Plasma vitamin B-12 is bound to 2 proteins, transcobalamin and haptocorrin (). Transcobalamin carries a minor part of the circulating vitamin B-12, and only ≈10% of the protein is saturated with vitamin B-12 (2
). Transcobalamin transports vitamin B-12 into all cells of the body and is responsible for the transport of ≈4 nmol of vitamin B-12 every day (3
FIGURE 1. Cobalamin [vitamin B-12 (B12)] and its binding proteins in human plasma. The figure shows the relation between the total concentration of the vitamin B-12 binding proteins in plasma and the distribution of vitamin B-12 and its analogs on the proteins. (more ...)
Haptocorrin is an almost fully saturated vitamin B-12 binding glycoprotein of unknown function that carries the major part of circulating vitamin B-12 and, in addition, the inactive forms of the vitamin, the so-called analogs. The metabolism of the protein is slow, with a turnover of ≈0.1 nmol vitamin B-12 every day (4
We and others have established methods for research purposes that are suitable for measurement of transcobalamin and haptocorrin, whether saturated or not (7
). However, clinicians have been interested mainly in measurements of total vitamin B-12 (10
) and holoTC.
The fact that only vitamin B-12 that binds to transcobalamin is available for cells has fostered the concept that measurement of holoTC would be more clinically meaningful than measurement of total vitamin B-12 (all of the vitamin B-12 that binds to transcobalamin and haptocorrin). Several years ago, Victor Herbert suggested staging vitamin B-12 status with holoTC as the first marker to decline (11
). A few studies on vegetarian populations have confirmed this concept (12
Whereas plasma vitamin B-12 and holoTC concentrations can be used as a measure of the amount of vitamin B-12 available for the body's cells, the metabolites tHcy and MMA mirror any lack of vitamin B-12 within the cells. Both plasma tHcy and MMA accumulate in vitamin B-12–deficient patients (). In general, tHcy has low specificity because it also increases in patients with folate and possibly thiamine and vitamin B-6 deficiency (14
). However, in a folate-fortified population, tHcy's specificity as a marker of vitamin B-12 deficiency is considerably better (15
). MMA is a sensitive marker of vitamin B-12 deficiency, and an elevated MMA concentration is often used as a gold standard for classification of a patient's status as vitamin B-12 deficient or nondeficient. Major drawbacks are the low specificity of marginally elevated MMA values and the test's limited availability (16
FIGURE 2. Markers of cobalamin [vitamin B-12 (B12)] status. The figure shows the relation between vitamin B-12 deficiency markers. Holotranscobalamin (holoTC) transports vitamin B-12 into the cells by binding to a specific receptor, CD320. In the cell, vitamin (more ...)
In otherwise healthy individuals, all 4 tests (vitamin B-12, holoTC, tHcy, and MMA) have a strong relation to vitamin B-12 intake, with steady state concentrations at a daily intake of 4–7 μg vitamin B-12 (17
). Indirectly, such studies suggest that all 4 markers may be useful for monitoring a population's vitamin B-12 status over time.