Studies on Intrinsic Factor and Pernicious Anemia: I. Oral Uptake of Vitamin B12In Pernicious Anemia with Increasing Doses of an Intrinsic Factor Concentrate
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Intrinsic factor
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Except in one patient (Case 404) who received juice stored for 14 days, the juice was either fresh or not more than three days old.Other workers have used pooled gastric juice which may have been stored.Campbell, Hall, and Morgan (1949) state that the intrinsic factor in gastric juice is not destroyed by storage at 50 C. for three months, but did not indicate whether there is a lessening of activity.Hall et al. (1949) found that Berkefeld-filtered gastric juice was active in a proportion of 150 ml. per 5 ,ug. of vitamin Bl2, but comparisons with unfiltered gastric juice are not mentioned.In our Case 201 Seitz filtration of gastric juice apparently led to loss of all or most of its intrinsic factor activity.How Efficiently is Vitamin B,.Absorbed When Given Oraly With Gastric Juie ?It is obvious from the Table that the results are very variable.In four out of eight of my patients the effect of vitamin B,2 given orally with gastric juice was about as effective as if the same dose of vitamin had been injected into these patients.In two others the corrected oral-dose/parenteral-dose ratio was about 10: 1.In one case oral therapy failed completely, and in another the amount of gastric juice was too small.Calculations similar to those used for my cases can be applied to the first three cases reported by Berk et al. (1948).These patients received 5 ,ug. of vitamin B1, with 150 ml.-of normal gastric juice daily for 10 days.The increase in red blood cells in 10 days was approximately equivalent to that which would have been expected from single injections of 10, 5, and 5 ,ug.In other words, the amounts of vitamin B1., given orally with gastric juice were
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In six patients with pernicious anemia, absorption of vitamin B12 bound to intrinsic factor was low as measured by the Schilling's test. Collection of urine was complete and the activity of intrinsic factor used was checked in other pernicious anemia patients. Nutritional deficiency, drug induced malabsorption, ileal or pancreatic diseases were excluded by clinical, radiological and biological investigations. This vitamin B12 malabsorption was selective and reversible within a few months after treatment with parenteral vitamin B12. Mechanisms of this ileal dysfunction are discussed.
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1. The absorption of radioactive cobalamin was measured by a whole-body counting technique in control subjects and in patients with pernicious anaemia. 2. The absorption of cyanocobalamin by patients with pernicious anaemia was decreased by charcoal but not by bile or saliva. 3. The absorption of cyanocobalamin by control subjects was not affected by food but was significantly increased by pentagastrin. With pentagastrin the absorption of cyanocobalamin was significantly greater than that of hydroxocobalamin. The hog intrinsic factor-mediated absorption of cyanocobalamin by patients with pernicious anaemia was significantly depressed by pentagastrin. 4. The effect of increasing the mass of hog intrinsic factor concentrate on the absorption of cyanocobalamin by patients with pernicious anaemia could be described by a function relating the amount absorbed, the mass of intrinsic factor and two constants. The relationship implies that when the mass of intrinsic factor is small the amount of cyanocobalamin absorbed is directly proportional to the mass of intrinsic factor but that absorption approaches a saturation value with increasing mass of intrinsic factor. In physiological terms the function implies that absorption is proportional to the amount of cyanocobalamin attached to receptor sites but that cyanocobalamin attached to receptor sites may become detached and either reattached or lost to absorption. 5. With oral doses of 25 μg and 50 μg, control subjects absorbed more cyanocobalamin and hydroxocobalamin than patients with pernicious anaemia. At both dose levels control subjects absorbed more cyanocobalamin than hydroxocobalamin but no difference was observed in patients with pernicious anaemia. The intrinsic factor mechanism therefore influences amounts absorbed at such dose levels and appears to be a factor in the differences in absorption of cyanocobalamin and hydroxocobalamin. 6. The use of double-tracer techniques makes it possible for each subject to act as his own control in studies of vitamin B12 absorption. The value of this technique is stressed.
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Introduction
Parenteral injection of cyanocobalamin (Vitamin B12) is well established as an effective and reliable treatment for pernicious anemia. In contrast, currently available preparations for oral use have proved to be much less dependable.1A study was initiated in 1950 in the hematology clinic of The Johns Hopkins Hospital to determine whether relatively large amounts of pure cyanocobalamin, when administered orally without intrinsic factor or other adjuvants, would provide adequate therapy for patients with pernicious anemia. The early results of this investigation2-4as well as those obtained in other clinics5-11were favorable. This paper provides further observations on a group of patients receiving various doses of orally administered cyanocobalamin for periods of up to six and one-half years.Materials and Methods
The diagnosis of pernicious anemia had been well established by clinical and hematological criteria in each patient chosen to participate in this study. In manypernicious anemia
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1. Hematologic and clinical remissions were induced 11 times in 8 patients with pernicious anemia in relapse, and in 1 patient with non-pernicious megaloblastic anemia, by small oral doses of purified vit. B12 without added intrinsic factor. The effective dosage range was 5 to 16.8 μg per day. 2. Unequivocal failure occurred in 1 case of relapsed pernicious anemia. 3. These results further confirm the suggestion that in pernicious anemia there is a quantitative rather than a qualitative change in gastric secretion, and that variations in the amounts of intrinsic factor remaining in pernicious anemia patients may be responsible for varying responses to oral vit. B12. 4. A trial period of vit. B12 alone should precede any study with a vit. B12 plus intrinsic factor preparation.
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