Abnormal Intestinal Permeability in Subgroups of Diarrhea-...

[Guest guest]

Thanks for forwarding this study, ne!

Supports why MRT/LEAP works for D-IBS and PI-IBS, but is much less effective

for C-IBS. Also, interesting is the increase in atopy among D-IBS ---

We're anecdotally hearing from patients frequently that after avoiding their

LEAP reactive foods, that their " hay fever " subsides substantially or

completely.

I had one LEAP patient with a 12 year history of hay fever whenever the

orange trees bloomed (he'd moved to Florida). After eliminating his LEAP

reactive

foods, he had no allergy symptoms whatsoever when the orange trees bloomed

after that.

I also had one patient with a 30 year history of asthma. She called me

approx. 1 1/2 years after her MRT testing/LEAP diet and reported that " my

pulmonologist fired me today! " Said her asthma was 100% gone except if she

caught a

bad cold or flu.

Jan Patenaude, RD

Director of Medical Nutrition

Signet Diagnostic Corp

In a message dated 6/20/2006 11:38:19 A.M. Mountain Daylight Time,

fivestar@... writes:

Colleagues, the following is FYI and does not necessarily reflect my own

opinion. I have no further knowledge of the topic. If you do not wish to

receive these posts, set your email filter to filter out any messages

coming from @nutritionucanlivewith.com and the program will remove

anything coming from me.

---------------------------------------------------------

NOTE: To view the article with Web enhancements, go to:

http://www.medscape.com/viewarticle/535694

Abnormal Intestinal Permeability in Subgroups of Diarrhea-Predominant

Irritable Bowel Syndromes

Simon P. Dunlop, M.D.; Hebden, M.D.; Eugene , M.B.; n

Naesdal, M.D.; Lars Olbe, M.D.; Alan C. Perkins, Ph.D.; Robin C.

Spiller, M.D.

Am J Gastroenterol. 2006;101(6):1288-1294. ©2006 Blackwell Publishing

Posted 06/15/2006

Abstract and Introduction

Abstract

Objectives: Irritable bowel syndrome (IBS) is a heterogeneous condition

and defined according to symptoms. Low-grade inflammation has been

associated with IBS, particularly that following infection, but whether

altered intestinal permeability profiles relate to irritable bowel

subtype or onset is uncertain. Our aim was to compare small and large

intestinal permeability in various subtypes of IBS to healthy controls.

Methods: Intestinal permeability was measured using 1.8 MBq of 51Cr-EDTA

and collecting urine over 24 h; Study 1: patients with

diarrhea-predominant postinfectious IBS (N = 15),

constipation-predominant IBS (N = 15), and healthy controls (N = 15);

Study 2: two groups of diarrhea-predominant IBS (D-IBS), one with a

history of onset after acute gastroenteritis (postinfectious) (N = 15)

and the other without such a history (nonpostinfectious) (N = 15) both

compared with healthy controls (N = 12).

Results: Permeability expressed as percentage of total dose excreted in

urine (median [inter-quartile range]). Study 1: Proximal small

intestinal permeability was increased in postinfectious IBS (0.19

[0.12-0.23]) in contrast to constipated IBS (0.085 [0.043-0.13]) and

controls (0.07 [0.035-0.19]) (p = 0.02). IBS patients with eczema,

asthma, or hay fever had increased proximal small intestinal

permeability compared with IBS patients without atopy (p = 0.02). Study

2: Small intestinal permeability was greater in nonpostinfectious

diarrhea-predominant IBS (0.84 [0.69-1.49]) compared with postinfectious

IBS (0.43 [0.29-0.63], p = 0.028) or controls (0.27 [0.2-0.39]), p = 0.001).

Conclusions: Small intestinal permeability is frequently abnormal in

diarrhea-predominant IBS. Those without a history of infectious onset

appear to have a more severe defect.

Introduction

Irritable bowel syndrome (IBS) is common, yet the mechanisms by which

symptoms arise are poorly understood. IBS is associated with

psychological disturbance,[1] food intolerance,[2,3] and prior

gastroenteritis.[4] Although normal by conventional criteria, colonic

biopsies from patients with IBS demonstrate evidence of increased

numbers of chronic inflammatory cells[5-9] and of immune activation.[10]

This suggests that at least in some IBS patients, low-grade inflammation

may be an important mechanism by which symptoms are generated.[11] We

have recently shown that postinfectious irritable bowel syndrome

(PI-IBS) is associated with increased numbers of mucosal

5-hydroxytryptamine-containing enterochromaffin (EC) cells, increased

mucosal lymphocytes, and less psychiatric illness than irritable bowel

patients without an infectious onset.[12] While inflammatory conditions

such as acute gastroenteritis,[13,14] celiac disease,[15] and Crohn's

disease[16] increase gut permeability, whether particular subtypes of

IBS are also associated with altered gut permeability is not well

established. Previous studies of gut permeability in IBS by other

authors have either assessed only the small bowel with dual sugar

probes,[17,18] or used poorly defined groups[19-21] prior to consensus

classification.[22,23] Our preliminary study[9] using the

lactulose/mannitol urinary excretion ratio showed increased small bowel

permeability in PI-IBS (who mostly had diarrhea-predominant IBS [D-IBS])

but did not assess colonic permeability. Furthermore, we could not

determine the specificity of this finding because we did not study IBS

patients either with diarrhea not because of prior infection or without

diarrhea. Our underlying hypothesis was that the increased permeability

was because of low-grade inflammation, which we have reported in mucosal

biopsies in both PI-IBS and D-IBS but not constipation-predominant IBS

(C-IBS).[24] We, therefore, undertook two separate studies with

different cohorts of patients and healthy controls. The aim of Study 1

was to compare proximal and distal small bowel and large bowel

permeability in PI-IBS to healthy controls and C-IBS patients. In Study

2 we determined whether the increased permeability in PI-IBS was

specific to this condition or found in all types of D-IBS.

Materials and Methods

Subjects

Patients who met the Rome II criteria for IBS[23] and who had completed

a full negative evaluation for other diseases in the University

Hospital, Nottingham gastroenterology outpatient clinic were included.

The evaluation included a detailed history, examination, sigmoidoscopy

and biopsy, full blood count, hematinics, electrolytes, antiendomysial

antibody, thyroid function, calcium, liver function tests, and where

relevant colonoscopy, barium follow through, SeHCAT scanning, and

duodenal biopsy. Patients with a positive lactose tolerance test whose

symptoms responded to a lactose-free diet were excluded. All healthy

controls were without gastrointestinal symptoms or disease and were

recruited through advertisements placed around the University Hospital.

The studies were approved by the Nottingham Research Ethics and the

University of Nottingham Medical School Ethics Committees. All subjects

gave written informed consent.

Study 1

Thirty patients with IBS were included. Fifteen patients with

postinfectious D-IBS, 15 with C-IBS, and 15 healthy controls completed

symptom questionnaires and underwent a general examination including

sigmoidoscopy without bowel preparation. Rectal biopsies were obtained

using endoscopic biopsy forceps (FB-13K-1, Olympus, Japan) and were

fixed, orientated, and immunostained for 5-hydroxytryptamine (5-HT)

containing EC cells as previously described.[25] Blood was taken for

full blood count, hematinics, thyroid function, liver function, calcium,

C-reactive protein, and antiendomysial antibody at the screening visit

if not done within 3 months. Subjects completed questionnaires for

gastrointestinal symptom rating score (GSRS)[26,27] IBS-quality of life

(IBS-QOL),[28] modified Talley bowel symptom,[29] and Hospital Anxiety

and Depression[30] on the study day, the time frame being " in the last

one week. " The GSRS questionnaire uses a Likert scale to produce

summated scores for abdominal pain syndrome (maximum 21), reflux

syndrome,[4] indigestion syndrome,[8] diarrhea syndrome,[1] and

constipation syndrome.[1] The IBS-QOL questionnaire also uses a summated

score for bowel symptoms (maximum 84), fatigue,[1] limitations of

activity,[8] and emotional function.[9] Higher scores indicate

increasing or more disabling symptoms. The ranges for scores on the

Hospital Anxiety and Depression scale are normal,[0-7] mild,[8-10]

moderate,[11-14] or severe.[4-21] Subjects were also asked if they had

ever been diagnosed with eczema, hay fever, or asthma in the past.

After an overnight fast, subjects emptied their bladders and consumed

1.8 MBq of 100 μL of 51chromium labelled

ethylene-diamine-tetra-acetate,51Cr-EDTA), (Amersham International,

Amersham, U.K.) in 100 mL of water followed by 200 mL (300 kcal) of a

nutritional supplement (Fortisip, Nutricia Ltd, Wiltshire U.K.).[31] The

composition of the test meal was protein 12 g, carbohydrate 36.8 g, and

fat 11.6 g. Eating or drinking was not allowed for the next 3 h. Food

was permissible after 5 h. Subjects collected their urine in three

containers with 0.5 mL 20% chlorhexidine for time periods 0-3, 3-5, and

5-24 h. The time periods were chosen to relate to permeability within

the proximal small intestine, distal small intestine, and large

intestine.[15,16,32] The collection times differ slightly from our

standard clinical test, which specifies collection from 0 to 6 h and 6

to 24 h because we felt that the 0 to 6 h will represent a component

because of proximal colonic permeability in many patients. Alcohol and

nonsteroidal antiinflammatory drugs were prohibited 1 wk prior to and

during the test. No subjects were taking cromoglycate, opiates, or

anticholinergic drugs likely to alter transit. Volumes of urine were

recorded and 1 mL aliquots were counted for radioactivity by a

γ-scintillation counter in triplicate (LKB Wallac 1282 compugamma

universal gamma counter, VA). Results were expressed as the percent

urinary excretion of the orally administered dose of 51Cr-EDTA. There

was negligible background radiation, as measured by radiation in the

absence of 51Cr-EDTA.

We also measured intestinal transit by using a modified technique by

Metcalf et al..[33] Two gelatin capsules, each enclosing 10 plastic

marker pellets coated with barium were taken at 8 a.m. for 3 days prior

to a plain abdominal X-ray taken at 9 a.m. on day 4 when gut

permeability was measured. Colonic transit in hours was estimated by

multiplying the number of visible markers on the X-ray by 1.2. Subjects

then consumed a standard test meal as part of another study to assess

5-HT release.[34]

Levels of fecal calprotectin were measured from a single stool sample,

which was frozen at −20° C until analysis. After thawing, mechanical

homogenization and centrifugation, the supernatant was quantified for

calprotectin, using ELISA with the Calprest kit (Eurospital SpA,

Trieste, Italy) as previously described.[35]

Study 2

To determine whether a postinfectious origin was important, we recruited

a further 30 patients attending our outpatients with symptoms of D-IBS.

Fifteen patients developed symptoms acutely after an episode of

gastroenteritis (postinfectious IBS, PI-IBS) while the onset of symptoms

in the other 15 patients was gradual and did not follow gastroenteritis

(nonpostinfectious IBS, nonPI-IBS). We also recruited a new cohort of 12

healthy controls (control group).

After the same dosing schedule in Study 1, urine was collected in two

containers with 0.5 mL 20% chlorhexidine for time periods 0-6 and 6-24

h.[31,36] These time periods have been our standard for many years and

were intended to separate small from large intestinal permeability,

though as we indicate above some of the isotope excreted in the urine

toward the end of the 0-6-h period may represent absorption from the

proximal colon.

Statistical Analysis

Parametric data are shown as mean (standard deviation) while

nonparametric data are reported as median (interquartile range).

Parametric data were analyzed by ANOVA and subsequently by t-tests.

Nonparametric data were analyzed by Kruskal-Wallis and Mann-Whitney

tests. Spearman's coefficient was used for correlation between

nonparametric data.

Results

Study 1

The age range was from 18 to 59 yr. The mean age ± SD was 38.5 ± 10.1 yr

in PI-IBS, 35.1 ± 11.2 yr in C-IBS, and 35.9 ± 10 in the control group

(p = 0.7). The proportion of women within each group was 47% in PI-IBS,

100% in C-IBS, and 67% in the controls with significant excess in C-IBS

(p = 0.006). Scores for gastrointestinal symptoms and psychological

distress were increased in the irritable bowel groups compared with the

controls as expected ( Table 1 ).

There was considerable variability of colonic transit, which ranged from

4.8 to 76.8 hr. Mean colonic transit was 49.4 ± 14.7 h in C-IBS, which

was significantly delayed compared with 26.7 ± 16.7 h in PI-IBS (p =

0.001) and 34.1 ± 16.8 in the controls (p = 0.014). However, there was

no significant acceleration of colonic transit in PI-IBS compared with

controls (p = 0.3).

One control was excluded from the analysis because the distal small

bowel permeability was more than 3.5 standard deviations from the

control group mean and he was suspected of not meeting the agreed

inclusion criteria. Proximal small bowel permeability was increased in

PI-IBS compared with controls (p = 0.037) and c-IBS (p = 0.004) ( Table

2 ). However, permeability was similar among the three groups for the

time periods relating to distal small bowel and large bowel. After

correction for multiple comparisons, there were no significant

correlations between permeability in any of the three time periods and

symptom scores for abdominal pain syndrome, constipation syndrome, or

diarrhea syndrome derived from the GSRS questionnaire, or bowel

symptoms, fatigue, activity limitation, or emotional function derived

from the IBS-QOL questionnaire. Permeability did not correlate with

bowel frequency per week for time periods 0-3 h (r = 0.257, p = 0.13),

3-5 h (r = 0.165, p = 0.3), or 5-24 h (r = −0.271, p = 0.075). There was

no correlation between intestinal permeability and colonic transit.

There was no correlation between the length of time since the original

infectious illness and permeability in the PI-IBS group.

All biopsies were normal by conventional criteria.[37] The number of EC

cells per high-powered view was 37.2 ± 14.6 in PI-IBS, 28.5 ± 9.9 in

C-IBS, and 28.8 ± 7.9 in controls (p = 0.095). There was no correlation

between the number of EC cells and small intestinal or colonic permeability.

Fecal calprotectin levels were not significantly different among PI-IBS

(35.7 ± 46.5), C-IBS (22.8 mg/L ± 27.9), or controls (30.82 ± 23.3) (p =

0.6). There was no correlation between calprotectin levels and permeability.

It has been suggested that food allergy might account for symptoms in

some IBS patients. There were 13 of 30 IBS patients who reported food

intolerance but there were no differences in permeability within the

proximal small intestine (p = 0.9), distal small intestine (p = 0.25),

or large intestine (p = 0.5) compared with those IBS patients without

food intolerance. However, in 13 of 30 IBS patients with a diagnosis of

atopy (asthma, eczema, or hay fever, PI-IBS N = 9 of 15, C-IBS N = 4 of

15) proximal small intestine permeability was increased at 0.19

(0.12-0.22) compared with those IBS patients without atopy, 0.08

(0.05-0.17) (p = 0.021). No differences in atopy status of the IBS

patients was seen in distal small intestine permeability (p = 0.5) or

large intestine permeability (p = 0.11).

Study 2

The age range was 17-63 yr. The mean age ± SD was 36.6 ± 13.9 yr in

PI-IBS, 39.5 ± 10.4 yr in nonPI-IBS, and 35.3 ± 5.9 yr in the control

group (p = 0.9). The proportion of women within each group was 47% in

PI-IBS, 45% in nonPI-IBS, and 50% in the controls (p = 0.9). Small

intestinal permeability was increased in PI-IBS (p = 0.028) and

nonPI-IBS (p = 0.001) compared with healthy controls ( Table 3 ) (Fig.

1). The increase in small bowel permeability was greater in nonPI-IBS

compared with PI-IBS (p = 0.004). For large bowel permeability, there

was no difference between PI-IBS and controls (p = 0.5). However, in

nonPI-IBS large bowel permeability differed significantly from controls

(p = 0.04) ( Table 3 ).

Figure 1.

Small (0–6 h) and large (6–24 h) bowel permeability in

nonpostinfectious IBS, postinfectious IBS, and controls. Median

indicated (IQR). Outliers shown as circle.

Discussion

We have shown that intestinal permeability profiles differ among IBS

subtypes with increased small bowel permeability both in PI-IBS and

D-IBS without an infectious onset when compared with both controls and

C-IBS. There is increasing evidence that some forms of IBS are

associated with low-grade inflammation of the intestine.[11,38] The site

of inflammation has been proposed as in the mucosa,[5-8] the

muscularis,[39] or the enteric nerves.[40,41] Although normal by

conventional criteria, we have previously described the quantitative

differences between 5-HT containing EC cells, T lymphocytes, and mast

cells in mucosal biopsies from patients with different subtypes of

IBS.[24] In that study PI-IBS was associated with increased EC cells and

lamina propria T lymphocytes, whereas diarrhea-predominant IBS without

an infectious onset was associated with increased lamina propria mast

cells and T lymphocytes. Our current study is therefore of particular

interest, as it too demonstrates differences among postinfectious IBS,

nonpostinfectious IBS, and controls, this time in terms of intestinal

permeability profile. The 3 and 5 h cutoffs in Study 1 were deliberately

chosen to ensure that we only assessed small bowel permeability, since

our own work[42] and others suggest a shorter small bowel transit in

D-IBS. This showed that the changes in PI-IBS are greatest proximally.

The standard 6 h cutoff currently used in our routine outpatient tests

and hence in Study 2 probably also assesses proximal colon

permeability,[43] but because this was not different between the study

groups we do not feel that this alters our conclusions that the main

abnormality is in the small bowel. The increase in isotope absorption

0-3 h may reflect in part the accelerated transit described by Gwee et

al.,[7] which would result in greater exposure of the small intestine to

the isotope. This idea that the main abnormality is in the small bowel

is compatible with our recent work showing increased 5-HT release in the

0-4 h postprandial period in PI-IBS,[44] which is likely to come from

the small intestine pointing to abnormalities in the small intestine as

well as the previously demonstrated abnormalities of rectal

histology.[45] Recently, the results of a study of 2,300 individuals

with acute food poisoning because of Escherichia coli O147 and

Campylobacter jejuni in ton, Ontario have also showed increased

small bowel permeability in those developing PI-IBS.[46]

Surprisingly we found the most severe defect in small bowel permeability

in nonpostinfectious IBS in which 5-HT probably plays a lesser role. An

alternative cause of abnormal permeability may be mast cell products

such as prostaglandins, substance P, and histamine. Mast cells are key

players in maintaining intestinal epithelial integrity as demonstrated

by animal models of immediate hypersensitivity[47,48] and Clostridium

difficile infection[49] in addition to the inflamed human colon[50] and

are closely related to nerve endings.[51] Increased mast cells have been

reported by others in the terminal ileum[6] and colon[8] in IBS but

whether there are also increased mast cells in the proximal small bowel

to account for our findings remains to be determined. Our previous study

showed increased mucosal mast cells in nonpostinfectious IBS[24] but

whether mast cells are increased in the small bowel in this IBS subtype

is unknown. Chronic stress in rodent models causes increased

permeability of the jejunum[52] and colon[53] in a mast cell-dependent

manner. Stress is known to increase release of mast cell products from

the healthy jejunum and much evidence suggests that stress acts via

corticotrophin releasing factor (CRF). Recent studies using CRF infusion

have demonstrated that this stimulates jejunal mast cells to release

mediators and increase permeability, an effect that is even more marked

in IBS patients.[54]

We found increased small bowel permeability in PI-IBS in Study 1 and

Study 2, as has a previous study.[9] Acute gastroenteritis causes

increased small bowel permeability,[13,14] which may persist in those

subsequently developing IBS.[9] The mechanism of increased small bowel

permeability in PI-IBS is unknown but it may be different to that in

nonpostinfectious diarrhea-predominant IBS. Firstly, mast cells have not

been shown to be elevated in PI-IBS[9,12,45] and furthermore, we found

the defect in small bowel permeability to be less severe than nonPI-IBS.

However, even if we speculate that increased or activated mast cells

cause abnormal small bowel permeability in nonPI-IBS, but not in PI-IBS,

this does not explain the increased proximal small bowel permeability in

PI-IBS, unless atopy was a confounding variable. Our study size was not

powered to compare permeability in atopic and nonatopic patients with

PI-IBS but this could be the subject of further study in terms of biopsy

and inflammatory cell quantification. Our study suggests that raised

numbers of EC cells in the large bowel do not alter its permeability.

A previous diagnosis of eczema, hay fever, or asthma was more common in

IBS patients in our study. While this may be a true phenomenon, it may

also be a consequence of hypervigilance, a common feature in functional

bowel disorders. Although not part of the original protocol, after our

analysis suggested the possible role of atopy, we went back to the

clinical notes to see if atopy played a role in Study 2. Notes were

reviewed for a history of eczema, asthma, or hay fever. There was a

single patient documented to have atopic symptoms in the PI-IBS group,

but four patients with atopy in the nonPI-IBS group. None of the healthy

controls in Study 2 had atopy. Small bowel permeability was not

significantly increased in IBS patients with atopy (0.76 [0.35-1.26], N

= 5) compared with IBS patients without atopy (0.63 [0.36-0.93], N = 25,

p = 0.7). In Study 1 we looked at the issue of atopy in healthy controls

but in fact bowel permeability was very low, not increased, in the two

controls with a previous diagnosis of atopy. Our post hoc analysis in

Study 1 showing that IBS patients with atopy appeared to have higher

permeability needs to be treated with caution as it was not the initial

aim of the study. Two of our healthy controls had a previous diagnosis

of hay fever and one of childhood asthma. If we exclude these

individuals, then the control value for proximal small bowel

permeability becomes 0.11 (0.04-0.28), difference between controls (N =

12) and atopic IBS (N = 13) p = 0.3. This suggests that our study is

underpowered to analyze these sub-groups and larger numbers are needed.

We found small and large bowel permeability in constipated IBS to be the

same as healthy controls. This is in keeping with our previous study,

which showed no increase in EC cells, mast cells, or T lymphocytes in

constipated IBS compared with healthy controls.[24]

The limitations to our study relate to the technique of gut permeability

testing using 51Cr-EDTA and patient recall regarding the onset of

symptoms. The normal range of intestinal permeability using 51Cr-EDTA

has been reported as showing significant variation in asymptomatic

controls.[19] This is in part related to geographical location of

different studies, as controls may suffer subclinical episodes of

enteric infection causing a wide range of intestinal permeability.[55]

In our current studies, all subjects were Caucasian who had been

resident in the U.K. life-long. In terms of classification, inevitably

some patients will not remember clearly whether their IBS symptoms

followed an infective episode or not. However, for this study, we were

able to categorize patients into PI-IBS or nonPI-IBS as far as we can be

certain in accordance with previous criteria.[12] Intestinal

permeability testing is not suitable for investigating patients with IBS

routinely because a variety of inflammatory conditions and drugs cause

altered gut permeability.

Despite these limitations, our current studies suggest that gut

permeability profiles relate to subtypes of IBS and onset of symptoms.

This is consistent with previous observations, which suggest low-grade

inflammation in diarrhea-predominant IBS but not in constipated IBS.

Although a standard course of oral prednisolone does not improve

symptoms of PI-IBS in the short or long term,[25] other targeted

therapies according to IBS subtype appear justified.

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Table 1. Symptom Scores Derived From HAD, GSRS, and IBS-QOL

Questionnaires and Proportion of Patients With Atopy in PostInfectious

IBS, Constipated IBS, and Healthy Controls

Table 1: Symptom Scores Derived From HAD, GSRS, and IBS-QOL

Questionnaires and Proportion of Patients With Atopy in PostInfectious

IBS, Constipated IBS, and Healthy Controls

Table 2. Proximal and Distal Small Bowel and Large Bowel Permeability in

Postinfectious IBS, Constipation-Predominant IBS, and Healthy Controls

Table 2: Proximal and Distal Small Bowel and Large Bowel

Permeability in Postinfectious IBS, Constipation-Predominant IBS, and

Healthy Controls

Table 3. Small and Large Bowel Permeability in Diarrhea-Predominant IBS

With and Without a History of Gastroenteritis (Postinfectious, PI-IBS

and Nonpostinfectious IBS, NonPI-IBS) Compared With Healthy Controls

Table 3: Small and Large Bowel Permeability in Diarrhea-Predominant

IBS With and Without a History of Gastroenteritis (Postinfectious,

PI-IBS and Nonpostinfectious IBS, NonPI-IBS) Compared With Healthy Controls

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Sidebar: Study Highlights

What is Current Knowledge

* Although symptoms of reflux are common, our knowledge of the

epidemiology and natural history of gastro-esophageal reflux disease is

sparse.

What is New Here

* The study adds population based epidemiological data of

esophagitis diagnosed in the period from 1983 to 2002 in a Danish County.

* Incidence of diagnosed esophagitis is increasing by calendar year

and age, is higher among males than among females, and is closely

related to the rate of endoscopy.

* Risk of esophageal adenocarcinoma is increased by a factor five

in all patients with previous diagnosed esophagitis, but most of these

cancers are related to the presence of Barrett esophagus.

Reprint Address

Robin Spiller, M.D., Division of Gastroenterology, University Hospital,

Nottingham, NG7 2UH

Simon P. Dunlop, M.D., Hebden, M.D., Eugene , M.B., n

Naesdal, M.D., Lars Olbe, M.D., Alan C. Perkins, Ph.D., and Robin C.

Spiller, M.D., Wolfson Digestive Diseases Centre and Division of Medical

Physics, University Hospital, Nottingham, United Kingdom

Disclosure: The authors declared no conflicts of interest.

--

Jan Patenaude, RD

Director of Medical Nutrition

Signet Diagnostic Corporation

_www.nowleap.com_ (http://www.nowleap.com/)

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