Journal of Gastroenterologvand Hepatology (19911 6, 125-130

Adonis 081593 1 9 9 100022D

IV. Helicobacter pylori and peptic ulceration: Histopathological aspects MICHAEL F. DIXON Department of Pathology, University of Leeds, Leeds, UK

INTRODUCTION While the presence of acid is necessary for the development of peptic ulceration, reduced mucosal resistance is increasingly acknowledged as the major factor in ulcerogenesis. The principal cause of diminished mucosal resistance to acid 'attack' is chronic inflammation. In this paper I shall explore the histopathological evidence which supports a link between H.pylori-associated chronic inflammation in the stomach and duodenum and peptic ulceration at these sites.

Chronic gastritis and peptic u l c e r a t i o n It has been known for more than a century that peptic ulceration is associated with gastritis.' More than 40 years ago both Hebbel and Magnus produced comprehensive descriptions of chronic gastritis based on stomachs removed for gastric ulcer (GU) and duodenal ulcer (DU) and claimed that such ulcers always arose on the basis of preexisting gastroduodenal inflammati~n.~.~ Subsequent studies have confirmed the almost universal presence of chronic gastritis in peptic ulceration, but the characteristics and distribution of the gastritis differ between GU and DU. The gastritis associated with duodenal ulceration predominantly affects the antnun; indeed, there is usually ~ - ~ antral little or no involvement of body m ~ c o s a . The mucosa shows superficial or full thickness infiltration by lymphocytes and plasma cells with occasional lymphoid follicles, and there is invariably a minor neutrophil polymorph component either within the lamina propria or infiltrating the foveolar and surface epithelium. Glandular atrophy is absent or mild and intestinal metaplasia is infrequent. Prepyloric G U are also accompanied by this pattern of gastritis. Proximal GU are associated with involvement of body mucosa in addition to antral gastritis6 Furthermore, glandular atrophy and intestinal metaplasia are consistent findings, their degree and extent increasing with advancing age.' Atrophy commences in the antrum and extends along the lesser curvature into the body mucosa.s Further foci of atrophy and metaplasia appear in the anterior and posterior walls which gradually enlarge and coalesce. so that much of the body mucosa shows an atrophic gastritis.' There is thus a gradual reduction in the area of acid-producing mucosa, and the border with 'alkaline' mucosa advances proximally with increasing age. GU are generally found in the alkaline

mucosa at this boundary.1° It follows therefore that there is an association between increasing age and more proximally situated ulcers.$* Viewed from a functional standpoint, it appears that the pattern of gastritis found in DU patients, namely, a diffuse antral gastritis with relative sparing of body muma, means that the parietal cell mass is unaffected by atrophy and permits normal acid production. On the other hand, in GU patients, multifocal atrophy leads to glandular loss in both antral and body mucosa, and the latter results in low& pepsin production and hypochlorhydria. In so far as acid production in GU patients is frequently lower than normal, it has long been accepted that diminished mucosal resistance is paramount in the causation at GU. Thus, patients with strictly antral gastritis are at much increased risk of DU and prepyloric ulcers compared with normals, whereas those with involvement of antrum and Corpus mucosa by atrophic gastritis are unlikely to develop DU, although there remains an increased risk of GU.12Patients with severe degrees of glanalar atrophy in body mucoaa will have suchjow acid levels that even with a vulnerable mucosa the ulcer risk is very low; this is in keeping with the 'no acid, no ulcer' dictum. The wrong association between gastritis and peptic ulceration does not prove a causal role for the former. Epidemiological evidence points to gastritis preceding niceration but there are few follow-up studies. Recently "'Sipponenet a2. reported on 9'10 year follow-up 0fpati-t~ with and without gastritis, of whom only 1 of 133 patients (0.8%) with a normal stomach at entry developed a new symptomatic ulcei (GUIDU), whereas 29 of 233 patients (12.4%) with antral gastritis developed ulcers. Interestingly, only 1 of 22 patients (4.5%) with moderate or severe body gastritis at entry developed an ulcer. On the basis of this and other studies it appears that although chronic gastritis is very common in the community only 10-15% will ever develop a symptomatic peptic ulcer.

Chronic duodenitis and d u o d e n a l ulcer The relation of pre-existing chronic duodenitis to duodenal ulceration remains a subjed of controversy. From a histopathological viewpoint the problem stems largely from a failure to recognize the normal range of duodenal morphology. It has been appreciated only iecently that minor increases in chronic inflammatory cells are part of the normal range and that a moderate or marked increase is

Correspondence: Michael F. Dixon, Department of Pathology, University of Leeds, Leeds LS2 9JT, UK. Accepted for publication 12 November 1990.

M . F. Dixon

126

required before the mucosa can be considered Pathological.13 Biopsies showing ‘significant’ chronic inflammatory cell infiltration together with a polmorph component (i.e. active chronic duodenitis) are virtually never Seen in symptomless heakhy volunteers. Furthermore, there is a close association between active chronic duodenitis and the development of an ulcer crater.14 An endoscopic parallel can be drawn from a study which followed the natural history of 219 patients with symptomatic duodenitis, 8206 of whom developed one or more ulcers during follow-up.15 A consistent histological finding in ‘significant’ duodenitis is surface gastric metaplasia, the appearance of patches of gastric-type mucous cells interspersed between the absorptive and goblet cells of the duodenal epithelium. The relevance of gastric metaplasia to duodenal inflammation is the subject of much debate. Certainly, small foci of gastric metaplasia can be found in normal healthy hdividuals; it was identified in 64% of the 50 volunteers 1 ~ a potential source examined by Kreuning et ~ 1 . However, of confusion in the recognition of surface gastric metaplasia can be that duodenal biopsies from close to the pyloms will sample the normal transitional zone between antral-type and small bowel-type duodenal m u ~ o s aWhere . ~ ~ such a possibility has been avoided the prevalence of gastric metaplasia in ‘healthy’ volunteers is much lower (22%).“ A skcond source of corhsion is the existence of gastric heterotopia. The term ‘heterotopia’ is best confined to cases showing a fully developed gastric glandular component including parietal and chief cells in addition to surface gastric epithelium, the appearances Being those of an island of body-type gastric mucosa within the duodenum. Again, scattered parietal cells (but not chief cells) can be seen in the Brunner’s glands of the ‘normal’ transitional mucosa of the proximal duodenum.19 Gastric heterotopia appear endoscopically as small sessile polyps or nodules and are found in approximately 1 of all individuals; only rarely are they associated with duodenitis.ao In keeping with the histogenesis of other forms of heterotopia, gastric heterotopia in the duodenum is considered to be a congenital misplacement of tissue akin, for example, to heterotopic pancreas, or gastric heterotopia in the upper oesophagus or in a Mcckel’s diverticulum. The term ‘heterotow’ has also been applied to the finding of scattered parietal cells among the indigenous cells of the duodenal mucosa (away from the transitional zone’ despite the likelihood of this also being an acquired metaplastic change. Thus, confusion can be avoided if ‘heterotopia’ is restricted to the fully developed and presumed congenital variety, while gastric metaplasia is used to describe an acquired change in differentiation where the surface epithelium consists of gastric type mucous cells, and, more rarely, Brunner’s glands and ducts contain parietal cells. Metaplasia probably results from a modulation of cellular differentiation from stem cells under the inffuence of As such, it can be viewed altered environmental as an adaptive defence response to adverse conditions. surface gastric mehaplasia in the duodenum can therefore be Seen to have biological advantage if the adver$l!la&or is an increased acid load reaching the duodenum, and there is accumulating evidence from humanz2**3 and experimental= studies to indicate that duodenal bulb acidity is an important dererminant of the extent of gastric metaplasia. It must be emphasized, however, that metaplasia is a consequence of any mucosal injury so that, once established, an erosive ‘’(,

duodenitis will lead to further metaplasia. Likewise, metaplasia will follow any ulcerative process affecting the duodenum and is seen, for example, in Crohn’s disease. Although the major cause of gastric metaplasia is hyperacidity, it appears that the presence and degree of chronic duodenitis are not related to acid output from the stomachzs*z6 and that active chronic duodenitis may not respond to acid-reducing treatment?’ Thus, although surface gastric metaplasia and duodenitis are closely associated they do not share a common pathogenesis. Glandular gastric metaplasia with the acquisition of parietal cells is impossible to explain in terms of a defence response in that it is likely to exacerbate rather than counteract any acid injury. I t seems likely that the appearance of parietal cells in the duodenum is a metaplastic response to an increased gastrin ‘drive’, similar to the increased numbers seen in the antral mucosa of some DU patients.28 It has been argued that the presence of parietal cells in the duodenum is a source of local acid production and which may contribute to the formation of endogenous acid production has been demonstrated by Congo Red staining in the margins of 20 of 23 duodenal ulcers.30 Although representing an intriguing additional factor, the role of local acid production within the duodenum awaits proper evaluation.

H . pyZoori, chronic gastritis and duodenitis There is now an irrefutable aetiological link between H. pylori and chronic gastritis and this has been attested to by numerous studies conducted throughout the world. The association applies particularly to active chronic gastritis, and this holds whether there is glandular atrophy or That H. pylori is not simply an opportunistic colonizer of already diseased mucosa is exemplified by its low prevalence in auto-immune gastritis,32in lymphocytic gasand in the bile reflux gastritis found in postoperative stomachs.3s A similar role for H. pylori in the aetiology of chronic duodenitis has been more difficult to establish. At first sight a direct role for the organism would appear to be denied by the fact that colonization by H. pylori is restricted to gastric epithelial cells, attachment being mediated by bacterial adhesins specific for glycoproteinj6 or glycolipidJ7moieties of the apical membrane of gastric surface and foveolar cells. T h e presence of gastric metaplasia, however, would allow such colonization to occur in the duodenum. We have demonstrated the close interrelations between gastric metaplasia, active chronic duodenitis and H. pylori-positive gastritis, 8 8 O L of cases of active duodenitis having both > 5”, gastric metaplasia and H. pylori-associated gastritis. Furthermore, active chronic duodenitis is rare in the absence of H.pylori gastritis, being seen in only one of our 34 patient^.^' In this study, organisms were demonstrable in the duodenum in only 53%, but others found duodenal H . pyloriin all of their 35 patients with histologically active d u o d e n i t i ~It. ~can ~ be argued therefore that active chronic duodenitis results from spread of H.p.yZori infection from the antrum to areas of gastric metaplasia in the proximal duodenum. In essence the process can be viewed as active chronic ‘gastritis’ in the duodenum. However, the presence of gastric metaplasia per se is independent of H. pylori gastritis, having an equal prevalence in H. pylori-positive

H. pylori and peptic ulcer: histopathology

127

and negative patients with dyspepsia. Gastric metaplasia is more extensive in H . pylon’-positive cases with duodenitis, but this increase could reflect additional metaplastic change consequent upon inflammation and erosion rather than a response to hypera~idity.~~ On those rare occasions when extensive gastric metaplasia occurs in a patient without H . pylori-associated gastritis, in response to acid injury in the Zollinger-Ellison syndrome, for example, metaplasia may be present without active chronic d ~ o d e n i t i s . ~Likewise, l-~~ congenital gastric heterotopia in H. pylori-negative individuals is uninflamed.44

H . pylori and gastric ulceration In so far as the vast majority of gastric ulcers occur against a background of chronic gastritis, it is to be expected that a high prevalence of H . pylori will be found in GU patients. This is indeed the case (Table l), on average 80% of patients being positive. It can be argued that damage to the gastric mucosa by either a direct cytotoxic effect or indirect injury consequent upon the immune response to the organism, leads to impaired mucosal resistance and predisposes to ulceration. Even where no H . pylori are detected, the gastritis may have resulted from infection. The hypochlorhydric stomach (consequent upon glandular atrophy) together with intestinal metaplasia, provide a hostile environment for H. pylori and the organisms may disappear or be difficult to identify.45 Thus, it can be argued that H. pylori-associated gastritis underlies the majority of gastric ulcers. Ulceration, however, is unlikely to be a direct consequence of H . pylori gastritis and is most llkely to be the result of acid attack on the weakened mucosa. Other injurious factors such as non-steroidal anti-inflammatory drugs, alcohol or duodenogastric bile reflux may also weaken mucosal defence and represent alternative or additional mechanisms which enable acid to induce erosions or ulceration.

NSAlDs bile reflux

H. pylori

4 REACTIVE (CHEMICAL) GASTRITIS

CHRONIC PAN-GASTRITIS

1

ATROPHY/INTESTINAL METAPLASIA

“’....?

NO CLINICAL IJISEASE

GASTRIC ULCER

GASTRIC CANCER

Figure 1 Relationship between H. pylmlassociated chronic gastritis and gastric ulcer. Most people affected exhibit no clinical disease. A few develop gastric ulcers, as the atrophic mucosa is more susceptible to injury by acid or other agents. In very few the atrophic mucosa may be acted on by carcinogenic factors leading to the development of gastric cancer. Gastric ulcers also arise as a direct response to NSAIDs and (possibly) bile reflux.

Duodenal ulceration is almost invariably accompanied by the form of gastritis most clearly linked to H. pylori. It is not surprising therefore that a very high prevalence of antral H. pylori infection is found in DU patients (Table 2).

In seeking to explain the association between H. pylori antral gastritis and duodenal ulceration some authors have invoked excessive gastrin p r o d ~ i c t i o n . Hypergastrin~~*~~ aemia has been demonstrated in H. pylori-positive p& tients, while an increase in the acid load delivered to the duodenum is implicated in DU. The role of hypergastrinaemia in such cases is controversial, however, and some investigators have not confirmed increases in acid output in H . pylori-positive patients.4sThere appear to be at least three possible mechanisms underlying hypergastrinaemia: (1) Ammonia liberated by H . pylm’ interferes with the normal acid feed-back on G cells.46 (2) G cells are directly stimulated by mediators produced by the inflammatory cell infiltrate. (3) Increased gastrin production is a com ensatory mechanism to counteract parietal cell depre ‘ion by a H . pylori product. That such a product exists has been demonstrated by Cave & V a r g ~ : . ~ ~ Naturally, if this latter mechanism applied, hypergastrinaemia would simply represent a homeostatic response and would not be expected to result in increased acid output. More fundamental is the link between gastric mrtaplasia, duodenal H . pylori infection and duodenal ulceration (Table 3). However, the finding of gastric metaplasia,

Table 1 H . pylon‘and gastric ulceration

Table 2 H . pylori and duodenal ulceration

H . pylori and duodenal ulceration

+

HP +

%

Study

n

33

19

58

34

30

88

54

39

72

66

61

93

67

49

73

10;‘

100

93

21

18

86

46

43

93

30

27

90

35

34

97

61

61

100

Fiocca er al., 1987” Pavia, Italy Coghlan et al., 1987b4 Dublin. Ireland Marshall et al., 1988”’ Perth, Australia Carrick et al., 19m3” Sydney. Australia OConnor et al., 198635 Lceds, UK Rauws & Tytgat 198963 Amsterdam; Netherlands

165

165

100

266

213

80

288

268

93

Study

n

Niemala et al., 198758 Oulu, Finland O’Connor et al., 198759 Leeds, UK Hui et al., 198760 Hong Kong Jiang et al., 198761 Shanghai, China Fiocca et al., 198762 Pavia, Italy Rauws & Tytgat, 19896’ Amsterdam, Netherlands Total

P

Total

Hp

%

M. F. Dixon

128

Table 3 Gastric metaplasia (GM) and duodenal H. pylmi in DU patients Study

GM No.

n

Johnston et al., 1 9 8 P 85 Marshall e t ul., 198865 88 46 Carrick et al., 198930

HP

Yo

81

92

42

92

Normal

82

96

Gastric

46 38

52

metaplasia

83 Pan-

which is held to be acid-induced, in duodenal biopsies from H. pylori-negative individuals suggests that there must be abnormalities of acid production or its delivery to the duodenum, which antedate the onset of H. pylori gastritis in people at risk of duodenal ulceration. These data seem consistent with the following sequence of events: (1‘1 People with ii duodenal ulcer ‘diathesis’ have gastric metaplasia in the duodenum, (2) When such individuals contract H. pylori infection they develop an antral chronic gastritis. ( 3 ) H. pylorz from the stomach may infect the metaplastic gastric epithelium in the duodenum and give rise to active chronic duodenitis. (4) Mucosal resistance is impaired as a result of direct bactcrial or indirect immune-mediated injury. ( 5 ) Acid-peptic attack on the weakened duodenal mucodYeads to erosion and ultimately to frank crater formation.

Patterns of H . pylori and peptic ulceration There is substantial evidence that both antral predominant chronic gastritis and chronic pan-gastritis with multifocal atrophy are caused by H. pylon‘. Why should these two patterns of involvement arise and have such clear and separate associations with DU and GU? There is evidence that the corpus is more resistant to gwtriiis in DU patients in that the rate of extension from tbe antrum and p r q r e s s i w of gastritis is much slower in such patients than in chronic gastritis patients in general.50

acid ioag

..............

.......,.Qastrin? .....

H. pylon‘

..........

i

............

Mpylorl

GASTRIC ! METAPLASiA

-I‘* 1

1

acidlpepsin

GU

H. pylori GASTRITIS

ULCER RISK

Antral predominant DU

Figure 3 Hypothetical relationship between acid production, development of gastric metaplasia, topographical pattern of H. pylori-associated gastritis and ulcer risk. Subjects with an intrinsically high acid output develop gastric metaplasia in the duodenum.When the same individuals acquire H. pylori infection they develop an antral-predominant gastritis. These two risk factors combine to predispose the subject to DU.

That there is no intrinsic or permanent barrier to inflammation is indicated by the finding of rapid extension of inflammation into the corpus after vagotomya6 and a ‘normal’ rate of progression of gastritis in the corpus of DU patients following a n t r e ~ t o m y .If~ ~we extrapolate from these findings to H. pylori infection, it seems likely that increased acid production is a factor in determining the relative resistance of the corpus to infection. This is supported by the low level of H. pylori infection in the Zollinger-Ellison ~ y n d r o m eHowever, .~~ the relative sparing of the corpus by gastritis in DU patients is not always paralleled by an absence of organisms. Helicobacter pylori can be found in the mucus overlying body mucosa, but it is possible that bacterial adhesion or some other pathogenic property is inhibited, and less inflammation ensues. If this hypothesis is true, increased acid production could underlie both the tissue response to H. pylori infection (i.e. antral restriction of gastritis) and the presence of gastric metaplasia in the duodenum -the two principal factors distinguishing DU and GU patients. Thus it can be argued that in most people H. pylori results in a diffuse chronic gastritis which leads with increasing age to multifocal atrophy and increased susceptibility to gastric ulceration, while a minority with a duodenal ulcer ‘diathesis’ exhibit relative restriction of gastritis to the antrum.

CHRONiC GASTRITIS,

antrum predominant

ACTIVE CHRONIC DUODENITIS

I

High

no

gastritis

Increased

ACID PRODUCTION

No.

...............................

DUODENAL ULCER

Figure 2 Relationship between H. pylori-associated chronic gastritis and duodenal ulceration. Subjects in whom an increased acid hvdd reaches the duodenum develop gastric metaplasia. If they subsequently acquire H. pylon infection the organisms con spread to areas of m r i c metaplasia and set up chronic inflammation.The role of increased gastrin production and consequent hyperacidity in promoting more gastric metaplasia is controversial.

CONCLUSIONS Evidence has been presented which implicates H . pylori in the pathogenesis of peptic ulceration. A consideration of the other factors involved is beyond the scope of this article, but it remains self-evident that peptic ulceration is a multifactorial disease. The interplay of acid attack and mucosal defence is modulated by many factors including environmental effects and genetic make-up. It is these factors that no doubt explain the wide discrepancy between the frequency of H . pylori infection (lifetime prevalence approximately 80%) and the comparatively small proportion who develop clinically detected peptic ulceration (lifetime prevalence around 10%).s3

H.pylori and peptic ulcer:

histopathology

While defective mucosal resistance resulting from H. pylori infection is the major, and a hitherto neglected, factor in peptic ufceration, several questions remain unanswered. For instance, if H.pylori-associated gastritis is a diffuse or multifocal process, why are 80% of gastric ulcers situated on the lesser curvature at the junction between atrophic antral type and body mucosa? Likewise, why are the majority of duodenal ulcers found on the anterior wall when gastric metaplasia is randomly distributed around the circumference? It could be that mucosa at these sites is more vulnerable than chronically inflamed mucosa elsewhere or, in the case of the duodenum, perhaps more acid is delivered to the anterior wall. For gastric ulcers some authors have invoked differences in blood supply or muscular weakness but such arguments are generally uncon~incing.~~ More persuasive is the suggestion by Oi and Sakurai that peptic ulcer is ‘the ulcer of junction’ between two mucosal tissues.ss It seems likely that junctional sites are intrinsically less stable than surrounding mucosa. Where the junction is occupied by metaplastic epithelium, reflecting as it does divergent differentiation, this adds further to the instability. This could explain the predilection for ulceration at the margin of Barrett’s mucosa and squamous epithelium, at the interface between antral mucosa showing intestinal metaplasia and body mucosa, and by analogy at the junction between gastric metaplasia and native mucosa in the duodenum. The ‘instability’ of metaplastic mucosa at junctional sites might also reflect perturbation of growth factor production so that, for example, variation in locally produced factors such as epidermal growth factor and transforming growth factor ct might underlie differences in regenerative capacity. The answer to this and allied questions will probably open up the next avenue for therapeutic advance in this condition and might have particular relevance for gastric ulceration. Most agents used in peptic ulcer treatment are aimed at reducing or neutralizing acid secretion and achieve healing by minimizing acid attack on the mucosa. Such treatments, however, have no effect on H. pylori and do not remedy the underlying gastritis or duodenitis.s6 Thus the mucosa remains vulnerable; following cessation of treatment and restoration of normal acid output, ulcer relapse is likely. In regard to DU, Goodwin has likened the inflamed mucosa to a ‘leaking roof’ where temporary dryness (healing) is assured if the rain (acid) is removed but permanent protection can only be achieved by mending the roof!57 In short, therapy which fails to address the role of H.pylon’ in the causation of the mucosal inflammation which predisposes to ulceration, is likely to confer only short-term benefit.

REFERENCES 1. CRUVEILHIER J. Traite d’anatomie pathologique generale. Balliere, Paris. 1862. 2. HEBBELR. Chronic gastritis: Its relation to gastric and duodenal ulcer and to gastric cancer. Amer. J. Pathol. 1943; 19: 43-71. H. A. The pathology of simple gastritis. J. Path. 3. MAGNUS Bact. 1946; 58: 431-9. J., SPINKR. & MITRAS. The antrum in patients 4. SCHRAGER with duodenal and gastric ulcers. Gut 1967; 8: 497-508.

129

5. TRIER J. S. Morphology of the gastricmucosainpatientswith ulcer diseases. Amer. 3. Dfg. Dis. 1976; 21: 138-40. 6. GEAR M. W. L., TRUELOVE S. C. & WHITEHEAD R. Gastric ulcer and gastritis. Guc 1971; 12: 639-45. 7. MAAROOS H. I., SALUPERE V., UIBOR., KEKKIM. & SIPPONENP. Seven year follow-up study of chronic gastritis in gastric ulcer patients. Scand. J . Guscroencerol. 1985; 20: 198-204. 8. KIMURAK. Chronological transition of the fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach. Gastroenterology 1972; 63: 584-92. 9. FUJISHIMA K., h.tISI’MI A. & AKAGI M. Histopathologic study on development and extension of atrophic change in the gastric mucosa. Gascroencerol.Yap. 1984; 19: 9-17. 10. TATSUTAM. & OKUDA S. Location, healing and recurrence of gastric ulcers in relation to fundal gastritis. Gastroenterology 1975; 69: 897-902. 11. STADELMANN 0.er ul. T h e peptic gastric ulcer: histotopographic and functional investigations. Scand.3. Gustroenreroi. 1971; 6: 613-23. 12. SIPPONEN P., SEI’PALA K., AARYNENM., HELSKE T. & KETTUNENP. Chronic gastritis and gastroduodenal ulcer: a case control study on risk of co-existing duodenal or gastric ulcer in patients with gastritis. Gut 1989; 30: 922-9. 13. JENKINS D., GOODALL A , , GILLETF. R . & SCOTT B. B. Defining duodenitis: quantitative histological study of mucosal responses and their correlations. J. Clin. Pathol. 1985; 38: 1119-26. 14. GREENLAW R.. SHEAHAN D. G., DE LUCAV.. MILLER D., MYERSON D. & MYERSON P. Gastrodqdenitis: a broader concept of peptic ulcer disease. Dig. as. Sci. 1980; 25: 660-72. IS. SIRCUSW. Duodenitis: a clinical, endoscopic and histopathological study. Q. 3. Med. 1985; 56: 593-600. 16. KREUNING J., BOSMAN F. T., KUIPER G., VAN DER WALA.

M. & LINDEMAN J. Gastric and duodenal mucosa in ‘healthy’ individuals. 3. Clin.Pathol. 1978: 31: 69-77. H. H. Definition of gastroduodenal junction in 17. LAW’SON healthy subjects. J. Clin.Pathol. 1988; 41: 393-6. 18. FITZGIBBONS P. L.,DOOLEY C. P., COHEN H. & APPLEMAN M. D. Prevalence of gastric metaplasia, i&unma~:on3 and Campylobucter pylori in the duod&um of members of a normal population. Anier. J . Clifi.I’athol. 1988; 90: 71 1-4.

19. LEELA K.,KANAGASUNTHERAM R. A microscopic study of the human pyloro-duodenal junction and proximal duodenum. Acta Anatom. 1968; 71: 1-laCpr .. 20. LESSELS A. M. & MARTIND. F. Heterotopic gastric mucosa in the duodenum. 3. Clin.Pathol. 1982; 35: 591-5. 21. SCOTT R. E. & FLORINE D. C. Cell cycle models for the aberrant coupling of growth arrest and differentiation in

hyperplasia, metaplasia and neoplasia. Amer. J . Pathol. 1982; 107: 342-7. 0. Heterotopic gastric epi22. JOHANSEN A. & HARTHANSEN thelium in the duodenum and its correlation to gastric disease and acid level. Acca Path. Microbiol. Scand. Section A. 1973; 81: 676-80. 23. PATRICK W. J. A., DENHAM D. & FORREST A. P.M. M ~ o u s change in the human duodenum: A light and electron microscopic study and correlation with disease and gastric acid secretion. Gut 1974; 15: 767-76. M., ISHIIH., Y W U U H., YAMAMOTO % 8~ 24. TATSUTA TA~GUC H. HEnhancement I by tetragastrin of experimental induction of gastric epithelium in the duodenum. Gut 1989; 30: 31 1-5. 25. GEARE. v. & DOBBINS W. 0. The histologic spectrum of

M. F. Dixon

130

proximal duodenal biopsy in adult males. Amer. 3. Med. SCi. 1969;257:90-9. 26. MEIKLED. D., TAYLOR K. B., TRUELOVE S. C. WHITEHEAD R. Gastritis, duodenitis and circulating levels of gastrin in duodenal ulcer before and after vagotomy. Gut 1976; 17: 719-28. 27. GUSLANDI M. Duodenitis. Lancet 1985;ii: 1437. 28, STAVE R., BRANDTZAEO P.,N Y ~ A W IK) & FAUSA0 . The transitional body-antrum zone in resected human stomachs: Anatomical outline and parietal cell and gastrin cell characteristics in peptic ulcer disease. Scand. J . Gastroented. 1978;13: 685-91. 29. KIRKR.M. An overlooked factor in duodenal ulceration and postoperative recurrence? Gut 1988;29: 1625-7. 30. CARRICK J., LEEA,, HAZELLS., RALSTON M. & DASKALOt ) o u L o s G. Campylobacter pylori, duodenal ulcer, and gastric metaplasia: possible role of functional heterotopic tissue in ulcerogenesis. Gut 1989; 30: 790-7. 31. DIXONM.F.Campylobacter pylori and chronic gastritis. In: Kathboiie 8.J ., Heatley R. V., eds, Campylobacter pylori and Gastroduodenal Disease. Blackwell Scientific Publications, Oxford. 1989;106-16. 32. FI.EJOUJ . F., RAIIAMEP., SMITHA. C. et al. Pernicious anaemia and Campylobacter-like organisms: Is the gastric antrum resistant to colonization? Gut 1989;30: 60-4. 33. DIXONM. F., WYATTJ. I., BURKED. A. & RATHBONE B. J. 1.vmphocytic gastritis: relationship to Campylobacter pylori infection. 9. PdioL. 1988; 154: 125-32. B. & HAOTJ. evaluation histologique 34.,&~LLEZ L.,WEYNAUD de la presence d’organismes de type Campylobacter dans les gastrite lymphocyuires. Acid Endoscop. lY87; 17: 41-50. H. J., DIXONM.P.,WYATTJ. I. et al. Effect of 35. O’CONNOR duodenal ulcer surgery and enterogastric reflux on Cumpylohucrer pyloridis. Lancet 1986;ii: 1178-81. 36. EVANS D. G., EVANS D. J.. MOUI.DSJ. J. & GRAf1AM D. Y. N-acer~lneuraminyllactose-hinding fibrillar haemagglutinin of Cawpyiobacterpylori: a putative colonizationfactor antigen. Infect. Immun. 1988; 5 6 2896-906. 37. LINGWOOD C. A., LAWH., PELLIZZARI A., SHERMAN P.& DRUMM B. Gastric glycerolipid as a receptor for Campylobacrcr pylori. I,ancc,r 1989;ii: 238-41. 3X. W Y A1 1 J . L., RA’I‘HBONEB. J., DIXON M. F. & HEATLEY R. V. CarnzwtdacrerpyWslurel acid induced gastric metaplasia in the pathogenesis of duodenitis. J. Clin. Pathol. 1987; 40: 841-8. 39. J W N S T O N B. J.. REED P. I. & A1.r M. H. Prevalence of Campylobacter pylori in duo!enal and gastric mucosa: relationship to inflammation. Scand. J . Gastroenterol. 1988; 23 (SUPPI,142): 69-75. 40. WYATT J. I., RATHBONE B. J., S O ~ A LG. A et al. Gastric epithelium in the duodenum: Its association with Helicobactm pvlori and inflammation. J. Clin. Pathol. 1990;43:981-6. 41. 1’hKKl5ll J . A. & RAWLINSD. C. Intestinal mucosa in the ZoJlim=-EJliaon syndrome.&Gut1965; 6: 286-9. D. & RUBIN C.E. The Zollinger42. SHIMoDA S . , SAUNDERS F k o n syndrome with steatorrhoea.The mechanism of fat and vitamin I312 malabsorption. Gaslroerrterokgy 1968;55: 705-8. 43. MANsBACHc. M., WILKINSR.M,*ROJUJN~0.& TYOR M. p. Intestinal mucosal function and structure in the steatorrhoea of Zollinger-Elliso!i syndrome. Arch. Intern. Med.

w.

1968: 121: 487-94. 44. HAWM N . Y., WILSONti. E., MAWIND. I:., I : A R ~ ~ ; ~

E*B.,m D D m c.,MILLER J. P. Duodenal gastric heterotoPia and Campylobacterpylori: an exception to the rule?J. Clin. 13ath01. 1989;42: 111L.

45. SIURALA M.,SIPPONEN P. & KEKKIM. Campylobacter pylori in a sample of Finnish population: relations to morphology and functions of the gastric mucosa. Gut 1988;29: 909-15. 46. LEVIS.,BEARDSHALL K., HADDAD G., PLAYPORD R., GHOSH P. & CALAM J. Campylobacter pylori and duodenal ulcers: the gastrin link. Lancet 1989; i: 1167-8. 47. MCCOLLK.E. L., FULLARTON G. M., EL NUJUMI A. M., MACDONALDA. M., BROWN I. L. & HILDtTCH T . E. Lowered gastrin and gastric acidity after eradication of Campylobacter pylori in duodenal ulcer. Lancet 1989; ii: 499-500. 48. BEHOLZ S., SCHMIDT F., WAGNER S . & FREISE J. Campylobacter pylori and gastric acidity. Amer.3. Gastroenterol. 1989; 84:201-2. 49. CAVED. R., VARGAS M. Effect of a Campylobacter pylori protein on acid secretion by parietal cells. Lancet 1989; ii: 187-9. 50. KEKKIM.,SIPPONEN P. & SIURALA M. Progression of antral and body gastritis in patients with active and healed duodenal ulcer and duodenitis. Scand. 3. Gastroenterol. 1984;19:382-8. 51. KEKKIM., SAUKKONEN M., SIPPONEN P., VARISK. & SIURALA M. Dynamics of chronic gastritis in the remnant after partial gastrectomy for duodenal ulcer. Scand. 3. Gastroenterol. 1980; 15: 509-12. 52. GRAHAM D. Y.Campylobacterpylori and peptic ulcer disease. Gastroenterology 1989;96: 615-25. 53. BORSCHG. M. A. Clinical significance of Campylobacter pylori. Europ. J . Gastroenterol. Hepat. 1989;1: 27-33. S. The location of gastric 54. 01M., OSHIDAK. & SUGIMURA ulcer. Gastroenterology 1959;36: 45-56. 55. Or M.& SAKURAI Y. The location of duodenal ulcer. Gastroenterology 1959;36: 60-4. 56. FULLMAN H.,VANDEVENTER G., SCHNEIDMAN D., WALSH J., ELASHOFF J. & WEINSTEIN W. ‘Healed’duodenal ulcers are histologically ill. Gastroenterology 1985;88: 1390. 57. GOODWIN C.S . Duodenal ulcer, Campylobacter pylori and the ‘leaking roof’ concept. Lancet 1988; ii: 1467-9. 58. NIEMALA S.,KARTTUNEN T . & LEHTOLA J. Campylobacterlike organisms in patients with gastric ulcer. Scand. J . Gastroenterol. 1987; 22: 487-90. 59. O’CONNOR H.J.,DIXONM. F., W Y ~ TJ.T I., AXONA. T. R., DEWAR E. P. & JOHNSTON D. Campylobacter pylori and peptic ulcer disease. Lancet 1987; ii: 633-4. 60. HUIW.M.,LAMS.K.,C w P . Y. et al. Pathogenetic role of Campylobacter pyloridis in gastric ulcer. 3. Gastroenterol. Hepatol. 1987; 2: 309-16, 61. JIANC S.J., LIUW. Z., ZHANGD. 2. et al. Campylobacter-like organisms in chronic gastritis, peptic ulcer, and gastric carcinoma. Scand. 3. Gastroenterol. 1987;22: 553-8. 62. FIOCCAR., VILLANIL., T U R P I N I R. & SOLCIAE. High incidence of Campylobacter-like organisms in endoscopic biopsies from patients with gastritis, with or without peptic ulcers. Digestion 1987; 38: 234-44. 63. RAUWS E. A. J. & TYTGAT G. N. J. Campylobacter pylori. Thesis published by Academic Medical Centre, Amsterdam. 1989;p. 20. 64. COCHLAN J. G., GILLWAND., HUMPHRIESH. et al. Campylobarter p.vbri and recurrence of duodenal ulcers: a 12 month follow-up study. Lancet 1987; ii: 1109-11. 65. MARSHALL B. J., GOODWINC. S., WARRENJ. R. et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of CmpyIobacter pylon‘. Lancet 1988;ii: 1437-41. ~66. ~ : ~BAYERD~RFFER E., OERTELH., LEHNN. et al. Topographic association between active gastritis and Campylobacter pylori colonisation. J . Clin. Pathol. 1989;42: 8349.