J Clin Pathol 1993;46:235-240

Bile reflux and intestinal metaplasia in gastricmucosa

G M Sobala, H J O'Connor, E P Dewar, R F G King, A T R Axon, M F Dixon

AbstractAim: To determine associations betweenenterogastric bile reflux and gastricmucosal pathology.Method: A retrospective study using fast-ing gastric juice bile acid measurementsand antral or prestomal biopsy speci-mens from 350 patients, 66 of whom hadpreviously undergone surgery that eitherbypassed or disrupted the pyloric sphinc-ter.Results: Bile reflux was positively associ-ated with reactive gastritis and negative-ly with Helicobacter pylon density. Afterstratification for previous surgery, age,and H pylon status, the histological fea-ture most strongly associated with bilereflux was intestinal metaplasia, includ-ing all its subtypes. The prevalence ofintestinal metaplasia was greatest inpatients with both H pylori infection andhigh bile acid concentrations. Bile refluxwas also positively associated with theseverity of glandular atrophy, chronicinflammation, lamina propria oedemaand foveolar hyperplasia.Conclusions: Bile reflux is a cause ofreactive gastritis. It modifies the featuresof H pylon associated chronic gastritis.The changes are not confined to patientswho have had surgery to their stomachs.The positive associations with atrophyand intestinal metaplasia have implica-tions for models of gastric carcinogene-sis.

C Clin Pathol 1993;46:235-240)

These data were presentedin part at the SpringMeeting of the BritishSociety of Gastroenterology,1991 and were thenpublished in brief abstractform in Gut.

Centre for DigestiveDiseases, The GeneralInfirmary, Leeds,West Yorkshire, LS13EXG M SobalaH J O'ConnorE P DewarR F G KingA T R AxonM F DixonCorrespondence to:Dr G M SobalaAccepted for publication2 September 1992

Enterogastric reflux of bile has long been sus-

pected to affect the gastric mucosa, but mosthistological studies of this topic have beenperformed before the discovery of Helicobacterpyloni and its major role in the aetiology ofchronic gastritis. Few clear conclusions havetherefore been drawn, although we previouslyreported an association between bile refluxand a distinctive reflux (now "reactive") gas-tritis,' and associations between bile refluxand intestinal metaplasia have also beennoted.2- Furthermore, bile reflux has usuallybeen sought only in the context of the stom-ach after surgery, and has largely beenneglected as a factor in non-surgical patients.The aim of this study was therefore to

determine the role of bile reflux in the causa-

tion of gastric mucosal pathology, specificallycontrolling for the presence of H pylon, in

patients both with and without previous gas-tric surgery. A large study population wasrequired to disentangle the effects of bilereflux from those of H pyloni infection. Weachieved this by performing a meta analysison gastric biopsy results and gastric juice bileacid measurements obtained during thecourse of our studies over the past 10 years.In particular, we sought to examine moreclosely the association we have previouslyreported between bile reflux and reflux orreactive gastritis, to report on the relativeimportance of the individual components ofthe histological reflux score we have previous-ly proposed,' and to confirm and furtherexplore the association between bile refluxand intestinal metaplasia. We also attemptedto derive a histological index predicting thepresence of abnormal bile reflux.

MethodsBiopsy and gastric juice bile acid results wereavailable from 350 patients who had partici-pated in five published studies.'45-7 The 168patients in the first three studies had beenselected for their known pathology or previ-ous gastric surgery; 60 of these had alsoundergone surgery that had destroyed orbypassed the pylorus. The fourth study com-prised 135 consecutive patients attending anopen access endoscopy clinic, excluding thosewith neoplastic disease. The 47 patients inthe last study were attending diagnosticendoscopy lists and were selected on criteriaof convenience of the timing of sample collec-tion and of absence of previous gastricsurgery. All patients had at least two biopsyspecimens taken from the antrum, or in the35 with Billroth gastrectomies, from the rem-nant of stomach within 5 cm of the stoma.

All patients gave informed consent. Thestudies were individually approved by thelocal research ethics committee.

Gastric juice was aspirated through a naso-gastric tube in the first two studies, and at thetime of endoscopy in the latter three. Bileacid concentration was then determined bythe steroid dehydrogenase method8 in thesame laboratory throughout.The biopsy specimens were fixed in 10%

formalin. After routine processing sectionswere taken at three levels and stained withhaematoxylin and eosin. Additional sectionswere stained with alcian blue (pH 2 5) andperiodic acid Schiff (AB/PAS) for neutral andacidic mucosubstances and by the modifiedGiemsa method9 for H pylori. If intestinal

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metaplasia was detected in the alcianblue/PAS stained section, new sections werecut and stained with the high irondiamine/alcian blue technique to demonstratesulphomucins.'0The sections were examined by one pathol-

ogist (MFD) who was unaware of the bileacid results and clinical condition. The fol-lowing eight features were noted and graded:chronic inflammatory cell infiltration; poly-morphonuclear activity (degree of neutrophilpolymorph infiltration); glandular atrophy;intestinal metaplasia; foveolar hyperplasia;oedema of the lamina propria; vasodilatationor congestion; and density of H pylori coloni-sation. Each feature was given a numericalscore 0-3 equivalent to absent (or normal),mild, moderate and severe. The first four fea-tures and H pylori density were graded in amanner analogous to that recommendedrecently in the Sydney system for the classifi-cation of gastritis." The other features weregraded so that a "reflux score" could be cal-culated. The score represents the sum of thegrades for foveolar hyperplasia, lamina pro-pria oedema, and vasodilatation or conges-

tion, less the grades for chronic inflammationand activity' plus 6. Thus the minimum scoreis 0 and the maximum is 15. In the past wehave taken scores greater than 10 to beindicative of reflux (reactive) gastritis.Where intestinal metaplasia was found in

the stained sections, the various subtypes'2were sought by using the high irondiaminobenzidine/alcian blue sections, andthe extent of each subtype (I, II, or III) wasalso graded on a four point scale.The bile acid results fell in a skewed distri-

bution and were therefore grouped intosix bands before analysis: 0 00-0-05 mmoIIl,0-06-0-20 mmol/l, 0-21-0-50 mmolIl, 0-51-1-00 mmol/l, 1-01-5'00 mmol/l, and > 5 00mmol/l. Associations between bile acid con-centrations and the histological scores forchronic inflammation, activity, atrophy,intestinal metaplasia, foveolar hyperplasia,lamina propria oedema and vascular conges-tion were sought using Cochran-Mantel-Haenszel x2 tests for non-zero correlation.The analyses were controlled by stratificationfor the possible confounding effects of previ-ous surgery bypassing or disrupting thepylorus, age, and the presence of H pylori.

Odds ratios and their 95% confidence inter-vals were calculated where appropriate.Differences in bile acids between differentdiagnostic groups were assessed by the non-parametric two-group Wilcoxon test.A new histological reflux index was con-

structed by stepwise logistic regression. Thedependent dichotomous variable was thepresence or absence of an abnormal gastricjuice bile acid concentration of > 1-00mmolIl. The independent variables were theeight graded histological features, includingHpylon density. The a values for variables toenter and remain in the analysis were set at0-05. The analysis was terminated when theresidual X2 test for variables not includedbecame non-significant.

Statistical analyses were performed usingthe SAS package v6 04 and EPI-INFO v5 0on an IBM compatible personal micro-computer.

ResultsThree hundred and fifty patients (212 men)were studied between 1979 and 1990. Themedian age was 49 years, range 18 to 88.The fasting gastric bile acid concentrations

in each diagnostic group are shown in table 1.Seven of 158 (4 4%) patients with normal

endoscopies had bile acid concentrationsgreater than 1 00 mmol/l, confirming that thisvalue can be considered the upper limit of thenornal range.

Concentrations were substantially higher inpatients who had undergone surgery thateither bypassed or disrupted the pyloricsphincter. Fifteen of the 43 patients with bileconcentrations above 1I00 mmolIl and 25 ofthe 30 patients with concentrations between0 50 and 1-00 mmol/l had not undergonesuch surgery.

HISTOLOGICAL FEATURESFiftytwo patients had normal gastric mucosa,of whom 3 9% had visible H pylon on histo-logical examination, 219 patients had chronicgastritis, (94 0% H pylon positive), and 79patients had reactive gastritis (16-5% Hpyloripositive).

Patients with H pylon were less likelyto have bile acid concentrations above100 mmol/l (26 of 129 (20 2%) Hpylon neg-

Table I Bile reflux v endoscopic diagnosis

Diagnosis n = Lower quartie Median Upper quartile p Value

Normal 158 0 00 0 00 0 10Duodenal ulcer 51 0 00 0 10 0 30 nsGastric ulcer 41 0 00 0-00 0-30 nsDuodenal andgastric ulcer 11 0 00 0 00 0 30 nsPernicious anaemia 6 0 00 0-05 1 10 nsHighly selectivevagotomy 23 0 00 0 00 0 10 nsVagotomy andpyloroplasty 12 0 00 0-20 0 95 0 07Vagotomy andgastrojejunostomy 13 0 30 0 50 3 70 < 0 0001Billroth I 19 0 00 0 40 2-70 < 0 001Billroth II 16 1 00 2-90 9-85 < 0 0001

Fasting gastric juice bile acid concentrations (medians and interquartile range; mmol/l) in the 10 different diagnostic groups; pvalues indicate whether results differ significantly from nonnal group, two tailed Wilcoxon test.

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Bile reflux and intestinal metaplasia in gastric mucosa

Table 2 Bile reflux: associations with histologicalfeatures

Mantel-HaenszelHistological X2 Direction offeature statistic (df = 1) p Value Association

Chronic inflammation 4 03 p < 0-05 PositivePolymorphonuclear activity 2-24 NSGlandular atrophy 8-24 p < 0 01 PositiveIntestinal metaplasia 17-29 p < 0 001 PositiveFoveolar hyperplasia 4 56 p < 0 05 PositiveLamina propria oedema 7-78 p < 0 01 PositiveVascular congestion 0 73 NS

Cochran-Mantel-Haenszel statistics for non-zero correlations between four-point histologicalscores and bile acid concentrations, analyses stratified for presence of previous surgery bypass-ing or disrupting the pyloric sphincter, age and H pylori status.

ative v 17 of 221 (7 7%) H pylon positive; p <0.001 x2).

In patients with H pylon infection, therewas a negative association between the histo-logical density of infection and bile acid con-centrations (Cochran-Mantel-Haenszel testfor non-zero correlation, stratified for previ-ous surgery and age; x2 = 5-45; p < 0 05).

Associations between the seven graded his-tological features and bile acid concentra-tions, stratified for previous surgery, age, andH pylon status, are shown in table 2. Therewere significant positive associations with thedegrees of foveolar hyperplasia, chronicinflammation, lamina propria oedema andglandular atrophy, and a highly significantpositive association with the degree of intesti-nal metaplasia.

INTESTINAL METAPLASIASixtythree of the 82 patients with intestinalmetaplasia had chronic gastritis and the rest

Table 3 Bile reflux v intestinal metaplasia and reactive gastritis

(a) % Prevalence ofBile acid intestinal metaplasiaconcentrations (b) Odds ratio (95% CI)(mmolll) n = Focal Moderate Extensive for reactive gastritis

0-00-0 05 181 13-8 3-3 1.1 1 00 (baseline)0-06-0-20 58 12-1 8-6 1-7 0-96 (0-42-2-19)0-21-0-50 38 13 2 2-6 0.0 2-04 (0 89-4 67)0-51-1-00 30 23-3 6-7 3-3 0-78 (0-25-2 47)1-01-5 00 26 30-8 11-5 3-8 4-36 (1-53-12-41)> 5-01 17 23-5 11-8 11-8 13-19 (3 70-47 08)

(a) Percentage prevalences of each grade of intestinal metaplasia (focal, moderate, extensive)according to bile acid concentration.(b) Mantel-Haenszel odds ratios and 95% confidence limits for the presence of reactive gastritisaccording to bile acid concentration, stratified for previous surgery bypassing or disrupting thepylorus. y2 for trend = 16-0; p < 0 001.

Table 4 Intestinal metaplasia, H pylori, and bile reflux

% Prevalence intestinal metaplasiaH pylori Bile refluxpresent? > I mmolNl? n = Focal Moderate Extensive

No No 103 5-8 1-9 1-9Yes No 204 18-6 5-9 1-0No Yes 26 30-8 3-9 7-7Yes Yes 17 23-5 23-5 5-9

Prevalence of each grade of intestinal metaplasia (focal, moderate, extensive) according to pres-ence ofH pyloni and of abnormal bile reflux.

Table S Logistic regression: predictors of bile reflux

Vanable p Value Odds ratio (95% CI)

Lamina propria oedema p < 0 0001 4-03 (2-36-6-86)Hpylori density p < 00001 0-30 (0-17-0-53)Chronic inflammation p < 0 001 2-33 (1-44-3-76)Intestinal metaplasia p < 0-05 1-81 (1-14-2-88)

Results of stepwise logistic regression to predict a fasting gastric juice bile acid concentration of> 1 00 mmol/l. The odds ratios reflect the change in the likelihood of a high bile concentrationassociated with an single increment in the score of each histological variable.

had reactive gastritis. The relation betweenbile acid concentrations and intestinal meta-plasia is shown in table 3.The prevalence of intestinal metaplasia was

greatest in patients with both H pylori infec-tion and a bile concentration of > 100mmol/l (table 4).

Fifty patients had type I intestinal metapla-sia, 53 had type II, and five had type III: 24patients had more than one type. Focalintestinal metaplasia was usually of type IIwhile extensive intestinal metaplasia waslargely of type I. Each individual type ofintestinal metaplasia occurred more often inpatients with bile acid concentrations above100 mmol/l than in those with lower bile acidconcentrations (type I, odds ratio = 3-2, 95%confidence interval = 1-4-7-0, p < 0'01; typeII, odds ratio = 3-3 (1-5-7-2), p < 0 01; typeIII, odds ratio = 11 4 (1-3-139), p < 0 05).Extensive type I intestinal metaplasia in apatient with bile reflux but without previousgastric surgery is shown in fig 1.

BILE REFLUX AND REACTIVE GASTRITISReactive gastritis was diagnosed when thepreviously defined "reflux score" was greaterthan 10. Such a diagnosis was more likelywhen bile acid concentrations were high(table 3). The sensitivity of a diagnosis ofreactive gastritis for a gastric juice bile acidconcentration of > 1 00 mmol/l was 60%,and the specificity 83%.

NEW HISTOLOGICAL BILE REFLUX INDEXThe results of the logistic regression areshown in table 5. A new index predictive ofbile reflux was constructed from the regres-sion coefficients: (new index) = (7 x laminapropria oedema) + (3 x intestinal metapla-sia) + (4 x chronic inflammation) - (6 xH pylon). A cutoff above 14 gave the highestcombined sensitivity (70%) and specificity(85%) for bile reflux of > 1 00 mmoll.

DiscussionThe limitations of this study must be consid-ered before any conclusions are drawn. Therewere sampling problems. Although analysis ofbile acid concentration in fasting gastric juicecorrelates well with other objective tech-niques of determining bile reflux, a singlemeasurement does not indicate the durationand may misrepresent the degree of bilereflux experienced by an individual."3Histological changes are often patchy and twomucosal biopsy specimens are not always rep-resentative. Therefore such a study willunderestimate the strength of any true associ-ations between bile reflux and gastric mucosalhistology. Any apparent associations mayhave been due to exposure to substancesother than bile in the enterogastric refluxate.Finally, this study is not an independent con-firmation of our previously reported findingsas there was overlap of subjects. Nevertheless,the results are important as this series is muchlarger than any published before in this field,with greater statistical power. It is also the

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Figure 1 Type Iintestinal metaplasia in apatient with fasting bileacid concentration of1 92 mmolll and anunoperated stomach.

first to grade biopsy specimens in a manneranalogous to that of the new Sydney classifi-cation of gastritis," although the two corpusbiopsy specimens required for a full classifica-tion were not available.

Several studies have attempted to correlatebile reflux with chronic inflammatory infiltra-tion in the gastric mucosa, usually unsuccess-

fully.'4 1' It is now known that chronicgastritis is aetiologically linked to infectionwith H pylo' 16 and that the intensity ofinflammation is related to the histological

Figure 2 Antral biopsy specimen from a patient with an unoperated stomach and afasting bile acid concentration of 8-95 mmolll, showing intestinal metaplasia and moderatechronic inflammatory cell infiltration. Scanty Helicobacters were present. Diagnosed asreactive gastritis (reflux score = 11), this probably represents a transitional case.

density of infection.'7 18 This correlation isstrong. Previous studies have failed to take itinto account and any effect of bile will havebeen masked. Controlling for the presence ofH pyloni infection, we did find a weak correla-tion between bile reflux and the density of thechronic inflammatory infiltrate. We alsoobserved a negative association between bileand H pylon density and so we conclude thatscantiness of H pylon with severe chronicinflammation should alert the observer to thepossibility of bile reflux. The logistic regres-sion confirmed that chronic inflammationpositively, and density of H pylon infectionnegatively, predict raised gastric juice bileconcentrations. These findings lend somesupport to our previously stated hypothesisthat bile reflux causes a gradual elimination ofH pyloni and subsequent resolution of thechronic inflammatory response, ultimatelygiving rise to the distinctive reactive gastritispicture. This phenomenon has so far onlybeen observed in the stomach after surgery.'9During this process intermediate stages arerepresented by few or no Helicobacters withpersistent chronic inflammatory cell infiltra-tion (fig 2).We also found that many patients with

reactive gastritis had little or no demonstrablebile reflux. This highlights the likelihood thatother chemical irritants such as non-steroidalanti-inflammatory drugs and possibly alcoholcause the same histological picture.2"22 Wedid not have detailed drug or alcohol historyon sufficient patients to control for these fac-tors.

This study casts some doubts on the validi-ty of the construction of the original "refluxscore". No association was found betweenvascular congestion and bile reflux, and theassociation with chronic inflammation waspositive rather than negative. However, thenegative emphases given to activity andchronic inflammation in the original scoreusefully served to bias it against Hpyloni asso-ciated chronic gastritis: few patients withHelicobacter associated chronic gastritis alsohave reflux scores greater than 1O. Thus reac-tive gastritis, so defined, is a distinct histolog-ical entity ("foveolar hyperplasia, oedema andcongestion without cellular inflammation").The new index derived by logistic regres-

sion differs in concept from the original refluxscore. This is an attempt to predict the pres-ence of bile reflux, rather than to define anew histological entity. Lamina propria oede-ma, intestinal metaplasia, and a disparitybetween H pyloni density and the degree ofchronic inflammation were found indepen-dently to predict bile reflux.

Associations between bile reflux andintestinal metaplasia have been reportedbefore but usually only following gastricsurgery.2 3 23 We suggest that bile reflux isalso a factor in the production of intestinalmetaplasia in the unoperated stomach. Themechanism of this association is debatable.The currently dominant hypothesis is thatintestinal metaplasia is a precancerous condi-tion, occurring as a result of exposure to

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Bile reflux and intestinal metaplasia in gastric mucosa

Duodenogastricbile reflux

Mucosal injury,erosions

Regeneration

Intestinal metaplasia(chiefly focal, type 11)

Regression

Normal gastric Intestmucosa (extensii

mutagens in hypochlorhydric gastric juice.24 It 1 Dixon MF, CJohnston D.

can certainly be argued that mutagens could entity?ICGinbe contained in or formed from the entero- 2 Houghton PWgastric refluxate. However, we have previous- CooperMJaly failed to find raised nitrosocompound Surg 1986;73concentrations in association with intestinal relation of clmetaplasia or bile reflux.4 An alternative Chung-Hua A

hypothesis is that intestinal metaplasia arises 4 SoaelaiGM)Pifrom divergent differentiation in regenerating pounds and t

mucosal histiepithelium following erosion or ulceration. sis.C rcinogeThere is some evidence to support this view. 5 Dewar EP, Dix_v-r** r * s * * ~~~~~~~~~~~ofgastritis inBile in the presence of acid causes erosions in operation. I'

experimental animals,25 although this has not 6 Dewar EP, Dixbeen shown in humans. Intestinal metaplasia of gastritis aIseems to originate during the regenerative 743-5O.

S2S 7Sobala GM, I

process in the healing of gastric erosions,26 is of Helicoba4common in the regenerative epithelium of Gastroenterol.

anSsuly2e re8 Dewar EP, K<gastric ulcers,27 and usually regresses with lysolecithin c

time.28 When the injury is repetitive and on a with gastric i

background of H pylon associated chronicgastritis, however, we suggest that intestinal 1983;70:401-metaplasia becomes more extensive and per-

SF,manent. This hypothesis is summarised in fig 1986;39:127'

10 Cook HG. Cai3 and is consistent with the view that intesti- eds. Theory ai

nal metaplasia is a defence response aimed at Edinburgh, CII Misiewicz IJ, Tprotecting the gastric mucosa against repeat- system: a n

ed bile damage in the same way that gastric Gastroenterolwhen12 Filipe MI, Jassmetaplasia develops in the duodenum when 12 risk. In:

subjected to a high acid load,29 and gastric carcinoma.

type epithelium appears in the lower oesopha- 13 Houghton P'igus in response to acid reflux. This hypothe- Cooper MJ,

acids and sciisis of the genesis of intestinal metaplasia mnc reflux. Bdiffers from that proposed by Correa. It mer- 14 Bechi P, Amoritsfurtherstudy. Gastic histolits furtherstd.trectomy. Ga

Progression

tinal metaplasiave, types I or 111)

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Current problems in rumour pathology: gastricEdinburgh: Churchill Livingstone, 1986:

7J, Mortensen NJMcC, Thomas WEG,Morgan AP, Davies ER. Intragastric bileintigraphy in the assessment of duodenogas-trJ Surg 1986;73:292-4.rosi A, Mazzanti R, Romagnoli P, Tonelli L.logy and fasting bile reflux after partial gas-

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Figure 3 Diagramsummarising hypothesis ofthe causation of intestinalmetaplasia.

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