The primary pathologic feature of PA is progressive destruction of the normal glands of the body of the stomach. This is associated with partial or complete loss of chief cells, which secrete pepsinogens, and the parietal cells, which secrete acid and intrinsic factor. When the last is complete, failure of vitamin B12 absorption occurs. Complete loss of intrinsic factor secretion may require many years or never occur. The gastric mucosa is infiltrated, homogeneously or in patchy distribution, with various numbers of polymorphonuclear and mononuclear leukocytes - predominantly the latter. Often the gastric body mucosa is partly or wholly replaced by small intestinal mucosa (metaplasia).

Experimentally, chronic inflammatory lesions of the gastric mucosa, glandular atrophy, and loss of gastric secretary function have been produced in immunization using gastric mucosal material Freund's complete adjuvant. Other species, such as rabbits, rats, mice, and guinea pigs, are resistant to these procedures. In dogs, the appearance of gastric lesions is associated more with development of cell-mediated immunity than with humoral ab. However, repeated injection of humoral gastric ab into rats has reduced gastric secretory in several weeks.

In pernicious anemia, humoral ab were found to 3 antigens of the gastric parietal cell. The most thoroughly characterized are a glycoprotein called Castle's intrinsic factor and a lipoprotein of microvilli of the parietal cell canalicular system. The third, which appears to be distinct from the latter, found in the surface membrane of the parietal cell. They are cell-specific. Serum parietal cell canalicular antibody is present, as determined by IF, in about 90% of patients with PA, and intrinsic factor antibody in 60 %. There are 2 types of intrinsic fact: Type I blocks the attachment of vitamin B12 to the intrinsic factor molecule, and type II attaches to intrinsic factor or the intrinsic factor-B 12 complex. Type II intrinsic factor antibody occurs with about half frequency of type I and only rarely occurs in the absence of type 1. Experimentally, the immunogenicity of the intrinsic factor antigenic site for type I antibody is greater than that for type II.

Evidence suggests that antibodies to intrinsic factor are capable of inhibiting intrinsic factor-mediated vitamin B 12 absorption in vivo, and parietal cell canalicular antibody inhibits acid secretion by the parietal cell. Antibodies to the parietal cell surface, in the presence of complement, have recently been shown to possess specific cytotoxicity.

Atrophic gastritis with PA is frequently undiagnosed, since the gastric lesion is usually asymptomatic. Mild to severe dyspepsia may occur together with impairment of appetite. PA is the expression of vitamin B12 deficiency. It is characterized by increasing weakness, fatigability, loss of appetite, and pallor. Loss of weight is common, but wasting is rare. Involvement of the nervous system, which is quite variable, may include peripheral neuropathy, damage to pyramidal tract and posterior column neurons, and disturbance of higher cortical functions.

Inheritance. PA displays a strong familial association, but how much is environmentally and how much genetically determined is still unknown. There is an association between PA and thyroid disease, especially thyrotoxicosis, which occurs frequently in close relatives of PA patients. Less strong associations have been claimed with diabetes mellitus and idiopathic Addison's disease. Three pieces of evidence converge to suggest that there is a genetic predisposition to pernicious anemia: the high prevalence of pernicious anemia in some racial groups but not in others, the high frequency of pernicious anemia in families within those racial groups, and the association of particular genetic markers among patients with pernicious anemia.

Pernicious anemia is predominantly a disease of people of Northern European origin. It is rare among Southern Europeans, Asians, Latin-Americans, and African and American Blacks. Interestingly when it occurs in African and American Blacks it appears at an earlier age than it does in White Europeans, and there is a higher frequency of antibodies to IEF.

Multiple cases of pernicious anemia have been reported in families, often for several generations, and this frequency may be as much as 20 times greater than in the normal population. There is a raised but not absolute concordance of pernicious anemia in monozygotic twins and there are intrafamilial aggregations of the autoimmune diseases associated with pernicious anemia, namely the thyroid autoimmune diseases, insulin-dependent diabetes mellitus and Addison's disease of the adrenal gland which may be expressed as frank or subclinical disease marked by the presence of autoantibodies specific to these diseases. The prevalence of gastric parietal cell antibodies in first-degree relatives of patients with pernicious anemia is 20% which is three times higher than that found in normal controls, and the frequency of autoantibodies to thyroid, pancreatic islet cells, and adrenal cortical cells is also higher among relatives.

The high frequency of gastric autoantibodies among relatives of patients with pernicious anemia is also in keeping with the high frequency of Type A gastritis among relatives. Studies by Varis and colleagues on a large population of patients with pernicious anemia and their relatives in Finland showed that the prevalence of autoimmune gastritis was 13% in relatives compared with controls. This familial aggregation of autoimmune gastritis was attributed to a genetic effect rather than an environmental factor. A delay in the onset of gastritis in males suggested that (maleness' may have a protective effect.

Blood group A and blue eyes are phenotypes which are common among Northern Europeans with pernicious anemia. Female gender on this phenotypic background potentiates predisposition to the autoimmune gastritis. Various histocompatibility leukocyte antigens (HLA) have also been associated with pernicious anemia...

PA also occurs in aquired immunoglobulin deficiency, most commonly of IgA but sometimes of IgG or IgM also.

Macrocytic anemia and hypersegmentation of the nuclei of the neutrophil granulocytes are the morphologic findings in the peripheral blood. Bone marrow aspirates show megaloblastosis blood.

Serum vitamin B12 values below 120 pg/mL (normal, 200 - 1500 pg /mL). Serum LDH activity is markedly elevated owing to excessive intramedullary destruction of red-blood cells. The excretion of methylmalonate in the urine is increased. Vitamin B12 therapy corrects all of this abnormalities except that some damage to the central nervous system may be irreversible.

The finding of circulating parietal canaliculare ab by complement fixation or IF almost certainly indicates chronic gastritis disease, although negative serologic findings do not exclude this diagnosis. Ab to intrinsic factor indicate the lesion of PA, with the rare exceptions of a few patients with thyroid disease. Cell-mediated immune tests are not yet generally available.

Clinically, other anemias and untreated myxedema and pituitary hypofunction may be confused with PA. The finding of megaloblastic anemia reduces the possibilities to 3 - deficiency of vitamin B12, of folic acid, or both. Unequivocal involvment of the nervous system points to the former. However, a deficiency of vitamin B12 may occur as a consequence of dietary deficiency (an unsupplemented vegetarian diet) or of malabsorption due to pancreatic or small intestine disease as well as a lack of intrinsic factor. Correction of vitamin B12 malabsorption by administration of intrinsic factor provides unequivocal evidence of the basic lesion of PA. Impaired absorption of vitamin B12 is demonstrable by a variety of tests using tracer doses of radioactive Cobalt-lableled vitamin B12 without and with intrinsic factor (eg, the Shilling test, in which urinary excretion of labeled vitamin B12 is the index of intestinal absorption). Aspirated gastric juice contains negligible intrinsic factor activity and no hydrochloric acid, even in response to powerful stimulants of secretion. The presence of serum ab to gastric ag may provide confirmatory evidence.

IM injections of vitamin B12 will maintain remissions in PA. Corticosteroids and immunosuppressive agents have only been used experimentally. There is no practical means at present of recognizing the gastric lesion sufficiently early to offer any hope of instituing therapy at a reversible stage of the disease.

The only important complication is gastric carcinoma, which is probably 3 times more common in patients with PA than in the population at large. No immunologic or other test has yet been devised which reliably identifies subjects prone to develop gastric carcinoma or provides early recognition of such a lesion.