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Editorials |
1 From the Department of Chemical Pathology, University of Pretoria, Pretoria, South Africa.
See corresponding articles on pages 904 and 911.
2 Address reprint requests to JB Ubbink, Department of Chemical Pathology, University of Pretoria, PO Box 2034, Pretoria 0001 South Africa. E-mail: jubbink{at}medic.up.ac.za.
Since the discovery of vitamins in the early years of this century, there has been exponential growth in the scientific knowledge of the metabolic effects of these micronutrients. An increased awareness of the role of vitamins in health and disease has spurred the demand for laboratory tests to evaluate the individual patient's vitamin status. Early analytic methods, which included microbiological, photometric, and fluorometric assays, often lacked sensitivity and specificity. These problems were largely solved with the advent of modern chromatographic techniques in vitamin analysis, but an unexpected problem of information overload then became apparent. For example, how does one relate an HPLC profile of all 6 biologically active vitamers of vitamin B-6 to vitamin B-6 nutritional status? Is a low serum pyridoxal 5'-phosphate (which is albumin bound and not directly available for cellular metabolism) concentration indicative of vitamin B-6 deficiency in the presence of a normal serum pyridoxal (the transport form of vitamin B-6) concentration? And how does one interpret the opposite situation, ie, low pyridoxal in the presence of normal pyridoxal 5'-phosphate concentrations? Similarly, the various forms of folic acid present in human serum and erythrocytes complicate the use of chromatography to measure folate nutritional status. It is therefore understandable that a microbiological assay is still the reference method for determining biologically active folate.
Because the interpretation of blood vitamin profiles is difficult, metabolic markers of vitamin status may be useful in assessing an individual's vitamin nutritional status. Earlier tests, so-called load tests, relied on stressing a metabolic pathway dependent on a particular vitamin: eg, the tryptophan and histidine load tests to assess vitamin B-6 and folate nutritional status, respectively. However, load tests are cumbersome and actually highlight the lack of adequate and sensitive metabolite assays suitable for determining nutritional status.
Stabler et al (1) and Allen et al (2) did pioneering work to establish the use of basal serum metabolite concentrations in assessing vitamin nutritional status. They showed that homocysteine accumulates in the circulation if its remethylation to methionine is impeded by folate or vitamin B-12 (cobalamin) deficiency, whereas methylmalonic acid (MMA) accumulates when cobalamin deficiency impairs the enzymatic conversion of l-methylmalonyl-CoA to succinyl-CoA. Similarly, the transsulfuration pathway functions suboptimally during vitamin B-6 deficiency with accumulation of cystathionine in the circulation. Determinations of these metabolites in serum to diagnose folate, cobalamin, and vitamin B-6 deficiencies is gaining acceptance in nutritional science; in fact, in this issue of the Journal there are 2 papers that use serum metabolite concentrations in defining vitamin nutriture (3, 4).
Both Stabler et al (3) and Carmel et al (4) investigated vitamin nutritional status of elderly black and white Americans. Stabler et al studied a cohort of physically disabled elderly women, whereas Carmel et al studied elderly Los Angeles inhabitants of both sexes. Ethnic differences in circulating vitamin B-6 (5) and cobalamin concentrations (6) have been noted before, but, as pointed out by Carmel et al, the metabolic relevance of these observations had been obscure. Analysis of metabolites allows a clearer picture of the implications of the lower vitamin B-6 (pyridoxal 5'-phosphate) and higher cobalamin concentrations commonly encountered in blacks. According to 95% references ranges for serum pyridoxal 5'-phosphate concentrations derived in white populations, many blacks would be considered to have suboptimal vitamin B-6 status. The data of Stabler et al show that lower serum vitamin B-6 concentrations in blacks do not indicate deficiency. If serum cystathionine concentrations are considered, only 3% of blacks in their cohort were vitamin B-6 deficient compared with 2% of the white subjects.
For vitamin B-12 status, serum MMA concentrations confirm the impression gained from cobalamin analyses that cobalamin deficiencies are less often encountered in blacks than in whites. Stabler et al found that 19% of white and 8% of black participants had elevated serum MMA concentrations and serum cobalamin concentrations <258 pmol/L. Carmel et al report similar figures for elevated MMA concentrations in blacks and whites. An interesting new finding is that vitamin B-12 status is a strong predictor of serum total homocysteine (tHcy) concentrations in the elderly. Using stepwise logistic regression analysis, Carmel et al showed that a low serum cobalamin concentration was a better predictor of hyperhomocysteinemia than were subnormal serum folate concentrations. Furthermore, in participants taking multivitamin supplements, serum tHcy concentrations were strongly influenced by the size of the daily cobalamin dose. In contrast, studies in younger people suggest that folate is the main determinant of serum tHcy concentrations (7), and that, compared with cobalamin, folate supplementation is more effective in lowering serum tHcy concentrations (8). These findings presumably reflect the higher prevalence of cobalamin malabsorption syndromes in the elderly than in younger people. It certainly serves as a reminder of the pitfalls of generalizing study results to the whole population.
Serum tHcy concentrations are of particular interest because not only do they serve as a metabolic indicator of folate and cobalamin deficiencies, but an elevated serum tHcy concentration is also linked to increased vascular disease risk. Carmel et al and Stabler et al report conflicting results on the ethnic differences in circulating tHcy concentrations. Stabler et al found significantly higher serum tHcy concentrations in elderly black women than in elderly white women but Carmel et al found just the opposite. Explanations for these diametrically opposed findings can only be suggested at this stage. Perhaps selection bias contributed to the different findings. Perhaps impaired renal function, which may be common in the elderly, confounded the results despite adjustment of data for serum creatinine concentrations. Newer, more sensitive tests of glomerular filtration rate, eg, serum cystatin C concentrations (9), may prove useful in elucidating the relation between renal function and circulating tHcy concentrations in future studies. Perhaps the higher serum tHcy concentrations in blacks found by Stabler et al are the result of particular dietary preferences of this subgroup. I hope that future studies will offer explanations for the different findings mentioned above.
Finally, although results from different centers are not yet totally consistent, it is nevertheless clear that much progress has been made in the assessment of vitamin nutritional status. The use of serum metabolite concentrations to assess vitamin nutriture holds much promise for the future definition of optimal micronutrient intakes. Future recommended dietary allowances for vitamins may increasingly rely on data derived from intermediary metabolism.
REFERENCES
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