Autoimmune gastritis (AIG) is an immunomediated disease targeting parietal cells, eventually resulting in oxyntic-restricted atrophy. This long-term follow-up study aimed at elucidating the natural history, histological phenotype(s), and associated cancer risk of patients with AIG consistently tested H. pylori-negative (naïve H. pylori-negative subjects).

Two-hundred eleven naïve H. pylori-negative patients (tested by serology, histology, molecular biology) with AIG (F:M=3.15:1; p<0.001) were prospectively followed up with paired biopsies (T1 vs T2; mean follow-up years:7.5 (SD:4.4); median:7). Histology distinguished non-atrophic versus atrophic AIG. Atrophy was further subtyped/scored as non-metaplastic versus metaplastic (pseudopyloric (PPM) and intestinal (IM)). Enterochromaffin-like-cell (ECL) status was categorised as diffuse versus adenomatoid hyperplasia/dysplasia, and type 1 neuroendocrine tumours (Type1-NETs).

Over the long-term histological follow-up, AIG consistently featured oxyntic-predominant-mononuclear inflammation. At T1, PPM-score was greater than IM (200/211 vs 160/211, respectively); IM scores increased from T1 to T2 (160/211 to 179/211), with no changes in the PPM prevalence (T1=200/211; T2=201/211). At both T1/T2, the prevalence of OLGA-III-stage was <5%; no Operative Link on Gastritis Assessment (OLGA)-IV-stage occurred. ECL-cell-status progressed from diffuse to adenomatoid hyperplasia/dysplasia (T1=167/14 vs T2=151/25). Type1-NETs (T1=10; T2=11) always coexisted with extensive oxyntic-atrophy, and ECL adenomatoid-hyperplasia/dysplasia. No excess risk of gastric or other malignancies was found over a cumulative follow-up time of 10 541 person years, except for (marginally significant) thyroid cancer (SIR=3.09; 95% CI 1.001 to 7.20).

Oxyntic-restricted inflammation, PPM (more than IM), and ECL-cell hyperplasia/neoplasia are the histological AIG hallmarks. Compared with the general population, corpus-restricted inflammation/atrophy does not increase the GC risk. The excess of GC risk reported in patients with AIG could plausibly result from unrecognised previous/current H. pylori comorbidity.

The earliest recorded history of autoimmune gastritis can be traced to 1849 in London, when Thomas Addison described "a very remarkable form of anemia" later called pernicious (fatal) anemia (PA). This was followed by the recognition of a gastric mucosal defect suspected to have a nutritional basis, the discovery of the megaloblast that characterized the anemia, the insufficiency of a dietary extrinsic factor characterized as vitamin B12 (cobalamin), and a gastric-secreted intrinsic factor. Treatment with vitamin B12 proved curative. The link between PA and gastritis and atrophy was first confirmed histologically after immediate fixation of the stomach postmortem and later, in the 1940s, by peroral tube biopsy. The causes of gastritis remained enigmatic until the era of autoimmunity, when autoantibodies were detected first to gastric intrinsic factor and then to gastric parietal cells. Hints of a dichotomy in pathogenesis of gastritis were crystallized by the description in 1973 of Type A (Autoimmune) and Type B (later, Bacterial) gastritis. Clarification was enhanced by identification in Type A gastritis of the autoantigen of the parietal cell antibody, by the alpha and beta subunits of gastric H+/K+ ATPase, and by the highly informative experimental murine model of postneonatal thymectomy autoimmune gastritis, and in Type B of the causative role of gastric infection with Helicobacter pylori (H. pylori). A denouement will require a full understanding of (1) the origin and pathogenetic contribution of antibody to intrinsic factor; (2) the connection, if any, between H. pylori infection and Type A autoimmune gastritis; and (3) the genetic contributions to gastritis, whether due to autoimmunity or to H. pylori infection.

We have analyzed the prevalence of pernicious anemia (PA) in all patients with autopsyverified gastric carcinoma (GC) registered during 1958-76 in a Swedish city, with one Department of Pathology serving approximately 240 000 inhabitants and with a high autopsy frequency. The prevalence was compared to that in a reference group of 917 sex- and age-matched individuals without GC. PA was found in 19 persons, 2.1%, (7 males and 12 females) in the GC group and in 13 persons, 1.4%, (5 males and 8 females) in the reference group. This difference is not significant (p less than 0.15). After exclusion of individuals with PA known for less than 5 years before death, the corresponding figures were 16 in the GC group against 8 in the control group. This difference is significant (p less than 0.05). Regarding individuals with a diagnosis of PA for greater than 10 or greater than 15 years, the prevalence was twice as high in the GC as in the reference group. The differences were again insignificant (p less than 0.10). PA as a risk factor for the development of GC has been overestimated probably due to inadequate reference groups. Only 2% of all GCs are associated with PA. Large-scale preventive search for GC in PA patients is thus unjustified.

Gastric cancer is a major health burden worldwide and prevention is the most promising strategy to control the disease. The available scientific evidence indicates that curing Helicobacter pylori infection results in a modest retardation of the precancerous process but does not prevent all cancers. Individuals at the highest risk should be cured of their infection and monitored endoscopically to detect dysplasia and "early" cancer, amenable to successful treatment.

The basic histopathological finding in gastric mucosa is chronic atrophic gastritis in patients with pernicious anemia.

We evaluated the frequency of Helicobacter pylori and pathological examinations of gastric mucosa in pernicious anemia (n = 30) by endoscopical findings and biopsy. The results were compared with gastric mucosa specimens of patients with H. pylori-positive nonulcer dyspepsia (n = 36) and H. pylori-negative nonulcer dyspepsia (n = 21).

H. pylori was diagnosed in 12 patients (40%) with pernicious anemia. Fundal biopsy examinations showed atrophic gastritis in 30 patients (100%), intestinal metaplasia in 13 patients (43.3%), lymphoid follicle in 15 patients (50%), and dysplasia in 6 patients (20%). Antral biopsy examinations showed atrophic gastritis in 8 patients (26.6%), intestinal metaplasia in 8 patients (26.6%), lymphoid follicle in 8 patients (26.6%), and dysplasia in 3 patients (10%). The frequency of fundal inflammation, atrophy, intestinal metaplasia, lymphoid follicle, and dysplasia and antral intestinal metaplasia and mild antral dysplasia were found to be higher in those in the pernicious anemia group than in the nonulcer dyspeptic patients. Antral inflammation, atrophy, and moderate and severe antral dysplasia were found to be higher in those in the nonulcer dyspeptic group.

Particularly, fundal precancerous lesions were found to be more frequent in patients with pernicious anemia independent of H. pylori.

Intestinal metaplasia in the stomach increases the risk of gastric cancer, and the increased risk is proportional to the extent of the metaplasia. This risk could be generated by one or more mechanisms: (1) the metaplastic tissue is an early step in a multistep induction process; (2) the metaplastic tissue is an epigenetic change that raises the pH of gastric juice by replacing oxyntic mucosa, favoring the growth of a bacteria capable of generating endogenous mutagens; and/or (3) the metaplasia is only a marker for chronic gastritis due to H. pylori infection or pernicious anemia. With the last mechanism, the inflammatory response favors intramural mutagenesis that might result in metaplasia or neoplasia as independent events. Finding gene rearrangements common to both metaplastic and neoplastic tissue may establish a direct link between them, but too few have been identified to account for the large number of stomach cancers that develop in high risk populations. Histochemical and immunochemical stains that identify enzymes or mucosubstances may suggest that metaplastic epithelial cells resemble small or large intestinal cells, but they are distinctly different from both. Moreover, these stains do not indicate whether a given cytologic change is genetic or epigenetic; therefore, they cannot be used to define the relationship between metaplasia and neoplasia. It is unnecessary for practicing physicians to await resolution of this question. It can be assumed that any person with extensive metaplasia is at high risk for gastric cancer and should be subject to periodic screening. The extent of the metaplastic process is probably more important than the metaplastic subtype.

The role of clinical trials as tools to elucidate the etiology of chronic gastritis is discussed. Three areas are briefly explored. The first one concerns the classification of chronic gastritis, a constellation of interconnected nosologic entities. The second refers to the histopathologic factors of chronic gastritis; preliminary results show that clearance of Helicobacter pylori decreases the inflammatory infiltrate and suggest that H. pylori alters cell ploidy. The third area refers to the multifactorial etiology of chronic gastritis and the role that clinical trials could play in its elucidation.

Attempts were made to examine the sexual effects on the induction of intestinal metaplasia in rats. The number and locus of intestinal metaplasia in the gastric region induced by 2,000 rads of X-ray were greater in the male than in the female. Alkaline phosphatase activity appeared in the male only. The intestinal metaplasia induced by stomach antigen injection in the male persisted longer than in the female. Moreover, the incidence of intestinal metaplasia caused by whole body irradiation in ovariectomized rats was significantly higher than in the sham-ovariectomized ones. Therefore, it is likely that male sex hormones are promoting while female sex hormones are inhibiting the development of intestinal metaplasia.

A distinction can be made between a precancerous condition and a precancerous lesion. The former is a clinical state associated with a significantly increased risk of cancer, whereas a precancerous lesion is a histopathological abnormality in which cancer is more likely to occur than in its apparently normal counterpart. Up to the present time atrophic gastritis, gastric ulcer, pernicious anaemia, gastric stumps, gastric polyps, and Ménétrier's disease have all been considered as precancerous conditions and lesions of the stomach. Of these, only atrophic gastritis, pernicious anaemia, gastric stumps, and certain types of gastric polyp can now be regarded as having any really significant malignant potential. The precancerous lesion common to these is epithelial dysplasia which can occur in ordinary (foveolar) gastric epithelium as well as in intestinal metaplasia. The criteria for grading dysplasia in gastric epithelium into mild, moderate, and severe grades are given, and attention is drawn to the problems of differentiating inflammatory or regenerative change from mild dysplasia and intramucosal carcinoma from severe dysplasia. The clinical and epidemiological implications of gastric dysplasia are discussed with suggestions for further research.

Gastric carcinoma was detected nine, 10, 18, and 21 years after the biopsy diagnosis of atrophic gastritis in four patients of a group of 40. The gastritis was presumed to be of the simple type. Tests of vitamin B(12) absorption in three patients gave normal results, no gastric autoantibodies were detected in the two patients tested, in all patients histological examination of the gastrectomy specimens revealed a multifocal gastritis differing from the diffuse gastritis of pernicious anaemia and in three patients the gastritis affected the antrum, which is unusual in pernicious anaemia. The 10% incidence of gastric carcinoma in 40 patients with simple atrophic gastritis followed for a mean period of 15 years is equivalent to that previously described in pernicious anaemia. However, in view of the relative incidence of atrophic gastritis with and without pernicious anaemia in the general adult population, it emerges that atrophic gastritis without pernicious anaemia is numerically the more important precursor of gastric carcinoma.