Gut 1995; 36: 198-202

Helicobacter pylori associated with a highprevalence of duodenal ulcer disease and a lowprevalence of gastric cancer in a developing nation

P J Hu, Y Y Li, M H Zhou, M H Chen, G G Du, B J Huang, H M Mitchell, S L Hazell

AbstractThis study examines the relationshipbetween Helicobacter pylori infection andpeptic ulcer disease and gastric cancer - inparticular, the presence or absence ofbac-teria, the grading of gastritis, and thedegree of inflammation in the antral andoxyntic mucosae. The grading of gastritisand the detection ofH pylon were deter-mined by histology using the Sydneysystem. Of the 1006 patients examined,34.5% had duodenal ulcer disease, 3.5%/ogastric ulcer disease, and 2% with coexis-tent ulceration. Most patients (50.2%) wereclassified as having non-ulcer dyspepsia.Altogether 2.40/o of patients had gastriccancer and two further patients hadcarcinoma in the gastric stump. Of theulcer disease patients, 87-2% had histologi-cal evidence of H pyloni infection. Afterpatients who had taken antibiotics or bis-muth compounds in the preceding fourweeks were excluded, 98.94%/o of the duo-denal ulcer disease, 100% of the gastriculcer disease, and 100%/ of the coexistentulcer disease patients had evidence ofH pyloni infection. In patients with gastriccancer who had not taken antimicrobialagents in the four weeks before endoscopy,83.3% had evidence ofH pylon infection.Thus, there was a high rate of duodenalulcer disease and a low rate of gastriculcer disease in southern China, an areaof low gastric cancer mortality. There wasa specific topographical relationshipbetween H pylon, the histologicalresponse, and gastroduodenal disease. Ourdata suggest that the status of a nation aseither 'developed' or 'developing' can notbe used to predict the upper gastrointesti-nal disease profile ofits population.(Gut 1995; 36: 198-202)

Keywords: Helicobacter pylon, peptic ulcer disease,gastric cancer.

In recent years we have investigated the rela-tionship between Helicobacter pylori infectionand upper gastrointestinal disease in thePeople's Republic of China. In previousreports we have reviewed the relationshipbetween H pylori and gastritis, examined theepidemiology of infection, and brieflyaddressed the relationship between infectionand peptic ulcer diseases.1-3 Although there isgood current evidence supporting the role of

H pylori in duodenal ulcer disease,4-9 therelationship between H pylori infection andgastric ulcer disease has remained relativelyneglected. 1013

Following a recent study of ours, we foundthat in southern China H pylori associatedgastritis looked similar to that reported in otherstudies where both the antral and oxynticmucosae had been investigated.3 In this study,however, we noted that in relation to uppergastrointestinal disease, there was a need toexamine further the specific topographical rela-tionship between H pylori and its associatedhistological response. This study aimed toextend our knowledge of the relationshipbetween H pylori infection, peptic ulcerdisease, and gastric cancer within a southernChinese population. In this investigation wehave focused on peptic ulcer disease andgastric cancer in relation to the presence orabsence of bacteria, the grading of gastritis,and factors such as the degree of inflammationin the antral and oxyntic mucosae.

Methods

PATIENTSThis study examined 1006 consecutivepatients who presented for endoscopicexamination at the Affiliated First Hospital,Sun Yat-Sen University of Medical Science,Guangzhou, Peoples Republic of China. Allpatients were from the local population andwere referred to the hospital for the investiga-tion of upper gastrointestinal symptoms ofunknown aetiology. The patients were notreferred from other endoscopy clinics orselected because of the severity of symptoms.Patients consisted of both outpatients andinpatients from all social strata. Because of themedical system in this region of China, theoutpatient population would represent a groupsimilar to that investigated by a private out-patient practice in many parts of the developedworld. Follow up patients were excluded fromthe study. Each patient was asked about theirantibiotic intake over the previous four weeks.Informed consent was obtained from eachpatient. The project conforms to the declara-tion of Helsinki and was approved by theDirector of the Guangzhou Health Bureau onadvice from the Scientific Affairs Committee.

ENDOSCOPIC EXAMINATIONPatients were examined using an Olympus

Affiliated FirstHospital, Sun Yat-SenUniversity ofMedicalScience, People'sRepublic ofChinaPJHuM H ZhouM H Chen

First MunicipalPeople's Hospital ofGuangzhou,Guangzhou, People'sRepublic ofChinaYYLiG G DuB J Huang

School ofMicrobiologyand Immunology,University ofNewSouth Wales, Sydney,AustraliaH M MitchellS L Hazell

Correspondence to:Dr S L Hazell, School ofMicrobiology andImmunology, University ofNew South Wales, Sydney,2052 Australia.Accepted for publication27 May 1994

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Q20 endoscope and the presence of lesionsin the gastroduodenal mucosa was noted.Differentiation was made between erosionsand true ulcers in the classification of disease.The criteria for inclusion in the ulcer group

were a circumscribed break in the mucosa withapparent depth and covered by an exudateas well as those patients with healing ulcers or

ulcer scarring. Ulcers located in the stomachor duodenum were classified as gastric andduodenal ulcers respectively. Where ulcersoccurred in both the stomach and the duo-denum simultaneously, these were classified as

coexistent ulcers. Where an ulcer occurredcoexistent with gastric malignancy, the patientwas classified as being in the gastric cancer

group.

BIOPSIESJumbo biopsy forceps (FB-25K) were used tocollect biopsy specimens from both the oxynticand antral gastric mucosae. In the antrum, twospecimens, one each from the anterior andposterior wall 2 cm from the pylorus, were

taken for histology. Similarly in the body, twobiopsy specimens, one each from the anteriorand posterior wall, midway between the antral-body junction and cardia, were collected forhistology. Specimens were not taken frompatients in whom there was a risk of complica-tions such as gastric bleeding.

HISTOLOGYBiopsy specimens for histological examinationwere fixed in 10% buffered formalin andprocessed routinely. Paraffin sections (5 pum)were cut and stained by haematoxylin andeosin, and for the presence of Hpylori by modi-fied Giemsa stain. Sections were graded forbacteria, inflammation (chronicity), poly-morphonuclear leukocytes (activity), atrophy,and intestinal metaplasia in accordance withthe recommendations of the working party thatdeveloped the Sydney system for the histologi-cal grading of gastritis.14

STATISTICS

X2 analysis with Yates's correction were per-formed using the SPSS program (SPSS Inc,IL, USA). Where multiple comparisons were

performed, the Bonferroni inequality wastaken into account to adjust the p values.

ResultsExamination of the 1006 patients by gastro-duodenoscopy showed that 403 (40%/o), agedfrom 16 to 70 years, had an endoscopic findingof peptic ulcer disease (348 duodenal ulcer,35 gastric ulcer, and 20 with coexistant ulcera-

tion) (Table I). Most patients, 505 (50.2%)aged 17 to 65 years, had no significant endo-scopically definable findings and were classi-fied as having non-ulcer dyspepsia (Table I).Twenty four (2.4%) of the patients were

diagnosed as having gastric cancer and were

in the age range of 32 to 72 years, with two

TABLE I Diagnosis of disease in the patient population

Sex ratio Mean ageDisease No (%) (male:female) (y)

Duodenal ulcer 348 (34 5) 2-05:1 42-7Gastric ulcer 35 (3.5) 2-89:1 51-0Coexistent ulcer 20 (2.0) 5-67:1 50.5Gastric cancer 24 (2.4) 20:1 53-8Non-ulcer dyspepsia 505 (50 2) 0.94:1 38-4Peristomal gastritis 28 (2.78) 3-65:1 55-7Stomal ulcer 2 (0.2) - 42-5Gastric stump

carcinoma 2 (0.2) - 52-5Oesophageal carcinoma 8 (0.8) 1:1 61-3Other 34 (3.4) - -

additional patients aged 50 and 55 yearshaving carcinoma in the gastric stump. Theremaining patients aged 39 to 80 years hadother disease manifestations, including stomalulceration, peristomal gastritis, and oeso-phageal carcinoma (Table I). Except for thenon-ulcer dyspepsia group and the oeso-phageal cancer patients (where men andwomen were in almost equal proportions) menpredominated in the disease groups (Table I).Of the 937 patients from whom biopsy

material was available, 885 were classified ashaving either ulcer disease, gastric cancer, ornon-ulcer dyspepsia (Table II). Three hundredand twenty eight of 376 patients with ulcerdisease (87-2%) had histological evidence ofHpylorn infection (87.2% in duodenal ulcerdisease, 90% in gastric ulcer disease, and 83-3%in coexistant ulcer disease - gastric plus duo-denal ulceration) (Table II). Of the 22 gastriccancer patients from whom biopsy specimenswere collected, 16 (72.7%) had histologicalevidence of Hpylori infection (Table II).When patients who had taken antibiotics or

bismuth compounds in the four weeks beforeendoscopy were excluded from the abovegroups, 308 of 311 (99%) of the ulcer diseasepatients had evidence of H pylori infection(98-9% in duodenal ulcer disease, 100% ingastric ulcer disease, and 100% in coexistantulcer disease) (Table II). Hpylori infection wasevident in 15 of 18 (83.3%) of the gastriccancer group (Table II). There was a signifi-cant association between the presence of Hpylori and peptic ulcer disease compared withthose patients diagnosed as having non-ulcerdyspepsia (X2= 57.35, DF= 1, p<0001).The grading of gastritis in 642 patients

diagnosed as having either peptic ulcer diseaseor non-ulcer dyspepsia who had not takenantimicrobial agents in the preceding fourweeks was determined. Of these patients, 498of 642 (77.6%) had histological evidence ofHpylori infection. All of these infected individ-uals had some degree of inflammation at one

TABLE II Incidence of Helicobacter pylori in principaldisease groups*

No infected] No infected/total (%)Disease total (%) adjusted groupt

Duodenal ulcer 286/328 (87.2) 271/274 (98.9)Gastric ulcer 27/30 (90.0) 25/25 (100)Coexistent ulcer 15/18 (83 3) 12/12 (100)Gastric cancer 16/22 (72 7) 15/18 (83.3)Non-ulcer dyspepsia 247/467 (52.9) 190/331 (57.4)

*Biopsy specimens contraindicated in 69 cases. tAdjusted toexclude patients who had a record of taking bismuth orantibiotics in the four weeks before endoscopy.

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Hu, Li, Zhou, Chen, Du, Huang, Mitchell, Hazell

TABLE III Histological grading ofgastritis in relation toHelicobacter pylori status in ulcer and non-ulcerdyspepsia patients who had not taken antimicrobial agentsbefore endoscopy

Chronic gastritisHelicobacterpylon Mild Moderate-severe Total (%)

Positive 16 482 498 (84.7)Negative* 82 8 90 (15-3)Total (%) 98 (16-7) 490 (83.3) 588 (100)

*Fifty eight patients negative for H pylori had no evidence ofgastritis.

or more sites in the stomach. Pangastritis-antral predominant was the most commongastritis presentation in 365 (73.3%) of thisgroup ofH pylori positive patients, followed byantral only gastritis (13.9%) and uniform pan-gastritis (1121/%). In the site where the gastritiswas most predominant, 96.3% of this group of498 patients had chronic gastritis graded asmoderate to severe (Table III). Of the 144 of642 (22.4%) patients in the H pylori negativegroup, 90 had some degree of inflammation atone or more sites in the stomach. This gastritiswas graded as mild in 82 of 90 (91.1%) cases(Table III) and was usually confined to theantrum (80%). There was a significant differ-ence between the severity of gastritis in theH pylori infected group compared with theuninfected group (X2=4177 1, DF= 1,p<roOOl).Of the 328 duodenal ulcer disease patients

from whom biopsy specimens had been taken,the topography of gastritis was pangastritis-antral dominant in 236 (71.9%), antralgastritis in 16.8%, and uniform pangastritis in11.3% (Table IV). Of the 30 gastric ulcerdisease patients, the topography of gastritis waspangastritis-antral dominant in 13 (43/3%),uniform pangastritis in 11 (36.70/o), pan-gastritis-body dominant in four (1 33%), and

TABLE iv Topography of gastritis in relation to gastroduodenal disease

Disease state (no (%lo))

Duodenal uker Gastric ulcer Coexistent ulcer GastricSite ofgastritis (DU) (GU) (GU plus DU) cancer

Antralonly 55(16-8) 2(67) 2(11.1) 2(9-1)Pangastritis - antral predominant 236 (72.0) 13 (43.3) 12 (66.7) 13 (59-1)Pangastritis 37 (11-3) 11 (36 7) 4 (22.2) 6 (27.3)Pangastritis - body predominant 0 (0) 4 (13-3) 0 (0) 1 (4.5)Body only 0 (0) 0 (0) 0 (0) 0 (0)Normal 0 (0) 0 (0) 0 (0) 0 (0)Total 328 30 18 22

TABLE V Topography of atrophy in relation to gastroduodenal disease

Disease state (no (%))

Distribution Severity Duodenal Gastric Coexistent Gastricofatrophy of atrophy ulcer ulcer ulcer cancer NUD

Antral only Moderate 20 (6-1) 5 (16-7) 3 (18-75) 1 (4.5) 10 (2.1)Severe - - - - _

Body only Moderate -

Severe - - -

Antral predominant Moderate - 3 (10) - 1 (4.5) 2 (0.4)Severe - - - 2 (9-1)

Body predominant Moderate - - - 1 (4.5) -

Severe - - - - -

Uniform Moderate - - - 1 (4.5) 3 (0.6)Severe - - - 2 (91) -

No atrophy 308 (93.9) 22 (73.3) 13 (81-25) 14 (63 6) 452 (96.8)Total with atrophy 20/328 8/30 3/16 8/22 15/467

(6.1) (26 7) (18-75) (36 4) (3.2)

NUD=non-ulcer dyspepsia.

antral only gastritis in two cases (6.7%) (TableIV). Where there was coexistant ulceration(gastric plus duodenal), the topography ofgastritis tended to be more antral than ingastric ulcer disease, whereas in gastric cancerthe topography of gastritis was similar to thatseen in gastric ulcer disease (Table IV). For thepurposes of statistical analysis, the antral andantral predominant groups were combined, aswere the body and body predominant groups,giving three broad groups (antral/antralpredominant, pangastritis, and body/body pre-dominant). Based on this classification, therewas a significant difference between one ormore of the disease states (duodenal ulcer,gastric ulcer, coexistant ulcer, and gastriccancer) in relation to the topography ofgastritis (X2=62A44, DF=6, p<O.OOl). Therewas, however, no significant difference seenbetween the topography of gastritis in thegastric ulcer, gastric cancer, and coexistantulcer groups (X2=5*491, DF=4, p=0-482 -

adjusted for Bonferroni inequality). Thus, itmay be concluded that there was a significantdifference between the topography of gastritisin cases of duodenal ulcer disease comparedwith the three other disease groups.

Atrophic changes were noted mostcommonly in cases of gastric cancer (Table V).Four of 22 gastric cancer patients (18.2%) hadsevere atrophy occurring either predominantlyin the antrum or uniformly throughout thestomach. A further 1 8.2% of the gastric cancerpatients had moderate atrophy ranging in dis-tribution from the antrum to uniformlythroughout the stomach. Moderate atrophywas noted in 6 /1% of patients with duodenalulcer disease, 26-7% of patients with gastriculcer disease, and 18.75% of patients withcoexistant ulceration. Atrophy was rare incases of non-ulcer dyspepsia (Table V).

DiscussionWhereas there are numerous reports confirm-ing the relationship between H pylon infectionand duodenal ulcer disease,4-9 data in relationto gastric ulcer disease is not as abundant. Inaddition, while the recent data on the associ-ation between H pyloni infection and gastriccancer is sufficiently strong for us to claim thata link exists between the two,15-28 it should benoted that association is the weakest test of anhypothesis. Further confirmatory studies arerequired.

This study aimed to investigate the relation-ship between infection with the gastric bac-terium H pylori and significant gastroduodenalpathology in a patient population from south-ern China. In addition, a further examinationof the relationship between infection, disease,and the presentation of gastritis was under-taken. Histology alone was used to assess thepresence or absence ofH pylori as we have pre-viously shown a high specificity and sensitivityusing this approach.3

This study has confirmed the strong associa-tion between H pylorn infection and duodenalulcer disease. Indeed, when we looked at thepatient group in whom a recent history of

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H pylori and disease in southern China 201

antimicrobial intake had been excluded, theassociation between infection and disease wasalmost absolute. Further, the prevalence ofduodenal ulcer disease in this patient popula-tion was high (-35%) by world standards,consistent with previous comparisons betweencentres such as Hong Kong and Sydney,Australia.29

In Guangdong province, 90% of the gastriculcer patients had evidence of H pylori infec-tion. When we again excluded those with arecent history of antimicrobial ingestion, thedata showed that all gastric ulcer patients wereinfected. In contrast, in many studies in devel-oped countries, H pylori has been associatedwith only about 70% of gastric ulcers.'1-3 Ahigh proportion of patients with gastric ulcera-tion not associated with Hpylori have, however,been found to be taking non-steroidal anti-inflammatory drugs (NSAIDs).3033 InGuangdong province the ingestion of NSAIDsis not widespread: in many respects in relationto gastric ulcer disease, therefore, it is perhaps a'cleaner' population. This may be a characteris-tic of this region of the world, as Indochinesemigrants living in Australia tend to ingest lessNSAIDs than Australian born inhabitants, yethave a high incidence of ulcer disease.34 In con-junction with the recent treatment studies ofGraham et al,13 the implication to be drawnfrom the southern China data is that in theabsence of NSAID ingestion, H pylori shouldbe considered the single most important con-tributor to the genesis of gastric ulceration.

Burnstein et al35 stated that in developedcountries infection with H pylori induces morepeptic ulcer disease than gastric cancer, withthe reverse being true in the developing world.Whereas this may be true in relation to thePeruvian population studied by Burnstein'sgroup compared with Europeans, it cannot beaccepted as a general principle. Even allowingfor probable patient selection bias, there was asignificantly higher prevalence of duodenalulcer disease in our southern Chinese patientgroup (34.5%) than in either the Peruvian(5.2%) or the European country groups(11 6%) studied by Burnstein et al (x2,p<O000 1), and a higher ratio of duodenal ulcerdisease to gastric ulcer disease (China 10.2: 1,Peru 1.2:1, Europe 2:1). The prevalence ofgastric ulcer was similar, if not slightly lower,than that seen in both Peruvian patients andthose from Europe. In our series, the preva-lence of gastric cancer (2.4%) was intermedi-ate to that seen in the Peruvian patients andthose from Europe.35 The finding of a lowerrate of gastric cancer in our series comparedwith Peru is consistent with the knowledge thatGuangdong province in southern China is anarea of relatively low gastric cancer mortalityby Chinese standards (8.3 deaths/100 000(age standardised-world)) *36 37 Our previousstudies in southern China, however, haveshown the overall prevalence of H pylori to be44-2%/, with infection rates of 23% in childrenunder 5 years.2 These rates are comparablewith those reported by Klein et al in Peru.38Thus, based on such comparisons, we foundno absolute correlation between the prevalence

of H pylori infection in a population and theprofile of upper gastrointestinal disease.The topography of gastritis and the develop-

ment of atrophy, intestinal metaplasia, and dys-plasia seem to be important factors associatedwith gastric cancer of Lauren's intestinaltype.39-43 Sipponen has noted that gastritis ofdifferent topographic types is broadly associatedwith different gastrointestinal disease states, andthat gastric and duodenal ulcers are extremelyrare in patients in whom the gastritis accom-panies severe atrophic changes in the corpusmucosa.42 In this study there was a lack ofextensive atrophy in the patient population;including the gastric cancer patients, in whomonly 36% had evidence of gastric atrophy.Distinct topographical patterns were noted forthe gastritis in gastric cancer and gastric ulcerpatients compared with duodenal ulcer patients.Pangastritis-antral predominant and antral onlygastritis predominated in the duodenal ulcerpatients; these forms occurring in almost 89%of patients. In the gastric ulcer patients, pangas-tritis of various forms was found in just over93% of patients. A similar pattern to this wasseen in the gastric cancer patients.As we and others have asserted in the past,

levels of gastric acidity may influence thedistribution of H pylori or gastritis, or both,which in turn may influence the diseaseprofile.3 42 44-47 Factors leading to gastriccancer may tend to change the pattern ofcolonisation of the bacterium and the topo-graphy of gastritis and thereby decrease theincidence of duodenal ulcer disease. Given thatatrophic gastritis and gastric atrophy precedethe development of a high proportion of gastriccancers, we suggest that in areas where there isa high prevalence of H pylori and a highincidence of duodenal ulcer disease, importantco-factors required for the development ofatrophy, intestinal metaplasia and gastriccancer may occur less commonly. Where suchco-factors are present, decreased acid outputassociated with atrophic changes may lead toa significant decrease in the incidence of duo-denal ulcer disease.

In conclusion, we have found a high rate ofduodenal ulcer disease and a relatively low rateof gastric ulcer disease in an area of low gastriccancer mortality in southern China. We havealso shown a topographical relationshipbetween H pylori, the inflammatory response,and gastroduodenal disease. Our data indicatethat a high prevalence ofH pylori infection willlead to a high overall incidence of uppergastrointestinal disease, however, the form ofsuch disease may be dictated by key environ-mental triggers.This work was supported in part by a grant from theInternational Development Program of Australian Colleges andUniversities and the National Health and Medical ResearchCouncil of Australia. Some of the data in this paper have beenpreviously presented in China.

1 Li YY, Hu PJ, Du GG, Hazell SL. The prevalence ofHelicobacter pylori infection in the People's Republic ofChina. AmJy Gastroenterol 1991; 86: 446-9.

2 Mitchell HM, Li YY, Hu PJ, Liu Q, Chen M, Du GG, et al.Epidemiology of Helicobacter pyloni in Southern China -identification of early childhood as the critical period foracquisition. 3rInfect Dis 1992; 166: 149-53.

3 Hu PJ, Li YY, Mitchell HM, Zhou MH, Chen MH, Du

202 Hu, Li, Zhou, Chen, Du, Huang, Mitchell, Hazell

GG, et al. Oxyntic and antral gastritis in the People'sRepublic of China: Diagnosis and relationship toHelicobacter pylori. Am J Gastroenterol 1992; 87: 741-5.

4 Marshall BJ, Goodwin CS, Warren JR, Murray R, BlincowED, Blackbourn SJ, et al. Prospective double-blind trial ofduodenal ulcer relapse after eradication of Campylobacterpylori. Lancet 1988; ii: 1437-42.

5 Coghlan JG, Gilligan D, Humphries H, McKenna D,Dooley C, Sweeney E, et al. Campylobacter pylori andrecurrence of duodenal ulcers - a 12 month follow-upstudy. Lancet 1987; ii: 1109-11.

6 Graham DY. Treatment of peptic ulcers caused byHelicobacter pylori. New Engl J Med 1993; 328: 349-50.

7 Nanivadekar SA, Sawant PD, Patel HD, Shroff CP, PopatUR, Bhatt PP. Association of peptic ulcer withHelicobacter pylori and the recurrence rate. A three yearfollow-up study. 7 Assoc Physicians India 1990; 1: 703-6.

8 Rauws EA. Campylobacter pylori as possible factor in pep-tic ulcer recurrence. Acta Gastroenterol Belg 1989; 52:320-3.

9 Yeomans ND. Bacteria in ulcer pathogenesis. Baillieres ClinGastroenterol 1988; 2: 573-91.

10 Leung KM, Hui PK, Chan WY, Thomas TMM.Helicobacter pylori-related gastritis and gastric ulcer - acontinuum of progressive epithelial degeneration. Am JfClin Pathol 1992; 98: 569-74.

11 Bell GD, Powell KU. Eradication of Helicobacter pyloriand its effect in peptic ulcer disease. ScandJ3 Gastroenterol1993; 28 (suppl 196): 7-11.

12 Hui PK, Chan WY, Cheung PS, Chan JKC, Ng CS.Pathologic changes of gastric mucosa colonized byHelicobacter pylori. Hum Pathol 1992; 23: 548-56.

13 Graham DY, Lew GM, Klein PD, Evans DG, Evans DJ,Saeed ZA, et al. Effect of treatment of Helicobacter pyloriinfection on the long-term recurrence of gastric or duo-denal ulcer, a randomized, controlled study. Ann InternMed 1992; 116: 705-8.

14 Price AB. The Sydney system: Histological division. JGastroenterol Hepatol 1991; 6: 209-22.

15 Correa P, Ruiz B. Campylobacter pylori and gastric cancer.In: Rathbone BJ, Heatley RV, eds. Campylobacter pylonand gastroduodenal disease. London: Blackwell ScientificPublications, 1989: 139-45.

16 Buruk F, Berberoglu U, Pak I, Aksaz E, Celen 0. Gastriccancer and Helicobacter pylori infection. BrJ Surg 1993;80: 378-9.

17 Correa P, Fox J, Fontham E, Ruiz B, Lin YP, Zavala D, etal. Helicobacter pylori and gastric carcinoma. Serum anti-body prevalence in populations with contrasting cancerrisks. Cancer 1990; 66: 2569-74.

18 Tatsuta M, Iishi H, Okuda S, Taniguchi H, Yokota Y. Theassociation of Helicobacter pylon with differentiated-typeearly gastric cancer. Cancer 1993; 72: 1841-5.

19 Forman D, Newell DG, Fullerton F, Yarnell JW, StaceyAR, Wald N, et al. Association between infection withHelicobacter pylori and risk of gastric cancer: evidencefrom a prospective investigation. BMJ 1991; 302: 1302-5.

20 Forman D. Helicobacter pylori infection: a novel risk factorin the etiology of gastric cancer. J Natl Cancer Inst 1991;83: 1702-3.

21 Fox JG, Correa P, Taylor NS, Zavala D, Fontham E,Janney F, et al. Campylobacter pylori-associated gastritisand immune response in a population at increased risk ofgastric carcinoma. Am J Gastroenterol 1989; 84: 775-81.

22 Jankowski J. Helicobacter pylori infection and gastriccancer. BMJ 1991; 302: 1534.

23 Nomura A, Stemmermann GN. Helicobacter pylori andgastric cancer. J7ournal of Gastroenterology and Hepatology1993; 8: 294-303.

24 Parsonnet J, Vandersteen D, Goates J, Sibley RK, Pritikin J,Chang Y. Helicobacter pylori infection in intestinal- anddiffuse-type gastric adenocarcinomas. J Natl Cancer Inst1991; 83: 640-3.

25 Scott N, Lansdown M, Diament R, Rathbone B, Murday V,Wyatt JI, et al. Helicobacter gastritis and intestinal meta-plasia in a gastric cancer family. Lancet 1990; 1: 728.

26 Sipponen P, Kosunen TU, Valle J, Riihela M, Seppala K.

Helicobacter pylori infection and chronic gastritis ingastric cancer. JClin Pathol 1992; 45: 319-23.

27 Forman D, Coleman M, Debacker G, Eider J, Moller H,Damotta LC, et al. An international association betweenHelicobacter pylori infection and gastric cancer. Lancet1993; 341: 1359-62.

28 Forman D. Helicobacter pylori infection and gastric car-cinogenesis. European Journal of Gastroenterology andHepatology 1992; 4 (suppl 2): S31-5.

29 Lam SK. Peptic ulcer: from epidemiology to cause. Journalof Gastroenterology and Hepatology 1989; 2: 1-6.

30 Graham DY, Smith JL. Gastroduodenal complications ofchronic NSAID therapy. Am Jf Gastroenterol 1988; 83:1081-4.

31 Soll AH, Weinstein WM, Kurata J, McCarthy D.Nonsteroidal anti-inflammatory drugs and peptic ulcerdisease. Ann Intern Med 1991; 114: 307-19.

32 Wallace JL. Gastric ulceration - critical events at theneutrophil endothelium interface. Canadian Jfournal ofPhysiology and Pharmacology 1993; 71: 98-102.

33 Schubert TT, Bologna SD, Nensey Y, Schubert AB,Mascha EJ, Ma CK. Ulcer risk factors - interactionsbetween Helicobacter pylori infection, nonsteroidal use,and age. AmJfMed 1993; 94 (4): 413-8.

34 Kolt SD, Kronborg IJ, Yeomans ND. High prevalence ofduodenal ulcer in Indochinese immigrants attending anAustralian university hospital J7ournal of Gastroenterologyand Hepatology 1993; 8: 128-32.

35 Burstein M, Monge E, Leon BR, Lozano R, Berendson R,Gilman RH, et al. Low peptic ulcer and high gastriccancer prevalence in a developing country with a highprevalence of infection by Helicobacter pylori. J ClinGastroenterol 1991; 13: 154-6.

36 Editorial committee for the atlas of cancer mortality in thePeople's Republic of China. Atlas of cancer mortality in thePeople's Republic of China. Beijing: China Map Press,1973.

37 Chen JS, Campbell TC, Li JY, Peto R. Diet, lifestyle andmortality in China. A study of the characteristics of 65Chinese countries. Oxford: Oxford University Press, 1990.

38 Klein PD, Graham DY, Gaillour A, Opekun AR, SmithEO. Water source as risk factor for Helicobacter pyloriinfection in Peruvian children. Lancet 1991; 337: 1503-6.

39 Correa P. Human gastric carcinogenesis - a multistep andmultifactorial process - first american cancer societyaward lecture on cancer epidemiology and prevention.Cancer Res 1992; 52: 6735-40.

40 Lauren PA, Nevalainen TJ. Epidemiology of intestinal anddiffuse types of gastric carcinoma - a time-trend study inFinland with comparison between studies from high-riskand low-risk areas. Cancer 1993; 71: 2926-33.

41 Lauren P. The two histological main types of gastric carci-noma: diffuse and so-called intestinal-type carcinoma: anattempt at a histo-clinical classification. Acta Pathologica etMicrobiologica Scandinavica 1965; 64: 31-49.

42 Sipponen P. Natural history of gastritis and its relationshipto peptic ulcer disease. Digestion 1992; 51 (suppl 1):70-5.

43 Sipponen P, Seppala K. Gastric carcinoma - failed adapta-tion to Helicobacter pylori. ScandJ3 Gastroenterol 1992; 27(suppl 193): 33-8.

44 Hazell SL, Hennessy WB, Borody TJ, Carrick J, Ralston M,Brady L, et al. Campylobacter pyloridis gastritis II:Distribution of bacteria and associated inflammation inthe gastroduodenal environment. Am J Gastroenterol1987; 82: 297-301.

45 Stolte M, Eidt S, Ohnsmann A. Differences in Helicobacterpylori associated gastritis in the antrum and body of thestomach. Z Gastroenterol 1990; 28: 229-33.

46 Hui WM, Lam SK, Ho J, Lai CL, Lok AS, Ng MM, et al.Effect of omeprazole on duodenal ulcer-associated antralgastritis and Helicobacter pylori. Dig Dis Sci 1991; 36:577-82.

47 Fich A, Talley NJ, Shorter RG, Phillips SF. Zollinger-Ellison syndrome. Relation to Helicobacter pylori-associated chronic gastritis and gastric acid secretion. DigDis Sci 1991; 36: 10-4.