folate deficiency

Signs of folate deficiency anemia most of the time are subtle. Anemia (macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency in adults. Folate deficiency anemia may result in feeling tired, weakness, changes to the color of the skin or hair, open sores on the mouth, shortness of breath, palpitations, lightheadedness, cold hands and feet, headaches, easy bleeding or bruising, low-grade fevers, loss of appetite, weight loss, diarrhea, decreased taste, irritability, and behavioral disorders.{{cite journal | vauthors = Haslam N, Probert CS | title = An audit of the investigation and treatment of folic acid deficiency | journal = Journal of the Royal Society of Medicine | volume = 91 | issue = 2 | pages = 72–73 | date = February 1998 | pmid = 9602741 | pmc = 1296488 | doi = 10.1177/014107689809100205 }}

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 and even spina bifida. 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.{{cite book|editor1-last=Kliegman|editor1-first=Robert M.|editor2-last=Stanton|editor2-first=Bonita M.D.|editor3-last=Geme|editor3-first=Joseph St.|editor4-last=Schor|editor4-first=Nina F| name-list-style = vanc |title=Nelson Textbook of Pediatrics|isbn=978-1-4557-7566-8|pages=317–20|edition=20th|date=2015-04-22|publisher=Elsevier Health Sciences }}

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.{{cite journal | vauthors = Oakley GP, Adams MJ, Dickinson CM | title = More folic acid for everyone, now | journal = The Journal of Nutrition | volume = 126 | issue = 3 | pages = 751S–55S | date = March 1996 | pmid = 8598560 | doi = 10.1093/jn/126.suppl_3.751S | doi-broken-date = 1 November 2024 }}{{cite journal | vauthors = McNulty H | title = Folate requirements for health in different population groups | journal = British Journal of Biomedical Science | volume = 52 | issue = 2 | pages = 110–19 | date = June 1995 | pmid = 8520248 }}{{cite journal | vauthors = Stolzenberg R | title = Possible folate deficiency with postsurgical infection | journal = Nutrition in Clinical Practice | volume = 9 | issue = 6 | pages = 247–50 | date = December 1994 | pmid = 7476802 | doi = 10.1177/0115426594009006247 }}{{cite journal | vauthors = Pietrzik KF, Thorand B | title = Folate economy in pregnancy | journal = Nutrition | volume = 13 | issue = 11–12 | pages = 975–57 | year = 1997 | pmid = 9433714 | doi = 10.1016/S0899-9007(97)00340-7 }}{{cite journal | vauthors = Kelly GS | title = Folates: supplemental forms and therapeutic applications | journal = Alternative Medicine Review | volume = 3 | issue = 3 | pages = 208–20 | date = June 1998 | pmid = 9630738 }}{{cite journal | vauthors = Cravo ML, Glória LM, Selhub J, Nadeau MR, Camilo ME, Resende MP, Cardoso JN, Leitão CN, Mira FC | title = Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B-12, and vitamin B-6 status | journal = The American Journal of Clinical Nutrition | volume = 63 | issue = 2 | pages = 220–24 | date = February 1996 | pmid = 8561063 | doi = 10.1093/ajcn/63.2.220 | doi-access = free }} Some research indicates that exposure to ultraviolet light, including the use of tanning beds, can lead to a folate deficiency.{{cite web |url=http://www.americanpregnancy.org/pregnancyhealth/tanningmethods.html |title=Pregnancy and Tanning |publisher=American Pregnancy Association |date=January 2014 |access-date=January 11, 2015}}{{cite journal | vauthors = Borradale D, Isenring E, Hacker E, Kimlin MG | title = Exposure to solar ultraviolet radiation is associated with a decreased folate status in women of childbearing age | journal = Journal of Photochemistry and Photobiology B: Biology | volume = 131 | pages = 90–95 | date = February 2014 | pmid = 24509071 | doi = 10.1016/j.jphotobiol.2014.01.002 | bibcode = 2014JPPB..131...90B | hdl = 10072/432100 | url = https://eprints.qut.edu.au/67491/1/67491.pdf }} 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.{{Cite book|title=Fifth Edition: Diseases of the Human Body|last=Tamparo|first=Carol| name-list-style = vanc |publisher=F. A. Davis Company|year=2011|isbn=978-0-8036-2505-1|location=Philadelphia, PA|page=337}}

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.{{cite journal | vauthors = Hoffbrand AV, Weir DG | title = The history of folic acid | journal = British Journal of Haematology | volume = 113 | issue = 3 | pages = 579–89 | date = June 2001 | pmid = 11380441 | doi = 10.1046/j.1365-2141.2001.02822.x | s2cid = 22925228 }} Thus, a deficiency in B₁₂ can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency.{{cn|date=July 2024}}

Folate (pteroylmonoglutamate) is absorbed throughout the small intestine, though mainly in the jejunum. Important steps in the absorption are reduction of the polyglutamate chain by pteroylpolyglutamate hydrolase (gamma-glutamyl hydrolase) and then transport across the brush border membrane by the proton-coupled folate transporter (SLC46A1). Diffuse inflammatory or degenerative diseases of the small intestine, such as Crohn disease, celiac disease, chronic enteritis or the presence of an entero-enteric fistula may reduce absorption.{{cite journal |last1=Halsted |first1=CH |title=The intestinal absorption of dietary folates in health and disease. |journal=Journal of the American College of Nutrition |date=December 1989 |volume=8 |issue=6 |pages=650–58 |doi=10.1080/07315724.1989.10720340 |pmid=2695555}}{{cite journal |last1=Visentin |first1=M |last2=Diop-Bove |first2=N |last3=Zhao |first3=R |last4=Goldman |first4=ID |title=The intestinal absorption of folates. |journal=Annual Review of Physiology |date=2014 |volume=76 |pages=251–74 |doi=10.1146/annurev-physiol-020911-153251 |pmid=24512081|pmc=3982215 }}

Some situations that increase the need for folate include:{{cn|date=July 2024}}

• bleeding
• kidney dialysis
• liver disease
• malabsorption, including celiac disease and fructose malabsorption
• pregnancy and lactation (breastfeeding)
• tobacco smoking
• alcohol consumption

Medications can interfere with folate metabolism, 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 disease, ulcerative colitis and rheumatoid arthritis.
• 5-fluorouracil
• hydroxyurea
• trimethoprim
• sulfasalazine (used to control inflammation associated with Crohn disease, ulcerative colitis and rheumatoid arthritis)
• triamterene (a diuretic)
• birth control pills (also related to the duration use of birth control pills) may reduce serum folate levels but without inducing clinically significant folate deficiency.{{cite journal | last1=Shere | first1=Mahvash | last2=Bapat | first2=Priya | last3=Nickel | first3=Cheri | last4=Kapur | first4=Bhushan | last5=Koren | first5=Gideon | title=Association Between Use of Oral Contraceptives and Folate Status: A Systematic Review and Meta-Analysis | journal=Journal of Obstetrics and Gynaecology Canada | publisher=Elsevier BV | volume=37 | issue=5 | year=2015 | issn=1701-2163 | pmid=26168104 | doi=10.1016/s1701-2163(15)30258-9 | pages=430–38| doi-access=free }}

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.{{cite web |url=http://www.mayoclinic.org/drugs-supplements/folate/evidence/hrb-20059475 |title=Folate: Evidence |publisher=Mayo Clinic |access-date=January 11, 2015}}

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.{{cite journal |last1=Gordon |first1=N |title=Cerebral folate deficiency. |journal=Developmental Medicine and Child Neurology |date=2009 |volume=51 |issue=3 |pages=180–82 |doi=10.1111/j.1469-8749.2008.03185.x |pmid=19260931|s2cid=7373721 }} Symptoms typically appear at about five months of age. Without treatment there may be poor muscle tone, trouble with coordination, trouble talking, and seizures. The causes of cerebral folate deficiency include mutations of genes responsible for folate metabolism and transport.{{cite journal |vauthors = Serrano M, Pérez-Dueñas B, Montoya J, Ormazabal A, Artuch R | title = Genetic causes of cerebral folate deficiency: clinical, biochemical and therapeutic aspects |journal = Drug Discovery Today |volume = 17 |issue = 23–24 |pages = 1299–306 | date =2012 | pmid = 22835503 |doi = 10.1016/j.drudis.2012.07.008 }} 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.{{cite journal | vauthors = Zhao R, Aluri S, Goldman ID | title = The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption | journal = Molecular Aspects of Medicine | volume = 53 | pages = 57–72 | date = 2017 | pmid = 27664775 | pmc = 5253092 | doi = 10.1016/j.mam.2016.09.002 }}

Folate deficiency can occur during pregnancy as a result of the increasing number of cells of the growing fetus, decreased absorption and intake of folate, maternal hormones that mediate its metabolism, vascular circulation of maternal and fetal blood and an increasing amount of blood resulting in dilution. Sickle cell anemia and living in areas of malaria result in even higher folate needs for women who are pregnant. When supplemented with 450 micrograms of folic acid per day, the risk of developing birth defects, specifically neural tube defects, is decreased. Supplementation to prevent birth defects is most effective one month prior to and during the first twelve weeks of pregnancy.{{cite journal|vauthors=Castillo-Lancellotti C, Tur JA, Uauy R|date=2013|title=Impact of folic acid fortification of flour on neural tube defects: a systematic review|journal=Public Health Nutr|volume=16|issue=5|pages=901–11|doi=10.1017/S1368980012003576|pmid=22850218|pmc=10271422 |doi-access=free}} Utilization of folic acid supplementation before conception has shown to result in a decrease in neural tube defects by 70%.{{cite journal|vauthors=Czeizel AE, Dudás I, Vereczkey A, Bánhidy F|date=2013|title=Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects|journal=Nutrients|volume=5|issue=11|pages=4760–75|doi=10.3390/nu5114760|pmc=3847759|pmid=24284617|doi-access=free}}

Folate deficiency is diagnosed with a blood test to measure the serum level of folate, 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{{cite web|title=FB12 – Clinical: Vitamin B12 and Folate, Serum|url=https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9156|website=www.mayomedicallaboratories.com|language=en}}).

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).{{cn|date=July 2024}}

More specifically, according to a 2014 UK guideline,{{cite journal | vauthors = Devalia V, Hamilton MS, Molloy AM | title = Guidelines for the diagnosis and treatment of cobalamin and folate disorders | journal = British Journal of Haematology | volume = 166 | issue = 4 | pages = 496–513 | date = August 2014 | pmid = 24942828 | doi = 10.1111/bjh.12959 | s2cid = 5772424 | doi-access = free }}

• A serum folate level of less than 7 nmol/L (3 μg/L) is indicative of folate deficiency;
• Red blood cell folate testing is not routinely performed, since serum folate is sufficient in most cases, however, if there is a strong suspicion of folate deficiency despite a normal serum folate level, a red cell folate test may be performed.
• Plasma total homocysteine is only measured in special circumstances. A level above 15 μmol/L could be indicative of a folate deficiency, but local reference ranges should be taken into account.{{cn|date=July 2024}}

Folate is acquired in the diet by the consumption of leafy green vegetables, legumes and organ meats.{{cite journal |last1=Centeno Tablante |first1=Elizabeth |last2=Pachón |first2=Helena |last3=Guetterman |first3=Heather M |last4=Finkelstein |first4=Julia L |title=Fortification of wheat and maize flour with folic acid for population health outcomes |journal=Cochrane Database of Systematic Reviews |volume=2019 |pages=CD012150 |date=1 July 2019 |issue=7 |doi=10.1002/14651858.CD012150.pub2|pmid=31257574 |pmc=6599881 }} When cooking, use of steaming, a food steamer, or a microwave oven can help keep more folate content in the cooked foods.{{cite web|url=http://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/retn/retn06.pdf|title=USDA Table of Nutrient Retention Factors, Release 6|date= 2007 |publisher=USDA|author=Nutrient Data Laboratory}}{{Cite news|url=https://www.nytimes.com/2006/10/17/health/17real.html|title=The Claim: Microwave Ovens Kill Nutrients in Food|last=O'connor|first=Anahad|date=2006-10-17|work=The New York Times|access-date=2017-07-10|language=en-US|issn=0362-4331|quote=spinach retained nearly all its folate when cooked in a microwave, but lost about 77 percent when cooked on a stove}}{{cite journal | vauthors = McKillop DJ, Pentieva K, Daly D, McPartlin JM, Hughes J, Strain JJ, Scott JM, McNulty H | title = 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 | journal = The British Journal of Nutrition | volume = 88 | issue = 6 | pages = 681–88 | date = 2002 | pmid = 12493090 | doi = 10.1079/bjn2002733 | doi-access = free }}

Folic acid is a synthetic derivative of folate and is acquired by dietary supplementation.{{cite journal |last1=Lassi |first1=Zohra S |last2=Salam |first2=Rehana A |last3=Haider |first3=Batool A |last4=Bhutta |first4=Zulfiqar A |title=Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes |journal=Cochrane Database of Systematic Reviews |date=28 March 2013 |doi=10.1002/14651858.CD006896.pub2 |pmid=23543547 |volume=2013 |issue=3 |page=CD006896|pmc=10069458 }} Multi-vitamin dietary supplements contain folic acid as well as other B vitamins. Non-prescription folic acid is available as a dietary supplement in some countries, and some countries require the fortification of wheat flour, corn meal or rice with folic acid with the intention of promoting public health through increasing blood folate levels in the population.{{cn|date=July 2024}}

After the discovery of the link between insufficient folic acid and neural tube defects,{{cite journal |vauthors = Czeizel AE, Dudás I, Vereczkey A, Bánhidy F | title = Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects | journal = Nutrients |volume = 5 |issue = 11 |pages = 4760–75 |date = 2013 |pmid = 24284617 |pmc = 3847759 | doi = 10.3390/nu5114760 | doi-access = free }} governments and health organizations worldwide made recommendations concerning folic acid supplementation for women intending to become pregnant. Because the neural tube closes in the first four weeks of gestation, often before many women even know they are pregnant, many countries in time decided to implement mandatory food fortification programs.{{cite web|url=https://fortificationdata.org/map-number-of-nutrients/|title=Map: Count of Nutrients In Fortification Standards|website=Global Fortification Data Exchange|access-date=30 April 2019}} A meta-analysis of global birth prevalence of spina bifida showed that when mandatory fortification was compared to countries with healthcare professionals advising women but no mandatory fortification program, there was a 30% reduction in live births with spina bifida,{{cite journal|vauthors=Atta CA, Fiest KM, Frolkis AD, Jette N, Pringsheim T, St Germaine-Smith C, Rajapakse T, Kaplan GG, Metcalfe A|display-authors=6|title=Global Birth Prevalence of Spina Bifida by Folic Acid Fortification Status: A Systematic Review and Meta-Analysis|journal=American Journal of Public Health|volume=106|issue=1|pages=e24–34|date=January 2016|pmid=26562127|pmc=4695937|doi=10.2105/AJPH.2015.302902}} with some countries reported a greater than 50% reduction.

Over 80 countries require folic acid fortification in some foods. Fortification of rice is common.{{cite journal |last1=Peña-Rosas |first1=Juan Pablo |last2=Mithra |first2=Prasanna |last3=Unnikrishnan |first3=Bhaskaran |last4=Kumar |first4=Nithin |last5=De-Regil |first5=Luz Maria |last6=Nair |first6=N Sreekumaran |last7=Garcia-Casal |first7=Maria N |last8=Solon |first8=Juan Antonio |title=Fortification of rice with vitamins and minerals for addressing micronutrient malnutrition |journal=Cochrane Database of Systematic Reviews |volume=2019 |issue=10 |date=25 October 2019 |doi=10.1002/14651858.CD009902.pub2|pmid=31684687 |pmc=6814158 }} The USDA has required the fortification of flour since 1998. Since then, Hispanics in the United States have seen the greatest reduction of neural tube defects. Canada has mandated folic acid fortification of flour since 1998 which has resulted in a 42% decrease in neural tube defects. Fortification of wheat and corn flour, milk and rice is required in Costa Rica which has led to a reduction of neural tube defects of as much as 60%.

Folate deficiency is very rare in countries with folic acid fortification programs.{{cite journal |last1=Bailey |first1=RL |last2=West KP |first2=Jr |last3=Black |first3=RE |s2cid=31765256 |title=The epidemiology of global micronutrient deficiencies. |journal=Annals of Nutrition & Metabolism |date=2015 |volume=66 Suppl 2 |issue=2 |pages=22–33 |doi=10.1159/000371618 |pmid=26045325|doi-access=free }} Overall, the worldwide prevalence of anemia due to folic acid deficiency is very low. However, data on the prevalence of deficiency amongst specific high risk groups is lacking.{{cn|date=July 2024}}

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.{{cite journal |vauthors = Desai A, Sequeira JM, Quadros EV |title = The metabolic basis for developmental disorders due to defective folate transport |journal = Biochimie |volume = 126 |pages = 31–42 |date = 2016 |pmid = 26924398 |doi = 10.1016/j.biochi.2016.02.012 }}

Studies suggest that insufficient folate and vitamin B₁₂ status may contribute to major depressive disorder and that supplementation might be useful in this condition.{{cite journal | vauthors = Coppen A, Bolander-Gouaille C | s2cid = 4828454 | title = Treatment of depression: time to consider folic acid and vitamin B12 |journal = Journal of Psychopharmacology |volume = 19 |issue = 1 |pages = 59–65 | date = 2005 |pmid = 15671130 |doi = 10.1177/0269881105048899 |url = https://www.ncbi.nlm.nih.gov/sites/entrez }}

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).{{cite journal | vauthors = Karakuła H, Opolska A, Kowal A, Domański M, Płotka A, Perzyński J | title = [Does diet affect our mood? The significance of folic acid and homocysteine] |journal = Polski Merkuriusz Lekarski |volume = 26 |issue = 152 |pages = 136–41 | date = 2009 | pmid = 19388520 |url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=vitamin+b-12+and+folate+as+treatment+for+and+prevention+of+depression+and+stress,+Vitamin+b12+and+folate&log$=activity }} 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.

{{Reflist}}

{{Medical resources

| DiseasesDB = 4894

| ICD11 = {{ICD11|5B5E}}

| ICD10 = {{ICD10|D|52||d|50}} {{ICD10|E|53|8|e|50}}

| ICD9 = {{ICD9|266.2}}

| ICDO =

| OMIM =

| MedlinePlus = 000354

| eMedicineSubj = med

| eMedicineTopic = 802

| MeshID = D005494

}}

{{Nutritional pathology}}

{{Authority control}}

{{DEFAULTSORT:Folate Deficiency}}

Category:Vitamin deficiencies

Category:Nutritional anemias