ADONIS 081593 199100041I

Journal of Gastroenterology and Hepatology (1991) 6, 238-243

The Sydney System: Auto-immune gastritis ROBERT G. STRICKLAND Department of Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, U S A

Abstract The association of gastric auto-immunity with chronic gastritis has been recognized for more than 30 years. Despite this, little is known about the initiation of auto-immune gastric mucosal injury or the role of gastric auto-antibodies in this disease process. The current review describes recent progress in our understanding of these fundamental questions on the origin and progression of auto-immune gastritis. In addition, evidence is presented (epidemiologic, clinical, pathologic and experimental) that strongly supports the view that auto-immune gastritis is a distinctive category of chronic gastritis with significant long-term sequelae. Key words: auto-immunity, gastritis.

INTRODUCTION In the 1980s, studies relating to the Gram-negative bacterium, Helicobacter pylori (HP) and to its identification as a gastric pathogen causally related to gastritis in humans has overshadowed significant advances in the field of gastric auto-immunity and the role of this pathogenetic mechanism in gastritis. This review focuses on recent studies of auto-immune gastritis (AIG)-in particular, work that is beginning to define the nature of gastric auto-immune reactions at the molecular level and to explore.the induction *phaseof AIG in a murine experimental model of organ-specific autoimmunity. The role of HP in AIG, together with a reappraisal of the clinical significance of AIG, are also presented.

HISTORICAL BACKGROUND T h e initial link between the immune system and diffuse chronic inflammatory disease of the gastric mucosa was established more than 30 years ago with the identification of circulating auto-antibodies to gastric intrinsic factor and to gastric parietal cells in patients with pernicious anaemia (PA) .1-4 In the 1960s, studies concentrated on characterization of these gastric auto-immune reactions and their clinicopathologic correlations. Two types of intrinsic factor antibodies (IFA) were described using radioassay; blocking (Type I) IFA was present in 70% and binding (Type 11) Parietal cell antiIFA was present in 30% of PA body (PCA) detectable by complement fixation or immunofluorescent techniques was found to be distinct from IFA and present in 80-90% of PA sera.4 The parietal cell antigen was shown to be microsomal and lipoprotein in nature and to be localized to microvilli of the secretory

canalicular system of this ~ e 1 1 .Immunopathologic ~*~ studies of the gastric mucosa in PA suggested a predominantly B-cell response and local production of both IFA and PCA was d e m ~ n s t r a t e d . ~ Early clinico-pathologic correlations showed that IFA was restricted to evolving or established PA.l0 PCA, while less restricted (2-40/, of adults), was strongly associated with chronic gastritis of variable severity.ll"Z A much higher prevalence of PCA and chronic gastritis (approximately 30%) was observed in PA relatives and patients with ~ *contrast, '~ a variety of endocrine disorders ~ i v i t i l i g o . ~By PCA was absent in gastritis associated with peptic ulceration or the post-gastrectomy state.lo In the 1970s, additional observations were made on the pathophysiology and course of AIG, on experimental gastric auto-immunity and on the prominent genetic factor in this disorder. It was shown that patients with PCA-positive atrophic gastritis displayed a pathophysiologic profile similar to fully developed PA (corpus-predominant gastritis with hypergastrinaemia) and that PA evolved almost exclusively from this form of gastritis.l5.l6 Auto-allergic models of chronic gastritis were induced by immunization with crude gastric mucosal antigens in several animal species17*18and biological effects of human gastric auto-antibodies were observed in v i v o in rodents and in an in vitro preparation of amphibian ~ t o m a c h . ~ ~ - ~ * The gastritis in first-degree PA relatives was shown to be largely corpus-predominant and immunogenetic studies suggested significant but weak linkage with the HLA-D locus.22-24

GASTRIC AUTO-IMMUNE REACTIONS: RECENT STUDIES In the past decade, several new observations have added significantly to our understanding of the nature of the parietal cell auto-antibody reaction.

Correspondence: Prof. R. G. Strickland, Department of Medicine, University of New Mexico School of Medicine, Albuquerque NM USA. Accepted for publication 14 December 1990.

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The Sydney System: Auto-immune gastritis

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Whereas initial descriptions had identified PCA as reH + K t-ATPase, the proton pump of the gastric parietal active to gastric microsomal antigen(s), studies using gascell, is the major parietal cell microsomal antigen. tric mucosal cell suspensions identified antibodies in PA A further study using similar methodology identified sera reactive to the surface of parietal cells.25This observareactivity in PA sera to pepsinogen in addition to H+K+tion was confirmed26and using a large panel of PA sera it A T P ~ sChief ~ . ~cell ~ destruction is a component part of the was suggested that the parietal cell surface antibody gastric pathology in PA and for the first time evidence is (PCSA) was distinct from that directed towards gastric emerging that gastric auto-immune reactions may extend microsomes (PCMA). A further study by this group of to involve both specialized cell types in the gastric mucosa. investigators demonstrated in vitro complement-dependThus, recent studies have uncovered additional heteroent cytotoxicity of PA sera containing PCSA using parietal geneity of gastric auto-antibodies beyond PCA and IFA (Fig. 1). The antigens involved in such reactions are begincell-enriched suspensions from canine gastric mucosa as ning to be understood at the molecular level and potential target cells.f7 Many of the sera tested in this assay conmechanisms whereby these auto-antibodies could contribtained both PCSA and PCMA but 10 of 12 PCSA-positute to gastric structural and functional impairment in vivo ive, PCMA-negative sera displayed cytotoxicity and 0 of 6 PCSA-negative, PCMA-positive sera were ~ y t o t o x i c . ~ ~ are readily evident. In addition to PCSA, reactivity to the gastrin receptor of parietal cells in PA sera was also proposed by these inTHE ORIGIN OF AIG: STUDIES OF vestigators.z* Serum IgG fractions from 6 of 20 PA sera were shown to inhibit specific binding of radiolabelled A MUHINE MODEL human G I 7 to isolated rodent parietal cells. Moreover, these sera inhibited gastrin-stimulated but not histamineHuman AIG is a disorder which in general remains clinicstimulated [14C]-aminopyrine accumulation in the parietal ally silent until vitamin B,, deficiency becomes manifest or cell preparations. Unfortunately, two subsequent attempts unless a suspected association (e.g. PA relative, endoto reproduce these findings by other investigators were crinopathy) initiates evaluation for subclinical disease. unsuccessfu1.29~30 Thus the existence of a gastrin-receptor Thus, knowledge about the induction phase of this disease auto-antibody in PA must be questioned at this time. in humans is quite unclear and indeed its onset has never In studies reported towards the end of the 1980s, been clearly defined in affected patients. It is apparent that workers in Sweden identified what appears to be the major most studies of human A I G have focused on the fully parietal cell microsomal antigen.29s31In the first report it expressed disorder in its advanced stage. was shown that PCMA-containing sera recognized In order to study the initiation of AIG we must therea 92 kDa protein in tubulovesicular membrane preparafore turn to experimental models of this disease. The most tions from porcine gastric mucosa, this preparation being promising model of AIG is that occurring in inbred mouse . ~ ' membrane rich in the enzyme H t K + - A T P ~ s ~These strains in response to 2 4 day neonatal thymectomy and/or preparations, but not porcine kidney membranes, rich in limited (1 week) neonatal administration of Cyclosporin Na+K+-ATPasewere shown to inhibit PCMA binding to A.33-35This results in the development of organ-specific gastric mucosa cell lysates in a dose-dependent fashion.31 auto-antibodies and inflammatory disease of the thyroid, In a subsequent report this group demonstrated that stomach, adrenal cortex, pancreatic islets, ovary, testis and PCMA was inhibitory to H'K' -ATPase activity of porprostate in a pattern similar to that occurring in organcine gastric mucosal tubulovesicular membranesz9 Morespecific auto-immune disease in humans. Variable suscepover, the degree of enzyme inhibition correlated directly tibility between inbred mouse strains and variable pattern with the titre of PCMA in individual sera tested.29 This and frequency of organ involvement in sensitive strains are work strongly indicates that canalicular membrane

Gastrin receptor? F

I

intrinsic factor

Figure 1 The human parietal cell, illustrating heterogeneity of the autoantibody response in PA serum

1

R . G. Strickland

240

key features reflecting the existence of genetic susceptibility in this The gastritis that occurs in this murine model displays a remarkable resemblance to human AIG Table 1.34q37 Thus, up to 50% of animals (BALB/c nu/ most susceptible) show chronic gastritis which is confined to the gastric corpus. Parietal cell and chief cell destruction is accompanied by marked mucosal lymphoid infiltration. T cell infiltration is prominent early and is followed by later (3 months) appearance of B cell predominance. In contrast to human AIG the gastric mucosa is hypertrophic due to marked foveolar cell hyperplasia. However, affected animals develop achlorhydria, impaired intrinsic factor secretion and vitamin B,, malabsorption when observed for a 12 month period. Parietal cell microsomal antibody appears within 3 months and there is complete concordance between PCMA and the presence of gastritis. In addition, there appear to be close similarities between the parietal cell microsomal antigenic target in murine and human AIG.38 The mechanisms involved in the induction of organspecific auto-immunity in this model are at present incompletely understood. Thymectomy before day 2 or after day 4, or delayed Cyclosporin A treatment, are not followed by organ-specific auto-immune disease. Normal adult T cells can prevent disease in thymectomy- or Cyclosporintreated animals. Adoptive transfer of disease can be accomplished by T cells but not serum from thymectomy animals. From these observations it is clear that the T cell is central to disease initiation in this model. It is

+

hypothesized that neonatal thymectomy or Cyclosporin administration leads to depletion of organ-specific suppressor T cells that function to restrain (normally present) ~ * ~ nature O and interacautoreactive effector T c e l l ~ . ~ The tions of such T cells are not fully defined. However, in animals with AIG delayed-type hypersensitivity, T cells reactive to gastric antigens appear to comprise part of the effector response.37 While this murine model closely mimics and is probably relevant to human AIG and associated organ-specific autoimmune endocrinopathy, it fails to explain how these disorders are actually initiated in humans. Moreover, loss of organ-specific T suppressor cells or demonstration of organ-specific autoreactive T effector mechanisms have not yet been identified in human AIG. Perhaps the identification of relevant auto-antigens at the molecular level, together with cloning of T cells involved in effector and regulatory phases of auto-immunity, will allow clearer understanding of the initial events in AIG in the

HELICOBACTER PYLORI IN AIG There is convincing evidence now that H . pylori is the major cause of chronic gastritis in humans. The high frequency of infection with this organism in adults inevitably raises questions on the role of H . pylon' in AIG. Could H . pylori be an initiating factor with auto-immune reactions supervening in a genetically determined subset of those infected?

Table 1 Comparison of human and murine experimental auto-immune gastritis ~~

~

Human AIG

Murine AIG

Corpus-predominant chronic gastritis

Yes

Yes

Chief parietal cell destruction

t

+

Lymphoid infiltration

T cell ( + ) B cell (+ +)

T cell early B cell late

Foveolar cell hyperplasia

Absent (atrophy, metaplasia)

++

Yes

Yes

+

50% at 12 months

Associated endocrinopathies

+ (variable frequency)

+ (variable frequency)

Systemic A1 disease

Absent

Absent

+ (?D locus)

+ (Non-H,)

PCA

Near complete concordance with gastritis

Concordance with gastritis complete

Parietal cell antigen

Membrane H', K+-ATPASE of secretory canaliculi

Microsomal, tubulovesicular membrane pro-

+

Not reported

Gastric morphology

Gastric function Hypo, achlorhydria Impaired if secretion, vitamin B,, absorption

Genetic susceptibility

IFA

tein

The Sydney System: Auto-immune gastritis

Recent studies in patients with advanced AIG or PA indicate that H. pylori colonization of the gastric mucosa is in fact less frequently observed in these patients than in the general p ~ p u l a t i o n .In ~ ~a 'study ~ ~ of 86 patients with PA, H. pylori was found to be present in only 3 of 86 corpus mucosal biopsies and 1 of 44 antral biopsies available from these patients.41 Six of the 44 antral biopsies (1 5 % ) in this study revealed gastritis of an equivalent grade of severity to that observed in the corpus mucosa and H. pylori was not detected in these 6 biopsies. Repeat biopsies 5 years later revealed unchanged histology and no new acquisition of H. ~ y l o r i . ~ , In a Finnish population-based study, H. pylori was found to be absent in all subjects defined by mucosal biopsy as corpus-predominant atrophic gastritis, whereas 95% of subjects with antral-predominant and 72",,, of those with pan-atrophic gastritis were colonized with this organism." Unpublished observations of circulating antibodies to H.pylori in patients with advanced AIG indicate a low frequency of positive serologic responses, suggesting lack of prior exposure to this organism. Thus, it appears that advanced AIG presents an unfavourable environment for colonization and/or persistent infection with H. pylori. This does not, however, eliminate a possible role of this organism in the initiation or earlier stages of AIG. There are no published studies which have investigated H. pylori colonization in less severe grades of chronic gastritis assqciated with gastric auto-immune reactions.

THE CLINICAL SIGNIFICANCE OF AIG: PREVALENCE & SEQUELAE AIG is an infrequent cause of chronic gastritis in humans. The prevalence of parietal cell auto-antibody is 2 4 % of the adult population in developed countries,43 and increases with advancing age (approximately 10% in the seventh and eighth decades). This age-related rise in PCA has been attributed to loss of immunoregulatory function among older subjects. In addition, advanced AIG constitutes a small fraction of all subjects with chronic gastritis. Thus, in Finnish population-based studies, atrophic gastritis was found to be present in approximately of subjects with gastritis. Only 10% of those with atrophic gastritis, however, were corp~s-predominant.~~ T h e major complication of AIG is Addisonian PA. FoIlow-up studies for periods of up to 15 years indicated, however, that only 15-200/b of patients with AIG progress to PA.15.16The only clear risk factor identified as a determinant for the transition of AIG to PA is the development of auto-immunity to gastric intrinsic factor.'O In addition to vitamin B,, deficiency, recent work has re-emphasized the occurrence of iron deficiency in patients with longstanding PA.45 It has long been held that Addisonian PA represents a significant risk factor for the development of gastric adenocarcinoma. Earlier studies estimated a 3-fold increase in risk of gastric cancer in PA above that observed in the general p o p ~ l a t i o nFurthermore, .~~ endoscopic screening in PA identified hyperplastic polyps in 20%, severe epithelial dysplasia in 304 and invasive adenocarcinoma in lo/, of 80 patients so

24 1

In view of the overall low prevalence of AIG, however, this form of gastritis is a numerically infrequent precursor of gastric epithelial rnalignancy;15 chronic gastritis due to H. pylori appears to be a quantitatively more significant premalignant lesion of the stomach. A rare form of gastric neoplasia, carcinoid tumour, does appear to be particularly associated with AIG. A survey of 30 patients with gastric carcinoid turnours found that 16 had either 'established PA or AIG.48The tumours in these 16 patients were multicentric, horrnonally silent and arose in atrophic corpus m u c o ~ aA. ~recent ~ report of endoscopic screening in 123 patients with PA identified 5 patients with . ~ addition, ~ solitary (4) or multiple (1) gastric c a r c i n o i d ~In argyrophil enterochromaffin-like cell (ECL) hyperplasia was present in the corpus mucosa in 40 of the 123 patients. It was suggested that sustained, longstanding hypergastrinaemia provides the stimulus for ECL hyperplasia and perhaps carcinoid neoplasia in AlG.49

CONCLUSIONS Auto-immune gastritis is a distinctive but low-prevalence form of chronic gastritis which frequently accompanies other organ-specific auto-immune diseases in humans. The mechanisms involved in the initiation of autoimmune gastritis remain uncertain but genetic susceptibility, together with a disturbance of organ-specific T cell imrnunoregulation, appear to be key factors. There is no direct evidence indicating involvement of environmental factors such as H. pylori infection in this form of chronic gastritis. Auto-immune gastritis displays significant variability in its clinicopathologic expression. In part this may relate to the spectrum of gastric auto-antibody respoiises and their respective effects on gastric structure and function. The gastritis itself is usually clinically silent and the clinical significance of auto-immune gastritis relates to the sequelae of advanced disease-namely, vitamin B,, deficiency, iron deficiency and gastric neoplasia.

REFERENCES 1 . TAYLOR K. B. Inhibition of intrinsic factor by pernicious anema sera. Lancet 1959; ii: 10643. 2. SCHWARTZ M. Intrinsic factor antibody in serum from patients with pernicious anemia. Lancet 1960; ii: 1263-67. 3. IRVINE W. J., DAVIES S. H., DELAMORE I. M. et al. Immunological relationship between pernicious anemia and thyroid disease. BM3. 1962; 2: 454-6. 4. TAYLOR K. B., ROITT I. M., DONIACH D. et al. Autoimmune phenomena in pernicious anemia: gastric antibodies. BMJ 1962; 2 : 1347-52. 5. GARRIDO-PINSON G. C., TURNER M. D., CROOKSTON J. H. et al. Studies of human intrinsic factor auto-antibodies. 3. Immunol. 1966; 97: 897-912. 6. SAMLOPP I. M., KLEINMAN M. S., TURNER M. D. et al. Blocking and binding antibody to intrinsic factor and parietal cell antibody in pernicious anemia. Gastroenterology 1968; 55:

575-83.

R. G. Strickland

242

7. BAURS., ROITTI. M. & DONIACH D. Characterization of the human gastric parietal cell autoantigen. Immunology 1965; 8: 62-8. 8. HOEDEMAEKER P. J. & ITO S. Ultrastructural localization of

gastric parietal cell antigen with peroxidase-coupled antibody. Lab. Invest. 1970; 22: 184-8. J . M. STRICKLAND R. G. et al. Autoanti9. BAURS., FISHER body -containing cells in the gastric mucosa in pernicious anemia. Lancet 1968; ii: 887-90. J. M., MACKAYI. R., TAYLOR K. B. et al. An 10. FISHER immunologic study of categories of gastritis. Lancet 1967; i: 176-80. K., HOEDEMAEKER P. J., ANDERS G. J. P. A. et al. 11. TEVELDE

A comparative morphological and functional study of gastritis with and without autoantibodies. Gastroenterology 1966; 51: 13-48,

12. WRIGHTR., WHITEHEAD, R., WANGELA. G. et al. Auto-

antibodies and microscopic appearance of gastric mucoia. Lancet 1966; i: 618-21. A. G., CALLENDER S. T., SPRAY G. H. et al. A fam13. WANGEL ily study of pernicious anemia. I autoantibodies, achlorhydria, serum pepsinogen and vitamin B,2. Brit. 3. Haemat. 1968; 14: 161-81. R. G. Gastritis. Front. Gastrointest. Res. 1975; 14. STRICKLAND 1: 12-48. 15. STRICKLAND R. G. & MACKAY I. R. A reappraisal of the

nature and significance of chronic atrophic gastritis. Amer. 3. f i g . Dis. 1973; 18: 42640. 16. IRVINEW. J., CULLEND. R. & MAWHINNEY H. Natural history of autoimmune achlorhydric atrophic gastritis. A 1-15 year follow-up study. Lancet 1974; ii: 482-5. 17. ANDRADA J. A., ROSEN. R. & ANDRADA E. C. Experimental autoimmune gastritis in the rhesus monkey. Clin. Exp. Zmmuno/. 1969; 4: 293-310. 18. KROHNK. J . E. & FINLAYSON N. D. C. Interrelations of humoral and cellular immune responses in experimental canine gastritis. Clin. Exp. Immunol. 1973; 14: 237-45. N. & GLASSG. B. J. Effect of prolonged administra19. TANAKA tion of parietal cell antibodies from patients with atrophic gastritis and pernicious anemia on the parietal cell mass and hydrochloric acid outputs in rats. Gastroenterology 1970; 58:

surface reactive autoantibody in pernicious anemia demonstrated by indirect membrane immunofluorescence. Clin. Exp. Immunol. 1983; 52: 341-9. H. J., COSGRAVE L. J., UNGARB. et al. 27. DE AIZPURUA Autoantibodies cytotoxic to gastric parietal cells in serum of patients with pernicious anemia. N. Engl. 3. Med. 1983; 309: 625-9. J., UNGARB. & T O HB. H. Autoantibody to 28. DEAIZPURUAH.

the gastrin receptor in pernicious anemia. N. Engl. J . Med. 1985; 313: 479-83. P., MARDHS., NORBERGL. et al. Parietal cell 29. BURMAN

antibodies in pernicious anemia inhibit H + , K '-adenosine triphosphatase, the proton pump of the stomach. Gastroenterology 1989; 96: 1434-8. A., HAMPSON S. E. et al. Absence of 30. SMITHJ. T . L., GARNER gastrin inhibitory activity in the IgG fraction of serum from patients with pernicious anemia. Gut 1989; 30: A721. F. A,, BURMAN P., LOOFL. et al. Major parietal 31. KARLSSON cell antigen in autoimmune gastritis with pernicious anemia is the acid-producing H f , K+-adenosine triphosphatase of the stomach. 3. Clin. Invest. 1988; 81: 475-9. 32. MARDHS. & SONGY-H. Characterization of antigenic structures in autoimmune atrophic gastritis with pernicious anemia. The parietal cell H, K-ATPase and the chief cell pepsinogen are the two major antigens. Acta Physiol. Scand. 1989; 136: 581-7. 33. KOJIMA A., TANAKA-KOJIMA Y., SAKAKURA T . et al. Spon-

taneous development of autoimmune thyroiditis in neonatally thymectomized mice. Lab. Invest. 1976; 34: 550-7. 0. & NISHIZUKA Y. Experimental 34. KOJIMAA., TAGUCHI production of possible autoimmune gastritis followed by macrocpic anemia in athymic nude mice. Lab. Invesc. 1980; 42: 387-95. S. & SAKAGUCHI N. Organ-specific autoimmune 35. SAKAGUCHI

disease induced by elimination of T cell subset. V. Neonatal administration of cyclosporin A causes autoimmune disease. 3. Immunol. 1989; 142: 471-80. A. & PREHNR. T . Genetic susceptibility to post36. KOJIMA thymectomy auto immune disease in mice. lmmunogenetics 1981; 14: 15-27. 37. FUKUMAK., SAKAGUCHIS., KURIBAYASH K. ec al.

482-94. 20. INADA M. & GLASSG. B. J. Effect of prolonged administra-

tion of homologous and heterologous intrinsic factor antibodies on the parietal and peptic cell mass and the secretory function of the rat gastric mucosa. Gastroenterology 1975; 69:

38.

396408. N., BITENSKY L., CHAYEN J. et al. Inhibition of 21. LOVERIDGE

parietal cell function by human gammaglobulin containing gastric parietal cell antibodies. Clin. Exp. Immunol. 1980; 41:

39.

264-70. 22. VARIS K., IHAMAKI T., HAKKONEN M. er al. Gastric morpho-

23.

24. 25.

26.

logy, function and immunology in first degree relatives of probands with pernicious anemia and controls. Scand. 3. Gastroenterol. 1979; 14: 129-39. THOMSEN M., JORGENSEN F., BRANDSBORG M. et al. Association of pernicious anemia and intrinsic factor antibody with HLA-D. Tissue Antigens 1981; 17; 97-103. UNGARB., MATHEWS J. D., TAITB. D. et al. HLA-DR patterns in pernicious anemia. Lancet 1981; i: 768-70. MASALAC., SMURRA G., DEPRIMAM. A. ec al. Gastric parietal cell antibodies. Demonstration by immunofluorescence of their reactivity with the surface of the gastric parietal cells. Clin. Exp. Immunol. 1980; 41: 271-80. DE AIZPURUA H. J., TOHB. H. & UNGARB. Parietal cell

40. 41.

42.

43.

Immunologic and clinical studies on murine experimental autoimmune gastritis induced by neonatal thymectomy . Gastroenterology 1988; 94: 274-83. MORIY., FUKUMA K., ADACHIY. et al. Parietal cell autoantigens involved in neonatal thymectomy-induced murine autoimmune gastritis. Studies using monoclonal autoantibodies. Gastroenterology 1989; 97: 364-75. TAGUCHI 0.& NISHIZUKA Y. Self tolerance and localized autoimmunity. Mouse models of autoimmune disease that suggest tissue-specific suppressor T cells are involved in self tolerance. 3. Exp. Med. 1987; 165: 146-56. ELSONC. 0. Do organ-specific suppressor T cells prevent autoimmune gastritis? Gastroenterology 1990; 98: 225-9. FLEJOUJ-F., BAHAMEP., SMITHA. C. el al. Pernicious anemia and Campylobacter-like organisms: is the gastric antrum resistant to colonization? Gut 1989; 30: 60-4. 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. STRICKLAND R. G. & HOOPER B. The parietal cell heteroantibody in human sera: Prevalence in a normal population and relationship to parietal cell autoantibody. Pathology 1972; 4: 259-63.

44. KEKKIM., SIURALA M., VARISK. ec al. Classificationprinci-

The Sydney System: Auto-immune gastritis

pals and genetics of chronic gastritis. Scand. J. Gastroenterol. 1987; 22 (suppl.): 1-28. 45. ATRAHH. I. & DAVIDSON R. J. L. Iron deficiency in pernicious anemia: A neglected diagnosis. Postgrad. Med. J . 1988; 6 4 110-1. 46. MOSBECH J. & VIDABAEK A. Mortality from and risk of gastric carcinoma among patients with pernicious anemia. BM3. 1950; 2: 3 9 0 4 . 47. STOCKBRUGGER R. W., MENONG. G., BEILBY J. 0.W. et al.

243

Gastroscopic screening in 80 patients with pertziciowmemia. Gut 1983; 24: 1141-7. 48. CARNEY J. A., GO V. L. W., FAIRBANKS V. F. et al. The syndrome of gastric argyrophil carcinoid tumors and nonantral gastric atrophy. Ann. Znt. Med. 1983; 99: 761-6. 49. BORCH K., RENVALL H. & LIEDBERG G. Gastric endocrine cell hyperplasia and carcinoid tumors in pernicious anemia. Gastroenterology 1985; 88: 638-48.