JOURNAL WATCH
GA S TROENTEROLOGY
From the publishers of The New England Journal of Medicine
Narrow-Band Imaging Is
Useful in Surveillance of BE
S creening and surveillance recom-
mendations for patients with Barrett
esophagus (BE) are based on the assump-
tion that this condition is premalignant.
Given the poor survival statistics for pa-
tients with esophageal cancer, the goal
of BE surveillance is early recognition of
dysplasia and neoplasia. For detection of
specialized intestinal metaplasia (SIM)
and dysplasia within the esophagus, re-
searchers have relied on chromoendos-
copy using various dyes. Recently, atten-
tion has turned to enhanced biomedical
optics, including narrow-band imaging
(NBI). NBI changes the optical filters of
the standard videoendoscope and uses
high-intensity blue light to image super-
ficial tissue structures, emphasizing
capillary and mucosal patterns. The
authors of two recent studies evaluated
the clinical usefulness of NBI in patients
with known or suspected BE.
One Dutch group performed a single-
center study of NBI plus magnifying
endoscopy in 63 patients. This dual
technique had a sensitivity of 94%, a
specificity of 76%, a positive predictive
value (PPV) of 64%, and a negative
predictive value of 98% for identifying
mucosal characteristics of SIM and high-
grade dysplasia (HGD).
A U.S. group performed a single-center,
prospective cohort study of 51 patients.
Histology was assessed in blinded fash-
ion and then correlated with NBI images.
The sensitivity of this strategy for de-
tecting SIM with HGD was 100%, the
specificity was 98.7%, and the PPV was
95.3%. No HGD was missed when bi-
opsies were limited to areas with identi-
fied irregular or distorted mucosal or
vascular patterns characteristic of HGD.
NBI was not helpful in distinguishing
areas of SIM with low-grade dysplasia.
Journal Watch (and its design) is a registered trademark of the Massachusetts Medical Society.
An editorially independent literature-surveillance newsletter summarizing articles from major medical journals
2006 Massachusetts Medical Society. All rights reserved.
December 2006
Comment:
Both groups demonstrated the practical,
technical advantage of NBI for targeting
biopsies in the inspection of mucosal mor-
phology in BE patients. This technique is
an alternative to chromoendoscopy, with
specific advantages over that technique.
In chromoendoscopy, complete and even
coating of the mucosa and accurate identi-
fication of vascular patterns through
the dye stain are problematic. A dye
spray catheter is required. In NBI, a
particular endoscope and processor are
necessary; thus, a cost is also incurred
for endoscopists who want to employ
this technique.
Mastering these techniques likely will
involve a learning curve, an issue these
studies did not evaluate. Better detec-
tion of HGD in surveillance of BE is
clearly needed. These results suggest
that NBI will be an extremely useful
advance in that direction.
David A. Johnson, MD
Kara MA et al. Detection and classification
of the mucosal and vascular patterns (mu-
cosal morphology) in Barretts esophagus
TA B L E O F C O N T E N T S
Narrow-Band Imaging Is Useful
in Surveillance of BE ........................... 93
Methylene Blue for Identifying
Dysplasia in BE .................................... 93
Alarm Features for
Upper Gastrointestinal Malignancy .... 94
CME: GERD Symptoms
Linked to Cardiac Dysrhythmias ........ 95
Low-Dose Aspirin
and Antithrombotic Drugs
in Upper Gastrointestinal Bleeding .... 95
Cost-Effectiveness of PPIs
for Peptic Ulcer Hemorrhage .............. 95
Clinical Practice Guideline Watch:
Should We Screen Routinely
for Hemochromatosis? ........................ 96
Lower Gastrointestinal Effects
of NSAIDs............................................. 96
Vol. 7 No. 12
by using narrow band imaging.
Gastrointest Endosc 2006 Aug; 64:155-66.
Sharma P et al. The utility of a novel
narrow band imaging endoscopy system
in patients with Barretts esophagus.
Gastrointest Endosc 2006 Aug; 64:167-75.
Methylene Blue for
Identifying Dysplasia in BE
T he purpose of endoscopy in diag-
nosis and surveillance of Barrett
esophagus (BE) is to detect dysplasia
and identify patients at high risk for
esophageal adenocarcinoma. Many
groups have evaluated chromoendoscopy
with various dyes as an adjunct for iden-
tifying dysplastic areas of BE. The dye
methylene blue (MB) has been used to
identify dysplasia and metaplasia, partic-
ularly in short-segment BE. This dye is
taken up by absorbent intestinal-type
epithelia, whereas squamous epithelia
and dysplastic BE cells take up little,
resulting in heterogeneous staining.
In this prospective, crossover study,
35 patients with BE and prior diagnoses
Nurses Can Interpret Small-Bowel
Capsule Endoscopy Accurately ........... 97
Another Small Step Forward
in Treating Patients with IBS............... 97
Vaccination in IBD Patients
Usually Is Inadequate .......................... 98
New Antibody Markers
in Crohn Disease ................................. 98
Adenomas in
Ulcerative Colitis Patients ................... 98
Case-Control Study of Colonoscopy ....... 99
Resection vs. Forceps Biopsy
of Submucosal Lesions ........................ 99
Cholangioscopic Assessment
of Dominant Strictures
in Primary Sclerosing Cholangitis ...... 99
Page 94
EDITOR- IN - CHIEF
M. Brian Fennerty, MD
Professor of Medicine
Section Chief of Gastroenterology
Department of Internal Medicine
Oregon Health Sciences University
Portland
DEPUT Y EDITOR
David J. Bjorkman, MD, MSPH (HSA),
SM (Epid.)
Dean
University of Utah School of Medicine
Executive Medical Director
University of Utah Medical Group
Salt Lake City
EXECUTIVE EDITOR
Catherine Tomeo Ryan, MPH
Massachusetts Medical Society
M A N AG I N G E D I T O R
Charleen M. Hamilton, PhD
Massachusetts Medical Society
A S S O C I AT E E D I T O R S
David A. Johnson, MD
Professor of Medicine
Chief of Gastroenterology
Eastern Virginia School of Medicine, Norfolk
Douglas K. Rex, MD
Professor of Medicine
Director of Endoscopy
Division of Gastroenterology/Hepatology
Indiana University Medical Center
Indianapolis
Stuart Sherman, MD
Professor of Medicine and Radiology
Director of ERCP
Division of Gastroenterology/Hepatology
Indiana University Medical Center
Indianapolis
Atif Zaman, MD, MPH
Associate Professor
Department of Gastroenterology and Hepatology
Oregon Health Sciences University, Portland
M A S S AC H U S E T T S M E D I C A L S O C I E T Y
Sharon S. Salinger, Staff Editor
Terri Autieri, Copy Editor
Mark Rossi, Layout
Christopher R. Lynch,
Vice President for Publishing
Alberta L. Fitzpatrick, Publisher
David G. Mecsas, Editorial Director
Art Wilschek, Christine Miller, Lew Wetzel,
Wayne Wickman, Advertising Sales
Robin Buttner, Design and Premedia
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JOURNAL WATCH GASTROENTEROLOGY
of dysplasia were randomized to MB-
directed biopsy (MBDB) or to random
4-quadrant biopsies in the first of two
endoscopies. Within 6 months, 30
patients crossed over to second endos-
copies, using the alternative biopsy
protocol. Standard biopsy forceps were
used for all biopsies.
Baseline histology for the 30 patients
showed low-grade dysplasia (LGD) in 17
patients, high-grade dysplasia (HGD) in
3, and no dysplasia in 10. At the second
endoscopies, histology showed LGD in
10, HGD in 8, and no dysplasia in 12. In
the 18 patients with histologic findings,
dysplasia was identified correctly by
random biopsy in 17 patients and by
MBDB in 8 (P=0.02).
Comment:
Mess and hassle, expense, and time are
inevitable costs associated with any
chromoendoscopy technique. Recently,
concern has also surfaced about MBs
safety profile, particularly regarding
DNA damage induced by exposure to
white light. This concern called into
question the value of MB-directed stain-
ing compared with random biopsy. Diffi-
culties in standardization of technique,
interpretation of findings, and the learn-
ing curve are other issues. In these study
patients, MB staining offered no advan-
tage and was, in fact, inferior to standard
biopsy technique. The loss of 14% of
patients before crossover might have
affected the studys power to show a dif-
ference but is unlikely to have affected
MBDBs relative performance. Advanced
endoscopic imaging techniques will
eventually allow electronic digital
chromoendoscopy, a more standard-
ized, viable, and applicable adjunct for BE
surveillance. David A. Johnson, MD
Lim CH et al. Randomized crossover study
that used methylene blue or random
4-quadrant biopsy for the diagnosis
of dysplasia in Barretts esophagus.
Gastrointest Endosc 2006 Aug; 64:195-9.
Alarm Features for
Upper Gastrointestinal
Malignancy
A larm symptoms in patients with
dyspepsia are an indication for
endoscopic evaluation, because they
are presumed to predict upper gastro-
intestinal (UGI) malignancy. However,
the predictive value of such symptoms
has never been rigorously evaluated.
Volume 7 Number 12
To address the diagnostic accuracy
of alarm symptoms for UGI malignancy,
investigators performed a literature
search for papers in which both the
presence of alarm symptoms and endo-
scopic diagnoses in patients with dys-
pepsia were reported. Among 2635
evaluated papers, 15 (involving 57,363
patients) met prespecified criteria and
were included in the analysis for general
alarm symptoms; 3 others were included
for individual alarm symptoms only.
Only 458 patients (0.8%) had endos-
copically documented UGI malignan-
cies. The results varied widely among
reports, with alarm symptom sensitivi-
ties ranging from 0% to 83%, and with
specificities ranging from 40% to 98%.
Significant heterogeneity between
studies was noted. In the trials, patients
were evaluated and malignancy was pre-
dicted by various strategies, including
global assessment by physicians, com-
puter models based on questionnaire
answers, and qualitative presence or
absence of individual alarm symptoms
(weight loss, dysphagia, and anemia only).
The pooled results showed that alarm
symptoms have limited sensitivity and
specificity for predicting UGI malignancy,
with a diagnostic odds ratio (positive
likelihood ratio divided by negative likeli-
hood ratio) of 7.49 (95% CI, 4.3712.8).
The area under the receiver-operating
characteristic (ROC) curve was 0.80. The
authors concluded that alarm symptoms
have limited predictive value and that
diagnostic strategies should be refined.
Comment:
This analysis includes studies with
substantially different populations and
methods, which results in significant
heterogeneity and suggests that combin-
ing data from these studies is problematic.
The low prevalence of malignancy
(<1%) in the study populations produces
a relatively high negative predictive value
and a low positive predictive value, in-
dependent of the diagnostic accuracy
of alarm symptoms. The poor likeli-
hood ratio and ROC values are more
convincing indicators that using alarm
symptoms in the diagnostic cascade
for dyspeptic patients provides limited
value. David J. Bjorkman, MD,
MSPH (HSA), SM (Epid.)
Vakil N et al. Limited value of alarm fea-
tures in the diagnosis of upper gastrointes-
tinal malignancy: Systematic review and
meta-analysis. Gastroenterology 2006
Aug; 131:390-401.
December 2006
GERD Symptoms
Linked to
Cardiac Dysrhythmias
M uch has been written about the
role of gastroesophageal reflux
disease (GERD) in the pathogenesis of
noncardiac chest pain, but GERD has
also been linked to disturbances in
cardiac rhythm. In the proposed patho-
physiologic mechanism behind this
link, an irritant esophagogastric stimu-
lus induces an alteration in the cardiac
conduction signaling or autonomic
modulation of the heart rate, resulting
in cardiac dysrhythmia. Good evidence
suggests that mechanical, electrical, and
chemical stimulation of the esophagus
can alter the balance between vagal and
sympathetic activities. Investigators in
Naples, Italy, assessed the relation be-
tween acid reflux in the esophagus and
neurocardiac function in patients with
supraventricular arrhythmias. They also
evaluated the effect of acid suppression
therapy in these patients.
In this prospective, single-center study,
32 patients with GERD symptoms plus
supraventricular cardiac dysrhythmias
and 9 control patients with GERD alone
underwent 24-hour intraesophageal pH
monitoring and ambulatory electrocardi-
ography (ECG). Hourly comparisons of
heart-rate variability and esophageal pH
were made. In 18 (56%) of the 32 patients
with dysrhythmia and in no control
patients, episodes of acid reflux and epi-
sodes of dysrhythmia were significantly
correlated (odds ratio, 2.26; 95% CI,
2.002.57; P<0.05). Following initial as-
sessments, all patients were treated with
the proton-pump inhibitor (PPI) esomep-
razole (40 mg daily). After 3 months
of PPI therapy, 81% of patients with dys-
rhythmia showed significant reductions
in cardiac symptoms (P<0.05).
Comment:
Sinus node activity is affected by con-
ditions such as assumption of an
upright posture, mental stress, and ex-
ercise that cause increases in sym-
pathetic tone. By contrast, vagal tone
is high during rest. The results of this
study suggest that, in some patients
with increased esophageal acid sensi-
tivity, acid reflux triggers exaggerated
firing of the esophageal-cardiac reflex.
This hypothesis seems to be supported
further by the significant effect of acid
inhibition on cardiac dysrhythmia in
such patients.
JOURNAL WATCH GASTROENTEROLOGY
This study is the first to show an
influence of esophageal stimulation on
autonomic function in patients with
otherwise-unexplained cardiac dys-
rhythmias. Extra-esophageal complica-
tions of GERD might extend beyond
noncardiac chest pain to supraventricu-
lar cardiac dysrhythmias in a subset of
patients. David A. Johnson, MD
Cuomo R et al. Oesophageal acid exposure
and altered neurocardiac function in
patients with GERD and idiopathic cardiac
dysrhythmias. Aliment Pharmacol Ther
2006 Jul 15; 24:361-70.
Low-Dose Aspirin and
Antithrombotic Drugs
in Upper Gastrointestinal
Bleeding
S everal scoring systems are available
to help predict outcomes of patients
with acute upper gastrointestinal bleeding
(UGIB). However, none of these scoring
systems takes into account the potential
effects of concurrent medications that
can precipitate or accentuate bleeding.
Investigators in Scotland addressed
the effect of low-dose aspirin, other anti-
thrombotic drugs, warfarin, and nonste-
roidal anti-inflammatory drugs (NSAIDs)
on the outcomes of patients with acute
UGIB. Blatchford clinical scores (Lancet
2000; 356:1318) were calculated for
510 patients. Alcohol consumption and
concurrent use of low-dose aspirin, other
antithrombotic drugs, warfarin, and
NSAIDs were noted.
Higher Blatchford scores correlated
with longer duration of admission and
requisite transfusion. Median Blatchford
scores were higher in patients who took
NSAIDs (score, 8), aspirin (7), or other
antithrombotics (6), or who had multi-
ple risk factors (7) than in patients who
had no risk factors (5). Patients whose
only risk factor was consumption of
>20 U of alcohol daily had a median
score of 4.
w w w.jwat ch .or g
Page 95
Comment:
The findings of this study do not dem-
onstrate that any of these drugs directly
cause worse outcomes in UGIB patients.
Rather, the association might be a mark-
er for comorbid illnesses that are not
captured by the scoring system. Further
study is needed to determine if use
of these agents directly affects patient
outcomes. David J. Bjorkman, MD,
MSPH (HSA), SM (Epid.)
Taha AS et al. Clinical outcome in upper
gastrointestinal bleeding complicating
low-dose aspirin and antithrombotic
drugs. Aliment Pharmacol Ther 2006
Aug 15; 24:633-6.
Cost-Effectiveness
of PPIs for
Peptic Ulcer Hemorrhage
H igh-dose proton-pump inhibitor
(PPI) therapy lowers risk for re-
bleeding in patients with bleeding pep-
tic ulcers and high-risk stigmata. Both
intravenous and oral PPIs are effective,
but the two routes of administration
have not been compared in a head-to-
head trial. Oral formulations would re-
duce costs of therapy substantially and
potentially could facilitate earlier hospi-
tal discharge. To evaluate the difference
in cost between the two routes of admin-
istration, investigators used a decision
analysis model of three post-endoscopic
approaches to treating bleeding peptic
ulcers: oral PPI therapy, IV PPI therapy,
or IV H2-receptor antagonists (H2RAs).
Probabilities of rebleeding and other
clinical outcomes were derived from
published data on patients with bleed-
ing peptic ulcers and high-risk stigmata
who received endoscopic therapy.
The investigators assumed that patients
with rebleeding would receive a second
round of endoscopic therapy and that
continued bleeding would lead to sur-
gery. Cost estimates were based on a
third-party payer assumption, using the
2005 Medicare fee schedule for hospital-
ization and procedures and average
wholesale prices for medications.
Page 96 JOURNAL WATCH GASTROENTEROLOGY Volume 7 Number 12

C L I N I C A L P R A C T I C E G U I D E L I N E W A T C H

Should We Screen Routinely for Hemochromatosis?

H ereditary hemochromatosis is a common genetic dis-

order in the U.S.; gene mutations are carried by 1 in 10
non-Hispanic white residents. Substantial iron overload,
which leads to end-organ damage, and especially to liver dis-
ease, occurs mainly in people who are homozygous for the
C282Y mutation or in those who are heterozygous for both
C282Y and H63D. Screening for hemochromatosis is attrac-
tive theoretically, but, so far, little evidence supports its
effectiveness. The U.S. Preventive Services Task Force has
released a report based on its systematic review of screening
via genetic testing for the C282Y mutation.
The Task Force reviewed study results from 1966 through
February 2005 and addressed three basic questions:
How much disease burden actually is attributable to
hemochromatosis?
Does early therapeutic phlebotomy treatment lead
to better outcomes?
Which (if any) high-risk groups would benefit most from
screening?
The Task Force found fair evidence that a low proportion of
people with C282Y mutations manifest the disease. Because
most patients with this mutation do not manifest disease,
identifying them before any clinical manifestation of disease
would lead to unnecessary work-ups, surveillance, and treat-
ment. The Task Force found poor evidence that early thera-
peutic phlebotomy improves survival in people who are
detected by screening versus those who receive phlebotomy
after clinical manifestation, and no evidence that any particular
group benefited from early intervention. A D recommenda-
tion (against routinely providing screening to asymptomatic
patients) was issued because the potential harms of genetic
screening were determined to outweigh the potential benefits.
Comment:
This systematic review was plagued by the limited research
that is available; published research studies have been solely
observational, with poor and inconsistent reporting. Further-
more, these reviewers looked at genetic screening only and
did not consider the role of measuring iron stores, such as
transferrin saturation and serum ferritin levels. Neither did
this review include long-term follow-up data from the HEIRS
study ( JW Gastroenterology Aug 2005, p. 64, and N Engl J
Med 2005; 352:1769), which will provide more robust data
about disease expression and outcome in the next few years.
What is most surprising is that the Task Force gave any rec-
ommendation other than I insufficient evidence. Before
we can abandon screening for hemochromatosis, we need
more data on possible benefits. At the time of publication,
the full text of the systematic review was available free of
charge at http://www.ahrq.gov/clinic/uspstf06/hemo-
chromatosis/hemochrev.htm Atif Zaman, MD, MPH
Whitlock EP et al. Screening for hereditary hemochromatosis:
A systematic review for the U.S. Preventive Services Task Force.
Ann Intern Med 2006 Aug 1; 145:209-23.

In the case-based analysis, the H2RA
approach was less effective and more
costly than other strategies. The oral
and IV PPI strategies had average costs
of US$6864 and $8009, and quality-
adjusted life-years (QALYs) gained of
0.9767 and 0.9783, respectively. Rebleed-
ing would occur in 13% of patients in the
oral PPI arm, compared with 6% in the
IV PPI arm. Calculated cost of using the
IV, instead of the oral, route of adminis-
tration was $708,735 to gain one addi-
tional QALY and $16,967 to prevent one
episode of rebleeding. Sensitivity analyses
showed the conclusions to be sensitive
only to changes in the 72-hour rebleed-
ing rate and length of hospitalization.
Either PPI strategy became dominant if
the rebleeding rate with the other strat-
egy increased approximately twofold.
Comment:
Even though their model was intention-
ally biased in favor of IV PPI therapy,
the authors concluded that, although IV
PPI therapy is more effective in prevent-
ing rebleeding than oral PPI therapy is,
the benefit is unlikely to overcome the
additional costs incurred. These results
differ from those of a previous analysis,
which suggested that IV PPI therapy
was more cost-effective ( JW Gastro-
enterology Nov 2004, p. 90, and
Aliment Pharmacol Ther 2004;
20:195). Both analyses relied on hetero-
geneous studies with varied methods in
different populations. Only with head-
to-head trials of IV and oral PPI therapies
will we be able to compare efficacy and
cost reliably until one is shown to
be superior, either is acceptable.
David J. Bjorkman, MD,
MSPH (HSA), SM (Epid.)
Spiegel BM et al. The cost-effectiveness and
budget impact of intravenous versus oral
proton pump inhibitors in peptic ulcer
hemorrhage. Clin Gastroenterol Hepatol
2006 Aug; 4:988-97. (http://dx.doi.org/
10.1016/j.cgh.2006.05.019)
www.jwatch.org
Lower Gastrointestinal
Effects of NSAIDs
I n patients who received nonsteroidal
anti-inflammatory drugs (NSAIDs),
risk for upper gastrointestinal ulceration
and bleeding has been well described.
However, risk for lower gastrointestinal
(LGI) bleeding, strictures, and other
complications has been recognized but
not investigated thoroughly. Few data
are available on LGI effects of non-
selective NSAIDs or the more-selective
cyclooxygenase-2 inhibitors (coxibs).
Industry-sponsored investigators re-
viewed the medical literature for studies
on the association of NSAID use and LGI
effects (integrity, lesions, and bleeding)
and found 46 papers that described 47
studies in which this issue was addressed.
(Variations in study design prevented
combining the data quantitatively in a
meta-analysis.) They found that nearly
all studies, regardless of design, showed
increased risk for changes in intestinal
permeability, presence of mucosal lesions,
perforations, and clinical bleeding epi-
December 2006
sodes among patients who took NSAIDs,
compared with controls. Differences in
the LGI effects of NSAIDs and coxibs
were reported by a few groups; in all but
one study, the effects of coxibs were less
severe than those of nonselective NSAIDs.
The authors note that increased risk
for gastrointestinal injury and clinical
LGI events with nonselective NSAIDs is
a consistent finding in trials of varying
designs, in which different specific
effects were evaluated. They also note
that data on the comparative differences
in injurious effects between coxibs and
nonselective NSAIDs is incomplete, be-
cause only a small number of trials have
addressed this issue.
Comment:
The studies used in this analysis varied
in many aspects population, specific
NSAID evaluated, study design, and out-
come measured. Nonetheless, the over-
whelmingly consistent finding in all
studies is that nonselective NSAIDs have
significant adverse LGI effects. The
relative difference between coxibs and
nonselective NSAIDs appears to favor
coxibs, but data are limited. The patho-
physiology of NSAID LGI effects is not
related clearly to prostaglandin inhibi-
tion, suggesting that the difference in
adverse events might be due to the char-
acter of the compounds themselves as
much as to their physiologic effects.
David J. Bjorkman, MD,
MSPH (HSA), SM (Epid.)
Laine L et al. Systematic review: The lower
gastrointestinal adverse effects of non-
steroidal anti-inflammatory drugs. Aliment
Pharmacol Ther 2006 Sep 1; 24:751-67.
Nurses Can Interpret
Small-Bowel Capsule
Endoscopy Accurately
C apsule endoscopy images are not
operator-dependent; therefore,
they can be read and used by nonphysi-
cian personnel. In two previous studies,
researchers have shown a high correla-
tion between endoscopists and nurses
interpretations of small-bowel capsule
endoscopy images.
In this study, a highly experienced
endoscopist and a highly experienced
endoscopy nurse were trained by the
same method to read small-bowel capsule
studies. They then read 41 consecutive
capsule studies blindly; 30 of these were
performed for obscure gastrointestinal
JOURNAL WATCH GASTROENTEROLOGY
bleeding. The nurse identified 65 possi-
ble problem areas, and the physician
identified 53. The nurses and the physi-
cians readings agreed perfectly on blood
in the lumen and on stenoses. The nurse
identified all lesions considered to be
significant by the endoscopist (100%
sensitivity), but the nurse also identified
12 areas that were considered to be
insignificant by the endoscopist.
Comment:
For this pair of subjects, pre-reading of
capsule studies by the nurse was an ideal
situation. The nurse used a reading style
that was exquisitely sensitive but one
that would be expected to result in a
few false positives. In general, if poten-
tially abnormal areas can be identified
by nurses for review by endoscopists,
the result could be extremely high sen-
sitivity and dramatic reductions in cost
and in time spent by endoscopists for
image review. Douglas K. Rex, MD
Bossa F et al. Detection of abnormal le-
sions recorded by capsule endoscopy. A pro-
spective study comparing endoscopists and
nurses accuracy. Dig Liver Dis 2006 Aug;
38:599-602.
Another Small Step
Forward in
Treating Patients with IBS
T he etiologies of irritable bowel syn-
drome (IBS) and the mechanisms
by which symptoms are produced vary
but include disorders of gut motility,
secretion, and sensation. In addition,
small-intestinal motility disorders can
result in small-intestinal bacterial over-
growth (SIBO), which can lead to ab-
dominal pain, distension, and diarrhea
all cardinal symptoms of IBS. IBS
patients have a high prevalence of SIBO,
and a few studies have indicated that
some IBS symptoms improve with anti-
biotic therapy, albeit with side effects.
In this study, investigators sought to de-
termine whether treatment with a new
nonabsorbable and well-tolerated anti-
biotic, rifaximin (Xifaxan), would im-
prove symptoms in patients with IBS.
Researchers enrolled 87 patients with
IBS (Rome I criteria) in this placebo-
controlled, randomized, double-blind,
industry-sponsored U.S. study. Patients
received either thrice-daily rifaximin
(400 mg/dose) or placebo for 10 days.
Overall, treatment was well tolerated,
and side effects were mild. Global
Page 97
symptom outcomes were assessed for
10 weeks. Specific symptoms also
were evaluated.
At 10 weeks, global symptoms im-
proved by 36% in the rifaximin group
and by 21% in the placebo group. The
authors did not provide information on
rates of complete, or even partial, relief
or on whether a finding of SIBO (based
on breath tests prior to therapy) corre-
lated with symptom improvement. In the
secondary analysis, evaluation of specific
symptoms indicated that improvement
was isolated to bloating; abdominal pain
and diarrhea did not improve.
Comment:
What do these findings mean to the cli-
nician? First, we have few robust thera-
pies for IBS in general, response to
other approved (or likely to be approved)
agents for this disorder, such as tegase-
rod (Zelnorm), lubiprostone (Amitiza),
or alosetron (Lotronex), is modest at
best. Thus, some patients likely would
benefit from new therapies such as rifax-
imin. Treatment effects with this agent
are limited to improving symptoms of
bloating, and no information was pro-
vided to allow us to quantify the thera-
peutic response or the number of patients
with marked or complete improvement.
Second, these findings suggest that
SIBO can play a role in IBS symptoms
and that development of effective thera-
pies for SIBO would be beneficial for
some patients. However, SIBO is not a
disease; rather, it is a consequence of in-
effective small-intestinal motility, and
the underlying dysmotility will still ex-
ist after SIBO is eliminated. One would
hypothesize that SIBO and IBS symp-
toms will reoccur in most patients who
initially respond and that retreatment or
chronic therapy for SIBO will be required.
Third, the safety and cost of long-term
or repeated therapy for SIBO is unknown,
and we must be cautious about embracing
emerging therapies before we understand
the long-term outcomes. An intriguing
possibility is to use antibiotics and pro-
kinetic therapies in combination, but
this approach has not been investigated.
Despite all these caveats, these findings
present a glimmer of hope that effective
therapies for IBS exist, even though the
disorder has frustrated patients and
physicians because of limited ability
to achieve symptom responses with
current therapies.
M. Brian Fennerty, MD
Page 98 JOURNAL WATCH GASTROENTEROLOGY Volume 7 Number 12

Pimentel M et al. The effect of a nonab-
sorbed oral antibiotic (rifaximin) on the
symptoms of the irritable bowel syndrome:
A randomized trial. Ann Intern Med 2006
Oct 17; 145:557-64.
Vaccination in IBD Patients
Usually Is Inadequate
antibodies (ANCA) are associated with
UC and also can be found in patients with
Crohn colitis. Anti-Saccharomyces cerevi-
siae antibodies (ASCA) are associated
with Crohn disease; anti-CBir, an antibody
against flagellin, also is associated with
Crohn disease (but not UC) and is found
in about 40% of patients with Crohn
disease who are ASCA-negative.
Comment:
The antibody story in IBD is complex,
but the prospect of highly accurate anti-
body profiles for diagnosis, differentiation
of UC from Crohn disease, and determina-
tion of disease severity is quickly moving
closer to reality. The roles of ALCA and
ACCA as adjuncts to current antibody pro-
files will have to be determined in clinical

D espite current recommendations

that immunocompromised adults be
considered for vaccination against influ-
enza, pneumococcal disease, varicella,
hepatitis B, and tetanus, vaccination rates
in this high-risk population remain inade-
quate. To determine the rates among
individuals with inflammatory bowel
disease (IBD), investigators surveyed
196 IBD patients at a tertiary care center
in Los Angeles.
One hundred sixty-nine patients
(median age, 35) completed the surveys.
Of the 146 with current or previous use
of immunosuppressive medications, 41
(28%) reported regularly receiving flu
shots, and just 13 (9%) reported ever
receiving pneumococcal vaccine. Of
the 75 patients considered to be at risk
for hepatitis B virus infection, only 23
(31%) had been vaccinated. Nineteen
patients (11%) did not have reliable his-
tories of chickenpox or varicella vacci-
nation. All 169 patients were considered
to be at risk for tetanus, yet only 76
(45%) could recall tetanus immuniza-
tion within the previous 10 years.
Comment:
We need to do better in immunizing
patients with IBD against vaccine-
preventable diseases and in increasing
patient awareness of the need for such
vaccination. An expert consensus
report on vaccination issues particular
to IBD patients was published in 2004
(Inflamm Bowel Dis 2004; 10:677).
Douglas K. Rex, MD
Melmed GY et al. Patients with inflamma-
tory bowel disease are at risk for vaccine-
preventable illnesses. Am J Gastroenterol
2006 Aug; 101:1834-40.
New Antibody Markers
in Crohn Disease
C ommercially available tests for anti-
bodies are valuable for diagnosing
inflammatory bowel disease (IBD), dif-
To extend this diagnostic benefit,
investigators identified antibodies di-
rected against sugars that are found in
studies. Douglas K. Rex, MD
Dotan I et al. Antibodies against laminari-
bioside and chitobioside are novel
the cell walls of bacteria and fungi. serologic markers in Crohns disease.
Anti-carbohydrate antibodies were eval- Gastroenterology 2006 Aug; 131:366-78.
uated using either glycan arrays (from
72 patients with Crohn disease, 56 pa-
tients with UC, and 4 healthy controls) Adenomas in Ulcerative
or enzyme-linked immunosorbent assays Colitis Patients
(ELISAs; in 124 patients with Crohn
disease, 106 patients with UC, and 101
controls). Antibodies directed against
D istinguishing sporadic adenomas
(also called adenoma-like mass
[ALM]) from colitis-associated adenomas
laminaribioside (anti-laminaribioside
(also called dysplasia-associated lesion
carbohydrate [ALCA]) and chitobioside
or mass [DALM]) requires assessing both
(anti-chitobioside carbohydrate [ACCA])
endoscopic and histologic features of the
were associated with Crohn disease.
lesion, as well as histologic features of
Using glycan arrays, the percentages
the surrounding mucosa. When sporadic
of the Crohn disease cohort in whom
adenomas are detected in ulcerative coli-
ALCA, ACCA, and ASCA were positive
tis patients, small studies have indicated
were 38%, 36%, and 67%, respectively;
that endoscopic resection can be per-
20.8% were negative for all three anti-
formed, and the patient should continue
glycan antibodies. Of 27 Crohn disease
to receive colonoscopic surveillance.
patients in whom ASCA was negative,
Researchers in this large German study
12 (44%) were ALCA- or ACCA-positive.
followed 148 consecutive ulcerative colitis
ALCA and ASCA were both associated
patients with adenomas. Sporadic adeno-
with small-intestinal disease and more
mas met strict histologic criteria and were
severe penetrating or stricturing dis-
scattered throughout the colon. One pa-
ease, but ACCA was not associated with
tient underwent prompt proctocolectomy,
localization or severity.
and a T2 carcinoma was found. Sixty pa-
Using ELISAs (with higher positive
tients underwent no polypectomy or
cutoff values), ALCA, ACCA, and ASCA
surgery (i.e., lesions were biopsied but
were positive in 27%, 25%, and 68% of
not removed). The remaining 87 pa-
Crohn patients. In the UC cohort, ALCA,
tients underwent polypectomy.
ACCA, and ASCA were positive in 4%,
Mean follow-up was 6 years. Among
5%, and 7%, respectively. In patients
the 60 patients who did not undergo
with non-IBD gastrointestinal diseases
polypectomy, 9 (15%) developed stage I
(e.g., celiac disease), ALCA, ACCA, and
carcinomas in the same bowel segment
ASCA were positive in 9%, 9%, and 13%,
as the adenoma; another 20 patients
respectively. In healthy controls, ALCA,
developed dysplasia (6, low-grade; 14,
ACCA, and ASCA were found in 2%, 12%,
high-grade) in the same segment as the
and 15%, respectively (see Table below).
adenoma. All patients with dysplasia
underwent proctocolectomy, and a T2
Antibody Results
carcinoma was discovered in 1 this
by Patient Group
patient died of recurrent colorectal
cancer. Among the 87 patients in whom
Patient Antibodies
polyps were removed endoscopically,
Group
Crohn disease
ALCA+

27%
ACCA+

25%
ASCA+

68%
83 (95%) had no neoplasia during
follow-up. Four developed low-grade
ferentiating ulcerative colitis (UC) from UC 4% 5% 7% intraepithelial neoplasia in segments
Crohn disease, and predicting disease other than those in which adenomas
Non-IBD 9% 9% 13%
course and severity in patients with IBD. had been removed, and 2 of these
For example, anti-neutrophil cytoplasmic controls 2% 12% 15%
December 2006
patients subsequently developed stage
I cancers in other bowel segments.
Comment:
These findings afford a remarkable op-
portunity to observe the natural history
of sporadic adenomas in ulcerative colitis
patients. The adenomas behavior can
be quite ugly, and they should be fully
resected endoscopically. If resection is
successful, the prognosis for the patient
is good, and colonoscopic surveillance
can continue. Douglas K. Rex, MD
Vieth M et al. Sporadic adenoma in ulcer-
ative colitis: Endoscopic resection is an ad-
equate treatment. Gut 2006 Aug; 55:1151-5.
Case-Control Study
of Colonoscopy
T he first study to demonstrate con-
vincingly that endoscopic screening
and removal of precancerous lesions pre-
vents colorectal cancer was a U.S. case-
control study of sigmoidoscopy, which
showed a 60% reduction in risk for
colorectal cancer mortality from distal
colon cancers following proctosigmoid-
oscopy (N Engl J Med 1992; 326:653).
This protective effect lasted for at least
10 years. Subsequently, another case-
control study, primarily of flexible
sigmoidoscopy, showed an 80% reduc-
tion in distal colon cancers and an ef-
fect duration of at least 16 years ( JW
Gastroenterology Sep 2003, p. 70,
and J Natl Cancer Inst 2003; 95:622).
Neither group could exclude a longer
duration of effect.
German investigators have performed
a similar study of screening colonoscopy.
They identified cases 380 people
with colorectal cancer that was not
diagnosed by screening (inflammatory
bowel disease cases and those with
documented colonoscopy <1 year prior
were excluded) and recruited 485
age- and sex-matched controls without
colorectal cancer. All participants were
interviewed, and medical records were
reviewed to determine whether polyps
had or had not been detected during
prior colonoscopies. In 79% of examina-
tions, self-reporting and medical re-
cords concurred on whether or not
polyps were detected and removed.
Previous negative colonoscopy was
3.5 times more common among controls
(27.6%) than among cases (7.9%). After
adjustment, the odds of developing
colorectal cancer for controls were 0.26
JOURNAL WATCH GASTROENTEROLOGY
(95% CI, 0.160.40), and this risk reduc-
tion persisted for longer than 20 years.
Odds ratios among controls were
numerically lower if the last negative
colonoscopy had occurred at age 55 or
older. The odds ratio was lower when
sigmoid or rectal cancers were consid-
ered alone (OR, 0.17; 95% CI, 0.090.32)
than when proximal cancers were
included (OR, 0.40; 95% CI, 0.210.72).
Comment:
This small study supports the hypothe-
sis that risk for colorectal cancer is sub-
stantially lower after negative colonos-
copy. These risk reductions remained
relatively constant with longer time
following the negative colonoscopy.
In a much larger study, the incidence
of cancer in 32,000 patients who had
negative screening colonoscopies was
compared with rates in reference popu-
lations ( JW Gastroenterology Jul 2006,
p. 55, and JAMA 2006; 295:2366); that
study showed a lesser degree of protec-
tion from negative colonoscopy, but the
level of protection rose during the sub-
sequent 10 years. Based on these collec-
tive findings, negative colonoscopy
clearly engenders a substantial and
durable reduction in risk for colorectal
cancer. Of course, we still dont know
why we dont see an even higher level
of protection. Widespread institution
of quality improvement measures and
improved colonoscopic technology no
doubt will increase colonoscopys pro-
tective effect. Douglas K. Rex, MD
Brenner H et al. Does a negative screening
colonoscopy ever need to be repeated? Gut
2006 Aug; 55:1145-50.
Resection vs.
Forceps Biopsy
of Submucosal Lesions
E ndoscopic ultrasound (EUS) is useful
in characterizing the echogenicity
and the wall-layer involvement of sub-
epithelial tumors (SETs), but it has lim-
ited accuracy for differentiating malig-
nant from benign SETs. The diagnostic
yields from two methods of characteriz-
ing SETs endoscopic submucosal-
mucosal resection (ESMR) and forceps
biopsy (using a large-capacity instrument
and a bite-on-bite technique to collect
eight specimens) were evaluated
prospectively in 23 consecutive patients
with EUS-identified SETs limited to the
submucosa.
Page 99
Eighteen SETs were located in the
stomach, 2 were in the esophagus, 2
were in the sigmoid colon, and 1 was in
the duodenum. Forceps biopsy was per-
formed first, followed by ESMR. Histo-
logic diagnoses were achieved in 21 pa-
tients: lipoma (7), pancreatic rest (6),
inflammatory fibroid polyp (2), heman-
gioma (2), leiomyoma (1), calcified
fibrous nodule (1), lymphangioma (1),
and neurofibroma (1). The diagnostic
yield of forceps biopsy was 17%, where-
as the diagnostic yield of ESMR was 87%
(P=0.0001). Five procedure-related
complications occurred: two immediate
bleeds, treated by endoscopic techniques;
one delayed bleed, which resolved spon-
taneously; and two self-limited episodes
of abdominal pain.
Comment:
EUS alone is inadequate to distinguish
benign from malignant subepithelial
lesions. These results show that ESMR
has a significantly greater diagnostic
yield than does biopsy alone, without
significant morbidity. No patient in this
study had cancer, so we cant compare
ESMR to biopsy for distinguishing
malignant lesions. A trial in which ESMR
is compared with EUS-guided fine-
needle aspiration (FNA) and EUS-guided
core biopsy, methods that probably
are less risky than ESMR, would be
interesting. Stuart Sherman, MD
Cantor MJ et al. Yield of tissue sampling
for subepithelial lesions evaluated by EUS:
A comparison between forceps biopsies
and endoscopic submucosal resection.
Gastrointest Endosc 2006 Jul; 64:29-34.
Cholangioscopic
Assessment of Dominant
Strictures in Primary
Sclerosing Cholangitis
C holangiocarcinoma develops in as
many as 10% of patients with pri-
mary sclerosing cholangitis (PSC) and
imparts a poor prognosis. Early diagno-
sis of cholangiocarcinoma at a more
treatable stage is difficult. German re-
searchers prospectively compared the
value of endoscopic retrograde cholan-
giography (ERC) and cholangioscopy
for differentiating between benign and
malignant dominant bile duct strictures
in 53 PSC patients. The cholangiograms
obtained by ERC were classified as be-
nign, probably benign, probably malig-
nant, or malignant, based on stricture
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Can you answer the following
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JOURNAL WATCH
GERD Symptoms Linked to GASTROENTEROLOGY
Cardiac Dysrhythmias (on page 95)? Massachusetts Medical Society
Investigators assessed the relation between acid 860 Winter Street
reflux in the esophagus and neurocardiac function Waltham, MA 02451-1413
in patients with supraventricular arrhythmias and
evaluated the effect of acid suppression in these
patients. Which of the following statements best
describes their findings?:
A. Episodes of acid reflux and episodes of cardiac
dysrhythmia were significantly correlated.
B. After 3 months of treatment with proton-
pump inhibitors, most patients showed
significant reductions in cardiac symptoms.
C. In patients with increased esophageal acid
sensitivity, acid reflux triggers exaggerated
firing of the esophageal cardiac reflex.
D. All of the above are true.
*Category: JW Gastroenterology: GERD, Dyspepsia
Exam Title: JW Gastroenterology
Posted Date: Nov 7 2006

CME Faculty: Norton Greenberger, MD

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Page 100 JOURNAL WATCH GASTROENTEROLOGY Volume 7 Number 12

length and configuration. One week
later, patients underwent repeat ERC
with tissue sampling and cholangioscopy.
The videotaped cholangioscopic images
were reviewed by two experienced
endoscopists who were blinded to pre-
vious findings; strictures were classi-
fied as benign or malignant. A final
diagnosis of malignancy was based on
positive tissue sampling, whereas a
benign condition was assumed when
tissue sampling was negative and the
patient experienced an extended
uneventful follow-up (2 years).
Twelve patients (23%) had malignant
stenoses, and 41 (77%) had benign ste-
noses. Stenoses longer than 1 cm were
significantly more likely to be malignant
than benign; stenoses at the bifurcation
were significantly more likely to be ma-
lignant than were those at the common
bile duct. The sensitivities of cholan-
gioscopy and ERC for detecting malig-
nancy were similar (P=0.25). However,
cholangioscopy was significantly more
specific (93% vs. 51%, P<0.001) and ac-
curate (93% vs. 55%, P<0.001), and its
positive predictive value (79% vs. 29%,
P<0.001) and negative predictive value
(97% vs. 84%, P=0.025) were signifi-
cantly higher.
Comment:
The relatively poor sensitivity of identify-
ing biliary strictures via ERC highlights
the need for additional methods to distin-
guish benign from malignant stenoses.
The appearance of a stricture on ERC is
not very specific, and these researchers
used the strictures length and configura-
tion as the distinguishing features. Clear-
ly, the results of tissue sampling should
have been included in the ERC analysis,
as this test is performed routinely when
suspicious strictures are evaluated.
Although the cholangioscopic findings
were highly accurate, a tissue sample is
important for a definitive diagnosis and
treatment planning. As most cholangio-
scopes allow for visually directed tissue
sampling, this should be performed
during the investigation. That a higher
cholangioscopic false-positive rate wasnt
reported is surprising, because most
strictures required dilation prior to chol-
angioscopy, thus altering the appearance
of the biliary epithelium. Cholangios-
copy plus ERC has not gained wide-
spread acceptance, because it usually
requires two operators and is technically
challenging, and because the scopes are
fragile, with high repair costs. However,
development is underway on single-
operator, four-way tip-deflection scopes.
Stuart Sherman, MD
Tischendorf JJ et al. Cholangioscopic
characterization of dominant bile duct
stenoses in patients with primary sclerosing
cholangitis. Endoscopy 2006 Jul;
38:665-9.
Arvanitakis M and Deviere J. Primary
sclerosing cholangitis and recognition
of bile duct cancer: Problem solved?
Endoscopy 2006 Jul; 38:743-4.
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