Intrinsic factor with patients

The authors suggest that in addition to Castle s intrinsic factor there may be an intramural intestinal B12 acceptor (analogous to apoferritin in iron absorption) which may be responsible for the partial mucosal block to Bi2 absorption in the intestine of normal human beings. A similar mechanism may be responsible for limiting the amount of B12 which can be absorbed even with added intrinsic factor in patients with pernicious anemia (see page 163). 

Oral vitamin B12 supplementation appears to be as effective as parenteral, even in patients with pernicious anemia, because the alternate vitamin B12 absorption pathway is independent of intrinsic factor. Oral cobalamin is initiated at 1 to 2 mg daily for 1 to 2 weeks, followed by 1 mg daily. 

Cyanocobalamin and the derivative hydroxo-cobalamin, given IM or deep subcutaneously, are indicated for treating vitamin B12 deficiency. Only in strict vegetarians oral preparations may be effective. Oral preparations with added intrinsic factor mostly are not reliably in patients with pernicious anemia. More than half the dose of cyanocobalamin injected is excreted in the urine within 48 hours and the therapeutic advantages of doses higher than 100 pg are questionable because of this rapid eiimination. As... 

Pernicious anemia results from defective secretion of intrinsic factor by the gastric mucosal cells. Patients with pernicious anemia have gastric atrophy and fail to secrete intrinsic factor (as well as hydrochloric acid). The Schilling test shows diminished absorption of radioactively labeled vitamin B12, which is corrected when intrinsic factor is administered with radioactive B12, since the vitamin can then be normally absorbed. 

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... 

This case prompted a report of 10 metformin- associated patients with cobalamin deficiency among 162 patients with vitamin Bi2 concentrations below 200 pg/ml (91). They had taken a mean dose of metformin of 2015 mg/ day for an average of 8.9 years. The mean vitamin B12 concentration was 140 pg/ml. All had normal serum folate and creatinine concentrations and no antibodies to intrinsic factor. In one patient there was malabsorption. 

Vitamin B12 is available in pure form for oral administration or in combination with other vitamins and minerals for oral or parenteral administration. The choice of a preparation always must be made with recognition of the cause of the deficiency. Although oral preparations may be used to supplement deficient diets, they are of relatively little value in the treatment of patients with deficiency of intrinsic factor or ileal disease. Even though small amounts of vitamin B12 may be absorbed by simple diffusion, the oral route of administration cannot be relied upon for effective therapy in the patient with a marked deficiency of vitamin B12 and abnormal hematopoiesis or neurological deficits. Therefore, the preparation of choice for treatment of a vitamin B12-deficiency state is cyanocobal-amin, and it should be administered by intramuscular or deep subcutaneous injection. 

Very little work has addressed the topic of individual differences in response to sleep deprivation. It is clear that such differences exist total sleep deprivation produces remission of symptoms in depressed patients but does not have such large impact on mood in normals patients with chronic insomnia should suffer from significant partial sleep deprivation but actually seem less sleepy than normals when tested with the MSLT (48,49). It is certainly possible that individual differences in response to sleep deprivation are related to individual differences in sleep requirement. However, these individual differences may also be related to other intrinsic factors (such as level of central nervous system arousal, biological rhythms, or personality) or extrinsic factors (such as characteristic activity or light exposure patterns). 

Examination of the bone marrow, although important, will only confirm that the hemopoiesis is megaloblastic. A deficiency of folic acid will also cause a megaloblastic anemia and it is not possible to identify the cause on the basis of morphology. A serum assay of both vitamins will usually indicate which is responsible. If the patient is vitamin B12 deficient, the next step is to carry out a vitamin B12 absorption test to confirm that the deficiency is due to a lack of intrinsic factor. Preferably this should not be done until the patient s vitamin B12 and hemoglobin levels have returned to normal, since the gastric and intestinal cells are also affected by a lack of vitamin B12 aborption may be less than optimal if it is attempted too early. Patients with pernicious anemia also have a histamine-fast achlorhydria and gastric atrophy. The disease appears to have an autoimmune basis and antibodies to intrinsic factor can be demonstrated in the serum of more than half of affected patients. 

Patients with severe atrophic gastritis may have impaired absorption of vitamin B12 and a reduced serum level of the vitamin, but this is not accompanied by either megaloblastic anemia or neuropathy. Parietal-cell antibodies have been found in 33% of patients with gastritis, none of these patients having pernicious anemia (12, V4). Intrinsic factor antibodies were not found, and this was not surprising since it is rare to find antibodies to intrinsic factor in the absence of pernicious anemia. Patients with superficial gastritis usually have normal vitamin B12 absorption and normal serum levels of the vitamin. 

Patients with exocrine pancreatic dysfunction may malabsorb vitamin B12 because a considerable part of the dietary vitamin may bind to R-proteins in the stomach. The R-proteins are normally broken down by pancreatic enzymes. The vitamin is released and binding to intrinsic factor then takes place. If the R-proteins are not degraded, then the vitamin B12 will remain bound to these proteins and will not be absorbed (M10). Harms and his colleagues (H27) measured vitamin B12 absorption in 19 children with exocrine pancreatic insufficiency and found the average absorption to be 8.0% compared to 59.2% in a control group. Adding pancreatin to the test dose of radiolabeled vitamin B12 increased absorption of the vitamin to an average of 61%. 

Schwartz, M., Intrinsic factor antibody in serum from patients with pernicious anaemia. Lancet 2, 1263-1267 (1960). 

Deficiencies of vitamin B12 can result from either low dietary levels or, more commonly, from poor absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia) or to a loss of activity of the receptor needed for intestinal uptake of the vitamin.5 Nonspecific malabsorption syndromes or gastric resection can also cause vitamin B12 deficiency. The vitamin may be administered orally (for dietary deficiencies), or intramuscularly or deep subcutaneously (for pernicious anemia). [Note Folic acid administration alone reverses the hematologic abnormality and thus masks the B12 deficiency, which can then proceed to severe neurologic dysfunction and disease. Therefore, megaloblastic anemia should not be treated with folic acid alone, but rather with a combination of folate and vitamin B12.] Therapy must be continued for the remainder of the life of a patient suffering from pernicious anemia. There are no known adverse effects of this vitamin. 

This observation led to the discovery that a dietary compound (extrinsic factor) was absorbed only after combination with a protein secreted by the normal stomach (intrinsic factor [IF]), and that the IF was missing from the secretions of the atrophic stomach found in patients with PA. The extrinsic factor, later named vitamin B12, was obtained in crystalline form in 1948, and its structure was defined by x-ray crystallography by Dorothy Hodgkins, an accomplishment for which she received the Nobel Prize for Chemistry in 1964. 

---