Abstract
The concentration of total vitamin B12 in serum is not a sufficiently sensitive or specific indicator for the reliable diagnosis of vitamin B12 deficiency. Victor Herbert proposed a model for the staged development of vitamin B12 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 B12 test. HoloTC is cobalamin (vitamin B12) 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 B12 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 B12 status any more reliably than total vitamin B12, 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 B12 deficiency. The author proposes an alternative model for the development of vitamin B12 deficiency.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2252-z) contains supplementary material, which is available to authorized users.
Highlights
This author proposes an alternative model (Fig. 5) in which the earliest onset of vitamin B12 deficiency, or the transition from Normal to Early Negative Vitamin B12 Balance, is not defined by a fall in HoloTC concentration from above one universally specified level to below another
Herbert’s hypothesis, describing the Biochemical and hematological sequence of events as negative vitamin B12 balance progresses, two decades later formed the basis for the introduction of the commercial holotranscobalamin (HoloTC, Active B12) immunoassay for the diagnosis of vitamin B12 deficiency
Vitamin B12 deficiency is defined by a change, in total vitamin B12, HoloTC or metabolite concentrations, from what is normal for the individual
Summary
Herbert’s model In his Herman Award Lecture of 1986, Victor Herbert proposed his Sequential stages in the development of vitamin B12 deficiency (Herbert 1987). HoloTC problems There are four problematic aspects of HoloTC, where there are major differences between authors: the value of the half-life of HoloTC; the correlation between HoloTC and total vitamin B12; sensitivity of HoloTC to recent absorption of vitamin B12; the value of HoloTC cut-off to detect negative vitamin B12 balance The latter two differences are the most important because they raise the questions of what it is that HoloTC concentration indicates, and whether or not it is possible to use it to reliably detect the early onset of vitamin B12 deficiency. Bamonti et al (2010) cited the conflicting findings of Chen et al (2005) and Bor et al (2004). Loikas (2007) commented on the apparently contradictory promotion of HoloTC as “the most sensitive and specific indicator of early vitamin B12 deficiency” and the proposed use of HoloTC as “a marker of vitamin B12 absorption”, concluding that “Reconciling
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