 lesion. C: T2 lesion
endoscopy and tattoo the site of the polyp.
 Lymph node metastasis ranges from 2% to 8%.
 The decision to undergo surgery with lymph node resection should be individualized for each patient based
on the adequacy of resection and the presence of high-risk histologic features.
 Adequacy of resection: confirm that the polyp was resected completely.
o A pedunculated polyp should be resected without evidence of invasion of the stalk.
o Sessile polyps should be resected with free margins. It is less likely to achieve adequate resection in
tumors with deep invasion of the submucosa in sessile polyps compared to pedunculated polyps.
 High-risk histologic features include poorly differentiated histology, lymphovascular invasion, tumor
budding ( or “sprouting”)141 and deep invasion > 1 mm [1000 µm] into the submucosa 139. The presence
of any of these features increases the risk of lymph node metastasis
 If the polyp was adequately resected and there are no high-risk histologic features, the risk of lymph node
metastasis is less than 2%, and surgery can be deferred. However, this also depends on the patient's
tolerance of the small risk of lymph node metastasis. Follow up endoscopy in 3 to 6 months.
 If the polyp was incompletely resected (involved polyp margins) or there are high-risk features, then
colectomy and removal of regional lymph nodes surgery is indicated.
 For malignant pedunculated polyps and cancer limited to the submucosa (T1) without unfavorable
histologic features (< 1 mm cancer free margin or high risk histologic features (see above), endoscopic
resection is sufficient.123, 142 However, this does not address the depth of invasion into the submucosa and
the real risk of lymphatic spread, in spite of the absence of unfavorable histologic features.
 Surgery with lymph node resection can be considered in patients with sessile malignant polyps, even with
favorable histologic features and clear margins (NCCN guideline). 142
 Malignant lesions with invasive carcinoma beyond the submucosa into the muscularis (T2 lesions -figure 20-C)
 Surgery is always indicated in these cases.
Colon cancer screening

Screening for Colorectal Cancer: US Preventive Services
A JAMA, 2021
Task Force (USPSTF) Recommendation Statement 143
Colorectal Cancer Screening: Recommendations for Physicians Am J Gastroenterol,
B and Patients from the U.S. Multi-Society Task Force (USMSTF) 2017 (updated
2021145)
on Colorectal Cancer 144 (AGA, ACG, ASGE)
Colorectal cancer screening for average‐risk adults: 2018 CA CANCER J
C
guideline update from the American Cancer Society (ACS) 146 CLI, 2018
Screening for Colorectal Cancer in Asymptomatic Average-

Ann Intern Med,
D Risk Adults: A Guidance Statement From the American 2019
College of Physicians (ACP) 147
Am J
(ACG) Clinical Guidelines: Colorectal Cancer Screening
E Gastroenterol,
2021148 2021
 Types of colon cancer screening tests
 Tests for cancer prevention detect cancer and polyps. These include colonoscopy, flexible sigmoidoscopy,
colon capsule, and CT colonography (CTC).
 Tests for cancer detection detect mainly cancer. These include Guaiac-based fecal occult blood testing
(hemoccult II and hemoccult II SENSA), fecal immunochemical test (FIT), and stool DNA.
 Tests that are not recommended are digital rectal exam, barium enema, and septin-9 blood test (see page 193).
 When to start colon cancer screening:
 In average risk patients, current guidelines recommend starting at age 45 years (ACS, NCCN, USPSTF-moderate
certainty/grade B recommendation, ACG-conditional recommendation, USMSTF-weak recommendations)
 The change from 50 years to 45 years cutoff started with the ACS guidelines in 2018, based on the increasing
incidence of CRC in young adults (see page 235 ) and results of predictive modelling.
 Other societies subsequently changed to 45 years, except ACP which kept the cutoff at 50 years.
 All guidelines recommend starting at age 50 as a “strong/grade A recommendation”.
 Family history of colon cancer (not related to a genetic syndrome) 144
 Single first-degree relative with CRC or advanced adenoma diagnosed at age ≥ 60 years
o Start screening at age 40, patients may choose any test, follow regular surveillance intervals.
 Single first-degree relative with CRC or advanced adenoma diagnosed at age < 60 years, or ≥2 first-degree
relatives with CRC or advanced adenoma regardless of age.
o Start screening at age 40 (or 10 years younger than the age of diagnosis of the youngest affected
relative), offer colonoscopy first. Offer FIT if patient refuses colonoscopy. Repeat colonoscopy every
5 years if normal.
 When to stop colon cancer screening
 Guidelines recommend stopping routine screening at age 75.
 In patients who are 75 to 85 years old, the decision to continue or stop screening should be made based on
the patient's life expectancy, assessment of risks and benefits of screening, and prior screening history.
 Patients with negative past screening tests (especially colonoscopy), should be considered to stop
screening at 75 or when the life expectancy is less than 10 years. 144
 Patients without prior CRC screening should be considered for screening up to age 85.
 Stop all screening at age 85.
 Table 15 shows the recommended CRC screening tests by different society guidelines. The USMSTF
categorizes tests into three tiers according to the performance characteristics and cost, with colonoscopy and
FIT listed as the preferred tests.
Table 15: Recommended CRC screening tests per society guidelines (listed on page 240)
A- USPSTF B-USMSTF C-ACS D-ACP E-ACG
 Colonoscopy q 10 -Tier 1  Colonoscopy q 10  Colonoscopy q 10 -Preferred
years  Colonoscopy q10 years years  Colonoscopy q 10
 CTC q 5 years years  CTC q 5 years  FlexSig q 10 years + years
 FlexSig q 5 years  Annual FIT  FlexSig q 5 years FIT q2 years  FIT q 1 year
 FlexSig q 10 years+ -Tier 2  Annual FIT  FIT q2 years -Consider these tests if
annual FIT  CTC q 5 years,  Annual gFOBT  gFOBT q2 years preferred tests not
 Annual FIT  FIT-fecal DNA q 3  Fecal DNA q 3 years  Not listed: CTC, stool feasible or patient
 Annual gFOBT years  Not listed: capsule DNA, capsule unwilling
 Fecal DNA q 3 years  FlexSig q 5 or 10 colonoscopy colonoscopy  CTC q 5 years
 Not listed: capsule years  FIT-fecal DNA q 3
colonoscopy -Tier 3 years
 Capsule colonoscopy q  FlexSig q 5-10 y
5y  Capsule colonoscopy q
5y
Stool testing
 Table 16 summarizes the performance characteristics of stool tests for CRC screening.
Table 16: Performance characteristics of stool tests for CRC screening (different studies)
Sensitivity for colon Sensitivity for Specificity for advanced
cancer advanced lesions lesions or colon cancer
Standard Guaiac FOBT 10-50% 10% 91-98%
Hemoccult II SENSA 50-75% 20-25% 94-96%
FIT 149, 150 60-90% 25-65% 98%
151
Stool DNA testing 50-90% 15% 93-97%
 Guaiac-based FOBT: Hemoccult II and Hemoccult II SENSA

 FOBT detects the presence of heme in a fecal sample (including upper GI bleeding source).
 Mechanism: guaiac is exposed to hydroperoxidase. In the presence of heme, this results in a fast oxidation
reaction, resulting in a blue color change.149 Vitamin C inhibits hydroperoxidase and may cause a false
negative result. Aspirin, NSAIDS and diet do not influence the results of hemoccult II.152
 FOBT was shown in multiple prospective studies to decrease CRC mortality. 153
 FOBT was shown to provide sustained CRC mortality 30 years after screening. Annual FOBT screening reduces
CRC mortality by 32%, whereas biennial screening (every 2 years) reduces mortality by 22%.154
 Fecal immunochemical test (FIT)
Recommendations on fecal immunochemical testing to
Gastroenterology,
screen for colorectal neoplasia: a consensus statement by
2017
the US Multi-Society Task Force on colorectal cancer 155
 FIT uses specific antibodies to detect human globin.
 FIT is more accurate than FOBT, and is specific for bleeding in the distal GI tract.
 There is no need for medication or dietary restrictions.
 In qualitative FIT test, a positive test is indicated by a change in color.
 In quantitative FIT test, an automated analysis provides a specific value of hemoglobin found in stool. The
cut-off value for a positive result is variable. A low threshold (20 mcg/g or lower) is recommended. 155
 Asymptomatic patients with +FIT and a negative colonoscopy do not need further investigation such as an EGD.
 A randomized trial compared FIT to colonoscopy for colon cancer screening. 156
 Participation rate was higher in the FIT group (34%) compared to colonoscopy group (25%).
 Colorectal cancer detection rate was similar in both groups (0.1%).
 The colonoscopy group had higher adenoma and advanced adenoma detection rates compared to the FIT group.
 Stool DNA testing

 The multitarget stool DNA (Cologuard™) is FDA approved for CRC in average risk adults ages ≥ 45 year
 Tests the stool for KRAS mutations, β-actin, aberrant NDRG4 and BMP3 methylation
 The test is a combined DNA+ a hemoglobin immunoassay (~FIT) in one kit.
 Sensitivity: 92% (DNA+FIT kit) vs. 74% (FIT alone) for CRC157
 Specificity: 90% (DNA+FIT kit) vs. 96% (FIT alone) for CRC
 Sensitivity 42% (DNA+FIT kit) vs. 24% (FIT alone) for advanced lesions
 A positive test is followed by a colonoscopy. A positive test followed by a negative colonoscopy occurs in
about 10% of positive results. The incidence of aerodigestive tumors is low in these cases (~2.4% over
median follow up of 5.3 years) and not different than the expected incidence of tumors in the general
population. Most would recommend no specific workup in this group of patients after a negative high
quality colonoscopy.158, 159 However, a discussion with the patient should be carried out and documented.
 A negative test is repeated every 3 years. Stool DNA is not recommended for high risk individuals.
Other tests
 Blood septin9 DNA test -Epi proColon®:Qualitative in vitro diagnostic test (PCR) for the detection of
methylated Septin9 DNA in whole blood specimens. Septin9 DNA methylation is associated with CRC
 Sensitivity for CRC: 68%; specificity for CRC: 78%; sensitivity for advanced lesions: 11%.
 It was FDA approved in April 2016 for average-risk persons who have refused other forms of CRC screening.
Per FDA approval, the Epi proColon test is “not intended to replace colorectal screening by colonoscopy” 160
 This test could have a role in non-compliant patients, or those who refuse all other tests for screening.
 Due to its test characteristics and low sensitivity, Septin9 is not recommended by current guidelines.
 Colon capsule---PillCam™ COLON 2 system (Medtronic®) was FDA approved in 2014 for visualization of
the colon and detection of polyps following incomplete colonoscopy
 For polyps ≥ 6 mm: sensitivity 88%, specificity 82%
 It is also approved to examine the colon in patients with lower GI bleeding who are at major risk with
colonoscopy and sedation. Colon capsule is not FDA approved as a primary test for colon cancer screening.
 Capsule colonoscopy every 5 years is mentioned as a screening test by the USMSTF, but not the other societies.
Colonoscopy
AGA Clinical Practice Update on Strategies to Improve Quality Gastroenterology,

of Screening and Surveillance Colonoscopy: Expert Review 161 2021
Endoscopic Removal of Colorectal Lesions-Recommendations

GIE 2020
by the US Multi-Society Task Force on Colorectal Cancer162
World Endoscopy Organization Consensus Statements on Post- Gastroenterology,

Colonoscopy and Post-Imaging Colorectal Cancer 163 2018
Quality indicators for colonoscopy 164 GIE, 2015
 Several non-randomized studies found that colonoscopy with polypectomy decreases the risk of colon cancer.
 A follow up study of patients who underwent colonoscopy and polypectomy in the national polyp study estimated
that colonoscopic removal of adenomatous polyps reduced the risk of death from colon cancer by 53%.165
 Another retrospective cohort study analyzed data from two previous prospective studies, and included
88,902 participants followed over 22 years.166 Results showed that colonoscopy reduces CRC mortality
from both proximal and distal colon cancer (overall hazard ratio was 0.32).
 Post-colonoscopy Colorectal Cancer (PCCRC): The world endoscopy organization published its
recommendations on the definition of PCCRC and its subcategories: 163
 PCCRC: CRC diagnosed after colonoscopy in which no cancer was found. The following are subcategories
of PCCRC.
 Interval cancer: CRC diagnosed before the next recommended screening or surveillance interval
 Non-interval cancer:
o Non-interval cancer type A: CRC diagnosed at the recommended screening or surveillance interval.
o Non-interval cancer type B: CRC diagnosed after the recommended screening or surveillance interval.
o Non-interval cancer type C: CRC diagnosed after colonoscopy in which there was no recommended
screening or surveillance interval, up to 10 years after the colonoscopy.
 PCCRC is most likely to occur due to missed polyps and incomplete resection of polyps than rapid progression
of carcinoma in between colonoscopies. Cancers are more likely to follow the serrated CRC pathway.
 The adenoma detection rate (ADR) is an important measure of colonoscopy quality.
The ADR was shown to be an independent predictor of the risk of PCCRC after screening colonoscopy.167, 168
For each 1% increase in ADR, there is a 3% decrease in PCCRC risk, and 5% decrease in fatal PCCRC risk. 168
 Selected colonoscopy quality indicators (check the full list in the references above):
 ADR > 30% in males, and > 20% in females. Average withdrawal time ≥ 6 minutes.
 Increasing the ADR through education and quality improvement initiatives results in reduction in
PCCRC risk (hazard ratio 0.63, p =0.006) and cancer death (HR 0.50, p = .035). 169
 Withdrawal time <6 minutes is associated with lower adenoma detection 170 and higher risk of PCCRC.171
 Cecal intubation rates of ≥ 90% in all cases, and ≥ 95% in screening colonoscopies
 >90% adherence to surveillance intervals after colonoscopy (see page 246).
 Split-dose 4-L PEG (Polyethylene glycol) solutions is currently the standard of care for bowel prep. Split dosing
results in better prep quality and higher ADR.172 See example of split-dose colon prep instructions below.
Sample split-dose colon preparation instructions:

1 day before your procedure – CLEAR LIQUID DIET
- Drink clear liquids ONLY throughout the entire day.
- Drink about 8 oz. (or 1 glass) of liquids per hour to prevent dehydration
o At 6 PM, start drinking the colon prep solution: Drink 8 oz. (one glass) of colon prep solution every 15
minutes until HALF of the gallon is gone.
o Keep the remaining half gallon of colon prep solution in the refrigerator.
o You can continue drinking clear liquids until bedtime.
Day of procedure
- If your procedure is in the morning (8 am-12 pm), wake up at 3 AM and drink the remaining half gallon
of colon prep solution (one glass every 15 minutes until complete).
o You should finish by 5 AM. We know this is early, but it will help you have a better test.
- If your procedure is in the afternoon (12 pm-4 pm), wake up at 6 AM and drink the remaining half gallon
of colon prep solution (one glass every 15 minutes until complete).
o You should finish by 8 AM.
- You may have a small sip of water to help take your blood pressure or other necessary medications.
- Other than your colon prep solution and a small sip for medications, do NOT take any food or drink on the day of
your procedure.
 Low residue diet appears is more tolerable with similar quality of bowel prep compared to clear liquid diet. 173
 Examples of low residue food include white bread, rice, pasta, macaroni and cheese, yoghurt, cheese slices,
pretzels, deli turkey, eggs, chicken nuggets, chicken breast, baked potato without skin, banans, apple sauce.
 Documentation of the quality of bowel preparation on all colonoscopy reports.
 During the colonoscopy, evaluate the prep quality after cleaning the colon, not at entry.
 Target adequate colon prep rate of >85% (“adequate” refers to prep quality that allows the patient to follow
regular surveillance intervals, and not to shorten the interval to the next colonoscopy)
 Techniques and technologies to improve adenoma detection during colonoscopy
 Second forward examination of the ascending colon increases ADR in the right colon.174
 Right colon retroflexion (Figure 21-A and video 8-4)
 Retroflexion in the right colon using the pediatric colonoscope allows the endoscopist to examine the
backside of colonic folds in the ascending colon. If an adult colonoscope with a wide turning angle is
used, care should be taken to avoid causing colonic injury.
 Studies suggest that performing two right colon exams in forward view is as good as doing an additional view in
retroflexion.175 One study found that after two forward exams of the right colon, an additional exam in the
retroflexed position detects ≥1 additional adenoma in 5% of patients. 176
 Consider two forward exams or adding retroflexion in older patients, males, or if polyps found on forward view.
 Wide-angle colonoscope (Fuse® colonoscope): This scope displays an endoscopic image over a 330o field
of view compared to the standard 170 o view.
 Distal colonoscope attachments
 Endocuff Vision ® (Olympus) is a distal endoscope attachment with multiple arms that divert
and flatten colonic folds during scope withdrawal. This device was FDA cleared for improving
adenoma detection during colonoscopy (video 8-5 and figure 21-B and 21-C). Video 8-4
 EndoRing® (US Endoscopy) is a distal scope attachment made of silicone-rubber. It has

two circular rings that attach to the tip of the endoscope (figure 21-D).
 In a randomized trial, the average adenoma per colon was higher with Endocuff (mean ±
standard deviation: 1.82 ± 2.58) compared to EndoRing (1.55 ± 2.42), and standard high
definition colonoscopy without distal attachments (1.53 ± 2.33).
o These methods had higher average adenoma per colon compared to the wide-angle Video 8-5
colonoscope (Fuse®) (1.30 ± 1.96). 177
 G-EYE® Colonoscope (figure 21-E) has an integrated balloon near its tip, which is inflated during
withdrawal to engage the colonic wall, straighten colonic folds, and centralize scope view. It was shown to
increase ADR.178
Figure 21. A: Right colon retroflexion. B: Endocuff Vision ® distal attachment. C: Endoscopic view
of Endocuff Vision during scope withdrawal. D: EndoRing ® E: G-EYE® Colonoscope (image
courtesy of FUJIFILM Medical Systems U.S.A., Inc.)
 Artificial intelligence (computer-assisted detection) is an emerging technology in which a computer module is

attached to the endoscopy processor, and a “deep learning” algorithm allows the computer to autonomously learn
to discern certain characteristics within the acquired images, differentiating normal from abnormal findings. As
such, the AI system can flag suspected polyps during a colonoscopy.179
 Computer aided detection was found to lower adenoma miss rate compared to routine white-light colonoscopy
(~14% vs. 40%, .77%, P<.0001180
Flexible sigmoidoscopy
 Flexible sigmoidoscopy was shown in randomized controlled trials to decrease colon cancer mortality. 181, 182
 It is performed every 5-10 years, with or without FIT every 3 years.
 If an adenoma is found on sigmoidoscopy, then a full colonoscopy should be performed.
 Flexible sigmoidoscopy does not decrease mortality from proximal colon cancer.166
CT colonography
 Most CT colonography (CTC) procedures require adequate bowel preparation and gas distension of the
colon, using a rectal catheter, to obtain good quality images.
 Newer CTC techniques use oral contrast to tag stool, eliminating the need for bowel prep.
 CTC was compared to optical colonoscopy in two large meta-analyses (table 17).183, 184
Table 17: Sensitivity and specificity of CTC for colorectal polyps

Small polyps (6 to 9 mm) Large polyps (≥ 10 mm)
Sensitivity 70% to 86% 85% to 93%
Specificity 86% to 93% 97%
Polyp surveillance
Recommendations for Follow-Up After Colonoscopy and

Gastroenterology,
Polypectomy: A Consensus Update by the US Multi-Society 2020
Task Force on Colorectal Cancer 118
Endoscopic Removal of Colorectal Lesions-Recommendations
GIE 2020
by the US Multi-Society Task Force on Colorectal Cancer162
Post-polypectomy colonoscopy surveillance: European

Endoscopy, 2020
Society of Gastrointestinal Endoscopy (ESGE) Guideline185
 Overall, there is high quality evidence supporting surveillance recommendations after a negative
colonoscopy or removal of adenomas. However, the quality of evidence for surveillance after removal of
serrated polyps is generally low.
 Table 18 summarizes the updated (2020) US Multi-Society Task Force recommended surveillance intervals
in patients with baseline average risk. These intervals assume an adequate bowel preparation quality to
detect lesions > 5 mm in size.
 In patients with fair/inadequate or poor bowel preparation, repeat the exam within 1 year.
 If there is a concern about the completeness of any polypectomy, colonoscopy should be repeated at
3-6 months to examine the site of the resected polyp.
 The USMSTF also published a new consensus statement on endoscopic removal of colorectal lesions that
complement the surveillance recommendations.
186
Table 18: Recommended surveillance intervals in patients with average risk (USMSTF 2020)
Baseline colonoscopy findings Surveillance
interval
No polyps 10 years *
Adenomatous polyps
1-2 adenomas < 10 mm 7-10 years
3-4 adenomas < 10 mm 3-5 years
5-10 adenomas <10 mm 3 years†
> 10 adenomas of any size on single exam 1 year§
Any adenoma ≥ 10 mm 3 year†
Any adenoma with advanced histology (TVA, VA or HGD) 3 years†
Piecemeal resection of adenoma (≥ 20 mm) 6 months**
Serrated polyps
≤ 20 hyperplastic polyps < 10 mm in rectum or sigmoid 10 years*
≤ 20 hyperplastic polyps < 10 mm proximal to sigmoid 10 years
hyperplastic polyp ≥ 10mm 3-5 years
1-2 SSPs < 10 mm 5 -10 years
3-4 SSPs < 10 mm 3- 5 years
5-10 SSPs < 10 mm 3 years
SSP > 10 mm , SSP with dysplasia, TSA 3 years
Piecemeal resection of SSP ≥ 20 mm 6 months**
Serrated polyposis syndrome (SPS) ‡ 1 year
Abbreviations: TVA; tubulovillous adenoma; VA: villous adenoma; HGD: high-grade dysplasia; TSA:
traditional serrated adenoma; SSP: sessile serrated polyp, but the preferred new terminology is SSL: Sessile
Serrated Lesion. 97
* Follow up is appropriate with either a colonoscopy or another CRC screening test.
† Follow up intervals after the first surveillance colonoscopy (at three years) depend on findings:
 Normal colonoscopy  repeat in 5 years (not 10 years)
 1-2 adenoma < 10 mm  repeat in 5 years (not 7-10 years)
 3-4 adenoma < 10 mm  3-5 years
 5-10 adenoma < 10 mm or adenoma ≥ 10 mm, or advanced histology (TVA, VA or HGD)
repeat in 3 years
§ Consider genetic testing if > 10 cumulative adenomas (FAP, MUTYH), consider age and family
history
‡ SPS is defined by any one of the following two criteria (WHO 2019): (see page 231 )
 ≥ 5 sessile serrated lesions (SSLs) or serrated polyps (includes HP) proximal to the rectum, all are > 5mm,
of which at least two are ≥ 10 mm in size.
 ≥ 20 cumulative SSLs or serrated polyps (includes HP) distributed throughout the colon, with at least 5
lesions located proximal to the rectum.
**Piecemeal resection of lesions ≥ 20 mm requires an intensive follow-up schedule:162
 Colonoscopy at 6 month, examine entire colon for synchronous lesions, carefully inspect the
polypectomy site for local recurrence, use advanced electronic imaging or chromoendoscopy,
obtain biopsy from the scar of polypectomy site)
 If no residual tissuerepeat colonoscopy in 1 year, then in 3 years.
 If residual tissue  perform completion polypectomy + ablation of margin (argon plasma
coagulation or snare tip) then repeat colonoscopy at 6 months, then 1 year, then q 3 years.
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507.e1.
9
253
/CHAPTER
Inflammatory Bowel
Disease
Chapter 9- Inflammatory bowel disease
Inflammatory bowel disease is a broad topic that covers a large amount of published literature.
The aim of this chapter is to focus on clinically important topics. This chapter assumes adequate
baseline knowledge of IBD such as clinical presentation, basic diagnostic testing, and the
differences between Crohn's disease and ulcerative colitis. There has been enormous progress
in the field of IBD in the past few years. Health maintenance is an important component of the
comprehensive management of IBD patients. A patient evaluation template that summarizes all
aspects of IBD patient management is provided at the beginning of the chapter. Treatment of
IBD has been revolutionized by the introduction of several new biologics and biosimilars. Due to
the availability of several treatment options, comparative effectiveness trials are emerging to
identify the most effective treatment options. The VARSITY trial compared IV vedolizumab to
Subq Adalimumab in UC, and is the first large scale comparative effectiveness trial of biologics
in IBD. The results have already influenced recommendations guideline recommendations for
biologics in UC. The optimal use of therapeutic drug monitoring is still not well defined, but it
has become a useful tool in managing loss of response to biologics. There are several new
concepts in colon cancer screening in IBD (overall risk of cancer, utility of random biopsies, role
of chromoendoscopy, and description of colonic lesions). The management of the post-operative
patients with Crohn’s disease has become clearer with the recent completion of randomized
trials and guidelines. Similarly, new data shed more light on the safety of IBD therapy during
pregnancy and lactation.
254 Chapter 9: Inflammatory Bowel Disease
Contents
Chapter 9- Inflammatory bowel disease Therapeutic drug monitoring—274

Clinical evaluation and basic concepts—255 Selected trials of biologics in inflammatory
Treatment of ulcerative colitis—260 bowel disease—276
5-aminosalicylates—260 IBD and colorectal cancer—279
Corticosteroids—262 Extra-intestinal manifestations of IBD—283
Thiopurines—262 Surgical therapy for ulcerative colitis—284
Methotrexate—265 Ileal pouch anal anastomosis—284
Treatment of acute severe ulcerative colitis—266 Surgical therapy for Crohn’s disease and post-
operative management—286
Treatment of Crohn’s disease—268
Approach to the management of the post-
5 aminosalicylates—268
operative patient with Crohn’s disease—288
Corticosteroids—268 Endoscopic management of Crohn’s disease
Methotrexate—269 strictures—290
Antibiotics—269 Fertility and pregnancy issues in IBD—292
Thiopurines—269 IBD and fertility—292
Biologic therapy for ulcerative colitis and Crohn’s General management concepts for IBD before
disease—269 and during pregnancy—292
Biosimilars—272 Medication safety and management during
Fistulizing and perianal Crohn’s disease—273 pregnancy—293
Biologic therapy for Crohn’s disease—273 References—295

Chapter 9: Inflammatory Bowel Disease 255
Clinical evaluation and basic concepts

ACG Clinical Guideline: Preventive Care in
Inflammatory Bowel Disease 1
 Epidemiology of inflammatory bowel disease in the United States 2

 Ulcerative colitis (UC): incidence 2-14 cases / 100,000 person-years, prevalence 238/100,000.
 Crohn’s disease: incidence 3-20 cases / 100,000 person-years, prevalence 201/100,000.
 Clinical manifestations and disease presentations
 UC: diarrhea, hematochezia, urgency, tenesmus, abdominal pain, fever.
 Crohn’s disease: abdominal pain, fever, diarrhea, weight loss, anorexia, fatigue, perianal pain, perianal
discharge. Less common presentations include pneumaturia or passage of stool through the vagina, which
is indicative of fistulizing Crohn’s disease.
● Look for signs and symptoms of IBD complications or extraintestinal disease manifestations
 Complications of IBD: Intestinal obstruction, perforation, megacolon, small bowel and colorectal
cancer. Other complications: B12 deficiency, osteopenia and osteoporosis, thromboembolism,
 Complications of IBD therapy (see side effects of 5-ASA on page 260 and thiopurines on page 262).
 Extraintestinal manifestations include arthralgias, skin lesions such as erythema nodosum and pyoderma
gangrenosum; oral aphthous ulcers, uveitis, scleritis, episcleritis (extraintestinal manifestations are
described on page 283).
 Primary sclerosing cholangitis (5% of UC and 2% of Crohn's patients have PSC).
● Symptoms do not correlate well with disease activity. Objective confirmation of inflammation with
endoscopy or imaging tests is usually required before escalating or de-escalating therapy.
 Physical examination
● Vital signs (fever, tachycardia), pallor, jaundice, eye redness and discharge, oral ulcers.
● Abdominal exam: tenderness, decreased bowel sounds, signs of chronic liver disease (PSC)
 Patients on corticosteroids may have minimal abdominal findings even in the presence of serious intra-
abdominal complications such as perforation. Consider abdominal imaging in these cases.
● Perianal exam: fistulas, fissures, tenderness, perianal cancer (see page 273).
● Skin exam: rashes, malignancy. Joint exam: swelling, tenderness.
● Melanoma risk is increased in IBD patients on anti-TNF, while Non melanoma skin cancer risk is increased
in IBD patients on thiopurines, tofacitinib and methotrexate.
● Other elements of medical history (past medical history, medications, social history, and vaccinations)
should be obtained. The optimal documentation should describe the patients’ overall disease course, and
current disease activity. Refer to page 258 for sample IBD clinical evaluation template for a
more comprehensive list.
● Other useful templates are available online (e.g. Cornerstones Health)
 Labs
● CBC can reveal leukocytosis (infection, steroids), leukopenia (thiopurines), and anemia (iron deficiency
[see page 257], B12, folate deficiency, anemia of chronic disease, drug induced [sulfasalazine, thiopurines]).
● Chemistry panel can reveal electrolyte imbalance and elevated liver enzymes (drug induced, PSC).
● Elevated ESR/ CRP, stool culture, ova and parasites, and C. difficile
● Fecal calprotectin: calprotectin is a neutrophilic cytosolic protein released by activated neutrophils. Stool
levels are elevated in intestinal inflammation.
 It can differentiate between inflammatory and non-inflammatory diarrhea (active IBD versus IBS).

It has a possible role to guide escalation of therapy in patients with Crohn’s disease (see CALM trial
page 276) and in monitoring of post-operative Crohn’s recurrence (see page 289).
● IBD serum markers (table 1): The main markers of Crohn’s disease are ASCA, OMP-C, and CBirAb.
 The main marker of ulcerative colitis is p-ANCA. Routine use of serum markers is not recommended.
Table 1: IBD serum markers

Antibody Antigen Main Test characteristics Test characteristics
association in Crohn’s disease in UC
p-ANCA Unknown protein in UC Positive in 10-25% Sensitivity 50-60%
the nuclear envelop of Specificity 90%
neutrophils
ASCA Cell wall component Crohn’s Sensitivity 55-65% Positive in 5%
of Saccharomyces disease Specificity 90%
cerevisiae
Anti-OmpC Outer membrane porin Crohn’s Sensitivity 40-50% Positive in 2%
protein of E. coli disease Specificity 90%
Anti-I2 Pseudomonas Crohn’s Sensitivity 55% Positive in 2%
fluorescens disease Specificity 75%
Anti-CBir1 CBir (Clostridium Crohn’s Sensitivity 50% Positive in 5%
(anti subphylum) disease Specificity 50%
flagellin)*
p-ANCA perinuclear anti-neutrophil cytoplasmic antibodies. ASCA: anti-Saccharomyces Cerevisiae antibodies
* Anti-CBir1 is associated with fibrostenotic and fistulizing disease Crohn's disease3
 Colonoscopy findings in IBD
● The typical endoscopic appearance of active ulcerative colitis is continuous colitis starting at the rectum
and extending to a variable distance proximally into the colon. The mucosa appears granular, friable, with loss
of vascular marking and superficial ulcerations.
 In partially treated UC, colonic involvement may appear patchy rather than continuous.
● Mayo endoscopic scoring system for UC:
 Mayo 0: Normal mucosa
 Mayo 1: Mild inflammation, diminished vascular markings, mild erythema, granularity and friability.
 Mayo 2: Moderate inflammation, marked erythema, absent vascular markings, contact friability, no ulcers)
 Mayo 3: Severe inflammation, spontaneous bleeding, ulcers
● Terminal ileal involvement is a feature of Crohn's disease.
 The terminal ileum is usually spared in UC, but can be involved in the form of backwash ileitis.
● Endoscopic findings in Crohn’s disease range from mild erythema with aphthous ulcerations
to severe colitis with deep ulcerations and surrounding granularity forming a cobblestone
appearance. Video 9-1
● In contrast to UC, Crohn's disease shows segmental colitis with normal intervening mucosa (skip areas,
video 9-1). Crohn’s disease may affect any part of the GI tract while ulcerative colitis affects the colon.
● Perform EGD in patients with Crohn’s disease and upper GI symptoms.
● Backwash ileitis may develop in UC due to "backwash" of cecal contents. This is more common in patients
with pancolitis, but it does not affect outcomes after pouch surgery pouch outcomes.4
● UC-related pan-enteritis is a rare entity that typically develops after colectomy for UC (with or without
ileal pouch anal anastomosis).
 Patients may develop diffuse (continuous) ulcerative inflammation in the stomach, duodenum,
jejunum, ileum (+/-pouchitis). The mucosa exhibits friability without deep ulcers, and there are no
skip lesions or strictures (contrary to Crohn’s disease). Severe bleeding and perforation may develop.
 The mechanism is unclear but could be related to massive T cell and cytokine mediated inflammatory
response attacking different part of the GI tract.5
 Differential diagnosis includes Crohn’s disease, infections, and ischemia.
 Biopsies reveal dense mixed cellular infiltrates, and are useful in excluding viral pathogens.6
 Treatment with IV methylprednisolone. Some case reports described the use of AZP and infliximab.
 Imaging studies
● Cross sectional imaging: CT enterography (CTE), MR enterography (MRE) -avoids radiation,
preferred in young patients; Barium studies
● Capsule endoscopy is useful to diagnose small bowel Crohn’s disease when performed after
negative ileoscopy in patients without clinical signs of obstruction.7 (Video 9-2).
● Capsule endoscopy should not be performed as a routine evaluation of the small bowel in all
patients with Crohn’s disease. It should not be performed routinely after negative MRE/CTE due to Video 9-2
7
its low yield.
● Obtain patency capsule and other imaging tests first to rule out small bowel strictures.
● Retention rates in patients with suspected or known Crohn’s disease are ~4% and 8%, respectively.
 These rates are decreased by half (but not eliminated) if patency capsule and small bowel imaging are
performed prior to capsule endoscopy.8
 Deep enteroscopy is useful to biopsy the small intestine and confirm the diagnosis of Crohn’s disease in cases of
isolated small bowel involvement.
 Histology
● Cryptitis, crypt abscesses, acute and chronic colitis with architectural distortion is the main histologic
finding in inflammatory bowel disease.
● The presence of non-caseating granulomas is characteristic of Crohn’s disease. However, this finding is
present in less than 30% of cases.
Iron deficiency anemia in IBD

 Iron deficiency anemia in IBD is caused by chronic blood loss or by reduced iron absorption due to increased
hepcidin production. Hepcidin is an acute phase reactant that inhibits ferroportin, which reduces iron
absorption (see chapter 4-Liver, figure 1).
 Treatment with oral supplements is recommended if Hgb >10 g/dL. Oral doses should not exceed 100 mg of elemental
iron/day, higher levels do not increase efficacy, and may increase side effects.9
● Ferric maltol (Accrufer®) is a new oral iron therapy that is recently FDA approved (2019) for the treatment
of iron deficiency in adults. It was shown to be non inferior to IV iron in patients with inactive IBD and
Hgb >8.0 g/dL 10. The recommended dose is one capsule 30mg BID on an empty stomach. It appears to
be better tolerated than other oral iron supplements. 11 It is currently available in Europe but not the USA.
 Treatment with intravenous iron is preferred in patients with severe inflammation, hgb<10 g/dL, or failure of
oral supplementation. It is more effective and better tolerated compared to most oral iron supplements. 12
● Examples of IV iron formulations that are available in the US:
 Iron Sucrose (Venofer®), Ferumoxytol (Feraheme®), Ferric Carboxymaltose (Injectafer®), Ferric
gluconate (Ferrlecit ®), Iron Dextran (INFED®)
 Ferric Carboxymaltose has been associated with hypophosphatemia. Therefore, monitor phosphate
levels in patients with risks factors for low phosphate such as malabsorption of fat soluble vitamins,
drugs affecting proximal renal tubular function (valproic acid, antiretrovirals such as tenofovir),
hyperparathyroidism, vitamin D deficiency, and malnutrition.
 Iron Dextran (INFED®) has a black box warning for anaphylaxis, and requires a test dose prior to infusion.
IBD CLINICAL EVALUATION TEMPLATE
Chief Complaint / Reason for Visit

History of presenting illness
(Demographics, brief description of disease type, location, current medication, and then chief
complaint and history of presenting illness, disease activity: stools, blood, urgency)
IBD related medical history

 IBD type: (Crohn’s/Ulcerative colitis/ IBD Unclassified)
 Diagnosis date: (Month/year)
 Disease location and extent:
o (ileocolonic, small bowel [location, length], colonic [location], other)
 Disease behavior: (stricturing, penetrating, fistulizing, perianal)
 Disease complications: (abscess, obstruction, C. difficile infection)
 Extraintestinal manifestations: (Skin, joint, eye disease, PSC)
 Past surgeries:
o (surgery date, type, resection location/length, anastomosis/stoma type, indication)
 Recent hospitalizations: (date/indication/ brief management during hospital stay)
 Most recent endoscopy/biopsy: (date/results of EGD / colon / capsule / enteroscopy,
histology).
 Most recent imaging: (date, results of imaging -CT, MRI, small bowel series)
 IBD related medications: (prior and current use, include dose): Steroids, 5-ASA,
Immunomodulators (6MP-AZP-MTX), Biologics (include years used, dose escalation,
antibodies, drug levels, reason for discontinuation-side effects, compliance)
 Labs required for therapy:
o (date, results of HBsAg, HBsAb, HBsAb QuantiFERON Gold/PPD, TPMT)
Other past medical and surgical history
Other medication history (NSAIDS, narcotics, over the counter drugs, herbal, special diet)
Allergies (type of allergy to drugs)
Family history (IBD, colorectal cancer, autoimmune disease)
Social history (smoking, alcohol, sexual history, TB risk factors-IV drug, travel, prison)
Review of systems
(Fever, weight changes, fatigue, eye symptoms, skin rash, joint disease, drug side effects)
Physical examination (vital signs, BMI, eye [pallor, jaundice], skin [rash], abdominal exam,
perianal exam, joints exam [redness, swelling])
LABS (CBC, liver/kidney panels, CRP/ESR, lipids, vitamin D/B12, ferritin, transferrin saturation,
other IBD labs above)
Imaging, endoscopy (IBD related results mentioned above, may add more details here)
Assessment (Type of disease/ location/ disease severity, disease activity [clinical signs and
symptoms, Hgb, ESR, CRP, fecal calprotectin, endoscopic activity]. Are symptoms related to
disease? Consider functional disorders)
Plan (continue / escalate / change therapy, mention dose), order labs, imaging, endoscopy and
indication for test, referrals for surgery, endocrine, rheumatology, dermatology)
Health maintenance
 Vaccinations: non-live vaccines: Annual Flu (all patients, vaccinate households if patient on
immunosuppression), Pneumococcal pneumonia (PCV13 then PPSV23-all patients), HPV
(patients ages 11-26, both males and females), Hepatitis A (all patients), Hepatitis B (all
patients), Tdap (all patients who Tdap not given in 10 years), Meningococcal (all patients age
16-23, college students, military, asplenia ,HIV), Zoster (shingles) (Shingrix® if age ≥ 50, or if
age ≥ 18 and at increased risk of HZ due to immunodeficiency or immunosuppression or if
starting tofacitinib; Zostavax live vaccine is not recommended), COVID-19: 2 doses+/-third
booster dose
 Cancer screening: Colonoscopy(see page 280), Pap smear Q1yr (all women on
immunosuppression), dermatologic exam for cancer screening Q1y (melanoma-all patients,
non-melanoma skin cancer if on 6MP/AZP), sunscreen with SPF≥30;Anal cancer: consider
screening (pap smear) if high risk (see page 273 )
 Bone health: DEXA scan[males older than 50 years, chronic steroids use ≥ 3 months,
postmenopausal women, history of low trauma fracture], vit D 25-OH, prescribe Ca/vit D if on
steroids, regular exercise
 Labs: 5-ASA (creatinine q 6 months, if stable q 1 year); steroids (vit D 25-OH); Thiopurines
(TPMT, CBC, LFTs at 2, 4, 8, 12 weeks, then q 3 months); Methotrexate (CBC, LFTs, Cr);
Biologics (QuantiFERON gold/PPD[annual assessment of TB risk], +/-CXR, HBsAg, HBcAb,
HBsAb [annual], CBC, LFTs, Cr [q3-6 months])
 Nutrition assessment: iron, ferritin level, Vit B12 level if ileal disease
 Other: Pregnancy counseling in women (www.ibdparenthoodproject.org), Mental health
evaluation (screen for stress, depression, anxiety), Screen for hypertension, Smoking
cessation, Avoidance of NSAIDs.
Treatment of ulcerative colitis

Am J
ACG Clinical Guideline: Ulcerative Colitis in Adults 13 Gastroenterol,
2019
Clinical Practice Guidelines for the Medical Management of Non Gastroenterology
hospitalized Ulcerative Colitis: The Toronto Consensus 14 2015
AGA Clinical Practice Guidelines on the Management of Gastroenterology,

Moderate to Severe Ulcerative Colitis 15 2020
American Gastroenterological Association Institute Guideline on Gastroenterology,

the Management of Mild-to-Moderate Ulcerative Colitis 16 2019
Evolving Considerations for Thiopurine Therapy for Inflammatory Gastroenterology

Bowel Diseases- A Clinical Practice Update: Commentary 17 2019
5-aminosalicylates
 The choice of initial treatment with 5-ASAs is based on the severity and extent of the disease.
 Mild to moderate UC: Give 5-ASAs in the form of topical and/or oral preparations (table 2).
 Topical 5-ASA preparations are used to treat distal UC.
 Suppositories are used to treat proctitis, enemas for proctosigmoiditis.
 In cases of mild to moderate disease beyond the left colon (pancolitis), the combination of topical and oral
5-ASA is recommended. Topical treatment in these cases alleviates symptoms arising from distal colitis,
leading to better symptom control compared to oral 5-ASAs alone.
 Oral preparations are designed to be released either in the colon, distal small intestine, or throughout the
GI tract, depending on their pharmacologic formulation (table 2).
 Once-daily dosing with 5-ASA is preferred compared to multiple time per day dosing to improve
compliance with the medication. 16
 Patients who are intolerant or refractory to topical 5-ASA, or are having difficulty using these preparations,
can be treated with rectal corticosteroid therapy (steroid foam- see next section, enemas, and suppositories). 16
 In patients refractory to optimized oral/topical 5-ASA, begin oral steroid therapy (see next section).
 Side effects of sulfasalazine
 Dose related side effects include nausea (3%), vomiting, alopecia, headache (5-10%), and folate
malabsorption.
 Non-dose related side effects include skin rash, pancreatitis, fever, arthralgias, hemolytic anemia, aplastic
anemia, agranulocytosis, male infertility-oligospermia (reversible), fibrosing alveolitis, pericarditis,
myocarditis, nephrotoxicity, hepatitis.
 Monitor CBC and liver function periodically, give folic acid supplementation.
 All 5-ASA products can rarely cause nephrotoxicity. Therefore, it is recommended to check serum creatinine
every three to six months while on treatment.
 Olsalazine causes a dose-dependent secretory diarrhea in 10-15% of patients.
 In patients who require step up therapy and achieve remission with biologic agents and/or immunomodulators,
or tofacitinib, AGA recommends stopping ASA therapy. 15
Table 2: 5-ASA preparations. Generics are available for some formulations

5-ASA drug Molecular structure and location of action Dose
Topical preparations
Mesalamine  Treats the distal 5-8 cm of the rectum  1 gm daily
suppositories
(Canasa®)
Mesalamine  Reaches the splenic flexure  60 ml (4 gm) at bed
enemas time, retained overnight
(Rowasa®)  Can also be given b.i.d.
Oral medications
pH-dependent release
Mesalamine  Tablet coated with a resin polymer (eudragit-S) ● 2.4 - 4.8 gm/day
(Asacol®-HD)  pH dependent release at pH ≥ 7 in the distal divided t.i.d.*
ileum and colon
Mesalamine  Coated with a gastro-resistant polymer  2.4-4.8 gm once daily
(Lialda®) (MMX®)
 pH dependent release at pH ≥ 7 in the distal
ileum and colon
Mesalamine  Capsule containing granules coated with a  400 mg q.i.d. or
(Delzicol®) resin polymer (eudragit-S) 800 mg t.i.d.
ileum and colon
Mesalamine  Capsule containing granules coated with a  1.5 gm/day (four 0.375
(Apriso®) gastro-resistant polymer (eudragit-L) gm capsules once daily)
jejunum, ileum and colon
Diffusion dependent release
Mesalamine  Consists of a gelatin capsule containing  1 gm q.i.d.
(Pentasa®) ethylcellulose coated microspheres of
mesalamine
 Mesalamine is released by diffusion across the
ethylcellulose membrane starting from the
duodenum and continuing into the rest of the
small intestine and colon
Bacterial dependent release†
Sulfasalazine  5-ASA ring attached to sulfapyridine with an  2-4 gm daily divided
(Azulfidine®) azo bond q.i.d.
Sulfasalazine  Azulfidine EN® is composed of enteric coated  2-4 gm daily divided
Delayed-Release tablets TID
(Azulfidine EN®)  Coating contains phthalates
Olsalazine  Two 5-ASA rings attached together with an azo  500 mg BID (two 250
(Dipentum®) bond, mg capsules BID)
Balsalazide  5-ASA ring attached to 4-aminobenzoyl  2.25 gm TID (three 750
(Colazal®) β alanine with an azo bond mg capsules t.i.d.)
Balsalazide  5-ASA ring attached to 4-aminobenzoyl  3.3 gm (three 1.1 gm
(Giazo®)‡ β alanine with an azo bond tablets ) b.i.d.
* 4.8 gm/day may increase response rate compared to the lower dose in cases of moderate to severe UC. 18
† Bacterial reductase splits the azo bond, and releases 5-ASA in the colon.
‡ Giazo® was only effective in males in clinical trials.
Corticosteroids
 Patients with mild to moderate UC who are intolerant or refractory to topical 5-ASA, or are having
difficulty using and retaining these preparations, can be treated with rectal corticosteroid therapy (steroid
foam, enemas, and suppositories). 16
 Budesonide foam is FDA approved for induction of remission in mild to moderate UC up to 40 cm from
the anal verge. It is effective in inducing remission19, and is easier to administer and retain in the rectum
compared to liquid enemas.
 Dose: 2 mg (one metered dose) twice daily for 2 weeks, followed by 2 mg once daily for 4 weeks.
 Corticosteroids are given to induce remission in patients who do not respond to topical and oral 5-ASAs,
and in patients admitted with acute severe ulcerative colitis. They are not given to maintain remission.
 Budesonide is a synthetic corticosteroid that can be given orally to induce remission in patients with mild
to moderate ulcerative colitis. It has minimal systemic bioavailability and enhanced topical potency.20 It
is available in several formulation to control the location of its release in the GI tract.
 The multimatrix (MMX) formulation (Uceris®) consists of coated tablets to control the release of
budesonide at pH ≥7 homogenously throughout the colon.
 Dose: 9 mg daily x 8 weeks
 In patients with more severe colitis, treatment with conventional steroids (prednisone) is indicated.
 Oral prednisone is given to patients with mild to moderate disease not requiring hospitalization.
 Dose is 40-60 mg PO for 2-4 weeks. Start dose taper once the patient is in stable remission. Total
treatment duration is usually 6-8 weeks.
 Continue 5-ASAs for maintenance therapy.
 Consider thiopurines and/or anti-TNF (see below).
 IV methylprednisolone is given to patients admitted with acute severe UC (see page 266).
 Dose is 40-60 mg IV once daily, or divided every 12 hours.
 Side effects of corticosteroids: acne, hirsutism, hyperglycemia, hypertension, ecchymosis, skin striae,
infections, osteoporosis, osteonecrosis, cataracts, glaucoma, myopathy.
Thiopurines
 The immunomodulators azathioprine (AZP) and 6-mercaptopurine (6-MP) should be considered in
patients who are not responding to maximum dosage of 5-ASAs or in patients requiring multiple steroid
courses.
 Thiopurines have a slow onset of action. They are usually started with steroids and continued after steroids
are tapered off.
 Thiopurine are metabolized through three main metabolic routes (figure 1).
 Understanding the thiopurine metabolic pathway helps in interpreting metabolites levels and
understanding the approach to management (see page 264).
Figure 1: Thiopurine metabolism.

AZP and 6-MP are metabolized through three main routes:
Oxidative pathway via xanthine oxidase (XO) yields 6-thiouric acid (6-TU)
Methylation via thiopurine methyltransferase (TPMT) yields 6-methyl mercaptopurine (6-MMP).
This enzyme has genetic polymorphisms, which affect its conversion to 6-MMP (see text)
Metabolite formation via hypoxanthine-guanine phosphoribosyltransferase (HPRT) yields 6-
thioinosine-5-monophosphate (6-TIMP) and 6-thioguanine (6-TGN)
 Starting thiopurine therapy
 Initial labs
 CBC, liver panel, TPMT levels. Consider checking for latent TB and chronic hepatitis B/C.
 The AGA guidelines suggests TPMT testing prior to initiating thiopurines to guide thiopurine
dosing. TPMT testing can be performed using TPMT genotyping test, which detects TPMT
gene mutations, or TPMT phenotyping, which measures enzyme levels.
o 90% of people have the wild type TPMT (normal or high TPMT enzyme activity).
● Give AZP at 2-2.5 mg/kg or 6-MP at 1-1.5 mg/kg.
● Monitor CBC every 2 weeks for 3 months then every 1 month.
o 10% are heterozygous for TPMT mutation (intermediate or low TPMT enzyme activity).
● Give AZP at 1-1.25 mg/kg or 6-MP at 0.5-0.75 mg/kg.
● Monitor CBC every 2 weeks for 3 months then every 1 month.
o ~0.3% are homozygous for TPMT mutation (absent TPMT activity).
● AZP and 6-MP are contraindicated.
o Of note, TPMT testing and appropriate dosing of thiopurines can prevent hematologic adverse
drug reactions (leukopenia and thrombocytopenia) in patients who have low or absent TPMT
activity. However, the overall rates of hematologic ADR are the same regardless of TPMT
testing.21 The number needed to test to prevent one event of leukopenia is ~200.
● All patients require close monitoring of CBC as above.
o TPMT deficiency results in increased 6-TGN levels, which leads to bone marrow
suppression, while TPMT excess results in increased 6-MMP levels, which leads to nausea,
vomiting, and hepatotoxicity (elevated liver enzymes).
 Side effects of thiopurines
 Dose independent side effects: rash, fever, arthralgias, pancreatitis (5%, usually during the first
month of treatment)17, hepatitis.
Dose dependent reactions: myelotoxicity, nausea, vomiting, and hepatotoxicity.

Other complications:
o Viral infections, opportunistic infections (especially if combined with biologics +/- steroids)
o Small risk of hepatic nodular regenerative hyperplasia (1% at 10 years) and other veno-
occlusive disease of the liver
o Non-Hodgkin's lymphoma (incidence rate of 4 in 10,000 person.years; more common in
males and patients <30 years old), non-melanoma skin cancer (2 times increased risk
compared to general population).
o Hepatosplenic T cell lymphoma (HSTCL)
● This rare, fatal lymphoma primarily affects men younger than 35 years old.
● The incidence is estimated at 1:45,000 patients who receive thiopurines. 22
 The risk of higher in men under the age of 35 (1:7500), especially men on both
thiopurines and anti-TNF (1:3500). 23
● It is linked to treatment with thiopurines (+/- anti-TNF), and occurs after at least 2 years of
treatment. The risk can be reduced by limiting the duration of treatment to < 2 years. 24
● One study showed that of 36 patients with HSTCL, 20 received combination therapy with
infliximab and a thiopurine and 16 received a thiopurine as monotherapy for IBD.23
 Four patients received adalimumab following infliximab and a thiopurine.
● HSTCL has not been reported in infliximab monotherapy or combination
(infliximab+MTX)
 Thiopurines metabolites testing
 Consider checking thiopurine metabolites (6-TGN and 6-MMP) if the patient is not responding
to treatment. Routine testing is not recommended in quiescent IBD. 25
 Metabolites levels can give clues about the patient's compliance, medication dosage, and
toxicity. These have management implications as listed in table 3.
Table 3: Thiopurines metabolites levels and corresponding management

6-TGN* 6-MMP* Likely cause Management
Low or Low or undetectable Noncompliance or low  Check compliance or
undetectable drug dose increase drug dose
Low < 230 High > 5700 Preferential 6-MMP  Decrease drug dose to 25-
shunting 50% of original dose, and add
allopurinol (100 mg) to
reverse 6-MMP shunting†
 Consider switching to
another agent
230-450 < 5700 Therapeutic range  Switch to or add another
agent if the patient is not
responding to treatment
> 450 > 5700 Toxicity range  Decrease dose
*
Metabolites blood level measurement unit is picomoles per 8 x 108 erythrocytes. †Allopurinol inhibits
xanthine oxidase. The exact mechanism by which it reverses 6-MMP shunting is unclear. Starting
allopurinol for this indication requires decreasing thiopurine dose and careful followup of CBC.
 Combination therapy of thiopurines with anti-TNF is superior to either therapy alone.

 The UC SUCCESS trial is a randomized, double-blind trial that assessed the efficacy of combination
therapy in anti-TNF naïve patients with mild to moderate ulcerative colitis (n=239). 26
 Patients were randomized to infliximab monotherapy, azathioprine monotherapy, or the two drugs
combined (infliximab + azathioprine).
 Corticosteroid-free remission at week 16 was achieved by 39.7% in infliximab/azathioprine group,
compared with 22.1% in infliximab alone (P = .017) and 23.7% in azathioprine alone (P = .032)
 Corresponding numbers for mucosal healing at 16 weeks: 62.8% in infliximab/azathioprine
compared with 54.6% in infliximab alone (P = .295) and 36.8% in azathioprine alone (P = .001).
 These results are similar to the results of the SONIC trial with similar design conducted in patients
with Crohn’s disease (see page 277).
 In general, combining thiopurines with anti-TNF biologics results in lower rates of anti-drug
antibodies and higher concentration of the biologic, and these factors lead to higher efficacy of
treatment. 17
 AGA suggests combining anti-TNFα agents, vedolizumab or ustekinumab with thiopurines or
methotrexate, rather than either therapy alone. 15
Methotrexate
 Several studies have shown that methotrexate monotherapy is not effective for induction and
maintenance of steroid-free remission in ulcerative colitis. 27, 28
►FDA approved biologic therapy for UC include infliximab, adalimumab, golimumab, vedolizumab,
ustekinumab. Tofacitinib is a Janus kinase inhibitor (small molecule) that is FDA approved for
ulcerative colitis (see pages 269 and 270).
Treatment of acute severe ulcerative colitis
Treatment of Hospitalized Adult Patients With Severe Ulcerative Am J Gastroenterol,

Colitis: Toronto Consensus Statements 29 2012
Am J
13
ACG Clinical Guideline: Ulcerative Colitis in Adults Gastroenterol,
2019
AGA Clinical Practice Guidelines on the Management of Gastroenterology,

Moderate to Severe Ulcerative Colitis 15 2020
 Hospital admission with close monitoring. NPO if severe disease or clear liquid diet as tolerated.
 Rule out complicated ulcerative colitis. Obtain an abdominal radiograph in all patients.
 Patients on chronic immunosuppression may have minimal symptoms, and may not manifest the
classic physical findings of perforation. In patients with severe symptoms, consider cross sectional
imaging (CT) to rule out perforation and abscess.
 Rule out co-existing infection.
 Check stool C. difficile toxin. If positive, treat with vancomycin (refer to chapter 8-Large intestine,
section on C. difficile infection).
 Perform flexible sigmoidoscopy and biopsy to document the severity of inflammation and rule out
CMV infection. Do not perform a full colonoscopy, and minimize air insufflation to avoid perforation
in severe colitis.
 Labs: CBC, complete metabolic panel, PPD/QuantiFERON, hepatitis B serologies.
 Venous thromboembolism (VTE) prophylaxis should be given to hospitalized patients with acute severe
UC.30
 The risk of VTE is 3-fold higher in IBD patients compared to the general population.
 The risk of VTE is 6-fold higher in hospitalized IBD flare compared to non-hospitalized flare.
 Options for anticoagulant thromboprophylaxis are low molecular weight heparin (e.g. enoxaparin),
low-dose unfractionated heparin, or fondaparinux.30
 In patients with severe bleeding, mechanical thromboprophylaxis is recommended.
 Start IV steroids with methylprednisolone at 40-60 mg once daily or divided b.i.d.
 In patients who respond to IV steroids, transition to oral prednisone. Taper steroids once the patient’s
symptoms are controlled and stable.
 Maintain remission using thiopurines, anti-TNF, or both. Vedolizumab is also an option for
maintaining remission in patients who respond to steroids.
 Management of patients who do not respond to IV steroids (within 48-72 hours):
 Obtain early surgical consult to consider colectomy.
 Consider repeat flexible sigmoidoscopy to evaluate endoscopic response to treatment.
 Consider infliximab, cyclosporin, or surgery (colectomy).
 Infliximab: 5 mg/kg IV at week 0, 2, 6, and then every 8 weeks
o In a placebo-controlled trial, infliximab was shown to be an effective rescue therapy in patients
who fail steroid treatment. It was associated with a lower rate of colectomy at 3 months
compared to placebo.31
 Cyclosporin: 2-4 mg/kg/day IV

o This medication is associated with significant toxicity, and requires blood level monitoring. It
should only be given by physicians experienced in prescribing cyclosporin.
o Side effects of cyclosporin include hypertension, electrolyte imbalance, seizures,
nephrotoxicity, and opportunistic infections.
 Several studies compared cyclosporin with infliximab for acute severe UC.
o In an open label multicenter European trial, 115 patients with acute severe ulcerative colitis not
responding to steroids were randomized to cyclosporin or infliximab.32
● In both treatment groups, Azathioprine was started on day 7 if there was a clinical response.
● Clinical response rate at day 7 was high in both groups (> 80%).
● There was no difference between both treatments in terms of relapse, treatment failure,
colectomy rates, and adverse events at day 98.
● A follow up study of these patients found that colectomy-free survival was similar at 1 and 5
years between cyclosporin and infliximab.33 The percentage of patients initially treated with
cyclosporin who subsequently received infliximab was 45.7% at 1 year and 57.1% at 5 years.
 Another open label pragmatic randomized trial (n=270, United Kingdom) of infliximab versus
cyclosporin in acute severe UC found no difference in outcomes (colectomy, adverse events)
between the two groups. The cost of using cyclosporin was less than using infliximab. 34
 A meta-analysis found no difference in outcomes between infliximab and cyclosporin in
randomized studies.35 In non-randomized studies, infliximab had higher treatment response and
lower colectomy rate at 12 months.
 A large multicenter retrospective study (1989-2013, Spain) found no difference in early and late
colectomy rate between cyclosporin and infliximab in patients with acute severe UC (treated after
2005). There was a higher rate of serious side adverse events in infliximab (26.5%) compared to
cyclosporin (15.4%). 36
o Including cases treated before 2005 resulted in a higher colectomy rate in cyclosporin (24.1%)
compared to infliximab (14.5%).
 Choosing between cyclosporine and infliximab should be based on the physician and hospital's
experience in dosing cyclosporine and monitoring for toxicity.
o Infliximab is easier to administer and requires no drug monitoring.
o Cyclosporin is not an effective treatment in prior non-response or intolerance to thiopurines.
o Sequential treatment with infliximab and cyclosporin should be considered individually and
based on local expertise. Some studies found increased risk of serious adverse events, while
other studies showed acceptable risk/benefit ratio from this approach. 29, 36, 37
 Assess response to cyclosporin and infliximab within 5-7 days.
 Patients who respond to infliximab should be continued on maintenance dosing at week 2, 6, and then
every 8 weeks. Consider adding a thiopurine. Patients who respond to IV cyclosporin should be
switched to oral cyclosporin. Start AZP or 6MP during steroid taper to maintain remission.
Vedolizumab is another option to maintain remission after cyclosporin.13
 Patients who do not respond to cyclosporin or infliximab should undergo colectomy.
Treatment of Crohn’s disease
ACG practice guidelines: management of

Crohn’s disease in adults 38
AGA Clinical Practice Update on Functional Clinical

Gastrointestinal Symptoms in Patients With Gastroenterology and
Inflammatory Bowel Disease: Expert Review 39 Hepatology 2019
AGA Clinical Practice Guidelines on the Medical
Management of Moderate to Severe Luminal and Perianal AGA, 2021
Fistulizing Crohn’s Disease40
 Features of severe Crohn’s disease: young age at onset of disease, smoking, history of bowel
resection, severe inflammation and deep ulcers on colonoscopy, elevated inflammatory markers,
extensive small and large bowel involvement, ileal and ileocolonic location, perianal disease,
stenosing or penetrating disease.38 These patients require a more aggressive management strategy
compared to patients with mild Crohn’s disease.
5 aminosalicylates
 5-ASAs can be considered in patients with mild colonic Crohn's disease.
 They are not effective for Crohn’s ileitis, fistulizing, or severe disease.
 Hypothetically, 5-ASA products with small bowel release (e.g. Mesalamine-Pentasa®) can be given
to treat small bowel disease involvement, but there are no studies to document their effectiveness.
They are not recommended by ACG for active Crohn’s disease.38
 If there is no response to 5-ASA, then thiopurines and/or biologic therapy should be started.
Corticosteroids
 Budesonide is effective for mild to moderate ileocolonic Crohn’s disease.
 It is less effective in cases of severe or extensive disease.
 It has fewer side effects compared to prednisone due to its limited absorption.
 The controlled ileal release formulation (Entocort®) consists of gelatin capsules filled with enteric-
coated granules that dissolve at pH ≥5.5. This releases the budesonide in the ileum and ascending
colon (pH-dependent and time-dependent controlled release).
 Dose: 9 mg PO once daily for 8 weeks for acute treatment of disease flare. Afterwards, budesonide
can be continued at 6 mg /day for up to 3 months, followed by drug tapering to complete cessation.
 Treatment for longer than 3 months does not provide any significant clinical benefit.
 Patients who do not respond to budesonide and those with moderate to severe Crohn’s inflammation
require prednisone treatment.
 Prednisone dose is 40 mg PO for 2-4 weeks. Start dose taper once the patient is in stable remission.
Total treatment duration is usually 6-8 weeks. In those with moderate to severe Crohn’s disease, the
patient should continue on other immunosuppressive medications for maintenance therapy
Methotrexate
 Methotrexate is a folate antagonist that inhibits thymidine synthesis by inhibiting dihydrofolate reductase and
thymidylate synthase.
 Methotrexate given intramuscularly was shown to be effective in the induction (25 mg IM or subq every 1
week) and maintenance (15 mg IM or subq every 1 week) of remission in steroid refractory or steroid
dependent Crohn’s disease.41 Methotrexate can also be given subcutaneously. PO dosing is not recommended.
 Results of the COMMIT trial suggest that methotrexate added to infliximab does not improve remission
rates in patients with Crohn’s disease who were induced into remission with steroids. 42
 Side effects: nausea, flu-like symptoms, myelotoxicity, allergic pneumonitis, hepatic fibrosis (with prolonged
use), viral infections (zoster), non-melanoma skin cancer. 17
 Prescribe folic acid (1mg/day). Monitor liver enzymes q3 months. Routine liver biopsies to monitor for
toxicity or after a specific cumulative dose of methotrexate are not recommended.
 Methotrexate is contraindicated in patients with preexisting liver disease or alcoholism. 43
Antibiotics
 Consider antibiotics for colonic or fistulizing Crohn’s disease. Ciprofloxacin and metronidazole are the most
commonly used antibiotics. Antibiotics should not be used to induce remission in Crohn’s disease. Long-term
metronidazole can cause irreversible parasthesia. Antibiotics are also used in perianal Crohn’s disease (page 273).
Thiopurines
 Thiopurines 6-MP and AZP are not effective in inducing remission. They are given to maintain remission in
Crohn’s disease after achieving remission by corticosteroids. Thiopurines can also be used as an adjunctive
therapy for active Crohn’s disease to reduce the formation of antibodies against biologics.
 6-thioguanine (6-TG) can be given in patients who are allergic to 6-MP or AZP; however, there is an increased
risk of veno occlusive disease and nodular regenerative hyperplasia of the liver. 17
 Dosing and metabolite testing are the same as in ulcerative colitis (see page 262).
Biologic therapy for ulcerative colitis and Crohn’s disease

 Starting biologic therapy in inflammatory bowel disease:
 Confirm that the patient's symptoms are related to active colitis (carefully evaluate clinical signs and
symptoms, vital signs, fecal calprotectin, endoscopy)
 Potential causes of functional symptoms in IBD patients are IBS, bile acid diarrhea, small bacterial
overgrowth, pancreatic exocrine insufficiency, carbohydrate malabsorption, celiac disease. 39
 Discuss risks and benefits of treatment with the patient.
 Screen for latent TB (PPD or QuantiFERON assay) and chronic hepatitis B.
 Review vaccination history (see page 259). Once started, maintain regular follow up. Assess clinical and
endoscopic response to treatment. Check CBC and liver panels every 3-6 months.
 FDA approved biologic therapy for UC and Crohn’s disease are listed table 4.
 AGA recommends infliximab or vedolizumab over Adalimumab in patients with moderate-severe ulcerative
colitis who are naïve to biologic agents15
 Tofacitinib is not FDA approved for biologic naïve patient (unless as part of clinical trial). 15
 For patients with previous exposure to infliximab (especially if primary non response), then tofacitinib or
Ustekinumab are recommended over vedolizumab of adalimumab for induction of remission. 15
 See page 273 for approach to loss of response and therapeutic drug monitoring.
 Selection of therapy based on comorbidities: Several comorbidities and extra-intestinal manifestations should
be considered when selecting therapy44 (table 5)
Table 4: FDA approved biologics, biosimilars, and small molecules for the treatment of IBD
Biologic Molecular Disease indication Dose
structure
Anti-TNFα
Infliximab Chimeric (mouse  UC, Crohn’s  Induction: 5 mg/kg IV at week 0, 2 , 6

(Remicade®) and human) IgG1 disease  Maintenance: 5 mg/kg IV every 8 weeks
antibody against ● Dose can be increased to 10 mg/kg
TNF ● Frequency can be changed to every 6
weeks
Infliximab reference product: Remicade® (Infliximab-hjmt)
FDA approved biosimilars: Inflectra® (infliximab-dyyb); Renflexis ® (Infliximab-abda); Ixifi® (infliximab-
qbtx);Avsola® (infliximab-axxq)
Adalimumab Fully human IgG1  UC, Crohn’s  Induction: 160 mg subq on day 1, then 80
(Humira®) antibody against disease mg at 2 weeks
TNF  Maintenance: 40 mg subq every 2 weeks,
starting at week 4.
 Frequency can be decreased to every 1 week
Adalimumab reference product: Humira® (adalimumab)
FDA approved biosimilars: Amjevita® (adalimumab-atto); Cyltezo® (adalimumab-abdm); Hyrimoz®
(adalimumab-adaz), Hadlima® (adalimumab-bwwd)
Golimumab Fully human IgG1  UC  Dose 200 mg subq week 0, then 200 mg
(Simponi®) antibody against week 2
TNF  Maintenance:100 mg subq q 4 weeks,
starting at week 6
Certolizumab PEGylated Fab'  Crohn’s disease  Induction: 400 mg subq week 0, 2, 4
(Cimzia®) fragment of a  Not preferred for  Maintenance: 400 mg subq every 4 weeks,
humanized antibody first line agent.* starting at week 8
against TNF
Anti-integrins (leukocyte adhesion molecule inhibitors) † -work in the blood vessels to prevent trafficking of
WBC in the tissue
Natalizumab Humanized  Crohn’s disease  Dose 300 mg IV every 4 weeks
(Tysabri®) monoclonal  Not recommended
antibody against due to risk of PML.
α4-β1 and α4-β7  Consider in patients
integrin with both Crohn’s
& multiple sclerosis
Vedolizumab humanized anti-  UC, Crohn’s  Induction: 300 mg IV at 0, 2, and 6 weeks
(Entyvio®) α4-β7 integrin (gut disease  Maintenance: 300 mg IV every 8 weeks ‡
specific)  Approved in patients  Assess response between weeks 10 to 14 and
who do not respond discontinue therapy if no response 45
or lose response to
anti-TNF
Anti-IL12/23
Ustekinumab Human monoclonal  Crohn’s disease  Induction: IV infusion dose is weight based
(Stelara®) antibody targeting  UC ● weight<55 kg:260 mg (2 vials); weight
the p40 subunit of 55-85 kg-390 mg (3 vials); weight >85 kg-
interleukin 12 and 520 mg (4 vials)
23  Maintenance:90 mg subq every 8 weeks
Small molecules
Tofacitinib Small molecule that  UC  Induction: 10 mg PO BID for at least 8 weeks
(Xeljanz®) Inhibits Janus  New FDA guidance  Maintenance: 5 or 10 mg PO BID
§ Kinase (JAK1 and recommends its use  Extended release formulation with once daily
JAK3), which is to certain patients dosing is also available (22 mg once daily or 11
involved in signal who have not mg once daily)
transduction in responded or cannot  Discontinue after 16 weeks of 10 mg BID if
cytokine-mediated tolerate one or more adequate therapeutic benefit is not achieved.
inflammatory TNF blockers.  Use lowest effective dose to maintain response.
pathways
Ozanimod Sphingosine 1-  UC  Initiate treatment with dose titration as follows:
(Zeposia®) phosphate receptor ● 0.23 mg once daily (days 1-4)
modulator ● 0.46 mg once daily (days 5-7)
(S1P1&S1P5) ● 0.92 mg once daily (day 8 and thereafter)
Regulates lymphocyte
migration from
lymphoid tissue to
sites of inflammation
‡‡
*A meta-analysis did not demonstrate benefit of certolizumab in inducing remission. 46 It can be used to treat
patients who lost response to other anti-TNF agents.
†Natalizumab is associated with progressive multifocal leukoencephalopathy (PML), which is a fatal
demyelinating disease of the CNS caused by the human polyoma virus (JCV). Natalizumab is an integrin
antagonist that blocks integrins with the α4 subunits, most importantly α4-β1 integrin (present in the CNS),
and the intestine specific α4-β7 integrin. Its action on α4-β1 integrin is responsible for its therapeutic effect in
multiple sclerosis, and it is the likely mechanism of JCV reactivation and PML. The risk of PML is highest in
patients with positive JCV antibody, long treatment duration (>2 years), and prior use of immunosuppressive
agents. Natalizumab should not be used in those who are JCV+, and patients should be tested for JCV q 6
months while on therapy. Long-term follow up studies have not reported any cases of PML in patients receiving
vedolizumab.47
‡Subcutaneous Vedolizumab at 108 mg q 2 weeks was shown to be effective for maintenance of remission up
to 52 weeks following vedolizumab IV induction (VISIBLE1 study). 48
§ The risk of varicella zoster virus (VZV) infection is elevated with Tofacitinib (up to 5.1 % in the 10-mg
maintenance group). Consider vaccination with the recombinant zoster vaccine prior to starting therapy.
Another side effect is hypercholesterolemia. The FDA issued updated guidance about tofacitinib (September
2021) requiring new black box warning about the increased risk of adverse events such as cardiovascular
events, malignancy, thrombosis, and mortality.
‡‡ Leads to transient bradycardia due to S1P1 modulation. Before initiating ozanimod, patients without
confirmed history of varicella (chickenpox) should be tested for antibodies to VZV. If antibody negative,
vaccination against VZV is recommended.
Table 5: Clinical comorbidities and consideration for biologic or small molecule selection in IBD
Comorbidity Consideration for biologic or small molecule therapy
Multiple sclerosis Natalizumab, vedolizumab
Heart Failure Ustekinumab, vedolizumab (avoid anti-TNF)
Coronary artery disease Avoid tofacitinib
Rheumatoid arthritis Anti-TNF
Ankylosing spondylitis Anti-TNF
Psoriasis Ustekinumab
Erythema nodosum Anti-TNF, ustekinumab
Biosimilars
 In an effort to decrease the cost of biologics and protect inventor and innovator interests, the Biologics
Price Competition and Innovation Act of 2009 [BPCIA] was signed into law by President Obama as part
of the Affordable Care Act.49 This law creates a licensure pathway for biologics that have been shown to
be biosimilar to or interchangeable with the reference product.
 The BPCIA defines a biosimilar as “biological product is highly similar to the reference product
notwithstanding minor differences in clinically inactive components” and that “there are no clinically
meaningful differences between the biological product and the reference product in terms of the safety,
purity, and potency of the product.”
 Biosimilars are not considered generics of the original medications, because exact replicas of the original
biologic cannot be made due to the complex structure of the biologic.
 Biosimilars have the same protein sequence (primary structure) but differ in glycosylation patterns. 38
These glycosylation patterns affect the protein’s complex quaternary structure.
 Biosimilars should have the same strength, dosage form, and route of administration as the reference product.
 Biosimilars have the potential to offer the biologic agent at a lower cost, thereby increasing access to
biologics for patients with IBD. Cost savings are likely to affect insurers and patients the most.
 The FDA suggests naming reference products and biosimilars by using two components: a core name that
is similar for all medications, and a suffix consisting of four lowercase random letters (at least three of the
four lowercase letters in the suffix must be distinct).
 Refer to table 4 on page 270 for a list of infliximab and adalimumab biosimilars.
Study highlight
Switching from originator infliximab to biosimilar CT-P13 compared with
maintained treatment with originator infliximab: (NOR-SWITCH) study.50
 This is a randomized, non-inferiority, double-blind, phase 4 multicenter trial in Norway.
 Study population: 482 adult patients on stable therapy with infliximab originator (reference biologic) who
were randomized to either continued infliximab originator or to switch to CT-P13 treatment (biosimilar
infliximab-dyyb –Inflectra®/Remsima®), with the same dosing regimen.
 Patients had multiple indications: Crohn’s disease (n=155), ulcerative colitis (n=93), spondyloarthritis
(n=91), rheumatoid arthritis (n=30), psoriatic arthritis (n=30), and chronic plaque psoriasis (n=35).
 Primary outcome and results: disease worsening at 52 weeks occurred in 26% of patients in the originator
group and 30% in the CT-P13 group.
 In Crohn’s disease, disease worsening occurred in 21% in the originator group and 36.5% in the
CT-P13 group (adjusted risk difference -14.3% was not statistically significant)
 In ulcerative colitis, disease worsening occurred in 9.1% in the originator group and 11.9% in the
CT-P13 group (adjusted risk difference -2.6% was not statistically significant)
 Of note, the study was not powered to demonstrate non-inferiority for individual diseases.
 Adverse events were similar in both groups. Trough drug concentrations and drug antibody levels were
similar between the groups during follow up. The authors concluded that switching from originator
infliximab to biosimilar was not inferior to continued treatment with the originator infliximab.
 A prospective observational study of 136 patients with Crohn’s disease and 38 with ulcerative colitis
showed that a reverse switch (from maintenance biosimilar CT-P13 to Remicade®) did not lead to any
difference in remission, drug trough levels, or antidrug antibody levels before and after the switch.51
 Other prospective randomized trials and comparative cohort studies found that it is safe to switch between
reference infliximab and biosimilar infliximab, and that initiating therapy with biosimilar in non-inferior
to initiating therapy with reference infliximab. 52, 53 54
Fistulizing and perianal Crohn’s disease
AGA Clinical Practice Guidelines on the Medical Management of Moderate to

AGA, 2021
Severe Luminal and Perianal Fistulizing Crohn’s Disease40
 Symptoms and signs of fistulizing Crohn’s disease include pneumaturia, passage of gas through the vagina,
urinary tract infections, psoas abscess or other intraperitoneal abscess, perianal fissure and abscess.
 Workup of suspected perianal disease includes examination under anaesthesia, fistulogram, barium studies,
rectal EUS, pelvic MRI, and pelvic CT scan. Endoscopy is performed to assess for rectal and colonic
inflammation.
 Malignant transformation of anal or perianal chronic lesions can occur in Crohn’s disease.
 Some reports found that anal squamous cell carcinoma is associated with HPV infection and perianal
Crohn’s disease.55-57 Anal cancer can be misdiagnosed as benign stricture.
 Perform a careful examination of the perianal area.
 Cases with persistent ulcerations, nodules, and abnormal granulation tissue should promptly be referred for
examination under anesthesia and biopsy.
 Consider screening for anal cancer with an anal pap smear in patients who are high risk (HPV, long-standing
perianal Crohn’s disease, HIV, men who have sex with men, and women with a history of cervical dysplasia).
 Complex fistulas are those with anal sphincter involvement, multiple external openings, rectovaginal fistula,
perianal abscess, anorectal stricturing, or severe rectal inflammation.
 Early surgical drainage with antibiotics should be performed in cases of perianal abscesses (>5mm in size),
prior to the use of anti-TNF agents. Smaller abscesses may not need drainage. 38
 Therapeutic options for complex fistulas include antibiotics (ciprofloxacin 500 BID, metronidazole 250-
500 TID, duration of 4-12 weeks), thiopurines, tacrolimus, anti-TNF therapy, seton placement, and surgery.
 Combining antibiotics with anti-TNF is more effective than anti-TNF alone, even in cases without a
perianal abscess.
 All anti-TNF agents can be considered for the treatment of fistulizing Crohn’s disease.
 Infliximab is FDA approved for fistulizing Crohn’s disease and has stronger evidence for fistula closure
than other anti-TNFs (adalimumab, certolizumab).
 Other biologics (vedolizumab, ustekinumab) might be effective based on subgroups analysis of
randomized controlled studies and case series. However, further studies are needed to define their role
in fistulizing Crohn’s disease.38, 58 The AGA recommends infliximab, adalimumab, ustekinumab, or
vedolizumab for perianal disease, in combination with antibiotics. 40
Biologic therapy for Crohn’s disease

 FDA approved biologic therapies for Crohn’s disease are infliximab, adalimumab, certolizumab, natalizumab,
vedolizumab, and ustekinumab (refer to table 4 on page 270).
 The AGA recommends the use of anti-TNF in combination with immunomodulators in patients with moderate
to severe Crohn’s disease who are naïve to both biologics and immunomodulators. 40
 Figure 3 shows a suggested algorithm for initiating infliximab therapy in Crohn’s disease, with a plan for
follow up and management of loss of response.
 In patients whose disease is controlled on infliximab, switching to adalimumab for the convenience of subq
dosing can result in loss of response, and is generally not recommended. 59
Therapeutic drug monitoring
American Gastroenterological Association Institute Guideline on Gastroenterology

Therapeutic Drug Monitoring in Inflammatory Bowel Disease 25 2017
Clinical
Appropriate Therapeutic Drug Monitoring of Biologic Agents for Gastroenterology
Patients With Inflammatory Bowel Diseases 60 and Hepatology,
2019
 Therapeutic drug monitoring (TDM) can be classified as “reactive” or “proactive” TDM

 Reactive TDM refers to measuring biologic trough levels and drug antibody levels in patients who have
lost response to a biologic. The results of TDM can guide drug dose optimization or changes.
 Reactive TDM is also recommended to guide thiopurine dosing (see page 264).
 Proactive TDM refers to measuring biologic trough levels and drug antibody levels proactively in
asymptomatic patients as part of routine clinical care, to optimize dosing and prevent future flares.
 Several studies on TDM have been performed, with different designs and mixed results61-64. T
 The ACG and AGA only recommend reactive TDM at this time.25, 38 More data on proactive TDM is needed.
 The IBD in pregnancy clinical care pathway report (AGA) suggests proactive TDM (measuring biologic
drug levels) in patients on biologics anticipating pregnancy, to optimize dosing prior to conception. 65
 Figure 3 shows a suggested approach to initiating anti-TNF with infliximab, follow-up, and reactive
therapeutic drug monitoring in Crohn’s disease. Table 6 provides details about drug concentration
targets during proactive and reactive TDM.
Table 6: Drug concentration targets for biologic agents during induction and maintenance
(Reference60, 66)
Maintenance drug Minimum drug

Post-induction drug trough concentration trough concentration to
Agent
target concentration achieve before
target abandoning
Infliximab Week 14 > 3 μg/mL therapy in active
> 10 μg/mL
> 3 μg/mL (minimum level) disease
> 7 μg/mL (associated with ↑ mucosal healing)
Adalimumab Week 4 > 5 μg/mL > 10 μg/mL
> 5 μg/mL (minimum level)
> 7 μg/mL (associated with ↑ mucosal healing)
Certolizumab Week 6 > 15 μg/mL -
> 32 μg/mL (minimum level)
Golimumab Week 6 > 1 μg/mL -
> 2.5 μg/mL (minimum level)
Vedolizumab Week 6 >12 μg/mL -
>20 μg/mL (minimum level)
Ustekinumab Week 8 >2 μg/mL -
>4 μg/mL (minimum level)
- Drug and antibody concentrations and interpretation of results applies similarly to biosimilars and the
originator drugs.60 The timing of trough levels should be just prior to the next administration of drug (within 24
hours before the next dose).25
Figure 2: Approach to initiating anti-TNF with infliximab, follow-up, and reactive therapeutic drug monitoring in
Crohn’s disease. This also apply to managing loss of response in patients with UC (assessing for active inflammation,
ruling out infection, adjusting the biologics empirically or by therapeutic monitoring).
* Starting anti-TNF therapy with adalimumab is an alternative to infliximab, and follows the same principles above.
** See page 290 for dilation of ileocolonic strictures in Crohn's disease.
‡The timing of trough levels should be just prior to the next administration of drug (within 24 hours before the next
dose).25 See table 6 for more details about drug concentration trough concentration targets. § In cases of low titer
antibodies, dose optimization may control the disease, as these antibodies might be transient and non-neutralizing. 25
A consensus panel recommends the following cutoffs to define “high antibody levels”: ANSER assay:10 U/mL,
RIDAscreen: 200 ng/mL, InformTx/Lisa Tracker:200 ng/mL.60
Selected trials of biologics in inflammatory bowel disease

 Early combined immunosuppression or conventional management in patients with newly diagnosed
Crohn's disease 67 (top down versus bottom up Crohn's treatment trial)
 This was an open label, randomized multicenter European trial of 133 patients randomized to either early
combined immunosuppression or conventional treatment. All patients had a recent diagnosis of Crohn’s
disease, and were naive to immunomodulators, steroids, and biologics.
 67 patients were assigned to early combined immunosuppression.
o Patients received three infusions of infliximab (5 mg/kg) at weeks 0, 2, and 6, plus azathioprine.
● Additional treatment with infliximab and/or corticosteroids was given as needed.
 66 patients were assigned to conventional management and received corticosteroids, followed by
azathioprine and infliximab if needed.
 Results (table 7): Remission rates at 26 and 52 weeks were higher in the early combined
immunosuppression group. Remission rates at 2 years were similar between the two groups.
Table 7: Remission in the early combined immunosuppression and conventional groups
Early combined
Conventional therapy P value
immunosuppression
Week 26 60% 35% 0.006
Week 52 61% 42% 0.028
Week 104 ~55% ~50% 0.43
 Endoscopic healing at 2 years (defined as no ulcers on colonoscopy) was higher in the early combined
treatment group (73%) compared to the conventional group (30%). A follow up study of the same cohort
showed that in patients who underwent ileocolonoscopy at 2 years, mucosal healing was the only factor
that predicted sustained, steroid-free remission 3 and 4 years after therapy was initiated. 68
 Limitations: patients were given intermittent dosing of infliximab rather than scheduled maintenance
infusions, which could have reduced efficacy in the early combined group.
Study highlight Effect of tight control management on Crohn's disease (CALM): a

multicenter, randomized, controlled phase 3 trial 69
 The CALM trial was an open-label, randomized, multinational (22 countries,

74 hospitals) controlled phase 3 trial of patients with endoscopically active Crohn’s
disease (n=244), and no previous use of immunomodulators or biologics. 69
 Patients were randomized to one of two groups:
 Tight control group (n=122): treatment escalation based on these failure criteria: fecal calprotectin
≥250 µg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use during the previous week.
 Clinical management group (n=122): treatment escalation based on CDAI scores and prednisone use.
 Treatment was escalated if the failure criteria were met. Escalation was performed stepwise as follows:
No treatment Adalimumab induction then adalimumab q2weeks  adalimumab q1 week
adalimumab q1week+AZP.
 The primary endpoint (mucosal healing with absence of deep ulcers at 48 weeks) was met in 46%
of patients in the tight control, compared to 30% in the clinical management group (p=0.01).
 The study suggests that management of active Crohn’s disease based on concentrations of fecal
calprotectin and CRP in addition to clinical symptoms leads to better outcomes compared to
clinical management alone.
Study highlight
The Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC trial) 70
 Study objective: compare the efficacy of infliximab, azathioprine, and combination infliximab plus
azathioprine in inducing and maintaining corticosteroid-free clinical remission in active Crohn’s disease.
 Study design: randomized, double blind, multi-center trial (conducted in 92 centers) from March 2005
through November 2008.Patients had no previous treatment with azathioprine, 6-MP, methotrexate, or any
anti-TNF agent. The study excluded patients with symptomatic strictures, abscesses, homozygous mutant
or heterozygous TPMT phenotype.
 Randomization groups
 IV infliximab 5 mg/kg plus daily oral placebo capsules (n=169).
 Oral azathioprine at 2.5 mg/kg/day plus placebo infusions (n=170).
 Combination therapy with infliximab and azathioprine (n=169).
 318 patients completed the 30-week trial, of whom 280 entered the extension trial up to week 54.
 The primary outcome was the rate of corticosteroid-free clinical remission at week 26.
 Results (figure 3 and 4): There were higher rates of remission and mucosal healing in the combination
therapy and infliximab groups, compared to the AZP group.
Figure 3: Remission at week 26 Figure 4: Mucosal healing at week 26

 Patients who had objective evidence of inflammation (high CRP level or observed mucosal lesions) had
the best clinical results with infliximab. In patients with a normal CRP level or no endoscopic lesions,
no significant differences were observed among the three study groups.
 Only 1% of patients in the combination group had positive infliximab antibodies at week 30 compared to 15%
in the infliximab group. The incidence of adverse events was similar between the three study groups.
 Conclusion: In patients with moderate to severe Crohn's disease who are naive to immunosuppressive
and biologic therapy, treatment with infliximab or combination infliximab-AZP is more likely to achieve
remission than treatment with AZP monotherapy.
 Some study limitations
 Azathioprine was started without steroids in two thirds of patients.
 Approximately one third of patients had no endoscopic lesions at baseline, but were enrolled based on
clinical symptoms. Mucosal healing was an “all or none” assessment based on the presence or absence
of mucosal lesions rather than an endoscopic scoring system.
 46% of patients in the azathioprine group had an incomplete assessment of mucosal healing at week 26,
and were assumed to have not achieved mucosal healing. This was higher than that in the infliximab
group (31%) or combination group (29%) and could have affected the results.
 The study did not address the question of whether combination therapy is superior to infliximab
monotherapy after failure of azathioprine.
Study highlight
Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis (VARSITY)71
 This was a phase 3b, double-blind, double-dummy, randomized, active-controlled, multicenter (245 centers),
multinational trial (34 countries). Patient population: moderately to severely active ulcerative colitis (n=769)
 Previous exposure to a TNF inhibitor other than adalimumab was allowed in up to 25% of patients.
 Randomization:
 IV vedolizumab (n=383) 300 mg on day 1 and at weeks 2, 6, 14, 22, 30, 38, and 46 (+Subq placebo).
 Subq adalimumab (n=386) 160 mg at week 1, 80 mg at week 2, and 40 mg q2weeks (+IV placebo).
 Dose escalation was not permitted in either group.
 The trial did not require a specific schedule for corticosteroid withdrawal. Tapering guidelines were provided
but loosely enforced in order to mimic clinical practice.
 Primary outcomes and results:
 Primary outcome: Clinical remission at week 52 was higher in vedolizumab group than in the adalimumab
group (31.3% vs. 22.5%; P = 0.006). This difference was also observed in the subgroup of patients with no
prior TNF exposure (34.2% vs 24.3%, p<0.05).
 Corticosteroid-free clinical remission occurred in 12.6% of the patients in the vedolizumab group and in
21.8% in the adalimumab group (the rate was lower in vedolizumab group but not statistically significant).
 The mean oral steroid dose at 52 weeks was similar between both groups.
 Endoscopic improvement was higher in the vedolizumab group than in the adalimumab group (39.7% vs.
27.7%, P<0.001).
 Rates of histologic remission were higher in the vedolizumab group compared to adalimumab.
 Both treatments were generally safe and well tolerated. The exposure-adjusted incidence rate of infection
was 23.4 per 100 patient-years in the vedolizumab group and 34.6 per 100 patient-years in the adalimumab
group (difference did not reach statistical significance)
 There were more cases of psoriasis in the adalimumab group.
 AGA guidelines (2020) recommend vedolizumab over adalimumab in patients with moderate-
severe ulcerative colitis who are naïve to biologic agents.15
 A recent trial (SEAVUE- published in abstract form) compared Ustekinumab to adalimumab in

moderate to severe Crohn’s disease (N=386). Clinical remission at 52 weeks were similar (65%
vs 61%,p=0.42) and other secondary endpoints were similar.72
IBD and colorectal cancer

AGA Clinical Practice Update on Endoscopic
Gastroenterology,
Surveillance and Management of Colorectal Dysplasia in
2021
Inflammatory Bowel Diseases: Expert Review73
SCENIC international consensus statement on
Gastrointestinal
surveillance and management of dysplasia in
endoscopy, 2015
inflammatory bowel disease, 2015 74
75 Gastrointestinal
The role of endoscopy in inflammatory bowel disease
endoscopy, 2015
 Factors associated with an increased risk of colorectal cancer in IBD:

 Male sex
 Younger age at onset of disease < 30 years old.
 Increased disease duration.
 More extensive colitis, backwash ileitis.
 Severe disease activity, uncontrolled inflammation, poor compliance with medications.
 Primary sclerosing cholangitis.
 First-degree relative with CRC diagnosed at age <50 years.
 Colonic strictures secondary to Crohn’s disease.
 The presence of inflammatory pseudopolyps was traditionally related to higher risk of malignancy.
However, a recent retrospective study of 462 patients found that pseudopolyps are associated with more
severe inflammation, but they did not independently increase the risk of advanced colorectal neoplasia.76
 Selected studies addressing the risk of colorectal cancer in IBD
 A meta-analysis published in 2001 showed that the cumulative risk of colon cancer in UC is 2% by 10
years, 8% by 20 years, and 18% by 30 years of disease duration. 77
 Studies that are more recent show a lower risk of malignancy in IBD.
 A population-based study from Olmsted County, Minnesota showed that the risk of colon cancer in UC
and Crohn’s disease was not increased. Cumulative risk of colon cancer in UC was 2% after 25 years.78
 Another study performed at St. Mark’s Hospital in London showed that the cumulative incidence of
CRC in UC is 2.5% after 20 years, 7.6% after 30 years, and 10.8% after 40 years. 79
 A population based study of 47,374 IBD patients in Denmark showed that the risk of CRC in UC or
Crohn’s disease was not increased compared to the general population. There was an increased risk of
CRC in UC patients diagnosed in childhood or adolescence and with concomitant PSC. 80
 A study among IBD patients of Kaiser Permanente of Northern California's database of members with
IBD (5053 with CD, 9822 with UC) showed 60% higher incidence of CRC compared to non-IBD
patients.81
 A meta-analysis based on 259,266 person-years at risk in population-based studies and 29,799 person-
years at risk in referral center studies showed that the standardized incidence ratio for CRC in IBD was
1.7 (i.e. patients with IBD have almost twice the risk of CRC compared to the general population). 82
This number was similar in UC and in Crohn’s disease.
o The cumulative incidence of CRC is 0.7%, 2.6%, and 6.6% at 10, 20, and 30 years of disease.
o However, including only population-based studies resulted in lower cumulative rates of cancer
(0.8%, 2.2 %, and 4.5%, respectively). Those with extensive colitis had higher risk (2%, 12%, and
21%, respectively).82
 A population based study of 96,447 patients with UC in Denmark and Sweden found that patients with
UC are at increased risk of developing CRC (HR 1.66), CRC death (HR 1·59) compared to individuals
without UC.83
 In summary, CRC risk is increased with IBD. However, the risk seems to be lower in clinical practice
compared to that reported in earlier studies from referral centers.
 Surveillance recommendations 73
 Perform a screening colonoscopy in all patients 8-10 years after disease diagnosis, and immediately
after the diagnosis of PSC.
 Determine the endoscopic and microscopic (histologic) extent of inflammation by performing a careful
examination and obtaining biopsies from all colonic segments. The extent of inflammation during this
colonoscopy (at 8-10 years after onset, not at diagnosis) will determine further course of action as
follows:
o In patients with ulcerative proctitis or proctosigmoiditis, surveillance is not recommended, as there
is no increased risk of malignancy.
o In patients with extensive left sided colitis, pancolitis, or Crohn’s disease involving more than one
third of the length of the colon, begin surveillance 1-2 years after the initial screening colonoscopy.
 Colonoscopy surveillance
 Equipment: use either high definition white light endoscopy with random biopsy or high definition
endoscopy and chromoendoscopy with targeted biopsy.
 The SCENIC guidelines recommend high definition endoscopy combined with chromoendoscopy with
targeted biopsy as the preferred method of screening.74 However, there are no long-term data to support
this preference. A meta-analysis of randomized controlled trials showed that chromoendoscopy was
associated with increased detection of patients with dysplasia compared to standard definition white light
endoscopy (RR, 2.12; 95% CI, 1.15-3.91), but not compared to high-definition white light endoscopy (RR,
1.42; 95% CI, 0.80–2.52). 84
 A recent randomized trial of 131 patients with longstanding UC found no significant difference for
neoplasia detection between narrow band imaging (21.5%) and chromoendoscopy (21.2%). 85
 A prospective randomized trial (n=102) found no difference in dysplasia detection between HD white light
endoscopy/random biopsy and HD chromoendoscopy/targeted biopsy (3.9% vs 5.6%, P = 0.749).86
 Another retrospective study of 440 colonoscopies in 401 patients with IBD did not find a difference in
dysplasia detection between chromoendoscopy and targeted biopsy and white light endoscopy and random
biopsy (11% vs 10%, p=0.8).87
 The ACG recommends that chromoendoscopy be performed in patients who are high risk for colorectal
cancer, but not necessarily performed in all patients undergoing surveillance colonoscopy, especially if high
definition white light endoscopy is performed. 38
 Chromoendoscopy technique: This technique requires a clean bowel preparation. The cecum is reached
and a dye (indigo carmine or methylene blue) is sprayed throughout the colon. This is done using the water
jet channel or the instrument channel using a spray catheter. This topical application of dye improves the
detection and characterization of dysplastic lesions during withdrawal.
 Colonoscopy can be performed using white light, but a high definition scope is recommended. 73, 74 If
colonoscopy is performed with standard definition, then chromoendoscopy is recommended.
 Both ACG and the SCENIC guidelines do not recommend using narrow band imaging for surveillance,
while AGA considers virtual chromoendoscopy an alternative to dye spray chromoendoscopy if using high
definition scopes.
 Obtaining random (nontargeted) biopsies of the normal appearing mucosa is controversial, because studies
have shown that the yield of random biopsies for dysplasia is low (≤0.2%), and that the majority of
dysplasia (>98%) is visible and diagnosed by targeted biopsy.73
 A reasonable approach would be to obtain random biopsies in high-risk patients if the procedure is done
by white light endoscopy (without chromoendoscopy).
 Obtaining several biopsies is still recommended to document the extent of endoscopic inflammation to
make future decisions about surveillance.
 If random non targeted biopsies are obtained, separate specimens in different jars by colonic segments
(cecum, ascending, transverse, etc.) or by insertion distance (70 cm, 60 cm, etc.).
 Colonoscopy findings
 The previously used terms (adenoma like dysplasia associated lesion or mass “DALM”) and (non-
Adenoma like DALM) should no longer be used to describe colonoscopic findings.
 Colonoscopic findings are generally categorized into visible and invisible dysplasia.74
o Visible dysplasia is described similar to colon polyps using the Paris classification (see chapter 8).
● Polypoid lesions: pedunculated (1p) or sessile (1s) (see figure 6).
● Non polypoid lesions: slightly elevated (2a), flat (2b), and depressed (2c)
● Describe the border of the lesion (distinct, indistinct border) and the presence of ulcerations.
Figure 5: Visible dysplasia in a patient with ulcerative colitis.

A: Raised sessile lesion (1s) with distinct border without ulcerations (arrows) in an area of inflammation.
B: The lesion was resected with hot snare. Histology showed high-grade dysplasia. Biopsy of the
surrounding mucosa showed chronic active colitis.
o Non-visible dysplasia: dysplasia identified by taking random biopsies of normal mucosa.

o Other findings:
● Inflammatory pseudopolyps: appear as confluent mucosal polyps in sites of previous inflammation.
Scarring of the surrounding area could be present. These lesions do not require resection or biopsy (they
are not premalignant), but they are markers of previous severe inflammation.
 A recent study did not show an association between pseudopolyps and increased risk of malignancy
(see page 279). 76
● Strictures: Colon strictures should be biopsied to exclude malignancy.
 Patients with strictures that cannot be traversed or sampled should be referred for
consideration of surgical resection.
 Management of colonoscopic findings
 Visible dysplasia: Lesions should be examined closely. Document size, location, appearance, and
determine the resectability based on endoscopic appearance.
o Resectable lesions should be resected using the appropriate method based on the lesion. Difficult lesions
can be referred for endoscopic submucosal dissection or advanced endoscopic mucosal resection.
● It is also recommended to biopsy the area adjacent to the lesion to determine that the dysplastic lesion
has been fully resected and that there is no residual invisible dysplastic tissue around the lesion.
● Surveillance colonoscopy is recommended following endoscopic resection.
 Patients with sessile lesions ≥10 mm that are removed piecemeal should have a repeat
endoscopy within 6 months to confirm complete resection, then every 1 year.
 Lesions ≤ 10mm should be followed by yearly colonoscopy
o Lesions deemed unresectable should be tattooed and biopsied. Confirmed unresectable dysplasia
should be referred to proctocolectomy. 75
 Non visible dysplasia: Patients with dysplasia found on random biopsies should undergo
chromoendoscopy with high definition endoscopes. Consider referral to an IBD specialist.
● During chromoendoscopy for follow up of invisible dysplasia, the site of previous dysplasia (e.g.
sigmoid colon) is carefully examined. If there are any visible lesions, these should be resected
endoscopically as above. If no lesions are found, repeat biopsies of that area should be obtained.
Further management options include intensive surveillance versus colectomy.
● Patients with confirmed dysplasia (by two pathologists), high-grade dysplasia, multifocal
dysplasia, or dysplasia found on multiple exams (metachronous lesions) are probably more
appropriate candidates for colectomy than patients without these high-risk features.
 There is no clear management guidance at this time and expert referral is recommended.
 If no dysplasia is detected, repeat colonoscopy interval can be individualized as follows (AGA guidance):73
o 1 year if there is moderate/severe inflammation, PSC, family history of CRC in first degree relative <50
years, or recent history of visible or invisible dysplasia.
o 2-3 years if there is mild inflammation, history of prior severe colitis, history if invisible dysplasia or high
risk visible dysplasia >5 years ago, or low risk dysplasia <5 years ago.
o 5 years if there is continuous disease remission and mucosal healing on ≥2 consecutive exams or minimal
historical colitis extent.
►Anal and perianal cancer: Patients with IBD have increased risk of anal canal cancer (see page 273).
Extra-intestinal manifestations of IBD

Extraintestinal Manifestations of Inflammatory
Gastroenterology,
Bowel Disease: Current Concepts, Treatment, and
2021
Implications for Disease Management 88
Table 8: Extra-intestinal manifestations of IBD.

Parallels
Manifestation and
Description Treatment options intestinal
prevalence in IBD
disease activity
Joint
 Peripheral arthritis  Arthralgia or  Treat intestinal -Type 1: yes
(5-20%) arthritis disease -Type 2: no
o Type 1: Asymmetric,  Affects large joints  Sulfasalazine
Pauciarticular (type 1) or small  Prednisone
(< 5 joints) joints (type 2)  Acetaminophen
o Type 2: Symmetric,  Non deforming  NSAIDS
Polyarticular
(≥ 5 joints)
 Central arthritis  Ankylosing  NSAIDS No

(IBD related spondylitis  Methotrexate
spondyloarthropathy) (sacroiliitis)  Anti-TNF agents
(5% )  Affects Crohn's >
UC
Skin
 Erythema nodosum (5%)  Raised painful  Treat intestinal Yes
erythematous disease
nodules on extensor  Prednisone
surfaces. Affects
Crohn's > UC
 Pyoderma gangrenosum  Pustule progressing  Prednisone Usually disease
(0.5-2%) to deep ulcer  AZP, Cyclosporin course is
 Can be preceded by  Infliximab independent of
trauma (pathergy)  Tacrolimus intestinal activity
 Tends to have  Dapsone
chronic debilitating  IV immunoglobins
course
 Can be peristomal
 Cutaneous Crohn’s  non-caseating  Steroids Usually disease
disease (also referred to granulomatous skin  Immunomodulators course is
as metastatic Crohn’s lesions  Anti-TNF independent of
disease)89 intestinal activity
Eye
 Ocular manifestations  Episcleritis  Prednisone -Episcleritis and
(10%)  Scleritis  Topical steroids scleritis: yes
 Uveitis  Infliximab -Uveitis: no
 Other extraintestinal manifestations

 Primary sclerosing cholangitis does not parallel intestinal disease activity.
 Metabolic bone disease
 Osteoporosis and osteopenia result from chronic inflammation, vitamin D deficiency, and chronic
steroids use.
 Bone mineral density (DEXA scan) should be measured in patients with risk factors: males older than
50 years, chronic steroids use > 3 months, postmenopausal women, and history of low trauma fracture.
 Measure 25-hydroxy vitamin D level. Give calcium (1200 mg/day) and vitamin D (1000 units/day).
 Bisphosphonates are an effective and well tolerated therapy for metabolic bone disease in IBD. 90
Consider referral to endocrinology.
 Renal disease
 Oxalate stones can form in patients with malabsorption and an intact colon secondary to increased
free oxalate colonic absorption and urinary excretion (enteric hyperoxaluria).
 Rare extra-intestinal manifestations include pulmonary nodules, pneumonitis, and pericarditis, sweet
syndrome (neutrophilic dermatosis-presents as fever with tender non-pruritic erythematous rash).91
Surgical therapy for ulcerative colitis
Endoscopic evaluation of surgically altered bowel in inflammatory bowel

disease: a consensus guideline from the Global Interventional Lancet, 2021
Inflammatory Bowel Disease Group 92
Treatment of pouchitis 93, Crohn's disease, cuffitis, and other Lancet

inflammatory disorders of the pouch: consensus guidelines from the Gastroenterol
International Ileal Pouch Consortium Hepatol 2022
 Indication for surgery in UC include refractory/fulminant disease, high-grade dysplasia or cancer, and
perforation.
 Option for surgery include total proctocolectomy with end ileostomy, total colectomy with end ileostomy,
total proctocolectomy with ileoanal anastomosis, and total proctocolectomy with ileal pouch anal
anastomosis.
Ileal pouch anal anastomosis

 Ileal pouch anal anastomosis (IPAA) is performed for the surgical treatment of ulcerative colitis. There
are two techniques to perform the IPAA (figure 6):
 Hand sewn approach: the ileal pouch is connected to the anal transitional zone after stripping the
mucosa off the distal rectum up to the dentate line (mucosectomy).
 This technique removes all the rectal mucosa that is diseased or can become diseased in the future.
However, it requires greater manipulation of the anal canal, and is associated with increased risk of
gas and stool incontinence.
 Stapled approach: the ileal pouch is connected to the distal rectal mucosa above the anal transitional
zone, leaving a short segment (2-3 cm) of rectal mucosa above the dentate line.
 This technique has better functional outcomes in terms of continence, but leaves a short segment
of diseased rectal mucosa that can cause fecal urgency. This remaining rectal mucosa requires
regular follow up as it can develop dysplasia and cancer.
Pouch
Pouch staple line
Figure 6: IPAA surgical techniques
 Evaluation of pouch symptoms

 Pouch endoscopy (pouchoscopy): the neoterminal ileum, pouch body, rectal cuff, and
transitional zone should be carefully examined (Video 9-3).
 Pouch problems Video 9-3
 Cuffitis
 This complication develops in the stapled IPAA and results in inflammation of the residual cuff of
rectal mucosa distal to the ileorectal anastomosis. (Video 9-3).
 Presents with bleeding and urgency.94
 Treatment: topical mesalamine, steroids.
 Pouchitis
 Inflammation of the pouch mucosa. This develops in ~25% of patients within 6 months, and 51%
of patients at 48 months post-surgery. 20% of patients with develop chronic pouchitis.
 Symptoms include urgency, frequency, diarrhea, abdominal pain. Bleeding is less common.
o Symptoms alone may not accurately identify patients with pouchitis. One study found low
correlation between these symptoms and objective evidence of inflammation.95
 Of note, most patients will have diarrhea immediately after IPAA surgery, and this improves in
within a few months. After recovery, most patients will have an average of 4-6 bowel movements
per day.96 Therefore, patients with isolated diarrhea immediately after surgery do not need workup
or endoscopy, and watchful waiting is reasonable.
 Ileal pouch symptoms (change in stool frequency, urgency, abdominal cramps, rectal bleeding) do
not correlate well with the presence of objective inflammation.
 A positive p-ANCA predicts the development of pouchitis post IPAA in up to 60% of patients. 97
Other risk factors for pouchitis include non-smoking patient and PSC.
o Consider secondary pouchitis due to Clostridium difficile, CMV, NSAIDS, ischemia, or
radiation-induced pouchitis.
 The main treatment of pouchitis is antibiotics.
o First line antibiotics are metronidazole (500 mg TID) or ciprofloxacin (500 mg bid), given for 2 weeks.
o If there is no response to initial treatment, give another 2-week course of antibiotics.
o If there is still no response to treatment (antibiotic refractory pouchitis), consider rifaximin, 5-
ASAs, steroids, immunomodulators, biologics.
● If pouchitis responds to antibiotics but frequently relapses (antibiotic dependent pouchitis),

prescribe antibiotics as needed for recurrent episodes.
● Other antibiotics: Rifaximin 400 mg TID, Tinidazole 2 gram daily.
o VSL#3 is a probiotic that decreases relapse rate after successful treatment of pouchitis.98, 99 It is
effective for primary prophylaxis against pouchitis (dose is 4.5x1011 CFU b.i.d.). It is not used
for the acute treatment of pouchitis.
 Distal ileitis results from backwash ileitis or Crohn’s disease.
 In backwash ileitis, there is diffuse erythema and inflammation without stricturing. The pouch inlet
is patent.
 In Crohn’s ileitis, there is significant inflammation with ulcerations and stricturing of the pouch inlet.
 Crohn’s disease of the ileal pouch
 An estimated 3.5-9% of patients who undergo IPAA for presumed UC will be found to have Crohn’s
disease.
 Crohn’s disease of the pouch can present as pouch inflammation, strictures, or fistulas.
 It is important to differentiate Crohn's disease of the pouch from surgical complications of IPAA.
o Surgery related complications include leakage and fistula formation. These typically present
early after surgery. Fistulas open at or around the surgical anastomosis.
o Fistulizing Crohn’s disease presents at any time after 6 months post-surgery. Fistulas open above
the surgical anastomosis.
Surgical therapy for Crohn’s disease and post-operative management

American Gastroenterological Association
Institute Guideline on the Management of Gastroenterology, 2018
Crohn’s Disease After Surgical Resection 100
ACG practice guidelines: management of
Crohn’s disease in adults 38
 Data from studies prior to the introduction of biologic therapy show that up to ~45% of Crohn's disease
patients will require at least one surgical resection within 10 years of diagnosis.101 This risk has decreased
to ~30-35% in recent years.
 The goal of surgery is to remove the affected intestinal segment and restore intestinal continuity. The most
common surgery for Crohn’s disease is ileocolonic resection and primary anastomosis.102
 Retrospective studies suggest that end-to-end anastomosis leads to better quality of life and less
healthcare utilization compared with side-to-side anastomosis.102
 Indications for surgery in Crohn’s disease
 Intestinal obstruction, refractory/fulminant disease, high-grade dysplasia or cancer, severe perianal
disease with complications (fistula/abscess), perforation, abscess, phlegmon.
 Preoperative anti-TNF does not increase the risk of post-operative surgical site infections, based on a
prospective cohort published in abstract form.103 However these patients require close monitoring,
consider planning the last dose of anti-TNF 4 weeks before surgery, and restarting 4 weeks after surgery.
 In the perioperative period, attempt percutaneous abscess drainage, optimize nutrition, give DVT
prophylaxis.104
 In patients who underwent colonic or ileocolonic resection, the disease most commonly recurs at the site
of surgical anastomosis.
 Natural history of Crohn’s disease post-surgery (without medical prophylaxis):

 Endoscopic recurrence develops in ~70-90% of patients at 1-year post resection.
 Most endoscopic recurrence is subclinical; however, some cases progress to clinically symptomatic
disease. This occurs in up to 30% of patients at 1 year and 50% at 5 years.105
 Symptoms include diarrhea, bleeding, and abdominal pain.
 This is followed by complications (fistulizing disease, obstruction).
 There is a 50% risk of repeat surgery in 5 years.
 Post-operative medical therapy
 Several medications have been shown to decrease the risk of post-operative recurrence of Crohn’s disease
 Mesalamine has minimal benefit in preventing post-operative recurrence. It could be considered in patients
post ileal resection and no other risk factors for recurrence (ACG). AGA recommends against its use due
to low quality evidence to support its use and the availability of other effective therapy.100
 Metronidazole can be used to prevent recurrence after small bowel surgery for Crohn’s disease.
However, the benefit of metronidazole is lost after stopping therapy and long-term treatment is not
practical and associated with intolerance in most patients.
 Thiopurines (azathioprine and 6-MP) have a modest effect on endoscopic and clinical recurrence at 1
and 2 years post-surgery. 106
 Infliximab:
 In a small randomized control trial (n=24), infliximab decreased the risk of endoscopic recurrence at 1
year after ileocolonic resection in Crohn’s disease (9.1% in infliximab group vs 84.6% in placebo).107
 The PREVENT study showed that infliximab decreased the rate of endoscopic, but not clinical
recurrence at 1 year post-surgery compared to placebo (see study highlight on the next page).108
 In a large network meta-analysis of 21 randomized trials with several interventions, anti-TNF
monotherapy lowered the risk of clinical relapse (RR, 0.02–0.20) and endoscopic relapse (RR, 0.005–
0.04).109
 Overall, anti-TNF therapy appears to be the most effective intervention for post-operative
prophylaxis.
Study highlight
Infliximab Reduces Endoscopic, but Not Clinical, Recurrence of Crohn’s Disease After
Ileocolonic Resection (PREVENT)108
 This is a multicenter, multinational study of 297 patients with Crohn’s disease who underwent
ileocolonic resections.
 Patients were randomized to infliximab (n=150) versus placebo (n=147). The primary endpoint was
clinical recurrence before or at week 76 or at week 104.
 Primary endpoints and results: clinical recurrence at week 76 occurred in 12.9% of infliximab group
compared to 20.0% in placebo group (p=0.97). Clinical recurrence at week 104 occurred in 17.7% of
infliximab group compared to 25.3% in placebo group (p=0.98). Endoscopic recurrence at week 76 was
lower in the infliximab group compared to the placebo group (30.6% vs 60.0%; P < .001).
 The authors concluded that Infliximab prevented endoscopic recurrence but did not prevent clinical
recurrence at 1 year. Considering the natural history of post-operative Crohn’s disease, the frequency
of symptomatic clinical recurrence is much lower than endoscopic recurrence. It is likely that a longer
follow up and increased sample size would have led to a statistically significant difference between
the groups.
 Post-operative surveillance colonoscopy can lead to better endoscopic outcomes by allowing drug
escalation in patients with asymptomatic endoscopic recurrence detected on colonoscopy.
Study highlight
Crohn's disease management after intestinal resection: a randomized trial (POCER) 110
 This is a multicenter, multinational study of 174 patients who underwent intestinal resection of
all macroscopic Crohn's disease.
 Patients were randomly assigned in 2:1 ratio to the following groups:
 Active care group (n=122) had standard drug therapy as outlined below. In addition, patients
underwent colonoscopy at 6 months. If the colonoscopy showed endoscopic recurrence, medical
therapy was escalated as follows:
 If not on thiopurine: start thiopurine. If already on thiopurine: add adalimumab. If already on
adalimumab 40mg q 2 weeks: increase to adalimumab q1week.
 Standard care group (n=52) did not undergo colonoscopy at 6 months
 Initial drug therapy for both groups: all patients received 3 months of metronidazole. Further therapy
was stratified according to the predicted risk of recurrence.
 High-risk patients (smoking, perforating disease, prior resection) received thiopurine (AZP or 6-
MP), and if intolerant, received adalimumab.
 Low-risk patients only completed the metronidazole without additional therapy.
 All patients had colonoscopy at 18 months
 Primary endpoint: endoscopic recurrence at 18 months.
 Results: Endoscopic recurrence at 18 months was lower in the active care group (49%) than the standard
of care group (67%), p=0.03.
 Conclusion: Active management of post-operative Crohn’s disease patients with surveillance
colonoscopy at 6 months and drug escalation as necessary leads to lower rates of endoscopic recurrence
at 18 months compared to standard treatment.
Approach to the management of the post-operative patient with Crohn’s disease

 Assess the patient’s risk of post-operative Crohn’s disease recurrence by considering several patient
and disease related risk factors (table 9).
 There is no validated risk scoring system at this time.
 All patients should quit smoking.
Table 9: Risk factors for disease recurrence

Patient related factors Disease related factors
 Young age at time of surgery (< 30 years)  Short duration of disease prior to surgery
 Young age at time of disease onset (< 2 years)
 Active cigarette smoking  History of prior resection
 No risk difference among genders  Small bowel or ileocolonic disease
 Fistulizing / penetrating disease
 Extensive small bowel disease > 50 cm
 Upper GI Crohn’s disease
 Consider postoperative prophylaxis according to the risk of recurrence.

 High-risk patients are smokers, have fistulizing disease, or ≥ 2 prior surgeries
 Start anti-TNF agents within 4 weeks post-surgery.
o Consider adding thiopurine to decrease the risk of immunogenicity and loss of response. 38
 If the patient is not a candidate for biologic therapy, thiopurines alone can be used instead. However,
they are less effective than biologics in preventing disease recurrence.
 In moderate risk patients (those with risk factors other than high risk), start AZP or 6-MP.
 Low risk patients are those with long disease duration, short segment of involved bowel and mild
inflammation.111 These patients do not need prophylactic medications.
 All patients require active surveillance for recurrence post-surgery
 Perform colonoscopy in all patients at 6-12 months post-surgery, even if they are asymptomatic.
 Consider using a pediatric colonoscope for easier intubation of terminal ileum.
 Assess endoscopic recurrence according to the Rutgeerts endoscopic recurrence score (table 10). 112
Table 10: Rutgeerts endoscopic recurrence score post ileocolonic resection for Crohn’s disease
Score Findings in the neo-terminal ileum Comments
0 Normal Risk of endoscopic progression
<10% in 10 years
1 ≤ 5 aphthous lesions Risk of endoscopic progression
20% in 5 years
2 > 5 aphthous lesions, normal intervening Clinical recurrence 50-100% in
mucosa 5 years
3 Diffuse aphthous ileitis with inflammation High likelihood of re-operation.
4 Diffuse inflammation, large ulcers, Severe recurrence
cobblestoning, stricturing
Score of 0 or 1: remission; score of 2 or 3: recurrence; score of 4: severe recurrence
In patients with endoscopic recurrence (score of ≥ 2), start therapy (thiopurine or anti-TNF) if not
already on treatment or intensify treatment regimen.
 In patients with severe recurrence, start anti-TNF (with or without thiopurines).
 If the patient is already on anti-TNF, consider checking anti-TNF drug level and drug antibodies to
guide further management (see page 275). Consider switching biologic therapy or optimizing the
dose of anti-TNF.
 In patients without endoscopic recurrence (score of zero or 1), continue current therapy and repeat
colonoscopy every 1-3 years.
 Fecal calprotectin
 Several studies have found an association between fecal calprotectin level and risk of endoscopic
recurrence of Crohn’s disease post-surgery.
 In a post hoc analysis of the POCER study (see page 288 ), the vast majority of patients with fecal
calprotectin concentrations ≤ 100 μg/g were in endoscopic remission (Rutgeerts score, i0 or
i1).113 Fecal calprotectin level >100 μg/g indicated endoscopic recurrence with 89% sensitivity and
58% specificity, and a negative predictive value (NPV) of 91%.
 Fecal calprotectin testing could select patients who need colonoscopy and avoid colonoscopy in
patients who are unlikely to have an endoscopic recurrence that affects disease management.
Endoscopic management of Crohn’s disease strictures
Practical guidelines on endoscopic treatment for Crohn's Lancet

disease strictures: a consensus statement from the Global Gastroenterol
Interventional Inflammatory Bowel Disease Group 114 Hepatol. 2020
Role of interventional inflammatory bowel disease in the
era of biologic therapy: a position statement from the GIE, 2019
Global Interventional IBD Group 115
 IBD related strictures are classified according to several characteristics as follows:115
 Intrinsic (inflammatory, fibrotic, mixed, malignant) vs. extrinsic strictures.
 Symptomatic vs. asymptomatic
 Related to Crohn’s disease, ulcerative colitis, or post-surgical.
 Benign vs. malignant
 Short (<4cm) vs. long (≥ 4 cm)
 Stricture characteristics: ulcerated, web-like, spindle shaped, angulated.
 Location in the GI tract
 Degree of narrowing: mild (passage of scope with mild resistance), moderate (passage of scope with
moderate resistance), severe (non-traversable with a pediatric colonoscope)
 Single vs multiple strictures
 Complexity: simple (single straight stricture) versus complex (associated with fistula and/or abscess).
 Presence or absence of prestenotic luminal dilation.
 A recent practical guideline statement provided the following recommendations for endoscopic
management of IBD related strictures. In general, these recommendations appear suited for advanced
interventional IBD physicians, rather than the general gastroenterologist.
 Obtain CT or MRI to evaluate the site and extent of stricture.
 Exercise caution in patients on systemic steroids who are at higher risk of adverse events.
 Continue biologics in patients undergoing endoscopic dilation
 Hold anticoagulants and anti-platelet agents prior to dilation.
 Use CO2 for insufflation. Obtain biopsy from the stricture to rule out malignancy.
 Consider dilation of IBD related strictures (inflammatory or fibrotic), even for patients with incidental
asymptomatic strictures because dilation can prevent progression to symptomatic strictures. The
presence of inflammation does not preclude dilation.
 Avoid dilation for strictures with deep ulcerations, and in patients with concurrent fistulas or abscess.
 Pre-stenotic luminal dilation and long strictures are associated with lower response to endoscopic dilation.
 Consider smaller caliber scopes (e.g. gastroscope).
 Balloon dilation should be performed stepwise to a maximum balloon diameter of 18-20
mm or to a lower diameter if the stricture is < 10 mm in diameter. The goal is to traverse
the stricture with the pediatric colonoscope without resistance (see figure 8 and video 9-4).
Video 9-4
 Carefully inspect the stricture post dilation to detect bleeding and/or perforation.
Figure 7: Endoscopic balloon dilation of ileocolonic anastomotic stricture in a patient with

Crohn’s disease. (A)The stricture is short, fibrotic, and non-inflammatory; (B) Gradual dilation using a
wire-guided balloon dilator was performed under fluoroscopy to a maximal diameter of 15 mm; (C)
fluoroscopic image during dilation; (D) post dilation appearance. See video 9-4 for more details.
 Other endoscopic interventions for IBD strictures:

 Endoscopic electroincision (using needle knife) +/- clip placement to maintain luminal patency.
 Metal stent placement across the stricture (off label use, there is a risk of stent impaction).
 Intralesional injection of steroids or other medication is not recommended.
 Other interventional procedures in IBD:115
o Endoscopic fistulotomy.
o Endoscopic drainage of abdominopelvic abscesses
o Endoscopic fistula injection of therapeutic agents (experimental) and endoscopic fistula closure.
o Endoscopic submucosal dissection and endoscopic mucosal resection of colonic dysplasia
o Endoscopic treatment of post-surgical anastomotic leaks.
Fertility and pregnancy issues in IBD
The second European evidenced-based consensus on reproduction J Crohn’s Colitis,

and pregnancy in inflammatory bowel disease 116 2015
The Toronto Consensus Statements for the Management of Gastroenterology,

Inflammatory Bowel Disease in Pregnancy 117 2016
Inflammatory Bowel Disease (IBD) in Pregnancy Clinical Care

Gastroenterology,
Pathway – A Report from the American Gastroenterological
2019
Association IBD Parenthood Project Working Group 65
IBD and fertility

 Infertility in males is increased after ileal pouch anal anastomosis (IPAA) due to the increased risk of
impotence and retrograde ejaculation.
 Reversible oligospermia can occur in up to 60% of male patients taking sulfasalazine.
 The effect of sulfasalazine on sperm count is not dose dependent; even small doses can cause
oligospermia. It is reversible upon stopping the medication. Sulfasalazine should be discontinued
three months before pursuing pregnancy.
 Methotrexate has been linked to altered spermatogenesis, and it should be stopped in men three
months before attempting conception.
 Women with active inflammation are at an increased risk of infertility.
 Women have three times increased risk of infertility post proctocolectomy and IPAA if deep pelvic
dissection is performed. In retrospective studies, laparoscopic IPAA was associated with lower rates
of infertility compared to the open approach. 118, 119
 Conventional ileostomy is not associated with increased infertility rates.
General management concepts for IBD before and during pregnancy
 A key priority is to keep the disease in remission to prevent adverse outcomes on mother and fetus.
 All women of reproductive age should receive preconception counselling to explain the implications
of IBD on future pregnancy, and to improve pregnancy outcomes. 117, 120
 The American Gastroenterological Association (AGA) has launched the IBD
Parenthood Project (http://www.IBDParenthoodProject.org), a new online resource
for patients who wish to learn more about IBD and pregnancy. The website has
important information about pregnancy in a patient-friendly format.
 IBD flares should be treated promptly and effectively. Flexible sigmoidoscopy (preferred) and
colonoscopy are considered safe in pregnancy. They should be performed if there is a strong
indication that will change clinical management (e.g. confirm flare, assess disease severity, and rule
out other causes of colitis).
 MRIs and Ultrasound are preferred imaging modalities in pregnancy to limit fetal radiation exposure. 117
 Avoid gadolinium MRI due its association with increased risk of stillbirths and neonatal death. 121
 Cesarean section is recommended in women with active perianal disease, rectovaginal disease
involvement, or in patients with an IPAA (to avoid risk of injury to the anal sphincter).
Medication safety and management during pregnancy

 Table 11 summarizes the pregnancy and lactation implications of IBD therapies.
 The FDA letter categories (A, B, C, D, X) are no longer used. They were replaced with narrative
summaries about potential risks in pregnancy, lactation, and reproduction in men and women.
 In general, most of the commonly used medications (aminosalicylates, immunomodulators, and
biologics) are now considered safe during pregnancy, with the exception of methotrexate
(contraindicated), and phthalate containing aminosalicylates (currently only sulfasalazine-delayed
release tablets contain phthalate, which should be avoided).
 It is safe to continue thiopurine treatment during pregnancy. However, thiopurines should not be
initiated during pregnancy due their delayed onset of action and the risk of pancreatitis and
leukopenia.
 Infliximab, adalimumab, golimumab, ustekinumab, and vedolizumab are IgG1 antibodies with active
placental transport throughout pregnancy, but mostly in the third trimester and near the time of
delivery. Natalizumab is an IgG4 antibody that also crosses the placenta. Certolizumab is not a full
antibody. It is a PEGylated, antigen-binding fragment of an anti-TNF antibody. It has minimal
placental transport.
 Despite the potential to cross the placenta, safety data from large prospective cohorts and registries
indicate that biologics are considered safe in pregnancy.
 Anti-TNF agents have more data to support their use in pregnancy compared to other biologics.
This data found no adverse events to the fetus. 122, 123 Vedolizumab and Ustekinumab have limited
safety data, but they are also considered safe due to similar characteristics with other biologics. 65
 Therefore, all biologics should be continued throughout pregnancy.
 To minimize placental transport near the time of delivery, the dosing schedule of biologics can be
adjusted so that the last dose of medication during pregnancy is given several weeks before delivery,
so that the drug reaches trough levels near the time of delivery. The biologic is then resumed 48 hours
after delivery. 65 Certolizumab does not require schedule adjustment.
 Biologics can be started during pregnancy to induce and/or maintain remission after an IBD flare.
 Post-partum
 Withhold live vaccines in infants younger than 6 months if the mother was given a biologic during
pregnancy (except certolizumab). A published report described a case of an infant who was exposed
to infliximab in utero and was given the BCG vaccine at 3 months of age. He later developed severe
infection and died at 4 months of age.124 Rotavirus is the only live infant vaccine in the USA.
 Results of studies from the PIANO (Pregnancy in Inflammatory Bowel Disease and Neonatal
Outcomes) registry show that very low levels of biologics are detected in breast milk of mothers who
are receiving biologics. However, these low levels of biologics do not affect infant outcomes. 125
Therefore, biologics are currently considered compatible with breastfeeding.
Table 11: Pregnancy and breastfeeding considerations for IBD therapies

Medication Pregnancy Breast feeding
Aminosalicylates  Sulfasalazine delayed release tablets (Azulfidine-EN) contain -Compatible with
(see page 261) phthalate. High doses of phthalates have been linked to breast feeding, but
urinary tract malformations in mice. Switching to another mesalamine products
formulation is recommended.117 preferred over
 Other aminosalicylates are currently free of phthalates and sulfasalazine65
can be continued with the same dosing.
 Supplement patients on sulfasalazine with folate 2 mg/day.
Metronidazole  Should be limited to short courses and avoided in first Unknown, not
trimester. recommended
Quinolones  Generally avoided (especially in first trimester) due to Unknown, probably
possible adverse effect on cartilage. safe for short courses
Rifaximin  Considered as treatment option for pouchitis Unknown, probably
 Due to the limited oral absorption, exposure to the fetus is safe
expected to be low.
Corticosteroids  Give for active flares. May avoid in first trimester due to -compatible with
small increased risk of oral clefts in some but not all studies. breast-feeding.
Not for maintenance therapy.
Azathioprine  Continue thiopurine monotherapy to maintain remission Compatible with
and 6-MP during pregnancy. breastfeeding
 If patient on combination therapy (thiopurine +biologic),
consider discontinuing the thiopurine and maintain the patient
on biologic alone. If this strategy is chosen, try to discontinue
thiopurine 3 months before pregnancy to allow time to ensure
sustained remission. 117
 Should not be initiated during pregnancy due their delayed
onset of action and the risk of pancreatitis
Cyclosporin  Overall safe, use minimal dose and as salvage treatment, Compatible with
maybe associated with premature birth (unclear). breastfeeding
Methotrexate  Contraindicated due to risk of abortion and congenital Contraindicated
malformations
 Women should receive at least one form of contraception
 Should be discontinued at least 3 months prior to conception
to allow adequate time for washout
Tofacitinib  Safety is unknown, limited data Safety unknown
Biologics
Infliximab  Consider therapeutic drug monitoring pre-pregnancy65 Compatible with
Adalimumab  Continue the biologic throughout pregnancy breast feeding
Golimumab  To minimize placental transport near the time of delivery, adjust
Ustekinumab dosing schedule so that the last dose is administered at a time to
Vedolizumab allow the drug to reach trough levels around the time of
Natalizumab anticipated delivery. (Infliximab, vedolizumab, ustekinumab:
30-32 weeks; adalimumab, golimumab: 36-38 weeks)
 Restart the medication post-partum.
 For infliximab, use pre-pregnancy weight for dosing
Certolizumab  Continue the biologic throughout pregnancy Compatible with
 No need to adjust dosing schedule breast feeding
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301
10
CHAPTER
Miscellaneous
GI topics
Chapter 10- Miscellaneous GI topics
This chapter has a few GI topics that do not fit into a specific organ system. Nutrition is
important for the boards as well as for our daily practice. Patients with severe diarrheal diseases,
malabsorption, and history of bariatric surgery are prone to developing multiple vitamin and
mineral deficiencies. Gastrointestinal neuroendocrine neoplasms are increasing in incidence due
to the higher detection of small rectal tumors during colonoscopy. These neoplasms have a
special classification system based on their histologic differentiation and proliferation level. It is
important to know the management of these tumors because they are often encountered
incidentally during EGD or colonoscopy. They can occasionally cause common GI symptoms such
as anemia and abdominal pain. Gastric GISTs are occasionally the cause of abdominal pain and
gastrointestinal bleeding. Board exams frequently ask about the molecular features, imaging
characteristics, and management of neuroendocrine tumors and GISTs.
302 Chapter 10: Misc. GI topics
Contents
Chapter 10- Miscellaneous GI topics

Nutrition—303
Gastrointestinal Neuroendocrine Neoplasms—306
Gastric neuroendocrine neoplasms—308
Duodenal Neuroendocrine Neoplasms—310
Small Intestine Neuroendocrine Neoplasms—310
Appendiceal Neuroendocrine Neoplasms—311
Colonic Neuroendocrine Neoplasms—311
Rectal Neuroendocrine Neoplasms—312
Carcinoid syndrome—313
Carcinoid Heart Disease—314
Gastrointestinal stromal tumors—314
References—316
Chapter 10: Misc. GI topics 303
Nutrition
 Vitamins and minerals

 Features of vitamin deficiencies and toxicities are presented in table 1.
Table 1: Features of vitamin deficiencies and toxicities

Vitamin Deficiency Toxicity
Water soluble
vitamins
B12  Etiology of B12 deficiency: pernicious anemia,  Not reported
(cobalamine) atrophic gastritis, post gastric bypass, small
intestinal bacterial overgrowth and ileal disease
 Manifestations: megaloblastic anemia,
subacute combined degeneration of the
posterior column of the spinal cord resulting in
loss of vibration and proprioception, increased
serum methylmalonic acid levels
Folate  Drugs that predispose to deficiency are  May lower seizure threshold
sulfasalazine, phenytoin, methotrexate  Treatment with folate in B12
 Manifestations: megaloblastic anemia, deficiency will correct
glossitis, diarrhea, neural tube defects in anemia but not neuropathy
newborns of women with deficiency
C  Scurvy: gingival inflammation and bleeding,  Diarrhea, bloating
petechiae, coiled hairs, perifollicular  False negative stool guaiac
hemorrhage, hyperkeratosis, impaired wound
healing
B1  Etiology: alcoholism, malnutrition,  Not reported
(Thiamine) malabsorption, renal dialysis, post bariatric
surgery*, TPN, high carbohydrate intake, high
shellfish consumption, hyperemesis
gravidarum, Anorexia Nervosa,
 Deficiency results in Beriberi:
 Cardiomyopathy (high output heart failure)
 Neurologic disease: peripheral sensory and
motor neuropathy, ataxia, abnormal mental
status, nystagmus and ophthalmoplegia
(Wernicke encephalopathy), chronic
memory impairment (Korsakoff syndrome)
B2  Chronic malabsorption, IBD, alcoholism  Not reported
(Riboflavin)  Manifestations: angular stomatitis, cheilosis,
seborrheic dermatitis, anemia
B3 (Niacin)  Etiology: alcoholism, chronic malabsorption,  Flushing, hepatitis
patients with Hartnup disease† and carcinoid
syndrome
 Manifestations: pellagra (photosensitive
dermatitis, dementia, diarrhea)
B5  Peripheral neuropathy  Not reported
(Pantothenic
Acid)
B6  Etiology: alcoholism, chronic malabsorption,  Peripheral neuropathy

(Pyridoxine) treatment with isoniazid, penicillamine
 Manifestations: angular stomatitis, cheilosis,
seborrheic dermatitis, peripheral neuropathy,
confusion, anemia
Fat soluble
Vitamins
A  Manifestations: follicular hyperkeratosis, night  Yellow-tinged skin
blindness, conjunctival and corneal dryness (carotenemia)
(xerophthalmia), increased risk of infection  Acute toxicity: intracranial
hypertension, nausea, vomiting
 Chronic toxicity: ataxia,
alopecia, hepatotoxicity,
exfoliating rash
D  Deficiency results in rickets in children and  Hypercalcemia,
osteomalacia in adults hyperphosphatemia
E  Etiology: fat malabsorption  Coagulopathy
 Manifestations: posterior column disease, cranial
nerve palsies, peripheral neuropathy, hemolysis
K  Etiology: antibiotic treatment, fat  Hemolytic anemia, jaundice
malabsorption, vitamin E toxicity
 Manifestations: easy bruisability, GI bleeding,
hematuria
* Refer to chapter 11, section on bariatric surgery
† Hartnup disease results in decreased intestinal absorption of tryptophan, the precursor of niacin
 B12 absorption
 Dietary B12 is present mainly in meats, fish, eggs, and other animal protein.
 B12 is released from food by the action of gastric pepsin.
 B12 binds the R factor (a glycoprotein secreted by the salivary glands).
 B12-R factor complex is broken down in the duodenum by pancreatic proteases.
 B12 is released, which then binds to intrinsic factor (produced by gastric parietal cells).
 B12-intrinsic factor is actively absorbed by specific receptors in the terminal ileum.
 Features of mineral deficiencies and toxicities are presented in table 2.
 Refeeding syndrome
 Refeeding syndrome refers to a group of clinical and metabolic findings in patients with severe
malnutrition who are given nutritional support (oral or TPN).
 Predisposing conditions include starvation, anorexia nervosa, BMI<16 kg/m2, chronic alcoholism,
intractable vomiting, Crohn's disease, and short bowel syndrome.
 During refeeding after prolonged starvation, the glycemia leads to increased insulin secretion, which
induces glycogen, fat, and protein synthesis. It also induces uptake of phosphate, calcium, K, and Mg
into the cells, which leads to their depletion from the circulation.
 Manifestations
o Metabolic: hypophosphatemia, hyperglycemia, hypomagnesemia, hypokalemia, fluid overload,
thiamine and other vitamin and mineral deficiencies.
o Other: cardiac (congestive heart failure, arrhythmias), GI (abdominal pain, vomiting, constipation),
neurologic (weakness, paraesthesia, ataxia, encephalopathy).
 Management: start with vitamin replacement (give thiamine, vitamin B, multivitamin, and trace element
supplementation), careful refeeding at a slow rate (10kcal/kg/day), slowly increase over 4-7 days,
monitor electrolyte levels (K, phosphate, Mg, calcium). 1
Table 2: Features of mineral deficiencies and toxicities

Mineral Deficiency Toxicity
Iron  Etiology: menstruation, GI blood loss, hookworm  Iron overload syndromes are
infections, upper intestinal disease, gastric bypass described in chapter 4-liver.
 Manifestations: microcytic anemia, angular
stomatitis, koilonychia (spoon nails)
Zinc  Etiology: malabsorption and chronic diarrheal  Abdominal pain, nausea,
diseases, alcoholism, post gastric bypass, vomiting, dizziness, neuropathy
penicillamine, acrodermatitis enteropathica*  Copper deficiency (zinc
 Manifestations: growth retardation in children, competes with copper
erythematous pustular rash around body orifices and absorption)
on the extremities, diarrhea, dermatitis, glossitis
Copper  Etiology: chronic diarrhea and malabsorption, renal  Acute toxicity: nausea vomiting,
dialysis, treatment with copper chelators, excess abdominal pain, diarrhea,
oral zinc intake, prolonged jejunal enteral nutrition, hepatitis
Menkes disease†  Copper overload is seen in
 Manifestations: hematologic (anemia, Wilson disease (see chapter 4-
neutropenia), neurologic (polyneuropathy, ataxia, liver)
spinal cord disease), thin hair, abnormal skin
pigmentation, decreased immunity, cardiomyopathy
Chromium  Manifestations  Rare
o Hyperglycemia, peripheral neuropathy, increased
free fatty acids, peripheral neuropathy, weight loss
Selenium  Manifestations: cardiomyopathy, myalgia, ataxia  Nausea, vomiting, diarrhea,
 Selenium deficiency is linked to Keshan disease peripheral neuropathy,
(endemic cardiomyopathy in China) and Kashin- headache, abnormal nails and
Beck disease (chronic osteochondropathy). Both can hair, skin rash
be prevented but not treated with selenium
supplementation
Manganese  Manifestations: hypocholesterolemia, weight loss,  Toxicity by industrial exposure
abnormal nail and hair growth leads to "manganese mania",
headaches, Parkinson-like
symptoms ‡
Biotin  Deficiency is rare, but has been described in  Not reported
patients with prolonged consumption of egg whites,
and infants fed elemental diet
 Manifestations: altered mental status, ataxia,
myalgia, seborrheic dermatitis, alopecia
* Acrodermatitis enteropathica is an autosomal recessive disease that leads to decreased zinc absorption
† Menkes disease is an x-linked recessive disorder that leads to copper deficiency
‡ Parkinson-like symptoms result from manganese deposition in the basal ganglia
Gastrointestinal Neuroendocrine Neoplasms
Diagnosis and management of

gastrointestinal neuroendocrine tumors: Cancer Treat Rev. 2016
An evidence-based Canadian consensus 2
National Comprehensive Cancer Network.

NCCN, 2018
Neuroendocrine and Adrenal tumors3
 General concepts
 Neuroendocrine neoplasms (NENs) are neuroendocrine malignancies arising from the neuroendocrine
cells. These cells are normally present in the GI tract and throughout the body. They synthesize and
secrete hormones and peptides in response to neurological and chemical signals.
 On electron microscopy, they contain dense secretory granules that store these various hormones
and peptides.
 Neuroendocrine neoplasms are subdivided into neuroendocrine tumors (NETs) and neuroendocrine
carcinoma (NEC) based on their histologic features and degree of differentiation (Table 3).
 In the luminal GI tract, these tumors are referred to as GI-NENs (GI-NET and GI-NEC)
o The term “carcinoid” refers to well-differentiated GI-NET grade 1 (see below). However, the
use of this term is discouraged, as it can be confused with carcinoid syndrome, and it is better
to define NETs by their location and actual grade of the tumor.
o The use of the terms “foregut”, ”midgut”, and ”hindgut” to classify the location is also
discouraged, and it is better to classify the tumors based on the actual location in the GI Tract.
 Similarly, pancreatic neuroendocrine neoplasms include pNET and pNEC- see chapter 6-pancreas.
o While most pNETS arise from the pancreas, some of these tumors (gastrinoma, somatostatinoma)
can also arise from extrapancreatic locations such as the stomach and small intestine.
 NETs are histologically, genetically and clinically distinct from NECs. NETs are not precursors of NEC.
 Other neuroendocrine neoplasms arise from locations outside the GI system (lung, thyroid, thymus, and
adrenals).
 Most neuroendocrine tumors arise from the luminal GI tract (small intestine [ileum] > rectum >
appendix > stomach), followed by the respiratory system.
 GI and pancreatic neuroendocrine neoplasms are classified as functional (secrete hormones leading to
symptoms) or nonfunctional tumors. The majority of neuroendocrine neoplasms are non-functional.
 The incidence of GI-NETs has been rising, and most cases occur in patients older than 50 years.
 Symptoms of GI-NET could be related to several tumor related events:
 Tumor growth and local complications such as abdominal pain, GI bleeding, obstruction, and ischemia.
 Neuroendocrine neoplasms can induce small intestinal ischemia by eliciting stromal fibrosis,
distortion of the mesentery and kinking of the mesenteric blood vessels.
 Serotonin produced by the tumor may induce vasoconstriction. They may also lead to mesenteric
vascular elastosis, characterized by deposition of thick elastic tissue in blood vessel walls, and this
may contribute to intestinal ischemia.4
 Hormone secretion (e.g. gastrinoma)
 Carcinoid syndrome (flushing, diarrhea, shortness of breath) –see page 313.
 Carcinoid heart disease (right-sided valvular heart disease and right sided heart failure) - see page 314.
 Biomarkers
 Serum chromogranin A: Chromogranins are glycoproteins that are stored in many endocrine and
neuronal tumors. Chromogranin A is elevated in various NETs. It is not sensitive nor specific for NETs,
and has no role in screening for NETs.
 However, chromogranin may have a role in follow up of patients with an established diagnosis of
NETs.
 Other biomarkers are acid phosphatase, pancreatic polypeptide, synaptophysin, neuron specific
enolase.
 Measurement of 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA) levels is recommended in
patients with small intestinal NETs and those with symptoms suggestive of serotonin excess. 2
 5-HIAA is an end product of serotonin metabolism
Tryptophan  5-hydroxytryptophan  5-hydroxytrptamine (serotonin) 

 5-hydroxyindolacetaldehyde  5-hydroxyindolacetic acid
 Foods high in serotonin and tryptophan should be restricted for 72 hours prior to urine collection.
 Diagnosis
 Biopsy or FNA of the primary tumor.
 Histology determines the degree of differentiation (well or poorly differentiated).
 Immunohistochemical staining for synaptophysin (figure 3 on page Error! Bookmark not defined.),
chromogranin, and low molecular weight keratins is used to confirm the diagnosis of NET.
 The ki-67 index assessment is used for NET grading and as a prognostic marker.
 Ki-67 is a nuclear protein that is increased in proliferating cells. Ki-67 immunohistochemical
staining is used to assess tumor cell proliferation (percentage of cells staining positive). This should
be performed in areas of highest mitotic activity (“hot spots”)
 Mitotic count: the number of cells that are undergoing mitosis per mm2 (1 mm2 =10 high power fields)
is also used to assess tumor proliferation. The mm2 unit is preferred over the 10 HPF (WHO 2019).
 Grading of GI-NET is based on the tumor’s histologic differentiation, ki-67, and mitotic count (table 3).
Table 3: Classification of GI neuroendocrine neoplasms based on histology and proliferation

markers (WHO 2019)
Category Grade* Ki-67 Mitotic Index histology

NET G1 Low <3% <2/mm2 Well differentiated
NET G2 Intermediate 3-20% 2-20/mm2 Well differentiated
NET G3 High > 20% >20/mm2 Well differentiated
2
Neuroendocrine carcinoma Considered > 20% >20/mm Poorly differentiated
(NEC) High grade
-Small cell and Large cell by definition
types
MiNEN † variable As above As above Well or poorly
Mixed neuroendocrine-non- differentiated
neuroendocrine neoplasm*
*If the levels of Ki-67 and mitotic index are discordant, then the higher grade is used to assign the grade
classification.
†
MiNEN refers to a neoplasms with mixed neuroendocrine and non-neuroendocrine components (adeno or
squamous), each neuroendocrine and non-neuroendocrine component should account for ≥30% of the tumor.
 Imaging modalities
 CT scan, MRI, EUS
 Endoscopy (EGD, colonoscopy, capsule endoscopy)
 Somatostatin receptor imaging: These imaging modalities utilize a tracer to detect somatostatin
receptors on the NEN. These should be performed, if available, especially in small intestinal GI-NETs,
and other scenarios in which the likelihood of metastasis is high. They are also used for workup of
metastatic NEN of unknown primary
 Somatostatin receptor scintigraphy (indium-111 labelled octreotide – “Octreoscan”)
 68Gallium- positron emission tomography [PET] (68Ga-DOTATOC, -DOTANOC, and
-DOTATATE).
o 68Ga-PET is generally preferred over Octreoscan due to its higher sensitivity.
Gastric neuroendocrine neoplasms
ENETS Consensus Guidelines Update for Neuroendocrinology,

Gastroduodenal Neuroendocrine Neoplasms 5 2016
 Gastric neuroendocrine neoplasms are divided into

neuroendocrine tumors (G-NETs type 1, 2, 3) and
neuroendocrine carcinoma (Figure 1) –also known
as type 4 neuroendocrine neoplasm (table 4).
 Types 1 and 2 arise from enterochromaffin cells.
 They are associated with chronic
hypergastrinemia due to atrophic gastritis (type
1) and Zollinger Ellison Syndrome (type 2).
 Type 3 are sporadic, typically large and more
aggressive tumors.
 Carcinoid syndrome is mostly associated with type
3 gastric NET. Rarely, type 2 gastric NETs lead to Figure 1: Neuroendocrine carcinoma of
carcinoid syndrome the stomach
 Type 1 and type 2 G-NETs can be removed endoscopically by endoscopic mucosal resection or
endoscopic mucosal dissection for prominent tumors.
 EGD surveillance of smaller tumors q 6-12 months is appropriate.
 If the gastric tumors are increasing in size and number during surveillance for type 1 G-NETS, then
antrectomy can be considered. Antrectomy relieves the G-cell mediated hypergastrinemia that leads
to ECL-cell hypertrophy. 6
 For patients with type 2 G-NETS, give PPI to treat acid hypersecretion.
 The primary gastrinoma should be localized and resection should be attempted.
 Consider treatment with somatostatin analogues (octreotide, lanreotide).
Table 4: Classification and features of gastric neuroendocrine neoplasms carcinoids 7, 8

Gastric
Gastric neuroendocrine tumors (NET) neuroendocrine
carcinomas (NEC)
Type 1 Type 2 Type 3 Type 4
Relative
70-80% 5% 10-15% 6-8%
frequency
Gender
F>M F=M F<M F=M
predominance
Cell of origin ECL ECL ECL Other†
Size and Small and > 2 cm,
Small and multiple > 2 cm, solitary
number multiple solitary
Location Fundus and body Fundus and body Any area Any area
Zollinger Ellison
Chronic atrophic
syndrome
Associated gastritis (H.
(gastrinoma) –usually None None
conditions pylori or
as part of MEN1
autoimmune)
syndrome
ZES presentation Anemia, abdominal pain/dyspepsia,
Usually
abdominal pain, anorexia, weight loss, liver and other
Clinical asymptomatic,
severe heartburn, organ metastasis
presentation incidental on
esophagitis, diarrhea, Type 3 may rarely present with
EGD
peptic ulcers carcinoid syndrome.
Antral G-cell
Present Absent Absent Absent
hyperplasia
Serum gastrin High High Normal Normal
Gastric acid
Low High Normal Normal
secretion
Histologic Well Moderately
Well differentiated Poorly differentiated
differentiation differentiated differentiated
Metastasis 2-5% 10-20% >50% 80-100%
Radical resection with
Endoscopic resection for small lesions (<
lymphadenectomy for non-metastatic
2 cm), surgery for large lesions.
lesions, Surgical or endoscopic wedge
Treatment of Surveillance of small (<10 mm) low-grade
resection if no lymphadenopathy on
gastric tumors lesions could be considered due to low
EUS3. Endoscopic resection can be
metastatic potential. Antrectomy in type 1
considered for small <1cm, low grade
G-NETS
(G1) type 3 tumors9
Prognosis Excellent Good Poor Poor
ECL: Enterochromaffin-like cells. MEN1: Multiple endocrine neoplasia type 1.
† e.g., serotonin, gastrin, or ACTH-secreting tumors, poorly differentiated endocrine carcinomas, and
mixed endocrine-exocrine tumors8
Duodenal Neuroendocrine Neoplasms

 Duodenal neuroendocrine tumors (d-NETs) are usually
small, solitary, and arise from the first or second part of
the duodenum (figure 2). The size of the tumor does not
correlate with the presence of metastasis.
 Types of d-NETS: gastrinoma (50-60%), non-functional NET
(20%), somatostatinoma (15%), neuroendocrine carcinomas
(<3%), and gangliocytic paraganglioma (< 2%). 6
 Zollinger Ellison syndrome is associated with multiple
duodenal gastrinomas
 Somatostatinomas are mostly located in the periampullary
area, and 20-30% of these lesions are associated with Figure 2: Duodenal non-functional
Neurofibromatosis type 1. neuroendocrine tumor
 Gangliocytic paraganglioma follows a benign course.
 The differential diagnosis of duodenal NET includes duodenal adenoma or adenocarcinoma, gastrointestinal
stromal tumors, and benign lesions (Brunner’s gland hyperplasia, lymphoid hyperplasia, neurofibroma,
schwannoma).6
 Diagnosis: EGD + biopsy (may not be diagnostic if superficial biopsies are obtained), EUS, CT, MRI.
 Small d-NETS can be managed by endoscopic resection if the lesion is limited to the submucosa and there is
no lymph node involvement. Other options for locoregional disease include local excision (transduodenal
resection), and pancreatectomy.
Small Intestine Neuroendocrine Neoplasms
ENETS Consensus Guidelines Update for Neuroendocrinology,

Neuroendocrine Neoplasms of the Jejunum and Ileum 10 2016
 Small intestinal neuroendocrine neoplasms of the jejunum and ileum (Si-NEN) have been increasing in incidence.
 Most Si-NEN are located within 60 cm of the ileocecal valve.
 Most tumors present with vague abdominal pain, intussusception, bowel obstruction, or bleeding. Si-NEN are
the most common tumors causing carcinoid syndrome.
 Si-NEN can induce local fibrosis in the mesentery of the affected organ. This leads to thickening of the walls
of mesenteric vessels (elastic vascular sclerosis), which results in intestinal ischemia.11
 Synchronous small bowel carcinoids are present in 25% of patients.
 It is important to examine the entire small bowel to rule out synchronous lesions. Somatostatin receptor
imaging should be performed in all patients with Si-NEN-see page 308.
 The size of the tumor does not correlate with the risk of metastasis. Tumors of small size may have already metastasized.
 Treatment: bowel resection and lymphadenectomy, regardless of tumor size. The laparoscopic approach is
feasible and preferred over the open approach, as long as it leads to a complete curative resection.
 Patients with large tumor burden, mesenteric infiltration, and multiple Si-NEN are not candidates for
laparoscopic approach and should undergo open surgery.
 Prophylactic cholecystectomy is recommended in patients who undergo resection of Si-NEN if they are
planned to undergo treatment with somatostatin analogues (due to the increased risk of cholelithiasis and its
associated complications in patients on these medications).
 There is no role for neoadjuvant or adjuvant treatment in patients with Si-NEN.10
 The 5-year overall survival rate is 72% for locoregional spread and 55% for Si-NENs with distant metastases.10
Appendiceal Neuroendocrine Neoplasms
ENETS Consensus Guidelines for

Neuroendocrinology, 2016
Neuroendocrine Neoplasms of the Appendix 12
 Appendiceal neuroendocrine neoplasms (NEN) are the most common tumors of the appendix.
 They are most frequently diagnosed incidentally at a rate of 3-5 /1000 appendectomies.
 It is rare for the tumor to cause appendicitis.
 It is also rare for these tumors to cause carcinoid syndrome.
 Most tumors are located in the tip of the appendix (60-75%), middle of the appendix (5-20%), and base (<10%).12
 Workup includes examination of the post-operative appendectomy specimen, CT, MRI, somatostatin receptor
imaging, serum chromogranin.
 Treatment of appendiceal NEN depends on the size, location of the tumor, WHO grading (G1, G2, G3), and
presence of vascular and lymph vessel involvement. The following management approach is based on the
ENETS 2016 guidelines. 12 Other guidelines may defer slightly in the management of tumors < 2 cm in size.
 Tumors that are ≤1 cm in size
 If the tumor is located in the tip or middle of the appendix, then simple appendectomy is adequate.
 If the tumor is located in the base, then right hemicolectomy is recommended.
 Tumors that are 1-2 cm in size
 If the tumor is located in the tip or middle of the appendix, then simple appendectomy is adequate as
long as there is no vascular or lymphatic invasion, mesoappendiceal tumor infiltration <3mm, and the
tumor is G1.
 If there is vascular or lymph node invasion, or if the tumor is G2, then right hemicolectomy (with lymph
node dissection) is recommended.
 Tumors ≥ 2 cm or those that extend beyond the muscularis propria are treated with right hemicolectomy.
 High Grade tumors (G3, neuroendocrine carcinoma) are treated with right hemicolectomy
 Appendiceal NEN have an overall good prognosis, but this is dependent on the tumor stage. Overall 5-year
survival is 70-85% (~100% for early stage tumors, but only 12-28% for advanced tumors).
 Adenocarcinoids, goblet cell carcinoid/carcinoma, and mixed adenoneuroendocrine carcinoma (MANEC)
were terms used to describe mixed tumors with neuroendocrine features and goblet cell/intestinal features.
 These terms were removed from the recent WHO 2019 classification of digestive system tumors, and the
tumor was renamed as Goblet cell adenocarcinoma of the appendix. It is no longer considered a subtype of
appendiceal NEN, but rather a subtype of adenocarcinoma of the appendix.
Colonic Neuroendocrine Neoplasms

 Colonic NEN (excluding the rectum) are rare and account for 8% of all neuroendocrine tumors. 13
 The most common location is the cecum and ascending colon.
 Incidence in whites > blacks, females > males.
 Presentation
 Usually present late, with metastasis present in 30% of cases at diagnosis.
 Mean size at diagnosis is 5 cm.
 Patients present with diarrhea, abdominal pain, and rectal bleeding. Carcinoid syndrome is rare.
 Treatment is with colonic resection and lymphadenectomy.
 Overall 5-year survival is 50%.
Rectal Neuroendocrine Neoplasms

 Rectal NEN are increasing in incidence especially in the 50-54 year old age group.14 This is likely to the
increased utilization of colonoscopy and increased detection of incidental lesions.
 Mean age at diagnosis is 56 years. They are more common in blacks > whites.
 Most tumors are small (< 1 cm) and are diagnosed incidentally during a colonoscopy (figure 3).
 Rectal NEN rarely cause carcinoid syndrome.
A B C
Figure 3: Rectal carcinoid. A: Rectal neuroendocrine tumor found incidentally during screening colonoscopy. This
rectal "polyp" had a rubbery consistency upon mucosal biopsy. B: Histology shows nests of monomorphic neuroendocrine
cells intermixed with normal crypts. C: Positive synaptophysin stain confirming a carcinoid tumor.
 T staging:
 T1: tumor invades the lamina propria or submucosa and ≤ 2 cm.
 T1a tumor: size <1 cm, T1b tumor: size 1-≤2 cm.
 T2: invades the muscularis propria or >2cm in size with invasion of lamina propria or submucosa.
 T3: invades through the muscularis propria into subserosal tissue.
 T4: invades the visceral peritoneum or other organs or structures.
 Tumor size correlates with the risk of metastasis: Rectal NEN <1cm: 2%; 1-2 cm: 10-15%; >2 cm: 60-80%.15
 Management
 Options for endoscopic resection of small (≤2 cm) non-metastatic T1 rectal NEN are submucosal lift and
hot snare resection with or without cap, band assisted EMR, or endoscopic submucosal dissection. Surgical
techniques (e.g. transanal resection) can be performed as an alternative if endoscopy is not feasible.
 During colonoscopy, if a small rectal polyp appears rubbery (rather than soft) during biopsy or snare
resection, then rectal NEN should be suspected, and the area should be tattooed for endoscopic marking.
 Patients with small tumors (<1 cm) that are completely resected endoscopically or surgically with negative
margins do not require further management or follow up.
 Patients with small tumors (<1cm) with indeterminate endoscopic resection margins should undergo repeat
endoscopy to assess for residual tumor. Further endoscopic or surgical resection should be considered if
residual tissue is encountered.
 Patients with rectal carcinoids that are ≥ 1cm in size should undergo rectal MRI or EUS to evaluate for the
depth of invasion and presence of lymphadenopathy.
 T1 lesions should undergo endoscopic or transanal resection. Patients with lesions 1-≤2 cm (T1b) should
undergo surveillance by endoscopy and MRI or EUS at 6 and 12 months.
 Tumors that are >2 cm in size, and other T2-T4 tumors:
o Further testing with abdominal/Pelvic MRI, somatostatin receptor imaging and chest CT should be
considered. Patients without metastatic disease should be considered for radical resection (low
anterior resection or abdominopelvic resection).
 High-risk features favoring metastatic behavior include size > 2 cm, poorly differentiated histology, lymphatic
and vascular invasion, high tumor grade, and muscularis propria invasion on EUS.
 Prognosis
 Rectal carcinoids have a good overall prognosis, with a 5-year survival of > 80%.
 Patients with small tumors without high-risk features have a 5-year survival of ~100%.
 Patients with local lymph node spread without distant metastasis have a 5-year survival of 55-75%.
 Patients with distant metastasis have a 15-30% 5-year survival.
Carcinoid syndrome
 Occurs in < 5% of patients with neuroendocrine tumors.
 Most patients with carcinoid syndrome have small intestinal neuroendocrine neoplasms (Si-NEN) with liver
metastasis. Carcinoid syndrome occurs in 30% of Si-NEN and liver metastasis
 Occasionally, patients with neuroendocrine neoplasms and retroperitoneal spread can develop carcinoid
syndrome due to the direct release of tachykinin and serotonin in the circulation and bypassing the liver. 10
 Pathophysiology
 Systemic release of vasoactive peptides (serotonin and bradykinin) results in cutaneous flushing, diarrhea,
and wheezing secondary to bronchospasm.
 Precipitating factors include stress, surgery, anesthesia, and chemotherapy.
 Carcinoid crisis
 Severe carcinoid syndrome resulting in severe flushing, tachycardia, hypotension, or hypertension. 16
 Octreotide and IVF are recommended prior to any procedure if there is a suspicion of carcinoid syndrome
to prevent carcinoid crisis.
 Labs: 24-hour urinary 5-hydroxy indole acetic acid (5-HIAA) should be tested with strict dietary restrictions.
It has a sensitivity of ~100% and a specificity of 85–90% for detecting a carcinoid syndrome.10
 Consider further imaging to assess disease progression. Order echocardiogram in patients with confirmed
carcinoid syndrome to examine for carcinoid heart disease (see below).
 Treatment
 Carcinoid syndrome
 Octreotide 250 mg subq t.i.d. An alternative medication is lanreotide 20-30 mg IM every 4 weeks.
 In patients with refractory symptoms of diarrhea and flushing consider additional treatment:
o Telotristat is an oral tryptophan hydroxylase inhibitor (inhibits conversion of tryptophan to
5-hydroxytryptophan). It was found to improve diarrhea and lower urinary 5-hydroxyindole acetic
acid levels in patients with carcinoid syndrome refractory to somatostatin analogues. 17
● Telotristat is FDA approved for use in combination with somatostatin analog therapy to control severe
diarrhea. It is not approved for the treatment of flushing associated with carcinoid syndrome.
o Consider hepatic arterial embolization and cytoreductive surgery in patients with predominant
hepatic disease. 18
 Carcinoid crisis
 Supportive care, IV fluids. Avoid regular vasopressors (epinephrine and norepinephrine) as these can
trigger further release of vasoactive peptides from the tumor.
 Octreotide infusion.
Carcinoid Heart Disease

 Carcinoid heart disease (Hedinger Syndrome) refers to right heart right-sided heart valvular disease and
right sided heart failure. It is caused by the effect of several tumor related vasoactive substances (e.g.
serotonin, prostaglandins, histamine, bradykinin, tachykinins) on the heart.19
 Most cardiac lesions are right sided. The most common lesion is tricuspid regurgitation.
 Left sided disease can occur in patients with patent foramen ovale.
 Carcinoid heart disease is present in ~50% of patients with carcinoid syndrome.
 Patients develop symptoms of dyspnea, fatigue, lower extremity edema, elevated jugular venous pressure,
and heart murmurs (tricuspid and pulmonary regurgitation).
 Workup: 24-hour urinary 5-HIAA, echocardiogram
 Treatment: treatment of right sided heart failure (e.g. diuretics), somatostatin analogues, balloon
valvuloplasty , surgical valve replacement
Gastrointestinal stromal tumors
 General concepts
 Gastrointestinal stromal tumors (GISTs) account for 1% of all GI cancers.
 They are the most common mesenchymal tumors of the GI tract.
 They most commonly arise in the stomach (60%), followed by the small intestine (30%), duodenum (~5%),
rectum, colon and esophagus. 20
 85-90% of GISTs have a specific genetic mutation in c-Kit or PDGFRA (table 5).
Table 5: GIST mutations

Mutation Frequency
c-Kit proto-oncogene > 80%
 This is a gain of function mutation of c-Kit, which encodes a
transmembrane receptor with tyrosine kinase activity.
 Most common mutation site is exon 11, followed by exon 9
Platelet derived growth factor receptor alpha (PDGFRA) 5-7%
No mutation (wild type GIST) ~15%
 Tumor staining
 90% of GISTs are CD117 (+), 70% are CD34 (+). In contrast, leiomyomas are smooth muscle actin (+)
and desmin (+), while schwannomas are S100 (+).
 GISTs are thought to originate from the interstitial cells of Cajal.
 Pathologic types include spindle cell (70-80%), epithelial (20-30%), and mixed type (< 5%).
 Patients with neurofibromatosis type 1 (von Recklinghausen disease) develop multiple small intestinal
GISTs. These GISTs are c-Kit, PDGRA, and CD117 negative. 21, 22
 Diagnosis
 CT scan, MRI, PET scan
 EGD shows a submucosal mass with normal or ulcerated overlying mucosa (figure 4-A).
 Mucosal biopsies are usually non-diagnostic.
 EUS shows a hypoechoic mass originating from the fourth sonographic wall layer (muscularis).
 FNA shows spindle cells with eosinophilic cytoplasm that stain positive for c-Kit (figure 4-B and C).
A B C
Video 10-1
Figure 4: Gastric GIST. A: Submucosal mass in the proximal gastric body. B: FNA shows spindle cells with
elongated nuclei and eosinophilic cytoplasm. C: Positive c-Kit stain. Video 10-1 shows the endoscopy, EUS,
and pathology of this gastric GIST.
 Treatment
 Surgical resection
 General surgical concepts for GIST
o Wide surgical margins are not required. GISTs rarely spread to local lymph nodes.
Lymphadenectomy is unnecessary unless there is lymph node enlargement.
 Gastric GISTs are treated with laparoscopic wedge resection with negative margins.
o Consider surveillance of asymptomatic GISTs that are smaller than 2 cm in size.
o Refer for resection if there is interval growth or development of symptoms.
o Endoscopic full thickness resection of gastric GISTs originating from the muscularis propria is
increasingly being reported. Endoscopic submucosal dissection is used followed by tumor resection
and endoscopic closure using clips or sutures. 23-25
 Small bowel GISTs are treated with segmental resection with negative margins.
 Follow up post resection with CT scan every 3-6 months for 5 years then every 1 year.
 Imatinib (Gleevec®)
 This is a receptor tyrosine kinase inhibitor. It inhibits the growth of GISTs and induces apoptosis.
 It is FDA approved as a first line treatment of metastatic or unresectable GISTs, and as adjuvant therapy
following complete resection of GIST with high-risk features.
o High-risk features include any ruptured GIST (recurrence risk is near 100%)26, tumor size > 10 cm,
or tumor size > 5 cm with > 5 mitoses/HPF.
o The FDA approved indication includes any GIST ≥ 3 cm.
 Duration of treatment is unclear, but is at least 3 years.
o Treatment for 3 years improves overall survival compared to 1 year. 27
 Side effects of imatinib are periorbital edema, diarrhea, myalgia, musculoskeletal pain headache, and skin rash.
 The standard dose is 400 mg once daily.
o A higher dose of 400 mg twice daily is indicated in patients with disease progression on standard
dose, or in patients with exon 9 c-Kit mutation.
 Sunitinib (Sutent®)
 Inhibits multiple receptor tyrosine kinases.
 It is FDA approved for the treatment of imatinib-resistant, metastatic, or unresectable GIST. The
standard dose is 50 mg/day.
 Regorafenib (Stivarga®)
 This is a multikinase inhibitor that is FDA approved for the treatment of locally advanced, unresectable,
or metastatic GIST unresponsive to imatinib or sunitinib.
 Prognosis
 The 5-year survival following resection is 50-65% (range 40-100% depending on multiple factors).
 Gastric GISTs have better prognosis than other tumors.
 Larger tumors have a worse prognosis.
 Radiologic indicators of a favorable response to imatinib treatment:
 Decrease in tumor size by more than 10%.
 Change in CT tumor appearance to a more homogenous and hypodense tumor.28
 Unfavorable prognostic factors include exon 9 mutation, wild type GIST, and incomplete resection.
References
1.
Mehanna H, Nankivell PC, Moledina J, Travis J. Refeeding syndrome-- 15. Mani S, Modlin IM, Ballantyne G, Ahlman H, West B.
awareness, prevention and management. Head & neck Carcinoids of the rectum. J Am Coll Surg 1994;179(2):231-
oncology 2009;1:4-4. 48.
2. Singh S, Asa SL, Dey C, et al. Diagnosis and management of 16. Öberg KE. The Management of Neuroendocrine Tumours:
gastrointestinal neuroendocrine tumors: An evidence-based Current and Future Medical Therapy Options. Clinical
Canadian consensus. Cancer Treat Rev 2016;47:32-45. Oncology 2012;24(4):282-93.
3. National Comprehensive Cancer Network (NCCN) 17. Kulke MH, Horsch D, Caplin ME, et al. Telotristat Ethyl, a
Guidelines. Neuroendocrine and Adrenal tumors. Version Tryptophan Hydroxylase Inhibitor for the Treatment of
4.2018- January 07,2019 (NCCN.ORG). 2018. Carcinoid Syndrome. J Clin Oncol 2017;35(1):14-23.
4. Landau M, Wisniewski S, Davison J. Jejunoileal 18. National Comprehensive Cancer Network. Colon Cancer
Neuroendocrine Tumors Complicated by Intestinal Ischemic (Version 3.2014).
Necrosis Are Associated With Worse Overall Survival. Arch http://www.nccn.org/professionals/physician_gls/pdf/colon.
Pathol Lab Med 2016;140(5):461-6. pdf. Accessed March 7, 2014. .
5. Delle Fave G, O'Toole D, Sundin A, et al. ENETS Consensus 19. Grozinsky-Glasberg S, Grossman AB, Gross DJ. Carcinoid
Guidelines Update for Gastroduodenal Neuroendocrine Heart Disease: From Pathophysiology to Treatment -
Neoplasms. Neuroendocrinology 2016;103(2):119-24. ‘Something in the Way It Moves'. Neuroendocrinology
6. Sato Y, Hashimoto S, Mizuno K-I, Takeuchi M, Terai S. 2015;101(4):263-73.
Management of gastric and duodenal neuroendocrine tumors. 20. Lai ECH, Lau SHY, Lau WY. Current management of
World journal of gastroenterology 2016;22(30):6817-28. gastrointestinal stromal tumors – A comprehensive review.
7. Scherübl H, Jensen RT, Cadiot G, Stölzel U, Klöppel G. International Journal of Surgery 2012;10(7):334-40.
Management of early gastrointestinal neuroendocrine 21. Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal
neoplasms. 2011;3(7):133-9. stromal tumors in patients with neurofibromatosis 1: a
8. Borch K, Ahrén B, Ahlman H, et al. Gastric Carcinoids: clinicopathologic and molecular genetic study of 45 cases.
Biologic Behavior and Prognosis After Differentiated Am J Surg Pathol 2006;30(1):90-6.
Treatment in Relation to Type. Annals of Surgery 22. Takazawa Y, Sakurai S, Sakuma Y, et al. Gastrointestinal
2005;242(1):64-73. stromal tumors of neurofibromatosis type I (von
9. Evans JA, Chandrasekhara V, Chathadi KV, et al. The role of Recklinghausen's disease). Am J Surg Pathol
endoscopy in the management of premalignant and malignant 2005;29(6):755-63.
conditions of the stomach. Gastrointest Endosc 2015;82(1):1- 23. Zhou P-H, Yao L-Q, Qin X-Y, et al. Endoscopic full-
8. thickness resection without laparoscopic assistance for gastric
10. Niederle B, Pape UF, Costa F, et al. ENETS Consensus submucosal tumors originated from the muscularis propria.
Guidelines Update for Neuroendocrine Neoplasms of the Surgical Endoscopy 2011;25(9):2926-31.
Jejunum and Ileum. Neuroendocrinology 2016;103(2):125- 24. Zhang B, Huang LY, Wu CR, et al. Endoscopic full-thickness
38. resection of gastric stromal tumor arising from the muscularis
11. Qizilbash AH. Carcinoid tumors, vascular elastosis, and propria. Chin Med J (Engl) 2013;126(13):2435-9.
ischemic disease of the small intestine. Dis Colon Rectum 25. Aslanian HR, Sethi A, Bhutani MS, et al. ASGE guideline for
1977;20(7):554-60. endoscopic full-thickness resection and submucosal tunnel
12. Pape UF, Niederle B, Costa F, et al. ENETS Consensus endoscopic resection. VideoGIE 2019;4(8):343-50.
Guidelines for Neuroendocrine Neoplasms of the Appendix 26. Hohenberger P, Ronellenfitsch U, Oladeji O, et al. Pattern of
(Excluding Goblet Cell Carcinomas). Neuroendocrinology recurrence in patients with ruptured primary gastrointestinal
2016;103(2):144-52. stromal tumour. Br J Surg 2010;97(12):1854-9.
13. Ramage JK, Goretzki PE, Manfredi R, et al. Consensus 27. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three
guidelines for the management of patients with digestive years of adjuvant imatinib for operable gastrointestinal
neuroendocrine tumours: well-differentiated colon and stromal tumor: a randomized trial. JAMA
rectum tumour/carcinoma. Neuroendocrinology 2012;307(12):1265-72.
2008;87(1):31-9. 28. Choi H, Charnsangavej C, Faria SC, et al. Correlation of
14. Montminy EM, Zhou M, Maniscalco L, et al. Contributions computed tomography and positron emission tomography in
of Adenocarcinoma and Carcinoid Tumors to Early-Onset patients with metastatic gastrointestinal stromal tumor treated
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2007;25(13):1753-9.
11
317
CHAPTER
Endoscopy
Chapter 11-Endoscopy
The goal of this chapter is to broaden your endoscopic knowledge and expand your endoscopic
techniques. The GI boards commonly ask about post ERCP pancreatitis and gastric submucosal
lesions. If you practice advanced endoscopy or intend to learn it, you will find the sections on ERCP
and enteral stenting techniques helpful in introducing basic and new concepts to adopt in your
practice. Techniques such as the needle knife precut should be learnt under close supervision of a
more experienced endoscopist. Any endoscopist can learn how to use the detachable snare, which is
a useful tool safer resection of large pedunculated polyps. The main complications of bariatric
surgery are discussed at the end of this chapter. All endoscopists should familiarize themselves with
the post bariatric surgery anatomy and associated complications. Bariatric endoscopy (e.g. gastric
balloons) is not discussed in this chapter.
318 Chapter 11: Endoscopy
Contents
Chapter 11-Endoscopy
Endoscopy in pregnancy—319
Capsule endoscopy—320
Endoscopic Retrograde Cholangiopancreatography (ERCP)—321
ERCP adverse events—321
Techniques for biliary access in difficult cannulation—322
Techniques without precut papillotomy—323
Techniques with precut papillotomy—323
Sphincteroplasty for extraction of large bile duct stones—325
Cholangioscopy—326
ERCP for hilar strictures—326
Enteral stenting—328
Endoscopic Ultrasound—329
Detachable snares (endoloops)—330
Endoscopy in the bariatric surgery patient—330
References—334
Chapter 11: Endoscopy 319
Endoscopy in pregnancy
Guidelines for endoscopy in pregnant Gastrointestinal Endoscopy,

and lactating women 1 2012
 General principles
 Endoscopy in pregnancy requires a clear indication and a detailed informed consent.
 Indications for endoscopy in pregnancy 1
 Significant GI bleeding.
 Severe diarrhea.
 Biliary disease (gallstone pancreatitis, choledocholithiasis, cholangitis).
 Endoscopy for any strong suspicion of malignancy (e.g. cecal mass seen on imaging).
 Severe dysphagia.
 If possible, defer endoscopic procedures until after the first trimester.
 Fetal monitoring during endoscopy is indicated in pregnant patients after 24 weeks of gestation. All
procedures should be performed in consultation with obstetrical staff who should be available to assist in
the periprocedural management of the patient.
 It is reasonable to consult anesthesia to perform the sedation during endoscopy for all pregnant patients.
This ensures adequate safety and ideal monitoring during endoscopy, and allows the physician to focus on
the endoscopic procedure to minimize procedure time.
 Endoscopy is contraindicated in the presence of obstetric complications, such as placental abruption or eclampsia.1
 ERCP in pregnancy
 Obtain an ultrasound and/or MRCP to confirm the biliary diagnosis (e.g. stricture, stone) and the need for
therapeutic ERCP. While ERCP is generally considered safe throughout pregnancy, it is better to delay
ERCP until the second or third trimester, if possible.
 Obtain detailed informed consent.
 Patient positioning: avoid the supine position. The left lateral position is the best for the patient in the
second or third trimester.
 Minimize radiation exposure: Minimize fluoroscopy time; avoid spot films and magnification views.
 Shield the patient's lower abdomen and the fetus.
 Remember that Xray passes from underneath the patient upwards when using the fluoroscopy C-arm,
so the lead apron or shielding mat should be placed underneath the patient.
 Older stationary fluoroscopy units pass the Xray from above the patient downwards, so the shield should
be placed on top of the patient. Fetal xray exposure can be minimized with these maneuvers, but it
cannot be completely avoided due to internal scatter of Xray.
 Avoid complex biliary intervention and prolonged attempts at stone extraction. Consider placing a plastic
stent (10F or larger) to achieve biliary drainage. Repeat ERCP after delivery to clear the CBD.
 Sphincterotomy is safe during pregnancy. Place the grounding pad on the patient's back so that to minimize
electric current flow through the amniotic fluid.
 Patients with symptomatic gallstones (biliary pain, choledocholithiasis, cholecystitis, and pancreatitis)
should be strongly considered for cholecystectomy during pregnancy to decrease the rate of recurrent
symptoms and hospitalizations.2, 3
 Laparoscopic cholecystectomy is safest in the second trimester.
Capsule endoscopy
Gastrointestinal Endoscopy,
Wireless capsule endoscopy 4
2013
Clinical Practice Guidelines for the Use

Gastroenterology. 2017
of Video Capsule Endoscopy 5
 Types of capsule endoscopy

 Capsules that capture images and transmit them wirelessly to a recorder.
 Capsules that capture images and stores them inside the capsule (CapsoCam®). These capsules need to be
retrieved from the stool to download the images from the capsule.
 Indications for capsule endoscopy: Workup of potential small bowel bleeding, iron deficiency anemia after negative
EGD and colonoscopy, evaluation for suspected Crohn's disease, diagnosis and evaluation of symptoms in celiac
disease, evaluation of suspected small bowel tumors, surveillance in patients with polyposis syndrome.
 Contraindications: Patients with known or suspected GI stricture or obstruction, patients with pacemakers or
other implantable electromedical devices (this applies to wireless capsules only). Patients with swallowing
disorders. The capsule is MRI non-compatible.
 Patient preparation: Consider small bowel preparation (2 L polyethylene glycol) prior to capsule endoscopy,
as it can improve mucosal visualization. The use of simethicone to improve visibility is controversial.
 Capsule retention is defined as retention of the capsule in the GI tract for at least 2 weeks.
 Capsule retention rates in different conditions are shown in table 1.
Table 1: Capsule retention rates in different conditions
Condition Capsule retention rate
Obscure GI bleeding 1.5%
Known Crohn’s disease 5%
Suspected Crohn's disease 1.4%
Normal volunteers 0%
 A normal small bowel follow through prior to capsule endoscopy does not rule out the possibility of capsule retention.
 Other risk factors capsule retention: NSAIDS use (leads to strictures), radiation enteritis, small bowel tumors.
 In patients with suspected GI strictures and a concern for capsule retention, perform a patency study with
a patency capsule prior to capsule endoscopy. A patency capsule has a dissolvable body and a
radiofrequency chip that can be detected with a hand held scanner or seen on xray.
 The pill completely dissolves after 30 hours of ingestion; therefore, capsule retention does not occur.
 Patency is proven if any of the following occurs:
o The capsule cannot be detected in the patient’s body after 30 hours.
o The capsule is detected and imaging shows that it is in the colon.
● The patency capsule passes intact. If the body of the capsule has disintegrated, then patency is not proven.
 Capsule retention rarely leads to spontaneous perforation.
 Management of capsule retention
 Stop any NSAIDs.
 If the patient is asymptomatic and the capsule has been retained for less than 2 weeks, then
conservative management and close follow up with abdominal x-rays is reasonable.
 If capsule is retained at a Crohn’s disease stricture, consider steroids, infliximab, or other anti-TNF agents.
 Options for capsule retrieval from the small bowel include deep enteroscopy and surgery.
 If the capsule is retained behind a small bowel mass or other specific pathology, then surgery is
indicated for resection of the diseased segment and capsule retrieval.
Endoscopic Retrograde Cholangiopancreatography (ERCP)
Gastrointestinal Endoscopy,
Adverse events associated with ERCP 6
2017
International consensus recommendations for Gastrointestinal endoscopy,
difficult biliary access7 2016
Papillary cannulation and sphincterotomy
Endoscopy, 2016
technique s at ERCP 8
ERCP adverse events
 Post ERCP pancreatitis (PEP): Risk factors for PEP are shown in table 2.
Table 2: Risk factors for PEP
Patient related Procedure related*
 Prior ERCP induced pancreatitis  Biliary balloon dilation of intact biliary sphincter to <12 mm. †
 Suspected or confirmed sphincter of  Difficult cannulation requiring multiple cannulation attempts 9
Oddi dysfunction  Pancreatic endoscopic sphincterotomy
 Female gender  Multiple pancreatic contrast injections
 Absence of chronic pancreatitis  Sphincter of Oddi manometry
 Normal bilirubin
*Biliary sphincterotomy and stone extraction per se are not risk factors for PEP
Needle knife precut sphincterotomy does not independently increase the risk of PEP 9-11
†Large Biliary ballon dilation without prior sphincterotomy was not found to increase PEP rates 12.
 Several meta-analysis studies showed that pancreatic stents decrease the risk of PEP with an odds ratio of
0.22 and a number needed to treat of eight.13, 14 Pancreatic stents for this indication are 3 to 5 F in size and
3 to 8 cm in length. All pancreatic stents are similarly effective in preventing PEP. 15
 Indications for placing a pancreatic stent to prevent PEP:
 Biliary sphincterotomy for suspected or confirmed sphincter of Oddi dysfunction.
 Biliary balloon dilation of the intact biliary sphincter (dilation after prior sphincterotomy (see page 325)
does not require PD stent placement).
 After pancreatic wire placement to aid biliary access, (double guidewire technique-see page 323).
 Endoscopic ampullectomy
 Pancreatic sphincterotomy.
 Difficult cannulation (see page 322)
 Rectal indomethacin was shown in a landmark randomized controlled trial to decrease the risk of PEP in
high risk patients undergoing ERCP.16 Subsequent meta-analysis studies confirmed the effectiveness of
rectal indomethacin or diclofenac in reducing the risk of PEP.17
 Post sphincterotomy bleeding
 Risk factors: Coagulopathy or anticoagulation within less than 3 days post sphincterotomy,
cholangitis prior to ERCP, bleeding during ERCP. Bleeding risk is not increased with
aspirin or NSAIDS use, and is not related to the length of the sphincterotomy or extension
of prior sphincterotomy.
 Treatment: epinephrine injection at the apex of the sphincterotomy (video 11-1). Video 11-1
 Other techniques: sphincterotome wire coagulation, bipolar electrocoagulation, endoclips,
argon plasma coagulation, metal stent placement, and angiographic embolization.
 Other ERCP adverse events

 Perforation (duodenum, periampullary, bile duct or pancreatic duct perforations).
 Post ERCP cholangitis (especially if bile ducts are injected with contrast without adequate drainage- see
page 327)
 Post ERCP cholecystitis (especially after fully converted bile duct stent placement that blocks the cystic
duct takeoff)
 Duodenoscope related infections include bacteremia and multidrug resistant organism transmission.
 Bacterial transmission was linked to difficulty in cleaning the ERCP elevator in the distal tip
 Duodenoscopes with disposable tip and single use duodenoscope (disposable scopes) were developed
to facilitate or eliminate scope reprocessing, and many are FDA-cleared for this indication 18
Techniques for biliary access in difficult cannulation
 Selective cannulation of the bile duct or pancreatic duct is the most critical step of ERCP.
 Unsuccessful and prolonged ERCP   Risk of post ERCP pancreatitis (PEP), delays therapy.
 Avoid diagnostic ERCPs and use alternative diagnostic methods such as MRCP or EUS.
 ERCP Quality metrics published by ASGE list the following benchmarks for successful cannulation of the duct of
interest: >98% in all patients , and >90% in native papilla
 Steps of standard biliary cannulation using sphincterotome/cannula and wire +/- targeted brief contrast injection
 Achieve optimal position: scope tip below the papilla, in stable short position. The long position may need to be
used to achieve a favorable position below the ampulla.
 Careful inspection of the ampulla to identify papillary orifice and trajectory of the bile duct
 80% of cases: single opening with short common channel
 10-15%: separate opening of the pancreatic and bile ducts at the ampulla
 <5%: single opening with long common channel
 First touch at the ampulla should be at the 10-11 o’clock position, then achieve the trajectory of the bile duct
 Wire guided cannulation (WGC) has higher success (RR 1.07), lower PEP (RR 0.51), lower precut need (RR
0.75) compared to contrast guided cannulation.
 Physician controlled wire is preferable and is associated with lower PEP compared to assistant controlled wire
 Initial success rates with standard cannulation are 70-80%.
 Definition of difficult cannulation:
 European definition (ESGE): Any of the following criteria:
o > 5 attempts at cannulation (contacts with papilla while attempting cannulation)
o > 5 minutes attempting to cannulate following visualization of the papilla
o ≥ 2 pancreatic guide wire cannulation or opacification
 International Concensus definition:
o > 5 cannulation attempts
o >10 minutes attempting to cannulation
 Causes of difficult cannulation: Ampulla more distal or more proximal , small size, complete obstruction, large,
floppy, mobile papilla, periampullary diverticulum, tumor infiltration, malignancy (causes friability)
 When initial attempts at wire guided biliary cannulation fail, then alternative techniques should be used to achieve
cannulation. Avoid repeatedly trying the same failed technique, as this increases the risk of PEP.
 If the pancreatic duct is repeatedly cannulated, then this cannulation should be used to aid in biliary
cannulation, and to insert a prophylactic pancreatic stent. Techniques that could be attempted in this
situation are the double guidewire technique, transpancreatic septotomy, cannulation over a pancreatic
stent, or needle knife precut over a pancreatic stent.
 If the pancreatic duct cannot be cannulated, then needle knife precut without a pancreatic stent should be
considered if the endoscopist has adequate experience with this technique.
 A precut papillotomy is a cut at the ampulla performed before achieving deep biliary access ("pre" refers
to pre-cannulation). The precut can be performed using the sphincterotome or the needle knife.
 These techniques are described below (figure 1). A suggested approach to difficult cannulation is shown in figure 2.
Techniques without precut papillotomy

 Double guidewire technique (figure 1-A)
 Place a guidewire in the PD. Attempt cannulation alongside the guidewire. Aim the sphincterotome at 11
o'clock relative to the PD wire (1 o'clock), forming an X configuration with the wire.
 A pancreatic stent should be placed in these patients to decrease the risk of post ERCP pancreatitis. 19, 20
 Cannulation over a pancreatic stent (figure 1-C): Place a guidewire in the PD, and then place a pancreatic
stent. Reattempt cannulation over pancreatic stent.
Techniques with precut papillotomy

 Transpancreatic septotomy (also called transpancreatic precut sphincterotomy) with PD stent (figure 1- B
then C, videos 11-2, 3, 4). Once a wire is placed deeply in the PD, perform a transpancreatic sphincterotomy
in the direction of the bile duct (11 o'clock).
 The goal of this cut is to expose the biliary orifice, or to allow for easier attempts at cannulation closer
to the biliary orifice. Once the cut is performed, place a PD stent.
 Reattempt cannulation of the CBD after PD stent placement. Aim the sphincterotome at 11 o'clock
relative to the PD stent (1 o'clock), forming an X configuration with the stent
 Needle knife techniques: These techniques require familiarity and experience with the needle knife device.
They are generally not recommended for junior endoscopists. Before attempting this technique, confirm that
there is a strong indication for therapeutic ERCP.
 The goal of the needle knife is to perform a shallow mucosal cut to "un-roof" the ampulla and expose the
bile duct orifice inside the ampullary tissue. 4147202169382684
 Needle knife over pancreatic stent (figure 1-D). This is the safest approach to use (and learn) the needle
knife. The PD stent defines the anatomy and protects the pancreatic sphincter.
 Cannulate the PD, then place a PD stent.
 Cut with the needle knife in the 11 o'clock direction over the PD stent, to expose the biliary orifice.
 Needle knife without pancreatic access (videos 11-5, 6, 7). This relatively difficulty technique requires using
the needle knife directly on the ampulla without the aid of a pancreatic stent.
 Place the needle knife inside the ampullary orifice. Cut in the 11 o'clock direction.
 Spread the cut edges of the ampulla and carefully examine the exposed ampullary tissue around the precut.
 Look for the bile duct orifice, which may appear as a small nipple or a slit in the ampullary tissue.
 If the biliary orifice is not apparent, gently probe the tissue with the wire looking for the bile duct.
 Consider using the regular sphincterotome to attempt cannulation after the precut. This allows you to
change the orientation of cannulation in the direction of the bile duct (video 11-7).
 Needle knife fistulotomy is a variation of the needle knife technique in which the ampulla is punctured
above the orifice, and the bile duct is accessed directly through the ampullary mound (Figure 1-E and 1-F).
Video 11-2 Video 11-3
Video 11-4 Video 11-5
Figure 1: Techniques for biliary access in difficult cannulation.

A: Double guidewire technique; B: Transpancreatic septotomy; C:
Cannulation over pancreatic stent; D: Needle knife over pancreatic stent.
E: Needle knife fistulotomy (inset shows location of the cut on the
ampulla, above the orifice). Video 11-6 Video 11-7
F: Wire insertion following the fistulotomy
over pancreatic stent; D: Needle knife over pancreatic stent.
Figure 2: Suggested approach to difficult biliary cannulation (see text). Needle knife precut and
fistulotomy should be performed by experienced endoscopist. If the endoscopist is not experienced in needle
knife, this step should be skipped. All patients with difficult cannulation should receive rectal indomethacin to
prevent post ERCP pancreatitis.
Sphincteroplasty for extraction of large bile duct stones
International consensus guidelines for endoscopic Gastrointestinal

papillary large-balloon dilation21 endoscopy, 2016
Updated guideline on the management of

Gut, 2017
common bile duct stones22
 Biliary balloon dilation after partial endoscopic sphincterotomy (also called biliary sphincteroplasty) is an
effective technique for extraction of large biliary stones.
 It is comparable in efficacy to large sphincterotomy and mechanical lithotripsy. 23
 Avoid this technique in patients with impacted large stones and a distal bile duct stricture. 21
 Technique (video 11-8) (figure 3)
 Cannulate the bile duct and obtain an initial cholangiogram. (Fig 3-A, C)
 Assess the size of the stone. Assess the size of the bile duct above the tapered distal segment. Video 11-8
 Perform a sphincterotomy. (Fig 3-B)
 Depending on the size of the sphincterotomy and the stone, decide if you want to attempt
extraction of the stone using an extraction balloon.
 If the stone is too large, then perform ampullary dilation.
 Position a wire guided balloon dilator across the ampulla. The size of the balloon dilator should be larger
than the stone, but should not exceed the size of the bile duct proximal to the tapered distal segment.
 Inflate the balloon gradually to the required size using contrast. Under fluoroscopy, maintain dilation to 30-
60 seconds after the disappearance of the waist in the balloon. (Fig 3-D, E,F, G)
 Do not inflate the balloon alongside the stone as this can result in CBD perforation. Reattempt stone
extraction using an extraction balloon or a basket. (Fig 3-H, I)
 Other options for large biliary stone extraction are mechanical basket lithotripsy; and cholangioscopy with
electrohydraulic or laser lithotripsy
Figure 3: Ampullary
large balloon dilation
after sphincterotomy
(sphincteroplasty)
for large biliary stone
extraction (see text).
Cholangioscopy
 Cholangioscopy is the direct visualization of the bile duct. The most common platform is the digital Single Operator
Cholangioscopy. A 10 French scope is inserted through the therapeutic channel of the duodenoscope, and is
controlled using its own angulation wheels by the same endoscopist. It has a 1.2 mm channel to insert small biopsy
forceps and lithotripsy probes.
 The main applications of cholangioscopy
 Treatment of large bile duct stones using electrohydraulic lithotripsy or laser lithotripsy (Figure 4).
 Evaluation of indeterminate biliary stricture by direct visualization and biopsy
Figure 4: Cholangioscopy and electrohydraulic lithotripsy. A- The picture-in-picture display shows the
choledochoscope inserted through the ampulla, and a large stone in the bile duct. B. The electrohydraulic lithotripsy
probe (arrow) is positioned in front of the bile duct stone without directly contacting it. The bile duct is filled with
saline solution (not water). Once current is delivered to the electrodes at the tip of the probe, an electric spark is created,
and the liquid around the tip of the probe expands, creating “shockwaves” that fragment the stone. C- The fragments
are then extracted using a balloon tipped catheter in the normal fashion.
ERCP for hilar strictures
ASGE guideline on the role of endoscopy in the Gastrointestinal

management of malignant hilar obstruction 24 endoscopy, 2021
 The Bismuth-Corlette classification of perihilar tumors is shown in table 3. 25
 Principles of hilar stenting
 Obtain MRCP/CT scan to delineate the hepatobiliary anatomy and plan the ERCP.
 In patients with unresectable malignant hilar obstruction, percutaneous drainage is an alternative to ERCP. 26
 If a liver lobe appears atrophied, avoid stenting that side as it will not achieve biliary drainage, and may precipitate
cholangitis.
 The goal is to drain >50% of the non atrophic liver volume. 24
 Give periprocedural antibiotics. Minimize contrast injection.
 For Bismuth type 1 strictures, a single stent is sufficient for adequate drainage (Figure 5).
 Bismuth type 2, 3 and 4 strictures
 In patients with cholangitis, all affected liver segments should be drained
 Otherwise, one-sided stenting is generally considered adequate if 50% of the liver volume will be
drained.
o This will relieve jaundice and itching in most cases.
o Stent the other side if there is persistent or recurrent cholangitis.
 Bilateral stenting is ideal but is not always necessary. It is more technically challenging.
o Avoid prolonged manipulations and attempts to stent the contralateral hepatic duct.
o Avoid injecting contrast into ducts that you do not plan to stent. The risk of cholangitis and mortality
is higher if both hepatic lobes are opacified but only one lobe is drained. 27
● Try to drain any lobe that gets opacified during ERCP to avoid cholangitis.
● If this lobe cannot be drained, give post procedural antibiotics to prevent cholangitis.
Table 3: Bismuth classification of hilar strictures

Type Description
1 Tumor involves the common hepatic duct and
spares the bifurcation of the right and left
hepatic ducts
2 Tumor involves the common hepatic duct and
extends to the bifurcation
3a Tumor involves the common hepatic duct,
bifurcation, and extends into the tertiary
branches of the right hepatic duct
3b Tumor involves the common hepatic duct,
branches of the left hepatic duct
4 Tumor involves the common hepatic duct,

branches of both the right and left hepatic
ducts or Multicentric tumor
Figure 5: Bismuth type 1 hilar stricture (left panel).

A single metal stent was used to traverse the stricture (right panel)
Enteral stenting
Core curriculum for endoluminal stent placement 28 GIE 2020
ASGE guideline on the role of endoscopy in the management of

GIE 2021
benign and malignant gastroduodenal obstruction 29
 Esophageal stenting with self-expandable metal stents (SEMS)

 Choose the optimal stent diameter, length and covering by evaluating the indication for stenting and
stricture characteristics such as diameter and location. Size of the stent: Use smaller stent diameters for
tight strictures. In cases with wider strictures or tracheo-esophageal fistula without a stricture, choose a larger
stent diameter. In cases of tumors in the distal esophagus where stent placement across the GE junction is
planned, choose a wider stent diameter to decrease the migration rate.
 Stent covering: For tracheo-esophageal fistula, a fully covered or partially covered stent is appropriate.
● In cases of temporary metal stent placement for benign indications, covered stents are preferred as
they are more easily removed. However, partially covered and uncovered stents have been
successfully removed. Metal stents are not FDA approved for this indication.
● Endoscopic suture fixation of fully covered metal stents is recommended to prevent migration.
● For malignant strictures, use partially covered or uncovered stents to decrease migration rates.
o Length: Ideally, the stent should traverse the stricture with 2 cm of length above and below the stricture
o The stent's length on the package reflects its length when fully expanded.
o If the stricture is very tight, the stent will not fully expand and will extend
longer that its reported length. For example, a 15 cm tight stricture can be
traversed with a 12-15 cm stent with enough distance above and below
the stricture. Longer strictures may require two overlapping stents. Video 11-9 Video 11-10
 Technique of esophageal stent placement (video 11- 9,10)
 The stent should be placed under radiologic guidance with or without endoscopic guidance. Endoscopic
guidance ensures optimal placement by deploying the stent under direct visualization.
 If the stricture is too tight, then dilation prior to stent insertion should be performed.
 The ultrathin (5 mm) endoscope can be used to traverse the stricture.
 Mark the distal and proximal ends of the stricture with paper clips.
 Pass a wire across the stricture. A stiff wire is preferred. However, any wire can be used.
 Pass the stent over the wire. Deploy the stent gradually under radiologic and endoscopic guidance.
 Consider traversing the stent to examine its position, use caution to avoid dislodgement.
 Post-procedure: Prescribe PPI if the stent traverses the GE junction to treat acid reflux.
 Stent diet: Patients should be provided with specific instructions about the appropriate stent diet: food
should be soft and moist, and chewed thoroughly before swallowing.
 Duodenal stenting is indicated in cases of malignant duodenal obstruction.
 Consider a surgical bypass instead of a duodenal stent is life expectancy is more than 3 months.
 If biliary obstruction is present, try to stent the biliary system first. It the stricture cannot be
Video 11-11
traversed, consider duodenal stenting followed by biliary stenting.
 Procedure: A wire is placed through the stricture, and the stent is inserted over the wire through the scope.
Ideally, the stent should extend from the prepyloric area to the pre-ampullary area.
 Colonic stenting can be used to palliate incurable colorectal cancer, or as a bridge to surgery to allow bowel
preparation before surgery. Bevacizumab treated patients have a higher risk of perforation post colonic stenting.30
Endoscopic Ultrasound
 Gastric EUS: The appearance of gastric wall layers on endoscopic ultrasound is shown in table 4 and video 11-11.
 Gastric submucosal lesions are shown in table 5. Figure 6 shows two common EUS lesions: GIST and lipoma.
Table 4: EUS-gastric wall layers

EUS Color Gastric wall
Layer layer
First White Mucosa
Second Black
Third White Submucosa

Fourth Black Muscularis Video 11-12
propria
Fifth White Serosa
Table 5: Gastric submucosal lesions

Submucosal lesion EUS layer EUS appearance Notes
Gastrointestinal Second or Hypoechoic mass Usually located in
stromal tumor (GIST)* fourth proximal stomach
Lipoma Third Hyperechoic Soft consistency
Aberrant pancreas Third Heterogeneous echogenicity Usually
with central anechoic ductal prepyloric/antral
structure in the majority of cases location
Carcinoid* Second or Hypoechoic
third
Cysts Third Anechoic
Varices Third Anechoic with positive doppler
*GISTs and carcinoids are described in more detail in chapter 10-miscellaneous GI topics.
Figure 6: Endoscopic ultrasound.

A: GIST appears as a hypoechoic mass
originating from the 4th EUS layer
(muscularis propria).
B: Lipoma appears as a hyperechoic mass
in the submucosa.
 The differential diagnosis of large gastric folds is summarized in table 6. 31

Table 6: Differential diagnosis of thick gastric folds
Infectious Neoplastic
 Secondary syphilis , TB, CMV, H. pylori  Adenocarcinoma , Linitis plastica, Lymphoma
Infiltrative Proliferative
 Sarcoidosis, Amyloidosis,  Ménétrier's disease, Zollinger-Ellison syndrome
 Gastritis (Eosinophilic, Granulomatous, Vascular
Lymphocytic)  Portal hypertensive gastropathy, Gastric varices
Detachable snares (endoloops)
Endoscopic Removal of Colorectal Lesions-Recommendations by the US

GIE 2020
 The main indication of the endoloop is to prevent bleeding after hot snare resection of large pedunculated polyps.
 USMSTF recommends using prophylactic detachable snare or clips for pedunculated polyps with a head of
≥20mm and stalk ≥ 5 mm. 32
 It is important for endoscopists to familiarize themselves with the endoloop before attempting placement. An
incorrect technique may lead to significant complications, most importantly bleeding.
 Endoloops consist of a nylon oval loop hooked to a metal coil and covered by an outer sheath (figure 7-A).
They are manufactured by Olympus®.
 Technique for endoloop placement around large pedunculated polyps (figures 7 and 8, video 11-12)
 Consider prophylactic injection of epinephrine at the base of the polyp prior to endoloop placement. This
serves as an additional method to prevent post polypectomy bleeding.
 Have epinephrine, injection needle, and endoclips ready in case bleeding occurs.
 Place the polyp in a favorable position (6 o'clock).
 Cover the endoloop by pushing the sheath forward (figure 7-A).
 Insert the endoloop through the scope.
 Pull the sheath backward to expose the endoloop (figure 7-B).
 Use the handle to close the loop tightly around the polyp stalk (figure 7-C).
 Do not apply excess tension to avoid transection of the stalk.
 Once the endoloop is closed, it cannot be reopened. Opening the handle will deploy the endoloop.
 Deploy (release) the endoloop by opening and pushing the handle outward (figure 7-D).
 Close the resection snare on the stalk and cut at least 3-5 mm above the endoloop. This prevents the
endoloop from falling off after resection of the polyp.
Video 11-13
Figure 7:
5: Steps of endoloop placement. (see text) Figure 8: Endoloop assisted polypectomy.
A: Pedunculated duodenal polyp. B: Endoloop
placement. C: Endoloop release. D: Post resection.
This polyp was also injected with epinephrine prior
to resection
Endoscopy in the bariatric surgery patient
AGA Clinical Practice Update on Evaluation and

Management of Early Complications After AGA, 2021
Bariatric/Metabolic Surgery: Expert Review33
American Association of Clinical
Clinical Practice Guidelines for the Perioperative Endocrinologists, The Obesity
Nutritional, Metabolic, and Nonsurgical Support Society, and American Society for
of the Bariatric Surgery Patient 34 Metabolic & Bariatric Surgery,
2013
 Indications for bariatric surgery

 Class 3 obesity (BMI ≥ 40). Class 2 obesity (BMI of 35-39.9) combined with obesity related
complications.
 Classification of bariatric surgery is shown in table 7.
Table 7: Classification of bariatric surgeries

Malabsorptive Restrictive Combination
 Jejunoileal bypass  Gastric banding  Roux-en-Y Gastric bypass
 Sleeve gastrectomy (RYGP)
 Vertical banded  Fobi-Capella Gastric Bypass
gastroplasty  Biliopancreatic diversion
 Figure 8 shows the surgical anatomy in different bariatric surgeries.
 It is important to know the patient's anatomy before endoscopy, and plan any therapeutic technique.
 Consider radiologic imaging such as upper GI barium study and CT.
 The Roux-en-Y Gastric Bypass (RYGP) is the most common type of bariatric surgery.
 Pouch configurations
o Stapled gastric pouch without complete separation from the remnant stomach (figure 9-A).
● This configuration is performed using the open surgical approach and cannot be performed with
laparoscopy.
o Divided (disconnected) gastric pouch (figure 9-B).
● This configuration is performed using either the laparoscopic or the open approach. It is
associated with a lower rate of gastrogastric fistula.
 The laparoscopic divided RYGP is the preferred and most commonly performed surgery.
 The blind J limb at the proximal (G-J) anastomosis is variable in length (figure 9-A). It can be absent
if the surgeon performed an end-to-end rather than an end-to-side anastomosis (see an example of an
end-to-end G-J anastomosis in figure 9-F).
 There are no afferent and efferent limbs at proximal (G-J) anastomosis in RYGP. A long blind J limb
can be misinterpreted as an afferent or efferent limb of a Bilroth 2 surgery.
 The distal (J-J) anastomosis is usually not reachable using the regular EGD scope.
 Most complications arise at the proximal (G-J) anastomosis.
 The Fobi-Capella gastric bypass (or Fobi pouch gastric bypass) is a variation of the RYGP (figure 9-
f). In this surgery, a restrictive ring (Fobi ring) is placed around the distal part of the gastric pouch.
Figure 9: Postoperative anatomy in different bariatric surgeries.

A: Roux-en-Y gastric bypass with a stapled gastric pouch; B: Roux-en-Y gastric bypass
with a divided gastric pouch; C: Vertical banded gastroplasty; D: Sleeve gastrectomy;
E: Adjustable gastric band; F: Fobi-Capella gastric bypass (Fobi pouch gastric bypass)
 Post-operative complications
 Anastomotic leaks
 Present within two weeks of surgery.
 Sites of leakage include the proximal (G-J) anastomosis, distal (J-J) anastomosis, staple line of the
gastric pouch or the remnant stomach.
 Clinical features: abdominal pain, dyspnea, tachypnea, tachycardia, peritonitis
 Diagnosis: upper GI Gastrografin study, CT
 Surgical re-exploration is usually required.
 Other early complications: intestinal obstruction, GI bleeding, wound infection, DVT / PE.
 Marginal ulcers
 Etiology: smoking, H. pylori infection, NSAIDS, ischemia, suture reaction, gastric acidity due to a long
gastric pouch or a gastrogastric fistula.
 Treatment: PPI: Open capsule form of PPIs may reduce the time to healing in patients with marginal ulcers. 35
o Smoking cessation, stop NSAIDS, treat H. pylori, PPI, sucralfate, surgical revision.
 Band related complications include band stenosis, erosion, and slippage.
 Anastomotic strictures
 Anastomotic strictures can be safely dilated using a balloon dilator. Start at a low dilation diameter and
dilate gradually over multiple sessions (figure 10). Aim for a dilation diameter of ~12 mm. Do not over-
dilate the anastomosis to avoid recurrent weight gain.
Figure 10: Dilation of a tight gastro-jejunal stricture.

A: Predilation appearance. B: Balloon dilation using through-the-scope balloon dilator to 8 mm.
C: Post-dilation appearance. Further balloon dilations were performed to dilate the stricture to 12 mm.
 Dumping syndrome: This complication occurs most commonly after RYGB.

 Early manifestations (within 15 minutes of eating) result from the rapid emptying of large amount of
sugars and nutrients into the duodenum, leading to large fluid shifts. Patients develop abdominal
distension, pain, nausea, vomiting, diarrhea, flushing, and tachycardia.
 Late manifestations (after 2-3 hours of eating) result from the sudden hyperglycemia (due to rapid
delivery of simple sugars and carbohydrates to the small intestine) with subsequent high insulin secretion,
eventually leading to hypoglycemia.36 Patients develop symptoms of hypoglycemia such as dizziness,
confusion, sweating, and flushing.
 Treatment consists of dietary changes such as decreasing simple sugars and increasing protein, complex
carbohydrates and fiber. Patients should be instructed to separate solid and liquid intake.
 Dumping syndrome usually resolves within the first year after surgery.
 Nutritional deficiencies after bariatric surgery (refer to chapter 10)
 Common nutritional deficiencies include calcium, iron, folic acid, vitamin D, K, A, B12, zinc, copper,
selenium and thiamine (B1) deficiency.
 Thiamine deficiency should be suspected in patients with intractable nausea and vomiting associated with
neurologic manifestations (altered mental status, lower extremity weakness, numbness, gait
abnormalities, nystagmus) or heart failure symptoms (wet beriberi).
o Give thiamine before glucose, as glucose administration can worsen thiamine deficiency.
o Dose of thiamine: 500 mg IV / day for 3-5 days, then 250 mg IV/day for 3-5 days, then 100 mg
PO/day maintenance therapy.34
o Treatment should be given once the diagnosis is suspected, preferably immediately following a blood
draw for thiamine levels.
 Routine supplementation with calcium (calcium citrate 1200-1500 mg/day) and twice-daily multivitamin
plus minerals is recommended after bariatric surgery. 34
 Routine follow-up labs include CBC, lipid panel every 6-12 months, bone DEXA scan at 2 years, and
annual B12, folic acid, vitamin A levels, and 24-hr urine calcium excretion. Tests for copper, zinc, and
selenium should be performed if there are suggestive clinical features (see chapter 10).
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335
Links to the video content
Video Title Duration QR Code URL (case sensitive) QR Code
1-1 Band-assisted 1:37 http://goo.gl/DS1x8Y

EMR (1)
1-2 Band assisted http://goo.gl/rYODi8

EMR (2)
1-3 HIV idiopathic 0:30 https://youtu.be/7s6N24nn_3U

ulcer
7-1 Ulcer bleeding 1:52 http://goo.gl/SLK5O5

hemostasis
7-2 Mallory Weis http://qr.w69b.com/g/mcDQ2R

Tear endoclip Tmo
7-3 Endoscopic 2:03 http://goo.gl/iWSGJP

confirmation of
Blakemore
7-4 GAVE-APC 1:44 http://goo.gl/xK89mz
7-5 Diverticular 2:12 http://goo.gl/ONldUa

bleeding
hemostasis
7-6 Cameron 0:47 http://goo.gl/1YB15M
erosions
8-1 C. Difficile 0:58 http://goo.gl/LY0YKc

Colitis
8-2 Diversion colitis 0:44 http://goo.gl/G3Trjd
8-3 Familial 0:43 https://youtu.be/BjJZuSBdt_k

adenomatous
polyposis
8-4 Right colon 0.54 http://goo.gl/t4Akf4
retroflexion
8-5 Endocuff 1:13 http://qr.w69b.com/g/ujzNa4iF

Vision® G
9-1 Crohn's colitis 1:10 http://goo.gl/FWzhZO
9-2 Small Bowel 1:59 https://youtu.be/uuX-noTI3iI

Crohn's Disease
Capsule
Endoscopy
336 Videos
QR QR
Video Title Duration URL (case sensitive)
Code Code
9-3 Pouchoscopy 1:57 https://youtu.be/ZnmCLX3fY1E
9-4 Anastomotic 3:23 https://youtu.be/TDZZ0DflE

Stricture dilation QU
10-1 Gastric GIST 1:37 http://goo.gl/ZzA5G8
11-1 Post 1:29 http://goo.gl/DggKQo

sphincterotomy
bleeding
11-2 Transpancreatic 3:21 http://goo.gl/oRfOaz
septotomy 1
11-3 Transpancreatic 2:02 http://goo.gl/BBtQAO

septotomy 2
11-4 Transpancreatic 3:43 http://goo.gl/AHgxOI

septotomy 3
11-5 Needle knife 2:40 http://goo.gl/ZpmLQf

cannulation 1
11-6 Needle knife 3:02 http://goo.gl/QOsMYO

cannulation 2
11-7 Needle knife 3:38 http://goo.gl/M4boKU

cannulation 3
11-8 Ampullary 2:37 http://goo.gl/peDT5U

balloon dilation
11-9 Esophageal Stent 3:35 http://goo.gl/t5e2w2

1
11-10 Esophageal Stent 3:32 http://goo.gl/JNrgEU

2
11-11 Duodenal stent https://youtu.be/t1zcFVaVS0

8
11-12 EUS gastric wall 0:21 http://goo.gl/cNwhMI
layers
11-13 Endoloop 3:35 http://goo.gl/XwVuui

assisted
polypectomy
All videos are available on the book’s YouTube Channel:
337
Index
Artificial intelligence in polyp detection, Biotin, 305

A 245 BISAP score, 149
Ascites, 110 Bismuth classification of hilar
Aberrant pancreas, 329 Atlanta classification of peripancreatic strictures, 327
Abnormal pancreaticobiliary junction, fluid collections, 151 Boerhaave syndrome, 175
135 Attenuated FAP, 227, 229 Bouveret's syndrome, 137
Acetaminophen toxicity, 100 Autoimmune Hepatitis, 101 BRAF mutation, 235
Achalasia Autoimmune pancreatitis, 160 Brainerd diarrhea, 218
botulinum toxin, 23 subtypes, 161 breath testing-SIBO, 58
classification, 21 treatment, 160 Budd-Chiari Syndrome, 89
Heller myotomy, 23 Avatrombopag, 112 Budesonide, 102, 218, 262, 268
Per Oral Endoscopic Myotomy Buspirone, 38
(POEM), 24
pneumatic dilation, 23 B
Acid exposure time, 7 C
B1 (Thiamine), 303
Acotiamide, 38
B12, 303 Cameron erosions, 187
Acrodermatitis enteropathica, 305
Absorption, 304 Campylobacter, 199
Acute Alcoholic hepatitis:, 93
B2 (Riboflavin), 303 Candidal esophagitis, 27
Acute colonic pseudo-obstruction
B3 (Niacin), 303 Cannabinoid hyperemesis syndrome,
colonoscopic decompression, 224
B5 (Pantothenic Acid), 303 35
Neostigmine, 224
B6 (Pyridoxine), 304 Capsule endoscopy, 188, 320
Acute fatty liver of pregnancy, 71
Bacillus cereus, 202 Carbohydrate malabsorption, 57
Acute fatty liver of pregnancy (AFLP).,
Backwash ileitis, 256 D-xylose test, 57
72
Balloon expulsion testing, 213 Hydrogen breath test, 57
Acute hepatitis B infection, 79
Balloon-occluded anterograde Stool osmotic gap, 57
Acute liver failure, 108
transvenous obliteration (BATO), Carcinoid, 306
Acute pancreatitis, 149
183 Carcinoid heart disease, 306, 314
fluid collections in, 151
Balloon-occluded retrograde Carcinoids
Ranson's criteria, 150
transvenous obliteration (BRTO), Carcinoid syndrome, 313
Acute variceal bleeding, 180
182 Caroli disease, 136
Balloon tamponade, 180
Balsalazide, 261 Caustic ingestion, 17
Esophageal stent, 181
Baltimore criteria for veno-occlusive Celiac crisis, 61
Management, 180
disease, 92 Celiac disease, 60
TIPS, 181
Barrett's Esophagus, 9 Clinical manifestations, 60
Adalimumab, 270
Definition, 9 Conditions associated with, 61
Adenomyomatosis, gallbladder, 139
Endoscopic mucosal resection, 12 Dermatitis herpetiformis, 61
Adjustable gastric band, 332
Endosopic exam, 10 Diagnosis, 61
Aflatoxin, 99
management, 10 Endoscopic findings, 61
Alcoholic liver disease, 93
Photodynamic therapy, 12 Non-responsive celiac disease, 63
Alosetron, 215
Radiofrequency ablation, 11 Refractory celiac disease, 63
Alpha one antitrypsin deficiency, 77
Risk of malignancy, 9 Treatment, 62
Ambulatory pH monitoring, 4
Bezafibrate, 107 Certolizumab, 270
Aminosalicylates, 261
Bezlotoxumab, 207 ch1, 3
Anastomotic leaks, 333
Bile acid malabsorption tests, 210 Chagas' disease, 21
Anastomotic strictures, 333
Bile duct anatomy, 135 Cholangiocarcinoma, 139
Angiography, 189
Bile leak CA 19.9, 139
Angiosarcoma of the liver, 99
following cholecystectomy, 137 Diagnosis, 139
Ankylosing spondylitis, 283
following liver transplant, 142 Treatment, 140
Annular Pancreas, 147
Biliary complications after liver Cholangioscopy, 326
Anorectal manometry, 212
transplantation, 140 Choledochal cysts, 136
Aorto-enteric fistula, 175
Bile leaks, 142 Choledocholithiasis, 138
APACHE II score, 149
Biliary strictures, 141 Cholerheic diarrhea, 55
Artificial intelligence, 245
Biologic therapy, 270, 273, 275 Cholestatic hepatitis, 99
Biosimilars, 270, 272 Cholesterolosis-gallbladder, 139
338
Chromium, 305 Portopulmonary hypertension, 115 Endoscopic Functional Luminal

Chromoendoscopy, 280 Congestive hepatopathy, 92 Imaging Probe (EndoFLIP), 22
Chromosomal instability pathway, 235 Constipation, 211 Endoscopic Ultrasound, 329
Chronic constipation, 211 Copper, 305 Gastric EUS, 329
anorectal manometry, 212 Correa precancerous cascade, 46 Endoscopy in pregnancy, 319
Functional defecatory dysfunction, Cowden Syndrome, 230 Endoscopy in the bariatric surgery
212 CpG Island hypermethylation patient, 331
opioid induced, 213 Phenotype (CIMP), 236 Anatomy, 332
radiopaque marker study, 213 CREST syndrome, 105 Nutritional deficiencies, 333
Secretagogues, 213 Crohn's disease. See Inflammatory Enhanced liver fibrosis (ELFTM) test, 96
slow transit constipation, 212 bowel disease Entamoeba histolytica, 200
wireless motility capsule, 213 Cronkhite-Canada Syndrome, 232 Enterohepatic circulation, 55
Chronic diarrhea, 209 CT Enterography, 189 Eosinophilic Esophagitis, 13
Etiology, 209 CT colonography, 245 Clinical manifestations, 13
Treatment, 211 Cuffitis, 285 Diagnostic criteria, 13
Workup, 209 Cyclic Vomiting Syndrome, 35 endoscopic findings, 13
Chronic Pancreatitis Cyclosporin, 125 Treatment, 14
Complications, 157 CytospongeTM, 10 ERCP
Diagnosis, 154 Advanced cannulation techniques,
etiology, 153 322
D
Genetic mutations, 153 ERCP in pregnancy, 319
treatment, 154 Deep enteroscopy, 188 Extraction of large CBD stones, 325
chronic pancreatitis -associated Defecatory disorders, 212 Pancreatic stent, 321
osteopathy, 159 Defecography, 213 Post sphincterotomy bleeding, 321,
Cirrhosis, 110 Defibrotide, 92 322
Clostridioides difficile infection, 204 Dermatitis herpetiformis, 61 Erythema nodosum, 283
Clostridium botulinum, 203 Desmoid tumors, 229 Escherichia coli, 196
Clostridium difficile infection Diaphragmatic breathing, 36 Diffusely adherent E. coli, 197
Diagnosis, 204 Diarrhea after ileal resection, 55 Enteroaggregative E. coli, 197
Fecal microbiota transplantation, Diversion colitis, 219 Enterohemorrhagic E. coli, 196
207 Domperidone, 34 Enteroinvasive E. coli, 196
recurrent Clostridium difficile DOTATATE scan, 168 Enteropathogenic E. coli, 196
infection, 207 Double balloon enteroscopy, 188 Enterotoxigenic E. coli, 196
stool tests, 205 Double bubble sign, 147 Esophageal stenting, 328
Clostridium perfringens, 202 Drug Induced Liver Injury, 98 Esophageal stents for variceal
CMV esophagitis, 27 Acetaminophen toxicity, 100 bleeding, 181
Cobalamine, 303 Isoniazid hepatotoxicity, 98 Esophageal variceal bleeding, 180
Collagenous colitis, 217 Dumping syndrome, 333 Esophagitis, 27
Colonic ischemia, 221 Duodenal stenting, 328 Candida, 27
Vascular supply of the colon, 221 Dyspepsia, 36 CMV, 27
Colonic polyps, 225 Alarm features, 37 Eosinophilic, 13
adenomatous polyps, 225 Functional dyspepsia, 36 HSV, 27
Juvenile polyps, 226 Functional dyspepsia treatment idiopathic esophageal ulcers, 27
serrated polyps, 225 trial (FDTT), 38 EUS-guided gastroenterostomy, 167
Colonic transit testing, 213 Rome IV criteria for functional Extracorporeal Liver Assist Device
Colorectal cancer, 235 dyspepsia, 36 (ELAD®), 109
Colon cancer screening, 240 Subtypes, 36
Genetic pathways, 235
F
Polyp surveillance, 245
staging, 237 E
Familial adenomatous polyposis, 228
treatment, 238 Attenuated FAP, 229
Echinococcus granulosus, 118
Complications of cirrhosis and portal MutYH (MYH) associated polyposis,
Electrohydraulic lithotripsy, 326
hypertension, 110 229
Eluxadoline, 215
Ascites, 110 Spigelman staging of duodenal
Endocuff Vision ®, 244
Hepatopulmonary syndrome, 116 polyposis, 229
EndoFLIP, 22
Hepatorenal syndrome, 115 Familial colorectal cancer type X, 233
339
Fat malabsorption, 55 Refractory GERD and functional Occupational exposure to hepatitis

Fecal calprotectin, 210, 255, 289 heartburn, 6 C, 87
Fenofibrate, 107 Surgical therapy, 5 Treatment, 86
Feraheme, 257 Gastrointestinal stromal tumors, 314 Hepatitis D, 88
Ferric gluconate (Ferrlecit ®)., 257 Gastroparesis, 33 Hepatocellular adenoma, 117
Ferric maltol (Accrufer®), 257 Gastric Electrical Stimulation, 34 Hepatocellular carcinoma, 119
Fibroscan®, 96 Medication induced gastroparesis, Diagnosis, 121
Fidaxomicin, 206 33 Ethanol injection, 123
Fobi-Capella gastric bypass, 332 Giardia lamblia, 200 Fibrolamellar HCC, 124
Focal nodular hyperplasia, 118 Gilbert syndrome, 69 Hypoglycemia in HCC, 120
Folate, 303 Glucagonoma, 169 Lenvatinib, 123
Food poisoning, 202 gluten disorders, 63 Microwave ablation, 123
Functional biliary sphincter disorder, Golimumab, 270 Nivolumab, 123
138 Granulomatous hepatitis, 99 Radiofrequency ablation, 123
Guaiac-based FOBT, 241 Regorafenib, 123
Sorafenib, 123
G
Staging, 121
H
Gallbladder cancer, 139 Surveillance, 120
Gallstones, 137 Hamartomatous polyposis syndromes, Transarterial chemoembolization
Prophylactic cholecystectomy, 137 229 (TACE), 123
Gardener syndrome, 227 Bannayan-Riley-Ruvalcaba Treatment, 122
Gastric adenocarcinoma, 48 syndrome, 231 Hepatopulmonary syndrome, 116
Histologic Subtypes, 48 Cowden Syndrome, 230 Hepatorenal syndrome, 115
Gastric Adenocarcinoma and Proximal Juvenile polyposis syndrome, 230 Hepatosplenic T cell lymphoma, 264
Polyposis of the Stomach (GAPPS, Peutz-Jeghers syndrome, 229 Hepatotoxicity. See Drug induced liver
227 Hedinger Syndrome, 306, 314 injury
Gastric Adenocarcinoma and Proximal Helicobacter pylori Hereditary diffuse gastric cancer, 49
Polyposis of the Stomach (GAPPS), Indications for testing, 39 Hereditary nonpolyposis colorectal
45 Testing modalities, 40 cancer, 232
Gastric Antral Vascular Ectasia-GAVE, Treatment, 42 Hirschsprung disease, 212
185 HELLP syndrome, 71, 72 HSV esophagitis, 27
Gastric intestinal metaplasia, 46 Hemangioma, 117 HSV hepatitis, 70
Gastric lymphoma, 50 Hemobilia, 187 Hydatid cysts, 118
Lugano staging, 50 Hemochromatosis, 72 Hypergastrinemia, 43
Gastric per-oral endoscopic myotomy Hemostatic powder, 177 gastrinoma triangle, 44
(G-POEM), 34 hemosuccus pancreaticus, 158 General approach to, 43
Gastric polyps, 45 Hemosuccus pancreaticus, 187 Secretin stimulation test, 44
Fundic Gland polyp, 45 Hepatic adenomatosis, 117 Hyperplastic polyps, 225
gastric adenomas, 45 Hepatic Encephalopathy Hy's Law-Drug induced liver injury, 98
Hyperplastic polyps, 45 Lactulose, 114
Gastric Stress ulcers, 179 Management, 113 I
Gastric varices, 182 Rifaximin, 114
Gastrinoma, 169 Hepatitis B, 79 IBD clinical Evaluation Template, 258
Gastroesophageal Reflux Disease, 3 Antiviral resistance, 82 Iberogast ®, 38
Clinical manifestations, 3 HBV prophylaxis in patients Ileal Pouch Anal Anastomosis, 284
Endoscopic findings, 3 receiving immunosuppressants, Imatinib, 315
Etiology, 3 82, 84 Immune checkpoint inhibition-
Extraesophageal GERD, 8 medications, 81 induced colitis, 220
LINX® Reflux Management System, Occupational exposure to hepatitis Immune checkpoint inhibitors
6 B, 83 hepatitis, 101
Los Angeles classification, 3 Pregnancy and hepatitis B, 83 inflammatory bowel disease
Manometry, 4 Stages of infection, 80 Chromoendoscopy, 280
Medical therapy, 5 Treatment, 80 Clinical trials of biologics in Crohn’s
Non Erosive Reflux Disease, 3 Hepatitis C, 86 disease, 276
pH monitoring, 4 HCV sexual transmission, 87 pregnancy and lactation, 292
Inflammatory bowel disease
340
Biologic therapy, 269, 270 Keshan disease, 305 Mayo Postoperative Mortality Risk
Biologic therapy for Crohn’s Killian's triangle, 15 Score, 113
disease, 273 King's College criteria for liver Meckel's diverticulum
Biosimilars, 270, 272 transplantation, 110 GI bleeding, 187
clinical evaluation template, 258 nuclear scan, 189
clinical manifestations, 255 Melanosis Coli, 223
L
Extra-intestinal manifestations, 283 Ménétrier's disease, 41
health maintenance, 258 Larazotide, 62 Mesalamine, 261
Ileal Pouch Anal Anastomosis, 284 Laryngopharyngeal reflux, 8 Methotrexate in Crohn's disease, 269
Iron deficiency anemia, 257 Latiglutenase, 62 methynaltrexone, 214
Malignancy in IBD, 279 Lenvatinib, 123 Metoclopramide, 33
Post-operative recurrence of Lesar-Trelat sign Microsatellite instability, 232
Crohn’s disease, 286, 288 Gastric cancer, 48 Microscopic colitis, 217
serum markers, 256 Hepatocellular carcinoma, 120 histology, 217
Surgical therapy for Crohn’s Lille score, 93 Microvesicular steatosis, 99
disease, 286 Linaclotide, 214, 216 Milan criteria, 122
Therapeutic drug monitoring, 275 LINX® Reflux Management System, 6 Mineral deficiencies, 305
Therapeutic drug monitoring, 264, Lipoma, 329 Mirizzi's syndrome, 137
274 Listeria monocytogenes, 203 Mirtazapine, 38
Thiopurine metabolism, 262 Liver disease in pregnancy, 70 Molecular Absorbent and
Treatment of acute severe Acute Fatty Liver of Pregnancy, 71 Recirculating System (MARS), 109
ulcerative colitis, 266 HELLP syndrome, 71 Motility disorders of the esophagus,
Treatment of Crohn’s disease, 268 Intrahepatic cholestasis of 19
Treatment of ulcerative colitis, 260 pregnancy, 71 distal esophageal spasm, 25
vaccinations, 258 Pre-eclampsia, 72 Functional esophagogastric
infliximab, 220 Liver Reporting & Data System (LI- junction outflow obstruction, 26
Infliximab, 270 RADS), 121 Nutcracker esophagus, 25
Injectafer, 257 Liver transplantation, 124 Scleroderma, 26
Insulinoma, 168 Drug-drug interactions, 126 MRI defecography, 213
Interval CRC cancer, 243 Immunosuppressive medications, MR-Proton density fat fraction for
Intraductal papillary mucinous 125 steatosis (MR -PDFF), 96
neoplasm, 163 Long-chain 3-hydroxyacyl-CoA Mucinous cystic neoplasm, 163
Intrahepatic cholangiocarcinoma, 124 dehydrogenase and AFLP, 71 Muir Torre Syndrome, 233
Intrahepatic cholestasis of pregnancy, Lower GI bleeding, 186 Multiple Endocrine Neoplasia (MEN)
71 Management, 186 type 1, 170
Intrahepatic cholestasis of pregnancy Lubiprostone, 214, 216 MutYH associated polyposis, 227, 229
(ICP), 71 Lumen apposing metal stent (LAMS), Mycophenolate mofetil, 125
Intraoperative enteroscopy, 189 151
Iron deficiency, 305 Lumen apposing metal stent (LAMS), N
Iron overload syndromes, 72 167
Iron Sucrose, 257 Lusutrombopag, 112 N-acetyl cysteine, 100
Irritable bowel syndrome, 214 Lymphocytic colitis, 217 NAFLD fibrosis score, 96
classification, 215 Lynch syndrome. See Hereditary NAFLD Fibrosis-4 score, 96
diagnostic criteria, 215 nonpolyposis colorectal cancer naldemedine, 214
FODMAP diet, 216 Lynch Syndrome, 232 naloxegol, 214
Ischemic colitis, 221 Natalizumab, 270
Isoniazid induced hepatotoxicity, 98 Necrolytic migratory erythema, 169
M
Neuroendocrine Neoplasms, 306
J Macrovesicular steatosis, 99 Appendiceal, 311
Maddrey's discriminant function, 93 Colonic, 311
Juvenile polyps, 226 Magnetic resonance elastography, 96 Duodenal, 310
Juvenile polyposis syndrome, 230 Mallory bodies, 93 Gastric, 308
Manganese, 305 Rectal, 312
Marginal ulcers, 333 Small Intestine, 310
K
Mayo endoscopic scoring system for Nivolumab, 123
Kashin-Beck disease, 305 UC, 256 nodular regenerative hyperplasia, 269
341
Nodular regenerative hyperplasia, 119 Portal vein thrombosis, 90, 152 Seattle criteria for veno-occlusive
Non alcoholic fatty liver disease, 95 Portopulmonary hypertension, 115 disease, 92
Liver biopsy in NASH, 96 Post ERCP cholangitis, 322 Secretin stimulation test
Vitamin E, 97 Post ERCP pancreatitis in hypergastrinemia, 44
Non celiac gluten sensitivity, 63 Pancreatic stent, 321 Segmental Colitis Associated with
Norovirus, 199 post operative jaundice, 69 Diverticulosis, 221
Nutcracker esophagus, 25 Post-colonoscopy Colorectal Cancer, SeHCAT test, 210
243 Selenium, 305
Pouchitis, 285 Septin 9, 242
O
Prague classification of BE, 10 Serous cystadenoma, 164
Obeticholic acid, 106 Pre-eclampsia, 72 Serrated neoplasia pathway, 235
Obscure GI bleeding, 187 Primary Biliary Cirrhosis, 105 Serrated polyposis syndrome, 231
Capsule endoscopy, 188 Primary sclerosing cholangitis, 103 serum ascites albumin gradient, 110
Etiology, 187 progressive multifocal Sessile serrated lesion, 225
Missed lesions on EGD and leukoencephalopathy (PML), 271 Shigella, 198
colonoscopy, 187 Protein losing enteropathy, 56 Short Bowel Syndrome, 59
pharmacologic provocation, 189 Etiology, 56 D-lactic acidosis, 59
small bowel endoscopy, 188 Technetium-99m-labeled albumin Single strip sign, 222
small bowel imaging, 188 scintigraphy, 56 Sinusoidal obstruction syndrome, 92
OctreoScan, 308 Prucalopride, 213 Sirolimus, 125
Ogilvie's syndrome, 224 Pseudoachalasia, 21 Sleeve gastrectomy, 332
Olsalazine, 261 pseudocyst, 157 Small bowel bleeding, 187
Opioid induced constipation, 213 Pseudomembranous colitis, 205 Small intestinal lymphoma, 65
Orthotopic liver transplantation, 124 Pseudopolyps, 281 B cell lymphomas, 65
Ozanimod, 271 Pyoderma gangrenosum, 283 Enteropathy-associated T-cell
Pyogenic liver abscess, 88 lymphoma, 65
Mantle cell lymphoma, 65
P Post-Transplant
R
Lymphoproliferative Disease, 66
Pancreas divisum, 147
Radiation Associated Vascular Ectasia T cell lymphoma, 65
Pancreatic cysts, 162
(RAVE), 219 Small intestinal tumors, 64
Pancreatic neuroendocrine
Radiation proctitis, 219 Solid pseudopapillary neoplasm, 164
neoplasms, 168
Radioembolization, 123 Somatostatin receptor imaging, 308
Pancreaticobiliary maljunction, 135
Radiofrequency ablation Somatostatinoma, 169
Paris classification of colonic
Barrett's esophagus, 11 Somatropin, 60
neoplasia, 226
Radionuclide scan, 188 SONIC trial, 277
Peliosis hepatis, 99
rectoanal inhibitory reflex, 212 Sorafenib, 123
Pelvic floor dysfunction, 212
Refeeding syndrome, 304 Sphincter of Oddi dysfunction, 138
Penicillamine, 76
Regorafenib, 123 Spigelman staging of duodenal
Pentoxifylline, 93
Regorafenib, 315 polyposis in FAP, 229
pepsinogen, 47
Rifabutin, 41 Spontaneous bacterial peritonitis
Peptic ulcer disease bleeding, 175
Rifamycin, 202 (SBP), 112
Forrest classification of PUD, 177
Rifaximin, 202, 207, 215 Spontaneous bacterial pleuritis, 112
Management, 175
Right colon retroflexion, 244 Staphylococcus aureus food
Peptide YY, 55
Rituximab, 160 poisoning, 202
pH monitoring, 4
Rotavirus, 199 stealth lesion, 118
Pityriasis rotunda, 120
Roux-en-Y gastric bypass, 332 Stool DNA testing, 242
Plecanatide, 214, 216
Rumack-Matthew nomogram, 100 stress-related mucosal injury, 179
Polymerase proofreading-associated
Rutgeerts endoscopic recurrence String sign, 162
polyposis (PPAP), 227
score in Crohn's disease, 289 Sulfasalazine, 261
Polyp surveillance, 245
Sunitinib, 315
polyposis syndromes
Surgical risk assessment in cirrhosis,
Familial adenomatous polyposis, S 113
228
Porcelain gallbladder, 137 Sacral nerve stimulation, 214
Portal biliopathy, 91 Salmonella, 197
Portal hypertensive gastropathy, 185
342
Turcot syndrome, 227 Vitamin A, 304

T
Tylosis, 16 Vitamin C, 303
Tacrolimus, 125 Vitamin D, 304
Talicia®, 41 Vitamin deficiencies, 303
U
Tardive dyskinesia, 34 Vitamin E, 304
Teduglutide, 60 UC-related pan-enteritis,, 256 Vitamin K, 304
Tegaserod, 216 UGI bleeding in patients with Von Hippel–Lindau disease, 170
Telotristat, 313 cirrhosis, 179 Vonoprazan, 5
Tenapanor, 216 Upper GI bleeding, 175
Therapeutic drug monitoring, 274 Ursodiol, 106 W
Therapeutic drug monitoring, 264 Ustekinumab, 270
Therapeutic drug monitoring, 274 Walled off pancreatic necrosis, 151
thioguanine, 269 wheat allergy, 63
V
Thiopurines metabolites testing, 264 Whipple disease, 64
Timed barium swallow, 21 vaccinations in IBD, 258 Wide-area transepithelial sampling
Tofacitinib, 271 Vanishing bile duct syndrome, 99 (WATS-3D), 10
Traditional serrated adenoma, 226 vedolizumab, 220 Wilson disease, 75
Transient Elastography, 96 Vedolizumab, 270 Wireless motility capsule, 213
Traveler's diarrhea, 201 Venofer, 257
Trefoil factor 3, 10 Vertical banded gastroplasty, 332 Y
Trichuris Trichiura, 201 Vibrio cholerae, 195
Trientine, 76 Vibrio parahaemolyticus, 195 Yersinia enterocolitica, 198
Tropheryma whipplei, 64 Vibrio vulnificus, 195
Tumors of the esophagus, 16 VIPoma, 169
adenocarcinoma, 16 Z
Viral Hepatitis, 78
squamous cell carcinoma, 16 Hepatitis B, 79 Zinc, 305
staging, 16 Hepatitis C, 86
Treatment, 16 Hepatitis D, 88
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Gastroenterology

Emad Qayed, M.D., M.P.H.

Third Edition Copyright © 2022 Emad Qayed Update 3.00 (1/2022)

All rights reserved.

Previous edition Copyright © 2014, 2019, Emad Qayed

Emad Qayed, MD, MPH, FACG, AGAF

To my wife Yara and my children Bassem, Zaina, and Mazen

To all my GI trainees and colleagues

For kindle users:

Alexa GI trivia Skill

Just say” Alexa, open gastroenterology clinical focus” (USA only)

Chapter 1- Esophagus ....................................... 1 Small Intestinal Bacterial Overgrowth..........................57

Gastric adenocarcinoma .............................................. 48 Hepatitis C .....................................................................86

Hereditary diffuse gastric cancer ................................. 49 Treatment of hepatitis C ..........................................86

Gastric lymphoma........................................................ 50 Occupational exposure to hepatitis C .....................87

References .................................................................... 51 HCV sexual transmission..........................................87

Chapter 3-Small intestine ............................... 51 Hepatitis D.....................................................................88

Malabsorption.............................................................. 55 Hepatitis E .....................................................................88

Diarrhea after ileal resection ................................... 55 Pyogenic liver abscess ..................................................88

Fat malabsorption.................................................... 55 Vascular diseases of the liver........................................89

Protein losing enteropathy...................................... 56 Budd-Chiari Syndrome.............................................89

Carbohydrate malabsorption.................................. 57 Portal vein thrombosis.............................................90

UGI bleeding in patients with cirrhosis...................... 179 Colonic polyps.............................................................225

Acute variceal bleeding .............................................. 180 Paris classification of colonic neoplasia......................226

Primary prophylaxis of esophageal variceal bleeding183 Gastrointestinal polyposis syndromes .......................226

Secondary prophylaxis of esophageal variceal bleeding Adenomatous polyposis syndromes .........................227

Traveler's diarrhea ................................................. 201 .....................................................................................232

Food poisoning ...................................................... 202 Colorectal cancer ........................................................235

Chronic diarrhea......................................................... 209 Colon cancer screening ..............................................240

Chronic constipation .................................................. 211 Stool testing............................................................241

Irritable bowel syndrome........................................... 214 Other tests..............................................................242

Non-IBD colitides........................................................ 217 Colonoscopy...........................................................242

Microscopic colitis.................................................. 217 Flexible sigmoidoscopy ..........................................245

Diversion colitis ...................................................... 219 CT colonography ....................................................245

Chronic radiation proctitis ..................................... 219 Polyp surveillance .......................................................245

Immune checkpoint inhibition-induced colitis References ..................................................................247

IBD and fertility...................................................... 292 Endoscopic Ultrasound.............................................. 329

Gastroesophageal Reflux Disease (GERD)

ACG Clinical Guideline for the Diagnosis and Management Am J Gastroenterol,

Modern diagnosis of GERD: the Lyon Consensus 2 Gut, 2018

AGA Clinical Practice Update on Functional Heartburn:

o LA class A: one or more mucosal breaks < 5 mm in length.

Table 2: Symptom index and symptom sensitivity index8

Threshold Abnormal if > 50% Abnormal if >10%

o Laparoscopic Magnetic Sphincter Augmentation (MSA). The LINX® Reflux Management

ASGE guideline on screening and surveillance of Barrett’s Gastrointestinal

AGA Clinical Practice Update on Endoscopic Treatment of Barrett's Gastroenterology,

 Endoscopic examination in BE:

 If BE or dysplasia is present: repeat EGD and ablation.

Guidelines on eosinophilic esophagitis: evidence-based United European

ACG Clinical Guideline: Evidenced Based Approach to

 Definition: cricopharyngeal bar (CPB) describes the radiologic abnormality that

Tumors of the esophagus

Table 4: TNM staging of esophageal cancer

 Treatment for esophageal cancer (squamous cell carcinoma and adenocarcinoma)

Table 5: Types of caustic ingestions

Motility disorders of the esophagus

ACG Clinical Guideline: Diagnosis and

ASGE guideline on the management of