Folic acid, a precursor of active B9
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Folate deficiency is a low level of folate in the body. Also known as vitamin B9, it 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. Folate deficiency anemia is the term given for this medical condition.
Signs and symptoms
Loss of appetite and weight loss can occur. Additional signs are weakness, sore tongue, headaches, heart palpitations, irritability, and behavioral disorders. In adults, anemia (macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency.
In infants and children, folate deficiency can slow growth rate. 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.
Late studies suggested an involvement in tumorogenesis (especially in colon) through demethylation/hypomethylation of fast replicating tissues.
Some of the symptoms can also result from a variety of medical conditions other than folate deficiency. It is important to have a physician evaluate these symptoms so that appropriate medical care can be given.
Studies suggest that folate and vitamin B12 status may play a role in depression. 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).
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.
Low plasma B12 and low plasma folate has been found in studies of depressive patients. Furthermore, some studies have shown that low folate levels are linked to a poor response of antidepressant treatment, and other studies also suggest that a high vitamin B12 status may be associated with better treatment outcomes. Therefore, not only does adequate consumption of these two vitamins help decrease the risks of developing depression, but they can also help in the treatment of depression when antidepressant drugs are used.
A deficiency of folate can occur when the body's need for folate is increased, when dietary intake 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. Some research indicates that exposure to ultraviolet light, including the use of tanning beds, can lead to a folate deficiency.
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. 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, binding to specific receptor proteins. Diffuse inflammatory or degenerative diseases of small intestine like Crohn's disease, coeliac disease, chronic enteritis or entero-enteric fistulae may reduce activity of pteroyl polyglutamase (PPGH), a specific hydrolase required for the purpose, and thereby reduce folate absorption leading to folate deficiency. Folate deficiency does not occur after resection of the terminal ileum as rest of small intestine is preserved.
Some situations that increase the need for folate include the following:
- certain anemias
- kidney dialysis
- liver disease
- malabsorption, including celiac disease
- pregnancy and lactation (breastfeeding)
- tobacco smoking
- alcohol consumption
Medications can interfere with folate utilization, including:
- anticonvulsant medications (such as phenytoin, primidone, carbamazepine or valproate )
- metformin (sometimes prescribed to control blood sugar in type 2 diabetes)
- methotrexate, an anti-cancer drug also used to control inflammation associated with Crohn's disease, ulcerative colitis and rheumatoid arthritis.
- sulfasalazine (used to control inflammation associated with Crohn's disease, ulcerative colitis and rheumatoid arthritis)
- triamterene (a diuretic)
- oral contraceptives
When methotrexate is prescribed, folic acid supplements are sometimes given with the methotrexate. The purpose of methotrexate is to inhibit dihydrofolate reductase and thereby reduce the rate de novo purine and pyrimidine synthesis and cell division. Folate supplementation is beneficial in patients being treated with long-term, low-dose methotrexate for rheumatoid arthritis (RA) or psoriasis to avoid macrocytic anemia caused by folate deficiency. However, it is counterproductive to take a folic acid supplement with methotrexate in cancer treatment. Although the folic acid inhibition of methotrexate is normally seen as a side effect in Rheumatoid Arthritis, it is a part of the therapeutic effect of the drug in cancer. Methotrexate inhibits cell division and is particularly toxic to fast dividing cells, such as rapidly dividing cancer cells. It would therefore be wise to consult with a physician before taking a folic acid supplement while concurrently prescribed methotrexate.
Prevention and treatment
Folate deficiency during human pregnancy has been associated with an increased risk of infant neural tube defects. Such deficiency during the first four weeks of gestation can result in structural and developmental problems. NIH guidelines recommend oral B vitamin supplements to decrease these risks near the time of conception and during the first month of pregnancy.
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