Holotranscobalamin (HoloTC, Active-B12) and Herbert's model for the development of vitamin B12 deficiency: a review and alternative hypothesis

The concentration of total vitamin B-12 in serum is not a sufficiently sensitive or specific indicator for the reliable diagnosis of vitamin B-12 deficiency. Victor Herbert proposed a model for the staged development of vitamin B-12 deficiency, in which holotranscobalamin (HoloTC) is the first indicator of deficiency. Based on this model, a commercial immunoassay has been controversially promoted as a replacement for the total vitamin B-12 test. HoloTC is cobalamin (vitamin B-12) attached to the transport protein transcobalamin, in the serum, for delivery to cells for metabolism. Although there have been many published reports supporting the claims for HoloTC, the results of some studies were inconsistent with the claim of HoloTC as the most sensitive marker of vitamin B-12 deficiency. This review examines the evidence for and against the use of HoloTC, and concludes that the HoloTC immunoassay cannot be used to measure vitamin B-12 status any more reliably than total vitamin B-12, or to predict the onset of a metabolic deficiency, because it is based on an erroneous hypothesis and a flawed model for the staged development of vitamin B-12 deficiency. The author proposes an alternative model for the development of vitamin B-12 deficiency.