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

[helvella]

Note: This paper is presented by its own authors as a hypothesis rather than a wholly proved and accepted theory.

However, excess folic acid has been identified as an issue many times. Typically, a GP prescribes 5 milligram doses, every day, and the patient continues taking that indefinitely. Eventually, they feel terrible and reduce the dose - and feel much better.

Modest folic acid supplementation (e.g. 200 to 400 micrograms a day) is much less likely to be an issue.

I suggest anyone on higher dose folic acid (or folate) considers whether their dose could be too high. Get tested. If appropriate, discuss with healthcare professionals. Adjust as needed.

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

Advances in Nutrition, Volume 13, Issue 1, January 2022, Pages 16–33, doi.org/10.1093/advances/nm...

Published: 11 October 2021

ABSTRACT

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.

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

Rest of article is behind paywall:

academic.oup.com/advances/a...

[JGBH]

Thank you for this link. I have been wondering about this interaction, for quite a while. Looking forward to hearing more following this hypothesis.

[Imaaan]

So is it saying a high intake of folic acid would eventually drop b12 levels? If that's the case, I wonder if taking the same amount of b12 and folic acid would curb that. Thoughts???

[helvella Administrator Thyroid UK in reply to Imaaan]

Exactly my thought!

(Assuming not suffering Pernicious Anaemia or other "can't absorb" issue.)

[Imaaan in reply to helvella]

That was an Olympic speed response, gold medal goes to ya. Thanks for sharing your thoughts.

[tegz]

It's not well known but the number of people with methylation issues due to genetics is high.Half the population have snps on either the Mthfr or COMT genes which means that Folic Acid or Methyl B12 may be unsuitable to take.

The solution, from those in the know, inc.one USA M.D, is to use Folinic Acid & Adenosyl or Hydroxyl version of B12.

These are more costly & I never detected the difference -but not a heavy user of either.

I take both by default, however.

[Barrister]

So how does this affect those of us who also take Methotrexate (for inflammatory arthritis) who are prescribed 5mg folic acid 6 days a week to help prevent side effects from the Methotrexate and folate deficiency? Will the possibility of folate deficiency (we aren’t tested for folate deficiency as a rule) be enough to mitigate the risk of Vit B 12 deficiency? (I do have PA).

Clemmie

[helvella Administrator Thyroid UK in reply to Barrister]

I am genuinely glad you asked.

While my answer is simple: I don't know.

I'd consider emailing the paper's author(s). Unlikely this will be widely known and they might be among the few who just might know.