Excess folic acid and vitamin B12 deficiency: clinical implications?

Authors: MILLER, JOSHUA - Rutgers University; SMITH, ANDRE - Rutgers University; TROEN, ARON - Hebrew University Of Jerusalem; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SELHUB, JACOB - Tufts University

Submitted to: Food and Nutrition Bulletin
Publication Type: Review Article
Publication Acceptance Date: 1/12/2024
Publication Date: 6/1/2024
Citation: Miller, J.W., Smith, A., Troen, A., Mason, J.B., Jacques, P.F., Selhub, J. 2024. Excess folic acid and vitamin B12 deficiency: clinical implications?. Food and Nutrition Bulletin. https://doi.org/10.1177/03795721241229503.
DOI: https://doi.org/10.1177/03795721241229503

Interpretive Summary:

Technical Abstract: Background: In the 1940s-1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the widespread use of folic acid supplements. Objectives: The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians. Results: Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and non-elevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency. Conclusion: The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses.