Abstract
Based on Victor Herbert’s model for sequential stages in the development of vitamin B12 deficiency, the holotranscobalamin (HoloTC) immunoassay has controversially been promoted as a more specific and sensitive replacement for the total vitamin B12 test, for the diagnosis of deficiency. There have been no longitudinal studies, by means of experimental cobalamin deficiency, because ethical considerations prevent such risky studies on patients or healthy human volunteers. The objective was to provide a detailed record of the response of HoloTC, compared to total vitamin B12 and metabolites, to the development of experimental vitamin B12 deficiency in an initially replete human subject. This 54 year old male, with a vitamin B12 deficiency possibly caused by a defect in the intracellular cobalamin metabolism, ensured an initially replete condition by means of oral doses of cyanocobalamin supplements at 1000 μg/day for 12 weeks. The subject then depleted himself of vitamin B12, by withholding treatment and using a low-cobalamin diet, until significant metabolic disturbances were observed. The responses of serum total vitamin B12 and HoloTC and the two metabolites, plasma methylmalonic acid and homocysteine, were monitored by weekly blood tests. HoloTC was not significantly more sensitive than either total serum vitamin B12 or total homocysteine, and was much less sensitive than methylmalonic acid. HoloTC decreased from an initial concentration of >128 pmol/L to a minimum of 33 pmol/L on day 742, the only day on which it fell below the lower limit of the reference interval. Total vitamin B12 decreased from an initial concentration of 606 pmol/L to a minimum of 171 pmol/L on day 728. Total homocysteine increased from an initial concentration of 8.4 μmol/L to a maximum of 14.2 μmol/L on day 609. Methylmalonic acid unexpectedly contained four distinct peaks; initially at 0.17 μmol/L, it first exceeded the upper limit of the reference interval on day 386, finally reaching a maximum peak of 0.90 μmol/L on day 658. The results of this experiment are inconsistent with Herbert’s hypothesis that HoloTC is the earliest marker of vitamin B12 deficiency, and therefore do not support his model for the staged development of vitamin B12 deficiency.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-1740-5) contains supplementary material, which is available to authorized users.
Highlights
IntroductionOther researchers have reviewed the HoloTC immunoassay (Morkbak et al 2005; Aparicio-Ugarriza et al 2014)
Based on Victor Herbert’s model for sequential stages in the development of vitamin B12 deficiency (Herbert 1987a, 1994), the holotranscobalamin (HoloTC) immunoassay has controversially been promoted as a more specific and sensitive replacement for the total vitamin B12 test, for theOther researchers have reviewed the HoloTC immunoassay (Morkbak et al 2005; Aparicio-Ugarriza et al 2014)
Commencing in March 2007, this author used himself as the subject of an experiment to investigate the sensitivity of total vitamin B12, HoloTC and the two metabolites, methylmalonic acid (MMA) and total homocysteine, to the onset of vitamin B12 deficiency
Summary
Other researchers have reviewed the HoloTC immunoassay (Morkbak et al 2005; Aparicio-Ugarriza et al 2014). This author’s detailed review of Herbert’s model and the HoloTC immunoassay, and suggested alternative hypothesis for the development of vitamin B12 deficiency, has been submitted to this journal as a separate article. Golding SpringerPlus (2016)5:184 immunoassay, several experimenters reported results that do not support the claim that HoloTC is the earliest and most sensitive indicator of vitamin B12 deficiency (Miller et al 2005; Clarke et al 2007; Schrempf et al 2011; Palacios et al 2013; Remacha et al 2014).
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