We are all familiar with the concerns about folate deficiency and we want to make sure everyone has enough folate to avoid neural tube defects, poor pregnancy outcomes, and cancer. Folic acid has been promoted by public health departments and it is a regular part of most diets because of flour fortification. But now there are concerns about the effect of too much folic acid, or rather, too much unmetabolized folic acid.

But before we get too far, let’s review the terminology. Folic acid refers to the synthesized, oxidized compound that was discovered in the 1940s. It is what you find in dietary supplements and food fortification. In the liver, folic acid is converted by the enzyme, dihydrofolate reductase, to the usable form, tetrahydrofolate. When this mechanism is overwhelmed or too slow, folic acid can build up in the serum, which is referred to as unmetabolized folic acid (UMFA).

Folate refers to the water-soluble B-vitamin that we find naturally in whole foods. Folates found naturally in food include 5-methyltetrahydrofolate (5-MTHF), 10-formyltetrahydrofolate, and 5-formyltetrahydrofolate.

Some studies have shown that folic acid intake is associated with cancer progression and growth (colorectal, breast, prostate).[1] High UMFA might be responsible for these negative effects. As little as 300 to 400 mcg of folic acid can elevate serum UMFA, while consumption of naturally occurring folates does not increase UMFA.[2] Therefore, some authors suggest that it is the synthetic form of the vitamin (folic acid) that causes problems and that natural folates (in food) are not problematic. However, more research is needed to answer these questions.

While there is increasing concern about adverse health effects of excess folic acid intake and high UMFA, high 5-MTHF may not be desirable either. It could actually be that the cancer-promoting effect of folic acid is due to supraphysiologic levels of tetrahydrofolate (THF), the bioactive form of the vitamin. 5-MTHF could also increase THF. Therefore, either high 5-MTHF levels or high UMFA levels may be contraindicated in patients with cancer risk.

The bottom line is that when it comes to folic acid, too little or too much could lead to problems. It isn’t wise to give high doses of folic acid (or folate) to patients without evidence that they need it. Testing 5-MTHF can help a clinician determine if the patient requires no folate supplementation, a reduced or maintenance dose of folate, or a high dose of folate. Serum UMFA will tell a clinician if the patient is having trouble metabolizing folic acid and needs to reduce folic acid vitamins and fortified foods.

Studies suggest that too little folate causes disease and too much folic acid may also cause disease.[1–5] The old adage, “everything in moderation,” probably holds true, not just for folate but for all nutrients. We can’t say all vitamins are good and we can’t say all vitamins are bad; there are many factors that determine if a vitamin is good or bad, and at what quantities, for a given individual. Having to sort through all of these complexities for each patient reminds us of the wisdom of individualized medicine. Testing UMFA and 5-MTHF can help determine that a patient doesn’t have too little folate or too much folic acid, but the amount that is just right.

~ Cass Nelson-Dooley

References

1. Kim YI. Folic acid fortification and supplementation--good for some but not so good for others. Nutr Rev. Nov 2007;65(11):504-511.

2. Bailey RL, Mills JL, Yetley EA, et al. Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged > or =60 y in the United States. Am J Clin Nutr. Aug 2010;92(2):383-389.

3. Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. Jun 1997;65(6):1790-1795.

4. Powers HJ. Folic acid under scrutiny. Br J Nutr. Oct 2007;98(4):665-666.

5. Solomons NW. Food fortification with folic acid: has the other shoe dropped? Nutr Rev. Nov 2007;65(11):512-515.