Gastric causes of cobalamin malabsorption

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(Tables 5.5 and 5.6) Pernicious anaemia

Pernicious anaemia (PA) may be defined as a severe lack of intrinsic factor due to gastric atrophy. It is a common disease in north Europeans but it occurs in all countries and ethnic groups. The overall incidence is about 120 per 100 000 population in the UK, but there is wide variation between one area and the next. The prevalence rate in Western countries may be as high as 2-3%. The ratio of incidence in men and women is approximately 1:1.6 and the peak age of onset is 60 years, with only 10%

Table 5.6 Malabsorption of cobalamin may occur in the following conditions but is not usually sufficiently severe and prolonged to cause megaloblastic anaemia.

Gastric causes

Simple atrophic gastritis (food cobalamin malabsorption)

Zollinger-Ellison syndrome

Gastric bypass surgery

Use of proton pump inhibitors

Intestinal causes Gluten-induced enteropathy Severe pancreatitis HIV infection Radiotherapy Graft-versus-host disease

Deficiencies of cobalamin, folate, protein, ?riboflavin, ?nicotinic acid

Therapy with colchicine, para-aminosalicylate, neomycin, slow-release potassium chloride, anticonvulsant drugs, metformin, phenformin, cytotoxic drugs

Alcohol of patients presenting being less than 40 years of age. In some ethnic groups, notably black people and Latin Americans, the age of onset of PA is generally lower. The disease occurs more commonly than by chance in close relatives, in subjects with other organ-specific autoimmune diseases (see below), in those with premature greying, blue eyes and vitiligo, and in persons of blood group A. An association with human leucocyte antigen (HLA) 3 has been reported in some but not all series and in those with endocrine disease, with HLA-B8, -B12 and -BW15. The life expectancy is normal in women once regular treatment has begun. Men have a slightly subnormal life expectancy as a result of a higher incidence of carcinoma of the stomach than in control subjects.

Diagnosis

This is usually suspected from the clinical picture and the findings of megaloblastic anaemia due to cobalamin deficiency. A lack of IF may be demonstrated by cobalamin absorption studies. Tests for circulating gastric autoantibodies are also important.

Tests of gastric secretion

Direct measurements on gastric juice following pentagastrin stimulation are now rarely performed. Hydrochloric acid or pepsin production and intrinsic factor output were previously measured.

Serum assays

The serum gastrin level is usually raised in PA (> 200 |g/L), the hormone coming from endocrine cells in the gastric fundus.

Raised serum gastrin also occurs in simple atrophic gastritis. Serum pepsinogen I levels are low (below 30 |g/L) in over 90% of those affected.

Gastric biopsy

This usually shows atrophy of all layers of the body and also fundal atrophy, with loss of glandular elements, an absence of parietal and chief cells and replacement by mucous cells, a mixed inflammatory cell infiltrate and perhaps intestinal metaplasia. The infiltrate of plasma cells and lymphocytes contains an excess of CD4 cells. The antral mucosa is usually well preserved. Helicobacter pylori infection is infrequent in pernicious anaemia, but it has been suggested that H. pylori gastritis may represent an early phase of atrophic gastritis, which is gradually replaced, in some individuals, by an immune process with disappearance of H. pylori infection.

Immune phenomena

In addition to the appearance of gastric mucosa, there is a large body of evidence that suggests that immune mechanisms play an important role in the pathogenesis of PA. This aspect of the disease is discussed next under four main headings.

Antibodies to gastric antigens

IF antibodies. Two types of IF antibody may be found in the sera of patients with PA: both are immunoglobulin (Ig) G. One, the 'blocking' or 'type I' antibody, prevents the combination of IF and cobalamin, whereas the other, the 'binding' 'type II' or 'precipitating' antibody, which attaches to IF whether joined to cobalamin or not, prevents attachment of IF to ileal mucosa. The blocking antibody occurs in the serum of about 55% of patients and the binding antibody in 35%. IF antibodies cross the placenta and cause temporary IF deficiency in the newborn infant. Pernicious anaemia patients also show cellmediated immunity to IF. An increased CD4/CD8 lymphocyte ratio in blood has been described in PA patients with IF antibodies.

IF antibodies are rarely found in conditions other than PA. Type I antibody has been detected rarely in the sera of patients without PA but with thyrotoxicosis, myxoedema, Hashimoto's disease or diabetes mellitus, and in relatives of PA patients. IF antibodies have also been detected in gastric juice in about 80% of PA patients. These antibodies may reduce absorption of dietary cobalamin by combining with small amounts of remaining IF in the gastric juice. Achlorhydria favours the formation of this antigen-antibody complex.

Parietal cell and gastrin receptor antibodies. Parietal cell antibody is present in the sera of almost 90% of adult patients with PA, but it is frequently present in other subjects. Thus, it occurs in as many as 16% of randomly selected female subjects aged over 60 years and in a smaller proportion of younger control subjects; it is found more frequently than in control subjects in relatives of

PA patients. These antibodies are also found more frequently in patients with simple atrophic gastritis, chronic active hepatitis and thyroid disorders and their relatives, as well as in Addison's disease, rheumatoid arthritis and other conditions. The parietal cell antibody is directed against the a- and P-subunits of the gastric proton pump (H+,K+-ATPase). The sera of PA patients may also contain an autoantibody to the gastrin receptor, although this test is not used clinically.

Association with other 'autoimmune' diseases There is a clinical association between PA and thyroid diseases, vitiligo, hypoparathyroidism and Addison's disease. These diseases are often found in close relatives of patients with overt disease due to one of these conditions.

Response to steroid therapy

Steroid therapy improves the gastric lesion, at least temporarily, in a proportion of patients with PA. There may be regeneration of the mucosa with a return of secretion of acid and IF, and an improvement in cobalamin absorption. When steroid therapy is withdrawn, there is a relapse within a few weeks. These findings suggest that an autoimmune process is continuously damaging the gastric mucosa in PA and preventing regeneration. Temporary remission of neurological symptoms has been observed in PA, erroneously diagnosed as multiple sclerosis and treated with steroids.

Hypogammaglobulinemia

PA is found more often than by chance in patients with a deficiency of IgA or with complete hypogammaglobulinaemia. These subjects resemble others with PA, except that they often present relatively early (before the age of 40 years), they have a lower incidence of serum IF and parietal cell antibodies, and they may show intestinal malabsorption. They may also have a history of recurrent infections. The gastric lesion is similar to that in other causes, except that plasma cells are absent from the inflammatory cell infiltrate and the antrum is involved. Serum gastrin levels are normal.

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