Autoimmune gastritis

Autoimmune gastritis is a corpus-restricted chronic atrophic gastritis associated with circulating serum anti–parietal cell and anti–intrinsic factor antibodies and intrinsic factor deficiency, with or without pernicious anemia.

Clinical Manifestations

Most clinical manifestations of autoimmune gastritis become apparent only many years after the onset of the disease, when the parietal cell mass decreases beyond a critical point and the stomach becomes unable to produce sufficient amounts of acid, pepsinogens, pepsin, and intrinsic factor. Achlorhydria, the most direct result of the destruction of acid-producing oxyntic cells, typically occurs in the most advanced stages of the disease. Hypochlorhydria, however, may also occur in patients with moderate to large numbers of surviving parietal cells, suggesting that anti–proton pump antibodies or inhibitory lymphokines released by subsets of inflammatory cells may participate in the inhibition of acid secretion. Patients with corpus atrophy and achlorhydria have hypergastrinemia, which tends to correlate with the severity of the mucosal damage. Injury to chief cells leads to a reduction of pepsin activity in gastric juice and of pepsinogens in blood. A low serum pepsinogen I level (<20 ng/mL) is a sensitive and specific indication of corpus atrophy.

Many patients with autoimmune gastritis develop either iron deficiency or pernicious anemia. Hypochromic anemia is associated with corpus-restricted chronic atrophic gastritis in approximately 15% of patients. Achlorhydria seems to be the major contributor to the pathogenesis of iron deficiency anemia: gastric acid is important in the absorption of nonheme iron, which in Western diets supplies at least two thirds of nutritional iron needs. Pernicious anemia is usually preceded by corpus-restricted chronic atrophic gastritis and reduced acid secretion by approximately a decade, and it is generally associated with a histological pattern of end-stage atrophic gastritis. Pernicious anemia is a rarely diagnosed condition, with a reported prevalence of less than 1% even in elderly persons in high-incidence countries. Its true prevalence could be higher, but most patients are successfully treated by hematologists or general practitioners for their anemia and cobalamin (vitamin B 12) deficiency, and they are never referred to a gastroenterologist for the evaluation of atrophic gastritis, pepsinogens levels, or anti–parietal cell antibodies. Cobalamin deficiency affects the rapidly proliferating gastrointestinal epithelium, and patients with severe deficiency may complain of a sore tongue, which may be smooth and beefy red. Anorexia with moderate weight loss may also be evident, possibly accompanied by diarrhea and other gastrointestinal symptoms. Neurological manifestations include numbness and paresthesia in the extremities, weakness, and ataxia. There may be sphincter disturbances.

Autoimmune gastritis is a risk factor for hyperplastic and adenomatous polyps, carcinomas, and endocrine tumors. Polyps are found in 20% to 40% of patients with pernicious anemia, and they are mostly sessile, smaller than 2 cm in diameter, and often multiple. Most polyps are hyperplastic, but up to 10% contain dysplastic foci. Gastric cancers associated with pernicious anemia are of the intestinal type and arise from intestinal metaplasia, a finding suggesting that the link between autoimmune gastritis and carcinoma may be intestinal metaplasia and its dysplastic transformation.

Pathogenesis

Autoimmune gastritis is substantially more common in patients with other diseases thought to be of immunologic origin (Graves disease, myxedema, thyroiditis, idiopathic adrenocortical insufficiency, vitiligo, and hypoparathyroidism) than in the healthy population. The high prevalence of specific familial histocompatibility haplotypes such as human leukocyte antigen (HLA)-B8 and HLA-DR3 in patients with corpus-restricted atrophic gastritis is another strong indicator of its autoimmune origin. The precipitating factors, however, remain unknown. The hypothesis that autoimmune gastritis could be initiated by H.pylori infection has received considerable attention. A high prevalence of antibodies with high specificity for gastric mucosa antigens has been reported in patients with H.pylori–associated gastritis; preabsorption of the serum from these patients with H.pylori removed most of these autoantibodies. Furthermore, 20% of these patients had autoantibodies that reacted with the secretory canalicular structures of parietal cells, which are among the major targets in autoimmune gastritis. In other studies, H.pylori–positive patients with and without previously demonstrated anticanalicular antibodies had a 30% to 50% prevalence of anti–H +,K +-ATPase antibodies, in contrast to a less than 3% prevalence in noninfected persons. It has also been demonstrated that H.pylori lipopolysaccharides express Lewis x and y blood group antigens, which are also expressed by either H +,K +-ATPase or gastric epithelial cells. Collectively, this information lends support to the concept that a cross-mimicking mechanism between H.pylori and gastric mucosa antigens participates in the pathogenesis of autoimmune gastritis. This correlation, however, remains unproven, and much stronger biologic, clinical, and epidemiologic evidence is needed before H.pylori can be viewed as the cause of autoimmune gastritis.

Endoscopic Appearance

Atrophy causes a progressive thinning of the mucosa of the gastric corpus; this explains why few folds are left and why fine submucosal vessels are easily recognized on endoscopic examination, especially in advanced disease. The antral mucosa is endoscopically normal in the majority of cases. Polyps become common in the advanced stages of the disease; therefore, atrophic gastritis must be ruled out in patients in whom multiple hyperplastic gastric polyps are detected at endoscopy.

Histopathology

The main histopathological features of autoimmune gastritis are diffuse corpus-restricted chronic atrophic gastritis with mild to moderate intestinal metaplasia and, in the absence of concurrent H.pylori infection, a normal gastric antrum. This pattern is characteristic of the advanced stage of the disease and is found in patients with pernicious anemia. Persons with parietal cell antibodies and no pernicious anemia show a broad spectrum of atrophic changes, from minimal oxyntic gland loss to severe and diffuse atrophy of the oxyntic mucosa. In the early phases, one sees diffuse or multifocal, dense mononuclear cell infiltration of the lamina propria and lymphocytic infiltration of individual oxyntic glands. Later, marked atrophy of the oxyntic glands with diffuse mononuclear cell infiltration of the lamina propria develops. Pyloric metaplasia is extensive, whereas intestinal metaplasia tends to be still limited to few foci. The end stage is characterized by a great reduction in corpus mucosal thickness, foveolar hyperplasia, and replacement of oxyntic glands by pyloric, pseudopyloric, or intestinal metaplasia. The inflammatory infiltrate is minimal, although scattered lymphoid aggregates and follicles may be found.

In the majority of patients, the antral mucosa is either normal or shows only focal areas of mild chronic inflammation with intestinal metaplasia, similar in degree and extension to what is observed in the general asymptomatic population. Hyperplasia of gastrin cells secondary to achlorhydria is often seen. Enterochromaffin-like cell carcinoids may arise during the florid phase, but they are found more commonly in association with an end-stage histopathological pattern.

Diagnosis

Autoimmune gastritis should be suspected in patients with megaloblastic anemia, with evidence of clinically significant cobalamin deficiency with values lower than 150 pg/mL, or with multiple gastric polyps. The diagnosis must be confirmed by the characteristic histopathological findings of corpus-restricted atrophic gastritis and by the presence of serum anti–intrinsic factor or anti–parietal cell antibodies.

Management

The management of patients with autoimmune gastritis should address two aspects of the condition: the gastric lesions and the manifestations related to the cobalamin deficiency. Gastric mucosal atrophy is irreversible. Patients with extensive intestinal metaplasia and those with multiple polyps may be at increased risk of gastric cancer. Although there are no accepted guidelines, a surveillance gastroscopy every 1 or 2 years may represent a sensible empiric approach.

With cobalamin replacement, most abnormalities resulting from cobalamin deficiency undergo complete and lifelong correction, except for the neurological manifestations. Their improvement depends on the extent that irreversible changes in the nervous system may have occurred before treatment.