Perspective: The High-Folate-Low-Vitamin B-12 Interaction Is a Novel Cause of Vitamin B-12 Depletion with a Specific Etiology - A Hypothesis

Jacob Selhub*, Joshua W. Miller*, Aron M. Troen, Joel B. Mason, Paul F. Jacques

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Vitamin B-12 is a water-soluble vitamin that plays important roles in intermediary metabolism. Vitamin B-12 deficiency has many identifiable causes, including autoimmune and other gastrointestinal malabsorption disorders, dietary deficiency, and congenital defects in genes that are involved in vitamin B-12 trafficking and functions. Another putative cause of vitamin B-12 deficiency is the high-folate-low vitamin B-12 interaction, first suspected as the cause for observed relapse and exacerbation of the neurological symptoms in patients with pernicious anemia who were prescribed high oral doses of folic acid. We propose that this interaction is real and represents a novel cause of vitamin B-12 depletion with specific etiology. We hypothesize that excessive intake of folic acid depletes serum holotranscobalamin (holoTC), thereby decreasing active vitamin B-12 in the circulation and limiting its availability for tissues. This effect is specific for holoTC and does not affect holohaptocorrin, the inert form of serum vitamin B-12. Depletion of holoTC by folic acid in individuals with already low vitamin B-12 status further compromises the availability of vitamin B-12 coenzymes to their respective enzymes, and consequently a more pronounced state of biochemical deficiency. This hypothesis is drawn from evidence of observational and intervention studies of vitamin B-12-deficient patients and epidemiological cohorts. The evidence also suggests that, in a depleted state, vitamin B-12 is diverted to the hematopoietic system or the kidney. This most likely reflects a selective response of tissues expressing folate receptors with high affinity for unmetabolized folic acid (UMFA; e.g., hematopoietic progenitors and renal tubules) compared with those tissues (e.g., liver) that only express the reduced folate carrier, which is universally expressed but has poor affinity for UMFA. The biochemical and physiological mechanisms underlying this interaction require elucidation to clarify its potential public health significance.

Original languageAmerican English
Pages (from-to)16-33
Number of pages18
JournalAdvances in Nutrition
Issue number1
StatePublished - 1 Jan 2022

Bibliographical note

Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.


  • folate
  • folic acid
  • holotranscobalamin
  • homocysteine
  • methylmalonic acid
  • pernicious anemia
  • vitamin B-12


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