Metabolic signs of vitamin B12 deficiency in humans: computational model and its implications for diagnostics

Abstract

Early diagnostics of cobalamin (Cbl, vitamin B 12 ) deficiency is primarily based on measurements of the relevant metabolic markers in blood plasma-total B 12 , specific Cbl-saturated transporter holo-transcobalamin (holoTC), and substrates of Cbl-dependent enzymatic reactions methylmalonic acid (MMA) and homocysteine (Hcy). Concentrations of B 12 and holoTC decrease whereas MMA and Hcy increase under deficiency. Yet, the results of individual tests are often contradictory and do not guarantee unambiguous diagnosis. The current work describes the metabolic manifestation of vitamin B 12 deficiency in terms of flux equations fitted to data sets from literature. The model mathematically connects all the markers and presents 4 independent measurements as a single point (x, y) in the combined coordinates x = (holoTC·B 12 ) ½ and y = ½log 10 (MMA·Hcy). Pairwise averaging compensates for the individual fluctuations of the markers caused by (1) irregular spikes of holoTC, (2) delayed change of the total plasma B 12 buffered by an internal Cbl depot, and (3) variations in the production/ excretion velocities of MMA and Hcy. Bivariate distribution of the marker combinations (x, y) reveals several peaks of frequency in the analyzed mixed population. The peaks seem to represent the reference subgroups with different B 12 physiology and characteristic values of "wellness parameter": w = log 10 (holoTC n ) + log 10 (B 12n ) − log 10 (MMA n ) − log 10 (Hcy n ), where concentrations are normalized (eg, MMA n = MMA/MMA normal ). Dynamic response of the organism to B 12 intake is quantified and described as an additional analytical tool when classifying uncertain cases. The discussed mathematical approaches are of general applicability in diagnostics.

Interactions between plasma concentrations of folate and markers of vitamin B12status with cognitive performance in elderly people not exposed to folic acid fortification: the Hordaland Health Study

“…There is currently no 'gold standard' to define vitamin B 12 deficiency with respect to potential markers and cut-off points to be used (46,47) , although it has been recommended to include holoTC II and MMA as additional markers of vitamin B 12 status (48) . Fedosov (49) presented a mathematic model combining the concentrations of vitamin B 12 , MMA, holoTC II and tHcy to classify vitamin B 12 status without the use of pre-defined cut-off levels. In addition, single markers were examined for their potential to predict vitamin B 12 deficiency.…”

“…The optimal combinations of markers, cut-off levels and assays for vitamin B 12 status assessment have been the topic of debate since many years. Mathematic models combining the results of different markers may provide the best alternative for assessing vitamin B 12 status in the future (49) .…”

Association of Cognitive Impairment with Combinations of Vitamin B12–Related Parameters

“…We recently introduced a model in which we took all 4 markers of B 12 status into account and expressed the combined results either as a distribution surface [x ϭ (holoTC ϫ B 12 ) 1/2 ; y ϭ 0.5 ϫ log(MMA ϫ tHcy); z ϭ the number of participants] or as a "wellness score" (14 ).…”

“…After removal of outliers (total n ϭ 14) with holoTC Ͼ240 pmol/L (n ϭ 2), totalTC Ͼ2000 pmol/L (n ϭ 8), totalHC Ͼ2000 pmol/L (n ϭ 2), or totalHC Ͻ200pmol/L (n ϭ 2), 839 individuals were included for assessment of totalTC, TCsat, and totalHC as well as for calculations combining the 4 parameters B 12 1/2 and y ϭ 0.5 ϫ log(MMA ϫ tHcy)] were calculated for each individual on the basis of the previously presented model (14 ). These values were plotted as a 3-dimensional polygon according to their frequency on the (x,y) surface.…”

Vitamin B12 Deficiency in Pregnancy and Lactation: Is there a Need for Pre and Post-natal Supplementation?

“…However, MMA is affected by intestinal bacterial overgrowth and tHcy is elevated by deficiencies of vitamin B6, folate, and riboflavin. Recent investigations show that holoTC (the metabolically active fraction of B12 available to cells) is a more sensitive indicator of vitamin B12 status than the total serum vitamin B12 level or the serum concentration of MMA and plasma tHcys [26][27][28][29][30]. The reference values for non-pregnant women are often applied to assess B12 deficiency in pregnant women.…”