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

Abstract 

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(holoTC_n) + log₁₀(B_12n) − log₁₀(MMA_n) − log₁₀(Hcy_n), where concentrations are normalized (eg, MMA_n = MMA/MMA_normal). 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.