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    • Highlights from the 15th Annual Gastroenterology/Hepatology Update Chair Douglas K. Rex, MD Distinguished Professor of MedicineT Chancellor’s Professor his CME newsletter, based on the 2012 Gastroenterology/Hepatology Update Indiana University-Purdue University Indianapolis meeting, will provide expert perspectives from Indiana University School of Medi- Indianapolis, IN cine’s distinguished faculty on new developments in gastroenterology and hepa-tology. These insights will help busy gastroenterologists, internists, family practice physi- Learning Objectives This activity is designed for specialists in gastroenterology, internal medicine,cians, and other primary care providers evaluate results of recent breakthrough research family practice, and primary care. There are no prerequisites for this activity. At thefor their implications for today’s clinical practice. conclusion of this activity, participants should be able to: • Identify and screen patients with average and high risk for colorectalKey features of the 2012 program include presentations on new and updated clinical cancer to prevent colorectal cancer and reduce cancer mortality based on the American College of Gastroenterology guidelines.information, as well as treatment and management updates for gastroenterologic and • Examine patients for Barrett’s esophagus based on American College ofhepatologic diseases. A review of potentially practice-changing studies will be provided in Gastroenterology guidelines and conduct cost-effective surveillances.a number of areas, such as upper and lower gastrointestinal tract diseases, liver disease, • Use management strategies for gastroesophageal reflux disease (GERD)and pancreatobiliary disease. Finally, clinical recommendations will be offered to help recommended by the American College of Gastroenterology to improve quality of life in patients with GERD.improve practice and, ultimately, patient outcomes. • Evaluate and treat patients with abnormal liver test results and patients with viral hepatitis using American Association for the Study of LiverUpdate in Colorectal Cancer able way to distinguish HP from SSA/P Diseases screening guidelines to prevent cirrhosis in patients.Screening endoscopically.1 Most large serrated • Optimize outcomes of treatment for hepatitis C by considering the use of new protease inhibitors. lesions in the proximal colon are SSA/P. • Employ current guidelines regarding screening in a consistent manner so asDouglas K. Rex, MD, Distinguished In particular, SSA/P with cytological to identify and screen all patients at risk for hepatitis B infection.Professor of Medicine and Chancellor’s dysplasia is a dangerous lesion. • Apply current guidelines to identify patients at high risk for hepatocel-Professor, presented an update on colorectal lular carcinoma, screen using recommended modalities, and follow up with appropriate treatment or referral.cancer screening, including a discussion The commonly used CRC screening • Describe the implications for clinical practice of recent advances inabout the criteria by which the quality of tests in the United States are the guaiac- the management of lower gastrointestinal tract disease, GERD, andcolonoscopy can be evaluated. based fecal occult blood test (gFOBT), pancreatic and pelvic floor disorders. fecal immunochemical test (FIT), and CME InformationEvery colorectal cancer (CRC) is unique colonoscopy. Although not commonly Release Date: August 15, 2012.from a molecular standpoint and has used, the most promising stool test Valid for credit through August 14, 2013.its own unique genetic profile of muta- may be the fecal DNA test, because This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuingtions. However, gene mutations in 3 hypermethylated genes can be easily Medical Education (ACCME) through the joint sponsorship of Indiana Univer-general pathways define the molecular detected in the stools. A large-scale sity School of Medicine and Heath Focus, Inc. Indiana University School ofbasis of CRC: the chromosomal insta- randomized controlled trial of FIT Medicine is accredited by the ACCME to provide continuing medical education for physicians.bility pathway (CIN; tumor suppressor versus gFOBT in 20,623 participants Indiana University School of Medicine designates this enduring activity for aand oncogene mutations), the Lynch showed better adherence and positivity maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the creditpathway (mutations in mismatch repair rate for FIT (59.6% and 5.5%, respec- commensurate with the extent of their participation in the activity.genes), and the CpG island meth- tively) compared with gFOBT (46.9% To receive credit, participants must read this newsletter and submit theylator phenotype (CIMP) pathway and 2.4%, respectively).2 Septin 9 is activity evaluation form and posttest (passing score = 75% or higher). Length of time to complete the activity: 2 hours(hypermethylation of genes), which a new blood test not yet approved byaccounts for about 30% of colorectal the U.S. Food and Drug Administration Disclosure Informationcancers. The precursor for CIMP- (FDA) that tests for hypermethylation Commercial Support Indiana University School of Medicine and Health Focus, Inc. gratefullypositive tumors is not the traditional of the septin 9 gene. When compared acknowledge the unrestricted educational grant provided by Vertex.adenomatous polyp, but a different with the fecal DNA test, the septin Faculty Disclosuresort of polyp called a serrated lesion. 9 test performed poorly in terms of In accordance with the Accreditation Council for Continuing Medical EducationThe serrated lesions are classified specificity, as well as sensitivity, for (ACCME) Standards for Commercial Support, educational programs sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance,as hyperplastic polyp (HP); sessile stage I to stage III cancer and large independence, objectivity, and scientific rigor. All faculty, authors, editors, andserrated adenoma/polyp (SSA/P), adenomas.3 Computed tomographic planning committee members participating in an IUSM-sponsored activity are required to disclose any relevant financial interest or other relationshipwhich can be with cytological dysplasia (CT) colonography is another screening with the manufacturer(s) of any commercial product(s) and/or provider(s) ofor without cytological dysplasia; and technique that is seldom used in CRC commercial services that are discussed in an educational activity. Dr. Rex reported that he has received consulting fees and/or honoraria from Americantraditional serrated adenoma (TSA). surveillance. It is not approved by the BioOptics, Braintree, Boston Scientific, CheckCap, Epigenomics, ExactSSA/P is the main precursor of CIMP- U.S. Preventive Services Task Force Sciences, Given Imaging, and Olympus.high CRC. Presently, there is no reli- because of the radiation risk and likeli- Staff: Hassan Danesh, PhD, Monica Armin, and Dr. Deborah Teplow have disclosed that they have no potential or actual conflicts of interest. Note: Although it offers CME credits, this activity is not intended to provide1 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com extensive training or certification in the field.
    • hood of extracolonic findings. It is alsonot approved by Centers for Medicare& Medicaid Services because of insuf- How Do We Achieveficient data in the elderly and because itis less cost-effective than colonoscopy. Excellence in Screening?Capsule colonoscopy, which requiresextensive bowel preparation, is yetanother non–FDA-approved screening „„ Use high-quality colonoscopistsmethod, with a sensitivity greater than -- Should be able to quote ADR80% for polyps 6 mm and smaller and aspecificity of less than 80%. -- Should see split-dose preparationsThe adenoma detection rate (ADR), the -- Should see consistent photographicprimary measure of the quality of colo- documentation of cecal intubationnoscopy, varies greatly among gastro-enterologists; the lowest ADR ranges -- Should see appropriate use of follow-upfrom 7% to 15.5% and the highest ADR examsranges from 32.7% to 44%. Some of thefactors that may underlie the variabledetection rate are training (eg, lesion „„ Switch from gFOBT to FITrecognition, withdrawal technique, andwithdrawal time), personality, visual -- Avoid examining specimens from DREgaze patterns, and withdrawal time. Aprospective study demonstrated thatadequate bowel preparation results in adetection rate of 29.4% for any adenoma These cells define the intestinal meta- Esophagectomy is generally recognizedand a detection rate of 6.4% for large plasia. to have greater morbidity and mortalityadenomas (>1 cm) when compared with than any elective operation performedinadequate bowel preparation, which The risk of esophageal adenocarcinoma in the United States. A study assessedshowed a detection rate of 23.9% for any is associated with being a white male; the 30-day mortality in patients admitted toadenoma and a detection rate of 4.3% presence of BE, chronic gastrointestinal hospitals that performed from fewer thanfor large adenomas (P < .05).4 In bowel disease, or obesity; and a family history 2 esophagectomies per year to approxi-preparation, split-dosing has been of esophageal carcinoma. In fact, 85% mately 2 to 6 esophagectomies per year.10shown to provide more satisfactory of the cases of BE are in white males. The 30-day mortality rate decreased asresults than traditional dosing.5 Thus, The stages of BE are classified as simple the number of surgeries performed perthe components of good detection are a Barrett’s (no dysplasia), Barrett’s with year increased, suggesting that the highergood bowel preparation, adequate time, low-grade dysplasia, Barrett’s with high- the volume of esophagectomies, theand a sound technique. grade dysplasia (HGD), and adenocarci- better the results. However, factors such noma. The American College of Gastro- as the patient’s age and the existence ofBarrett’s Esophagus: Screening, enterology has specific recommendations comorbidities will increase the mortalitySurveillance, Diagnosis, and for the surveillance intervals for patients rate from esophagectomy.Treatment with BE.6 Three studies that assessed the risk of cancer development in patients EMR is not recommended for excisingDouglas K. Rex, MD, Distinguished with HGD who were followed up for long segments of BE because it is asso-Professor of Medicine and Chancellor’s 8, 7, and 5 years, respectively, suggest ciated with distortion of anatomy forProfessor, presented current perspectives that 6% to 8% of these patients develop subsequent radiofrequency ablation,on screening, surveillance, diagnosis, and cancer.7-9 stricture formation, bleeding, and perfo-treatment of Barrett’s esophagus. ration. EMR is an adequate therapy Nodular disease in BE patients must for BE if it fully removes the damagedBarrett’s esophagus (BE) is character- be removed by endoscopic mucosal lining. If there is residual Barrett’s tissueized by red (columnar) mucosa in the resection (EMR), which is an effec- after EMR, then RFA should be used toesophagus and described according tive therapy for nodules with HGD or complete ablation.to Prague’s classification based on intramucosal carcinoma and providesthe following criteria: (1) C: length of more accurate staging than endoscopic Hepatocellular Carcinoma: Thethe circumferential section; and (2) M: ultrasonography. The best treatment Growing Disease Burdenlength of any circumferential section, for flat disease is radiofrequencyplus the length of any tongues. Biop- ablation (RFA). Alternative therapies Paul Y. Kwo, MD, Professor of Medicine andsies will demonstrate goblet cells, include cryotherapy, photodynamic Medical Director, Liver Transplantation,which are not seen in the normal therapy, and argon plasma coagulation discussed key aspects of hepatocellular carci-stomach, but are seen in the intestine. or multipolar cautery. noma, from epidemiology to treatment.2 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
    • Hepatocellular carcinoma (HCC) isthe sixth most common cancer in the Prognosis of Patients With HCC:world and is the third leading cause ofcancer-related deaths. Although HCC Patient Survivalis associated with hepatitis B world-wide, hepatitis C has driven the rapid Therapy 1 Year 3 Yearsrise in HCC (50%-70% of all HCC cases)in the United States, where the age-adjusted incidence of HCC has doubledfrom 1985 to 1998. Other risk factors No radical therapy 54% 28%in the United States include alcoholuse, nonalcoholic fatty liver disease,inherited liver disease, smoking, and Surgical resection 81% 44%hemochromatosis. Ethanol injection 82% 38%Two key mechanisms are implicated inthe development of HCC: liver cirrhosisfollowing tissue damage (infectious or Transplatation 84% 74%toxic damage) and mutations occur-ring in 1 or more oncogenes or tumorsuppressor genes. The mean doubling Castells A, et al. Hepatology. 1993;18:11211. Llovet JM, et al. Hepatology. 1998;27:1572. Llovet JM, et al. Hepatology.time for the majority of HCC tumors 1999;29:62is 4 months,11 and these tumors arebiologically aggressive. The prog-nosis of symptomatic patients is very patients with no surveillance. Moreover, several key papers from 2011 on lower gastro-poor, particularly because 90% of the ability to provide liver transplantation intestinal tract disease.these individuals have underlying and the 3-year survival rate followingcirrhosis. Following intrahepatic diagnosis increased when the standard- Rifaximin therapy for patients withmetastases and vascular invasion, of-care surveillance is followed.12 irritable bowel syndrome withoutHCC can spread to the lungs, bones, constipation.17 Patients with irritableand adrenal glands. The current treatment options for HCC bowel syndrome (IBS) may have include surgical resection, liver transplan- altered intestinal microbiota, andThe first step in HCC screening is to iden- tation, transarterial chemoembolization systemic antibiotics have been usedtify the individuals at risk; that is, to iden- or radioembolization (yttrium-90 [Y90] with mixed results. Rifaximin is atify individuals with liver cirrhosis. Ultra- microspheres), stereotactic radiation, minimally absorbed, broad-spectrumsonography every 6 months to 12 months radiofrequency ablation, and sorafenib. antibiotic that has shown efficacy forwith assessment of alpha-fetoprotein The 5-year survival rate for surgical IBS in small-scale studies. Two multi-every 6 months is the current standard resection is 60% to 70%, and the tumor center, industry-supported, random-of care for screening high-risk patients recurrence rate is 50% in 3 years.13 Liver ized controlled trials (TARGET 1 and(hepatitis B carriers and patients with transplantation offers the best chance for TARGET 2) involved 1260 patients withnon–hepatitis-B cirrhosis), similar to cure in selected cases.14,15 Living donor IBS (Rome II criteria) without consti-guidelines of the American Association transplantation may provide timely pation, who were randomized in a 1:1for the Study of Liver Diseases. Alpha- transplantation. Radical (stereotactic ratio to rifaximin (550 mg by mouthfetoprotein assessment alone is not radiation and radiofrequency ablation 3 times daily) or placebo for 2 weeks.sufficient, unless imaging modalities therapies are effective for small tumors The primary end point was the propor-are not available. The common prac- before orthotopic liver transplanta- tion of patients who reported adequatetice at Indiana University is to perform tion (OLT). Radioembolization (Y90) relief of IBS symptoms for at least 2magnetic resonance imaging (MRI) in nontransplant patients appears to weeks of the first 4 weeks after treat-every 9 months, or dual-phase helical improve survival. Sorafenib conferred a ment completion. The secondary endCT or ultrasound every 6 months to 12 survival benefit in unresectable HCC16 point was relief of IBS-related bloating.months if the body mass index is normal. and is being studied in multiple patient The primary and secondary end points populations with HCC. were reached in 40.7% and 40.2% ofHCC is diagnosed by dual-phase helical patients, respectively, in the rifaximinCT scan or MRI with intravenous contrast. Breakthrough Papers on Lower arm compared with 31.7% and 30.3% inA retrospective analysis of 269 patients Gastrointestinal Tract in 2011 the placebo arm (P < .001). The resultswith cirrhosis and HCC showed HCC indicated a durable response to rifax-was diagnosed at stages 1 and 2 in 70% Charles J. Kahi, MD, MSc, Associate imin over 3 months and a safety profileof patients in the group with standard- Professor of Clinical Medicine and Chief, of rifaximin that is similar to placebo.of-care surveillance, 37% of patients with Gastrointestinal Section, Roudebush VA However, a very high response ratesubstandard surveillance, and only 18% of Medical Center, Indianapolis, reviewed was seen in the placebo arm.3 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
    • Fidaxomicin versus vancomycin Regular use of aspirin and NSAIDs was increased risk of death in the absence offor Clostridium difficile infection.18 associated with an increased risk of transplantation) or rapid worsening ofIncreasing disease severity and recur- diverticulitis and diverticular bleeding. liver function despite medical therapy.rence rates have been observed in Clos- These results have important clinical The results demonstrated that thetridium difficile infection (CDI), which and public health implications given 6-month survival of those who under-is usually treated with metronidazole the prevalence of diverticulosis and went early liver transplant was higheror vancomycin. Fidaxomicin is a new NSAID use in the elderly. Aspirin and than that of 26 matched nonrandomizedmacrocyclic antibiotic with no cross- NSAIDs should be used with caution in control patients (77% vs 23%; P < .001).resistance with other antibiotics. The patients at risk of diverticular compli- However, 3 patients resumed drinkingpresent study was a noninferiority cations. posttransplantation. The study showedmulticenter phase III randomized that early liver transplantation cancontrolled trial of 629 adults random- Breakthrough Papers in improve survival in patients with a firstized in a 1:1 ratio to fidaxomicin (200 Hepatology in 2011 episode of severe alcoholic hepatitis notmg twice daily) or to vancomycin (125 responding to medical therapy.mg 4 times daily) for 10 days. The Marco A. Lacerda, MD, Associate Professorprimary end point at 4-week follow-up of Clinical Medicine, reviewed several papers Rifaximin treatment in hepaticwas clinical cure, defined as resolution from 2011 in hepatology with implications encephalopathy.22 A total of 299of diarrhea and no need for additional for clinical practice. patients who were in remission fromCDI therapy. The secondary end point recurrent hepatic encephalopathy (HE)was CDI recurrence within 4 weeks High-dose ursodeoxycholic acid is resulting from chronic liver diseaseafter therapy. Clinical cure rates with associated with the development received either rifaximin at a dosagefidaxomicin were noninferior to clinical of colorectal neoplasia in patients of 550 mg twice daily (140 patients) orcures rates with vancomycin (88.2% vs with ulcerative colitis and primary placebo (159 patients) for 6 months.85.8%). The results showed that recur- sclerosing cholangitis.20 Patients The primary end point was the timerence rates were significantly lower in with ulcerative colitis and primary to the first breakthrough of HE, andthe fidaxomicin group (15.4% vs 25.3%; sclerosing cholangitis (UC/PSC) are the secondary end point was the timeP = .005). Lower recurrence rates were at higher risk for colorectal neoplasia. to the first hospital admission due toseen in patients with non-nucleosome In this study, patients with UC/PSC HE. Rifaximin was superior to placeboassembly protein-1 strains (69% relative who were previously enrolled in a in maintaining remission from HE andreduction). Fidaxomicin can be poten- trial of high-dose ursodeoxycholic acid significantly reducing hospitalizationstially advantageous in the treatment of (UDCA) were analyzed for the devel- due to HE-related episodes. No obviousCDI because a reduction in recurrence opment of colorectal neoplasia. Of the cognitive deficits or impaired quality ofalso likely decreases person-to-person 56 patients enrolled in the previous life were observed after rifaximin treat-transmission (“global cure”). More- study, 25 were in a UDCA group and ment.over, fidaxomicin is bactericidal specifi- 31 were in a placebo group. Surveil-cally against C. difficile, but preserves lance colonoscopy and pathology Atorvastatin and antioxidants for thenormal anaerobic flora (less recurrence, (mean time = 4.4 years) indicated that 9 treatment of nonalcoholic fatty liverpossibly less vancomycin-resistant of the 25 (36%) UDCA-treated patients disease: the St Francis Heart Studyenterococci). However, its use may be developed neoplasia (1 cancer, 1 high- randomized clinical trial.23 Nonalco-precluded by the expense: $2800 for a grade, 7 low-grade). Three of the 31 holic fatty acid liver disease (NAFLD)10-day course. (9.7%) patients in the placebo group is defined as a spectrum from benign developed neoplasia (1 cancer, 1 high- steatosis to necroinflammatory changesUse of aspirin or nonsteroidal anti- grade, 1 low-grade; hazard ratio = 4.4; and fibrosis. In this study, 1005 patientsinflammatory drugs increases risk P = .02). This study demonstrated that were randomized to receive atorvastatinfor diverticulitis and diverticular long-term use of high-dose UDCA in (20 mg), vitamin C (1 g), and vitamin Ebleeding.19 Case-control studies have patients with UC/PSC is associated with (1000 IU) or matching placebo as part ofsuggested a higher prevalence of increased risk of colorectal neoplasia. the St Francis Heart Study randomizednonsteroidal anti-inflammatory drug clinical trial. Follow-up was an average(NSAID) use in patients with compli- Early liver transplantation for severe of 3.6 years. CT scans of the patients werecated diverticular disease (bleeding, alcoholic hepatitis.21 This study used to calculate liver to spleen ratios indiverticulitis). This was a prospective analyzed the effect of early liver trans- 455 patients at baseline and at follow-up.study of a large cohort of men (N = plant (patients with < 6-month sobriety) The study demonstrated that after 4 years47,210; aged 40-75 years) enrolled in on 6-month survival of 26 patients with of therapy, atorvastatin plus vitamins Cthe Health Professionals Follow-up severe alcoholic hepatitis. The patients and E lowered the risk of moderate-to-Study. Methods included supplemen- had no prior episodes of alcoholic hepa- severe hepatic steatosis by 70% in the 80tary questionnaires and assessment of titis and had scores of 0.45 or higher patients who had NAFLD at baseline.aspirin and nonaspirin NSAID use and according to the Lille model (which Baseline triglyceride levels (odds ratiodiverticulitis or diverticular bleeding. calculates scores ranging from 0 to 1, [OR] = 1.003; P < .001) and body massBleeding risks for aspirin and NSAIDS with a score of at least 0.45 indicating index (OR = 0.10; P < .001) were indepen-were similar (hazard ratio = 1.7). nonresponse to medical therapy and an dent predictors of NAFLD.4 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
    • Breakthrough Papers in Upper 10% to 15% of patients by performing a of intestinal transplantation and illustratedGastrointestinal Tract in 2011 duodenal bulb biopsy in addition to distal its cost benefit as compared with parenteral duodenal biopsies. Therefore, duodenal nutrition.Lee McHenry, MD, Professor of Medicine bulb biopsy should be performed in addi-and Medical Director, IU Spring Mill tion to distal duodenal biopsy in patients Intestinal failure is defined as theMedical Clinics, Carmel, Indiana, examined with suspected celiac disease. inability of the intestinal tract to main-breakthrough papers in upper gastrointes- tain adequate nutritional status andtinal tract from 2011, including papers on Laparoscopic antireflux surgery vs fluid/electrolyte balance. It resultsHelicobacter pylori, celiac disease, and esomeprazole treatment for chronic from a loss or absence of sufficientgastroesophageal reflux disease. GERD: the LOTUS randomized clinical functional intestinal area. Manage- trial.26 This was a randomized multicenter ment approaches include medical orRandomized study comparing levo- parallel-group study of 554 patients with surgical alteration of the damaged area,floxacin, omeprazole, nitazoxanide, chronic gastroesophageal reflux disease parenteral nutrition, and intestinaland doxycycline versus triple therapy (GERD). The remission rates of the transplantation. Intestinal transplanta-for the eradication of Helicobacter laparoscopic 360-degree Nissen fundo- tion has many advantages over otherpylori.24 H. pylori is a Class I carcinogen. plication with posterior crural repair treatment options: it replaces normalThe current standard of care (proton were compared with esomeprazole intestinal anatomy and continuity;pump inhibitors plus amoxicillin and (20-40 mg/d). At the 5-year follow-up, the patient is able to eat and drink; itcla-rithromycin) fails in 30% of patients, the remission rate (the need for more provides a chance for definitive curemainly because of drug resistance to clar- than 40 mg of esomeprazole) was 93% in of disease; parenteral nutrition can beithromycin. This study was a randomized, the medical arm and 85% in the surgical stopped, which decreases infection risk;prospective, open-labeled trial of LOAD-7 arm. The 5-year remission rates in this and it leads to a reversal of liver injury.(levofloxacin once daily; omeprazole once study are higher than those in previous However, it is also associated with thedaily; nitazoxanide [antiprotozoal agent] studies. It appears from these results risks of major surgery, host rejection,twice daily, and doxycycline once daily that we are losing some of the durability and life-long immunosuppression.for 7 days) or LOAD-10 (the same regimen of the surgical repair. However, consid-for 10 days); the combined efficacy of the ering the long-term side effects of proton An isolated intestinal transplant is indi-LOAD therapies was compared with pump inhibitors, such as osteoporosis cated when there is intestinal failure inLAC therapy (lansoprazole, amoxicillin, and pneumonia, antireflux surgery may the absence of any other organ failureand clarithromycin). The eradication be an acceptable option in the future. and when the normal function of liver,rates of LOAD-7 and LOAD-10 were stomach, and pancreas are intact. A modi-88.9% and 90%, respectively, and the Pregnancy outcome and risk of celiac fied multivisceral transplant is performedcombined LOAD efficacy was 89.4%, disease in offspring: a nationwide case- when there is intestinal failure in thewhich was significantly higher than that control study.27 This was a population- absence of liver failure and the liver func-of LAC therapy (73.3%). These results based case-control study that evaluated tion is normal, but there is dysfunction ofare particularly robust considering that the risk of celiac disease in newborns the stomach and intestine, with or withoutthese efficacies were determined in the who were exposed to cesarean delivery pancreatic dysfunction. A multivisceralintention-to-treat population. (elective or emergency) and adverse fetal transplant is usually indicated in intestinal events (low Apgar score, small for gesta- failure accompanied by liver failure, withA prospective study of duodenal tional age, low birth weight, and preterm). or without the dysfunction of stomachbulb biopsy in newly diagnosed and A comparison of 11,000 offspring with and pancreas. Intestinal transplantation isestablished adult celiac disease.25 The biopsy-verified celiac disease with 53,000 also considered for certain nontraditionalgold standard to diagnose celiac disease age- and sex-matched control patients indications, such as diffuse mesentericis biopsy of the more distal duodenum found a positive association between thrombosis, benign/low-grade malig-showing villous atrophy (VA). In this celiac disease and elective cesarean nant tumors involving the mesentericstudy, the biopsy findings of the duodenal delivery. Newborns who were small for root, neuroendocrine tumors (carcinoid,bulb and distal duodenum of patients gestational age had a 21% increased risk insulinoma, others), desmoid tumors,with newly diagnosed and established of celiac disease; whereas, other preg- abdominal catastrophes/fistulas, radia-celiac disease were compared with nancy exposures did not increase the risk tion enteritis, trauma, and enteropathies/those of control patients. The diagnosis of future celiac disease. The emergency dysmotility disorders.was considered positive only when the cesarean did not increase the risk, thusMarsh stage 3 criteria were met (epithelial the bacterial flora of the newborn may For isolated and modified multivis-lymphocytes, hyperplasia, and partial play a role in the development of celiac ceral transplants (liver excluded), theVA). Interestingly, patients with newly disease. 1-year risk of rejection is 45% to 50%.diagnosed celiac disease (9%) and with For multivisceral transplants (liverestablished celiac disease (14%) were more Intestinal Transplantation: included), the 1-year risk of rejection islikely to have VA in the duodenal bulb Definition, Advantages, and Risks 15%. The liver is known to be protectivealone than were control patients. Hence, against rejection. Additional complica-this study is important because it would Richard Mangus, MD, Assistant Professor of tions include graft versus host disease;enable the diagnosis of an additional Surgery, described the advantages and risks posttransplant lymphoproliferative5 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
    • disorder; disease recurrence; andpseudo-obstruction that encompassesobstruction, chronic rejection, and Intestinal Transplantationnarcotic addiction (chronic pain). OutcomesBetween 2005 and 2007, 28 centers world-wide reported to the worldwide databaseof all intestinal transplants that 389 intes- Patient Survivaltinal transplants were performed on 377patients. In the United States, 151 trans- Age group 1 year 5 yearsplants were reported in 2010 (16% fewerthan in 2009). There were 17 centers withat least 1 transplant and 6 centers with 10 18 to 34 years 81% 70%or more intestinal transplants. 35 to 49 years 80% 63%Intestinal transplantation has beenshown to be a cost-effective therapyand is superior to continued par- 50 to 64 years 93% 38%enteral nutrition in appropriatelyselected patients. Costs for intestinal 65+ years 100% N/Atransplantation, including the initialhospitalization for the transplant, From the Organ Procurement and Transplant Network (U.S.), 2002-2007range from $200,000 to $500,000.There are frequent hospital readmis-sions posttransplant, but these admis-sions decrease markedly after the second the oral agents. Pregnant women with a terferon (peg IFN) and ribavirin andyear. The cost benefit of transplantation viral load over 108 copies are candidates were carrying the CC allele on the IL28Breaches parity with parenteral nutrition for lamivudine, tenofovir, or telbivu- gene showed a very high cure rate of 75%after 2 years to 3 years posttransplant dine. HBV reactivation is common after to 80% with a short treatment duration.28and is more cost-effective thereafter. chemotherapy/immunosuppression and can be fatal. Screening for hepatitis B The 2 new protease inhibitors, boceprevir surface antigen and anti-HBc proteins is and telaprevir, have been approved forViral Hepatitis Update essential in such patients, and long-term genotype 1 HCV infection. These are HBV prophylaxis should be considered. administered in combination with pegPaul Y. Kwo, MD, Professor of Medicine and Finally, individuals with HBV DNA IFN/ribavirin and have improved theMedical Director, Liver Transplantation, above 2000 IU and alanine aminotrans- response rate to 70%. For genotypes 2described new developments in the treat- ferase levels above the upper limit of and 3, the peg IFN/ribavirin therapy isment of hepatitis B and hepatitis C, and normal are candidates for therapy. the standard of care. It is important togave practical clinical tips. consider drug-drug interaction before Hepatitis C administering these drugs, becauseHepatitis B There are 170 million to 200 million carriers both strongly inhibit CYP3A4/5 and areIn the Unites States, there are approxi- of the hepatitis C virus (HCV) worldwide, partially metabolized by CYP3A4/5.mately 2 million people infected with with 3 million to 4 million carriers in thehepatitis B virus (HBV), and the mode United States. Currently, 25% of the HCV Higher sustained virologic responseof transmission is usually sexual trans- patients have cirrhosis. The greatest risk rates have been reported in peg IFN/mission or unsafe injections or transfu- factors associated with acute HCV infec- ribavirin plus telaprevir–treated patientssions. The risk of vertical transmission tion are injection drug use (43%) and other (75%) than in those treated with pegof HBV infection is highest in neonates. high-risk behaviors, along with exposure IFN/ribavirin alone (75% vs 44%; P <The current treatment options for HBV to infected blood. Two long-term follow- .0001).29 The side effects associated withinclude interferon injections and 5 oral up studies of interferon treatment have telaprevir treatment are rash, anemia,agents. The preferred first-line therapy demonstrated undetectable HCV RNA in drug-related eosinophilia, nausea, peri-is entecavir-tenofovir (oral agents). 99% of patients after an average follow-up anal symptoms, and diarrhea. BoceprevirTenofovir is effective against lamivudine of 4.1 years and 5.6 years, suggesting that plus peg IFN/ribavirin has been moreresistance, but entecavir is not. Without HCV is curable. effective for the treatment of patientsprevious lamivudine treatment, both coinfected with HCV/HIV than peg IFN/tenofovir and entecavir have high rates In the United States, genotype 1 is the ribavirin alone (61% vs 27%).30 Bothof viral suppression with minimal resis- most common form of hepatitis C, drugs are effective in nonresponderstance. Lamivudine and telbivudine are followed by genotypes 2 and 3. Recently, (patients not responding to interferon).second-line agents. Interferon is used it was reported that individuals with Anemia caused by boceprevir treatmentless frequently in the United States than genotype 1 who were treated with pegin- is manageable.6 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
    • What’s New in PancreaticDisorders and Treatment What I Tell Patients RegardingEvan L. Fogel, MD, MSc, Professor ofClinical Medicine, reviewed the most current Treatment of Hepatitis Cdata related to pancreatic disorders and theirtreatment. „„ HCV can be cured in 75% of all casesThe main clinical features of chronicpancreatitis include abdominal pain „„  herapy is evolving: about half of all genotype Tand exocrine and endocrine insuffi- 1 individuals can be treated with 6 months ofciency. Pain management is achievedthrough medical, endoscopic, and therapysurgical intervention. The commonlyused surgical procedures are Whipple, „„  enotype 2/3 still has sustained viral response GPuestow, Frey’s, and Beger’s proce- rates of >75% with peginterferon/ribavirindures. However, the procedure that isbeing used with increasing frequency „„ L-28 CC genotype will identify those who can Iis total pancreatectomy with auto-isletcell transplantation (TP-AIT). Patients be treated for shorter durationundergoing surgery receive transplanta-tion of native islet cells to prevent the „„ Silymarin ... don’t botherrisk of diabetes, which is directly relatedto the islet cell yield. Most patients haveless pain after surgery, and 50% to 80%are narcotic independent at the 2-year with genetic mutations.32 However, Evaluation and Treatment ofto 4-year follow-up. Quality of life for the study suffered from the following Pelvic Floor Disorderspediatric patients after TP-AIT was limitations: the proportion of geneticsignificantly improved in a single-center mutations (PRSS1, SPINK1) in control Diane M. Settles, MD, Assistant Professor ofprospective study of 19 children (aged populations is unknown, magnetic Clinical Medicine, gave a complete overview5-18 years, mean = 14.5) with chronic or resonance cholangiopancreatography of pelvic floor disorders and an evaluation ofacute recurrent pancreatitis.31 The study is not the gold standard for diagnosis available treatment options.concluded that the majority of patients of PD, and the coexistence of a geneticcan be weaned off narcotic medications mutation with PD does not preclude The pelvic floor is a hammock made upafter surgery, and insulin independence other therapeutic options (ie, minor of connective tissues, muscles, and neural(or minimal use) can be achieved in more papilla therapy). structures. Symptoms of pelvic floor disor-than 60% of patients. ders (PFDs) include urinary incontinence Post-ERCP pancreatitis (PEP) is the most (UI), pelvic organ prolapse, fecal incon-Pancreatic divisum (PD) is a congenital common major complication in 1% to tinence (FI), and dyspareunia. It is still aabnormality of the pancreas, with a 10%, as high as 30% of patients under- question whether dyssynergic defecation isworldwide incidence of 7%. The vast going ERCP (endoscopic retrograde a symptom of true pelvic floor dysfunction.majority of patients with PD are entirely cholangiopancreatography). Reducing FI is the second most common reason forasymptomatic. In patients who are the pressure gradient across the pan- patients to be admitted to a nursing facility.symptomatic, minor papilla therapy, creatic sphincter with a pancreatic duct A survey of 1961 women found that greaterwhich enlarges stenotic orifices either stent may lower the frequency of this than 23% of women had at least 1 PFD; 15%endoscopically or surgically, improves complication.33 Thus, temporary, small- had UI, 9% had FI, and 2.9% had pelvicsymptoms in 75% to 80% of cases. diameter PD stents lower the frequency organ prolapse. However, this may be anMutational analysis of control patients and severity of post-ERCP pancreatitis underrepresentation, because women areand patients with unexplained pancre- in high-risk patients, and they are now often embarrassed to report problems ofatitis showed that the frequency of considered standard care. The efficacy of incontinence.PD was no different in patients with various pharmacologic agents for preven-idiopathic pancreatitis (5%), alcoholic tion of PEP has been studied. Udenafil, a Pregnancy/delivery, parity, age,pancreatitis (7%), and control patients phosphodiesterase type 5 inhibitor, was obesity, ethnicity, smoking, chronic(7%), but PD frequency was higher in not effective in the prevention of PEP.34 pulmonary conditions, and menopausepatients with the genetic mutations However, a meta-analysis supported the have been linked to PFDs. AccordingPRSS1 (16%), SPINK1 (16%), and CFTR use of NSAIDs in the prevention of PEP.35 to the National Health and Nutrition(47%). It was concluded that PD alone In this study, prophylactic rectal indo- Examination Survey data, PFDs areshould no longer be considered an methacin was also shown to significantly more common among women whoindependent cause of pancreatitis, reduce the incidence and severity of PEP have had at least 1 child. In premeno-rather it acts as a cofactor in patients in high-risk patients. pausal women, parous women have7 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
    • a higher prevalence of stress urinary a randomized controlled trial of 171 for diagnosing IBD. In a recent meta-incontinence and UI, and in postmeno- patients.38 Biofeedback is the main- analysis of 60 studies with almost 1000pausal women, parity has little effect stay of therapy in patients who fail to patients, the ASCA and p-ANCA statuson UI. Sphincter defects are associated respond to supportive medication. was evaluated in patients with IBDwith parity; however, anal sphincter versus patients with functional boweldefects are most commonly associated disease.41 It was found that the sensitivitywith the first pregnancy.36 A range of Diagnostic Testing in of a positive ASCA result with a nega-7% to 60% of pregnant women expe- Inflammatory Bowel Disease tive p-ANCA result was approximatelyrience UI and 6% experience FI. One 60%. The specificity was not perfectmechanism of injury during preg- Michael V. Chiorean, MD, Associate (92%), and in a population with a lownancy and childbirth is neural injury Professor of Clinical Medicine, Fellowship pretest probability, such as patients withthat can occur as a result of operative Program Director, described the most current nonspecific symptoms, this would leaddelivery, prolonged second stage approaches to diagnostic testing for inflam- to a substantial number of false positiveof labor, or high birth weight. The matory bowel disease, including their relative results. p-ANCA seems to have a highersecond mechanism is anal sphincter advantages and disadvantages. overall accuracy, and if a patient is bothdisruption, which is associated with ASCA-positive and p-ANCA-positive,gross and occult injuries, role and Calprotectin and lactoferrin are the 2 this provides some strength to the diag-risk of episiotomy, maternal birth fecal biomarkers commonly used in nosis because the specificity dramati-position, and epidural use. According the diagnosis of inflammatory bowel cally increases. However, few patientsto a Cochrane Review of 21 studies disease (IBD) in clinical practice. with IBD are both ASCA-positive andperformed to assess the role of elective The advantages of these markers are p-ANCA-positive.cesarean in preserving maternal pelvic that they are fairly sensitive and theyfloor function, it was concluded that provide a full bowel screen because In previous studies, the correlation ofelective emergency cesarean surgery signs of inflammation anywhere in the calprotectin and lactoferrin with diseasecannot be recommended for protecting gastrointestinal tract will be reflected activity as measured by the endoscopicanal continence. in the assays. These markers can detect index has been shown to be similar, and inflammation in patients without an these 2 markers seem to be better thanThe evaluation of PFDs can be elevated C-reactive protein level or an C‑reactive protein in predicting diseaseperformed using different techniques. elevated sedimentation rate. Assays activity. In a study performed at IndianaA physical examination is composed are convenient because stool samples University, a good correlation of fecalof a detailed neurologic examination, are routinely collected in IBD cases. calprotectin with endoscopic diseaseperianal inspection, and a detailed They are also relatively inexpensive activity in patients with both UC andrectal examination that should include compared with other diagnostic tests Crohn’s disease was established.42the assessment of resting and squeezing ($40 and $60 for insurance payers).tone and attempted defecation. Mano- The disadvantage of using these fecal In summary, fecal inflammatory markersmetric testing of anorectal abnormalities biomarkers is their nonspecificity; (calprotectin and lactoferrin) are usefulin patients with defecation disorders they may be elevated in patients using in IBD diagnosis because they are sensi-confirmed diagnosis in 90% of the cases, NSAIDs and those suffering from infec- tive and inexpensive, offer a full bowelprovided new information in 80% of tions or malignancy. In a meta-analysis screen, and can detect inflammation incases, and influenced treatment in 84% of pooled data from 30 studies including patients without elevated C‑reactiveof cases. Anal endosonography for the almost 6000 patients with established protein levels. However, their non-assessment of the thickness and integ- IBD, the sensitivity of calprotectin specificity is a disadvantage. Serologicalrity of sphincters, and pelvic magnetic (threshold = 50 mcg/g - 100 mcg/g) was markers (ASCA and p-ANCA) haveresonance imaging for recognition of found to be greater than 90% and the modest specificity; however, their lowexternal anal sphincter atrophy are the specificity was 80% to 90%.39 In a meta- sensitivity precludes their use in theother methods to evaluate PFDs. analysis of 6 studies of adults and chil- diagnosis of IBD. dren with suspected IBD and a pretestPFDs can be managed through lifestyle probability of 40%, the sensitivity and Best Use of 5-Aminosalicylates,modifications, medications, Kegel specificity of calprotectin were 93% and Immunomodulatory Agents,exercises, biofeedback, surgery, sacral 96%, respectively.40 These data suggest Probiotics, Diet, Alternativenerve stimulation, and artificial sphinc- that the use of calprotectin would Therapies in IBDters. Loperamide, lomotil, and codeine prevent a large number of patientsare the common medications used to from undergoing further testing, and Monika Fischer, MD, Assistant Professor ofreduce the frequency of incontinence. delayed diagnosis would occur in only Clinical Medicine, reviewed the most currentHormone replacement therapy showed 6% of the patients. data on the treatment of IBD, includinga 65% improvement in symptoms, and changing recommendations related to the use25% of patients were asymptomatic Anti-Saccharomyces cerevisiae antibodies of 5-aminosalicylates.after 6 months of treatment.37 Biofeed- (ASCA) and perinuclear antineutrophilback has been shown to improve cytoplasmic antibodies (p-ANCA) are 5-aminosalicylates (5-ASAs) continue tosymptoms in 60% of the patients in the most extensively studied markers be first-line therapy for ulcerative colitis8 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
    • (UC). The American College of Gastro- Underdosing of thiopurine analogs is natalizumab for Crohn’s disease at 10enterology IBD Task Force has strongly a form of undertreatment, and dosages weeks are 56% and 37%, respectively.recommended 5-ASAs for the induction should be modified on the basis of thiopu- In terms of durability, infliximab andof remission in UC and to prevent relapse rine methyltransferase enzyme activity. adalimumab show a loss of responsein quiescent UC. The recommendation Regular monitoring for myelosuppression over time (13% and 20.3% per patientis based on 11 high-quality randomized is essential during thiopurine treatment. year, respectively). All 4 agents arecontrolled trials, and the optimum dose To achieve continuous remission, thio- intravenous infusions or subcutaneousof mesalamine is 2.4 g or the equivalent purines should probably be continued injections, each with certain limita-for both indications. Rare, but serious, indefinitely; withdrawal is associated tions. All have similar safety profilesside effects include interstitial nephritis, with a high risk of relapse even after stable and are associated with risk of infec-pancreatitis, pneumonitis, pericarditis, remission of several years. tion, demyelinating disease, congestiveand hepatitis. Up to 8% of patients are heart failure, hepatitis, and lympho-5-ASA intolerant. Once-daily dosing of Evidence suggests that IBD is primarily proliferative disease. Infliximab and5-ASAs has been shown to achieve better caused by a dysregulated mucosal adalimumab can cause infusion-sitecompliance, higher efficacy, and better inflammatory response to intestinal reactions and lupus-like reactions.outcomes.43 The combined approach bacteria in genetically susceptible indi-of oral 5-ASAs plus topical 5-ASAs as viduals. The majority of currently used The Study of Biologic and Immuno-first-line therapy is highly effective in IBD therapies modulates the immune modulator Naive Patients in Crohn’smildly severe to moderately severe system. Therapies that modulate the gut Disease (SONIC) demonstrated thatactive UC. The current recommendation flora may prove to be quite successful in combination therapy of infliximab andsuggests oral mesalamine plus topical the future. Dietary intake is related to the azathioprine (2.5 mg/kg) was superior tomesalamine for inducing, as well as for risk of developing IBD. However, there that of infliximab or azathioprine mono-maintaining, remission. However, 80% are no data to support diet as a form of therapy.46 Another study showed thatof patients favor oral treatment alone. treatment in Crohn’s disease and UC. the administration of hydrocortisoneThus, patient preference highly affects Probiotics have great therapeutic poten- before infliximab infusion in patientsdrug adherence. tial in IBD management; however, the with Crohn’s disease decreases the risk lack of evidence and the cost consider- of developing antibodies to infliximab.47Based on a meta-analysis of 3 random- ations have limited probiotics to adjuvant A combined approach using infliximab,ized controlled trials of mesalamine therapy only. methotrexate, and sphincter-sparing(4g/d), 5-ASAs are no longer recom- surgery in patients with severe fistu-mended for induction or maintenance of lizing Crohn’s disease was effective inremission in Crohn’s disease. Although Best Use of Biologic Agents: achieving short-term response.48 Cipro-the prevention of colitis-related cancer by Agent Selection, Monitoring, floxacin has also been used effectively in5-ASAs has been actively studied, none Dosing, and When to Stop combination with infliximab in the treat-of the previous studies have conclusively ment of fistulizing Crohn’s disease withshown any impact of 5-ASAs on colitis- Debra J. Helper, MD, Associate Professor an improved outcome: a response of 73%related cancer risk. of Clinical Medicine and Medical Director, in the combination group versus 39% in Inflammatory Bowel Disease Center, the placebo group.49The common immunomodulatory discussed new developments in the treatmentagents used in the treatment of UC are of Crohn’s disease, including recommenda- Disease activity before and after therapythe thiopurine analogs, azathioprine tions for when to adjust treatment with with biologic agents can be monitored by(AZA) and 6-mercaptopurine (6-MP), and specific agents by stopping, adjusting doses, various tests, such as C-reactive protein,methotrexate (MTX). AZA and 6-MP are or switching agents. sedimentation rate, fecal calprotectinrecommended for maintenance, but not or lactoferrin, endoscopy, radiographicfor induction of remission of UC. MTX The current FDA-approved drugs for imaging, and capsule imaging. To monitoris not recommended for UC induction or moderate-to-severe, as well as refractory, the biologic agent itself, in case of anmaintenance, but the recommendation is Crohn’s disease are the IgG anti–tumor increase in symptoms, parameters suchbased on only 2 small studies. The efficacy necrosis factor monoclonal antibodies as the trough levels and peak levels ofrate of AZA in Crohn’s disease mainte- infliximab, adalimumab, certolizumab infliximab, as well as the human antichi-nance therapy after steroid (prednisolone) pegol, and natalizumab. meric antibody/antibodies to infliximabadministration was 42% compared with levels, can be measured. There are no7% for placebo (P = .001).44 In the case of In terms of efficacy, adalimumab commercially available ways to monitorthe addition of 6-MP treatment in children and certolizumab pegol show remis- adalimumab or certolizumab pegol. Evalu-with active steroid-dependent Crohn’s sion at weeks 20 to 30 compared with ations for tuberculosis, a complete blooddisease, the duration of steroid use was infliximab, which shows remission at count (at least once a year), and routineshorter (P < .001) and the cumulative week 4; however, the 3 agents appear liver and kidney tests are common practicesteroid dose required was lower (P < .01). to be basically equivalent in terms of to monitor complications. The exceptionMoreover, there was less relapse in the their ability to induce remission. Their is natalizumab, which is associated with6-MP group than in the placebo group (P response rates range from 40% to 70%. the complication of progressive multifocal= .007).45 The response and remission rates of leukoencephalopathy, for which an anti-9 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
    • outcome. Am J Med. 2008;121(2):119-126. 32.  ertin C, Pelletier AL, Vullierme MP, et al. Pancreas divisum is Bbody test for JC virus is available. Based on 13.  lovet JM, Fuster J, Bruix J. Intention-to-treat analysis of sur- L not a cause of pancreatitis by itself but acts as a partner ofprevious studies, specific information on gical treatment for early hepatocellular carcinoma: resection genetic mutations. Am J Gastroenterol. 2012; 107(2):311-317.dosing is available, along with algorithms versus transplantation. Hepatology. 1999;30(6):1434-1440. Epub 2011 Dec 13.for dose adjustments and agent switching. 14.  azzaferro V, Regalia E, Doci R, et al. Liver transplantation for M 33.  houdhary A, Bechtold ML, Arif M, et al. Pancreatic stents for C the treatment of small hepatocellular carcinomas in patients prophylaxis against post-ERCP pancreatitis: a meta-analysis with cirrhosis. N Engl J Med. 1996;334(11):693-699. and systematic review. Gastrointest Endosc. 2011;73(2):275-The factors to be considered while stop- 15.  ao FY, Bass NM, Nikolai B, et al. Liver transplantation for hepatocel- Y 282.ping a biologic agent are reaction, infec- lular carcinoma: analysis of survival according to the intention- 34.  h HC, Cheon YK, Cho YD, et al. Use of udenafil is not associ- Otion, malignancy, neurologic symptoms, to-treat principle and dropout from the waiting list. Liver Transpl. ated with a reduction in post-ERCP pancreatitis: results of a 2002;8(10):873-883. randomized, placebo-controlled, multicenter trial. Gastroin-worsened congestive heart failure, skin 16.  lovet J, Ricci S, Mazzaferro V, et al, for the SHARP Investiga- L test Endosc. 2011;74(3):556-562. Epub 2011 Jul 28.lesions, and loss of response. tors Study Group. Sorafenib improves survival in advanced 35.  lmunzer BJ, Waljee AK, Elta GH, et al. A meta-analysis of E hepatocellular carcinoma (HCC): results of a phase III rectal NSAIDs in the prevention of post-ERCP pancreatitis.All anti–tumor necrosis factor agents are randomized, placebo-controlled trial (SHARP trial). J Clin Oncol. Gut. 2008;57(9):1262-1267. Epub 2008 Mar 28. 2007;25(suppl):18S. Abstract LBA1. 36.  ultan AH, Kamm MA, Hudson CN, Thomas JM, Bartram CI. Scategory B drugs, except natalizumab, 17.  imentel M, Lembo A, Chey WD, et al. Rifaximin therapy for P Anal-sphincter disruption during vaginal delivery. N Engl Jwhich is a category C drug. There has been patients with irritable bowel syndrome without constipation. N Med. 1993;329:1905-1911.no convincing evidence of adverse effects Engl J Med. 2011;364(1):22-32. 37.  onnelly V, O’Connell PR, O’Herlihy C. The influence of oestro- Dof biologic agents on the fetus to date. It is 18.  ouie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus L gen replacement on faecal incontinence in postmenopausal vancomycin for Clostridium difficile infection. N Engl J Med. women. Br J Obstet Gynaecol. 1997;104(3):311-315.recommended that infliximab be withheld 2011;364(5):422-431. 38.  orton C, Chelvanayagam S, Wilson-Barnett J, Redfern S, Kamm Nfrom week 30 of pregnancy, if possible, 19.  trate LL, Liu YL, Huang ES, Giovannucci EL, Chan AT. Use of S MA. Randomized controlled trial of biofeedback for fecal inconti-and be resumed after delivery. Overall, an aspirin or nonsteroidal anti-inflammatory drugs increases risk nence. Gastroenterology. 2003;125(5):1320-1329.individualized therapy is required for best for diverticulitis and diverticular bleeding. Gastroenterology. 39.  on Roon AC, Karamountzos L, Purkayastha S, et al. Diagnostic v 2011;140(5):1427-1433. precision of fecal calprotectin for inflammatory bowel diseasedisease control during pregnancy. 20.  aton JE, Silveira MG, Pardi DS, et al. 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Hospital volume B 30.  allolas L, Pmol L, Rivero A, et al. Boceprevir plus peginter- M and surgical mortality in the United States. N Engl J Med. feron/ribavirin for the treatment of HCV/HIV co-infected pa- 2002;346(15):1128-1137. Read this newsletter and receive 2.0 hours of CME credit. tients: end of treatment (week 48) interim results. Presented11.  heu JC, Sung JL, Chen DS, et al. Growth rate of asymptom- S To get your CME credit immediately, simply log onto: at EASL 2012, April 20, 2012, Barcelona, Spain. Abstract 366. atic hepatocellular carcinoma and its clinical implications. www. 2012GIHepUpdate.com 31.  ellin MD, Freeman ML, Schwarzenberg SJ, et al. Quality of B Gastroenterology. 1985;89(2):259-266. to take the posttest and download your certificate. life improves for pediatric patients after total pancreatec-12.  travitz RT, Heuman DM, Chand N, et al. Surveillance for S © 2012. Indiana University and Health Focus, Inc. 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