Gastroenterology Clinical Focus: High Yield GI and Hepatology Review for Boards and Practice [1st ed.] 9781492209959

Table of contents :
List of abbreviations......Page 2
Chapter 1- Esophagus......Page 9
Chapter 2- Stomach......Page 40
Chapter 3-Small intestine......Page 70
Chapter 4-Liver......Page 88
Chapter 5- Biliary tract......Page 176
Chapter 6- Pancreas......Page 190
Chapter 7 - GI bleeding......Page 223
Chapter 8- Large intestine......Page 246
Chapter 9- Inflammatory bowel disease......Page 321
Chapter 10- Miscellaneous GI topics......Page 373
Chapter 11-Endoscopy......Page 394
Links to the video content......Page 424

Citation preview

List of abbreviations A1-AT

Alpha-1 Antitrypsin

AAA

Anti-Actin Antibodies

AASLD

American Association for the Study of Liver Disease

ACG

American College of Gastroenterology

ADA

Adalimumab

ADR

Adenoma Detection Rate

AFLP

Acute Fatty Liver of Pregnancy

AGA

American Gastroenterology Association

ALKP

Alkaline Phosphatase

ALT

Alanine Aminotransferase

AMA

Antimitochondrial antibodies

ANA

Anti Nuclear Antibodies

ANCA

Anti Cytoplasmic Cell Antibodies

Anti-LC1

Anti-Liver Cytosol 1

Anti-LKM

Anti-Liver-Kidney Microsomal-1

Anti-SLA/LP APC ASMA AST AVM

Anti-Soluble Liver/Liver Pancreas Antigen Argon Plasma Coagulation Anti Smooth Muscle Antibody

Aspartate Aminotransferase Arterio Venous Malformation

AZP

Azathioprine

BCG

Bacille Calmette-Guérin

BCS

Budd-Chiari Syndrome

BE B.i.d. BMI

Barrett's Esophagus Twice daily Body Mass Index

BPM BT BUN C4 CA 19-9

Beats Per Minute Botulinum Toxin Blood Urea Nitrogen Complement Factor 4 Carbohydrate Antigen 19-9

CBC

Complete Blood Count

CBD

Common Bile Duct

CCK

Cholecystokinin

CCK-RF CDI CE CEA CFTR CNS CP

Cholecystokinin releasing factor Clostridium Difficile Infection Capsule Endoscopy Carcinoembryonic Antigen Cystic fibrosis Transmembrane Conductance Regulator Central Nervous System Chronic Pancreatitis

CPB

Cricopharyngeal Bar

CRC

Colorectal Cancer

CRP

C-Reactive Protein

CTP

Child-Turcotte-Pugh Score

CTRC CVS DCBE DES DF DM DRE EATL EGD

Chymotrypsinogen C Cyclic Vomiting Syndrome Double Contrast Barium Enema Diffuse Esophageal Spasm (Maddrey's) Discriminant Function Diabetes Mellitus Digital Rectal Examination Enteropathy-associated T-cell lymphoma Esophagogastroduodenoscopy

EIA

Enzyme Immunoassay

EMR

Endoscopic Mucosal Resection

ENT

Ear Nose Throat

EoE

Eosinophilic Esophagitis

EOW

Every Other Week

ERCP

Endoscopic Retrograde Cholangiopancreatography

ESR

Erythrocyte Sedimentation Rate

ESWL

Extracorporeal Shock Wave Lithotripsy

ETOH

Alcohol

EUS

Endoscopic Ultrasound

EVL

Endoscopic Variceal Ligation

FAP

Familial Adenomatous Polyposis

FD

Functional Dyspepsia

FIT

Fecal Immunochemical Test

FlexSig FOBT GB

Flexible Sigmoidoscopy Fecal Occult Blood Test Gallbladder

GEL

Granulocyte Epithelial Lesion

GEJ

Gastroesophageal Junction

GES

Gastric Electrical Stimulation

GERD GIST HAART

Gastroesophageal Reflux Disease Gastrointestinal Stromal Tumor Highly Active Anti-Retroviral Treatment

HAV

Hepatitis A Virus

HBIG

Hepatitis B Immunoglobulin

HBV

Hepatitis B Virus

HCV

Hepatitis C Virus

HDL

High Density Lipoprotein.

HDV HELLP

Hepatitis D Virus Hemolysis, Elevated Liver enzymes, Low Platelets

HEV

Hepatitis E Virus

HHC

Hereditary hemochromatosis

HIDA scan

Hydroxy Imino Diacetic Acid Scan

HPF

High Power Field

HPS

Hepatopulmonary Syndrome

HPV

Human Papilloma Virus

IBD

Inflammatory Bowel Disease

IBS

Irritable Bowel Syndrome

ICP

Intracranial Pressure

ICC

Intrahepatic cholangiocarcinoma

IDA

Iron Deficiency Anemia

IDCP

Idiopathic Duct-Centric Pancreatitis

IHC

Intrahepatic Cholangiocarcinoma

INF

Interferon

INH

Isoniazid

IPMN

Intraductal Papillary Mucinous Neoplasm

IPVDs

Intra Pulmonary Vascular Dilations

IVF

Intravenous Fluids

JVP

Jugular Venous Pressure

LDLT LES MALT MC MCN MELD MMR

Living Donor Liver Transplant Lower Esophageal Sphincter Mucosa Associated Lymphoid Tissue Microscopic colitis Mucinous Cystic Neoplasm Model for End Stage Liver Disease Mismatch repair

6-MP mTOR NAFLD NASH NE NET NSAIDS NSBB

6- Mercaptopurine mammalian Target of Rapamycin Non Alcoholic Fatty Liver Disease Non Alcoholic Steatohepatitis Nutcracker Esophagus Neuroendocrine Tumors Non-Steroidal Anti-Inflammatory Drugs Non Selective Beta Blockers

OCP

Oral Contraceptive Pill

OGIB

Obscure GI Bleeding

OVB

Oral Viscous Budesonide

PAS

Periodic Acid–Schiff

PBC

Primary Biliary Cirrhosis

PCR

Polymerase Chain Reaction

PD PDGRA PE PEG PEG-INF PEGJ PEI POEM PPH PPI PPM

Pancreatic Duct Platelet Derived Growth Factor Receptor Alpha Push Enteroscopy Percutaneous Endoscopic Gastrostomy Peginterferon Percutaneous Endoscopic Gastrojejunostomy Percutaneous Ethanol Injection Per Oral Endoscopic Myotomy Portopulmonary Hypertension Proton Pump Inhibitors Parts Per Million

PRBC

Packed Red Blood Cells

PRSS1

Protease Serine 1

PSC

Primary Sclerosing Cholangitis

PT

Prothrombin Time

PTC

Percutaneous Transhepatic Cholangiography

PUD

Peptic Ulcer Disease

PVT

Portal Vein Thrombosis

Q.i.d.

Four times daily

Q.d.

Once daily

RBC

Red Blood Cells

RBV

Ribavirin

RCT

Randomized Controlled Trial

RFA

Radiofrequency Ablation

RUQ

Right Upper Quadrant

SAAG

Serum Ascites Albumin Gradient

SBE

Small Bowel Enteroscopy

SBS

Short Bowel Syndrome

SCT

Stem Cell Transplantation

SEER

Surveillance Epidemiology and End Results database

SEMS

Self Expandable Metal Stent

SIBO

Small Intestinal Bacterial Overgrowth

SMA

Superior Mesenteric Artery

SMV

Superior Mesenteric Vein

SOS SPINK-1 SPS T.i.d. TACE TCA TI TIPS

Sinusoidal Obstruction Syndrome Serine Protease Inhibitor Kazal Type 1 Serrated Polyposis Syndrome Three times daily Transarterial Chemoembolization Tricyclic Antidepressant Terminal Ileum Transjugular Intrahepatic Portosystemic Shunt

TMP/SMX TPN

Trimethoprim/Sulfamethoxazole Total Parenteral Nutrition

TB

Tuberculosis

UC

Ulcerative Colitis

ULN

Upper Limit of Normal

VHL

Von Hippel–Lindau

VIP

Vasoactive Intestinal Peptide

ZES

Zollinger-Ellison Syndrome

Chapter 1- Esophagus Introduction Gastroesophageal Reflux Disease (GERD) Treatment Refractory GERD Extraesophageal GERD Barrett's Esophagus Eosinophilic Esophagitis Cricopharyngeal bar Tumors of the esophagus Caustic ingestions Motility disorders of the esophagus Esophagitis in HIV References

Introduction Esophageal disorders are common in clinical practice. They account for 10% of board questions. The main disorders are GERD, Barrett's esophagus, and achalasia. Eosinophilic esophagitis is relatively uncommon; however, it is increasing in incidence. There is an abundance of recent published literature as well as two recently published practice guidelines about eosinophilic esophagitis. New topics and concepts relating to the esophagus include Barrett's esophagus ablation techniques (cryotherapy and radiofrequency ablation), PPI responsive esophageal eosinophilia, classification of achalasia according to pressure topography, and per oral endoscopic myotomy (POEM). These are all described in this chapter. For the boards, high yield topics are pH monitoring, esophageal manometry, esophageal malignancy, and Barrett's esophagus.

Gastroesophageal Reflux Disease (GERD)

ACG Guidelines for the Diagnosis and Management of Gastroesophageal Reflux Disease, Am J Gastroenterol, 2013

1

ACG Practice Guidelines: Esophageal Reflux Testing, Am J Gastroenterol, 2007 2 Etiology 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, and delayed gastric emptying. Clinical manifestations Esophageal symptoms: heartburn, regurgitation, dysphagia, odynophagia, chest pain. Extra-esophageal manifestations: asthma, cough, and laryngitis (described later). 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 Most patients will have a normal endoscopy. Non Erosive Reflux Disease (NERD): the presence of typical symptoms of reflux with no evidence of esophageal mucosal injury at endoscopy. 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 : LA class A: one or more mucosal breaks < 5 mm in length. LA class B: one or more mucosal breaks > 5 mm in length. LA class C: mucosal breaks extending between one or more mucosal folds, involving less than 75% of the circumference of the esophagus.

LA class D: mucosal breaks extending between one or more mucosal folds, involving more than 75% of the circumference of the esophagus. In many cases, describing the exact extent and severity of inflammation is more useful than categorizing esophagitis into one of the above classes. Patients with severe erosive esophagitis should undergo a repeat EGD after PPI treatment to evaluate for the presence of Barrett's esophagus.1 Manometry Manometry has a limited role in the diagnosis of GERD. It is required prior to surgical fundoplication to rule out dysmotility disorders. Most patients will have a normal manometry. pH monitoring Role of pH monitoring in GERD Document abnormal esophageal acid exposure in an endoscopy-negative patient being considered for antireflux surgery. Evaluate patients with persistent symptoms after anti-reflux surgery. Evaluate patients with reflux symptoms refractory to PPI. Evaluate patient with non-cardiac chest pain, asthma, or ENT problems. BRAVO® wireless pH recording The capsule is placed 6 cm above the GE junction. The patient continues a usual diet, and records symptoms over the duration of the study. Acid reflux is defined as a decrease in pH to < 4. Components of the pH monitoring study are listed in table 1. Table 1: Components of the pH monitoring study

Symptom index and symptom sensitivity index (table 2) 2 These indices are used to correlate GERD symptoms (regurgitation, heartburn, chest pain, etc...) with acid exposure events (pH of < 4). In other words, they provide an estimate of the strength of association between symptoms and acid reflux. Table 2: Symptom index and symptom sensitivity index

2

Symptom association probability (SAP) SAP expresses the likelihood that the patient's symptoms are related to reflux. 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%.2, 3 Treatment Medical therapy H2 blockers are reasonable for mild and infrequent GERD. PPIs are the mainstay of treatment for more severe GERD. Surgical therapy Laparoscopic fundoplication is the most common surgical treatment. *** Study highlight

LOTUS (Long-Term Usage of Esomeprazole vs. Surgery for Treatment of chronic GERD) clinical trial 4 This is a large randomized multicenter European trial comparing laparoscopic

antireflux surgery (LARS) vs. esomeprazole treatment for chronic GERD. 554 patients with established GERD (esophageal mucosal breaks on endoscopy and/or abnormal 24-hour pH monitoring) and previous response to PPIs (40 mg daily for 3 months). 266 patients were randomized to esomeprazole (20 mg daily). The dose could be titrated up to 40 mg daily then 20 mg b.i.d. if symptom control was inadequate. 288 patients were randomized to LARS. 248 actually had the surgery, 40 were cancelled for various reasons. Surgery was performed by experienced surgeons in academic centers. Results showed that both treatments were highly effective in treating GERD. Remission rates at 5 years were slightly higher in the esomeprazole group (92%) vs. 85% in the LARS group (log-rank p = .048). There was no perioperative mortality and only 3% of patients had in-hospital morbidity. Conclusions In GERD patients who initially respond to PPI, maintenance PPI therapy has high remission rates after 5 years. LARS is an option for patients who are not willing to stay on PPI and has similarly high GERD remission rates. *** The LINX® Reflux Management System This device consists of a small flexible band of magnetized beads that is surgically implanted around the lower esophageal sphincter (LES) to augment its pressure and prevent reflux. The magnetic attraction between the beads keeps the LES closed. Swallowing forces separate the beads temporarily to allow food and liquid to pass into the stomach. (figure 1) Figure 1: LINX® Reflux Management System (Courtesy of Torax® Medical, used with permission

The device was FDA approved in March 2012 for the treatment of GERD. A single arm prospective study of LINX® in 44 patients with GERD evaluated patients at 4 years post implantation and demonstrated long-term clinical benefits.5 80% of patients had pH normalization. Mean acid exposure time decreased from 11.9% to 3.8%. 100% of patients had improved quality of life. Three patients had the device removed: one patient needed an MRI (the device is MRI non-compatible), one had severe dysphagia, and one had continued reflux. The most common side effect was dysphagia. This occurred in 42% of patients. It was generally mild and resolved by 3 months after implantation. Refractory GERD Definition: persistent bothersome GERD symptoms despite twice daily PPI therapy. Management Optimize PPI therapy. Give PPI 30-60 minutes prior to meals. Consider gastric emptying study in patients with refractory GERD symptoms. Perform an upper endoscopy to exclude other etiologies and evaluate for erosive esophagitis and Barrett's esophagus. If the patient has a normal endoscopy (or mild LA class A esophagitis), proceed with pH testing. The test can be performed off PPI for 7 days, or on PPI. In patients with typical GERD symptoms: perform pH testing ON PPI to evaluate for persistent reflux symptoms despite acid suppression. Impedance testing in conjunction with pH is recommended to evaluate for non-acid reflux.1

If pH testing is positive for acid reflux, confirm compliance with b.i.d. PPI. Consider adding an H2 blocker at bedtime. If pH testing is negative for acid reflux (normal esophageal acid exposure and negative symptom reflux association) in a patient with ongoing symptoms, this is referred to as "functional heartburn". The etiology of functional heartburn is unknown, but it could be related to esophageal hypersensitivity. Treatment is empiric. Consider TCAs or SSRIs. Avoid anti-reflux surgery. In patients with atypical GERD symptoms: perform pH testing OFF PPI to confirm or exclude the diagnosis of GERD. Preferably, this should be performed in conjunction with impedance testing. If pH testing is negative for acid reflux, the patient does not have GERD. Stop PPI. If pH testing is positive for acid reflux, this proves the presence of GERD. However, it does not explain why the patient has persistent GERD symptoms while on PPI therapy. Consider repeat pH testing on PPI versus surgical therapy for GERD. Non-acid reflux 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. 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 cases of 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 drowsiness and dizziness. Surgical fundoplication is controversial in non-acid reflux. Extraesophageal GERD Established extraesophageal reflux syndromes include asthma, cough, laryngitis, and dental erosions. Other possible GERD related syndromes include pharyngitis, sinusitis, and otitis. Laryngitis Referred to as "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, consider reflux monitoring prior to PPI trial. 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.6 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

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Gastroenterology, 2012 7

The role of endoscopy in Barrett’s esophagus and other premalignant conditions of the esophagus, Gastrointestinal Endoscopy, 2102 8

Diagnosis, Surveillance and Therapy of Barrett’s Esophagus, Am J Gastroenterol, 2008 9

American Gastroenterological Association Technical Review on the Management of Barrett's Esophagus, Gastroenterology, 2011 10 Definition Barrett's esophagus (BE) is the change in the esophageal epithelium that is recognized endoscopically as intestinal metaplasia (salmon colored mucosa) and is confirmed histologically by demonstrating intestinal metaplasia and goblet cells. 9 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 recent population based study showed that the absolute annual risk of adenocarcinoma is 0.12% (incidence rate of 1.2 cases per 1000 person-years).11 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 and high grade dysplasia. Endoscopic examination in BE Perform a thorough and careful examination. Document important measurement (figure 2):Diaphragmatic pinch, Lower esophageal sphincter (LES), Circumferential extent of BE (C), Maximum extent of BE (M)

If a hiatal hernia is present, document its length and extent. Figure 2: Endoscopic landmarks in BE In this example, there is a 3 cm hiatal hernia. BE is reported as C2/M4.

Prague classification of BE: report the length of BE as C/M as shown in figure 2. Carefully examine the BE mucosa for any nodularities or ulcerations. Any suspicious area should be biopsied separately. Biopsy protocol: 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 biopsies every 1 cm.Consider using a large biopsy forceps. Management of BE with or without dysplasia (table 3)

Table 3: Management of BE

While guidelines mention active endoscopic surveillance as a management option for low and high grade dysplasia, most physicians will perform endoscopic ablation for dysplasia, especially high grade dysplasia. Treatment should be individualized according to the patient's age, co-morbidities, availability of endoscopic and surgical treatments, and local expertise. All patients should receive acid suppression with PPI to treat the underlying GERD. Endoscopic 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) RFA is FDA approved for the treatment of BE with dysplasia. *** Study Highlight

Radiofrequency Ablation in Barrett’s Esophagus with Dysplasia12 This is a large randomized multicentre 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 receive RFA or sham procedure. 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 3). Figure 3: Primary Outcomes of RFA versus sham at 12 months

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 group compared to control. Strictures occurred in 6% of patients. Most strictures required one or two dilation sessions. *** Following complete eradication of BE, endoscopic surveillance should be performed. The optimal surveillance intervals are not clear due to lack of long term data. EGD is generally performed every 3-6 months for 1 year. If there is no recurrent BE, surveillance can be performed annually. Recurrence of BE is common after RFA: one retrospective study showed that the recurrence rate is 20% after 1 year and 33% after 2 years.13 Endoscopic spray cryotherapy Cryotherapy is the newest endoscopic modality for ablation of dysplastic BE. Liquid nitrogen is sprayed endoscopically under direct visualization. Similar to RFA, the depth of treatment is very superficial (~2 mm). Small non randomized prospective studies showed that cryotherapy was effective in the treatment of BE with high grade dysplasia or intramucosal carcinoma.14 Complications include chest pain, dysphagia, and mild esophageal strictures.

Photodynamic therapy (PDT) 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. In a randomized controlled trial, PDT with omeprazole was shown to be superior to omeprazole alone in complete ablation of HGD (77 vs. 39%). 15 There was less progression to cancer in the PDT group (13%) compared to the omeprazole only group (28%). Complications: photosensitivity reactions occurred in 69% of patients. Esophageal strictures were common and developed in 36% of patients. This treatment has been largely replaced by RFA and cryotherapy. Endoscopic mucosal resection (EMR) 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. 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. The main indication for EMR in BE is resection of nodular dysplasia or early esophageal adenocarcinoma extending to the superficial submucosa. 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.7 EMR is important for accurate staging. It will often show intramucosal carcinoma or superficial submucosal carcinoma in lesions initially diagnosed as high grade dysplasia. 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

ACG Clinical Guideline: Evidenced Based Approach to the Diagnosis and Management of Esophageal Eosinophilia and Eosinophilic Esophagitis, Am J Gastroenterol, 2013

16

Eosinophilic esophagitis: updated consensus recommendations for children and adults, J Allergy Clin Immunol, 2011

17

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 diagnosis16 Presence of esophageal symptoms. >15 eosinophils per high power field in esophageal biopsies. Eosinophilia limited to the esophagus that persists after PPI treatment. Absence of other causes of esophageal eosinophilia, most importantly GERD. Other causes of esophageal eosinophilia include eosinophilic GI disease, celiac disease, Crohn's disease, achalasia, graft versus host disease, vasculitis, and connective tissue disease. Clinical manifestations Dysphagia is the most common symptom in adults. Other clinical features include food impactions, chest pain, heartburn, and upper abdominal pain. Endoscopic findings are suggestive but not diagnostic of EoE. Esophageal rings, longitudinal furrows, white patches or specks (often mistaken for candida), esophageal strictures, and narrowed esophagus. Endoscopy will be normal in ~15% of cases.18 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). In patients with suspected eosinophilic esophagitis, obtain biopsies from the stomach and duodenum to rule out eosinophilic gastroenteritis. Figure 4 shows a suggested approach to differentiate between the different causes of isolated esophageal eosinophilia.

Figure 4: Suggested approach to differentiate between the different causes of isolated esophageal eosinophilia (see text)

.

In patients with esophageal eosinophilia found on biopsies, give PPI trial (20-40 mg) b.i.d. for 8 weeks. This should be done even if the clinical picture is highly suggestive of (EoE). Repeat EGD and biopsy If symptoms and eosinophilia persist despite PPI therapy, this establishes the diagnosis of eosinophilic esophagitis. If symptoms and eosinophilia resolve, this could be due to one of the following: PPI responsive esophageal eosinophilia (PPI-REE): this is a newly defined clinical

entity. These patients have symptoms and signs suggestive of eosinophilic esophagitis, but their symptoms and eosinophilic infiltration respond to PPI therapy. GERD: patients will have typical GERD symptoms and signs (esophagitis, Barrett's esophagus), or a positive pH study. Treatment Topical steroids Swallowed fluticasone: 880-1760 mcg/day (e.g. 220 mcg 2-4 puffs b.i.d.). 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. Note that the only placebo controlled randomized trial of fluticasone in EoE showed no difference in dysphagia relief between placebo and fluticasone, despite significantly eliminating esophageal eosinophilia.19 Swallowed budesonide: 1 mg b.i.d., given as an oral viscous budesonide (OVB). 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 per 1 gram of budesonide.20 Consider maintenance therapy in patients with severe symptoms, such as those with prior stricture or food impaction or those who relapse after treatment. Maintenance therapy options are OVB at 1 mg/day or fluticasone 880 mcg/day. PO steroids: give prednisone if topical preparations are not effective. Dietary elimination Six-food elimination diet (SFED): this diet removes the most common food allergens including milk, wheat, soy, eggs, nuts, seafood. 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. 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, and avoid over aggressive dilation. Inspect the mucosa after each dilation. Stop if there is a mucosal tear. Complications include chest pain (2%), esophageal tears and perforations (0.3%).21

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 5).22 Figure 5: Cricopharyngeal bar seen on barium swallow

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). 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 Maloney or a Savary dilator to try to disrupt the tight upper esophageal sphincter. 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. 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. Clinical manifestations 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

Treatment 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). A retrospective analysis of the SEER database showed that 5-year survival of patients with such early tumors was similar between those who received endoscopic therapy and those treated with surgery.23 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 11endoscopy. 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.8 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.24

Caustic ingestions Types of caustic ingestions (table 5)

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. 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.26 Carefully examine the esophagus, stomach, and duodenum. Document the extent of injury. The Zargar's endoscopic grading of caustic esophageal injury and corresponding management recommendations are summarized in table 6. Table 6: Zargar's endoscopic grading of caustic esophageal injury

Other treatments Carafate, PPI. Steroids are not recommended. Prophylactic esophageal stenting is not recommended. Give antibiotics for suspected or confirmed perforations. Late complications Strictures Strictures can be multiple and tortuous. Therefore, consider obtaining a barium swallow prior to endoscopy to characterize the strictures and plan the procedure. Savary dilation is preferred for multi-level or tortuous strictures. Squamous cell carcinoma Increased risk in patients with history of lye or caustic esophageal injury. Screening is recommended 15-20 years after ingestion, to be repeated every 1-3 years.

Motility disorders of the esophagus

ACG Clinical Guideline: Diagnosis and Management of Achalasia, Am J Gastroenterol, 201324

Featured review: Esophageal motility disorders in terms of pressure topography: the Chicago Classification, J Clin Gastroenterol 2010 27 High resolution manometry and pressure topography The high resolution manometry catheter has multiple sensors spaced 1 cm apart along the length of the catheter. The pressure data from the manometry tracing is converted into color, forming a pressure topography. A normal pressure topography is shown in figure 6-A. Notice the upper and lower esophageal sphincters and the normal wave progression of esophageal peristalsis. Normal lower esophageal sphincter (LES) pressure ranges between 10-45 mmHg. Figure 6:Esophageal pressure topography. A: normal swallow. The upper and lower pressure lines correspond to the upper and lower esophageal sphincters (UES and LES), respectively. B: Type 2 achalasia with panesophageal pressurization (described later) .

Achalasia Clinical manifestations: dysphagia (solids and liquids), chest pain, regurgitation, weight loss. 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. Normal peristalsis requires normal progression of a series of contractions and relaxations. Therefore, loss of relaxation results in aperistalsis and abnormal contractions. Infection with the parasite Trypanosoma Cruzi (Chagas' disease) can lead to achalasia. The esophageal dysmotility is confined to the mid and distal esophagus where smooth muscles form the muscular layer of the esophagus. Pseudoachalasia can occur due to any of the following causes: 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. Paraneoplastic achalasia from extraintestinal malignancy (e.g. lung cancer). These patients will have positive antineuronal antibodies (also called anti-Hu antibodies). Suspect pseudoachalasia in older patients with a short duration of symptoms (less than 6 months), and rapid weight loss.28 Workup: barium swallow (bird's beak appearance). EGD with retroflexion to rule out a tumor. Manometric features of achalasia include both of the following: Esophageal aperistalsis: this can result in simultaneous esophageal contractions. Contractions can be of low or high amplitude. None of these contractions is peristaltic. LES pressure abnormality: all cases have absent or incomplete deglutitive relaxation of the LES, with a residual pressure > 8 mmHg. Resting pressure is usually elevated (> 45 mmHg), but can be normal. False negative manometry for achalasia can be encountered with conventional manometry without pressure topography. 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. Classification of achalasia based on pressure topography: Type 1: classic achalasia. No pressurization in the esophagus, failed peristalsis. Type 2: achalasia with esophageal compression (figure 6-B) In this type there is compartmentalized pressurization (>30 mmHg) spanning the entire length of the esophagus in at least 20% of swallows.29 Type 3: spastic achalasia (also called vigorous achalasia on conventional

manometry) In this type there are spastic esophageal contractions 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. One small study found that type 2 achalasia patients were the most likely to respond to therapy, while type 3 patients had the least response to therapy.29 Another retrospective study also showed that 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.30 Larger studies are needed to characterize the response of achalasia subtypes to different endoscopic and surgical treatments. Management of achalasia (figure 7) Figure 7: Suggested approach to the management of achalasia.

POEM is still considered investigational, and therefore was not included in this algorithm.*Repeated injections have been associated with a more difficult and less effective myotomy 31

Pneumatic dilation A special balloon dilator (Rigiflex®, Boston scientific) is used to break the muscular fibers of the lower esophageal sphincter. The balloon is passed over the wire and positioned across the GE junction (confirmed with fluoroscopy). It is then inflated to 30, 35, or 40 mm for 30 to 60 seconds. The goal of pneumatic dilation is to achieve a post dilation LES pressure of < 10 mmHg. The regular through-the-scope balloon dilators are not effective due to their small size. Efficacy of pneumatic dilation 70-90% immediate response rate.32, 33 One study showed that one-third of the patients treated by dilation would relapse

during a 4-year follow up period.33 Repeated dilations after relapse are effective. Response rate for dilation after prior myotomy is ~50%. 34 Predictors of therapeutic failure Patient related: age younger than 40 years, male, pre-dilation LES pressure > 20 mmHg. Procedure related: single dilation, small balloon (< 30 mm), post dilation LES pressure > 10 mmHg. Side effects of pneumatic dilation: perforation (2-5%), reflux esophagitis (2%). Botulinum toxin injection Mechanism of action: botulinum toxin (BT) inhibits the excitatory acetylcholinereleasing neurons, resulting in decreased LES pressure. Technique: BT 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). Efficacy of botulinum toxin injection 70-90% initial response rate. Relapse occurs in 50% of patients within 6-12 months. Laparoscopic Heller myotomy Partial fundoplication should be performed in conjunction with myotomy to decrease the risk of GERD. Efficacy: immediate response is achieved in more than 85% of patients. Long term response varies among studies, but is estimated at 85% in 10 years and 70% at 20 years. Per Oral Endoscopic Myotomy (POEM) This is a recently developed, completely per oral technique. Steps of the procedure A mucosal incision is made at the level of the mid esophagus. This serves as an entry point. A submucosal tunnel is then created using endoscopic submucosal dissection (ESD) technique. The circular muscle bundle is dissected starting above the GE junction and extending below the lower esophageal sphincter. The mucosal entry incision is closed with endoclips. Initial results of small studies show an excellent short term response. One prospective study of 70 patients who underwent POEM showed that 82 % of patients were in symptom remission at 12 months after the procedure. 35 Due to the lack of long term data, the procedure is still considered investigational. Diffuse esophageal spasm (DES) Clinical presentation: dysphagia and chest pain. In some cases, barium swallow shows the classic appearance of "corkscrew"

esophagus. Manometry Intermittent, simultaneous, non-peristaltic contractions in ≥ 10% of swallows, with a mean pressure of ≥ 30 mmHg. These contractions are intermixed with normal peristalsis in other swallows. There is normal LES relaxation. Nutcracker esophagus (NE) Clinical presentation is similar to diffuse esophageal spasm. Manometry Peristaltic contractions with peak pressure >180 mmHg. Normal LES relaxation. Treatment of DES and NE Trial of TCA, calcium channel blockers, nitrates. Two small randomized controlled trials showed that botulinum toxin injection improves dysphagia and chest pain in patients with DES and NE.36, 37 Functional esophagogastric junction obstruction Clinical presentation is mainly with dysphagia. Manometry shows normal esophageal peristalsis, with impaired LES relaxation. Possible underlying etiologies include post fundoplication, paraesophageal hernia, eosinophilic esophagitis, or variant achalasia with preserved peristalsis.27, 38 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. 39

Esophagitis in HIV Candida esophagitis Patients present with oral thrush, dysphagia, and mild odynophagia. Endoscopy reveals white mucosal plaques and esophagitis of variable severity. 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 eosinophilic intranuclear inclusions. 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 8) Multinucleated giant cells, nuclear moulding, and margination of the nuclear chromatin (3 Ms). Intranuclear eosinophilic droplet-like bodies (Cowdry type A bodies) are pathognomonic. Figure 8: HSV esophagitis. Esophageal biopsy shows multinucleated giant cells, with nuclear moulding and margination of nuclear chromatin (arrows)

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 1-2). 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. Medical therapy IV/PO steroids. Thalidomide (200 mg/day) is effective in healing HIV idiopathic ulcers.40

Chapter 2- Stomach Introduction Gastroparesis Cyclic Vomiting Syndrome Rumination syndrome Dyspepsia Helicobacter pylori Menetrier's disease Hypergastrinemia and Zollinger-Ellison syndrome Gastric polyps Gastric adenocarcinoma Hereditary diffuse gastric cancer Gastric lymphoma References

Introduction Gastroduodenal disorders account for 15% of the GI board questions. H. pylori remains an important and common disease, and is presented in some detail in this chapter. Gastroparesis is common in clinical practice and it is important to know the limitations and possible side effects of treatment. Dyspepsia has a clear diagnostic approach; however, treatment of functional dyspepsia is generally disappointing. It is important for gastroenterologists to accept the diagnosis of functional dyspepsia, provide reassurance to the patient, and avoid an extensive workup in typical cases. Topics that are less common in practice, but appear on the boards are gastric lymphoma, gastric carcinoids, and gastrinoma. Peptic ulcer disease bleeding is covered in chapter 7. Gastric carcinoids and GISTs are important for the boards, and are discussed in chapter 10.

Gastroparesis

Clinical Guideline: Management of Gastroparesis, Am J Gastroenterol, 2013

1

Etiology Gastroparesis is most commonly idiopathic, diabetic, or post-surgical. 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. 2 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. 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 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. 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: Mild (11-20%), moderate (21-35%), severe (36-50%), and very severe (> 50%). 3 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, cyclic vomiting syndrome (described later), and rumination syndrome (described later). 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. Medications Metoclopramide Central and peripheral dopamine antagonist and serotonin 5-HT3 antagonist. It is FDA approved for treatment of gastroparesis for less than 12 weeks. A black box warning was added to the drug label due to neurologic side effects, mainly tardive dyskinesia and dystonia. Tardive dyskinesia Occurs more commonly in elderly female patients, and is associated with treatment duration of more than 3 months. The absolute risk of tardive dyskinesia related to metoclopramide is unclear. It is estimated to be less than 1%. General guidelines for using metoclopramide in gastroparesis: Use the minimal effective dose. Start at 5 mg before meals, up to 20 mg q.i.d. 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. Domperidone Domperidone is a peripheral dopamine antagonist. It does not cross the blood-brain barrier. Neurologic side effects are minimal. It is not available in the USA. It can only be prescribed through an investigational new drug clearance from the FDA. It can lead to QT interval prolongation. Therefore, obtain a baseline EKG and a repeat EKG while on treatment. Dose: 10-20 mg PO q.i.d. Erythromycin Mechanism of action: motilin receptor agonist, stimulates antral contractions. It can be given as IV or PO. Dose is 40 - 250 mg every 8 hours. Limit to 2 weeks per treatment course, after which treatment becomes less effective due to the development of tachyphylaxis. Tricyclic antidepressants are not effective in gastroparesis. A large randomized trial (NORIG) showed that nortriptyline is not effective in patients with idiopathic gastroparesis.4 Antiemetics: consider ondansetron 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. Other options include venting gastrostomy, jejunostomy, or PEG-J placement. Surgical options for extreme cases include gastrojejunostomy, pyloroplasty or gastrectomy.1 Gastric electrical stimulation (GES) GES mainly improves symptoms of nausea and vomiting in patients with refractory diabetic gastroparesis.5 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.

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 III diagnostic criteria 6 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. Absence of nausea and vomiting between episodes. 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. Chronic cannabis use can result in a syndrome similar to CVS. Management Treatment during the acute episode Supportive care, hydration. Give antiemetics (ondansetron, phenergan) and consider anxiolytics (benzodiazepines). Inter-episode treatment Prophylactic therapy: consider propranolol, amitriptyline (25-50 mg/day). Avoid stress, avoid fasting, and maintain good sleep hygiene.

Rumination syndrome In this disorder, there is effortless regurgitation of undigested food few minutes after eating. There is no retching or nausea. Most commonly affects adolescents, with a strong female preponderance. Associated with stress and anxiety. Rome III diagnostic criteria 6 Must include both of the following: Persistent or recurrent regurgitation of recently ingested food into the mouth with subsequent spitting or re-mastication and swallowing. Regurgitation is not preceded by retching. Supportive criteria Regurgitation events are usually not preceded by nausea. Regurgitant contains recognizable food with a pleasant taste. Treatment is with behavioral therapy, which focuses on postprandial diaphragmatic breathing to compete with the urge to regurgitate.

Dyspepsia

ACG Guidelines for the management of dyspepsia, Am J Gastroenterol, 2005

7

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 or a functional disorder (functional dyspepsia). Peptic ulcer disease, gastritis, esophagitis, and malignancy can cause symptoms of dyspepsia. Examples of medication-induced dyspepsia: NSAIDS, iron, narcotics, colchicine, acarbose. Rome III criteria for functional dyspepsia (FD) Must include both of the following: 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). Criteria fulfilled for the last 3 months with symptom onset ≥ 6 months prior to diagnosis. FD is further divided into two subtypes: Post prandial distress syndrome Postprandial fullness Early satiation Epigastric pain syndrome Moderate intermittent epigastric pain that is not generalized and 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. The two subtypes can coexist. This classification is mainly used for research purposes. Workup and initial management of uninvestigated dyspepsia EGD is indicated in patients with dyspepsia who are older than 55 years, or who

present with alarm features.7 Alarm features include bleeding, anemia, early satiety, weight loss, dysphagia, recurrent vomiting, family history of GI malignancy, prior GI malignancy, or peptic ulcer disease. In patients who are younger than 55 years old and do not have alarm features, a trial of PPI treatment or H. pylori test and treat strategy is reasonable. If there is a high background prevalence of H. pylori (> 10%), start with the test and treat strategy for H. pylori, rather than empiric PPI. If the patient responds to PPI, stop treatment after 4-8 weeks. If symptoms recur, give another course of PPI or consider long term treatment. If PPI treatment and H. pylori eradication fails to improve symptoms, proceed with EGD. If EGD is normal, then treat as FD. Avoid performing multiple EGDs and imaging studies in patients with typical features of FD. Treatment options for FD PPI treatment for 4 weeks: 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 9 herbs. A placebo controlled trial showed benefit in FD.8 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. 9 Tricyclic antidepressants (TCAs) TCAs are more effective in patients with functional abdominal pain and IBS. Small studies show limited benefit in FD. Functional dyspepsia treatment trial (FDTT) is a prospective double blind placebo controlled trial of 292 patients with FD. Early results show that amitriptyline relieved symptoms of FD in 53% of patients compared to placebo (40%) and escitalopram (40%). 10

Patients with normal gastric emptying had better relief with amitriptyline compared to those with delayed gastric emptying. Full results of this trial are pending. Acotiamide This 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). 11 Acotiamide is not available in the United States. Buspirone 5-hydroxytryptamine 1A receptor agonist. 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.12 Buspirone did not improve gastric emptying.

Helicobacter pylori

ACG Guideline on the Management of Helicobacter pylori Infection, Am J 13

Gastroenterol, 2007

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 group 1 carcinogen. Eradication of H. pylori decreases the risk of developing gastric cancer. A meta-analysis of 6 randomized trials included 3388 patients who received eradication therapy and 3307 untreated patients.14 All studies were conducted in Asia where there is a high incidence of gastric cancer. 1.1% of patients treated with eradication therapy developed gastric cancer compared to 1.7% of untreated patients (relative risk 0.65). The main indications for H. pylori testing are listed in table 1.13 H. pylori screening is recommended prior to bariatric surgery in high prevalence areas.15 Table 1: Indications for testing for H. pylori

Steps of the urea breath test (figure 1) Figure 1: Urea breath test. (see text)

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. H. pylori testing modalities are listed in table 2. Table 2: H. pylori testing modalities. *Other H. pylori tests that are not routinely available include culture and sensitivity, and PCR.

Gastric biopsy protocols for H. pylori are shown in figure 2.16 Figure 2: Gastric biopsy protocols for H. pylori. Obtain mucosal biopsies from all these sites (one jar). Any of these two biopsy protocols is acceptable.

Indications for testing to prove H. pylori eradication after antibiotic therapy: Any patient with an H. pylori-associated ulcer. Patients with persistent dyspeptic symptoms. Patients with H. pylori-associated MALT lymphoma. Patients who have undergone resection of early gastric cancer. Treatment regimens for H. pylori are listed in table 3. Table 3: Treatment regimens for H. pylori.

Menetrier'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. 17 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.17 Molecular pathogenesis: enhanced signaling through the receptor tyrosine kinaseepidermal growth factor receptor (RTK-EGFR).18 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.17 Treatment: supportive care. Consider octreotide. Gastric resection in severe cases.

Hypergastrinemia and Zollinger-Ellison syndrome

ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms: Functional Pancreatic Endocrine Tumor Syndromes, Neuroendocrinology. 2012

19

Hypergastrinemia is defined as fasting serum gastrin level greater than 200 pg/mL. Etiology (table 4) Hypergastrinemia can be classified as appropriate (due to decreased gastric acid production) or inappropriate (with normal or increased gastric acid production). Table 4: Etiology of hypergastrinemia

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 locations are the distal duodenum and jejunum.

Diagnostic approach to suspected ZES (figure 3) ZES should be suspected in the following clinical conditions:19 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 elevated >10 times the ULN, the demonstration of low gastric pH is sufficient to diagnose ZES. In cases where the elevation of gastrin is less pronounced, the diagnosis of ZES requires the demonstration of abnormal secretin stimulation test. 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%).20, 21 Basal acid output in ZES is greater than 15 meq/hr. However, this test is generally unavailable. Figure 3: General approach to the patient with elevated serum gastrin and suspected ZES *Gastric pH and secretin stimulation test should be performed off PPI (see text) †Serum gastrin is a good initial screening test and is elevated in > 98% of ZES patients

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.22 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. 23 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: 24 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, or octreoscan. 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 Figure 4: The gastrinoma triangle. (See text)

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 parathyroidectomy prior to gastrinoma resection surgery.

Gastric polyps 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. Multiple FGPs arise in patients with familial adenomatous polyposis and MUTYH associated polyposis. 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.16 Hyperplastic polyps Hyperplastic polyps develop as a result of chronic inflammation, including H. pylori infection and autoimmune gastritis. They are commonly located in the antrum. 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.16 Gastric adenomas Gastric adenomas are histologically similar to colonic adenomas. They are considered premalignant and require resection in all cases. Surveillance EGD is recommended one year following resection.

Gastric adenocarcinoma 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 accurate 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).25 These histologic subtypes have distinct clinical, morphological, and molecular characteristics (table 5).

Table 5: Comparison between the intestinal and diffuse subtypes of gastric adenocarcinoma

Figure 5: Intestinal type gastric adenocarcinoma

Figure 6: Poorly differentiated gastric adenocarcinoma showing "signet ring" malignant cells (arrows

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.26 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. 27

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.26 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: 28 Two or more documented cases of diffuse gastric cancer in first or second degree rela​tives, with at least one diagnosed before the age of 50. Three or more cases of documented diffuse gastric cancer in first or second-degree rela​tives, 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. 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.29 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.28

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: 30 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:31 (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 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. Perform a follow up EGD every 6 months for 2 years then every 1 year. 75% of patients will achieve complete remission with H. pylori eradication. 25% will not respond treatment. These patients have a more extensive and aggressive disease with a positive t (11; 18) translocation. 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 with or without chemotherapy. 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 carcinoids and gastrointestinal stromal tumors (GISTs) are discussed separately in Chapter 10-Miscellaneous GI topics.

Chapter 3-Small intestine Introduction Malabsorption Diarrhea after ileal resection Fat malabsorption Protein losing enteropathy Carbohydrate malabsorption Small Intestinal Bacterial Overgrowth Short Bowel Syndrome Celiac disease Whipple disease Small intestinal tumors Small intestinal lymphoma References

Introduction 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. Board questions commonly cover this topic as well.

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). Figure 1: Enterohepatic circulation of bile acids in normal conditions

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 (choleretic diarrhea). The liver can compensate for the lost bile acids, and the 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). IgA-TTG for celiac disease. Fecal elastase to test for pancreatic insufficiency. D-Xylose test An abnormal D-Xylose test suggests small intestinal mucosal disease. Normal results suggest pancreatic or other non-small bowel etiologies of steatorrhea. Described in more detail later in the chapter. 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. 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 as a result of lymphatic or venous outflow obstruction leading to protein leakage from the mucosa. Table 1: Etiology of protein losing enteropathy

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. Abnormal if > 27 ml/day. 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 A1AT 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. 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]. D-Xylose test Tests 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 The patient ingests 25 grams of D-Xylose. A blood sample is collected one hour after ingestion. Levels < 20 mg/dL are abnormal. 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. False positive results can occur in SIBO. 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 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. 2 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: diabetes, scleroderma. Acid suppression: vagotomy, atrophic gastritis and achlorhydria, PPI. Other etiologies include celiac disease, chronic renal failure, radiation enteritis, Crohn's disease, chronic pancreatitis, chronic liver disease, and cirrhosis. Clinical manifestations: bloating, steatorrhea, diarrhea, abdominal pain, weight loss. Labs Increased folate levels due to increased bacterial synthesis. Low B12 levels due to increased bacterial usage of B12. Diagnosis Gold standard: proximal jejunal aspirate of ≥ 105 colony forming units/mL. Hydrogen breath test General concept: anaerobic bacteria ferment a test substrate (glucose or lactulose), producing hydrogen that is detected in breath samples. The test is abnormal if there is a rise in hydrogen concentration: (PPM: parts per million) > 20 PPM within 2 hours after ingestion of lactulose. > 12 PPM within 3 hours after ingestion of glucose. Late peaks in hydrogen are due to colonic bacterial fermentation of the substrate. Test limitations Rapid absorption of glucose in the proximal small intestine may result in a false negative result. Rapid intestinal transit results in a false positive early peak of hydrogen due from colonic fermentation rather than SIBO. Therefore, some tests label 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. 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. 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: Doxycycline 100 mg b.i.d., metronidazole 500 mg t.i.d., ciprofloxacin 500 mg b.i.d., trimethoprim-sulfamethoxazole two pills 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 Recurrence after treatment is common. Patients can be given repeated courses of antibiotics as needed for symptom control. 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 vascular events (SMA or SMV thrombosis), midgut volvulus, Crohn's disease, trauma and radiation enteritis. 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.3 Diagnosis The diagnosis is based on the clinical presentation, mainly the development of neurologic symptoms following ingestion of carbohydrate in a patient with SBS. 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 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 Loperamide (2-4 mg every 8 hours). Diphenoxylate with atropine (2.5-5 mg every 8 hours). Tincture of opium (5-10 drops every 8 hours). Clonidine (0.2 mg PO b.i.d. or transdermal patch). Octreotide (50-100 mcg subq b.i.d. or t.i.d.). PPIs are given to inhibit excess gastric secretion. Medications to enhance bowel adaptation Teduglutide (Gattex®) FDA approved for the treatment of SBS. Glucagon like peptide 2 (GLP-2) is normally secreted from the ileum and colon and improves intestinal adaptation and proliferation. Teduglutide is a GLP-2 analogue given as a subcutaneous injection that enhances the structural and functional integrity of the remaining intestine in SBS.4 There is a risk of acceleration of neoplastic growth. 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%.5

Celiac disease

ACG Clinical guidelines: Diagnosis and Management of Celiac Disease, Am J Gastroenterol, 2013 6 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).7 An estimated 3 million people in the United States have celiac disease. Most cases are undiagnosed. Clinical manifestations Gastrointestinal manifestations Malabsorption, steatorrhea, abdominal pain, bloating, intussusception. Non Gastroenterological manifestations Iron deficiency anemia (IDA) Up to 15% of patients presenting for endoscopy for iron deficiency anemia have celiac disease. This association appears to be mostly related to 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.8 Another study showed that the prevalence of celiac disease is low (0.33%) in an urban, predominately male, black population with IDA.9 Other nutritional deficiencies include vitamins A, D, E, K, B12 and folate deficiency. Metabolic bone disease (osteopenia, osteoporosis), hyposplenism, spontaneous abortion, infertility, chronic fatigue. Abnormal liver function tests Patients may have a mild elevation of liver enzymes. Liver biopsy shows non-specific hepatitis. Test for celiac disease in patients with idiopathic mild elevation of liver enzymes. Conditions associated with celiac disease Type 1 DM. Autoimmune diseases: thyroiditis, Addison disease, Sjögren's syndrome. 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 Serologic testing should be performed in patients on gluten containing diet. IgA-tissue transglutaminase antibody (IgA TTG) Sensitivity ~95%, specificity > 95%. This test is recommended as the first line test for celiac disease. 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 IgGTTG, or IgG deamidated gliadin peptides. 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, and are no longer recomm​ended for celiac disease testing. 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. 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. Take four biopsies from the distal second portion, and 1-2 biopsies from the bulb. 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

Table 3 shows possible dilemmas encountered in the workup of celiac disease.

Table 3: Dilemmas in the diagnosis and workup of celiac disease

Treatment Refer to a dietician to start a gluten free diet. Patients should avoid all wheat, barley, and rye. In August of 2013, the FDA published new regulations to define the term "glutenfree". 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 and supplement as necessary. Non-responsive celiac disease Definition: persistent symptoms, signs or laboratory abnormalities typical of celiac

disease despite 6 to12 months of dietary gluten avoidance.6 Management Confirm the diagnosis. Review the results of prior serology and biopsy. Check for noncompliance with the gluten free diet, which is the most common cause of non-responsive celiac disease. Ask about intentional intake of gluten. Refer to a dietician experienced in celiac disease to assess for inadvertent gluten intake. 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. If the duodenal biopsy is normal, consider alternative or co-existing disease such as lactase deficiency, microscopic colitis, SIBO, IBS or pancreatic insufficiency. Perform a colonoscopy and biopsy if diarrhea is present. 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 This is less severe than type 2, with a five-year survival is ~90%. Small intestinal biopsy shows normal (polyclonal) intraepithelial lymphocytes (IELs). Type 2 refractory celiac disease This is a more severe disease with a five-year survival is less than 50%. Characterized by the presence of an abnormal clonal population of IELs. These can demonstrate loss of normal CD3 or CD8 expression. 10 This type can progress to enteropathy-associated T-cell lymphoma (described later), ulcerative jejunoileitis or rarely to mesenteric lymph node cavitations. Evaluate for lymphoma using SBE, capsule endoscopy, CT, MRI, or PET scan. Treatment options include glucocorticoids (prednisone, budesonide) and thiopurines.

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 manifestations11 Cognitive dysfunction is the most common symptom. Pathognomonic findings are present in less than 20% of patients with neurologic disease. Oculomasticatory myorhythmia (eye and jaw movement). 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 is not recommended.

Small intestinal tumors The most common small intestinal tumors are listed in table 4. Table 4: Small intestinal tumors

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 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). IPSID is characterized by overproduction of a monoclonal immunoglobulin α heavy chain. The etiology is likely infectious. Many reports showed an association with Campylobacter jejuni infection. 12 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. Marginal B cell lymphoma Diffuse large B cell lymphoma 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.13 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. Highly aggressive. The main treatment is chemotherapy. T cell lymphoma Enteropathy-associated T-cell lymphoma (EATL) Most commonly associated with type 2 refractory celiac disease. The most common site of involvement is the small intestine, followed by the mesenteric and abdominal lymph nodes.14 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 EATL has a poor prognosis, with a median overall survival of 10 months.14 Many patients die from acute intestinal complications such as perforation and bleeding. Treatment Chemotherapy, surgery, stem cell transplantation. Gluten free diet. Other lymphomas 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%).15 The median time to disease onset is 6 months, but it can vary between 1 week and 9 years.15 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.

Chapter 4-Liver Introduction Liver function tests Liver disease in pregnancy Hemochromatosis and iron overload syndromes Wilson disease Alpha one antitrypsin deficiency Viral hepatitis Hepatitis A Hepatitis B Acute hepatitis B Chronic Hepatitis B Chronic hepatitis B and pregnancy Occupational exposure to hepatitis B HBV prophylaxis in patients receiving immunosuppressants Hepatitis C Introduction Treatment of hepatitis C Occupational exposure to hepatitis C HCV sexual transmission Hepatitis D Hepatitis E Pyogenic liver abscess Vascular diseases of the liver Budd-Chiari Syndrome Portal vein thrombosis Sinusoidal obstruction syndrome Congestive hepatopathy Alcoholic liver disease Non alcoholic fatty liver disease Drug Induced Liver Injury Acetaminophen toxicity

Autoimmune Hepatitis Primary sclerosing cholangitis Primary Biliary Cirrhosis Acute liver failure Complications of cirrhosis and portal hypertension Ascites Hepatic Encephalopathy Hepatorenal syndrome Portopulmonary hypertension Hepatopulmonary syndrome Benign Liver tumors Hemangioma Hepatocellular adenoma Focal nodular hyperplasia Nodular regenerative hyperplasia Primary Liver Malignancies Hepatocellular carcinoma Fibrolamellar HCC Intrahepatic cholangiocarcinoma Liver transplantation References

Introduction Hepatology is a broad specialty that covers a wide range of disorders. 25% of the GI boards' questions are liver related. This chapter is thorough and covers all the important subjects. Favorite topics for the boards are liver diseases of pregnancy, hepatitis B, metabolic liver diseases, cholestatic disorders, and complications of cirrhosis and portal hypertension. AASLD guidelines are extremely thorough. It is very useful to access the articles and read the summarized recommendations. Hepatitis B therapy with tenofovir and entecavir has high efficacy and minimal resistance rates. There is a therapeutic revolution underway in the management of hepatitis C. This chapter contains basic clinical information about the newly approved protease inhibitors. Treatment regimens are expected to continue to evolve as more medications are approved. The reader is advised to check frequently for updates about HCV treatment. A good website for such updates is hcvguidelines.org. Liver transplantation is mentioned in brief at the end of this chapter with a focus on immunosuppressive drugs.

Liver function tests General concepts in patients with abnormal liver enzymes Obtain a thorough clinical history including risk factors for liver disease and complete medication history. Ask the pharmacy about previous and current prescriptions. ALT and AST elevation High ALT and AST levels >1000 IU/L occur in cases of medication induced liver injury, acute viral hepatitis, ischemic hepatitis, and mushroom poisoning. LDH is elevated in ischemic hepatopathy. The degree of elevation of liver enzymes correlates poorly with hepatocellular necrosis. Occasionally choledocholithiasis can cause severe elevation of liver enzymes with normal bilirubin and ALKP levels. The clinical history of abdominal pain in patients with risk factors for gallstones will aid in establishing the diagnosis. Elevated AST/ALT ratio is suggestive of advanced alcoholic liver disease, rather than heavy alcohol drinking without liver disease.1 Celiac disease can present with mild elevation of liver enzymes. Test for celiac disease in patients with elevated liver enzymes of unclear etiology. Gilbert syndrome is the most common cause of mild unconjugated hyperbilirubinemia. It is caused by reduced activity of uridine diphosphatase glucuronyl transferase. It has an autosomal dominant inheritance. 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 extrahepatic 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 (discussed later). Sepsis induced cholestasis Sepsis due to any cause can lead to conjugated 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. 2 Search for underlying cholangitis, liver infection, UTI, pneumonia and other infections.

"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. Bilirubin levels range between 10 to 40 mg/dl, while AST, ALT and ALKP are < 5 times ULN.3 Treatment is supportive: treat sepsis, adjust the TPN, and stop any offending medications. Liver biopsy is rarely required.

Liver disease in pregnancy 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 More commonly due to HSV-2 (~60% of cases) than HSV-1 (~40%).4 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.4 Other lab abnormalities include leukopenia, coagulopathy, and thrombocytopenia. HSV hepatitis can progress to fulminant hepatic failure. Consider empiric treatment in patients with fulminant hepatic failure while awaiting the results of HSV serologies. Treatment of choice is with acyclovir. Other diseases relevant to pregnancy include hepatitis B (discussed here), autoimmune hepatitis (discussed here), and hepatocellular adenoma (discussed here). 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 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.5, 6 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. ERCP in pregnancy is discussed in chapter 11- endoscopy. Liver disease specific to pregnancy (table 1) Intrahepatic cholestasis of pregnancy (ICP) ICP is the most common liver disease specific to pregnancy One study showed that there is an association between ICP and several liver and biliary disorders including hepatitis C and non alcoholic fatty liver disease.7 Therefore, it is recommended to test for viral serologies and monitor for normalization of liver enzymes post partum. HELLP (hemolysis, elevated liver enzymes, low platelets). Acute fatty liver of pregnancy (AFLP).

Hyperemesis gravidarum Persistent vomiting with weight loss of > 5% of pre-pregnancy body weight.8 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, promethazine, cyclizine, doxylamine, dimenhydrinate.8 Pre-eclampsia Affects 5-10% of pregnancies. Risk factors include nulliparity, age > 40 years, chronic hypertension and diabetes. Clinical features include hypertension, proteinuria, edema, abdominal pain, and jaundice. Labs may reveal elevated ALT and AST, and bilirubin (< 5 mg/dL). Pre-eclampsia can progress to eclampsia, AFLP, HELLP, hepatic rupture and infarction.

Table 1: Liver diseases specific to pregnancy

Hemochromatosis and iron overload syndromes

Diagnosis and management of hemochromatosis: 2011 Practice Guideline, AASLD, 2011

12

Iron overload syndromes are listed in table 2.

Table 2: Iron overload syndromes

Intestinal iron absorption (figure 1) Figure 1: Intestinal iron absorption (see text)

DMT1: Ferrous iron transporter divalent metal ion; DcytB: Duodenal cytochrome B; FPN: Ferroportin; Tf: Transferrin; Hp: Hephaestin

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.13 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). Mutations in ferroportin lead to "ferroportin disease". This is an autosomal dominant form of iron overload. Iron predominantly accumulates in reticuloendothelial macrophages. Early in the disease, there is a characteristic increase in ferritin level with low transferrin saturation. Hepcidin is a negative regulator of iron absorption. It is synthesized in the liver in response to excess iron. 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. African iron overload This disease is described in Sub Saharan Africa. It was previously thought to be related to drinking beer with high iron concentrations (brewed in large iron containers). However, a mutation in ferroportin was found in many affected patients, suggesting a genetic etiology of the disease that is exacerbated by high dietary ingestion of iron. 12

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 proteins transferrin receptor 2 (TFR2) and the hemochromatosis protein (HFE) are involved in sensing transferrin saturation. Mutation of either protein can lead to a reduction in hepcidin production and increased iron absorption. HFE associated hereditary hemochromatosis Hereditary hemochromatosis (HHC) is an autosomal recessive disease that results from a mutation of the HFE gene (chromosome 6). HHC leads to increased intestinal iron absorption and parenchymal iron deposition in multiple organs. The most common mutations are C282Y and H63D. Genotypes that lead to HHC: C282Y/C282Y (C282Y homozygote) This is the main disease genotype and is present in 90% of patients with HHC. C282Y/H63D (compound heterozygote) Most patients with this genotype have elevated iron indices; however, significant iron overload is uncommon.14 The following genotypes do not lead to iron overload: C282Y heterozygotes (C282Y/wild type), H63D homozygotes (H63D/H63D), and H63D heterozygotes (H63D/wild type) HHC 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. Serum ferritin and transferrin saturation are elevated in 40-60% of female patients and 75-100% of male patients who are C282Y homozygotes. 15 Iron overload related disease is much less common. 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. 15 Symptomatic patients present with fatigue, abdominal pain, weight loss, arthralgia, impotence, amenorrhea, and congestive heart failure symptoms. Physical exam may reveal hepatomegaly, skin pigmentation, arthritis of the second and third metacarpophalangeal joints, diabetes, testicular atrophy, and

splenomegaly. Diagnosis Iron parameters suggestive of HHC are shown in table 3.

Table 3: Iron parameters in HHC.

HFE mutation analysis is recommended in patients with any of the following: Elevated ferritin (> 200 ng/mL in women and > 300 ng/mL in men) who have no signs of inflammatory disease.16 Transferrin saturation > 45%.12 Liver biopsy in HHC 12 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. Note that the cut-off age criteria (age > 40 years) was removed from the latest guidelines. Iron deposition is seen in parenchymal cells Hepatic iron stores measurement Hepatic iron concentration (HIC) is > 4,000 mcg/gm dry weight Hepatic iron index > 1.9 Treatment Phlebotomy of one unit of blood per week, until hematocrit is < 35%, ferritin is 2050 ng/ml, and transferrin saturation is < 50%. 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, or testicular atrophy. Improvement of portal hypertension and reversal of hepatic fibrosis. Improved skin pigmentation, fatigue, diabetes, 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. Genetic counseling Test siblings of the patient for the HFE mutation.

To avoid testing the patient's children, test the spouse. 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:An update, AASLD, 2008

17

European association for the study of the liver Clinical Practice Guidelines: Wilson’s disease, Journal of hepatology, 2012

18

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. 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. 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. They can also be seen in cholestatic liver disease such as primary biliary cirrhosis. 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 that of 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 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. 17 Liver histology Liver histology is non-specific and can resemble other chronic liver diseases such as autoimmune hepatitis and 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 types 1 and type 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 KayserFleischer rings) Treatment General concepts 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 these medications 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. 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 17 Initial treatment: 750-1500 mg/day divided b.i.d. or t.i.d.

Maintenance therapy: 750-1000 mg/day. 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.19 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

American Thoracic Society/European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency, Am J Respir Crit Care Med, 2003

20

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.20 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. 20

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.20 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.

Viral hepatitis Hepatitis A General concepts 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). Clinical manifestations 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. URSO 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). Post exposure prophylaxis If the exposed is a healthy person between 12 months and 40 years, give HAV vaccine within 2 weeks of exposure. HAV Immunoglobulin can be given as an alternative. If the exposed person is older than 40 years, immunocompromised, or with chronic liver disease, give both HAV vaccine and the HAV immunoglobulin.

Hepatitis B

Practice guidelines: Chronic hepatitis B, AAASLD, 2009 21 Hepatitis B is a DNA virus of the hepadnaviridae family of viruses.

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. < 1% of these patients develop acute fulminant hepatitis. More than 95% of patients will recover completely. < 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.22 Interferons should be avoided. Treatment with any of the oral antivirals is appropriate.

Chronic Hepatitis B Chronic hepatitis B infection (acquired at birth) passes through several stages (table 4).

Table 4: Stages of chronic hepatitis B infection

Treatment 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. The AASLD management approach to HBV treatment is shown in figure 2 . Figure 2: AASLD algorithm for the management and follow up of chronic hepatitis B infection. (Adapted from Lok AS, et al. Chronic hepatitis B: update 2009. Hepatology 2009;50(3):661-2, with permission)

For compensated cirrhosis, treat if HBV DNA > 2000 IU/mL. Consider treatment in those with HBV DNA < 2000 IU/mL. For decompensated cirrhosis or acute hepatitis B, treatment is always indicated. Consider treatment in high risk pregnant females (discussed later) and patients receiving immunosuppression (discussed later). 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

First line medications are those with a high resistance barrier (entecavir or tenofovir). Lamivudine is cheaper but has a high rate of resistance. 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 is associated with Fanconi syndrome and renal insufficiency in patients treated for HIV/HBV co-infection (rare). HIV/HBV coinfection:21 (HAART: Highly Active Anti-Retroviral Treatment) If the patient is not on HAART and is not anticipated to be started on HAART: Treat with peg interferon-alpha (if CD4 > 500 and HBeAg+) or adefovir. This treatment has no anti-HIV effect. If the patient is starting HAART and HBV treatment: Treat with lamivudine + tenofovir or emtricitabine + tenofovir. If the patient is already on HAART: 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 If HBV DNA > 2000 IU/mL, switch or add alternative drug. If HBV DNA > 60 and < 2000 IU/mL (partial response) 23 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. If HBV DNA is negative, continue therapy. The main goal of treatment is to achieve a negative HBV DNA at week 48. Treatment endpoints In patients with HBeAg (-) disease, treat until HBsAg clearance. In patients with cirrhosis, consider stopping treatment if the patient achieved HBsAg clearance. Otherwise, treat indefinitely. In patients with HBeAg (+) disease, treat for 6-12 months after HBeAg seroconversion. Antiviral resistance 21 Resistance rates to antiviral therapy are shown in table 6. 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). 21

This is followed by the biochemical breakthrough (increase in serum ALT). Management Confirm that the patient is compliant with therapy. Confirm antiviral resistance with genotypic testing. Switch or add medications as outlined in table 6.

Table 6: Rate of viral resistance to hepatitis B therapy and corresponding management

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. Discuss risks and benefits of treatment. 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 (>108). 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). The medications used in these studies were lamivudine and telbivudine. Management approach Measure HBV DNA at the end of the second trimester (week 26-28).24 If the mother has a prior child with HBV (+) (regardless of her DNA level), or if

HBV DNA is > 106, consider treatment with antivirals to decrease the risk of transmission. If HBV DNA < 106, antivirals are not recommended. At delivery Cesarean section is not recommended as there is no consistent evidence that it reduces the risk of neonatal transmission. Give HBIG and vaccination to the newborn. Postpartum If antivirals were started during pregnancy, consider continuing treatment after delivery. This depends on the mother's plans for future pregnancy and breastfeeding. Breastfeeding is safe in patients with chronic hepatitis B who are not on antiviral therapy. It is not recommended while on antiviral therapy due to lack of safety data. Lamivudine is not recommended for long term use due to the high rate of viral resistance. If treatment is discontinued after delivery, monitor the patient for the development of a flare for at least 6 months.

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 25

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).25

Table 8: recommended post exposure prophylaxis for exposure to HBV (CDC 25)

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. If HBsAg (+), this indicates active HBV infection. Treat with antivirals. Start treatment two weeks before immunosuppressive treatment is initiated, and continue until six months after treatment completion.

If HBsAg (-), HBcAb (+), HBsAb (+/-), this indicates prior exposure to HBV. There is a low risk for reactivation, even if HBsAb is (+). Monitor HBV DNA for reactivation during immunosuppressive treatment. Consider antivirals in high risk patients (BMT patients or those receiving rituximab). If only HBsAb is (+), this indicates immunity to HBV. Treatment is not indicated.

Hepatitis C

Recommendations for Testing, Managing, and Treating Hepatitis C, AASLD, IDSA 2014- http:/www.hcvguidelines.org, Introduction 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. HCV is the most common cause of chronic hepatitis and cirrhosis in the USA. Most hepatitis C acute infections progress to chronic infection. Both the CDC and the U.S. Preventive Services Task Force (USPSTF) recommend one-time testing for HCV-Ab of all people born during the 1945-1965 time period, regardless of their risk factors for hepatitis C.26, 27 There has been a tremendous improvement in drug regimens and treatment success over the past decade. In late 2013, two new antivirals (Simeprevir and Sofosbuvir) were FDA approved for the treatment of HCV.

Treatment of hepatitis C The goal of HCV therapy is to achieve sustained virologic response (SVR), defined by an undetectable HCV RNA at six months after the completion of therapy. SVR indicates HCV cure. General factors influencing SVR High fibrosis score on liver biopsy is associated with lower SVR. Caucasian race has a higher SVR compared to non-Caucasian race. Higher BMI is associated with a lower SVR​​. Genotype 1a has ~10% lower SVR compared to genotype 1b. Prior partial response or null response is associated with lower SVR. IL-28B genotype (SVR is higher in CC genotype > CT > TT). Newly approved HCV antiviral therapy

Simeprevir (Olysio®) is a protease inhibitor. It is FDA approved for HCV genotype 1. Treatment regimens are shown in figure 3. Figure 3: Simeprevir treatment regimens.

Sofosbuvir (Sovaldi®) is an RNA polymerase inhibitor.

It is FDA approved for use in genotypes 1, 2, 3, or 4. It is associated with high cure rates (> 90%) using a 12-week course of therapy for most patients. The recommended treatment regimens for treatment naive patients and prior relapsers are shown in table 9 (HCVguidelines.org). Regimens will continue to evolve. Check for updates frequently.

Table 9: Recommended HCV treatment regimens for treatment-naive or prior relapsers 28

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%). 25 Management Test the exposed individual for baseline anti-HCV Ab and liver enzymes. Consider HCV RNA in 4-6 weeks after exposure if earlier diagnosis is desired. Test for anti HCV Ab, HCV RNA, and liver enzymes in 4-6 months. There is no role for post exposure immunoglobulin or other antiviral treatments. 15%-25% of patients with acute HCV infection spontaneously resolve their infection.25 Therefore, treatment should be withheld during the first 6 months after the onset of infection.

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. 29 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.30

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. 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 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%). Hepatitis E does not lead to chronic hepatitis.

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. Antibiotics should be given for at least 6 weeks. Treat the underlying source of infection. 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. 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 intraabdominal infection).

Vascular diseases of the liver

Vascular Disorders of the Liver, AASLD, 2009 31

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 10) Multiple risk factors can coexist and result in a hypercoagulable state and thrombosis. Clinical manifestations 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.

Table 10: Risk factors for Budd-Chiari syndrome

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. Chronic presentation Patients present with chronic symptoms and develop portal hypertension and cirrhosis. 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. 31 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 Angioplasty with or without stent placement: this aims to relieve the obstruction of the inferior vena cava or hepatic veins. Thrombolysis: direct injection of thrombolytics into the thrombosed vein should be considered in acute Budd-Chiari syndrome. 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.33 Therefore, TIPS is recommended in patients who do not improve on anticoagulation.34 Surgical portosystemic shunts have high rates of perioperative complications in patients with advanced liver disease. Liver transplantation is indicated in patients with fulminant hepatic failure or chronic BCS with decompensated cirrhosis.

Portal vein thrombosis Risk factors for portal vein thrombosis (PVT) are shown in table 11.

Table 11: Risk factors for portal vein thrombosis

Clinical manifestations PVT can be asymptomatic or present with abdominal pain, nausea, vomiting. In addition, PVT can lead to portal hypertension and esophageal and gastric varices. Diagnosis Doppler ultrasound, CT scan, MRI. 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 portal vein thrombosis: anticoagulation is indicated in all patients to induce recanalization of the portal vein and prevent further extension of the thrombosis. Treat for at least 3 months.31 Consider long term anticoagulation, especially in patients with hypercoagulable states or those with extensive thrombosis.

Chronic portal vein thrombosis Screen for esophageal and gastric varices and treat with beta blockers or endoscopic band ligation for primary prevention. Consider anticoagulation in patients with permanent prothrombotic states. Portal vein thrombosis in patients with cirrhosis: current guidelines recommend that anticoagulation in patients with cirrhosis and acute or chronic PVT should be considered on a case by case basis.31 However, recent retrospective and prospective studies have shown benefit of anticoagulation in cirrhosis with acute or subacute thrombosis, with increased recanalization rates, and low bleeding complications. 35-37 In these patients, rule out malignant portal vein thrombosis. Screen for esophageal and gastric varices. Varices per se are not a contraindication for anticoagulation. Start anticoagulation once esophageal varices are banded or treated with beta blockers. In patients with adequate renal function, consider low molecular weight heparin for anticoagulation instead of coumadin. There is no evidence for anticoagulation in patients with cirrhosis and chronic PVT.

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 (SCT). Ingestion of herbal teas containing pyrrolizidine (e.g. bush tea) has been linked to the development of SOS in developing countries.38 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 SCT. 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 12):

Table 12: Criteria for the diagnosis of sinusoidal obstruction syndrome after SCT

Other supportive tests Doppler ultrasound shows reversal of portal venous flow, abnormal hepatic venous flow pattern, and gallbladder wall edema. 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. Measurement of the hepatic venous pressure gradient: a value of > 10 mmHg is highly specific for SOS.41 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 or tissue plasminogen activator (t-PA) are not recommended.31 Prophylaxis AASLD guidelines do not recommend for or against any type of prophylactic regimen due to insufficient evidence.31 Agents that can be considered are ursodiol, low molecular weight heparin, and defibrotide.

Congestive hepatopathy Congestive hepatopathy refers to liver disease secondary to passive congestion and elevated central venous pressure. Etiology: right sided heart failure (most common cause), constrictive pericarditis, severe pulmonary hypertension.42 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, as there is no pressure gradient between the portal and the central venous systems. Labs Mild elevation in ALT, AST and bilirubin. Prothrombin time can be prolonged in severe cases. Imaging Cardiac echocardiogram is performed to evaluate the right and left ventricular function. Abdominal imaging (CT/MRI) can show signs of liver congestion such as 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. 42 "Nutmeg liver" is a term used to describe the gross appearance of the congested liver. 42 Liver biopsy Histology shows atrophy, sinusoidal distention, fibrosis extending between the central veins, forming a "reversed lobulation" pattern. 43 Treatment Treat underlying cardiac disease. Diuretics. Paracentesis as needed.

Alcoholic liver disease

Alcoholic Liver Disease practice guidelines, AASLD, 2010

44

Acute alcoholic hepatitis Clinical presentation: jaundice, fever, ascites, encephalopathy, and coagulopathy. 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) 4.6 x [patient's PT-control PT (seconds) ] + serum bilirubin (mg/dL)

Liver biopsy is rarely required for diagnosis Features of alcoholic liver disease include macrovesicular steatosis, neutrophil infiltrate, Mallory bodies (eosinophilic material within the cytoplasm of hepatocytes). These findings are not specific, and can be seen in non-alcoholic steatohepatitis. Treatment Alcohol abstinence. Nutritional support. Corticosteroid therapy Indications for corticosteroids include DF > 32 or hepatic encephalopathy. Contraindications for corticosteroids include sepsis, hepatorenal syndrome, and GI bleeding. These patients were excluded from the studies of corticosteroids in alcoholic hepatitis. Treatment regimen: prednisolone 40 mg daily for 30 days, then dose taper over 23 weeks. The Lille score is calculated on day 7 to determine if there is a response to corticosteroids.45 A Lille score ≥ 0.45 indicates lack of response to treatment with a 6-month survival rate of < 25%. Discontinue steroids. A Lille score < 0.45 indicates a good response with a 6-month survival rate of 85%. Continue steroids.

Calculators: http://gihep.com

Pentoxifylline Consider pentoxifylline if corticosteroids are contraindicated. Pentoxifylline improves in-hospital mortality in severe alcoholic hepatitis and reduces the risk of developing hepatorenal syndrome.46 Dose: 400 mg t.i.d. for 28 days. 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). 47

There was a trend towards a lower incidence of hepatorenal syndrome at 6 months in the prednisolone-pentoxifylline group compared to the prednisoloneplacebo group (8.4 % vs. 15.3%). However, this did not reach statistical significance (p=0.07).

Non alcoholic fatty liver disease

The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease, AASLD,ACG,AGA, 2012 48 Non-alcoholic fatty liver disease (NAFLD) includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). NAFL: hepatic steatosis without inflammation, in the absence of known causes of liver steatosis such as: Alcohol: defined as consumption of > 21 drinks/week in men and > 14 drinks/week in women. Hepatitis C, TPN, abetalipoproteinemia, short bowel syndrome, rapid weight loss. Medications: amiodarone, diltiazem, corticosteroids, methotrexate, tamoxifen, protease inhibitors such as zidovudine, and valproate. NASH: hepatic steatosis with inflammation, with or without fibrosis. Prevalence NAFL affects ~30% of US adults. NASH affects ~3% of US adults. Risk factors DM, dyslipidemia, obesity, metabolic syndrome (table 13). Table 13: Metabolic syndrome

Pathophysiology (two hit hypothesis) First hit: insulin resistance results in increased liver gluconeogenesis, increased adipose tissue lipolysis and decreased fatty acid oxidation. The released fatty acids are taken up by the liver leading to increased lipogenesis. This results in increased fat storage and macrovesicular steatosis. Second hit: once steatosis develops, oxidation of fatty acids in the hepatocyte leads to the formation of reactive oxygen species, which induce inflammatory cytokines and trigger inflammation.49 The end result is steatohepatitis, fibrosis, and cirrhosis. Prognosis Fatty liver is generally benign. The long term risk of cirrhosis is low (< 5%). In contrast, the 10-year risk of cirrhosis in NASH is ~20%. 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.) Test for risk factors for NASH such as diabetes and dyslipidemia. Measure BMI. Liver biopsy Liver biopsy is the gold standard for diagnosis. Findings include steatosis, necroinflammation, ballooning hepatocytes, Mallory bodies, fibrosis. Indications for liver biopsy 48 Patients with increased risk of steatohepatitis and advanced fibrosis: Patients with the metabolic syndrome. Patients with high NAFLD fibrosis score. This non-invasive scoring system is based on several lab values. It was shown to predict the level of fibrosis in patients with NAFLD.50

Patients in whom liver biopsy is needed to exclude other etiologies of liver disease. Management Treatment of metabolic syndrome. Treat cardiovascular risk factors. The most common cause of death in NAFLD is cardiovascular disease. Low salt diet. Smoking cessation. Weight loss A weight loss of 5-10% can improve steatosis and steatohepatitis.

Bariatric surgery should not be performed specifically for NASH. Insulin sensitizers Metformin did not show a major benefit on liver histology in randomized controlled trials. It is not recommended for the treatment of NASH. Pioglitazone ***

Study highlight

(PIVENS) Trial: Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH 51 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 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. 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. Most studies of pioglitazone in NASH were conducted in non-diabetic patients. Pioglitazone can be used to treat biopsy proven steatohepatitis. However, it is not FDA approved for non-diabetics in the USA. *** 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.48 There is no evidence to support its use in patients with diabetic NASH or NASH cirrhosis.

Drug Induced Liver Injury Drug induced liver injury (DILI) is the most common cause of acute liver failure DILI is most commonly related to acetaminophen overdose. Patterns of liver injury Hepatocellular: elevation of ALT and AST. The level of enzyme elevation does not correlate with the severity of liver injury. Severe liver enzyme elevation combined with jaundice is associated with a poor prognosis (Hy's Law). 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 so great that it affected the excretory function of the liver, hence the poor prognosis.52, 53 Cholestatic: elevation of ALKP/bilirubin Drug induced cholestasis per se does not indicate a poor prognosis. Mixed pattern 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). 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. Total drug dose is a risk factor for methotrexate toxicity. 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. 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. Minocycline, nitrofurantoin, diclofenac, propylthiouracil, atorvastatin, and methyldopa can cause liver injury with a presentation similar to autoimmune hepatitis. Patients may develop positive ANA, and liver biopsy may show interface hepatitis. 54 Patterns of liver injury (table 14)

Table 14: Patterns of liver injury

Acetaminophen toxicity Acetaminophen (APAP) toxicity is the most common cause of acute fulminant liver failure. APAP toxicity can result from a single acute overdose or after multiple supratherapeutic doses (chronic ingestion of > 4 gm/day). Metabolism (figure 4) Figure 4: APAP metabolism and toxicity (see text) NAC: N-acetyl cysteine ; NAPQI: N-acetyl-pbenzoquinoneimine

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. Medications and conditions that lower threshold for APAP hepatotoxicity: Drugs that induce cytochrome p450: Isoniazid, phenytoin, carbamazepine, phenobarbital. Drugs that compete with glucuronidation: zidovudine, trimethoprim/sulfamethoxazole. Conditions with reduced glutathione stores: 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 and liver failure. Elevated 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. 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. NAC improves outcome even if given beyond 24 hours of ingestion.55 Dose of NAC Oral: 140 mg/kg loading dose, followed by 17 doses of 70 mg/kg every 4 hours 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.

Autoimmune Hepatitis

The Diagnosis and Management of Autoimmune Hepatitis, AASLD 2010

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Introduction Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver characterized by circulating antibodies and characteristic histopathologic findings 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 (table 15) Table 15: Classification of AIH

Presentations Asymptomatic patients with AIH present with elevated liver enzymes. Symptomatic patients can present with acute hepatitis or chronic hepatitis and

cirrhosis. African American patients have a higher frequency of cirrhosis at presentation. 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. The presence of ductopenia or ductular inflammation may suggest the presence of an AIH-primary biliary cirrhosis overlap syndrome (discussed here and in the PBC section here ). 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). Indications for treatment (table 16) Table 16: Absolute and relative indications for treatment in AIH.

Patients with evidence of cirrhosis on biopsy but without active inflammation (inactive cirrhosis) do not benefit from treatment. Treatment: Any of these regimens is acceptable: 54 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 30 mg/day for 1 week, 20 mg/day for 1 week, 15 mg/day for 2 week then maintenance therapy (≤ 10 mg/day). Azathioprine 50 mg/day (or use a weight-based dose of 1-2 mg/kg). Treat for a minimum of 2 years. Monitor liver enzymes and γ-globulin every 3-6 months.

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. 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, withdraw treatment over a 6-week period with close observation of liver enzymes. Relapse after withdrawing treatment occurs in up to 60% of patients Restart AZP and prednisone. Taper off prednisone and increase AZP to 2 mg/kg. Continue AZP indefinitely. Other treatments: mycophenolate mofetil, budesonide, plasmapheresis. Liver transplantation is highly successful in AIH. Recurrence occurs in about 30% of patients and is usually mild. In patients with AIH-primary biliary cirrhosis 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. Azathioprine is categorized as pregnancy FDA risk category D. However, it seems to be safe 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. Monitor patients closely in the peripartum 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. 54 AZP is considered "probably safe" in breastfeeding.

Primary sclerosing cholangitis

Diagnosis and Management of Primary sclerosing cholangitis, AASLD 2010 56 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. 75% of patients are males. Mean age of diagnosis is ~40 years. Clinical manifestations 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%. Imaging MRCP can provide diagnostic images and preclude the need for a diagnostic ERCP. Findings include multiple areas of stricturing and beading in the intra- and extrahepatic biliary tree. ERCP is helpful when there is progressive jaundice or cholangitis to rule out a stone, dominant stricture, or cholangiocarcinoma. 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 mediumsized and/or large bile ducts. This finding is characteristic of PSC but is uncommon. Risk of malignancy 57 Cholangiocarcinoma Cumulative lifetime incidence in PSC is 10-15%. CA19-9 In patients with PSC, a CA19-9 value of 503U/ml was found to be the best cutoff for the diagnosis of cholangiocarcinoma.58

Screening is controversial. Consider yearly imaging and CA19-9 levels. Gallbladder cancer Lifetime cumulative risk is 2%. Yearly ultrasound is recommended by the AASLD. PSC is a significant risk factor for CRC in UC patients. Yearly colonoscopy is recommended. Small duct PSC Characterized by cholestatic liver enzymes elevation, normal cholangiography, and classic PSC findings on liver 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.59 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. 60 Endoscopic therapy: stricture balloon dilation with or without stent placement is indicated in patients with a dominant stricture. Brush cytology should be obtained as well as other workup for cholangiocarcinoma. Prophylactic antibiotics are given to patients with recurrent cholangitis. 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.61

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis Practice Guideline, AASLD 2010 62 Introduction Definition: primary biliary cirrhosis (PBC) 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. Clinical manifestations 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. Normal or mild elevation of ALT and AST. Hyperlipidemia: 50% of patients have an increase in both LDL and HDL. Most studies have shown that hyperlipidemia in PBC is not associated with an increased risk of cardiovascular disease.63, 64 Antimitochondrial antibodies (AMA) are present in 95% of patients with PBC. AMAs are antibodies against the E2 component of pyruvate dehydrogenase enzyme present on the inner mitochondrial membranes. AMAs are not cytotoxic and not related to disease activity. They persist with treatment. Other antibodies: ANA. 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 patients who are AMA positive with the

typical biochemical profile of PBC. 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. 65 Treatment Ursodiol (URSO®) - Ursodeoxycholic acid (epimer of chenodeoxycholic acid). Mechanism of action 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. Ursodiol increases the export of intracellular bile acids into the canaliculus, therefore protecting the hepatocytes from the harmful effects of bile acids.66 Ursodiol is the only 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 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 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. Add cholestyramine. Consider rifampin, naltrexone. Patients with PBC have an increased risk of osteoporosis and bone fractures. Therefore, check bone density scan every 2-4 years, and give calcium and vitamin D supplementation. Liver transplantation is highly successful in patients with PBC. Atypical cases of PBC Some patients have the typical symptoms and histologic findings of PBC, but with negative AMA. This condition has been called autoimmune cholangiopathy, immune cholangitis, autoimmune cholangitis, or AMA negative PBC. These patients usually have positive ANA and anti smooth muscle antibody. Treatment is the same as PBC. Steroids should be given if liver biopsy shows significant lobular inflammation suggesting overlap with autoimmune hepatitis.

Acute liver failure

AASLD Position Paper: The Management of Acute Liver Failure, Hepatology, 2011

67

Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group, Critical Care Medicine, 2007

68

Definition of acute fulminant hepatic failure: 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. 67 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. Encephalopathy develops due to cerebral edema and increased intracranial pressure, rather than porto-systemic shunting. Labs 67 Obtain a CBC, renal and hepatic panels, INR, ABG, serum lactate.

APAP level, toxicology screen, ETOH level.

Viral serologies: HAV-IgM Ab, HBsAg, HBc-IgM Ab, HCV Ab, HSVIgM Ab. Autoimmune antibodies (ASMA, ANA). Consider Wilson's disease in patients younger than 40 years, especially if there is a low AKLP and high bilirubin. Imaging Ultrasound with doppler or MRI/CT to rule out Budd-Chiari syndrome and check for underlying chronic liver disease and cirrhosis. 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 17). Table 17: Treatment of specific etiologies of ALF

Consider placement of an intracranial pressure (ICP) monitoring device. Management of elevated ICP (> 25 mmHg) and cerebral edema Quiet room. Head of bed elevation. Mannitol is the first line treatment of cerebral edema. Hypertonic saline with a goal serum sodium 145-155 meq/L can be given in high risk patients to prevent cerebral edema. Other treatment options include hypothermia, barbiturate coma. Goal ICP < 25 mmHg. 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.

Screen for infections. Avoid prophylactic antibiotics. Give PPI for prophylaxis of GI bleeding. Vasopressors (norepinephrine is preferred) Recommended in patients with refractory hypotension. Goal MAP ≥ 75 mmHg to achieve a cerebral perfusion pressure (CPP) of 60-80 mmHg (note that CPP = MAP ICP). Liver transplantation Indications for liver transplantation in ALF are shown in table 18. Table 18: King's College criteria for liver transplantation in ALF

Etiologies associated with poor prognosis 67 Idiosyncratic drug reaction, acute hepatitis B, autoimmune hepatitis, mushroom poisoning, Budd Chiari syndrome, Wilson disease. Most patients with mushroom poisoning will require liver transplantation.

Complications of cirrhosis and portal hypertension

Management and Treatment of Patients With Cirrhosis and Portal Hypertension: Recommendations From the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program, Am J Gastroenterol, 200969

Ascites

Management of Adult Patients with Ascites Due to Cirrhosis, AASLD 2013 70 Paracentesis and ascites workup Routine tests include ascetic fluid cell count, protein, and albumin levels. Calculate the serum ascites albumin gradient (SAAG). SAAG > 1.1 indicates portal hypertension related ascites. Total protein of < 2.5 g/dL: cirrhotic ascites. Total protein of ≥ 2.5 g/dL: cardiac ascites (congestive heart failure, constrictive pericarditis) or Budd-Chiari syndrome. 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). 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, amylase, and triglyceride levels. Fluid CA-125 is not helpful, and should not be ordered for any indication. Treatment of cirrhotic ascites Limit dietary sodium to 88 meq (2 grams) per day. Diuretics: spironolactone +/- furosemide.

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 nonurinary losses). This will create a negative sodium and fluid balance. 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 hour 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.71 This can be an alternative to performing a 24-hour urine collection. If Na/k ratio is > 1, then the patient should be losing weight, unless he/she is not compliant with sodium restriction. Limit or avoid NSAIDS, ACE inhibitors. Diuretic resistant (refractory) ascites70 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 and 160 mg of furosemide), or development of treatment related complications (renal failure, electrolyte imbalance). Treatment In patients with refractory ascites, consider discontinuing beta blockers, as they have been associated with increased mortality.72 This is especially important in patients with borderline or low blood pressure, and those with worsening azotemia. Serial therapeutic paracentesis is the first line treatment for resistant or refractory ascites. Consider other treatment options such as midodrine (7.5 mg t.i.d.) and TIPS. Refer 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. Treatment of active SBP Intravenous ceftriaxone or twice-daily PO norfloxacin for 7 days. Avoid quinolones in patients who received quinolone prophylaxis as they may have a resistant organism. Treat with another antibiotic. Give albumin on day 1 (1.5 gm/kg) and day 3 (1 gm/kg). Albumin was shown to decrease the risk of renal failure and increase survival.73 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.74 Performing a repeat paracentesis to document response to treatment is not recommended, unless the patient has atypical or persistent symptoms after treatment. Primary prophylaxis against SBP Indications Patients at high risk of SBP Ascitic fluid protein < 1.5 g/dL and at least one of the following: Serum creatinine ≥ 1.2 mg/dL Blood urea nitrogen ≥ 25 mg/dL Serum sodium ≤ 130 meq/L 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. 75

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 doublestrength tablet once daily. IV ceftriaxone given in GI bleeding. Intermittent dosing is not recommended due to development of 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. Most effusions are right sided (80% of cases). Treatment: sodium restriction, diuretics, thoracentesis. Consider TIPS in refractory cases.

Chest tube insertion is contraindicated, as it has been associated with complications of electrolyte abnormalities, renal failure, and inability to remove the tube. Pleural fluid analysis with PMN ≥ 250 cells/mm3 is consistent with infected fluid (spontaneous bacterial empyema) and could be present in the absence of SBP. Treat with antibiotics for 7-10 days. GI bleeding (Refer to chapter 7-GI bleeding, section on GI bleeding in patients with cirrhosis)

Hepatic Encephalopathy Stages of hepatic encephalopathy (HE) are shown in table 19.

Table 19: Stages of hepatic encephalopathy

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. 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. Medical treatment Lactulose Mechanism of action: 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, thereby lowering plasma ammonia level. Antibiotics Rifaximin Semisynthetic analog of rifampin, minimally absorbed (oral bioavailability is < 0.4%). Inhibits the beta-subunit of RNA polymerase. A randomized, double-blind controlled trial showed that lactulose and rifaximin was more effective than lactulose alone for the treatment of overt hepatic encephalopathy. 76 Complete reversal of HE was achieved in 76% in the combination treatment group compared to 50% in the lactulose alone group. There was a shorter hospital stay and lower mortality in the combination group compared to the lactulose alone group. Rifaximin is FDA approved for the prevention of recurrent HE. *** Study highlight

Rifaximin Treatment in Hepatic Encephalopathy 77 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. Inclusion criteria: two episodes of overt HE, MELD < 25. 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. Intervention: rifaximin 550 mg b.i.d. versus placebo. Lactulose was administered to ~90% of patients in both groups at baseline. Primary endpoint: the time to the first breakthrough episode of HE. Duration of study: 6 months. 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 as compared to the 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. Diagnostic criteria Cirrhosis with ascites. Serum creatinine > 1.5 gm/dL. Lack of improvement after diuretic withdrawal and volume expansion with albumin. Absence of nephrotoxic drugs, shock, infection, or hypovolemia. 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). Subtypes of HRS Type 1: rapidly progressive renal failure with poor prognosis. Type 2: stable renal failure with better prognosis than type 1. 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 HRS Vasoconstrictors and albumin infusion Albumin (1 gram/kg/day) Vasoconstrictors Terlipressin is preferred but is not available in the US. Midodrine (5-7.5 mg PO every 8 hours) combined with octreotide (100-200 mcg subq every 8 hours). Norepinephrine infusion (0.5–3 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

Background Portopulmonary hypertension (PPH) is defined as the presence of pulmonary arterial hypertension in association with portal hypertension, with or without liver disease.78 PPH is present in 2-4% of patients with cirrhosis. Incidence in males = females. Diagnostic criteria 78 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. Clinical manifestations 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 78 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 patients ≥ 65 years old. Positive contrast enhanced echocardiography suggestive of IPVD (see below). Clinical manifestations 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). A contrast agent, usually agitated saline, is injected intravenously. The appearance of bubbles in the left heart within 3-6 heart beats after they appear in the right heart indicates the presence of IPVDs. If bubbles appear in the left heart within three beats of injection, this suggests intra-cardiac shunting. Nuclear scanning: technetium-labeled macroaggregated albumin study. 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. 79 Patients should have an expedited referral and evaluation for liver transplantation.80

Benign Liver tumors 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. 81 More common in females than males. The size of the lesions does not correlate with the presence of symptoms. Imaging CT scan shows peripheral arterial enhancement with gradual filling of contrast. The lesion may have areas of calcification. Hemangiomas have no malignancy or rupture risk. Treatment Asymptomatic patients are managed conservatively and 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. Risk factors HCAs are strongly associated with OCP, especially prolonged OCP use of > 5 years. 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 and III In patients with glycogen storage disease, HCAs show a strong male predominance. Genetic subtypes of HCA 82 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.

Surgical resection if the patient is symptomatic or lesion size > 5 cm. Women with HCA > 5 cm should avoid pregnancy. 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).83 Pregnant women with HCA < 5 cm should be monitored with serial ultrasounds.

Focal nodular hyperplasia Focal nodular hyperplasia (FHN) is the second most common benign tumor of the liver. It presents as a well-circumscribed mass. 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. 84 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. FNH has no malignancy or rupture risk. CT shows a hypodense or isodense lesion on non-contrast sequences that becomes hyperdense in the arterial phase. The central scar is seen in one third of patients. Treatment Asymptomatic patients are managed conservatively and require no specific follow up. If the patient is on OCP, monitor the lesion with ultrasound over 2-3 years for any progression in size. 81 Symptomatic patients are treated with surgical resection.

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. NRH has equal gender predominance. It usually affects middle-aged patients. Liver histology A special reticulin stain demonstrates nodules of hepatocytes compressed with surrounding reticulin fibers. In contrast to cirrhosis, there is no fibrosis in NRH. 85 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

Management of Hepatocellular Carcinoma: An Update, AASLD, 2011 86

EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma, EASL, 2012 87 Epidemiology Hepatocellular carcinoma (HCC) accounts for 85-90% of primary liver malignancies. It is the third most common cause of cancer death worldwide. 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) 88 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 (refer to the section of HBV treatment). 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. 89 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 form of hypoglycemia. 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. 90 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, and a 37% reduction in cancer mortality. HCC surveillance is recommended in the following patients: 86

All patients with cirrhosis, regardless of etiology. Patients with Hepatitis B without cirrhosis who meet any of the following criteria: Asian male hepatitis B carriers over age 40. Asian female hepatitis B carriers over age 50. Hepatitis B carrier with family history of HCC. African/North American Blacks with hepatitis B. Patients on the liver transplant list. Surveillance methods Ultrasound (US) every 6 months Sensitivity is 65%, specificity > 90%. The most recent AASLD guidelines removed AFP as a surveillance method due to its low sensitivity and specificity. The European association for the study of the liver (EASL) also recommends against the use of AFP for HCC surveillance due to its high false positive results, while the national comprehensive cancer network (NCCN) still includes AFP in its screening recommendations 87, 91 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 5.

Figure 5: Diagnostic algorithm for suspected HCC. (Adapted from Bruix, J. et al. Hepatology, 2011. 53(3): p. 1020-1022, with permission)

Diagnosis Cross sectional imaging (figure 6)

Figure 6: HCC. A: T2 MRI shows an enhancing mass on the arterial phase; B: Delayed washout of the same lesion.

The typical radiologic appearance is arterial enhancement (the lesion appears brighter than the rest of the liver) and venous or delayed washout of contrast (the lesion appears darker than the rest of the liver). This appearance is highly specific for HCC and precludes the need for biopsy. Intrahepatic cholangiocarcinoma may have arterial enhancement but lacks delayed washout. Dysplastic nodules do not show arterial enhancement. AFP AFP should not be used to diagnose HCC as it lacks specificity. 86 Mild elevations in AFP can be seen in some cases of intrahepatic cholangiocarcinoma.92 Staging The Barcelona-Clinic Liver Cancer (BCLC) staging system and management is shown in figure 7.

Figure 7: The BCLC staging system for HCC. CTP: Child-Turcotte-Pugh; PST: Performance status; OLT: Orthotopic liver transplantation; PEI: Percutaneous ethanol injection; RFA: Radiofrequency ablation. TACE: Transarterial chemoembolization. (Adapted from Bruix, J. et al, Hepatology, 2011. 53(3): p. 1020-1022, with permission)

Treatment Surgical resection Surgery 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 93 This pivotal study enrolled 48 patients with cirrhosis and HCC. 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. All patients underwent OLT. After pathologic review of the explanted liver, 35 patients met the predetermined criteria and 13 did not. Results four years post OLT are shown in table 20.

Table 20: Results four years post OLT

The authors concluded that OLT is an effective treatment for small unresectable HCC. *** Other studies have confirmed that patients with HCC within the Milan criteria have an overall survival of >70 % at 5 years post OLT. Transplanting patients outside of the Milan criteria (expanded criteria) is controversial. 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 MELD exception points. The most important predictor of recurrence of HCC is macro or microvascular invasion in the surgical specimen. If OLT waiting time is expected to be > 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) 86 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%. Survival in patients with solitary HCC < 3 cm treated with PEI is similar to surgical resection. Radiofrequency ablation (RFA) Efficacy is similar to PEI in lesions < 2 cm. However, it requires less treatment sessions. The 5-year survival is 70%. RFA is superior to PEI in patients with lesions > 2 cm. RFA is generally avoided in subcapsular lesions, as there is an increased risk of peritoneal seeding. Outcomes in patients with solitary HCC < 2 cm who are treated with RFA are similar to surgical resection. 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. Post-embolization syndrome Occurs in > 50% of patients. Presents with fever, abdominal pain, and ileus. Treatment is supportive. It resolves in most patients within 48 hours. Sorafenib Sorafenib was FDA approved for the treatment of HCC based on the "SHARP" study. 94 This study showed that in patients with CTP class A and advanced HCC, sorafenib treatment resulted in improved survival compared to placebo (10.7 vs. 7.9 months).

Side effects of sorafenib included diarrhea, hand-foot skin reactions, and alopecia. 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%. 95

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.96 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. 97 Liver transplantation is performed in some expert centers but remains experimental at this time.

Liver transplantation

AASLD Practice Guidelines: Evaluation of the Patient for Liver Transplantation, AASLD, 2005

80

Overall survival post orthotopic liver transplantation (OLT): 85-90% at 1 year, 75% at 5 years. Immunosuppressive drugs used post OLT are shown in table 21 (the first five are the most important).

Table 21: Immunosuppressive drugs

Drug-drug interactions (tables 22 and 23)

Table 22: Important drug interactions with cyclosporin and tacrolimus

Table 23: Clinically relevant drug interactions with mycophenolate mofetil

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. Recurrent hepatitis C infection post liver transplantation Graft reinfection is universal among hepatitis C patients. Recurrent hepatitis C graft infection is associated with rapid progression of fibrosis. ~ 30% of patients will develop cirrhosis after 5 years. Differentiating between acute cellular rejection versus recurrent hepatitis C following OLT is achieved by careful examination of the liver biopsy (table 24).100 Clinical and laboratory findings are non-specific.

Table 24: Acute cellular rejection versus recurrent hepatitis C

Biliary complications after liver transplantation are discussed in chapter 5-biliary tract.

Chapter 5- Biliary tract Introduction Anatomy and developmental anomalies Bile duct anatomy Choledochal cysts Gall bladder disease Gallstones Choledocholithiasis Gallbladder polyps Biliary complications after liver transplantation Biliary strictures Bile leaks References

Introduction 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, do not automatically perform an ERCP. Use the scoring system suggested by ASGE to predict the likelihood of common bile duct stones, and order noninvasive imaging studies (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.

Anatomy and developmental anomalies Bile duct anatomy Figure 1 shows the anatomical variations of the intrahepatic bile ducts. For the gastroenterologist, 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.

Choledochal cysts

Figure 2 shows the different types of choledochal cysts. Figure 2: Types of choledochal cysts

Table 1 summarizes the different types of choledochal cysts and their management. Table 1: Choledochal cysts

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.1 The overall lifetime risk of malignancy is 10-15%, which is 20-30 fold increased compared to the general population. The risk increases with increasing age. In some cases, there is an abnormal biliopancreatic junction. The pancreatic duct drains into the bile duct, which increases the risk of malignancy of the bile duct and gallbladder. This increased risk is likely related to pancreatic reflux and chronic inflammation.

Gall bladder disease Gallstones Types of gallstones Cholesterol stones are the most common type in adults. These are 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 Increasing 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 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 refers to 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. It is only 50% sensitive for CBD stones. 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".

The risk of coexisting GB malignancy is ~ 20%. 3 Patients with choledochal cysts, or abnormal biliopancreatic junction. Patients with GB polyps > 10 mm. Astronauts with gallstones before long duration space missions (controversial).4 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. 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. Choledocholithiasis

ASGE: The role of endoscopy in the evaluation of suspected choledocholithiasis, GIE 2010 5 ● In patients with gallstone complications such as biliary pain or acute gallstone pancreatitis, use the following scoring system to decide on further biliary workup prior to cholecystectomy.

Table 2: Predictors of choledocholithiasis and corresponding management (ASGE) 5

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.6 Cholecystectomy should be performed in these patients. Follow up ultrasound every 6-12 months is recommended in poor surgical candidates and those with polyps smaller than 10 mm.

Cholangiocarcinoma Risk factors of cholangiocarcinoma: PSC (cumulative incidence of ~9% after 10 years),7 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. 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: 8 In the absence of cholangitis: sensitivity 78%, specificity 83%. 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.9 Tissue acquisition in suspected malignant biliary strictures remains suboptimal (table 3). Combining different techniques increases the diagnostic yield.

Table 3: Tissue acquisition modalities in cholangiocarcinoma

Treatment Biliary drainage ERCP with stenting is the treatment of choice. Refer to chapter 11-endoscopy for the Bismuth-Corlette classification of perihilar tumors and principles of hilar stenting. 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

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

Biliary complications after liver transplantation Types of biliary anastomosis Duct to duct anastomosis. 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. Living donor liver transplantation (LDLT) 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. Right liver graft recipients have higher rates of complications compared to left liver graft recipients. Bile leaks occur in up to 10% of donors. Biliary strictures Clinical manifestations 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. Most patients require 3-5 ERCP sessions. Prognosis Long term success rate is 70-100%. Choledochojejunostomy strictures are treated with percutaneous dilation and stent placement. ERCP for choledochojejunostomy strictures is technically challenging, requires special instruments, and is not available in all centers.

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 away from the anastomosis. Risk factors18 Ischemic strictures develop secondary to hepatic artery thrombosis. These present within 1 year after transplantation. Immunogenic: ABO incompatibility, autoimmune hepatitis, PSC. 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. 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 retransplantation.19 Patient survival is not affected. Bile leaks 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. 20 Due to slower healing in liver transplant patients, stents are kept for a longer duration compared to those placed for bile leaks following cholecystectomy. 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.

Chapter 6- Pancreas Introduction Developmental anomalies Acute pancreatitis Chronic Pancreatitis Etiology Diagnosis Treatment Complications Autoimmune pancreatitis Pancreatic cysts and tumors Intraductal papillary mucinous neoplasm Mucinous cystic neoplasm Serous cystadenoma Solid pseudopapillary neoplasm Pancreatic adenocarcinoma Pancreatic neuroendocrine tumors Insulinoma Gastrinoma Glucagonoma VIPoma Somatostatinoma Familial syndromes associated with pancreatic NET References

Introduction Pancreatic disorders account for 10% of the GI boards' questions. Favorite topics are pancreatic cysts and neuroendocrine tumors. Acute pancreatitis is common in clinical practice. It is important to identify the etiology and assess the severity of the acute episode. Aggressive, but careful fluid resuscitation is important to prevent the development of pancreatic necrosis. It is imperative to be knowledgeable of the different types of pancreatic fluid collection, as they differ in their management approach. Treatment of pain in chronic pancreatitis remains generally disappointing. Randomized trials of surgical versus endoscopic therapy are important to review. However, keep in mind that they may not apply to your chronic pancreatitis patients, and the result of therapy will vary in clinical practice. 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. However, most patients with classic pancreatic cancer presentations (severe obstructive jaundice, pain, and weight loss) will have pancreatic cancer.

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%) 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%) 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) 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 1F)

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 complains of intermittent abdominal pain, vomiting, and symptoms of gastric outlet obstruction. 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

Acute pancreatitis

ACG Guideline: Management of Acute Pancreatitis, Am J Gastroenterol, 2013

2

AGA Institute Technical Review on Acute Pancreatitis, Gastroenterology 2007

3

Definition: requires two of the following criteria:2 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 include post-ERCP pancreatitis (see chapter 11 -endoscopy), hypertriglyceridemia, hypercalcemia, and abdominal trauma. Drug-induced pancreatitis: AZP/6-MP, valproate, ACE inhibitors, aminosalicylates, furosemide, and many other medications. Classification 4 Acute interstitial pancreatitis Acute inflammation in the pancreas and peripancreatic tissue without necrosis. Overall mortality is 3%. Acute necrotizing pancreatitis Acute inflammation associated with pancreatic and/or peripancreatic necrosis. Overall mortality is 17% (up to 30% in infected necrosis). 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, rising BUN and hematocrit.2 Scoring systems are generally difficult to use and not practical. Examples are: Ranson’s score for establishing severity of acute pancreatitis (table 1).

Table 1: Ranson’s criteria for establishing severity of acute pancreatitis

A score of ≥ 3 indicates severe pancreatitis.

The acute physiologic and chronic health evaluation (APACHE II) score A score ≥ 8 indicates severe pancreatitis. 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). Signs of inadequate resuscitation include increasing hematocrit levels, tachycardia, hypotension, and decreased urine output. Maintain a urine output of > 0.5 ml/kg/hour. IV Analgesia, O2, NG tube if significant nausea and vomiting. Nutrition Enteral feeding (nasogastric or nasojejunal tube) is the preferred method of providing nutrition in patients with acute pancreatitis who are unable to tolerate PO.

Enteral feeding is associated with fewer complications compared to TPN. Limitations to enteral feeding include severe ileus and difficulty inserting a nasojejunal tube. Randomized trials showed that in severe AP, nasogastric tube feeding demonstrated similar safety and efficacy compared to nasojejunal feeding.2, 5 Therefore, nasogastric feeding is an acceptable alternative if a nasojejunal tube cannot be placed. 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. Right upper quadrant ultrasound is more sensitive for gallstones than CT scan, and should be performed in all patients with suspected cholelithiasis. Antibiotics in necrotizing pancreatitis This topic is still controversial. ACG guidelines state that antibiotics are not recommended in patients with necrotizing pancreatitis, while the AGA guidelines recommend restricting antibiotics to patients with extensive pancreatic necrosis (>30%). 2, 3 Recommended antibiotics are imipenem-cilastatin, meropenem, or a combination of a quinolone and metronidazole. 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. 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. 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. In cases when there is a lower level of suspicion of choledocholithiasis, non invasive tests such as EUS or MRCP can be performed for further workup (see chapter 5-biliary tract). Cholecystectomy is indicated in all patients with acute biliary pancreatitis to prevent recurrence. Consider ERCP and sphincterotomy in patients who are not surgical

candidates. Peripancreatic fluid collections in the setting of acute pancreatitis Peripancreatic fluid collections are classified according to the time they develop in relation to the acute pancreatitis episode (table 2). Fluid collections develop following acute interstitial or acute necrotic pancreatitis. Table 2: Revised Atlanta classification of peripancreatic fluid collections in acute pancreatitis 4

Fluid collections can be sterile or infected. In the case of suspected infection, CT guided aspiration of the fluid collection for gram stain and culture should be performed. Most acute peripancreatic fluid collections resolve spontaneously. Observation and repeat imaging in 8-12 weeks is reasonable in most patients without infection. Pancreatic necrosis Sterile necrosis: most patients will improve with supportive care. If the patient has persistent symptoms of nausea, vomiting, abdominal pain, and

inability to tolerate oral diet, then surgical or endoscopic debridement is indicated. Infected necrosis: the classic approach is surgical debridement. In a clinically stable patient, an alternative approach is expectant management with intravenous antibiotics and supportive care for several weeks before attempting definitive management. This will give time for the necrotic collection to mature, liquefy, and become walled off to allow for easier debridement. 3 Debridement options for walled off pancreatic necrosis include surgical necrosectomy, endoscopic (transgastric or transduodenal) necrosectomy, or percutaneous drainage.

Chronic Pancreatitis Etiology Etiologies and risk factors for chronic pancreatitis (CP) are summarized in table 3. Table 3: Classification of etiologies of chronic pancreatitis according to the TIGAR-O system6

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 4. Table 4: Genetic mutations linked to the development of CP

Diagnosis Functional tests Non invasive tests 72-hour fecal fat collection: this test is considered 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. Invasive tests (available in few referral centers) Secretin stimulation test (double tube test) Test concept 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, and is only available in few referral centers. Structural tests All structural tests are more sensitive for late CP than for early CP. Radiologic tests include Xray, ultrasound, MRI, CT. Endoscopic tests include ERCP and EUS. ERCP features of CP include dilated main pancreatic duct, dilated side branches, strictures, and stones. EUS features of CP are discussed in chapter 11- endoscopy.

Treatment

Confirm the diagnosis of CP by carefully reviewing the patient's history and diagnostic tests. 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. Medical therapy of pain in CP Consider referral to a specialized pain clinic. Treat coexisting depression. Analgesics include tylenol, NSAIDS, and tramadol. Narcotics carry a high risk of addiction. Trial of 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). Exogenous pancreatic enzymes denature CCK-RF, which limits CCK release and 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. Figure 2: Prop osed mechanism of actio n o f pancreatic enzymes in relieving pa in of CP. CCK-RF: cholecystokinin relea sing factor

Endoscopic therapy Limited to advanced cases of CP with pancreatic duct (PD) obstruction or stones.

The ideal candidate for endoscopic therapy is the patient with PD stone or stricture in the head of the pancreas with upstream ductal dilation. The goal is to improve pancreatic drainage and thus decrease intrapancreatic pressure. 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, 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. 7 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. It provides short term pain relief (average duration of 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 (Berger and Frey procedures), or total pancreatectomy. Studies comparing endoscopic and surgical therapy *** Study highlights

Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis 8 This is a randomized trial of 39 patients with severe advanced CP and distal obstruction of the PD without an inflammatory mass. Patients were randomised to either endoscopic therapy (n=19) with sphincterotomy, lithotripsy, PD stenting or pancreaticojejunostomy (n=20). 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. The study was terminated early due to the superior outcomes in the surgical group. Results of the five-year follow up of this study was published separately and showed that 68% of patients treated with endoscopic therapy required additional procedures compared to only 5% in the surgery group.9

47% of the patients in the endoscopy group eventually underwent surgery. Pain relief was superior in the surgical group compared to the endoscopic group. *** Study highlights

A Prospective, Randomized Trial Comparing Endoscopic and Surgical Therapy for Chronic Pancreatitis 10 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. 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). 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. ***

Complications Pancreatic pseudocyst Definition: peripancreatic fluid collection that develops more than 4 weeks after acute pancreatitis and has a well defined wall. It develops as a consequence 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 is causing minimal symptoms, consider watchful waiting and repeat imaging every 3-6 months.

Cyst drainage options Endoscopic drainage Cyst gastrostomy or cyst duodenostomy (with or without EUS) Transpapillary pancreatic stenting: consider this option if the cyst is small and if there is clear communication with the PD. Bridging the site of ductal leakage will increase the chances of successful cyst resolution. Percutaneous drainage 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. Treatment of asymptomatic strictures is controversial. Endoscopic therapy 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. Placement of a covered metal stent for treatment of CP biliary strictures has the potential to treat these strictures with less ERCP sessions. However, covered metal stents are not FDA approved for this indication, and further studies are required to characterize their role in these benign strictures. Surgical treatment is associated with the highest long term success. Choledochoduodenostomy 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 during ERCP. Pancreatic ascites and pleural effusion. The fluid has a characteristically high amylase level (>1000 IU/mL). Evaluate for pancreatic leakage with CT/MRCP/ERCP. Treatment Conservative management if there is a small volume ascites or pleural effusion. TPN, octreotide. PD stent is indicated if there is a documented PD leakage. Needle aspiration. Surgical resection and drainage. 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 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).

Start with a formulation containing 16,000-20,000 units per pill. Give 2-3 pills per meal. Titrate up to 2500 units/kg/meal. Higher doses have been associated with fibrosing colonopathy (rare). Endocrine dysfunction Diabetes is a late manifestation of CP. Most patients require insulin. Since pancreatic alpha cells that produce glucagon are also destroyed, there is a higher incidence of hypoglycemia in these patients. Pancreatic adenocarcinoma CP increases the risk of pancreatic adenocarcinoma. The cumulative risk is around 1.8% after 10 years and 4% after 20 years of follow up. 11 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 70.12

Autoimmune pancreatitis

International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology, Pancreas, 2011 13 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. Table 5: Autoimmune pancreatitis subtypes

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 delayed rim enhancement, and absence of pancreatic ductal dilation. Atypical features: focal pancreatic enlargement. Abrupt cutoff of the PD with upstream pancreatic atrophy is suggestive of malignancy. Serology: elevated serum IgG4 ≥ 2 folds ULN. Ca 19-9 can be elevated in AIP. Similarly, IgG4 can be elevated in 10% of patients with pancreatic cancer. Other organ involvement Response to steroids therapy Treat with steroids and repeat pancreatic imaging, Ca 19-9 and IgG4 in 2-4 weeks. Objective improvement of abnormal imaging and a decreasing Ca 19-9 is suggestive of AIP. Improvement of clinical symptoms is not specific to AIP. A rising Ca 19-9 is suggestive of another diagnosis, possibly cancer. A decrease in IgG4 levels should not be considered diagnostic of AIP. Falsely elevated IgG4 due to malignancy can also decreases with steroid therapy.14 Furthermore, IgG4 levels remain elevated in many patients with AIP treated with steroids. Therefore, IgG4 does not appear to be useful in disease monitoring.15 Treatment Initial treatment: prednisone 40 mg /day for 4 weeks, then taper the dose by 5 mg/week. Relapse occurs in up to 40% of patients. Treat with repeat steroids. Consider maintenance low dose steroids or thiopurines for at least 2 years.

Pancreatic cysts and tumors

ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts, Am J Gastroenterol, 200717

International consensus guidelines for the management of IPMN and MCN of the pancreas, Pancreatology, 2012 18 Pancreatic cystic neoplasms (table 6) Differentiating between the different types of pancreatic cysts requires careful review of the clinical history, cross sectional imaging, EUS, and cyst fluid characteristic. Table 6: Characteristics of pancreatic cystic neoplasms

Intraductal papillary mucinous neoplasm Intrapapillary mucinous tumors (IPMNs) are intraductal papillary epithelial growths that overproduce mucous leading to ductal dilation or obstruction. Ductal obstruction can result from the papillary growth or mucin and can lead to acute pancreatitis. IPMNs are located in the main PD in 60% of cases, in side branches in 30% (branch

duct IPMN), and in both locations in 10% of cases. Fluid characteristics Small volume, viscous, mucoid fluid with high amylase and high CEA. 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, main PD diameter ≥ 10 mm, presence of lymphadenopathy, atypical FNA cytology. Management approach Main duct IPMN: surgical resection is indicated. Risk of malignancy is estimated at 70%. Branch duct IPMN General indications for surgery: symptomatic lesions, suspicious features including presence of intramural nodules, mass, size > 3 cm, positive or suspicious cytology. Patients without indications for surgery should be followed with repeated imaging studies (EUS/MRI/CT). Figure 3 summarizes the management approach for branch duct IPMN.18 Figure 3: Management of branch duct IPMN . Patients who are not surgical candidates or who refuse surgery should be closely followed with repeat imaging .

Mucinous cystic neoplasm Imaging characteristics Mucinous cysts are usually large (> 5 cm), monolocular, and may have calcification in their wall (eggshell calcification). Fluid characteristics Large volume, mucoid fluid with high viscosity, high CEA, and low amylase. Cytology reveals mucin secreting epithelial cells with or without dysplasia or malignant features. The cooperative pancreatic cyst study showed that a CEA level above a cutoff of 192 ng/mL was more accurate compared to EUS morphology and cytology in the diagnosis of mucinous cystic lesions of the pancreas.19 Surgical resection is recommended due to the high malignant potential of these cysts.

Serous cystadenoma Imaging characteristics: usually small (< 5 cm), and has multiple microcysts with thin septation forming a honeycomb appearance. 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, usually bloody, low CEA, low amylase. Cytology reveals a glycogen rich cellular aspirate (PAS positive). Malignant transformation is rare, therefore surgery is recommended only in symptomatic patients.

Solid pseudopapillary neoplasm 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.20 Immunostaining is positive for vimentin, CD10, and beta-catenin.21 Malignant transformation is uncommon but has been described. Surgical resection should be attempted in patients who are fit for surgery.

Pancreatic adenocarcinoma Epidemiology In the United States, the estimated incidence of pancreatic cancer in 2013 is ~ 45,220 new cases.22 It is the 4th leading cause of cancer death in the United States. 22 Risk factors Obesity, smoking, pancreatic cancer in a first-degree relative, cystic fibrosis, chronic pancreatitis and hereditary pancreatitis. Other syndromes that predispose to pancreatic cancer are shown in table 7.

Table 7: Syndromes that predispose to pancreatic cancer.

Clinical manifestations Weight loss, anorexia, abdominal pain, back pain, jaundice, itching, nausea, vomiting. Physical findings include cachexia, jaundice, and hepatomegaly. Courvoisier’s sign: enlarged palpable gallbladder. Trousseau sign: superficial venous thrombosis. Acute pancreatitis is an uncommon presentation of pancreatic cancer (~1%).28 Pancreatic cancer is found in up to 6% of patients with non-alcoholic, non-gallstone related acute pancreatitis.28 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. 29 Diagnosis Imaging: CT, MRI, ERCP, EUS-FNA CT-guided biopsy of the pancreas or of a metastatic lesion. Tumor markers 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. Whipple pancreaticoduodenectomy is the most common surgery. Only 10-15% of patients are resectable at presentation. 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 given. Issues in the endoscopic management of patients with pancreatic cancer Palliation of malignant gastric outlet obstruction Surgical gastrojejunostomy and endoscopic stent placement should both be considered in patients with pancreatic cancer and gastric outlet obstruction. One randomized controlled trial showed that gastrojejunostomy has better long term symptom relief compared to endoscopic stent placement. 30 There were more major complications and recurrent obstructive symptoms requiring reintervention in the endoscopic stent group compared to gastrojejunostomy. In general, endoscopic stent placement should be considered in patients with expected survival of less than 3 months and in those who are not surgical candidates. Preoperative biliary drainage in patients with pancreatic head cancer and obstructive jaundice. *** Study Highlight

Preoperative Biliary Drainage for Cancer of the Head of the Pancreas 31 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. Patients were randomized to one of the following groups: 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. Surgery alone within 1 week after diagnosis. 67% of patients underwent pancreatic resection (Whipple procedure), while 30% underwent a palliative bypass procedure. 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. The authors concluded that routine preoperative biliary drainage in patients undergoing surgery for pancreatic head cancer increases the rate of complications. Study limitations The rate of ERCP complications was higher compared to other studies and clinical practice. There was an overall 75% initial success rate of ERCP, which is relatively low. 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). 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 pancreatico​duodenectomy analyzed results from 10 heterogeneous studies (8 retrospective and 2 randomized controlled trials).32 337 patients had endoscopic stent placement and 412 patients did not have a stent. There was no difference between the two groups in post-operative mortality and morbidity. Summary 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.

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.

Pancreatic neuroendocrine tumors

ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms: Functional Pancreatic Endocrine Tumor Syndromes, Neuroendocrinology. 2012 33 Pancreatic neuroendocrine tumors (NET) can be functional or nonfunctional. Most nonfunctional tumors are malignant. Functional tumors secrete different hormones leading to symptoms of hormonal excess. Diagnosis depends on detecting an elevated hormonal level combined with imaging studies, such as CT, MRI, and EUS for tumor localization. Octreoscan detects somatostatin receptors that are present on most neuroendocrine tumors.

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 with elevated serum insulin and c-peptide levels. The plasma insulin to glucose ratio is > 0.3. Treatment Surgical resection. Medical therapy includes diazoxide and somatostatin analogues (octreotide).

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.33 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 (ZollingerEllison 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 VernerMorrison 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 pancreatic NET 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. Components of MEN 1 Parathyroid tumors (95% of cases) Pancreatic NETs (60%-80% of cases)

Patients characteristically develop multiple NETs. Gastrinomas are the most common, followed by insulinomas. Most gastrinomas (> 70%) are located in the duodenum.33 Pituitary tumors (50% of cases ) In MEN type 2 syndrome, patients develop medullary carcinoma of the thyroid, pheochromocytoma, and hyperparathyroidism. They do not develop pancreatic NET. Von Hippel–Lindau (VHL) disease This is an autosomal dominant disorder caused by a mutation in the VHL tumor suppressor gene on chromosome 3. 34 Patients develop a variety of tumors. The most common tumors are retinal and central nervous system hemangioblastomas, renal cell carcinoma and pheochromocytomas. In addition, patients develop pancreatic cysts and non-functional NET in 10-17% of cases. Neurofibromatosis type 1 Up to 10% of patients develop pancreatic NET, most commonly duodenal somatostatinoma. Tuberous sclerosis: there is a possible increased risk of pancreatic NET in these patients.35

Chapter 7 - GI bleeding Introduction Peptic ulcer disease bleeding Gastric Stress ulcers UGI bleeding in patients with cirrhosis Acute variceal bleeding Portal hypertensive gastropathy Gastric Antral Vascular Ectasia Lower GI bleeding Obscure GI bleeding References

Introduction 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 obscure GI 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. Do not forget to test and treat H. pylori in patients with peptic ulcer disease. Achieve confidence in dealing with bleeding varices by mastering the banding technique. Familiarize yourself with the insertion technique and handling of the Blakemore tube. In obscure GI bleeding, consider a repeat upper endoscopy with a careful examination focusing on possible missed lesions (e.g. duodenal ulcers, Cameron lesions, GAVE). In obscure overt GI bleeding, obtain multiple complementary studies of the small bowel in search of an underlying etiology. Keep in mind the possibility of small bowel malignancy especially in younger patients.

Peptic ulcer disease bleeding

International consensus recommendations on the management of patients with non variceal upper gastrointestinal bleeding, Ann Intern Med 2010

Management of Patients With Ulcer Bleeding, Am J Gastroenterol 2012

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Clinical manifestations 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). 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. Transfuse PRBC to a Hgb of 7 gm/dL. ***

Study highlight Transfusion strategies for acute upper GI bleeding 3 This randomized controlled trial enrolled 921 patients with severe acute upper GI bleeding. Inclusion criteria: confirmed melena or bloody nasogastric tube output. Exclusion criteria: low risk upper GI bleeding (Rockall score of 0), massive hemorrhage, acute coronary syndrome, transient ischemic attacks, Hgb >12 gm/dL 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. Randomization was performed according to the presence or absence of cirrhosis. Transfusion was given one unit at a time and Hgb was checked following each unit. All patients had an upper endoscopy within 6 hours of presentation. Standard of care was followed in terms of medical and endoscopic therapy. Results 31% of patients had cirrhosis. Bleeding was due to PUD in 49% of patients 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

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. 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.4 Medical management before endoscopy 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. Pre-endoscopic PPI therapy does not decrease re-bleeding rates or mortality. Patients who receive pre-endoscopic PPI are more likely to have non-bleeding ulcers during endoscopy, and are less likely to need endoscopic therapy. 5 IV erythromycin IV erythromycin improves mucosal visualization during endoscopy, increases the diagnostic yield, and decreases the need for a second look endoscopy.2, 6 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. Endoscopy EGD is recommended within 24 hours of an upper GI bleeding episode. A large observational study included (4,478 patients) showed no difference in mortality or the need for surgery between early endoscopy (< 12 hours) and later endoscopy (> 24 hours). There was a trend towards decreased rebleeding in patients who underwent early endoscopic therapy. Late endoscopy (>24 hours) was associated with increased length of hospital stay.7 The Forrest classification and management of peptic ulcer bleeding is shown in table 2.

Table 2: Forrest classification and management of peptic ulcer bleeding

Video 7-1 Management post endoscopy PPI therapy Patients who receive endoscopic therapy for high risk lesions should be treated with IV PPI drip for 72 hours. This was shown to decrease the risk of rebleeding and mortality.8 Low dose PPI IV once or twice daily appears to have similar efficacy to the high dose IV drip.9, 10 For low risk lesions, 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. 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%). 11 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. 12 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.12 Salvage therapies 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. 13 Angiographic embolization 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%. 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.

Gastric Stress ulcers Gastric stress ulcerations 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.14 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

Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis, AASLD 2007

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Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis, Am J Gastroenterol 2007

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Acute variceal bleeding is the most common cause of UGI bleeding in patients with cirrhosis. Other etiologies include peptic ulcer disease, portal hypertensive gastropathy, AVMs, 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.17

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. Consider fresh frozen plasma in patients with coagulopathy, and platelet transfusion in patients with severe thrombocytopenia. However, the optimal use of these blood 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). IV terlipressin is the only medication shown to decreased mortality. It is not available in the USA. Antibiotics should be administered to all patients with cirrhosis and upper GI bleeding, regardless of the etiology. Antibiotics decrease the risk of infections (mainly spontaneous bacterial peritonitis), rebleeding, and mortality. 18 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.19, 20 Non-selective beta blockers (NSSB) should be started prior to discharge (described later). 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. EVL has a failure rate of 10-20%. 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. 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. Confirm correct placement with an abdominal Xray. Alternatively, endoscopy can be performed immediately after placement to confirm the presence of the gastric balloon in the gastric lumen

(video 7-2) Once correct placement is confirmed, the gastric balloon should be inflated with 300-400 ml of air and clamped. The tube is then pulled upwards until resistance is felt, at which point the gastric balloon is tamponading the GE junction. 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. Transjugular intrahepatic portosystemic shunt (TIPS) TIPS is used in patients who fail endoscopic therapy. Polytetrafluoroethylene (PTFE) covered stents are associated with less stent dysfunction compared to bare stents. The main complication of TIPS is the development of encephalopathy as a result of portosystemic shunting.

TIPS has been evaluated in high risk patients with variceal bleeding as an adjunct to endoscopic therapy rather than salvage therapy (see study highlight next). ***

Study highlight

Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding 21 Study population: 63 patients with acute variceal bleeding and Child Pugh cirrhosis class C (score of 10-13) or class B with active bleeding on endoscopy. Study design: prospective randomized clinical trial. Treatment groups 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. 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). The 1-year survival was higher in the early TIPS group compared to the standard therapy group (86% versus 61%, p < 0.001). 21 Conclusion and summary 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 The benefits of early TIPS should be weighed against the risk of precipitating encephalopathy and worsening hepatic failure. *** Gastric varices Types of gastro-esophageal varices (GEV) and isolated gastric varices (IGV) (figure 1): Figure 1: Sarin classification of gastric varices. (see text)

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 gastric fundus. IGV2 are isolated gastric varices outside the gastric fundus. Management GEV1 are generally managed like esophageal varices. Cyanoacrylate injection therapy can be attempted if available (see below). IGV 1 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. Endoscopy treatment Endoscopic sclerotherapy is associated with high rebleeding rates and has been largely abandoned. Endoscopic variceal obturation therapy with cyanoacrylate tissue glue or thrombin is the treatment of choice when available. It has a high success rate (> 90%).23 Uncommon but serious complications include thromboembolism, sepsis, and death. 24 Interventional radiology TIPS Balloon-occluded retrograde transvenous obliteration (BRTO) This is a recently introduced technique in which 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 xaccess the gastric varices. 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%). 25 Esophageal varices bleeding prophylaxis EGD is indicated in all patients with cirrhosis to screen for esophageal and gastric varices.15 If no varices are seen, repeat EGD in 3 years in patients with compensated cirrhosis. In patients with decompensated cirrhosis, repeat EGD annually. In patients with small varices, consider beta blockers or repeat EGD in 2 years. In patients with medium or large varices that have not bled, give NSSB or perform EVL for primary prophylaxis. In patients who previously bled, both beta blockers and EVL are recommended for secondary prevention. Non-selective beta blockers (NSBB) NSBB decrease portal flow and portal pressure. One meta-analysis showed that NSBB decrease the risk of bleeding by 44% and the risk of death from bleeding by 42%. 26 The number needed to treat to prevent one bleeding episode is 6. Medication: propranolol (starting dose of 20 mg twice daily) and nadolol (starting dose of 20-40 mg once daily). The most common method of titrating the dose of NSBB is to measure the heart rate, with dose titration to a rate of 55-60 BPM. The most accurate method of titrating the dose of NSBB is to measure the hepatic venous pressure gradient (HVPG). The goal of therapy is to decrease HVPG by 20% compared to baseline measurements. Decreasing the HVPG to less than 12 mmHg eliminates the risk of bleeding from esophageal varices, but not gastric varices. Once NSBB are initialed, surveillance EGD is not required. If the patient cannot tolerate NSBB, then EVL should be performed. EVL EVL ablates the esophageal varices but does not decrease portal pressure. Repeat EVL every 2-4 weeks until obliteration of esophageal varices. Guidelines recommend surveillance EGD at 1-3 months post obliteration then every 6-12 months to check for recurrence. TIPS TIPS is not recommended for the primary prophylaxis of esophageal variceal bleeding.

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. Beta blockers 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". 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 and spindle cell proliferation. Endoscopic treatment with argon plasma coagulation (APC) is effective (video 7-3

Other treatments include OCP, 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.

Lower GI bleeding

ASGE Guideline: the role of endoscopy in the patient with lower-GI bleeding, Gastrointestinal endoscopy, 2005

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Definition of lower GI bleeding (LGIB) The classic definition 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 that is accessible using a regular colonoscope. Etiologies The most common etiologies of LGIB are diverticulosis and AVMs. 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 increases the rates of early control of bleeding, reduces rebleeding and surgical intervention rates, and improves short-term morbidity and mortality.28, 29 However, 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.30, 31 Urgent colonoscopy will likely identify active bleeding and provide a more definitive diagnosis. Examples of therapeutic endoscopic therapy: APC treatment of AVMs. Epinephrine injection and endoclip placement for active diverticular bleeding (video 7-4).

In cases of massive GI bleeding, angiography is indicated for localization and therapy.

Obscure GI bleeding

AGA Institute technical review on obscure gastrointestinal bleeding, Gastroenterology 2007

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ASGE standards of practice: The role of endoscopy in the management of obscure GI bleeding, Gastrointestinal Endoscopy 2010

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Obscure GI bleeding (OGIB) can be defined as bleeding from the GI tract without an obvious source after EGD and colonoscopy. OGIB is classified as overt (visible bleeding with hematochezia or melena) or obscure (iron deficiency anemia due to GI blood loss, with or without hemoccult positive stool). Etiology: OGIB is caused by either missed lesions on EGD or colonoscopy (table 3), or by mid GI bleeding (see below). Table 3: Missed lesions on EGD and colonoscopy

Video 7-5 If the patient has recurrent OGIB, and there is a suspicion of an upper GI source, 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. Mid GI bleeding (table 4) can be defined as bleeding from a source that is not reachable with an upper endoscope or a colonoscope (extends from the ampulla of Vater to the terminal ileum). Table 4: Etiology of mid GI bleeding.

Small bowel endoscopy 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) Diagnostic yield CE has higher yield compared to push enteroscopy in patients with OGIB (50% vs. 24%). 34 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 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.35 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. 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). Double balloon enteroscopy (DBE) DBE can examine 240 -300 cm of the small bowel (100-140 cm of the ileum). 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. 36 Deep enteroscopy has the advantage of being both a diagnostic and therapeutic procedure, compared to CE, which is purely diagnostic. 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 has a low yield for small bowel lesions. A prospective randomized study showed that in patient with obscure GI bleeding (including a negative push enteroscopy), the diagnostic yield for capsule endoscopy was 30% compared to 7% in small bowel follow through.37 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. A positive scan is followed by angiography for further localization and treatment. Scans for Meckel's diverticulum 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.38 CT Enterography (CTE)

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.39, 40 Consider CTE in OGIB, even in patients with negative CE. 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. IOE is reserved for patients with continued overt OGIB in which other techniques (CE, deep enteroscopy, angiography) are unsuccessful.

Chapter 8- Large intestine Introduction Gastrointestinal infections Bacterial infections Vibrio cholerae Viral infections Parasitic infections Traveler's diarrhea Food poisoning Clostridium difficile infection Chronic diarrhea Chronic constipation Irritable bowel syndrome Non-IBD colitides Microscopic colitis Diversion colitis Ischemic colitis Colonic polyps Paris classification of colonic neoplasia Gastrointestinal polyposis syndromes Adenomatous polyposis syndromes Familial adenomatous polyposis Attenuated FAP MutYH (MYH) associated polyposis. Hamartomatous polyposis syndromes Peutz-Jeghers syndrome Juvenile polyposis syndrome Cowden syndrome Bannayan-Riley-Ruvalcaba syndrome Serrated polyposis syndrome Cronkhite-Canada Syndrome Hereditary nonpolyposis colorectal cancer (HNPCC / Lynch Syndrome)

Colorectal cancer Management of advanced and malignant polyps Colon cancer screening Stool testing Colonoscopy Flexible sigmoidoscopy CT colonography Polyp surveillance References

Introduction Important GI topics are discussed in this chapter. 20% of the GI boards' questions cover the large intestine (including IBD - chapter 9). Infectious diarrhea is an all-time favorite exam topic. Clostridium difficile infection is an extremely important and common disease. Fecal microbiota transplantation is rapidly gaining acceptance as an effective treatment for recurrent C. difficile. However, it is still considered investigational and requires an investigational new drug application to be submitted to the FDA. . A summary of chronic diarrhea is presented with a focus on etiology. Chronic constipation and IBS are common in our practice. Lubiprostone and linaclotide are chloride channel activators approved by the FDA, and are described in this chapter. All GI physicians have to be knowledgeable of all types of colon polyps, including the more recently described serrated polyps. Lynch syndrome seems to be underdiagnosed in clinical practice, and it is imperative to test for this syndrome in patients with suggestive clinical features. Other polyposis syndromes (FAP, Peutz-Jeghers, etc.) are uncommon in our 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.

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. Clinical manifestations 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. Clinical manifestations 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. Clinical manifestations 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 (described later), 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 is supportive. Antibiotics are usually not required. 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 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 has been 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. Clinical features 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 have not been shown to 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 (described above). Clinical features 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%), HUS, 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, t rimethoprim-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, t rimethoprim-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. Treatment is supportive.

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 (nonmotile, 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. Stool antigen and PCR. 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. 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 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, 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. 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.

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.9 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. Clinical manifestations 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 10 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. 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. 11 Salmonella is the most common cause of bacterial food poisoning, followed by Clostridium perfringens, Campylobacter and Staph aureus.11 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. Treatment is supportive. 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. 12 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.12

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.

Clostridium difficile infection

ACG Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile infections, Am J Gastroenterol, 2013

13

Background Clostridium difficile is a gram positive, anaerobic, spore-forming rod. C. difficile infection (CDI) is implicated in 10–25% of cases of antibiotic-associated diarrhea. Risk factors Old age (> 65 years), prolonged hospital stay, immunosuppression (HIV, steroids, chemotherapy), colonic disease (IBD), antibiotics, 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. This strain also produces an additional toxin called "binary toxin". The role of this toxin in C. difficile induced colonic injury is still unclear. Clinical manifestations Watery diarrhea, abdominal pain, fever, leukocytosis. Severe cases may develop colonic ileus and dilation (toxic megacolon). Diagnosis Stool studies

Only stools from patients with diarrhea should be tested for C. difficile.13 Repeat testing or testing for cure should not be performed.13 The most commonly used tests for C. difficile are shown in table 1. Three possible testing strategies using these tests are shown in figure 1. Testing for toxin A & B should not be performed as the only test for CDI, as it lacks adequate sensitivity and specificity. Table 1: Stool tests for C. difficile infection

Figure 1: Three possible testing strategies for CDI.

Some testing kits combine bo th the EIA for GDH and EIA for toxin A&B in o ne step (strategy A). If these tests are discord ant, then a PCR is perfo rmed to confirm the presen ce or absen ce of C. difficile. Alternativ ely, PCR can be performed as the first and o nly test (strategy B). Strategy C has multiple steps and is less practical to p erform.

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. The classic appearance of pseudomembranous colitis is diagnostic of CDI (video 81).

Histology shows varying degrees of mucosal inflammation. 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.14 CDI in the setting of IBD

It is difficult to differentiate CDI from an IBD flare based on the endoscopic appearance. The most common endoscopic findings of CDI in a patient with IBD are nonspecific edema and friability. Pseudomembranes are uncommon15. 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. 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.16 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.). Treatment according to severity of infection 13 Mild to moderate infection Treat with metronidazole 500 mg t.i.d. for 10 days. If there is no response in 5-7 days, the patient cannot tolerate metronidazole, or the patient is pregnant or breastfeeding: give vancomycin 125 mg q.i.d. for 10 days. Severe infection Criteria: albumin < 3 g/dL + either WBC >15,000/mm3 or abdominal tenderness. Treatment Vancomycin 125 mg PO q.i.d. for 10 days. Vancomycin was shown to be superior to metronidazole in severe CDI.17 Fidaxomicin 200 mg PO t.i.d. for 10 days. Fidaxomicin (Dificid®) is a new FDA approved treatment for CDI. 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. 18, 19 ***

Study highlight:

Fidaxomicin versus Vancomycin for Clostridium difficile Infection 18

This is a phase 3 prospective, multicenter, double-blind, randomized trial comparing fidaxomicin with vancomycin for the treatment of CDI. 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. Results (table 3) 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

Follow up was limited to 4 weeks after treatment completion, which could have missed later recurrences in both groups. 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. *** Severe and complicated infection Defined by any of the following criteria (ACG):13 Admission to the intensive care unit. Signs: altered mental status, ileus, significant distension, hypotension, and fever >

38.5 °C. Labs: WBC > 35,000/mm3 or < 2,000/mm3, lactate > 2.2 mmol/L, end organ failure. Treatment Vancomycin 500 mg PO every 6 hours 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. 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. 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. Recurrent CDI Defined as recurrent symptoms of CDI within 8 weeks of treatment. 20-30% of patients treated with metronidazole or vancomycin experience a recurrence. 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 First recurrence Repeat last treatment regimen (metronidazole, or vancomycin if severe recurrence, or fidaxomicin) Second recurrence: treatment options include: 20, 21 Vancomycin taper therapy 125 mg PO q.i.d. for 1-2 weeks then b.i.d. for 1 week, then every day for 1 week, then every 2 days for 4 doses, then every 3 days for 5 doses. Vancomycin pulse therapy 125 mg every 2 days or 500 mg every 3 days for 3 weeks. Rifaximin 550 mg b.i.d. for 3 weeks. Rifaximin "chaser" Vancomycin at a dose of 125 mg PO q.i.d. for 14 days, followed by rifaximin 400 mg b.i.d. for 14 days. Third recurrence: consider fecal microbiota transplantation (FMT) There is mounting evidence that shows that FMT is a safe and effective treatment for recurrent CDI.

There is no clear consensus about the most appropriate delivery method for FMT. The procedure can be performed through a nasoduodenal tube or a colonoscope. *** Study highlight

Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile 22 This small open label trial randomized patients with recurrent CDI to one of three treatment regimens: Standard regimen of vancomycin (500 mg PO q.i.d. For 14 days). Standard regimen of vancomycin with bowel lavage. 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. Analysis of stool samples of some patients showed restoration of microbiota diversity 2 weeks following fecal infusion. Table 3: Results - cure and relapse rates per treatment group

A meta-analysis of 289 patients from 25 published articles showed that the overall success rate of FMT was 91.2%.23 Shorter duration of symptoms and gastroduodenal route of administration was associated with treatment failure. The FDA requires physicians to submit an investigational new drug (IND) application prior to using FMT for the treatment of CDI not responsive to standard therapies. However, the FDA's position about FMT is evolving.

The AGA has created a website specifically to keep physicians and patients up-to-date about FMT (fmt.gastro.org).

It is important for any physician intending to use this treatment to obtain a detailed consent explaining the experimental nature of this therapy.

Chronic diarrhea

The role of endoscopy in the management of patients with diarrhea, 24 Gastrointestinal Endoscopy, 2010

AGA medical position statement: Guidelines for the evaluation and management of chronic diarrhea, Gastroenterology, 1999

25

Definition Decrease in stool consistency or increased frequency of defection (> 3/day) that lasts longer than 4 weeks. Etiology Watery diarrhea Osmotic: osmotic laxatives, carbohydrate malabsorption. Secretory Bile acid malabsorption. Endocrine disorders: hyperthyroidism, Addison's disease, pheochromocytoma. Dysmotility: diabetic autonomic neuropathy, post-vagotomy diarrhea, IBS. Neoplastic disease Colon cancer, villous adenoma, intestinal lymphoma. Functional pancreatic endocrine tumors (gastrinoma, VIPoma, somatostatinoma). Medullary thyroid carcinoma: paraneoplastic diarrhea secondary to calcitonin production. Carcinoid syndrome. Inflammatory diarrhea IBD, microscopic colitis, radiation colitis, intestinal ischemia. Infectious enteritis or colitis: C. difficile, CMV, parasitic infections, Whipple disease. Fatty diarrhea (steatorrhea) Pancreatic exocrine insufficiency, bile acid deficiency. Fat malabsorption: SIBO, short bowel syndrome, celiac disease. Medication-induced diarrhea Important medications to remember are metformin, NSIADS, PPI, antibiotics, magnesium supplements, and colchicine. Artificial sweeteners such as sorbitol can cause chronic osmotic diarrhea.

Workup Detailed history and physical examination. ) Rule out fecal incontinence as a cause of chronic diarrhea, especially in elderly patients. Labs CBC, chemistry, HIV test. Consider celiac serologies, thyroid function testing. Stool studies The stool osmotic gap = 290 - [ (stool Na + stool K) x2 ] If > 100 → osmotic diarrhea, if < 50 → secretory diarrhea. Stool pH < 5 is suggestive of carbohydrate malabsorption. ● Stool fat staining and quantification. ● Stool ova and parasites (Ameba, Giardia, Cyclospora, and Cryptosporidium). In refractory watery diarrhea of unclear etiology, test for paraneoplastic diarrhea. Check serum gastrin, VIP, calcitonin, and somatostatin levels. In cases of suspected carcinoid syndrome, order a 24-hour urine collection for 5-hydroxyindoleacetic acid (5-HIAA). Colonoscopy In cases of normal colonoscopic exam, obtain colonic mucosal biopsies to rule out microscopic colitis. Other diseases that may show on biopsy are quiescent IBD, eosinophilic colitis, amyloidosis.24 Biopsy of the normal cecum can show non specific inflammation.26 Therefore, it is reasonable to avoid the cecum and start obtaining biopsies from the ascending colon. Examine the terminal ileum in patients with diarrhea. Rule out Crohn's disease, carcinoid, TB, lymphoma, adenocarcinoma, or NSAIDs induced ulcers. Biopsy of the normal terminal ileum has a low yield (0-4%), and is not routinely recommended. 24 Upper endoscopy (EGD or enteroscopy) with small intestinal biopsy. Consider small bowel imaging with CT/MRI in patients with inflammatory diarrhea. Breath tests for suspected carbohydrate malabsorption and tests for fat malabsorption are discussed in chapter 3-small intestine. Treatment Treat underlying etiology. Empiric treatment Diphenoxylate with atropine (Lomotil®), loperamide. Cholestyramine trial for suspected bile acid malabsorption. Fiber supplementation.

Chronic constipation

AGA Medical Position Statement on Constipation, Gastroenterology, 2013 27 Rome III criteria for the diagnosis of chronic constipation Two or more of the following during at least 25% of defecations: Straining, lumpy or hard stool, sensation of incomplete evacuation, sensation of anorectal obstruction, manual maneuvers to facilitate evacuation, less than 3 defecations per week. Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis IBS and chronic constipation IBS is a common cause of chronic constipation. In contrast to IBS, pain is not a major symptom in chronic functional constipation. Secondary constipation Medication induced constipation: opioids, calcium channel blockers, anticholinergics, TCAs, oral iron replacement. Diabetes mellitus, Parkinson's disease, scleroderma, hypothyroidism, hypokalemia, hypercalcemia. Mechanical obstruction is an uncommon cause of chronic constipation. This is usually apparent from the clinical history. 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 2). It is difficult to determine the underlying pathophysiology based on clinical features. However, the clinical presentation can provide some useful clues (see below). Slow transit constipation Decreased colonic motility leading to infrequent defecation and constipation. A clinical history of less than two defecations per week and laxative dependence is suggestive of slow transit constipation. 28 Figure 2: Classification of chronic functional constipation based on the underlying pathophysiology

Functional defecatory disorder Dyssynergic defecation: characterized by paradoxical contraction or inadequate relaxation of the pelvic floor muscles during attempted defecation.29 Inadequate defecatory propulsion: inadequate propulsive forces during attempted defecation. Clinical features Use of digital maneuvers to induce defecation suggests dyssynergia. Other symptoms include fecal urgency and straining during defecation. The digital rectal examination (DRE) is an important part of the clinical evaluation. 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. 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 50 years, or if there are any alarm features for colon cancer. First line treatment is a trial of high fiber diet and laxatives. Osmotic laxatives: polyethylene glycol, magnesium citrate. 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.

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. The presence of this reflex excludes Hirschsprung disease (important in children). 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 3B). Some patients have paradoxical anal contraction with attempted defecation (figure 3C).29 Figure 3: 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

The main abnormality in patients with inadequate defecatory propulsion is the demonstration of inadequate propulsive forces with or without dyssynergia during attempted defecation.29 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 5 markers at day 5. The distribution of the markers can distinguish between slow transit and dyssynergic defecation (figure 4). Figure 4 : 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.30 However, the wireless motility capsule is not yet standardized, and is significantly more expensive than traditional tests.31 Further research is needed to evaluate its role in chronic constipation. Other tests Barium defecography can demonstrate anatomic abnormalities of the anorectal region such as an enterocele. MR defecography evaluates pelvic floor anatomy. Other treatment options Dyssynergic defecation Bisacodyl or glycerin suppositories. Biofeedback therapy 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. Chloride channel activators (table 4)

Both lubiprostone and linaclotide are FDA approved for treatment of chronic idiopathic constipation and IBS. Table 4: Chloride channel activators.

Phase 3 trials for chronic constipation : Lubiprostone 32, Linaclotide33. Other medications Prucalopride (Resolor®) is a 5-HT4 agonist that is approved in Canada and Europe for the treatment of chronic constipation.

In a randomized, placebo controlled trial, prucalopride was shown to improve bowel function and decrease symptoms in patients with severe chronic constipation.34 Most common side effects are headache, nausea and diarrhea Currently this drug is not FDA approved in the USA. Surgical therapy Subtotal colectomy and ileorectal anastomosis can be considered in patients with

slow transit constipation that is refractory to other therapies.

Irritable bowel syndrome

AGA Medical Position Statement on Irritable bowel syndrome, Gastroenterology, 2002 35

An Evidence-Based Systematic Review on the Management of Irritable Bowel Syndrome, Am J Gastroenterol, 2009

36

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: 7-10% of people have IBS. Rome III diagnostic criteria 37 Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with two or more of the following: Improvement of pain with defecation. Onset associated with a change in frequency of stool. Onset 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), or mixed IBS. Risk factors for post-infectious IBS include female gender, severe and prolonged gastroenteritis, pre-existing psychiatric illness such as anxiety and depression. Diagnosis Perform a limited workup. Consider the following tests in some patients: Labs: CBC, chemistry. Colonoscopy in patients older than 50, or those with alarm features such as rectal bleeding, weight loss, and anemia. Colonoscopy is not recommended in patients younger than 50 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. 36 Routine testing for small bowel bacterial overgrowth is not recommended. Treatment

Reassure the patient, explain the functional nature of pain, and establish realistic treatment goals. Treat associated depression. Medications Loperamide treats diarrhea, but does not improve abdominal pain. Rifaximin (400 mg-550 mg) t.i.d. for 10-14 days. Phase 3 trials showed that rifaximin 550 mg t.i.d. improved symptoms in patients with IBS without constipation.38 Long term data on rifaximin is lacking. Rifaximin is not FDA approved for IBS. Chloride channel activators (described earlier in table 4) Lubiprostone 8 mcg b.i.d., linaclotide 290 mcg once daily. Polyethylene glycol solution. Consider fiber supplements in patients with constipation (e.g. psyllium). TCAs, SSRIs, and antispasmodics are effective therapies for IBS (table 5). Table 5: Medications used to treat IBS

Alosetron (Lotronex®) 5HT-3 receptor antagonist that was used to treat women with IBS-D. It was withdrawn from the market due rare but life threatening complications of ischemic colitis and severe constipation. Currently available only through a special prescribing program. Tegaserod (Zelnorm®) 5HT-4 receptor agonist, effective for treatment of IBS-D. Withdrawn from the market in 2007 due to increased cardiovascular side effects such as myocardial infarction and unstable angina.

Dietary changes Low FODMAP diet FODMAP stands for Fermentable Oligo-, Di- and Mono-saccharides, and Polyols. 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. 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.39

Consider referral to a dietician and a trial of low FODMAP diet for 6-8 weeks. Examples of high FODMAP food sources: broccoli, cabbage, wheat, rye, lentils, chickpeas, apples, nectarines, peaches, watermelon, mushrooms, artificial sweeteners and many others. Full lists of FODMAP food sources can be found online, or refer to the methods section of the study mentioned above.

Non-IBD colitides Microscopic colitis 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 such as thyroid disease, celiac disease, IBD, type 1 diabetes and rheumatoid arthritis. Risk factors Smoking. Medications: PPI (lansoprazole), ranitidine, statins, NSAIDS, SSRI, aspirin, acarbose. 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. Clinical manifestations Chronic watery diarrhea of variable severity. 50% of patients have abdominal pain. Colonoscopy reveals normal colonic mucosa. Occasionally it shows minor mucosal changes such as erythema, subtle irregularities, and erosions (figure 5). Figure 5: Subtle mucosal changes in a patient with lymphocytic colitis

Biopsies obtained only from the left colon may miss the diagnosis. Therefore, obtain multiple biopsies from both right and left colon. Histology

Lymphocytic colitis Increased intraepithelial lymphocytes (IEL) of the surface and crypt epithelium (>20 per 100 epithelial cells) with normal crypt architecture. Surface epithelial injury. Chronic inflammation in the lamina propria. Collagenous colitis Characterized by the presence of a subepithelial pink collagen band (>10 microns in thickness). Less pronounced intraepithelial lymphocytosis compared to lymphocytic colitis. Intact crypt architecture. Differential diagnosis of diarrhea and increased colonic intraepithelial lymphocytes: Brainerd diarrhea This refers 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 1983.40 It is likely caused by an unidentified infectious agent. It can cause colonic inflammation on biopsy with increased IELs. Celiac disease Present in 15% of patients with LC. Mild colonic epithelial lymphocytosis without surface epithelial injury or inflammation can be present in celiac disease.41 LC is strongly associated with refractory celiac disease. Resolving acute infectious colitis. Crohn's disease. Treatment Stop medications that could be related to MC. Budesonide One randomized controlled trial demonstrated efficacy of budesonide (9 mg/day) in 42 patients with LC. Response rate at 6 weeks was 86% in the budesonide group compared with 48% in the placebo group.42 Unfortunately, there is a high relapse rate after stopping budesonide treatment (6080%). The long-term benefit and safety of budesonide for MC is still unclear. Other treatment options include loperamide, bismuth subsalicylate, cholestyramine, thiopurines (6-MP and azathioprine), and 5-aminosalicylates.

Diversion colitis Diversion colitis is an inflammatory colitis that occurs in colonic segments that are diverted away from the fecal stream. It commonly affects colonic segments 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. Symptomatic patients may complain of abdominal pain, tenesmus, rectal bleeding, or mucous discharge. Diagnosis (video 8-2)

Endoscopic findings include friability, erythema, and superficial ulcerations. These are non-specific and can occur in infectious colitis or IBD. Histology shows prominent mucosal lymphoid hyperplasia associated with a chronic inflammatory infiltrate.43 The presence of crypt architectural distortion favors the diagnosis of IBD. Treatment Restoration of colonic continuity is the treatment of choice. Short chain fatty acids enemas can be tried in patients who are not surgical candidates.

Ischemic colitis Vascular supply of the colon (figure 6) Figure 6: Colonic blood supply. (see text)

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).

Table 6: Etiology of acute colonic ischemia

Clinical features 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. Figure 7 shows the distribution of colonic ischemia in a study of 313 patients with biopsy proven or compatible ischemic colitis.44 Figure 7: Distribution of colonic ischemia. Distribution of disease is defined by the most proximal extent of involvement.4 4

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 Findings include mucosal edema, transmural thickening, intestinal pneumatosis, and perforation. 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.45 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 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 Mucosal pallor, areas of erythema, thickening, submucosal edema, and hemorrhage.

In advanced cases, the mucosa appears black and gangrenous. Gangrene is the only specific finding of ischemic colitis. Segmental distribution of colitis and rectal sparing are suggestive of the diagnosis, but are not specific. Strictures may form in areas of colitis, and can mimic malignancy. 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 Findings on mucosal biopsy are usually non-specific and include mucosal and submucosal edema, hemorrhage or necrosis, inflammatory cell infiltrates, capillary thrombi, crypt atrophy and destruction. The only pathognomonic findings of ischemic colitis are mucosal infarction and the presence of "ghost cells" (preserved cell outline without cellular content). 44 Prognosis 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.46 Treatment Supportive care. Stop any offending medications. Consider IV antibiotics in severe cases. Laparotomy is indicated in cases of perforation or gangrene.

Acute colonic pseudo-obstruction (Ogilvie's syndrome) Definition: massive colonic dilation with 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 for decompression, frequent position changes. This conservative management is successful in 77-96% of patients. If there is no response, consider neostigmine. Neostigmine Mechanism of action 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: 2.5 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%).47

Consider polyethylene glycol solution (17 grams b.i.d.) after initial decompression to increase stool output and decrease colonic distension recurrence rate.48 Colonoscopic decompression 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. Contraindications to colonoscopy include peritonitis or perforation. Colonoscopy in this setting is technically more difficult and is associated with a higher rate of perforation (~3%). Technique Use a regular colonoscope. Minimize air insufflation. Advance the scope at least to the hepatic flexure. Aspirate air during withdrawal. 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. Surgery 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 1 cm or more, villous or tubulovillous histology, or those with high grade dysplasia. Serrated polyps Hyperplastic polyps (HP) HPs are very common. They account for 70-95% of all serrated polyps. Most polyps are small and located in the distal colon. They have no malignant potential. 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 adenoma/polyp with or without cytological dysplasia (SSA/P) SSA/Ps account for 5-25% of serrated polyps, and are more commonly located in the proximal colon. 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 8). Figure 8: Subtle SSA/P with a yellow mucous cap. NBI: narrow band imaging

Histology shows crypt distortion with serration, branching, and dilation at the base of the crypt. SSA/Ps have a significant malignant potential. They are the main precursors of hypermethylated colorectal cancer (CpG island hypermethylation phenotype), which develops though the epigenetic pathway (described later) Traditional serrated adenoma Uncommon , less than 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.49 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.50 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 (described later).

Paris classification of colonic neoplasia This is a useful morphologic classification of superficial colonic neoplastic lesions (figure 9).51 The same classification is used for superficial neoplasia of the esophagus and stomach. Figure 9: 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 (table 7). Table 7: Classification of GI polyposis

Adenomatous polyposis syndromes Adenomatous polyposis syndromes are summarized in table 8. Table 8: Adenomatous polyposis syndromes

Familial adenomatous polyposis

Guidelines for the clinical management of familial adenomatous polyposis (FAP), Gut, 2008 52 Colonic adenomas: patients with the APC mutation start developing adenomas at a young age. The colon eventually develops thousands of adenomas. 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.53 If subtotal colectomy is performed, surveillance of the rectal pouch every 6-12 months is recommended. 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%. Surveillance recommendations: forward and side viewing duodenoscope every 1-3 years after the age of 20. 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 9). Surveillance is performed according to the polyposis stage (table 10). Consider polypectomy for polyps larger than 1 cm in size or those that show high grade dysplasia on biopsy. Argon plasma coagulation (APC) can be used to ablate small flat polyps. 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 9: Spigelman scoring of duodenal polyposis.54

Table 10: Risk of malignancy and recommended surveillance method and interval

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. 56 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 shows proliferations of the 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 11). Table 11: Cancer risks and screening recommendations in Peutz-Jeghers syndrome.

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 at least every 3 years. Screening EGD is recommended 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 12 summarizes the clinical features and screening recommendations. Table 12: Cowden syndrome: clinical features and screening recommendations

Bannayan-Riley-Ruvalcaba syndrome This is an autosomal dominant disease that 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.60

Serrated polyposis syndrome Serrated polyposis syndrome (SPS) was formerly known as hyperplastic polyposis syndrome. World health organization's definition: SPS is characterized by any one of the following criteria: ≥ 20 serrated polyps throughout the colon. Any number of serrated polyps proximal to the sigmoid colon in a patient with a first-degree relative with SPS. At least 5 serrated polyps proximal to the sigmoid colon of which at least 2 are ≥ 1 cm in size. SPS is associated with a higher risk of CRC, but the exact risk is unknown. Guidelines recommend yearly colonoscopy.61 Family members of patients with SPS have 5 times increased risk of CRC and should be screened starting at age 40.

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 immunemediated. 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.

Hereditary nonpolyposis colorectal cancer (HNPCC / Lynch Syndrome) Background HNPCC or Lynch syndrome is the most common colon cancer syndrome. Accounts for approximately 5% of cases of colon cancer. Mean age at diagnosis of CRC in HNPCC is 44 years. Right-sided tumors occur in 70% of patients. Synchronous tumors occur in 20% of patients, while metachronous tumors occur in 25%. HNPCC has an autosomal dominant inheritance with high penetrance. Most cases are caused by a germline mutation of one of the DNA mismatch repair (MMR) genes: hMSH2 and hMLH1. Less commonly affected MMR genes are hMSH6, hPMS1, and hPMS2. Loss of MMR can be caused by either a germline mutation of MMR genes (as in HNPCC), or by epigenetic silencing of MMR expression which occurs in sporadic colon cancer. Microsatellite instability 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 PCR. Tumors that are microsatellite unstable are divided into MSI-high and MSI-low tumors.62 Tumors that do not have MSI are called microsatellite stable (MSS) or non-MSI tumors. The vast majority of HNPCC tumors are MSI-high. 10-15% of sporadic colon cancers are MSI-high. Patients with those tumors have a better long term survival compared to patients with MSI-low tumors.62 Original Amsterdam criteria for HNPCC Three or more relatives with colorectal cancer (one must be a first-degree relative of the other two). Colorectal cancer involving at least two generations. One or more colorectal cancer cases diagnosed in a patient younger than 50 years old. Bethesda guidelines for testing for HNPCC Colorectal cancer diagnosed in a patient younger than 50 years old. Presence of synchronous or metachronous CRC, or other HNPCC related cancers regardless of age.

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: 63 Tumor infiltrating lymphocytes Mucinous/signet-ring histology Medullary growth pattern Crohn's-like reaction Absence of dirty necrosis CRC diagnosed in a patient with one or more first degree relatives with an HNPCCrelated 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. Diagnosis A suggested algorithm for testing for HNPCC is shown in figure 10. The most specific test for HNPCC is gene sequencing of the MMR genes. However, workup usually starts by performing immunohistochemistry for the MMR proteins (figure 10-A). If MLH1 staining is absent, then it is recommended to test for BRAF mutation. If BRAF mutation is present, this rules out HNPCC and confirms sporadic colon cancer. BRAF mutation is present in 70% of colon cancer cases with absent MLH1 staining. If BRAF mutation absent, proceed with MLH1 gene sequencing to test for HNPCC. In cases of absent MLH2 staining without a genetic mutation of MLH2, this could be secondary to a germline mutation of EPCAM (epithelial cell adhesion molecule) resulting in MSH2 inactivation.64 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 10-B). Figure 10: Suggested algorithm for testing for Lynch syndrome. Both testing strategies A and B are acceptable (see text)

Management Table 13 summarizes the main cancer risks and screening recommendations in HNPCC.

Table 13: Cancer risks and screening recommendations in HNPCC.

Muir Torre syndrome This is a variant of HNPCC associated with mutation in MLH1 and MSH2. Presents with features of Lynch syndrome in addition to sebaceous gland tumors, skin basal cell and squamous cell carcinomas, and keratoacanthomas.

Colorectal cancer

ASGE guideline: Role of endoscopy in the staging and management of colorectal cancer, Gastrointestinal endoscopy, 2013 66 Epidemiology Colon cancer is the third most common cancer in males and females and the second most common cause of cancer death. Estimated number of new cases in the USA in 2013 is 142,820 (8.6% of all new cancer cases), with ~ 50,830 deaths (8.8% of all cancer deaths).67 The lifetime risk of colon cancer is ~6%. 90% of cases occur in patients older than 50. 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 shown 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 colon cancer.68 Protective factors There is strong evidence that aspirin decreases the risk of colon cancer and prevents the recurrence of adenomas. Other possible protective factors include calcium and vitamin D, high fiber, low fat diet. Colon cancer genetic pathways (figure 11) Chromosomal instability pathway accounts for 80% of cases. Hereditary: caused by FAP and MutYH associated polyposis. Acquired: caused by mutations in APC, KRAS, SMAD, and P53 genes. Mismatch repair pathway accounts for 20% of cases. Mutator phenotype (hereditary) pathway This is the cancer pathway in HNPCC/Lynch syndrome. It starts with a 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 carcinogen in these patients.69-71

Epigenetic (acquired) pathway This is also called "serrated" pathway. In this epigenetic pathway, DNA hypermethylation leads to silencing of certain oncogenes, leading to the development of sporadic colon cancer. CpG Island hyperMethylation Phenotype (CIMP): hypermethylation of CpG dinucleotides present in the promoter sequences of MLH1 leads to silencing of that gene and the development of colon cancer. Most of these cancers are caused by the BRAF mutation. BRAF mutations are not present in HNPCC. Figure 11: Colon cancer genetic pathways

Clinical presentation Bleeding, weight loss, anemia, altered bowel habits, bowel obstruction. Diagnosis: colonoscopy, CT scan. Staging and prognosis

The TNM classification is the most common staging system (table 14 and 15). Table 14: TNM staging of colorectal cancer.

Table 15: Colon cancer stage and five-year survival

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. 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.73, 74 Patients who undergo complete resection of metastasis are also candidates for chemotherapy. The most commonly used regimen is 5-fluorouracil, leucovorin, and oxiplatin. 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, 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.75 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 Advanced polyps are polyps with carcinoma in situ, intraepithelial or intramucosal carcinoma (figure 12-A) Figure 12: Colon wall layers and depth of invasion of advanced and malignant polyps. A: Intramucosal carcinoma. B: T1 lesion. C: T2 lesion

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, as the risk of lymph node metastasis is zero%. Malignant polyps are those with cancer invasion beyond the muscularis mucosa Polyps with invasive carcinoma into the submucosa (T1 lesions-figure 12-B) If the polyp has not been tattooed, repeat the 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. A pedunculated polyp should be resected without evidence of invasion of the stalk. 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, and deep invasion beyond the upper third of the submucosa. 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. ASGE and NCCN guidelines recommend that for malignant pedunculated polyps and cancer limited to the submucosa (T1) without unfavorable histologic features (< 1 mm cancer free margin, poorly differentiated histology, vascular or lymphatic invasion), endoscopic resection is sufficient.66, 76 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 76). Polyps with invasive carcinoma beyond the submucosa into the muscularis (T2 lesions figure 12-C) Surgery is always indicated in these cases.

Colon cancer screening

A-American College of Gastroenterology Guidelines for Colorectal Cancer 77 Screening 2009, Am J Gastroenterol, 2009

B-Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline of the American cancer society(ACR), US Multisociety Task Force (USMSTF), and the American College of Radiology (ACR)

78

C-Screening for Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement

79

Types of colon cancer screening tests Tests for cancer prevention detect cancer and polyps. These include colonoscopy, flexible sigmoidoscopy, and CT colonography (CTC). Tests for cancer detection detect mainly cancer. Guaiac-based fecal occult blood testing (hemoccult II and hemoccult II Sensa) Fecal immunochemical test (FIT) Stool DNA When to start colon cancer screening: In average risk patients, start at age 50. ACG recommends starting at age 45 in African Americans. Family history of colon cancer (not related to a genetic syndrome) Single first-degree relative with CRC or advanced adenoma diagnosed at age ≥ 60 years Guideline A (ACG): colonoscopy at age 50 (same as average risk) Guideline B (ACA, USMSTF, ACR): start screening at age 40. Patients may choose any test. Two second-degree relatives with colorectal cancer Guideline B (ACA, USMSTF, ACR): start at age 40. Patients may choose any test. Single first-degree relative with CRC or advanced adenoma diagnosed at age younger than 60 years or two first-degree relatives with CRC or advanced adenomas at any age:

Guidelines A+B: Colonoscopy every 5 years starting at age 40, or 10 years younger than age of diagnosis of the youngest affected relative. When to stop colon cancer screening The USMSTF recommends 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 and an assessment of risks and benefits of screening. Consider colonoscopy (or other screening tests) if the estimated life expectancy is more than 7 years. Stop all screening at age 85. Table 16 shows the recommended CRC screening tests by different society guidelines. Table 16: Recommended CRC screening tests per society guidelines (listed here)

Stool testing Table 17 summarizes the performance characteristics of stool tests for CRC screening.

Table 17: Performance characteristics of stool tests for CRC screening (different studies)

Guaiac-based FOBT: Hemoccult II and Hemoccult II SENSA FOBT detects the presence of heme in a fecal sample, including that resulting from an 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.80 Vitamin C inhibits hydroperoxidase and may cause a false negative result. Aspirin, NSAIDS and diet do not influence the results of hemoccult II.82 FOBT was shown in multiple prospective studies to decrease CRC mortality.83 FOBT was shown to provide sustained CRC mortality 30 years after screening. Annual FOBT screening reduces CRC mortality by 32%, whereas biennial screening reduces mortality by 22%.84 Fecal immunochemical test (FIT) 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 75 ng/mL. A randomized trial compared FIT to colonoscopy for colon cancer screening. 85 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 ColoSure™ is the only commercially available stool DNA test in the USA. It detects methylation of the vimentin gene. This epigenetic change is associated with CRC.

This test requires the patient to submit an entire bowel movement for testing. A positive test is followed by a colonoscopy. The optimal repeat testing interval is unclear. ACG recommends testing every 3 years.

Colonoscopy 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%.86 Another retrospective cohort study analyzed data from 2 previous prospective studies, and included 88,902 participants followed over 22 years.87 Results showed that colonoscopy reduces CRC mortality from both proximal and distal colon cancer (overall hazard ratio was 0.32). The adenoma detection rate (ADR) is an important measure of colonoscopy quality. The ADR is calculated as follows:

The ADR was shown to be an independent predictor of the risk of interval colorectal cancer after screening colonoscopy.88 General requirements for an effective screening colonoscopy program Cecal intubation rate ≥ 95%. ADR > 25% in males, and > 15% in females. Average withdrawal time ≥ 6 minutes. Documentation of the quality of bowel preparation on colonoscopy reports. Multiple studies confirmed that the use of split dose preparation regimens result in better colon preparation quality compared to single dose regimens the day before the procedure. Use of the correct surveillance intervals after colonoscopy (described later).

Flexible sigmoidoscopy Flexible sigmoidoscopy was shown in randomized controlled trials to decrease colon cancer mortality.89, 90 It is performed every 5 years, with or without stool hemoccult SENSA 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.87

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 18).91, 92 Table 18: Sensitivity and specificity of CTC for colorectal polyps

*** Study highlight

Accuracy of CT Colonography for Detection of Large Adenomas and Cancers93 This is a large multicenter trial of 2531 asymptomatic patients 50 years or older undergoing routine screening for colon cancer. 9% of patients had a first-degree relative with colon cancer. All patients underwent CT colonography with bowel preparation, stool and fluid tagging. Patients underwent same day colonoscopy. The results of CTC were compared to colonoscopy. Results (table 19) For large adenomas (≥ 10 mm), sensitivity was 90% and specificity was 86%. Sensitivity was lower for smaller adenomas. Table 19: Performance characteristics of CTC in detecting adenomas of different sizes

Polyp surveillance

Guidelines for Colonoscopy Surveillance After Screening and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer, Gastroenterology, 2012

61

Post-polypectomy colonoscopy surveillance: European Society of Gastrointestinal Endoscopy (ESGE) Guideline, Endoscopy, 2013

94

There is high quality evidence that supports the current surveillance recommendations after negative colonoscopy or removal of adenomas. On the other hand, the quality of evidence for surveillance after removal of serrated polyps is still evolving. Table 20 summarizes the current recommended surveillance intervals in patients with baseline average risk. These intervals should be adjusted according to the bowel preparation quality and polypectomy techniques. Bowel preparation quality Current recommendations assume a good bowel preparation quality. In patients with a negative colonoscopy and fair/adequate bowel preparation (can detect polyps > 5 mm in size), repeating the exam after 5 years is reasonable. In patients with fair/inadequate or poor bowel preparation, repeat the exam within 1 year. Polypectomy technique In patients with large sessile polyps (≥ 2 cm) that are removed by piecemeal polypectomy, repeat endoscopy should be performed in 2-6 months to examine the polypectomy site for any recurrent or residual adenomatous tissue. If there is a concern about the completeness of any polypectomy, colonoscopy should be repeated within 3-6 months to examine the site of the resected polyp.p

Table 20: Recommended surveillance intervals in patients with average risk 61

Chapter 9- Inflammatory bowel disease Introduction Clinical aspects and general concepts Treatment of ulcerative colitis 5-aminosalicylates Corticosteroids Thiopurines Biologic therapy for ulcerative colitis Major clinical trials of biologics in ulcerative colitis Infliximab Adalimumab Golimumab Treatment of acute severe ulcerative colitis Treatment of Crohn’s disease 5 aminosalicylates Budesonide Methotrexate Antibiotics Thiopurines Fistulizing and perianal Crohn’s disease Biologic therapy for Crohn’s disease Clinical trials of biologics in Crohn’s disease Infliximab Adalimumab Certolizumab Natalizumab IBD and colorectal cancer Extra-intestinal manifestations of IBD Surgical therapy for IBD Ileal pouch anal anastomosis Post operative recurrence of Crohn’s disease Endoscopic balloon dilation for Crohn’s disease strictures

Fertility and pregnancy issues in IBD IBD and fertility Disease activity in pregnancy Conventional therapies in pregnancy Biologics in pregnancy References

Introduction 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. Important topics are the types of 5-aminosalicylates, thiopurine metabolites testing, types of biologics and their indications. In addition, colon cancer in IBD, approach to the post surgical IBD patient, and fertility/pregnancy issues in IBD are relevant to our daily practice. In this chapter, a summary of biologic trials in IBD is presented. It is important to know some details about these trials, especially when you make management decisions about starting or switching biologics. Biologic trials are less important for the boards as it is unlikely that you will get detailed questions. The SONIC trial in particular is an important landmark trial in GI, and should be known to all GI physicians.

Clinical aspects and general concepts Clinical manifestations Ulcerative colitis (UC): diarrhea, hematochezia, urgency, tenesmus, abdominal pain, fever. Crohn’s disease (CD): 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. Physical examination Fever, abdominal tenderness, decreased bowel sounds. Patients on steroids will have minimal abdominal findings even in the presence of serious intra-abdominal complications such as perforation. Consider abdominal imaging in these cases. Examine the perineum for perianal fistulas or fissures. Extraintestinal manifestations are described later in the chapter. Vaccination history Keep track of vaccinations including annual flu vaccine, pneumococcus, diptheria and pertussis, varicella (contraindicated in immunosuppresion), zoster. Offer hepatitis A and B vaccination if not already immunized. Labs CBC can reveal leukocytosis (infection, steroids), leukopenia (thiopurines), and anemia (iron, B12, or folate deficiency, anemia of chronic disease). Chemistry panel can reveal electrolyte imbalance and elevated liver enzymes (drug induced, PSC). ESR, CRP, stool C. difficile testing. 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.

Table 1: IBD serum markers

Endoscopic findings in IBD The typical endoscopic appearance of active ulcerative colitis is continuous colitis starting at the rectum and extending to a variable distance 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. 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. In contrast to UC, Crohn's disease shows segmental colitis with normal intervening mucosa (skip areas, video 8-1).

Terminal ileal involvement is a feature of Crohn's disease. Histology

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.

Treatment of ulcerative colitis

ACG Ulcerative Colitis Practice Guidelines in adults, Am J Gastroenterol, 2010

2

5-aminosalicylates 5-ASAs are given in the form of topical and/or oral preparations (table 2). The choice of initial treatment with 5 aminosalicylates (5-ASA) is based on the severity and extent of the disease. Topical preparations are used to treat distal UC. In cases of pancolitis, topical treatment 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 coating (table 2). If the patient is not responding to oral and topical ASA products, begin steroid therapy. 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 (reversible), fibrosing alveolitis, pericarditis, myocarditis, nephrotoxicity, hepatitis. All 5-ASA products can rarely cause nephrotoxicity. Therefore, it is recommended to check serum creatinine every six months while on treatment. Olsalazine causes a dose-dependent secretory diarrhea in 10-15% of patients.

Table 2: 5-ASA preparations

Corticosteroids Prednisone is 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. Oral prednisone is given to patients with mild to moderate disease not requiring admission. Dose is 40-60 mg PO for 2-4 weeks. Start dose taper once the patient is in remission. Total treatment duration is usually 6-8 weeks. Continue 5-ASAs for maintenance. Consider thiopurines and/or anti-TNF (see below). IV methylprednisolone is given to patients admitted with acute severe UC (see section on acute severe UC). Dose is 40-60 mg IV once daily, or divided every 12 hours.

Thiopurines The immunomodulators azathioprine 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 the approach to management (see below). Figure 1: Thiopurine metabolism.

Starting thiopurine therapy Initial labs CBC, liver panel, PPD, TPMT levels. Consider checking for latent TB and chronic hepatitis B and C. TPMT testing can be performed using TPMT genotyping test, which detects TPMT gene mutations, or TPMT phenotyping, which measures enzyme levels. 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. 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 1-2 weeks for 3 months then every 1 month. ~0.3% are homozygous for TPMT mutation (absent TPMT activity). AZP and 6-MP are contraindicated. TPMT testing and appropriate dosing of thiopurines can prevent early leukopenia. Delayed leukopenia can still occur even with normal enzyme levels. TPMT deficiency results in increased 6-TGN levels, which leads to BM

suppression. TPMT excess results in increased 6-MMP levels, which leads to nausea, vomiting, and hepatotoxicity. Side effects of thiopurines GI upset (nausea, vomiting, abdominal pain), acute pancreatitis (3%), liver toxicity, non-Hodgkin's lymphoma (incidence rate of 4 in 10,000 person.years). Thiopurines metabolites testing Consider checking thiopurine metabolites (6-TGN and 6-MMP) if the patient is not responding to treatment. 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

Biologic therapy for ulcerative colitis

The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD, Am J Gastroenterol, 2011 4

European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease, J Crohns Colitis. 2009 5 Starting biologic therapy in IBD Confirm that the patient's symptoms are related to active colitis. Discuss risks and benefits of treatment with the patient. Screen for TB (Chest xray, PPD, and/or gamma interferon assay) and chronic hepatitis B/C. Review vaccination history (described earlier). 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 includes infliximab, adalimumab, and golimumab (table 4).

Table 4: FDA approved biologics for the treatment of IBD

Major clinical trials of biologics in ulcerative colitis Infliximab ACT 1 &2 trials 6 (Infliximab in outpatients with active ulcerative colitis)

The aim of these trials was to assess the efficacy of infliximab in outpatients with moderate to severe, endoscopically active UC. These trials excluded patients with prior exposure to anti TNF agents. Study design: multicenter, randomized, double-blind, placebo-controlled trials. 364 patients in each trial. Patients received infliximab 5 mg or 10 mg/kg or placebo at weeks 0, 2, and 6 and then every 8 weeks through week 22 in ACT 2 or week 46 in ACT 1. The primary endpoint was clinical response at week 8. Secondary endpoints were clinical response or clinical remission with discontinuation of corticosteroids at week 30 in both studies and at week 54 in ACT 1. Infliximab was superior to placebo in achieving clinical response and remission, mucosal healing, and corticosteroid-sparing effects during 30 to 54 weeks of therapy. Subsequent follow up of the same cohort of patients revealed the following: Patients treated with infliximab were less likely to undergo colectomy through 54 weeks than those who received placebo. 7 Long-term treatment with infliximab for up to three additional years was effective and well tolerated (ACT 1 and 2 extension trials). 8

Adalimumab ULTRA-1 9 (Induction therapy with adalimumab for ulcerative colitis) 8-week, multicenter, randomized, double-blind, placebo-controlled study of adalimumab (ADA) and placebo for the treatment of active ulcerative colitis. 390 ambulatory patients with moderately to severely active UC despite treatment with corticosteroids and/or immunosuppressants. The study excluded patients with prior exposure to anti TNF agents, and those with proctitis only on endoscopy. The primary endpoint was remission at week 8 (mayo score ≤ 2 with no subscore > 1). Treatment groups and results are shown in table 5.

Table 5: Treatment groups and primary endpoint results in UlLTRA-1 trial

Conclusion: ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and/or imunosuppressants. Comments on the ULTRA-1 study Analysis of secondary endpoints showed that there was a slight and statistically significant benefit in improving the symptoms of bleeding and physician's global assessment score in the ADA160/80 group compared to placebo. The clinical response, mucosal healing and stool frequency scores did not differ between the three groups. There was a higher remission rate in patients with weight < 82 kg versus weight > 82 kg. This suggests that for adalimumab in UC, a high dose is needed to achieve remission. There was a higher remission rate in patients with CRP < 10 mg/L and in those with less extensive disease. This suggests that adalimumab is more effective in patients with less severe disease. ULTRA 2 10 (Adalimumab for induction and maintenance of remission in ulcerative colitis) Study objective: evaluate the efficacy of adalimumab for induction and maintenance of remission in patients with moderate to severe ulcerative colitis. Study design: randomized, double blind, placebo controlled, multi-center trial. The study enrolled 494 outpatients with moderately-to-severely UC for at least 3 months and a Mayo score of 6−12 points (endoscopy subscore of at least 2), despite

treatment with steroids and/or AZP or 6-MP.

Previous use of anti-TNF agents other than adalimumab was permitted if the patient had discontinued its use due to a loss of response or intolerance to the agent for > 8 weeks. Patients were randomly assigned to receive subcutaneous injections of adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week beginning at week 4, or matching placebo. Patients were followed through week 52. Co-primary efficacy endpoints were clinical remission at week 8 and week 52. Results (figure 2) Figure 2: Results of ULTRA-2.

Overall rates of clin ical remissio n at week 8 were 16.5% on ad alimumab and 9.3% on placebo (p = .019); correspondin g v alues for week 52 were 17.3% and 8.5% (p = .004 ). Among patients who had previo usly received anti-TNF agents, rates of remission at week 8 were 9.2% on adalimumab and 6.9% on placebo (p = .559); corresponding values for week 52 were 10.2% and 3% (p = .039).

Secondary endpoints of improved clinical response, mucosal healing, steroid discontinuation, and health-related quality of life (IBDQ) were achieved with adalimumab therapy.

Adalimumab should be considered in patients with active moderate to severe UC failing steroids and/or immunomodulators, especially if they need the convenience of subcutaneous dosing.

Golimumab PURSUIT-SC trial 11 (Induction therapy with Golimumab for ulcerative colitis) Combined phase 2 and 3, double-blind, placebo-controlled trial. This study showed that golimumab induction dose regimens of 200/100 mg and 400/200 mg given subq (week 0/week 2) were similarly effective in inducing clinical remission, achieving mucosal healing, and improving health-related quality of life at week 6. PURSUIT-M trial 12 (Maintenance therapy with Golimumab for ulcerative colitis) This is a phase 3, double-blind trial, placebo controlled trial. 464 UC patients who responded to golimumab induction were randomly assigned to placebo or subq injections of 50 or 100 mg of golimumab every 4 weeks through week 52. Results (table 6) Golimumab 50 and 100 mg were more effective than placebo in achieving clinical response maintained through week 54 and mucosal healing at both week 30 and 54. Golimumab 100 mg was more effective than placebo in achieving remission at both week 30 and 54 weeks. Table 6: PURSUIT-M clinical trial results

Treatment of acute severe ulcerative colitis

Treatment of Hospitalized Adult Patients With Severe Ulcerative Colitis: Toronto Consensus Statements, Am J Gastroenterol, 2012

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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. Perform flexible sigmoidoscopy and biopsy to rule out CMV infection. Avoid full colonoscopy; minimize air insufflation to avoid perforation in severe colitis. 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 and start a thiopurine. 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 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.14 Cyclosporin: 2-4 mg/kg/day This medication is associated with significant toxicity, and requires blood level monitoring. It should only be given by physicians experienced in prescribing cyclosporin. Side effects of cyclosporin include hypertension, electrolyte imbalance, seizures, nephrotoxicity, and opportunistic infections. The only randomized comparative study of cyclosporine and infliximab was an

open label multicenter European trial. 15 115 patients with acute severe ulcerative colitis not responding to steroids were randomized to cyclosporin or infliximab. 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 at day 98 or colectomy rates. Choosing between cyclosporine and infliximab should be based on the physician and hospital's experience in dosing cyclosporine and monitoring for toxicity. Infliximab is easier to administer and requires no drug monitoring. Cyclosporin is not an effective treatment in patients with prior non-response or intolerance to thiopurines. Avoid sequential treatment with infliximab and cyclosporin, as this is associated with an increased risk of serious adverse events.13 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. 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, Am J Gastroenterol, 2009

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AGA Institute Technical Review on the Use of Thiopurines, Methotrexate, and Anti–TNF-a Biologic Drugs for the Induction and Maintenance of Remission 17 in Inflammatory Crohn’s Disease, Gastroenterology 2013 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. If there is no response to 5-ASA, then thiopurines and/or biologic therapy should be started.

Budesonide 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. 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.

Methotrexate​​ Methotrexate 25 mg per week given intramuscularly was shown to be effective in the induction and maintenance of remission in steroid refractory or steroid dependent Crohn’s disease.18 Methotrexate added to infliximab was not superior to infliximab alone in maintaining remission in patients with Crohn’s disease (see COMMIT trial).

Antibiotics Ciprofloxacin and metronidazole are the most commonly used antibiotics. Consider antibiotics for colonic or fistulizing Crohn’s disease (not for small intestinal disease).

Long term metronidazole can cause irreversible paraesthesia.

Thiopurines The immunomodulators 6-MP and AZP are given to maintain remission in Crohn’s disease. Dosing and metabolite testing are the same as in ulcerative colitis (described earlier).

Fistulizing and perianal Crohn’s disease Workup of suspected perianal disease includes examination under anaesthesia, rectal EUS, and/or pelvic MRI. Endoscopy is performed to assess for rectal and colonic inflammation. 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 abscess. Therapeutic options for complex fistulas include antibiotics, thiopurines, anti-TNF therapy, seton placement, and surgery. All biologics have been shown to promote fistula closure. The evidence for infliximab in fistula closure is stronger than that for adalimumab and certolizumab (see ACCENT 2 trial).

Biologic therapy for Crohn’s disease

Position statement: The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD, Am J Gastroenterol, 2011 4 Factors associated with higher primary response to biologic therapy: Short disease duration, inflammatory disease, colonic disease location, non-smoking patient. Before starting any biologic agent, check for TB and chronic hepatitis B and C. Discuss risks and benefits of treatment with the patient. FDA approved biologic therapies for Crohn’s disease are infliximab, adalimumab, certolizumab, and n​​atalizumab (table 4). Infliximab is the most widely used biologic with the longest clinical experience. 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. Figure 3: Approach to initiating anti-TNF therapy with infliximab and

subsequent follow-up. *Dilation of ileocolonic strictures in Crohn's disease is describ ed later. Starting an ti-TNF therapy with adalimumab is an alternative, and fo llows the same principles above. An assa y was recen tly d eveloped to test for ad alimumab drug and an tibody levels (availa ble at a nserad a.com) 19

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. ***

Study highlight

Infliximab SWITCH trial 20 Open label prospective controlled trial. 73 patients with stable Crohn’s disease on infliximab for more than 6 months. Patients were randomized to continue infliximab or switch to adalimumab. Patients were followed for 1 year after randomization. The primary endpoint was the proportion of patients who needed rescue therapy with steroids or increasing doses of anti-TNF, or those who had to stop the assigned antiTNF. Results Dose optimization or interruption of treatment occurred in 47% of patients in the adalimumab group and in 16% of patients in the infliximab group (p =0.006). Ten patients interrupted adalimumab treatment while only one interrupted infliximab (28% vs. 2%, p=0.003). Of the 10 patients who interrupted adalimumab, six did so because of loss of tolerance and four had loss of efficacy. Eight were started back on infliximab and successfully treated. Conclusion While many patients will benefit from the convenience of home dosing of adalimumab, it is generally not recommended to change biologic therapy solely for this reason. Patients who are already responding to treatment with infliximab should be counselled about the possibility of loss of response when switching to adalimumab. *** Natalizumab Natalizumab is FDA approved for moderate to severe Crohn’s disease not responsive to other agents. It was withdrawn from the market in 2005 after three cases of progressive multifocal leukoencephalopathy (PML) were reported. PML is a fatal demyelinating disease of the CNS caused by the human polyoma virus (JC virus). Mechanism of action of natalizumab and effect on the CNS Integrins are proteins involved in lymphocyte adhesion and migration. Natalizumab

is an integrin antagonist that blocks integrins with the α4 subunits, most importantly α4-β1 integrin (present in the CNS), as well as the intestine specific α4-β7 integrin. Natalizumab's action on α4-β1 inetegrin is responsible for its therapeutic effect in patients with multiple sclerosis. However, inhibition of CNS lymphocyte adhesion and migration is also the likely mechanism of JCV reactivation and the development of PML. Vedolizumab (Entyvio®) is an integrin antagonist that specifically blocks the intestinal α4-β7 integrin. It is effective in treating UC and Crohn's disease (awaiting FDA approval). PML has not been reported in patients receiving vedolizumab; however, long-term data is not available. Natalizumab was reintroduced in 2006 under strict FDA watch through he CDTOUCH® (Crohn’s disease-Tysabri Outreach: Unified Commitment to Health) prescribing program. Only physicians and pharmacies enrolled in this program can prescribe and dispense natalizumab. Risk of PML with natalizumab (table 7) Table 7: Estimated PML incidence in natalizumab users in multiple sclerosis21

Overall incidence is 1:1000 after 12 months of treatment. Risk factors The most important risk factor is a positive JCV antibody.21 JCV antibody negative: overall incidence is less than 0.09/1000 patients. JCV antibody positive: overall incidence is 3.8 /1000. Longer duration of treatment (> 2 years). Prior exposure to immunosuppression. Natalizumab-induced PML most commonly presents with cognitive dysfunction, motor, language, and visual abnormalities. Diagnosis: CSF JCV DNA, brain MRI, brain biopsy is the gold standard. Prognosis of natalizumab-induced PML is better than AIDS related PML. Recommendations for prescribing natalizumab and minimizing PML risk: Enroll in the CD-TOUCH® program.

Test for anti JCV antibody prior to natalizumab use. Discuss risks and benefits according to the patient's risk of developing PML. If anti JCV negative: low risk of PML. Prescribe natalizumab. Repeat anti JCV annually as there is a 1-2 % risk of seroconversion. If anti JCV positive: consider short term natalizumab (less than 1-2 years) After three months of treatment with natalizumab, reassess the patient for clinical benefit. If the disease is not improved, discontinue the medication. Hepatosplenic T cell lymphoma (HSTCL) This rare, fatal lymphoma primarily affects men younger than 35 years old. It has been linked to treatment with thiopurines with or without infliximab. 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.22 Four patients received adalimumab following infliximab and a thiopurine. It has not been reported in infliximab monotherapy or combination infliximab with methotrexate.

Clinical trials of biologics in Crohn’s disease Infliximab ACCENT 1 trial 23 (Maintenance therapy with infliximab for Crohn’s disease) Randomized controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn’s disease who respond to a single infusion of infliximab (given at week 0). Responders to infliximab at week 2 were randomized to placebo, infliximab 5 mg/kg at week 2, 6 and every 8 weeks, or infliximab 5 mg/kg at week 2, 6 and then 10 mg/kg every 8 weeks. Results (table 8) Table 8: Results of the ACCENT 1 trial

Conclusion: Infliximab every 8 weeks was effective in maintaining remission and response in patients who respond to initial induction with one dose of infliximab. There was no difference between infliximab 5 mg or 10 mg/kg every 8 weeks. ACCENT II trial 24 (infliximab in fistulizing Crohn’s disease)

This clinical trial evaluated the efficacy of infliximab maintenance therapy for fistulizing Crohn’s disease in patients who were treated with a three-dose induction regimen of infliximab. 306 adult patients with one or more perianal and enterocutaneous fistulas were included. Patients with enterovaginal fistulas were enrolled if they had at least one other enterocutaneous fistula. Patients were given infliximab at week 1, 2, and 6. Concurrent therapies for Crohn’s disease were permitted.

Setons were removed by week 2 of the study. Clinical response at week 14 A response was defined as a reduction of at least 50 percent from baseline in the number of draining fistulas. 195 patients had a response and 87 had no response to treatment. Both responders and non-responders were randomized to infliximab 5 mg/kg every 8 weeks or placebo, and followed until week 54. Loss of response was defined as recurrence of draining fistulas, the need for a change in medications, or the need for additional medical or surgical therapy for Crohn’s disease. Results In patients who had a clinical response at week 14, loss of response was higher in the placebo maintenance group compared to the infliximab group. Time to loss of response was longer in the infliximab group compared to placebo (table 9). Table 9: ACCENT 2- Results in the responders group

In patients who had no clinical response at randomization, there was no difference between infliximab and placebo (table 10). Table 10: Accent 2-Results in the non-responders group

Conclusion In patients with fistulizing Crohn’s disease who have a response to induction therapy with infliximab, continuing infliximab maintenance therapy every 8 weeks increases the time to loss of response and increases the likelihood of maintaining response at 54 weeks. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease 25 (top down versus bottom up Crohn's treatment trial) Open label, randomized multicenter European trial.

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. 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 11) Remission at 26 and 52 weeks was higher in the early combined immunosuppression group. Remission at 2 years was similar between the two groups. Table 11: Remission in the early combined immunosuppression and conventional groups

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.26 Limitations: patients were given intermittent dosing of infliximab rather than scheduled maintenance infusions, which could have reduced efficacy in the early combined group. Conclusions and summary Early combined treatment with infliximab and immunomodulators, results in an earlier remission compared to conventional therapy. Rates of remission were similar between the two groups at 2 years. Endoscopic healing was higher in the early combined treatment group, and this was correlated with sustained steroid free remission in a separate follow up study.

***

Study highlight

The Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC trial) 27 Study objective: to compare the efficacy of infliximab, azathioprine, and combination infliximab plus azathioprine in inducing and maintaining corticosteroidfree clinical remission in patients with active Crohn’s disease. Study design: randomized, double blind, multi-center trial (conducted in 92 centers) from March 2005 through November 2008. Patient population Patients had no previous treatment with azathioprine, 6-mercaptopurine, methotrexate, or any anti-TNF biologic 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 4 and 5) Results show increased rates of remission and mucosal healing in the combination therapy and infliximab groups, compared to the AZP group. Figure 4: Remission at week 26

Figure 5: 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. There was one case of TB in the combination therapy group. 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 Exclusion of the heterozygous TPMT phenotype may have excluded patients

who have a favorable response to AZP monotherapy. 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 skewed the results in favor of the infliximab and combination group. The study did not address the question of whether combination therapy is superior to infliximab monotherapy after failure of azathioprine. *** 28 COMMIT trial (Combination of Maintenance Methotrexate-Infliximab Trial) 50-week double blind, multicenter controlled trial. 126 patients (infliximab naive) with active Crohn’s disease who were started on prednisone within the last 6 weeks were randomized to one of two groups: Infliximab (5 mg/kg, at weeks 1, 3, 7, and then every 8 weeks). Infliximab plus methotrexate (25 mg subq every 1 week). Steroids were withdrawn by week 14. Results showed no difference in remission rates between both groups at week 14 and 50. By week 50, 30.6% of patients in the combination infliximab plus methotrexate group had failed treatment compared to 29.8% of those assigned to infliximab alone group (p = .63). Conclusion: adding methotrexate to infliximab does not improve remission rates in patients with Crohn’s disease who are receiving treatment with prednisone.

Adalimumab CLASSIC 1 trial 29 (Induction therapy with adalimumab for Crohn’s disease) This is a randomized, multicenter, double-blind, placebo-controlled, dose-ranging trial for adalimumab induction. 299 patients with moderate to severe Crohn’s disease were randomized to one of four groups (table 12). Patients who received prior infliximab therapy were excluded. The optimal induction dosing regimen for adalimumab was shown to be 160 mg at week 0 followed by 80 mg at week 2 (table 12).

Table 12: CLASSIC 1-Treatment groups and Remission at week 4

CLASSIC 2 trial 30 (Maintenance therapy with adalimumab for Crohn’s disease) 276 patients from CLASSIC 1 enrolled in CLASSIC 2. All patients initially given open label adalimumab 40 mg every 2 weeks for 4 weeks. 55 patients achieved remission at week 4, and these were randomized to adalimumab versus placebo. Remission rates at week 56 are shown in table 13. Table 13: Classic 2- Treatment groups and remission at week 56 in patients who were in remission at week 4

204 patients were not in remission at week 4. These patients were given open label adalimumab at 40 mg subq every 2 weeks. The dose could be increased to 40 mg every 1 week during the trial. Remission was achieved in 46% of these patients. Conclusion: Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn’s disease naive to anti-TNF treatment. There were no significant differences in efficacy between adalimumab given every 2 weeks and every 1 week dosing regimens. CHARM trial 31 (Maintenance therapy with adalimumab for Crohn’s disease) Randomized trial of adalimumab vs. placebo in patients with moderate to severe Crohn’s disease. 50 % of patients had prior infliximab exposure. Patients with a previous infliximab initial non-response were excluded.

854 patients were enrolled and received open label adalimumab. Adalimumab was given at a dose of 80 mg subq at week 0, and 40 mg at week 2. Patients were assessed for response at week 4 and classified as responders and nonresponders. Both responders and non-responders were randomized to adalimumab 40 mg subq every 2 weeks and adalimumab 40 mg subq every 1 week. Primary endpoints were percentages of randomized responders who achieved clinical remission at weeks 26 and 56. Table 14 shows the results in the week 4 responders group. Table 14: CHARM trial-results in the week 4 responders group

At 1 year, remission rates were 42-48% in infliximab naive, 31-34% in previous infliximab treated patients, compared with 10-14% in placebo-treated patients. Subgroup analysis showed that patients with fistulas at baseline had greater fistula closure in the adalimumab groups compared to the placebo group. There were no differences in efficacy between the 40 mg every 2 weeks and 40 mg weekly regimens. This study had a significant withdrawal rate. ~30% of patients withdrew from the study before week 26. Conclusion: Among patients who responded to adalimumab, both adalimumab every 2 weeks and every 1 week were significantly more effective than placebo in maintaining remission in moderate to severe Crohn's disease through 56 weeks. ADHERE trial 32 (Adalimumab long-term maintenance of response in Crohn’s disease) Open label extension of CHARM trial (duration of follow up was up to 2 years). Patients received adalimumab 40 mg every 2 weeks, and their dose could be increased to every 1 week as needed. Adalimumab demonstrated sustained maintenance of clinical remission and reductions in hospitalization during long-term treatment for Crohn’s disease. GAIN trial 33 (Gauging Adalimumab Efficacy In Infliximab Non Responders) This is a 4-week, randomized, double-blind, placebo-controlled trial of adalimumab

treatment in patients previously treated with infliximab who lost response or were intolerant to infliximab. Patients who were primary non responders to infliximab were excluded. 325 patients were randomly assigned to receive induction doses of adalimumab (160 mg at week 0 and 80 mg at week 2) or placebo. At week 4, remission rate was 21% in the adalimumab group compared to 7% in the placebo group (p < 0.001). GAIN extension trial 34 (abstract) 310 patients who completed the GAIN trial were enrolled in an open label extension trial, and received adalimumab 40 mg every 2 weeks for one year. Remission rate among all patients was 29% at 1 year. Remission rates were 40% among patients who were responders to adalimumab at the beginning of the trial.

Certolizumab

PRECISE 1 35 (Induction therapy with Certolizumab for Crohn’s disease) This was a randomized, double-blind, placebo-controlled trial. It enrolled 662 adults with moderate to severe Crohn’s disease, stratified according to their CRP level. Primary analysis was performed in patients with baseline CRP ≥ 10 mg/L. Patients received 400 mg of certolizumab or placebo subcutaneously at weeks 0, 2, 4 and then every 4 weeks. The primary endpoints were induction of a response at week 6 and a response at both weeks 6 and 26 in patients with a baseline CRP ≥ 10 mg/L. Response at week 6 was achieved in 37% of the certolizumab group compared to 26% of placebo (p = 0.04). Response at both week 6 and 26 was achieved in 22% of the certolizumab group compared to 12% of placebo (p = 0.04). The authors concluded that certolizumab was associated with a modest improvement in response rates, as compared with placebo. Remission rates were similar in both groups at week 6 and 26.

PRECISE 2 36 (Maintenance therapy with Certolizumab for Crohn’s disease) The study enrolled 668 patients who were entered in the induction phase of the trial and given certolizumab 400 mg at week 0, 2, 4.

428 patients with clinical response at week 6 were randomized to either certolizumab or placebo every 4 weeks through week 24. Primary endpoint: patients with baseline CRP ≥ 10mg/L who received certolizumab were more likely to maintain response at week 26 (62%) compared to placebo (34%, p < 0.001). For all patients at week 26, certolizumab group was more likely to maintain clinical response (63%) compared to placebo (36%) and achieve remission (48% vs. 29%, p < 0.001). Patients who previously received infliximab had a lower response rate and remission at week 26 compared to patients who were naive to biologic therapy. WELCOME trial 37 (Certolizumab for Crohn’s disease after loss of response to infliximab) 539 patients with moderate to severely active Crohn’s disease and secondary failure to infliximab were enrolled in a 26-week trial. Patients received open label induction with subq certolizumab 400 mg at weeks 0, 2, and 4. Patients with clinical response at week 6 were randomized to certolizumab every 2 or 4 weeks. The primary endpoint was clinical response at week 6. Results: 62% of patients had clinical response to open-label induction therapy with certolizumab. Remission at week 6 was 39%. Response rate at week 26 with certolizumab every 2 weeks (40%) was similar to every 4 weeks (37%).

Natalizumab

ENACT 1 38 (Natalizumab induction for Crohn’s disease) Patients with moderate to severe disease received natalizumab 300 mg IV or placebo at weeks 0, 4, 8. 40% of patients had prior anti-TNF exposure, and 25% were refractory to anti-TNF. Patients who were exposed to an anti-TNF agent in the previous 3 months were excluded. Clinical response and remission rates at week 10 were not significantly different between the natalizumab group and placebo (table 15).

Table 15: Results of the ENACT-1 study

Subgroup analysis showed that in patients with high CRP or in those on concomitant immunosuppression (AZP, 6-MP or methotrexate), treatment with natalizumab was associated with a significantly higher rate of remission and response at week 10, compared to placebo. ENACT-2 38 (Natalizumab for Crohn’s disease maintenance treatment) Patients who had a response to natalizumab in the ENACT-1 trial were randomly assigned to natalizumab or placebo (week 12 to 56). The primary endpoint was the rate of sustained response at week 26. 28 % of patients assigned to placebo had a sustained response through week 36 (48 of 170), as compared with 61% of patients randomly reassigned to natalizumab (103 of 168, p < 0.001). ENCORE trial 39 (Natalizumab induction for Crohn’s disease) This international multicenter randomized placebo-controlled trial evaluated the efficacy of natalizumab induction therapy in patients with Crohn’s disease. 509 patients with moderate to severe Crohn’s disease with objective evidence of inflammation defined by an elevated CRP (> 2.87 mg/L). 50% of patients were previously treated with anti-TNF agents. Patients were given natalizumab 300 mg IV at week 0, 4, 8, or placebo. The primary endpoint was induction of clinical response at week 8 sustained through week 12. Primary endpoint was achieved in 48% of the natalizumab group and 32% of placebo (p < 0.001). Conclusion: this study showed that natalizumab is an effective induction therapy in patients with elevated CRP and active Crohn’s disease.

IBD and colorectal cancer

Guideline: AGA Technical Review on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease, Gastroenterology, 2010

40

Factors associated with an increased risk of colorectal cancer in IBD: Increased disease duration. More extensive disease. Primary sclerosing cholangitis. Family history of colorectal cancer. Colonic strictures secondary to Crohn’s disease. Multiple inflammatory pseudopolyps. 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. 41 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.42 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.43 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.44 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.45 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. Surveillance recommendations 40 Perform a screening colonoscopy in all patients 8-10 years after the onset of colitis symptoms.

Determine the endoscopic and microscopic extent of inflammation by performing a careful examination and obtaining biopsies from all colonic segments. The extent of inflammation will determine further course of action as follows: In patients with ulcerative proctitis or proctosigmoiditis, surveillance is not recommended, as there is no increased risk of malignancy. 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 technique Obtain four-quadrant biopsies every 10 cm. Get more intensive biopsies in patients with strictures or multiple pseudopolyps. Biopsy or resect any raised lesion. Obtain a biopsy of the surrounding mucosa. Separate specimens in different jars by colonic segments (cecum, ascending, transverse, etc.) or by insertion distance (70 cm, 60 cm, etc.). The optimal colonoscopy screening interval is not clear. In general, perform the first two exams every 1-2 years. If no dysplasia, extend screening interval to every 2-3 years. In patients with PSC, perform yearly colonoscopic surveillance. Chromoendoscopy with targeted biopsies of abnormal mucosa is an alternative to regular white light colonoscopy. Dysplasia Colonic dysplasia in IBD is a marker that concurrent adenocarcinoma might be present in the colon. Even if the area of dysplasia is completely resected, there remains a risk of adeno​carcinoma in the other colonic segments. Dysplasia in IBD can be classified as raised or flat dysplasia. Raised lesions in IBD can be due to raised dysplasia, or inflammatory "pseudopolyps" that result from chronic inflammation. A raised lesion with dysplasia is referred to as dysplasia associated lesion or mass (DALM). DALMs can be secondary to a sporadic adenoma (adenoma-like DALM), or due to dysplasia as a result of IBD (non adenoma-like DALM). Always biopsy any raised lesion and its surrounding mucosa as this will help differentiate between the two types. Adenoma like DALMs are most likely sporadic and not related to inflammation, while non-adenoma like DALMs occur in areas of inflammation and active IBD. The characteristics of these lesions are compared in table 16. The classification of dysplasia and raised lesions is summarized in figure 6. Figure 6: Dysplasia and raised lesions in IBD

Table 16: Characteristics of adenoma and non-adenoma like DALMs in IBD

Management of flat dysplasia Flat high grade dysplasia Colectomy is indicated as the risk of adenocarcinoma is up to 37%.43 Flat low grade dysplasia The AGA does not recommend for or against colectomy due to insufficient evidence.40 The rate of concurrent adenocarcinoma are variable in the literature, but can be as high as 20%.43 However, low grade dysplasia can remain stable for many years or regress spontaneously. Confirm with an expert pathologist the absence of high grade dysplasia. Discuss the diagnosis with the patient and consider colectomy versus intensive surveillance with colonoscopy and biopsy every 3-6 months.

Extra-intestinal manifestations of IBD Table 17: Extra-intestinal manifestations of IBD

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 such as those with severe disease, low BMI, and steroid use for longer than 3

months. 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.47 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.

Surgical therapy for IBD 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 7): 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 with an increased risk of gas or 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. Figure 7: IPAA surgical techniques

Evaluation of pouch symptoms Pouch endoscopy (pouchoscopy): the neoterminal ileum, pouch body, and transitional zone should be carefully examined and biopsied. Pouch problems Cuffitis

This complication develops in the stapled IPAA and results in inflammation of the residual cuff of rectal mucosa distal to the ileo-rectal anastomosis. Presents with bleeding and urgency.48 Treatment: topical mesalamine, steroids. Pouchitis Inflammation of the pouch mucosa. Symptoms include urgency, frequency, diarrhea, abdominal pain. Bleeding is less common. A positive p-ANCA predicts the development of pouchitis post IPAA in up to 60% of patients.49 Other risk factors for pouchitis include non-smoking patient and PSC. Consider secondary pouchitis due to Clostridium difficile, CMV, NSAIDS, ischemia, or radiation-induced pouchitis. The main treatment of pouchitis is antibiotics. First line antibiotics are metronidazole or ciprofloxacin, given for 2 weeks. If there is no response to initial treatment, give another 2-week course of antibiotics. 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), give antibiotics as needed for recurrent episodes. VSL#3 is a probiotic that decreases relapse rate after successful treatment of pouchitis.50, 51 It can also 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. Surgery related complications include leakage and fistula formation. These typically present early after surgery. Fistulas open at or around the surgical anastomosis. Fistulizing Crohn’s disease presents anytime after 6 months post surgery. Fistulas

open above the surgical anastomosis.

Post operative recurrence of Crohn’s disease Data from studies prior to the introduction of biologic therapy show that up to 70% of Crohn's disease patients will require at least one surgical resection within 10 years of diagnosis.52 In patients who underwent colonic or ileocolonic resection, the disease most commonly recurs at the site of surgical anastomosis. Endoscopic recurrence occurs in up to 90% of patients at 1-year post resection. Most endoscopic recurrence is subclinical; however, some cases progress to clinically symptomatic disease. Clinically symptomatic recurrence occurs in up to 30% of patients at 1 year and 50% at 5 years. 53 Symptoms include diarrhea, bleeding, abdominal pain, and intermittent obstruction. Assess the risk of postoperative disease recurrence by considering patient and disease related risk factors (table 18). Table 18: Risk factors for disease recurrence

Consider postoperative prophylaxis according to the risk of recurrence. High risk patients are those with fistulizing disease or two prior surgeries or multiple risk factors. Strongly consider starting biologic therapy post operatively.

If the patient is not a candidate for biologic therapy, thiopurines can be started instead. However, they are less effective than biologics in preventing disease recurrence. In moderate risk patients, start AZP or 6-MP. Low risk patients are those with long disease duration, short segment of involved bowel and mild inflammation.54 These patients do not need prophylactic medications. Perform colonoscopy in all patients at 6-12 months post surgery, regardless of their clinical symptoms. Assess endoscopic recurrence according to the Rutgeerts endoscopic recurrence score (table 19). 55 Table 19: Rutgeerts endoscopic recurrence score post ileocolonic resection for Crohn’s disease

In patients with endoscopic recurrence (score of ≥ 2), start therapy if not already on treatment or intensify treatment regimen. Start biologics with or without thiopurines in patients with severe recurrence.

Endoscopic balloon dilation for Crohn’s disease strictures A retrospective study with a large number of patients evaluated the success rate of balloon dilation in 138 patients who underwent 237 dilatations.56 Most patients (84%) had anastomotic strictures in the ileal and ileo-colonic area. All strictures were less than 5 cm in length. All dilations were performed with a throughthe-scope balloon dilator, 8 cm long, and 18 mm in diameter in a stepwise fashion (15– 16.5–18 mm). Median follow-up was 5.8 years. The overall immediate success of the first dilation was 97% (defined as the ability to pass an adult colonoscope through the stricture). 12 patients (5%) had serious complications. These included six perforations, five GI bleeding cases, and one severe abdominal pain. Recurrent obstructive symptoms led to repeat dilation in 46% of patients and surgery in 24%. Another retrospective study showed that the long term success of endoscopic dilation is higher in anastomotic strictures as compared to recurrent inflammatory Crohn's disease strictures.57 In summary, endoscopic balloon dilation has a high immediate success rate but a variable long term success. Dilation in patients with acute inflammation carries a high risk of perforation, while dilation of fibrotic, anastomotic strictures appears to be safer and more effective. This can be considered as an alternative to surgery in carefully selected patients.

Fertility and pregnancy issues in IBD

European Crohn’s Colitis Organization (ECCO):European evidenced-based consensus on reproduction in inflammatory bowel disease, J Crohns Colitis, 2010

58

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. Methotrexate has been linked to altered spermatogenesis. Women have three times increased risk of infertility post proctocolectomy and IPAA if deep pelvic dissection is performed. Conventional ileostomy is not associated with increased infertility rates.

Disease activity in pregnancy If conception occurs during remission, one third of patients relapse during pregnancy. This risk is similar to non-pregnant IBD patients. If conception occurs during active disease, symptoms will improve in one third of patients, worsen in one third, and remain unchanged in one third of patients. There is no increased risk of disease flare post partum.

Conventional therapies in pregnancy Table 20 summarizes the pregnancy and lactation risk of conventional therapies. Most medications are pregnancy class B or C. Methotrexate is class X.

Table 20: Pregnancy and lactation risk of conventional therapies for Crohn's disease.

Biologics in pregnancy

The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD With the European Crohn’s and Colitis Organization: Pregnancy and Pediatrics, Am J Gastroenterol, 2010 59 If the mother has active IBD during pregnancy, then continuing or starting biologic

therapy is a reasonable approach to control her disease during pregnancy. If the mother’s IBD is in remission during pregnancy, then consider stopping the biologic during pregnancy to minimize fetal exposure. Infliximab and adalimumab are IgG1 antibodies with active placental transport throughout pregnancy, but mostly in the third trimester. Hold infliximab and adalimumab during the third trimester. Withhold live vaccines in infants younger than 6 months if the mother was given infliximab or adalimumab. 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.60 Rotavirus is the only live infant vaccine in the USA. Other live infant vaccines are oral polio and BCG. Certolizumab has minimal placental transport. Therefore, it is reasonable to continue its use throughout pregnancy. Table 21 summarizes the recommendations from the London position statement on the use of biologics in pregnancy, men attempting conception and breastfeeding.59 Table 21: Safety of biologic therapy in pregnancy, lactation, and men attempting conception

Delivery in patients with Crohn’s disease Cesarean section is recommended in women with active perianal disease, rectovaginal disease involvement or in patients with an IPAA.

Chapter 10- Miscellaneous GI topics Introduction Nutrition Gastrointestinal carcinoids Gastric carcinoids Small bowel carcinoids Appendiceal carcinoids Colonic carcinoids Rectal carcinoids Carcinoid syndrome Gastrointestinal stromal tumors Hereditary angioedema References

Introduction 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. Carcinoids and GISTs are not uncommon, especially gastric GISTs and rectal carcinoids. Board exams frequently ask about the molecular features, imaging characteristics, and management of these tumors.

Nutrition Vitamins and minerals. Features of vitamin deficiencies and toxicities are presented in table 1.

Table 1: Features of vitamin deficiencies and toxicities (water soluble vitamins)

Table 1: Features of vitamin deficiencies and toxicities (fat soluble vitamins)

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

Table 2: Features of mineral deficiencies and toxicities

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, chronic alcoholism, intractable vomiting, Crohn's disease, and short bowel syndrome. Manifestations Metabolic: hypophosphatemia, hyperglycemia, hypomagnesemia, hypokalemia, fluid overload, thiamine and other vitamin and mineral deficiencies. Other: cardiac (congestive heart failure, arrhythmias), GI (abdominal pain, vomiting, constipation), neurologic (weakness, paraesthesia, ataxia, encephalopathy).

Gastrointestinal carcinoids General concepts GI carcinoids are neuroendocrine tumors arising from the neuroendocrine cells of the GI tract. The more general term “neuroendocrine tumors” also includes pancreatic islet cell tumors and pancreatic neuroendocrine cell tumors (see chapter 6-pancreas). GI carcinoids most commonly arise in the ileum, followed by the rectum and appendix. Biomarkers Serum chromogranin A, acid phosphatase, pancreatic polypeptide. Elevated 24-hour urine 5 hydroxyindoleacetic acid (5-HIAA) levels. Foods high in serotonin should be restricted during the study period. Imaging modalities CT scan, MRI, EUS, octreoscan (good for detecting metastasis), PET scan. Histopathologic staining: synaptophysin (stains all carcinoids, see figure 1), chromogranin, neuron specific enolase. Ki-67 is a proliferation marker. Gastric carcinoids

Table 3: classification of gastric carcinoids 3, 4

Small bowel carcinoids Most small bowel carcinoids are located within 60 cm of the ileocecal valve. Most tumors presents with vague abdominal pain, intussusception, bowel obstruction, or bleeding. Small bowel carcinoids are the most common tumors causing carcinoid syndrome. Small bowel carcinoids 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.5 Synchronous small bowel carcinoids are present in 25% of patients. It is important to examine the entire small bowel to rule out synchronous lesions. Tumors of very small size may have already metastasized. Treatment 6 Jejunal and ileal carcinoids: bowel resection and lymphadenectomy, regardless of tumor size. Duodenal carcinoids: endoscopic resection or local surgical excision. Overall 5-year survival is 40-80%. Appendiceal carcinoids Carcinoids are the most common tumors of the appendix. Treatment Tumors that are localized and smaller than 2 cm in size are treated with appendectomy. Tumors larger than 2 cm or those that extend beyond the muscularis propria are treated with right hemicolectomy. Appendiceal carcinoids have a good prognosis with an overall 5-year survival of 70100%. Goblet cell carcinoids of the appendix (also called adenocarcinoids) These are mixed tumors with neuroendocrine features and goblet cell/intestinal features. 7 In contrast to classic carcinoids, chromogranin A is absent or minimal in goblet cell carcinoids. They are more aggressive compared to traditional carcinoids. Treatment is with right hemicolectomy +/- chemotherapy. Colonic carcinoids Colonic carcinoids (excluding the rectum) are rare and account for 8% of all carcinoid tumors. 8 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 carcinoids Rectal carcinoids are increasing in incidence, likely due to increased detection. Mean age at diagnosis 56 years. They are more common in blacks > whites. Most tumors are small (< 1 cm) and are diagnosed incidentally during a colonoscopy (figure 1). Figure 1: Rectal carcinoid A: Rectal carcinoid 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.

Rectal carcinoids rarely cause carcinoid syndrome. The risk of metastasis in rectal carcinoids and their management depend on tumor size (table 4). Table 4: Size, risk of metastasis and corresponding management of rectal carcinoids

Endoscopic resection of small carcinoids (< 2 cm) can be performed using saline lift, hot snare resection with or without cap or band assisted EMR. High risk features favoring metastatic behavior include size > 2 cm, poorly differentiated histology, lymphatic and vascular invasion, high tumor proliferative index (mitotic index, Ki-67) 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 carcinoid tumors. Most patients with carcinoid syndrome have small bowel carcinoids with liver metastasis. 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. 9 Octreotide and IVF are recommended prior to any procedure if there is a suspicion of carcinoid syndrome to prevent carcinoid crisis. Carcinoid heart disease is present in ~50% of patients with carcinoid syndrome. Heart disease results from fibrotic changes induced by serotonin. Most cardiac lesions are right sided. The most common lesion is tricuspid regurgitation. Treatment Carcinoid syndrome Octreotide 250 mg subq t.i.d. An alternative medication is lanreotide subq every 4 weeks. 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.

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. 10 85-90% of GISTs have a specific genetic mutation in c-Kit or PDGFRA (table 5). Table 5: GIST mutations

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. 11, 12 Diagnosis CT scan, MRI, PET scan EGD shows a submucosal mass with normal or ulcerated overlying mucosa (figure 2A). Mucosal biopsies are usually non-diagnostic. A: Submucosal mass in the proximal gastric body.

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 2-B and C). 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 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. Consider surveillance of asymptomatic GISTs that are smaller than 2 cm in size. Refer for resection if there is interval growth or development of symptoms. Endoscopic full thickness resection of gastric GISTs originating from the muscularis propria is increasingly being reported in China. Endoscopic submucosal dissection is used followed by tumor resection and endoscopic closure using clips or sutures.13, 14 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. High risk features include any ruptured GIST (recurrence risk is near 100%)15, tumor size > 10 cm, or tumor size > 5 cm with > 5 mitoses/HPF. The FDA approved indication includes any GIST ≥ 3 cm. Duration of treatment is unclear, but is at least 3 years. Treatment for 3 years improves overall survival compared to 1 year.16 Side effects of imatinib are periorbital edema, diarrhea, myalgia, musculoskeletal pain headache, and skin rash. The standard dose is 400 mg once daily. 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.17 Unfavorable prognostic factors include exon 9 mutation, wild type GIST, and incomplete resection.

Hereditary angioedema

2010 International consensus algorithm for the diagnosis, therapy and management of 18

hereditary angioedema, Allergy, Asthma & Clinical Immunology 2010

Hereditary angioedema (HAE) is a rare disease characterized by recurrent episodes of angioedema involving the skin, upper respiratory and gastrointestinal tracts. HAE is classified into three types that defer in their presentation and pathophysiology (table 6). HAE type 1 and 2 is caused by decreased C1 inhibitor (C1-INH) level or function. C1-INH is a protein that inhibits multiple components of the complement and the kinin pathways. Decreased C1-INH level or function leads to elevated bradykinin levels (resulting in symptoms of HAE), and unopposed proteolysis of C4 (resulting in low C4 levels). HAE type 3 is not related to abnormal C1-INH (see table 6 below).

Table 6: Classification of hereditary angioedema 18

Clinical manifestations Non-pruritic skin swelling without urticaria. Laryngeal edema can cause life threatening airway compromise. Gastrointestinal angioedema leads to nausea, vomiting, diarrhea, and colicky abdominal pain. 18 Triggers of HAE attacks: mild trauma, stress, ACE inhibitors, estrogen containing medications. Diagnosis: check C4 level, C1-INH level, and C1-INH functional levels. A normal C4 during a symptom episode excludes the diagnosis of type 1 and 2 HAE. Abdominal CT scan shows small or large bowel edema and ascites. Treatment Airway management is a priority in patients with laryngeal edema and airway compromise. Give recombinant human C1-inhibitor. Danazol is given for prophylaxis against future attacks.

In summary, think of HAE in patients with recurrent colicky abdominal pain of unknown etiology and those with recurrent angioedema. Obtain a good family history, and check C4 levels during attacks. Refer to the guideline above for more specific details about diagnosis and management.

Chapter 11-Endoscopy Introduction Endoscopy in pregnancy Antibiotic prophylaxis for endoscopic procedures Capsule endoscopy ERCP Post ERCP Pancreatitis Post sphincterotomy bleeding Techniques for biliary access in difficult cannulation Techniques without precut papillotomy Techniques with precut papillotomy Sphincteroplasty for extraction of large CBD stones ERCP for hilar strictures Enteral stenting Endoscopic Ultrasound Detachable snares (endoloops) Endoscopy in the bariatric surgery patient References

Introduction The goal of this chapter is to broaden your current endoscopic knowledge and expand your endoscopic techniques. The GI boards commonly ask about antibiotic prophylaxis, 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 for you to adapt 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 endoloop, which is a useful tool for the safe 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 complications to be able to perform a safe and effective endoscopy in these patients.

Endoscopy in pregnancy

Guidelines for endoscopy in pregnant and lactating women, Gastrointestinal Endoscopy, 2012 1 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). 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 the 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 The FDA pregnancy classes for common medications are shown in table 1. Table 1: FDA pregnancy category for common medications

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.

Antibiotic prophylaxis for endoscopic procedures

Antibiotic prophylaxis for GI endoscopy, Gastrointestinal Endoscopy, 2008

4

Indications for antibiotics prophylaxis ERCP for bile duct obstruction where incomplete drainage is anticipated (e.g. PSC, hilar strictures). Antibiotics should be given in these cases to prevent cholangitis. ERCP in which a pancreatogram is performed in a patient with sterile pancreatic collection communicating with the pancreatic duct. EUS-FNA of pancreatic fluid collections. EUS-FNA of any cystic lesion along the GI tract. Percutaneous endoscopic gastrostomy or jejunostomy. Cardiac conditions, bioprosthetic joints, and grafts are not an indication for prophylaxis.

Capsule endoscopy

Wireless capsule endoscopy, Gastrointestinal Endoscopy, 2013

5

Capsule types in the USA PillCam® SB2 (Given Imaging) EndoCapsule® (Olympus Corporation) Both capsules are 11 x 26 mm in size. Indications Obscure GI bleeding or iron deficiency anemia, evaluation of known or suspected Crohn's disease, celiac disease, or suspected small bowel tumor. Contraindications Patients with known or suspected GI stricture or obstruction. Special considerations The capsule is MRI non-compatible. The patient cannot undergo an MRI procedure while undergoing capsule endoscopy. 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 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 2. Table 2: Capsule retention rates in different conditions

A normal small bowel follow through performed prior to capsule endoscopy does not rule out the possibility of capsule retention.

In patients with suspected GI strictures and a concern for capsule retention, perform a patency study with a patency capsule prior to capsule endoscopy. Other risk factors for small bowel capsule retention: NSAIDS use (leads to small bowel strictures), radiation enteritis, small bowel tumors. 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: The capsule cannot be detected in the patient’s body after 30 hours. The capsule is detected and imaging shows that it is in the colon. The patient sees the patency capsule pass 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. Prior to referring for a deep enteroscopy (single or double balloon), it is helpful to check the time the capsule took to reach the lesion and the total small bowel time to determine the appropriate method of deep enteroscopy (anterograde or retrograde). Measure the time it took the capsule to reach the lesion. If the lesion is reached within the first two thirds of the total small bowel time, then perform an anterograde deep enteroscopy. If the lesion is reached within the distal third of the small bowel time, then perform a retrograde deep enteroscopy. For more on capsule endoscopy and the diagnostic yield for GI bleeding, refer to the chapter 7-GI bleeding, section on obscure GI bleeding.

ERCP Post ERCP Pancreatitis Risk factors for post ERCP pancreatitis (PEP) are shown in table 3. Table 3: Risk factors for PEP

A meta-analysis showed that pancreatic stents decrease the risk of PEP with an odds ratio of 0.22 and a number needed to treat of 8.8 Pancreatic stents that are used 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. 9 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 (described later) does not require PD stent placement. After pancreatic wire placement to aid biliary access (double guidewire techniquedescribed later). Other indications include endoscopic ampullectomy, pancreatic sphincterotomy, and cases with difficult cannulation. Rectal indomethacin was shown in a randomized controlled trial to decrease the risk of PEP in high risk patients undergoing ERCP. ***

Study highlight

A Randomized Trial of Rectal Indomethacin to Prevent Post ERCP Pancreatitis 10 This is a multicenter, randomized, placebo-controlled, double-blind trial. 602 patients with risk factors for PEP were enrolled. These included a clinical suspicion of SOD (~80% of patients), pancreatic sphincterotomy (57%), history of PEP (16%), difficult cannulation (26%), precut sphincterotomy (5%), and ampullectomy (3%). Patients were randomized to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Pancreatic stents were placed in ~80% of patients. The primary outcome was the development of PEP. Rate of PEP was 16.9% in the placebo group and 9.2% in the rectal indomethacin group (p=0.005), while that of moderate or severe PEP was 4.4% in the rectal indomethacin compared to 8.8% in the placebo group (p=0.03). ***

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).

Other hemostatic techniques include bipolar electrocoagulation, clip placement, and argon plasma coagulation. Severe bleeding that cannot be controlled endoscopically may require angiographic embolization.

Techniques for biliary access in difficult cannulation Introduction 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 is comfortable 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 (described in more details next

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. It is recommended that a pancreatic stent be placed in these patients to decrease the risk of post ERCP pancreatitis.11, 12 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 with PD stent (figure 1- B then C, videos 11-2,3,4)

***

***

Also called transpancreatic precut sphincterotomy. Once a wire is placed deeply in the PD, perform a transpancreatic sphincterotomy in the direction of the bile duct (11 o'clock)-(fig 1-b). 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. (fig 1-c) 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; therefore, they are generally not recommended for junior endoscopists. Prior to 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. Cutting should not be deep, as this increases the risk of perforation. 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, and 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 technique is the most difficult, as it 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. 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. A suggested approach to difficult biliary cannulation is shown in figure 2. Figure 2: Suggested approach to difficult biliary cannulation

Sphincteroplasty for extraction of large CBD stones

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. 13

Technique (video 11-8) Cannulate the bile duct and obtain an initial cholangiogram. Assess the size of the stone. Assess the size of the bile duct above the tapered distal segment. Perform a sphincterotomy. 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, observe the disappearance of the waist in the balloon. 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.

ERCP for hilar strictures The Bismuth-Corlette classification of perihilar tumors is shown in table 4. 14 Table 4: Bismuth classification of hilar strictures

Principles of hilar stenting Obtain MRCP/CT scan prior to ERCP to delineate the hepatobiliary anatomy and plan the ERCP. If a liver lobe appears atrophied, avoid stenting that side as it will not achieve biliary drainage, and may precipitate cholangitis. Give periprocedural antibiotics. Minimize contrast injection. For Bismuth type 1 strictures, a single stent is sufficient for adequate drainage. Bismuth type 2, 3 and 4 strictures One-sided stenting is generally considered adequate. This will relieve jaundice and itching in most cases.

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. Avoid prolonged manipulations and attempts to stent the contralateral hepatic duct. 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. 15 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.

Enteral stenting Duodenal stenting Duodenal stenting is indicated in cases of malignant duodenal obstruction. Explore surgical candidacy and consider a surgical bypass instead of a duodenal stent. If the expected survival is more than 3 months and the patient is a good surgical candidate, then palliative gastrojejunostomy is a better option and provides better long term outcomes. If biliary obstruction is present, try to stent the biliary system first. It the stricture cannot be 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. If the stent's delivery system is too large to fit through the scope's channel, a stiff (e.g. Savary) guidewire is inserted through the stricture. The scope is withdrawn and the stent is inserted directly over the wire. The scope is then passed alongside the stent to confirm position. The stent should be placed with the proximal end through the pylorus and the distal end ideally in the pre-ampullary area. 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 In cases of a tight stricture, choose a smaller stent diameter. 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. Note that Metal stents are not FDA approved for this indication. For malignant strictures, use partially covered or uncovered stents to decrease migration rates. Length Ideally, the stent should traverse the stricture with 2 cm of length above and below the

stricture The stent's length on the package reflects its length when it is fully expanded 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 require placing two overlapping stents. Technique of 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 easily traverse the stricture. Mark the distal and proximal ends of the stricture with paper clips. Pass a wire across the stricture. A stiff wire (e.g. Savary) 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. However, this should be done carefully to avoid dislodgement of the stent. 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 which types of food are recommended, and which should be avoided to prevent stent occlusion. Patients should be advised to have small frequent meals and to eat slowly. Food should be soft and moist, and chewed thoroughly before swallowing. Colonic stenting If the stricture is in the distal 25 to 30 cm of the rectum and sigmoid, the stent can be passed directly over a stiff wire, rather than though the scope. Otherwise, it has to be passed through a scope with a large therapeutic channel and using a long wire (450 cm). Bevacizumab treated patients have a higher risk of perforation post colonic stenting.16

Endoscopic Ultrasound Gastric EUS The appearance of gastric wall layers on endoscopic ultrasound is shown in table 5 and

video 11-11. Gastric submucosal lesions are shown in table 6. Figure 3 shows two common EUS lesions: GIST and lipoma. Table 5: EUS-gastric wall layers

Table 6: Gastric submucosal lesions

Figure 3: 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 7 17

Table 7: Differential diagnosis of thick gastric folds

Pancreatic EUS The EUS criteria for the diagnosis of chronic pancreatitis are shown in table 8. Table 8: EUS criteria for the diagnosis of chronic pancreatitis (Rosemont classification)

18

Detachable snares (endoloops) The main indication of the endoloop is to prevent bleeding after hot snare resection of large pedunculated polyps. 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 4-A). They are manufactured by Olympus. Technique for endoloop placement around large pedunculated polyps (figures 4 and 5, video 11-12)

Video 11-12 Figure 4: Steps of endoloop placement. (see text)

Figure 5: 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

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. Endoscopic technique Place the polyp in a favorable position (6 o'clock). Cover the endoloop by pushing the sheath forward (figure 4-A). Insert the endoloop through the scope. Pull the sheath backward to expose the endoloop (figure 4-B). Use the handle to close the loop tightly around the polyp stalk (figure 4-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 4D). 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.

Endoscopy in the bariatric surgery patient

Role of endoscopy in the bariatric surgery patient, Gastrointestinal endoscopy 2008

19

Clinical Practice Guidelines for the Perioperative Nutritional, Metabolic, and Nonsurgical Support of the Bariatric Surgery Patient, American Association of Clinical Endocrinologists, The Obesity Society, and American Society for 20

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 (table 9) Table 9: Classification of bariatric surgeries

Figure 6 shows the surgical anatomy in different bariatric surgeries. Figure 6: Postoperative anatomy in different bariatric surgeries. A: Roux-en-Y gastric bypass with a stapled gastric pouch (performed using the open approach); B: Roux-en-Y gastric b ypass with a divided gastric pouch (performed using the laparoscopic or open approach); C: Vertical banded gastroplasty; D: Sleeve gastrectomy; E: Adjustable gastric band; F: Fobi-Capella g astric bypass (Fo bi pouch gastric bypass)

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 Stapled gastric pouch without complete separation from the remnant stomach (figure 6-A). This configuration is performed using the open surgical approach and cannot be performed with laparoscopy. Divided (disconnected) gastric pouch (figure 6-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 6A). It can be absent if the surgeon performed an end-to-end rather than an end-toside anastomosis (see an example of an end-to-end G-J anastomosis in figure 6-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 6-f). In this surgery, a restrictive ring (Fobi ring) is placed around the distal part of the gastric pouch. Post operative complications Anastomotic leaks Present within 2 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 include abdominal pain, peritonitis, dyspnea, tachypnea, and tachycardia. Diagnosis: upper GI gastrografin study, CT scan. Surgical re-exploration is usually required. Other early complications include 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: smoking cessation, stop NSAIDS, treat H. pylori, PPI, carafate, 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 7). Aim for a dilation diameter of ~12 mm. Do not over-dilate the anastomosis to avoid recurrent weight gain. Figure 7: 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.21 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). Give thiamine before glucose, as glucose administration can worsen thiamine deficiency. Dose of thiamine: 500 mg/day for 3-5 days, then 250 mg/day for 3-5 days, then 100 mg/day maintenance therapy.20 Routine supplementation with calcium (calcium citrate 1200-1500 mg/day) and twice-daily multivitamin plus minerals is recommended after bariatric surgery.20 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 (refer to chapter 10).

Links to the video content 1-1 Band-assisted EMR http://youtu.be/Z_Q-f7XktXk

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1-2 HIV idiopathic ulcer http://youtu.be/DEcyECDiHyE

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7-1 Ulcer bleeding hemostasis http://youtu.be/C7fbvR_X284

7-2

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Endoscopic confirmation of Blakemore http://youtu.be/47b7KfPmGPw

7-3 GAVE-APC http://youtu.be/ZsXxlvSHS1Y

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7-4 Diverticular bleeding hemostasis http://youtu.be/wxiCAKO1L-w

7-5 Cameron erosions http://youtu.be/J69yhV9nTRk

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8-1 C. Difficile Colitis ggNZAipR0

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8-2

Diversion colitis

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http://youtu.be/y-

http://youtu.be/Sv9otcqMhEM

9-1 Crohn's colitis http://youtu.be/sJ8M1mlDis4

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10-1 Gastric GIST http://youtu.be/4f8hONnmVC8

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11-1 Post sphincterotomy bleeding http://youtu.be/i7TMxrpIGb0

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11-2 Transpancreatic septotomy 1 http://youtu.be/QbQU1_GbuvE

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11-3 Transpancreatic septotomy 2 http://youtu.be/LUtjXUKEF3Y

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11-4 Transpancreatic septotomy 3 http://youtu.be/prVDRoHrLik

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11-5 Needle knife cannulation 1 http://youtu.be/FEekIbfPBds

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11-6 Needle knife cannulation 2 http://youtu.be/Fz-5A4rdb00

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11-7

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Needle knife cannulation 3

http://youtu.be/58HiEws4Qtg

11-8 Ampullary balloon dilation http://youtu.be/0eQlgTX9bg4

11-9 Esophageal Stent 1 http://youtu.be/9kUt5L6VUww

11-10 Esophageal Stent 2 http://youtu.be/8miWQclj6IQ

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11-11 EUS gastric wall layers http://youtu.be/qPD3sHufdNs

11-12 Endoloop assisted polypectomy http://youtu.be/Q9o6ETEufwQ

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3:35