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Title: Folate–vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency

Author
item SELHUB, JACOB - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item MORRIS, MARTHA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item ROSENBERG, IRWIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/1/2008
Publication Date: 6/1/2009
Citation: Selhub, J., Morris, M., Jacques, P., Rosenberg, I. 2009. Folate–vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. American Journal of Clinical Nutrition. 89(2):702S-706S.

Interpretive Summary: Previous case reports suggest that high folic acid intake may affect the natural history if vitamin b12 deficiency, which affects many elderly individuals. However, verification of this hypothesis with experimental investigation by treating Vitamin B12 deficient patients with folic acid is unethical. Therefore, we sought to test the hypothesis that high intake of folic acid among individuals with inadequate B12 status would exacerbate the consequences of low B12 using a natural experiment that occurred with the implementation of folic acid fortification of enriched cereal grain products. With the use of data from the 1999–2002 National Health and Nutrition Examination Survey (NHANES), we evaluated the interaction between high serum folate and low vitamin B-12 status with respect to anemia and cognitive impairment, two consequences of vitamin B12 deficiency. Using subjects with normal plasma folate and normal vitamin B-12 status as the referent category, anemia was twice as prevalent for those with low vitamin B-12 status but normal serum folate and approximately 5 times more prevalent for those with low vitamin B-12 status and elevated plasma folate. Likewise, the prevalence of impaired cognitive function was also approximately 2-fold and 5-fold higher among those with low vitamin B-12 status but normal serum folate and those with low vitamin B-12 status and elevated plasma folate, respectively, relative to those with normal folate and vitamin B12 status. We also showed that elevated serum folate concentration resulted in higher circulating levels of metabolic markers of vitamin B12, homocysteine and methymalonic acid, among NHANES participants with inadequate serum vitamin B12 levels, whereas the opposite was seen among subjects with normal serum vitamin B-12. These interactions, which were not seen in NHANES III before fortification, imply that, in vitamin B-12 deficiency, high folate status is associated with impaired vitamin B12 metabolism.

Technical Abstract: Previous reports on pernicious anemia treatment suggested that high folic acid intake adversely influences the natural history of vitamin B-12 deficiency, which affects many elderly individuals. However, experimental investigation of this hypothesis is unethical, and the few existing observational data are inconclusive.With the use of data from the 1999–2002 National Health and Nutrition Examination Survey (NHANES), we evaluated the interaction between high serum folate and low vitamin B-12 status [ie, plasma vitamin B-12 , 148 pmol/L or methylmalonic acid (MMA) . 210 nmol/L] with respect to anemia and cognitive impairment.With subjects having both plasma folate _ 59 nmol/L and normal vitamin B-12 status as the referent category, odds ratios for the prevalence of anemia compared with normal hemoglobin concentration and impaired compared with unimpaired cognitive function were 2.1 (95% CI: 1.1, 3.7) and 1.7 (95% CI: 1.01, 2.9), respectively, for those with low vitamin B-12 status but normal serum folate and 4.9 (95% CI: 2.3, 10.6) and 5.0 (95% CI: 2.7, 9.5), respectively, for those with low vitamin B-12 status and plasma folate .59 nmol/L. Among subjects with low vitamin B-12 status, mean circulating vitamin B-12 was 228 pmol/L for the normal-folate subgroup and 354 pmol/L for the high-folate subgroup. We subsequently showed increases in circulating homocysteine and MMA concentrations with increasing serum folate among NHANES participants with serum vitamin B-12, 148 pmol/L, whereas the opposite trends occurred among subjects with serum vitamin B-12 _ 148 pmol/L. These interactions, which were not seen in NHANES III before fortification, imply that, in vitamin B-12 deficiency, high folate status is associated with impaired activity of the 2 vitamin B-12–dependent enzymes, methionine synthase and MMA–coenzyme A mutase.