1. Highlights from the 15th Annual
Gastroenterology/Hepatology Update
Chair
Douglas K. Rex, MD
Distinguished Professor of Medicine
T
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 the
for 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 colorectal
Key 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 of
hepatologic 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 Liver
Update 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 as
Douglas 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 in
about the criteria by which the quality of tests in the United States are the guaiac- the management of lower gastrointestinal tract disease, GERD, and
colonoscopy can be evaluated. based fecal occult blood test (gFOBT), pancreatic and pelvic floor disorders.
fecal immunochemical test (FIT), and CME Information
Every 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 Continuing
tions. 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 of
basis 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 a
and oncogene mutations), the Lynch showed better adherence and positivity maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the credit
pathway (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 the
ylator 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 by
accounts for about 30% of colorectal the U.S. Food and Drug Administration Disclosure Information
cancers. The precursor for CIMP- (FDA) that tests for hypermethylation Commercial Support
Indiana University School of Medicine and Health Focus, Inc. gratefully
positive 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 Disclosure
sort of polyp called a serrated lesion. 9 test performed poorly in terms of In accordance with the Accreditation Council for Continuing Medical Education
The 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, and
serrated 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 relationship
which can be with cytological dysplasia (CT) colonography is another screening with the manufacturer(s) of any commercial product(s) and/or provider(s) of
or 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 American
traditional serrated adenoma (TSA). surveillance. It is not approved by the BioOptics, Braintree, Boston Scientific, CheckCap, Epigenomics, Exact
SSA/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 provide
1 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com extensive training or certification in the field.
2. hood of extracolonic findings. It is also
not approved by Centers for Medicare
& Medicaid Services because of insuf- How Do We Achieve
ficient data in the elderly and because it
is less cost-effective than colonoscopy.
Excellence in Screening?
Capsule colonoscopy, which requires
extensive bowel preparation, is yet
another non–FDA-approved screening „„ Use high-quality colonoscopists
method, with a sensitivity greater than -- Should be able to quote ADR
80% for polyps 6 mm and smaller and a
specificity of less than 80%. -- Should see split-dose preparations
The adenoma detection rate (ADR), the
-- Should see consistent photographic
primary measure of the quality of colo- documentation of cecal intubation
noscopy, varies greatly among gastro-
enterologists; the lowest ADR ranges
-- Should see appropriate use of follow-up
from 7% to 15.5% and the highest ADR exams
ranges from 32.7% to 44%. Some of the
factors that may underlie the variable
detection rate are training (eg, lesion „„ Switch from gFOBT to FIT
recognition, withdrawal technique, and
withdrawal time), personality, visual -- Avoid examining specimens from DRE
gaze patterns, and withdrawal time. A
prospective study demonstrated that
adequate bowel preparation results in a
detection rate of 29.4% for any adenoma These cells define the intestinal meta- Esophagectomy is generally recognized
and a detection rate of 6.4% for large plasia. to have greater morbidity and mortality
adenomas (>1 cm) when compared with than any elective operation performed
inadequate bowel preparation, which The risk of esophageal adenocarcinoma in the United States. A study assessed
showed a detection rate of 23.9% for any is associated with being a white male; the 30-day mortality in patients admitted to
adenoma and a detection rate of 4.3% presence of BE, chronic gastrointestinal hospitals that performed from fewer than
for 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.10
shown to provide more satisfactory of the cases of BE are in white males. The 30-day mortality rate decreased as
results than traditional dosing.5 Thus, The stages of BE are classified as simple the number of surgeries performed per
the components of good detection are a Barrett’s (no dysplasia), Barrett’s with year increased, suggesting that the higher
good bowel preparation, adequate time, low-grade dysplasia, Barrett’s with high- the volume of esophagectomies, the
and 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 of
Barrett’s Esophagus: Screening, enterology has specific recommendations comorbidities will increase the mortality
Surveillance, 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 excising
Douglas 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 for
Professor, 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 damaged
Barrett’s esophagus (BE) is character- be removed by endoscopic mucosal lining. If there is residual Barrett’s tissue
ized by red (columnar) mucosa in the resection (EMR), which is an effec- after EMR, then RFA should be used to
esophagus and described according tive therapy for nodules with HGD or complete ablation.
to Prague’s classification based on intramucosal carcinoma and provides
the following criteria: (1) C: length of more accurate staging than endoscopic Hepatocellular Carcinoma: The
the circumferential section; and (2) M: ultrasonography. The best treatment Growing Disease Burden
length of any circumferential section, for flat disease is radiofrequency
plus the length of any tongues. Biop- ablation (RFA). Alternative therapies Paul Y. Kwo, MD, Professor of Medicine and
sies 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
3. Hepatocellular carcinoma (HCC) is
the sixth most common cancer in the Prognosis of Patients With HCC:
world and is the third leading cause of
cancer-related deaths. Although HCC
Patient Survival
is associated with hepatitis B world-
wide, hepatitis C has driven the rapid Therapy 1 Year 3 Years
rise in HCC (50%-70% of all HCC cases)
in the United States, where the age-
adjusted incidence of HCC has doubled
from 1985 to 1998. Other risk factors No radical therapy 54% 28%
in the United States include alcohol
use, nonalcoholic fatty liver disease,
inherited liver disease, smoking, and
Surgical resection 81% 44%
hemochromatosis.
Ethanol injection 82% 38%
Two key mechanisms are implicated in
the development of HCC: liver cirrhosis
following tissue damage (infectious or Transplatation 84% 74%
toxic damage) and mutations occur-
ring in 1 or more oncogenes or tumor
suppressor 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;29:62
is 4 months,11 and these tumors are
biologically 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 following
cirrhosis. Following intrahepatic diagnosis increased when the standard- Rifaximin therapy for patients with
metastases and vascular invasion, of-care surveillance is followed.12 irritable bowel syndrome without
HCC can spread to the lungs, bones, constipation.17 Patients with irritable
and adrenal glands. The current treatment options for HCC bowel syndrome (IBS) may have
include surgical resection, liver transplan- altered intestinal microbiota, and
The first step in HCC screening is to iden- tation, transarterial chemoembolization systemic antibiotics have been used
tify the individuals at risk; that is, to iden- or radioembolization (yttrium-90 [Y90] with mixed results. Rifaximin is a
tify individuals with liver cirrhosis. Ultra- microspheres), stereotactic radiation, minimally absorbed, broad-spectrum
sonography every 6 months to 12 months radiofrequency ablation, and sorafenib. antibiotic that has shown efficacy for
with 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 with
non–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 1:1
for the Study of Liver Diseases. Alpha- transplantation. Radical (stereotactic ratio to rifaximin (550 mg by mouth
fetoprotein 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 adequate
tice at Indiana University is to perform tion (OLT). Radioembolization (Y90) relief of IBS symptoms for at least 2
magnetic 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 end
CT 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% of
HCC is diagnosed by dual-phase helical patients, respectively, in the rifaximin
CT scan or MRI with intravenous contrast. Breakthrough Papers on Lower arm compared with 31.7% and 30.3% in
A retrospective analysis of 269 patients Gastrointestinal Tract in 2011 the placebo arm (P < .001). The results
with 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 profile
of 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 rate
substandard 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
4. Fidaxomicin versus vancomycin Regular use of aspirin and NSAIDs was increased risk of death in the absence of
for Clostridium difficile infection.18 associated with an increased risk of transplantation) or rapid worsening of
Increasing 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 the
tridium 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 higher
or vancomycin. Fidaxomicin is a new NSAID use in the elderly. Aspirin and than that of 26 matched nonrandomized
macrocyclic 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 drinking
present study was a noninferiority cations. posttransplantation. The study showed
multicenter phase III randomized that early liver transplantation can
controlled trial of 629 adults random- Breakthrough Papers in improve survival in patients with a first
ized in a 1:1 ratio to fidaxomicin (200 Hepatology in 2011 episode of severe alcoholic hepatitis not
mg twice daily) or to vancomycin (125 responding to medical therapy.
mg 4 times daily) for 10 days. The Marco A. Lacerda, MD, Associate Professor
primary end point at 4-week follow-up of Clinical Medicine, reviewed several papers Rifaximin treatment in hepatic
was clinical cure, defined as resolution from 2011 in hepatology with implications encephalopathy.22 A total of 299
of diarrhea and no need for additional for clinical practice. patients who were in remission from
CDI therapy. The secondary end point recurrent hepatic encephalopathy (HE)
was CDI recurrence within 4 weeks High-dose ursodeoxycholic acid is resulting from chronic liver disease
after therapy. Clinical cure rates with associated with the development received either rifaximin at a dosage
fidaxomicin were noninferior to clinical of colorectal neoplasia in patients of 550 mg twice daily (140 patients) or
cures 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 time
rence rates were significantly lower in with ulcerative colitis and primary to the first breakthrough of HE, and
the fidaxomicin group (15.4% vs 25.3%; sclerosing cholangitis (UC/PSC) are the secondary end point was the time
P = .005). Lower recurrence rates were at higher risk for colorectal neoplasia. to the first hospital admission due to
seen in patients with non-nucleosome In this study, patients with UC/PSC HE. Rifaximin was superior to placebo
assembly protein-1 strains (69% relative who were previously enrolled in a in maintaining remission from HE and
reduction). Fidaxomicin can be poten- trial of high-dose ursodeoxycholic acid significantly reducing hospitalizations
tially advantageous in the treatment of (UDCA) were analyzed for the devel- due to HE-related episodes. No obvious
CDI because a reduction in recurrence opment of colorectal neoplasia. Of the cognitive deficits or impaired quality of
also 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 the
normal anaerobic flora (less recurrence, (mean time = 4.4 years) indicated that 9 treatment of nonalcoholic fatty liver
possibly less vancomycin-resistant of the 25 (36%) UDCA-treated patients disease: the St Francis Heart Study
enterococci). 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 changes
Use of aspirin or nonsteroidal anti- grade, 1 low-grade; hazard ratio = 4.4; and fibrosis. In this study, 1005 patients
inflammatory drugs increases risk P = .02). This study demonstrated that were randomized to receive atorvastatin
for diverticulitis and diverticular long-term use of high-dose UDCA in (20 mg), vitamin C (1 g), and vitamin E
bleeding.19 Case-control studies have patients with UC/PSC is associated with (1000 IU) or matching placebo as part of
suggested a higher prevalence of increased risk of colorectal neoplasia. the St Francis Heart Study randomized
nonsteroidal 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 were
cated diverticular disease (bleeding, alcoholic hepatitis.21 This study used to calculate liver to spleen ratios in
diverticulitis). 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 years
47,210; aged 40-75 years) enrolled in on 6-month survival of 26 patients with of therapy, atorvastatin plus vitamins C
the 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 80
tary 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 ratio
diverticulitis or diverticular bleeding. calculates scores ranging from 0 to 1, [OR] = 1.003; P < .001) and body mass
Bleeding 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
5. Breakthrough Papers in Upper 10% to 15% of patients by performing a of intestinal transplantation and illustrated
Gastrointestinal 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 the
Medical Clinics, Carmel, Indiana, examined with suspected celiac disease. inability of the intestinal tract to main-
breakthrough papers in upper gastrointes- tain adequate nutritional status and
tinal tract from 2011, including papers on Laparoscopic antireflux surgery vs fluid/electrolyte balance. It results
Helicobacter pylori, celiac disease, and esomeprazole treatment for chronic from a loss or absence of sufficient
gastroesophageal reflux disease. GERD: the LOTUS randomized clinical functional intestinal area. Manage-
trial.26 This was a randomized multicenter ment approaches include medical or
Randomized 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 intestinal
and 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 other
pylori.24 H. pylori is a Class I carcinogen. plication with posterior crural repair treatment options: it replaces normal
The 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; it
cla-rithromycin) fails in 30% of patients, the remission rate (the need for more provides a chance for definitive cure
mainly because of drug resistance to clar- than 40 mg of esomeprazole) was 93% in of disease; parenteral nutrition can be
ithromycin. 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 the
daily; 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 in
LAC therapy (lansoprazole, amoxicillin, and pneumonia, antireflux surgery may the absence of any other organ failure
and 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 performed
combined LOAD efficacy was 89.4%, disease in offspring: a nationwide case- when there is intestinal failure in the
which 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 of
are particularly robust considering that the risk of celiac disease in newborns the stomach and intestine, with or without
these efficacies were determined in the who were exposed to cesarean delivery pancreatic dysfunction. A multivisceral
intention-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, with
A prospective study of duodenal tional age, low birth weight, and preterm). or without the dysfunction of stomach
bulb biopsy in newly diagnosed and A comparison of 11,000 offspring with and pancreas. Intestinal transplantation is
established adult celiac disease.25 The biopsy-verified celiac disease with 53,000 also considered for certain nontraditional
gold standard to diagnose celiac disease age- and sex-matched control patients indications, such as diffuse mesenteric
is 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 mesenteric
study, 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, thus
Marsh 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), the
VA). Interestingly, patients with newly disease. 1-year risk of rejection is 45% to 50%.
diagnosed celiac disease (9%) and with For multivisceral transplants (liver
established celiac disease (14%) were more Intestinal Transplantation: included), the 1-year risk of rejection is
likely to have VA in the duodenal bulb Definition, Advantages, and Risks 15%. The liver is known to be protective
alone 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 lymphoproliferative
5 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
6. disorder; disease recurrence; and
pseudo-obstruction that encompasses
obstruction, chronic rejection, and Intestinal Transplantation
narcotic addiction (chronic pain).
Outcomes
Between 2005 and 2007, 28 centers world-
wide reported to the worldwide database
of all intestinal transplants that 389 intes-
Patient Survival
tinal transplants were performed on 377
patients. In the United States, 151 trans- Age group 1 year 5 years
plants were reported in 2010 (16% fewer
than in 2009). There were 17 centers with
at 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 been
shown to be a cost-effective therapy
and is superior to continued par- 50 to 64 years 93% 38%
enteral nutrition in appropriately
selected patients. Costs for intestinal 65+ years 100% N/A
transplantation, including the initial
hospitalization for the transplant, From the Organ Procurement and Transplant Network (U.S.), 2002-2007
range 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 and
year. The cost benefit of transplantation viral load over 108 copies are candidates were carrying the CC allele on the IL28B
reaches 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.28
and 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 for
Viral Hepatitis Update essential in such patients, and long-term genotype 1 HCV infection. These are
HBV prophylaxis should be considered. administered in combination with peg
Paul Y. Kwo, MD, Professor of Medicine and Finally, individuals with HBV DNA IFN/ribavirin and have improved the
Medical Director, Liver Transplantation, above 2000 IU and alanine aminotrans- response rate to 70%. For genotypes 2
described new developments in the treat- ferase levels above the upper limit of and 3, the peg IFN/ribavirin therapy is
ment of hepatitis B and hepatitis C, and normal are candidates for therapy. the standard of care. It is important to
gave practical clinical tips. consider drug-drug interaction before
Hepatitis C administering these drugs, because
Hepatitis B There are 170 million to 200 million carriers both strongly inhibit CYP3A4/5 and are
In 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 the
hepatitis B virus (HBV), and the mode United States. Currently, 25% of the HCV Higher sustained virologic response
of 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 patients
sions. The risk of vertical transmission tion are injection drug use (43%) and other (75%) than in those treated with peg
of 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 with
include 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. Boceprevir
Tenofovir is effective against lamivudine of 4.1 years and 5.6 years, suggesting that plus peg IFN/ribavirin has been more
resistance, but entecavir is not. Without HCV is curable. effective for the treatment of patients
previous 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 Both
of viral suppression with minimal resis- most common form of hepatitis C, drugs are effective in nonresponders
tance. 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 treatment
less 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
7. What’s New in Pancreatic
Disorders and Treatment
What I Tell Patients Regarding
Evan L. Fogel, MD, MSc, Professor of
Clinical Medicine, reviewed the most current
Treatment of Hepatitis C
data related to pancreatic disorders and their
treatment.
„„ HCV can be cured in 75% of all cases
The main clinical features of chronic
pancreatitis include abdominal pain „„ herapy is evolving: about half of all genotype
T
and exocrine and endocrine insuffi- 1 individuals can be treated with 6 months of
ciency. Pain management is achieved
through medical, endoscopic, and therapy
surgical intervention. The commonly
used surgical procedures are Whipple, „„ enotype 2/3 still has sustained viral response
G
Puestow, Frey’s, and Beger’s proce- rates of 75% with peginterferon/ribavirin
dures. However, the procedure that is
being used with increasing frequency „„ L-28 CC genotype will identify those who can
I
is total pancreatectomy with auto-islet
cell transplantation (TP-AIT). Patients be treated for shorter duration
undergoing surgery receive transplanta-
tion of native islet cells to prevent the „„ Silymarin ... don’t bother
risk of diabetes, which is directly related
to the islet cell yield. Most patients have
less pain after surgery, and 50% to 80%
are narcotic independent at the 2-year with genetic mutations.32 However, Evaluation and Treatment of
to 4-year follow-up. Quality of life for the study suffered from the following Pelvic Floor Disorders
pediatric patients after TP-AIT was limitations: the proportion of genetic
significantly improved in a single-center mutations (PRSS1, SPINK1) in control Diane M. Settles, MD, Assistant Professor of
prospective study of 19 children (aged populations is unknown, magnetic Clinical Medicine, gave a complete overview
5-18 years, mean = 14.5) with chronic or resonance cholangiopancreatography of pelvic floor disorders and an evaluation of
acute 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 genetic
can be weaned off narcotic medications mutation with PD does not preclude The pelvic floor is a hammock made up
after 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 a
abnormality of the pancreas, with a 10%, as high as 30% of patients under- question whether dyssynergic defecation is
worldwide 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 for
asymptomatic. 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 greater
which 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 pelvic
symptoms in 75% to 80% of cases. diameter PD stents lower the frequency organ prolapse. However, this may be an
Mutational analysis of control patients and severity of post-ERCP pancreatitis underrepresentation, because women are
and patients with unexplained pancre- in high-risk patients, and they are now often embarrassed to report problems of
atitis 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 menopause
patients with the genetic mutations However, a meta-analysis supported the have been linked to PFDs. According
PRSS1 (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 are
should no longer be considered an methacin was also shown to significantly more common among women who
independent 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 have
7 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
8. 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 1000
pausal women, parity has little effect stay of therapy in patients who fail to patients, the ASCA and p-ANCA status
on UI. Sphincter defects are associated respond to supportive medication. was evaluated in patients with IBD
with parity; however, anal sphincter versus patients with functional bowel
defects are most commonly associated disease.41 It was found that the sensitivity
with 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 approximately
rience UI and 6% experience FI. One 60%. The specificity was not perfect
mechanism of injury during preg- Michael V. Chiorean, MD, Associate (92%), and in a population with a low
nancy and childbirth is neural injury Professor of Clinical Medicine, Fellowship pretest probability, such as patients with
that can occur as a result of operative Program Director, described the most current nonspecific symptoms, this would lead
delivery, prolonged second stage approaches to diagnostic testing for inflam- to a substantial number of false positive
of labor, or high birth weight. The matory bowel disease, including their relative results. p-ANCA seems to have a higher
second mechanism is anal sphincter advantages and disadvantages. overall accuracy, and if a patient is both
disruption, 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 patients
to a Cochrane Review of 21 studies disease (IBD) in clinical practice. with IBD are both ASCA-positive and
performed 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 they
floor function, it was concluded that provide a full bowel screen because In previous studies, the correlation of
elective emergency cesarean surgery signs of inflammation anywhere in the calprotectin and lactoferrin with disease
cannot be recommended for protecting gastrointestinal tract will be reflected activity as measured by the endoscopic
anal 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 than
The evaluation of PFDs can be elevated C-reactive protein level or an C‑reactive protein in predicting disease
performed using different techniques. elevated sedimentation rate. Assays activity. In a study performed at Indiana
A physical examination is composed are convenient because stool samples University, a good correlation of fecal
of a detailed neurologic examination, are routinely collected in IBD cases. calprotectin with endoscopic disease
perianal inspection, and a detailed They are also relatively inexpensive activity in patients with both UC and
rectal examination that should include compared with other diagnostic tests Crohn’s disease was established.42
the 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 markers
metric testing of anorectal abnormalities biomarkers is their nonspecificity; (calprotectin and lactoferrin) are useful
in 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 bowel
provided new information in 80% of tions or malignancy. In a meta-analysis screen, and can detect inflammation in
cases, and influenced treatment in 84% of pooled data from 30 studies including patients without elevated C‑reactive
of 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. Serological
rity of sphincters, and pelvic magnetic (threshold = 50 mcg/g - 100 mcg/g) was markers (ASCA and p-ANCA) have
resonance imaging for recognition of found to be greater than 90% and the modest specificity; however, their low
external anal sphincter atrophy are the specificity was 80% to 90%.39 In a meta- sensitivity precludes their use in the
other methods to evaluate PFDs. analysis of 6 studies of adults and chil- diagnosis of IBD.
dren with suspected IBD and a pretest
PFDs 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, Alternative
nerve stimulation, and artificial sphinc- that the use of calprotectin would Therapies in IBD
ters. Loperamide, lomotil, and codeine prevent a large number of patients
are the common medications used to from undergoing further testing, and Monika Fischer, MD, Assistant Professor of
reduce the frequency of incontinence. delayed diagnosis would occur in only Clinical Medicine, reviewed the most current
Hormone replacement therapy showed 6% of the patients. data on the treatment of IBD, including
a 65% improvement in symptoms, and changing recommendations related to the use
25% of patients were asymptomatic Anti-Saccharomyces cerevisiae antibodies of 5-aminosalicylates.
after 6 months of treatment.37 Biofeed- (ASCA) and perinuclear antineutrophil
back has been shown to improve cytoplasmic antibodies (p-ANCA) are 5-aminosalicylates (5-ASAs) continue to
symptoms in 60% of the patients in the most extensively studied markers be first-line therapy for ulcerative colitis
8 To earn CME credit, complete the posttest and evaluation at www.2012GIHepUpdate.com
9. (UC). The American College of Gastro- Underdosing of thiopurine analogs is natalizumab for Crohn’s disease at 10
enterology 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 and
of remission in UC and to prevent relapse rine methyltransferase enzyme activity. adalimumab show a loss of response
in quiescent UC. The recommendation Regular monitoring for myelosuppression over time (13% and 20.3% per patient
is based on 11 high-quality randomized is essential during thiopurine treatment. year, respectively). All 4 agents are
controlled trials, and the optimum dose To achieve continuous remission, thio- intravenous infusions or subcutaneous
of 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 profiles
side 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, congestive
and 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 and
5-ASAs has been shown to achieve better caused by a dysregulated mucosal adalimumab can cause infusion-site
compliance, 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’s
mildly severe to moderately severe system. Therapies that modulate the gut Disease (SONIC) demonstrated that
active UC. The current recommendation flora may prove to be quite successful in combination therapy of infliximab and
suggests oral mesalamine plus topical the future. Dietary intake is related to the azathioprine (2.5 mg/kg) was superior to
mesalamine 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 that
of patients favor oral treatment alone. treatment in Crohn’s disease and UC. the administration of hydrocortisone
Thus, patient preference highly affects Probiotics have great therapeutic poten- before infliximab infusion in patients
drug 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.47
Based 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 in
remission 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 in
5-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 with
shown 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.49
The common immunomodulatory discussed new developments in the treatment
agents used in the treatment of UC are of Crohn’s disease, including recommenda- Disease activity before and after therapy
the 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 calprotectin
recommended for maintenance, but not or lactoferrin, endoscopy, radiographic
for induction of remission of UC. MTX The current FDA-approved drugs for imaging, and capsule imaging. To monitor
is not recommended for UC induction or moderate-to-severe, as well as refractory, the biologic agent itself, in case of an
maintenance, but the recommendation is Crohn’s disease are the IgG anti–tumor increase in symptoms, parameters such
based on only 2 small studies. The efficacy necrosis factor monoclonal antibodies as the trough levels and peak levels of
rate 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 infliximab
administration was 42% compared with levels, can be measured. There are no
7% for placebo (P = .001).44 In the case of In terms of efficacy, adalimumab commercially available ways to monitor
the 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 blood
disease, the duration of steroid use was infliximab, which shows remission at count (at least once a year), and routine
shorter (P .001) and the cumulative week 4; however, the 3 agents appear liver and kidney tests are common practice
steroid dose required was lower (P .01). to be basically equivalent in terms of to monitor complications. The exception
Moreover, there was less relapse in the their ability to induce remission. Their is natalizumab, which is associated with
6-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
