Stomach pernicious anemia

In 1929, Castie (7) tied the work of Combe and Addison with that of Whipple, Miaot, and Murphy by ptoposiag that both an extrinsic factor and an intrinsic factor ate iavolved ia the coatrol of pernicious anemia. The extrinsic factor, from food, is vitamin 2- Th intrinsic factor is a specific B22-biading protein secreted by the stomach. This protein is requited for vitamin B 2 absorption. 

Vitamin B12 is essential to growth, cell reproduction, the manufacture of myelin (which surrounds some nerve fibers), and blood cell manufacture. The intrinsic factor, which is produced by cells in the stomach, is necessary for the absorption of vitamin B12 in the intestine A deficiency of the intrinsic factor results in abnormal formation of erythrocytes because of the body s failure to absorb vitamin B12, a necessary component for blood cell formation. The resulting anemia is a type of megaloblastic anemia called pernicious anemia. 

VITAMIN S12. Fhtients with pernicious anemia are treated with vitamin B12 by tiie parenteral route (IM) weekly stabilized. The parenteral route is used because tiie vitamin is ineffective orally due to the absence of tiie intrinsic factor in tiie stomach, which is necessary for utilization of vitamin B12. After stabilization, maintenance (usually monthly) injections are necessary for life... 

Intrinsic factor is produced by the parietal cells. Within the stomach, it combines with vitamin Bu to form a complex necessary for absorption of this vitamin in the ileum of the small intestine. Vitamin B12 is an essential factor in the formation of red blood cells. Individuals unable to produce intrinsic factor cannot absorb vitamin B12 and red blood cell production is impaired. This condition, referred to as Pernicious anemia, occurs as a result of an autoimmune disorder involving destruction of parietal cells. 

Castle then showed (1929) that beef muscle was as effective as liver in preventing pernicious anemia, provided it was administered with normal gastric juice. He therefore concluded two factors were involved—an extrinsic one which was a component in liver or muscle and an intrinsic factor which was secreted by the stomach. Major efforts were therefore directed at identifying the extrinsic factor in liver or other meats. 

Pernicious anemia is usually caused by poor absorption of the vitamin. Absorption depends upon the intrinsic factor, a mucoprotein (or rnuco-proteins) synthesized by the stomach lining.ad 1 Pernicious anemia patients often have a genetic predilection toward decreased synthesis of the intrinsic factor. Gastrectomy, which decreases synthesis of the intrinsic factor, or infection with fish tapeworms, which compete for available vitamin B12 and interfere with absorption, can also induce the disease. Also essential are a plasma membrane receptors 1 and two blood transport proteins... 

Bi2 (2). Corrinoids are sequestered from food sources by a glycoprotein of mass 45kDa called intrinsic factor, which is secreted in the stomach and binds B12 derivatives very tightly (for CN-Cbl, iC = 1.5 X 10 mol dm ). Several other proteins bind and transport B12 into cells (3). The disease pernicious anemia has been recognized since the early nineteenth century and linked to a deficiency of what William Castle called extrinsic factor (i.e., vitamin B12) in 1928 (1). This disease develops because of the failure of the patient to secrete sufficient intrinsic factor. 

It is well known that the proteolytic activity at pH 2 (peptic activity) is low or absent in pernicious anemia, though occasional patients secrete small quantities of pepsin in the stomach (G2I). Neither histamine stimu-... 

Taylor studied the activity curves of all the proteinases at different pH s in various diseases of the human stomach (T18-T20). He found that in pernicious anemia, cancer of the stomach, and duodenal ulcer the activity cun es of proteolytic enzymes differed from those of normals. Only one patient exhibited a curve with two normal maxima, and the... 

The work of the past 35 years has confirmed Castle s initial concept (C5-C10) of a principle in human gastric juice necessary for normal hematopoiesis (G2Q). Its lack in the gastric content of pernicious anemia patients was recognized, as early as 1929 (C5, C9), to be the essential defect leading to the development of pernicious anemia, through failure of the reaction between extrinsic factor, now known to be identical with vitamin B12, and intrinsic factor in normal human gastric juice. Other investigators confirmed that IF is formed by the fundus and body of the stomach in man (see G20) and by the pyloric end of the stomach in the hog (L2, M33), and that it is absent from saliva. 

Great progress has been made in the purification of IF. Whereas, 35 years ago, the dose of IF-containing material required for hematopoietic response in patients with pernicious anemia was about 40 g dried hog stomach, the most potent hog IF preparations processed during the last 2 years have shown activity at a dose as small as 40 [ig (B33, B34), one millionth the amount necessary 35 years ago (Table 11). Progress in its... 

Antibodies to intrinsic factor-active materials from human and hog stomach have been demonstrated in the sera of pernicious anemia patients by Taylor et al. (T9-T12) and Schwartz (S12, S13), and of rabbits immunized with these materials by Lowenstein et al. (L13). Antibody formation in rabbits is species specific, although antibodies have shown some cross-reactions. An antigenic factor common to human and hog material containing intrinsic factor probably produces formation of these antibodies (G75-G75b). 

In addition to these, another antibody to intrinsic factor may develop in a certain percentage of pernicious anemia patients, orally treated with hog intrinsic factor concentrate. As shown by Schwartz (S12, S13), this antibody is directed exclusively toward hog intrinsic factor concentrate and not human gastric juice or intrinsic factor derived from the human stomach. Apparently, it causes a topical antibody reaction at the mucosal level, hlocking the promoting action of hog intrinsic factor concentrate on intestinal absorption of vitamin B12 in these pernicious anemia patients. This produces refractoriness to oral treatment with vitamin B12 and hog intrinsic factor concentrate in many pernicious anemia patients (S15). 

A complement-fixing antibody in the serum of pernicious anemia patients, diabetics, and those widi iron-deficiency anemia has been detected against mucosal extracts of the fundus and body of the hmnan stomach and the microsomal fraction of gastric mucosal extracts (D8, 14, M8, M48, RIO, TI3). Immunofluorescent studies have shown that activity is directed against gastric parietal cell cytoplasm (15, RIO, T13) and probably represents another type of antibody, which develops about twice as frequently as the one directed against intrinsic factor in pernicious anemia serum (Fig. 27). 

C5. Castle, W. B., Observations on the etiologic relationship of achylia gastrica to pernicious anemia. I. The effect of the administration in patients with pernicious anemia of the contents of the normal human stomach recovered after the ingestion of beef muscle. Am. J. Med. Sci. 178, 748-764 (1929). 

K20. Kodejszko, E., Mucin level under normal conditions and in diseases of the stomach, duodenum, gall bladder and pernicious anemia. (In Polish.) Polskie Arch. Med. Wewnetrznej 18, 1-26 (1948). 

Burman, R, Mardh, S-, Norberg, L., and Karlsson, T, A. (1989). Parietal cell antibodies in pernicious anemia inhibit H,K-adenosine triphosphatase, the proton pump of the stomach. Gffsfrw Pi tcreJegy 96, 1434-1438. 

Vitamin B-12 is necessary for red biood ceiis to mature prop-eriy in the bone marrow. Peopie with pernicious anemia iose their abiiity to make intrinsic factor, a substance secreted by the stomach s membrane iining that enabies vitamin B-12 to be absorbed from the intestine. Without an adequate amount of vitamin B-12, the body is unabie to synthesize DNA properiy, which affects red blood cell production. 

A. Pernicious anemia occurs when the stomach does not produce adequate intrinsic factor for absorption of vitamin B12, which is required for the conversion of methylmalonyl CoA to succinyl CoA and homocysteine to methionine. A vitamin B12 deficiency results in the excretion of methylmalonic acid and an increased dietary requirement for methionine. The methyl group transferred from vitamin B12 to homocysteine to form methionine comes from 5 -methyl tetrahydrofolate, which accumulates in a vitamin B12 deficiency, causing a decrease in folate levels and symptoms of folate deficiency, including increased levels of FIGLU and decreased purine biosynthesis. 

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