In vitamin B12 deficiency, higher serum folate is assoicated with increased total homocysteine (tHcy) and methlmalonic acid (MMA) concentrations

Authors: Selhub, Jacob; MORRIS, MARTHA - TUFTS/HNRCA; Jacques, Paul

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/8/2007
Publication Date: 12/11/2007
Citation: Selhub, J., Morris, M.S., Jacques, P. 2007. In vitamin B12 deficiency, higher serum folate is assoicated with increased total homocysteine (tHcy) and methlmalonic acid (MMA) concentrations. Proceedings of the National Academy of Sciences. 104(50):19995-20000.

Interpretive Summary: In the late 1940s, people with severe vitamin B-12 deficiency due to the disease pernicious anemia were treated with folic acid. Reports on some of these cases detailed improvement in anemia but worsening, or precipitation, of neurologic problems. The exact explanation for these results is unknown. Because many elderly people have low vitamin B-12 status and also take vitamin supplements and consume highly fortified foods, such as fortified breakfast cereals, concerns have been raised about possible effects of their high folic acid intake. We recently investigated this question using data collected in the National Health and Nutrition Examination Survey (1999-2002) and found that elderly participants with low vitamin B-12 status but high circulating folate levels experienced more anemia and more cognitive impairment than participants with low vitamin B-12 status and lower serum folate levels. In the present study, we extended these findings by considering biochemical events occurring in people with the combination of low vitamin B-12 status and high folate status. We found that such people had higher circulating levels of homocysteine and methylmalonic acid than people with the combination of low serum vitamin B-12 and normal serum folate. Because methylmalonic acid builds up when a mitochondrial reaction involving vitamin B-12 fails to occur, these findings suggest that, in vitamin B-12 deficiency, higher folate status causes a redistribution of vitamin B-12, such that the mitochondrion is depleted even further of vitamin B-12 than it is when vitamin B-12 status us low and folate status is normal.

Technical Abstract: In a recent study of older participants (age >/= 60 y) 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 status and folate status. In the present study, we sought to determine the joint influence of serum folate and vitamin B12 concentrations on two functional indicators of vitamin B12 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 aged <20 y, were pregnant, had evidence of kidney or liver dysfunction, or reported a history of alcohol abuse or recent anemia therapy, left 4940 NHANES III participants and 5473 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/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 about 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.