VITAMIN B12 DEFICIENCY IN HUMANS

Evaluation of HoloTC as a Superior Diagnostic Marker of Vitamin B12 than Total Serum Vitamin B12

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.

Table of Contents

Introduction1

Discussion2

Material and Method4

Analyzed Data Sets7

Methods of Mathematical Analysis8

General Principles of Flux Approximation8

Dependence of Total Plasma B12 on holoTC (scheme 1)10

Dependence of MMA and Hcy on Cbl (scheme 2)12

Statistical Analysis of Distributions16

Dynamics of Metabolic Response20

Results20

Dependence of Total Plasma B12 on holoTC20

Dependence of Plasma MMA and Hcy on holoTC and B1221

Conclusions24

Evaluation of HoloTC as a Superior Diagnostic Marker of Vitamin B12 than Total Serum Vitamin B12

Introduction

The efficiency of the recycling system enables the liver to store vitamin B12 for several years. Prolonged vitamins B12reduction intake, impaired intestinal absorption, an accelerated loss and increased requirements of the vitamin can lead to vitamin B12 deficiency. Vitamin B12 deficiency is initially asymptomatic in most cases, but it can progress into disorders such as macrocytic anaemia and progressive neurological degeneration, of the central as well as the peripheral nervous systems. Hyperhomocysteinemia is another consequence of vitamin B12 deficiency, which is associated with cardiovascular disease, cerebral diseases and neural tube defects.

Literature Review

Vitamin B12, or cobalamin (Cbl), is an important cofactor in human metabolism. Its uptake from dietary sources (meet, milk, etc) requires an intricate transportation mechanism, which involves several specific protein carriers and receptors. Two major transporters of B12 in blood are transcobalamin (TC) and haptocorrin (HC). Transcobalamin is involved in distribution of B12 between different tissues, and the level of holo-transcobalamin (holoTC; TC·Cbl complex) increases after intake of a new portion of the vitamin (Allen, 1975, pp. 57-84). Later on, a part of the assimilated Cbl reappears in blood bound to the second carrier HC. The function of the latter is not completely elucidated, but storage of B12 and scavenging of B12 analogues are often mentioned in this context (Ball, 2004, pp.96-105).

Several publications have proven that Vitamin B12deficiency is a public health problemoften affecting elderly population as a result ofmalabsorption or possibleinadequate dietary intake. Low values have also been reported in vegetarians, and vegans. Early diagnosis of this disease is essential for prevention of further complications (Bor, 2005, pp. 2151-2155).

Methylmalonic acid (MMA) is a dicarboxylic acid is the gold standard in the diagnosis of vitamin B12 deficiency. Serum (or plasma) MMA is increased in the early stages of vitamin B12 deficiency. In MMA metabolism,vitamin B12 is a co-factor ofmethylmalonyl-CoA mutase which is responsible for the conversion of methylmalonic acid (MMA) tosuccinic acid (Figure 1).

During vitamin B12 deficiency, methylmalonyl-CoA mutaseenzyme activity is reduced, resulting in ...