In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations

In a recent study of older participants (age >= 60 years) in the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we showed that a combination of high serum folate and low vitamin B-12 status was associated with higher prevalence of cognitive impairment and anemia than other combinations of vitamin B-12 and folate status. In the present study, we sought to determine the joint influence of serum folate and vitamin B-12 concentrations on two functional indicators of vitamin B-12 status, total homocysteine (tHcy) and methylmalonic acid (MMA), among adult participants in phase 2 of the NHANES III (1991-1994) and the NHANES 1999-2002. Exclusion of subjects who were <20years old, were pregnant, had evidence of kidney or liver dysfunction, or reported a history of alcohol abuse or recent anemia therapy left 4,940 NHANES III participants and 5,473 NHANES 1999-2002 participants for the study. Multivariate analyses controlled for demographic factors, smoking, alcohol use, body mass index, self-reported diabetes diagnosis, and serum concentrations of creatinine and alanine aminotransferase revealed significant interactions between serum folate and serum vitamin B-12 in relation to circulating concentrations of both metabolites. In subjects with serum vitamin B-12 > 148 pmol/liter (L), concentrations of both metabolites decreased significantly as serum folate increased. In subjects with lower serum vitamin B-12, however, metabolite concentrations increased as serum folate increased starting at approximate to 20 nmol/L. These results suggest a worsening of vitamin B-12's enzymatic functions as folate status increases in people who are vitamin B-12-deficient.