Folate deficiency is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition.[1] It is characterized by the appearance of large-sized, abnormal red blood cells (megaloblasts), which form when there are inadequate stores of folic acid within the body.[2]

Folate deficiency
Folic acid structure.svg
Folic acid, a precursor of active B9
SpecialtyEndocrinology Edit this on Wikidata


Signs and symptomsEdit

Loss of appetite and weight loss can occur. Additional signs are weakness, sore tongue, headaches, heart palpitations, irritability, and behavioral disorders.[3] In adults, anemia (macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency.

Women with folate deficiency who become pregnant are more likely to give birth to low birth weight premature infants, and infants with neural tube defects. In infants and children, folate deficiency can lead to failure to thrive or slow growth rate, diarrhea, oral ulcers, megaloblastic anemia, neurological deterioration. An abnormally small head, irritability, developmental delay, seizures, blindness and cerebellar ataxia can also be observed.[4]


A deficiency of folate can occur when the body's need for folate is increased, when dietary intake or absorption of folate is inadequate, or when the body excretes (or loses) more folate than usual. Medications that interfere with the body's ability to use folate may also increase the need for this vitamin.[5][6][7][8][9][10] Some research indicates that exposure to ultraviolet light, including the use of tanning beds, can lead to a folate deficiency.[11][12] The deficiency is more common in pregnant women, infants, children, and adolescents. It may also be due to poor diet or a consequence of alcoholism.[13]

Additionally, a defect in homocysteine methyltransferase or a deficiency of Vitamin B12 may lead to a so-called "methyl-trap" of tetrahydrofolate (THF), in which THF is converted to a reservoir of methyl-THF which thereafter has no way of being metabolized, and serves as a sink of THF that causes a subsequent deficiency in folate.[14] Thus, a deficiency in B-12 can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency.

Folate (pteroylmonoglutamate) is absorbed throughout the small intestine, though mainly in the jejunum, binding to specific receptor proteins. Diffuse inflammatory or degenerative diseases of the small intestine, such as Crohn disease, celiac disease, chronic enteritis or entero-enteric fistulae, may reduce the activity of pteroyl polyglutamase (PPGH), a specific hydrolase required for folate absorption, and thereby leading to folate deficiency.


Some situations that increase the need for folate include the following:


Medications can interfere with folate metabolism, including:

When methotrexate is prescribed, folic acid supplements are sometimes given with the methotrexate. The therapeutic effects of methotrexate are due to its inhibition of dihydrofolate reductase and thereby reduce the rate de novo purine and pyrimidine synthesis and cell division. Methotrexate inhibits cell division and is particularly toxic to fast dividing cells, such as rapidly dividing cancer cells and the progenitor cells of the immune system. Folate supplementation is beneficial in patients being treated with long-term, low-dose methotrexate for inflammatory conditions, such as rheumatoid arthritis (RA) or psoriasis, to avoid macrocytic anemia caused by folate deficiency. Folate is often also supplemented before some high dose chemotherapy treatments in an effort to protect healthy tissue. However, it may be counterproductive to take a folic acid supplement with methotrexate in cancer treatment.[15]

Cerebral folate deficiencyEdit

Cerebral folate deficiency is when levels of 5-methyltetrahydrofolate are low in the brain as measured in the cerebral spinal fluid despite being normal in the blood.[16] Symptoms typically appear at about five months of age. Without treatment there may be poor muscle tone, trouble with coordination, trouble talking, and seizures.[16] The causes of cerebral folate deficiency include mutations of genes responsible for folate metabolism and transport.[17] Mutations of the SLC46A1 gene that encodes the proton-coupled folate transporter (PCFT) result in CFD syndromes with both systemic folate deficiency and cerebral folate deficiency. Even when the systemic deficiency is corrected by folate, the cerebral deficiency remains and must be treated with folinic acid.[18][16]


Folate deficiency is diagnosed with a blood test, measured as methyltetrahydrofolate (in practice, "folate" refers to all derivatives of folic acid, but methylhydrofolate is the quasi unique form of "folate" in the blood[19]).

Homocysteine is elevated (5-MTHF is used to convert homocysteine to methionine) as in vitamin B12 deficiency, whereas methylmalonic acid is normal (elevated in vitamin B12 deficiency and vitamin B6 deficiency).

Prevention and treatmentEdit

Folate is found in leafy green vegetables and organ meats. When cooking, use of steaming, a food steamer, or a microwave oven can help keep more folate content in the cooked foods, thus helping to prevent folate deficiency.[20][21][22]

Multi-vitamin dietary supplements contain folate as well as other B vitamins. Folate deficiency during human pregnancy has been associated with an increased risk of infant neural tube defects.[23] NIH guidelines recommend folate supplements to decrease these risks near the time of conception and during the first month of pregnancy.[24]


Folate deficiency during gestation or infancy due to development by the fetus or infant of autoantibodies to the folate receptor might result in various developmental disorders.[25]

Studies suggest that insufficient folate and vitamin B12 status may contribute to major depressive disorder and that supplementation might be useful in this condition.[26] The role of vitamin B12 and folate in depression is due to their role in transmethylation reactions, which are crucial for the formation of neurotransmitters (e.g. serotonin, epinephrine, nicotinamides, purines, phospholipids).[26][27] The proposed mechanism, is that low levels of folate or vitamin B12 can disrupt transmethylation reaction, leading to an accumulation of homocysteine (hyperhomocysteinemia) and to impaired metabolism of neurotransmitters (especially the hydroxylation of dopamine and serotonin from tyrosine and tryptophan), phospholipids, myelin, and receptors. High homocysteine levels in the blood can lead to vascular injuries by oxidative mechanisms which can contribute to cerebral dysfunction. All of these can lead to the development of various disorders, including depression.[26][27]


  1. ^ Huether S, McCance K (2004). "20". Understanding Pathophysiology (3rd ed.). Mosby. p. 543. ISBN 978-0-323-02368-9.
  2. ^ Tamparo C (2011). Diseases of the Human Body (Fifth ed.). Philadelphia, PA. p. 337. ISBN 978-0-8036-2505-1.
  3. ^ Haslam N, Probert CS (February 1998). "An audit of the investigation and treatment of folic acid deficiency". Journal of the Royal Society of Medicine. 91 (2): 72–3. doi:10.1177/014107689809100205. PMC 1296488. PMID 9602741.
  4. ^ Kliegman RM, Stanton BM, Geme JS, Schor NF, eds. (2015-04-22). Nelson Textbook of Pediatrics (20th ed.). pp. 317–320. ISBN 978-1-4557-7566-8.
  5. ^ Oakley GP, Adams MJ, Dickinson CM (March 1996). "More folic acid for everyone, now". The Journal of Nutrition. 126 (3): 751S–755S. doi:10.1093/jn/126.suppl_3.751S (inactive 2019-08-20). PMID 8598560.
  6. ^ McNulty H (June 1995). "Folate requirements for health in different population groups". British Journal of Biomedical Science. 52 (2): 110–9. PMID 8520248.
  7. ^ Stolzenberg R (December 1994). "Possible folate deficiency with postsurgical infection". Nutrition in Clinical Practice. 9 (6): 247–50. doi:10.1177/0115426594009006247. PMID 7476802.
  8. ^ Pietrzik KF, Thorand B (1997). "Folate economy in pregnancy". Nutrition. 13 (11–12): 975–7. doi:10.1016/S0899-9007(97)00340-7. PMID 9433714.
  9. ^ Kelly GS (June 1998). "Folates: supplemental forms and therapeutic applications". Alternative Medicine Review. 3 (3): 208–20. PMID 9630738.
  10. ^ Cravo ML, Glória LM, Selhub J, Nadeau MR, Camilo ME, Resende MP, Cardoso JN, Leitão CN, Mira FC (February 1996). "Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B-12, and vitamin B-6 status". The American Journal of Clinical Nutrition. 63 (2): 220–4. doi:10.1093/ajcn/63.2.220. PMID 8561063.
  11. ^ "Pregnancy and Tanning". American Pregnancy Association. January 2014. Retrieved January 11, 2015.
  12. ^ Borradale D, Isenring E, Hacker E, Kimlin MG (February 2014). "Exposure to solar ultraviolet radiation is associated with a decreased folate status in women of childbearing age". Journal of Photochemistry and Photobiology. B, Biology. 131: 90–5. doi:10.1016/j.jphotobiol.2014.01.002. PMID 24509071.
  13. ^ Tamparo C (2011). Fifth Edition: Diseases of the Human Body. Philadelphia, PA: F. A. Davis Company. p. 337. ISBN 978-0-8036-2505-1.
  14. ^ Hoffbrand AV, Weir DG (June 2001). "The history of folic acid". British Journal of Haematology. 113 (3): 579–89. doi:10.1046/j.1365-2141.2001.02822.x. PMID 11380441.
  15. ^ "Folate: Evidence". Mayo Clinic. Retrieved January 11, 2015.
  16. ^ a b c Gordon, N (2009). "Cerebral folate deficiency". Developmental Medicine and Child Neurology. 51 (3): 180–182. doi:10.1111/j.1469-8749.2008.03185.x. PMID 19260931.
  17. ^ Serrano M, Pérez-Dueñas B, Montoya J, Ormazabal A, Artuch R (2012). "Genetic causes of cerebral folate deficiency: clinical, biochemical and therapeutic aspects". Drug Discovery Today. 17 (23–24): 1299–1306. doi:10.1016/j.drudis.2012.07.008. PMID 22835503.
  18. ^ Zhao R, Aluri S, Goldman ID (2017). "The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption". Molecular Aspects of Medicine. 53: 57–72. doi:10.1016/j.mam.2016.09.002. PMC 5253092. PMID 27664775.
  19. ^ "FB12 - Clinical: Vitamin B12 and Folate, Serum".
  20. ^ Nutrient Data Laboratory (2007). "USDA Table of Nutrient Retention Factors, Release 6" (PDF). USDA.
  21. ^ O’connor, Anahad (2006-10-17). "The Claim: Microwave Ovens Kill Nutrients in Food". The New York Times. ISSN 0362-4331. Retrieved 2017-07-10. spinach retained nearly all its folate when cooked in a microwave, but lost about 77 percent when cooked on a stove
  22. ^ McKillop DJ, Pentieva K, Daly D, McPartlin JM, Hughes J, Strain JJ, Scott JM, McNulty H (2002). "The effect of different cooking methods on folate retention in various foods that are amongst the major contributors to folate intake in the UK diet". The British Journal of Nutrition. 88 (6): 681–688. doi:10.1079/bjn2002733. PMID 12493090.
  23. ^ Czeizel AE, Dudás I, Vereczkey A, Bánhidy F (2013). "Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects". Nutrients. 5 (11): 4760–4775. doi:10.3390/nu5114760. PMC 3847759. PMID 24284617.
  24. ^ "Fact Sheet for Health Professionals - Folate". National Institutes of Health. Retrieved January 11, 2015.
  25. ^ Desai A, Sequeira JM, Quadros EV (2016). "The metabolic basis for developmental disorders due to defective folate transport". Biochimie. 126: 31–42. doi:10.1016/j.biochi.2016.02.012. PMID 26924398.
  26. ^ a b c Coppen A, Bolander-Gouaille C (2005). "Treatment of depression: time to consider folic acid and vitamin B12". Journal of Psychopharmacology. 19 (1): 59–65. doi:10.1177/0269881105048899. PMID 15671130.
  27. ^ a b Karakuła H, Opolska A, Kowal A, Domański M, Płotka A, Perzyński J (2009). "[Does diet affect our mood? The significance of folic acid and homocysteine]". Polski Merkuriusz Lekarski. 26 (152): 136–141. PMID 19388520.

External linksEdit