Folate deficiency

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

Folate deficiency is a low level of folic acid and derivatives in the body. Also known as vitamin B9, folate is involved in adenosine, guanine, and thymidine synthesis (part of DNA synthesis). Signs of folate deficiency are often subtle. 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]

Signs and symptoms[edit]

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. Microcephaly, 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 B-12 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's disease, coeliac 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]


Folate deficiency is diagnosed with a blood test, measured as methyltetrahydrofolate (in practice, "folate" refers to all derivative of folic acid, but methylhydrofolate is the quasi unique form of "folate" in the blood[16]).

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 treatment[edit]

Folate is found in leafy green vegetables. Multi-vitamins also tend to include Folate as well as many other B vitamins. B vitamins, such as Folate, are water-soluble and excess is excreted in the urine.

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.[17][18][19]

Folate deficiency during human pregnancy has been associated with an increased risk of infant neural tube defects.[20] Such deficiency during the first four weeks of gestation can result in structural and developmental problems. NIH guidelines[21] recommend oral B vitamin supplements to decrease these risks near the time of conception and during the first month of pregnancy.


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 including autism spectrum disorders.[22]

Studies suggest that insufficient folate and vitamin B12 status may contribute to major depressive disorder and that supplementation might be useful in this condition.[23] 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).[23][24] The proposed mechanism, is that low levels of folate or vitamin B12 can disrupt transmethylation reaction, leading to an accumulation of homocysteine (hyperhomocisteinemia) 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.[23][24]


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