LETTER TO THE EDITOR Vitamin B12 deficiency: there's more than meets the eye Claudio Galli Scientific Affairs, Abbott Diagnostici, Rome, Italy

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diagnose a status of active B12 deficiency stems from the following observations: in the already mentioned study by Bamonti et al.5, the optimal threshold for HoloTC in subjects with suboptimal total B12 values was estimated to be 40 pmol/L (maximum phi correlation) and this threshold was verified by receiver operating characteristic curve analysis to have a sensitivity of 0.86 and a specificity of 0.66. It is of note that HoloTC values and the estimated cut-off were not affected by gender or age (p=0.54 and p=0.30, respectively) and that the area under the curve showed a better predictive ability for vitamin B12 deficiency through HoloTC determination than other "classical" cobalamin deficiency predictors (serum folate and total homocysteine). Thus, HoloTC concentrations, in addition to total circulating B12 levels, may guarantee a more accurate evaluation of the metabolic status of cobalamin4,5.

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Dear Sir, I appreciated the paper by Scarpa et al.1 on vitamin B12 deficiency in subjects with apparent normal serum levels and the comment by Cosar et al.2, also published in Blood Transfusion. Both authors correctly mentioned the potential relevance of low tissue levels and/or functional deficiencies and highlighted the importance of determining the levels of plasma total homocysteine (tHcY) and also methylmalonic acid, which is considered the "reference" indicator in order to evaluate the complete metabolic pattern of B12. As the difficulties of performing and interpreting the latter assay are well known2, an alternative way to ascertain the presence of subclinical or clinical deficiency of vitamin B12 is to determine the amount of its active fraction, holotranscobalamin (HoloTC, or active B12) i.e. the cobalamin–transcobalamin II complex released into the portal circulation and recognised by ubiquitous specific receptors. HoloTC is the biologically active form of vitamin B12 and represents only a fraction (10-30%) of total circulating vitamin B12, while the remaining fraction is bound to haptocorrin3 and is not metabolically active. The two circulating forms of vitamin B12 have complementary clinical significance: while it has been reported that a relevant fraction of individuals whose total B12 concentration is low show no clinical or biochemical evidence of cobalamin deficiency, it has also been shown that both neurological and metabolic abnormalities may be present when circulating levels of total B12 are within the normal range4 when active B12 levels are low. Furthermore, studies carried out in populations with supposedly low dietary intake of vitamin B12, such as vegetarians, vegans and elderly people, have indicated that HoloTC may be considered as an earlier indicator of vitamin B12 deficiency, and that its levels are modified quite rapidly after adequate dietary intake or supplementation of vitamin B123. From an analytical standpoint the correlation between the two forms of B12 is not linear; for example, when holoTC concentration was measured in 250 selected serum specimens from patients with low-intermediate levels (

Vitamin B12 deficiency: there's more than meets the eye.

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