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VITAMIN B12 DEFICIENCY

      Pathogenesis. The most common cause of vitamin B12. deficiency is a deficiency of gastric intrinsic factor, which causes the clinical picture of pernicious anemia. A more complete classification of the causes of vitamin B12, deficiency is shown in Table 20. Like most vitamin deficiency states, they can be classified into those caused by defective intake, defective absorption, and defective utilization.
      Inadequate dietary intake of vitamin B12 is rare, accept in populations that for religious or other reasons where to a very strict vegetarian diet. It may [?] also occur in total vegetarians, called vegans. The commonest cause of intrinsic factor deficiency is gastric atrophy, which is the basic underlying pathology of pernicious anemia. There is a rare congenital form of pernicious anemia that behaves as an autosomal recessive in which there is failure of intrinsic factor production. Total gastrectomy predictably leads to negaloblastic anemia after about two to six years, but vitamin B12 deficiency occurs only rarely after partial gastrectomy, unless there has been an extensive resection of the intrinsic-factor producing area. Since vitamin B12 is absorbed in the ileum, disease of this area causes vitamin B12 deficiency. Examples include surgical resection or involvement with regional ileitis, lymphoma, or tuberculosis of the ileum. Extensive disease of the small bowel, as occurs with tropical sprue or adult celiac disease, may occasionally cause vitamin B12 deficiency. There is a rare abnormality of the terminal ileum that causes a megaloblastic anemia in childhood and is usually associated with proteinuria; this is known as Imerslund’s syndrome. Certain structural disorders of the small bowel reduce the availability of vitamin B12. Any anatomic lesion that causes stasis and pooling of the lumenal contents with proliferation of bacteria may cause a situation in which vitamin B12 is taken up in the stagnant area and utilized by the bacteria. Such “blind loop” syndromes are caused by strictures of the small bowel, fistulas, and large diverticulae. A similar mechanism explains the megaloblastic anemia associated with the fish tapeworm (Diphyllobothrium latum).
      Acquired intrinsic factor deficiency is by far the commonest cause of vitamin B12 deficiency, and the associated clinical disorder is known as pernicious anemia. It was first described in 1885 at Guy’s Hospital, London, by Thomas Addison, and is sometimes known as Addisonian pernicious anemia. The basic defect is atrophy of the gastric mucosa, which results in an intrinsic factor deficiency. The etiology of the gastric atrophy is still far from certain. It seems likely that both genetic and autoimmune factors are involved. A genetic basis is suggested by the high incidence in certain races, such as Scandinavians, and by its association with blood group A. Furthermore, there is an increased incidence of the disorder among sibships and a markedly increased incidence of latent pernicious anemia within families. Latent pernicious anemia is characterized by lack of gastric acidity [caused by, yet necessary for meat and animal fat digestion] and decreased vitamin B12 absorption without the full hematologic features of pernicious anemia.
     The atrophic gastritis of pernicious anemia is characterized by lack of normal gastric mucosa with a striking lymphocytic infiltration and an absence of gastric acid and pepsin production even after full stimulation with histamine or with pentagastrin. The serum gastrin level is raised. An autoimmine basis for this pathology has been suggested by the finding of autoantibodies against the cytoplasm of the gastric parietal cell in the serum of 90 per cent of patients with pernicious anemia. It should be noted, however, that individuals who do not have the disorder may have the same antibody. This includes 60 per cent of all individuals with atrophic gastritis, 30 per cent of relatives of patients with pernicious anemia, and about 10 per cent of the normal adult population. Patients with pernicious anemia frequently have antibodies directed against parenchymal tissue of endocrine glands, most commonly the acinar glands of the thyroid. On the other hand, patients with primary myxedema, or Hashimoto’s thyroiditis, have a 30 per cent incidence of parietal cell antibodies and a 12 per cent incidence of coexisting pernicious anemia. Of more direct interest, however, is the finding that in about 57 per cent of patients with pernicious anemia there are anti-intrinsic factor antibodies in the serum, saliva, and gastric juice. These antibodies are polyclonal and may be IgG or IgA. It appears that they react to two different sites on the intrinsic factor molecule; there are blocking antibodies preventing the binding of vitamin B12 to intrinsic factor and binding antibodies that do not interfere with the attachment but impede absorption in the ileum. Intrinsic factor antibodies are found much less frequently than parietal cell antibodies in the general population and seem to be more specifically associated with pernicious anemia.
     It appears, therefore, that individuals with a genetic predisposition toward pernicious anemia may develop autoimmune damage to the gastric mucosa and anti­bodies to intrinsic factor. It is unclear, however, whether the production of autoantibodies is a primary event or is secondary to whatever causes damage to the gastric mucosa.
     Tissue and Neurologic Changes. There is a specific neurologic syndrome of vitamin B12 deficiency that is called subacute combined degeneration of the spinal cord. The pathologic changes are characterized by degenerative lesions in the dorsal and lateral columns. Early changes include swelling of individual myelinated nerve fibers and these lesions later coalesce into large foci involving many fiber systems. Similarly

patchy degeneration occurs in the white matter of the brain. This produces a variety of clinical pictures, including cerebral manifestations (“megaloblastic madness”), perversions of taste and smell, defects in vision with central scotomata and optic atrophy, ataxia due to reduced dorsal column function, peripheral neuropathy, and, in some cases, a spastic paraplegia or quadriplegia when the lateral columns are involved.
     In addition to the symptoms and signs of anemia and neurologic damage, patients with pernicious anemia have a lemon-yellow color due to slightly elevated unconjugated bilirubin, and about a third of them have palpable enlarged spleens.
     Diagnosis of Vitamin B12 Deficiency. The laboratory investigation of vitamin B12 deficiency is based on an understanding of its pathophysiology. The finding of a macrocytic peripheral blood picture with a megaloblastic bone marrow usually indicates either vitamin B12 deficiency or float deficiency. With vitamin B12 deficiency, the serum vitamin B12 level, as assayed micro biologically with Lactobacillus leishmanii or Euglena gracilis, or by isotope dilution, is reduced. In true pernicious anemia there is a histamine or penta­gastrmn-fast achiorhydria. Radioactive vitamin B12 absorption can be assayed by the Schilling test, in which a dose of 58Co- or 57Co-labeled cyanocobalamin is given by mouth at the same time as an intramuscular “flushing” dose of non radioactive cyanocobalamin, and the amount of radioactivity in the urine is measured. The reason for giving the intramuscular dose of vitamin B12 is that normally when the vitamin is taken by mouth, it enters the liver, and only after a large dose given by injection to preload the liver does sufficient orally administered B12 appear in the urine to be easily measured. In the absence of intrinsic factor reduced amounts of radioactivity appear in the urine. The second part of the Schilling test consists of giving radioactive vitamin B12 together with intrinsic factor, after which a considerable portion of the radioactivity appears in the urine if the patient has genuine intrinsic factor deficiency. If vitamin B12 is due to small bowel disease, absorption is not corrected by intrinsic factor. Absorption can also be measured by monitoring the patient in a whole-body counter. In cases in which a blind loop is suspected, vitamin B12 absorption can be measured before and after giving a course of broad-spectrum antibiotics, which destroy the bacteria in the stagnant loop. Structural disease of the small bowel requires radiologic investigation and jejunal biopsy. Another test for vitamin B12 deficiency is the measurement of methylmalonic acid in the urine, which is elevated if there is a vitamin B12 deficiency (see pp. 194 to 195).
 

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