Cobalamin Analogues Are Present in Human Plasma and Can Mask Cobalamin Deficiency because Current Radioisotope Dilution Assays Are Not Specific for True Cobalamin

Abstract

Since R protein binds cobalamin (vitamin B12) and cobalamin analogues, whereas intrinsic factor is highly specific for true cobalamin, we compared the serum cobalamin values obtained with these proteins in radioisotope dilution assays. With R protein, eight of 21 patients with cobalamin deficiency had serum cobalamin levels (mean, 204, range, 85 to 355 pg per milliliter) that overlapped with values for 74 normal subjects (mean, 576, range, 220 to 1230). With intrinsic factor, no patient values (mean, 36, range, less than 10 to 78 pg per milliliter) overlapped with the normal values (mean, 322, range, 130 to 785). Paper chromatography showed that these differences were due to the presence of cobalamin analogues. R protein constituted 51 to 85 per cent of the cobalamin-binding protein in 10 commercial serum cobalamin assay kits, which were said to contain "intrinsic factor". Human plasma contains cobalamin analogues that can mask cobalamin deficiency with current radioisotope dilution assays.

Holotranscobalamin remains unchanged during pregnancy. Longitudinal changes of cobalamins and their binding proteins during pregnancy and postpartum

“…Our results showed that measured holoHC was approximately twice as high as calculated holoHC. This supports the presence of analogues on HC 8 and suggests that the amount of analogues bound to HC increased during pregnancy. At present, we have no explanation to offer for this observation.…”

Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin.

“…Blood collections were performed for measurement of total serum vitamin B 12 (9,10) and holoTCII in all subjects at weekly intervals for the first month and at monthly intervals for 4 months. After 3 months of metformin therapy, oral calcium carbonate (1.2 g/day) was administered to the metformin group alone for 1 month.…”

“…After separation, serum samples were frozen immediately at Ϫ20°C until assayed (Simul-TRAC; Becton Dickinson, Orangeberg, NY). Vitamin B 12 and vitamin B 12 analogs were assayed by differential radioassay according to the modification by Kolhouse et al (9) of the method of Lau et al (10) using purified IF to measure cobalamin and R-binder to measure total corrinoids (9,10). The analogs are measured by the difference between the 2 assays; elevated levels of the analogs indicate bacterial overgrowth of the small intestine, except in rare cases of ingestion of the analogs themselves from alternative medicine sources, e.g., herbs, algae, or seaweed.…”

“…This finding is further supported by our in vivo observation of a reversal of metformin-induced serum holoTCII depression by oral calcium. As evaluated by differential radioassay, noncobalamin vitamin B 12 analogs constitute a significant percentage of total corrinoids in human serum (9,16). The absence of change in serum analogs or that of serum folate in our study suggests that bacterial overgrowth was not a significant factor in the depression of serum vitamin holoTCII or total vitamin B 12 levels (19).…”

Navigating the B12 Road: Assimilation, Delivery, and Disorders of Cobalamin

“…Both transcobalamin and intrinsic factor bind cobalamin in a base-on conformation, whereas the binding mode for haptocorrin depends on the lower axial ligand. In addition to cobalamins, haptocorrin can bind cobinamides, B 12 analogs that lack the DMB moiety, cannot be converted to the active cofactor forms by mammals, and account for ϳ40% of the total plasma corrins (29). Although a definitive role for haptocorrin remains to be established, its suggested functions include a role in B 12 storage and in removal of inhibitory corrinoid derivatives.…”