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

Early diagnostics of cobalamin (Cbl, vitamin B12) deficiency is primarily based on measurements of the relevant metabolic markers in blood plasma—total B12, specific Cbl-saturated transporter holo-transcobalamin (holoTC), and substrates of Cbl-dependent enzymatic reactions methylmalonic acid (MMA) and homocysteine (Hcy). Concentrations of B12 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 B12 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·B12)½ and y = ½log10(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 B12 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 B12 physiology and characteristic values of “wellness parameter”: w = log10(holoTCn) + log10(B12n) − log10(MMAn) − log10(Hcyn), where concentrations are normalized (eg, MMAn = MMA/MMAnormal). Dynamic response of the organism to B12 intake is quantified and described as an additional analytical tool when classifying uncertain cases. The discussed mathematical approaches are of general applicability in diagnostics.