Mariusz Rajczakowski
Nutritionist
9 min read | 3 months ago

Folic acid vs Folate – know the difference

Folic acid, sometimes referred to as folate or vitamin B9 is one of the B vitamins used mainly in childbearing age in order to prevent neural tube defects (NTDs). [1].

It is crucial to know that conversion from folic acid, folates and other folic acid metabolites to an active form: 5-methyltetahydrofolate (5-MTHF) vary significantly

This article will go over the common functions in the body, dietary sources, chemical difference between different forms of folic acid, health concerns and daily recommendations.

Folates functions

Accurate level of 5-MTHF (active form of folic acid) is essential to [2]:

  • synthesize DNA, RNA and for repair process
  • support normal cell division and growth
  • produce normal red blood cells (it is used to treat megaloblastic anemia – abnormal red blood cells)
  • regulate spermatogenesis (improve sperm counts, motility, and decreased numbers of abnormal forms)[3]
  • prevent major birth abnormalities (neural tube defects, including sping bifida and anencephaly)
  • maintain brain function (neurotransmiters)
brocolli

Folate deficiency

Folate deficiency can be caused by [1]:

    • gastrointestinal disorders (Crohn's disease, ulcerative colitis, coeliac disease)
    • excessive alcohol consumption
    • some genetic disorders
    • certain medicine usage (phentoin, sulfasalazine, trimethoprim-sulfamethoxazole)

The main sympthoms of deficiency include: glossitis, diarrhea, depression, confusion, anemia, fatigue, headaches, gray hair, mouth sores, poor growth and birth abnormalities.

Folate deficiency can also increase the likelihood of having a premature or low-birth-weight baby [4].

It can be diagnosed by examining complete blood count, vitamin B12 and serum folate levels, however measuring erythrocyte folate level (140 μg/L or lower) indicates deficiency more clearly.

Folate deficiency is treated by oral supplementation of 400-1000 μg folates per day.

Delicate balance

There is a homeostasis between folic acid, vitamin B12 and iron, a deficiency in one can be masked by the excess of another one and they must always be in balance [1].

mother_and_daughter

What is NTD?

Neural tube defects (NTDs) are common and devastating congenital malformations of the central nervous system. The most common (>90% of cases) are:

  • ancephaly (a total or partial absence of brain tissue, skull, and overlying skin)
  • sping bifida (herniation of spinal cord, meninges, or both through a defect of spine)

Both arises from incomplete closure of neural tube earlhy in gestation, often even before a woman is aware about pregancy, and this is why it is so improtant to prevents NTDs in all women in childbearing age by maintaining an accurate folate status [3].

asparagus

Does diet provide a sufficient folate?

Folates naturally present in food are 50% bioavailable compared to synthetic folic acid or used in food fortification. The reason being are the factors [3]:

  • food matrix sometimes bound folates and make them unavailable to retrieve
  • losses occured during food harvesting and processing (losses 50-89% after thermal processing)
  • poor stability of folates in the food (green vegetables)
  • effectiveness of intestinal deconjugation of polyglutamyl folates

Common folic acid found in supplements and fortified food is the most oxidised, monoglutamate form of folate was considered being the most bioavailable, however newer studies have shown that food folates can be almost as effective as folic acid supplements at improving folate status [5].

However to adjust the those differences between natural folates and syntetic folic acid, there were defined Dietary Folate Equivalents (DFE) are calculated as follows:

1 mcg of dietary folate = 1 mcg of food folate = 0.5 mcg of folic acid taken in the fasting state (the most potent) = 0.6 mcg of folic acid taken with food.

beans

Food sources

The highest folates source include:

Food Folate (mcg)
Beef liver, braised, 3 oz 215
Spinach, boiled, 1/2 cup 131
Black-eyed peas, boiled, 1/2 cup 105
Breakfast cereal, fortified 100
Asparagus, boiled, 4 spears 89
Brussels sprouts, frozen, boiled, 1/2 cup 78
Lettuce, romaine, shredded, 1 cup 64
Avocado, raw, sliced, 1/2 cup 59
Spinach, raw, 1 cup 58
Broccolli, chopped, frozen, cooked, 1/2 cup 52

Fortified foods

Many countries require their manufactures to enhance with folic acid at least one major cereal grain (mainly wheat).

The benefit of the introduction of mandatory folic acid has been demonstrated in the USA since 1998 as a reduction in neural tube defect birth.

However doubt have arised, because actual level of fortification is likeley to have over twice the amount mandated [25].

Fortification is controversial, not only because of individual liberty, but health concerns of long term health effect on society, especially when synthetic folic acid form is being used [1].

76 countries in the world mandatory (including: USA, Canada, Australia) add folic acid to cereal grain. No European Union country (as of Nov 2013) has mandated folic acid fortification [1].

How much is good enough?

Women with RBC (erythrocytes) folate levels lower than 150mcg/L were at high risk of a Neural Tube Defects during pregnancy

On the other hand women with levels over 400mcg/L had a 60% risk reduction [3].

Administration in doses: 100, 200, and 400mcg daily were associated with a 22%, 41% and 47% reduction in NTD risk, respectively.

Some authors suggested that doses over 400mcg offer little further benefit [3].

Women with a prior history of NTD affected pregnancy, a 4.0 mg daily dose starting at least one month prior to conception and continuing throughout the first trimester is the current United States recommendation [21].

According to most of recommendations, all women and teen girls at childbearing age who could become pregnant should consume 400mcg of folic acid equivalent daily (which equals 800mg of folates) from supplements, fortified foods, or both in addition to the folates they get naturally from food [21].

Folates metabolism

The active form of folic acid are: tetrahydrofolate (THF) and derivatives that perform all biological functions.

Dietary folate is converted into THF in the small intestine, however folic acid must undergo a reduction and methylation in the liver.

In some cases of the genes mutations it is necessary to administer folic acid as a end-product of the cycle: 5-MTHF and monitor folates and vitamin B12 status.

Genes variations and MTHFR polymorphism

MTHFR stands for methylene-tetrahydrofolate reductase.

It is an the last enzyme in the cycle that converts the folate metabolite into the active form called 5-MTHF, or, 5-Methyltetrahydrofolate.

The most common mutations are MTHFR C677T and MTHFR A1298C which can lead to decreased the MTHFR efficiency by 30-70% [28].

MTHFR C677T mutation is linked with recurrent pregnancy loss (RPL), risk of NTDs in women, male infertility and increased homocysteine level [29].

Patients with MTHFR deficiency (<1% activity vs controls) who had undetectable level of of cerebrospinal fluid - MTHF responded to treatment of calcium mefolinate (5-methyltetrahydrofolate) in dose of 15-60mg/kg/day resulted in increasment in CSF 5-MTHF as oppose to folic and folinic acid [24].

In animal studies supplementation Mefolinate (5-methyltetrahydrofolate), but not folic acid, decreases mortality in an animal model of severe methylenetetrahydrofolate reductase deficiency [23].

Which folates to choose

The forms of methylfolate that are biologically active are [27]:

  • L forms
  • 6(S) forms
  • L-5 forms
  • Metafolin
  • L-Methylfolate Calcium
  • Levomefolic Acid
  • Quatrefolic

The forms of methylfolate that are NOT biologically active are [27]:

  • D forms
  • 6(R) forms
mthfr

5-MTHF is a game changer

Studies have shown that supplementaion as 5-methylotetrahydrofolate ([6S]-5-methylTHF) as calcium salt (Metafolin, Merck Eprova AG, Schaffhausen) is as effective as folic in increasing blood folate indexes and lowering plasma homocysteine [13]

On top of this it doesn't mask vitamin B12 deficiency, doesn't produce unmetabolized folic acid in the circulation and it may be more efficient supplemntal souce during latation [Houghton 2006].

Some studies have shown that L-5-MTHF is significantly more potent than folic acid (FA) itself and is a better alternative to supplementation of FA especially in countries not applying a fortification program [11, 12].

The biggest advantage of 5-MTHF is that is well absorbed even when gastrointestinal pH is altered, its bioavailability is not affected by metabolic defects (as it is the final, active form of folate metabolites) and it may even have reduced interaction with drugs that inhibit dihydrofolate reductase [9,10].

Safety

Folates are water soluble, so the risk of acute toxicity is low, as an excess is regularly flushed out from the body through urine [1].

There is however growing concern worldwide, that prenatal high folic acid in the presence of low vitamin B12 causes epigenetic changes in the unborn predisposing them to metabolic syndromes, central adiposity and adult diseases such as Type 2 diabetes [22].

High doses of folic acid might also increase the risk of colorectal cancer and possibly other cancers in some people [4,7].

Unlike natural folates (form found naturally in food i.e. green leafy vegetables and certain supplements) which can be metabolized in the mucosa of small intesitine, folic acid (one of the form found in supplements and fortified foods) must be processed by specific enzyme – dihydrofolate reductase (DHR) in the liver.

This process is relatively slow and inefficient.

Subsequently, high intake of folic acid (supplements, fortified foods) leads to an excess of un-metabolized folic acid which circulate in the blood stream.

Unmetabolized folic acid

Studies have shown that unmetabolized folic acid in plasma reduces Natural Killer cytoxicity (immune system ability to rapidly respond to viral-infected cells and killing cancer cells [18].

Studies on eldery people have found that unmetabolized folic acid suffer effects of pernicous anemia (vitamin B12 deficiency)[26].

Another study has suggested that mandatory fortification and prevalent supplementation lead to high folates but also unmetabolized concentrations in maternal and fetal circulation which warrant additional investigation of folate excess nad long-term health outcomes of the offspring [20].

Drug interactions

There are a few drugs which can interfere with folic acid such as:

  • methotrexate (when taken to treat cancer)
  • phenytoin, carbamazepine, valproate (anti-epileptics)
  • sulfasalazine (when taken for ulcerative colitis)

If you take any of the above or having long-term pharmacotheraphy consult your pharmacist/doctor prior to folic acid supplementaion [1].

Takeaway notes

There are many diffetent forms of folic acid, but we humans seems to have trouble with converting synthetic form of folic acid (used as a supplement or during food fortification).

The unmetabolized folic acid may reduce some immune cell activity (NK), exacerbate vitamin B12 deficiency, and was linked with some forms of colorectal cancer.

The groups which require additional folic acid as a supplement are: women in childbearning age and nursing women (recommended dose: 800mcg/folates/daily – which is equivalent of 400mcg of folic acid/daily – particulary prior to pregnancy and during first trimester).

Current evidence suggest that folate status should be managed by well-balanced diet (naturally occuring folates) and folates supplements (preferably 5-MTHF forms) NOT by using folic acid (check your multivitamin as well), with also taking into consideration other nutrients relationship (iron, vitamin B12 levels).

Everyone else should be able to get plenty of folate in a diet with adequate vegetable consumption and do not need to supplement.

It is crucial to keep the balance between folates, iron and vitamin levels as an excess of one can mask deficency of other one.

References
  1. https://en.wikipedia.org/wiki/Folic_acid as seen on 2016/09/17
  2. http://www.medicalnewstoday.com/articles/219853.php as seen on 2016/09/17
  3. Dunlap B., Shelke K., Salem S.A., Keith L.G., Folic acid and human reproduction – ten important issues for clinicians. J Exp Clin Assist Reprod. 2011; 8: 2
  4. https://ods.od.nih.gov/factsheets/Folate-Consumer/ as seen on 2016/09/17
  5. Powers H.J., Folic acid under scrunity, British Journal of Nutrition 2007 October, vol 98, issue 4, 665-666
  6. Kim Y., Folic acid fortification and supplementation – good for some but not so good for others; Nutr Rev 2007 Nov; 65(11): 504-11
  7. Ami N., Bernstein M., Boucher F., Rieder M., Parker L., Canadian Paediatric Society, Drug Therapy and Hazardous Substances Committee, Folate and neural tube defects: The role of supplements and food fortification. Paediatr Child Health. 2016 Apr; 21(3): 145-54
  8. Wilson R.D., Genetics Commitee, Audibert F., Brock J.A., Carrol J., Cartier L., Gagnon A., Johnson J.A., Langlois S., Murphy-Kaulbeck L., Okun N., Pastuck M., Deb-Rinker P., Dodds L., Leon J.A., Lowel H.L., Luo W., Mac Farlane A., McMillan R., Moore A., Mundle W., O'Connor D., Ray J., Van den Hof M., Pre conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies. J Obstet Gynaecol Can. 2015 Jun, 37(6): 534-52
  9. Pietrzik K., Bailey L., Shane B., Folic acid and L-5-methyltetrahydofolate: comparison of clinical and pharmacodynamics. Clin Pharmacokinet 2010 Aug; 49(8): 535-48
  10. Scaglione F., Panzavolta G., Folate, folic acid and 5-methyltetrahydrofolate are not the same thing, Xenobiotica 2014 May; 44(5): 480-8
  11. Obeid R., Holzgreve W., Pietrzik K., Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects? J Perinat Med. 2013 Sep1; 41(5) 469-83
  12. Akoglu B., Schrott M., Bolouri H., Jaffari A., Kutschera E., Caspary W.F., Faust D., The folic acid metabolite L-5-methyltetrahydrofolate effectively reduces total serum homocysteine level in orthotropic liver transplant recipients: a double-blind placebo-controlled study. Eur J. Clin Nutr. 2008 Jun; 62(6): 796-801
  13. Venn B.J., Green T.J., Moser R., Mann J.I., Comparison of the effect of low-dose supplementation with L-5-methylohydrofolate or folic acid on plasma homocysteine: a ranomized placebo-controlled study. Am J Clin Nutr. 2003 Mar; 77(3): 658-62
  14. Chen H., Yang X., Lu M., Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. Arch Gynecol Obstet. 2016 Feb; 293(2): 283-90
  15. Rai V., Yadav U., Kumar P., Yadav S.K., Mishra O.P., Maternal methyenetetrahydofolate reductase C677T polymorphism and down syndrome risk: a meta-analysis from 34 studies. PloS One 2014 Sep 29; 9(9)
  16. Yang Y., Chen J., Wang B., Ding C., Liu H., Association between MTHFR C677T polymorphism and neural tube defect risks: A comprehensive evaluation in three groups of NTD patients, mothers and fathers. Birth Defects Res a Clin Mol Teratol 2015 Jun; 103; (6): 488-500
  17. Houghton L.A., Sherwood K.L., Pawlosky R., Ito S., O'Connor D.L., [6S]-5-Methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in bood folate concentrations during lactation. American Society for Clininical Nutrition 2006, vol. 83, no 4, 842-850
  18. Troen A.M., Mitchell B.M., Sorensen B., Wener M.H., Johnston A., Wood B., Selhub J., McTiernan A., Yasui Y., Oral E., Potter J.D., Ulrich C.M., Unmetabolized folic acid in Plasma is associeted with reduced natural killer cell cytoxicity among Postmenopausal Women. J. Nutr. 2006, vol. 136, no. 1, 189-194
  19. Wang S., Ge X., Zhu B., Xuan Y., Hyang K., Rutayisire E., Mao L., Huang S., Yan S., Tao F., Maternal Continuing Folic Acid Supplementation after the First Trimester of Pregnancy Increased the Risk of Large-for-Gestational-Age Birth: A population Based Birth Cohort Study. Nutrients 2016 Aug 15; 8(6)
  20. Plumptre L., Masih S.P., Ly A., Aufreiter S., Sohn K.J., Croxford R., Lausman A.Y., Berger H., O'Connor D.L., Kim Y.I., High concentrations of folate and unmetabolized folic in a cohort of pregnant Canadian women nad umbilical cord blood. Am J Clin Nutr 2015 Oct; 102(4): 848-57
  21. Centers for Disease Control Effectiveness in disease and injury prevention use of folic acid for prevention of spina bifida and other neural tube defects - 1983–1991.MMWR.1991 Aug 2;40(30):513–516
  22. Yajnik C.S., Deshmukh U.S., Maternal nutrition, intrauterine programming and conswquential risks in the offspring. Rev Enocr Metab Disord 2008 Sep; 9(3): 203-11
  23. Li D., Karp N., Wu Q., Melnzk S., James S.J., Royen. R., Mefolinate (5-methyltetrahydrofolate), but not folic acid, decreases mortality in animal model of severe methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis 2008 Jun; 31(3): 403-11
  24. Knowles L., Morris A.A., Walter J.H., Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency. JIMD Rep 2016 Feb 23
  25. Sweeney M.R., McPartlin J., Weir D.G., Daly L., Scott J.M., Postprandial serum folic acid response to multiple doses of folic acid in fortified bread. Br J Nutr. 2006 Jan, 95(1): 145-51
  26. Morris M.S., Jacques P.F., Rosenberg I.H., Selhub J., Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in realation to anemia, macrocytosis, and cognitive test performance in American seniors. Am J Clin Nutr. 2010 Jun; 91(6): 1733-44
  27. http://mthfr.net/l-methylfolate-methylfolate-5-mthf/2012/04/05/ as seen on 2016/09/20
  28. http://www.mthfrsupport.com.au/mthfr-important-in-preconception-and-pregnancy/ as seen on 2016/09/20
  29. Bezold G., Lange M., Peter R.U., Homozygous Metylnetetrahydofolate Reductase C677T Mutation and Male Infertility. N Engl J Med 2001; 344: 1172-1173

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