The High Folate/Low Vitamin B12 Interaction is a Novel Cause of Vitamin B12 Depletion: Testing a New Hypothesis - PROJECT SUMMARY / ABSTRACT
Clinical observations from the late 1940s/early 1950s suggested that high-dose folic acid (FA) supplements,
while temporarily alleviating megaloblastic anemia of B12 deficiency, led to relapse and exacerbation of
neurological symptoms in B12-deficient patients. This led to discontinuation of FA supplements to treat B12
deficiency by the early 1970s. However, the mechanism by which FA putatively caused exacerbation of B12
deficiency was never elucidated. The issue of exacerbation of B12 deficiency by exposure to excess FA was
rekindled after the institution of FA fortification in the United States in 1998 when subsequent epidemiological
cohort studies indicated that people with deficient serum B12 and elevated serum folate concentrations had
greater risk of anemia and cognitive impairment, greater elevations of functional biomarkers of B12 deficiency
[serum methylmalonic acid (MMA) and homocysteine (Hcy)], and greater decrease in serum concentrations of
the active form of B12, holotranscobalamin (holoTC) than those with deficient B12 and non-elevated folate.
Recently, we proposed a novel hypothesis to explain the exacerbation of B12 deficiency by exposure to
excess FA: Excess intake of FA depletes serum holoTC, thereby decreasing active B12 in the circulation and
limiting its availability for tissues. Depletion of holoTC by FA in individuals with low B12 status further reduces
the capability to deliver B12 to B12-dependent enzymes, leading to a more pronounced state of biochemical
deficiency as reflected by elevated MMA and Hcy in blood (PMID: 34634124). The overall goal of this
proposal is to test this hypothesis using data from the 2011-2012 National Health and Nutrition Examination
Survey (NHANES). The Specific Aims are (1) assess the associations of total folate status with serum
holoTC, MMA, and Hcy, (2) determine if the associations between folate status and holoTC, MMA, and Hcy are
specific to the form of elevated folate in serum (i.e., FA versus methyltetrahydrofolate), and (3) determine if the
associations between serum folate and holoTC, MMA, and Hcy are modified by B12 status, age, sex, renal
function (as indicated by serum creatinine), and race/ethnicity. To address these aims, we will utilize both
existing data from the NHANES 2011-2012 cohort, including serum total B12, total folate, FA, 5-
methyltetrahydrofolate, MMA, creatinine, and new measurements of key biomarkers not already available in
the cohort, including serum holoTC and Hcy. Associations among the variables will be assessed using
multivariate linear regression. The proposed studies will directly address the hypothesis that excess FA intake
exacerbates B12 deficiency as indicated by metabolic indicators of B12 status, and will identify characteristics
of individuals who are susceptible to these effects of excess FA (e.g., age, overall B12 status, and renal
function). The results will inform future research to determine the acute and long-term health effects of
depleted B12 status resulting from high FA intakes in populations exposed to FA fortification and FA-containing
supplements.
