Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review

Abstract

This report on vitamin B-12 (B12) is part of the Biomarkers of Nutrition for Development (BOND) Project, which provides state-of-the art information and advice on the selection, use, and interpretation of biomarkers of nutrient exposure, status, and function. As with the other 5 reports in this series, which focused on iodine, folate, zinc, iron, and vitamin A, this B12 report was developed with the assistance of an expert panel (BOND B12 EP) and other experts who provided information during a consultation. The experts reviewed the existing literature in depth in order to consolidate existing relevant information on the biology of B12, including known and possible effects of insufficiency, and available and potential biomarkers of status. Unlike the situation for the other 5 nutrients reviewed during the BOND project, there has been relatively little previous attention paid to B12 status and its biomarkers, so this report is a landmark in terms of the consolidation and interpretation of the available information on B12 nutrition. Historically, most focus has been on diagnosis and treatment of clinical symptoms of B12 deficiency, which result primarily from pernicious anemia or strict vegetarianism. More recently, we have become aware of the high prevalence of B12 insufficiency in populations consuming low amounts of animal-source foods, which can be detected with ≥1 serum biomarker but presents the new challenge of identifying functional consequences that may require public health interventions.

FIGURE 1

Digestion and absorption of dietary cobalamins. In the receptor-mediated active process for B12 absorption, dietary B12 is released in the stomach and bound to salivary R-binder. The R-B12 complex and IF are transported to the ileum where B12 is released from the R-binder and binds to IF. The IF-B12 complex enters the ileal enterocyte, IF is degraded, and the B12 is released through MRP1 to plasma, where it binds with and is transported on TC. More details are provided in Text Box 2. Reproduced with permission from reference . AMN, amnionless; B12, vitamin B-12; IF, intrinsic factor; MRP1, multidrug resistance protein 1; TC, transcobalamin.

FIGURE 2

B12 cellular uptake and metabolism. In mitochondria, B12 as 5-deoxyadenosylcobalamin is a cofactor for methylmalonyl-CoA mutase, which catalyzes conversion of methylmalonyl CoA to succinyl CoA. In cytoplasm as 5-methylcobalamin, it is a cofactor for methionine synthase, which catalyzes conversion of homocysteine to methionine. Enzymes: 1, methylmalonyl-CoA mutase; 2, methionine synthase reductase; 3, methionine synthase; 4, methylenetetrahydrofolate reductase. More details are provided in Text Box 4. Reproduced with permission from reference . B12, vitamin B-12; SAM, S-adenosylmethionine; TC, transcobalamin; THF, tetrahydrofolate.

FIGURE 3

Relation between the intake and percentage absorbed from a dose of B12 (17) based on data from Chanarin (16). Reproduced with permission from reference . B12, vitamin B-12.

FIGURE 4

Prevalence of abnormal B12 status biomarkers in the US population. Data were generated from NHANES 1999–2004 for the overall adult population and by the age groups listed. The cutoff value between low and normal serum B12 is 148 pmol/L and between normal and elevated MMA is 271 nmol/L. The figure demonstrates that the prevalence of “B12 deficiency” depends on which biomarkers are used (alone or in combination) and how cutoff values are defined. Reproduced with permission from reference . B12, vitamin B-12; MMA, methylmalonic acid.

FIGURE 5

Prevalence of low (<148 pmol/L) and marginal (148–221 pmol/L) plasma or serum B12 concentrations in selected representative national surveys and large nonrepresentative studies. B12, vitamin B-12; MRC, Medical Research Council; NDNC, National Diet and Nutrition Survey; OHAP, Oxford Healthy Aging Project; SALSA, Sacramento Area Latino Study on Agin.

FIGURE 6

Sites of genetic inborn errors of B12 metabolism. Reproduced with permission from reference . B12, vitamin B-12; cbl, prefix for genetic mutations affecting B12; MTHFR, methylenetetrahydrofolate reductase; TC, transcobalamin; THF, tetrahydrofolate.

FIGURE 7

Relation between B12 intake and serum biomarker concentrations. Reproduced with permission from reference . B12, vitamin B-12; Hcy, homocysteine; holo-TC, holotranscobalamin; MMA, methylmalonic acid. ^*,^**,^***Significantly different from lowest quintile of B12 intake: ^*P < 0.05, ^**P < 0.01, ^***P < 0.001.