Folic acid

Folic acid is the synthetic form of vitamin folate and is present in artificially enriched foods, and in vitamins.

Folate is a water soluble B vitamin found in meat and leafy green vegetables, fruits, grains and cereals which is necessary for DNA synthesis.

Vitamin B9.

It is essential to the synthesis of some amino acids, the synthesis of nucleotides, and therefore, to the creation and repair of DNA.

Folate deficiency causes or contributes to many disease states.

It is a best known risk factor for neural tube defects in developing fetuses  and there is evidence it can contribute to anemia, cardiovascular disease, and neurological disease in adult and elderly populations.

Known as folate, pteroylpolyglutamate, pteroylglutamic acid and vitamin B9.

Dihydrofolate is the dietary form of folate in green vegetables, egg yolks, yeast, liver and kidney.

Folic acid supplemental form of folate, and dihydrofolate, the food derived form of folate, are both converted to L-methylfolate, the active form of folate that crosses the blood brain barrier by 5, 10 – methylenetetrahydrofolate reductase (MTHFR).

Forms include folate, folic acid, folinic acid or leucovorin, tetrahydrofolate, methylenetetrahydrofolate and methyltetrahydrofolate.

Methyltetrahydrofolate (MTHF) is the bioavailable form and is the most important compound.

The major intracellular compounds are folate polyglutamtes

MTHF can cross the blood brain barrier into the CSF, which folic acid cannot.

Folate needed in the brain for the synthesis of norepinephrine, serotonin and dopamine.

Important for cell proliferation, central nervous system cell repair, and appropriate epigenetic expression of the genome.

Folate is absorbed in the intestines.

Folate is present in food in a polyglutamate form, which is then converted into monoglutamates by intestinal conjugase to be absorbed by the jejunum. 

Resorbed in the upper jejunum as monofolates.

Stores are sufficient for several months.

The liver converts folic acid to its different forms to serve bodily functions and they are in a dynamic equilibrium with each other.

In yeast, spinach, lentils and orange juice.

Polyglutamtes in foods are easily destroyed by cooking.

Converts homocysteine to methionine.

Essential for the formation of S-adenosylmethionine, the universal methyl donor and coenzyme.

Intracellular folates exist as 6 intervertable forms.

One form 5,10 methylenetetrahydrofolate is the essential 1-carbon donor and reduced folate substrate for thymidylate synthase, the enzyme that catalyzes methylation of deoxyuridine5-monophosphate to deoxythymidine-5-monophosphate.

Deficiency results in ineffective DNA synthesis, impaired erythropoiesis, with formation of megaloblasts and macrocytic anemia.

Deficiency results in acrostic or megaloblastic anemia,, neural tube defects in newborns, and excess homocysteine levels.

Folic acid as an adjunct to standard treatment with anti-depressants shows improvement in response rates.

Folate deficiency is the only dietary factor that has been shown to play a role in early cervical carcinogenesis.


Folate deficiency apparently facilitates incorporation of HPV DNA at a fragile chromosomal site, thereby establishing a basis for malignant transformation.

In a study of outpatient blood counts involving 9527 patients, 3% had macrocytosis( Sepp�).


The most common cause for macrocytosis was alcohol abuse.


In several other studies, vitamin B12 deficiency was the cause of macrocytosis in 5%-7% of patients.



In a study of 200 consecutive patients with MCVs over 100, the cause was established  in 80%: Sixteen of these patients had a low B12 level and 10 had a low folate level.



In recent years, folate has become an extremely unlikely cause of macrocytic anemias. 



In 1998, the Food and Drug Administration required folic acid fortification of enriched grain products in the United States to help decrease the risk of neural tube defects.

approximately 24% of Americans had a seeum folate level below 4.4 ng/L prior to mandatory fortification.

Following mandatory fortification of folate, the prevalence of low levels of serum folate decreased to under 1% of the population.

Since 1998, anemia due to folate deficiency has essentially disappeared in individuals who have access to fortified grain products.

Common social determinants of health among folate  deficient patients include birth outside of the United States, homelessness, and alcohol use disorder.


Folate deficiency is not the cause of anemia in any of the patients with low folate levels.



It is suggested folate analysis should be reduced or eliminated. 



Choosing Wisely campaign: Do not order red blood cell folate levels at all.


Deficiency may contribute to risk of developing cognitive deficits and depression.


Deficiency associated with oral clefts and congenital heart disease, malignancy, and atherosclerotic disease.


Decreases risk in pregnancy of having an infant with a neural-tube defect by 75%.


Risk factors for deficiency include: alcohol abuse, poor dietary intake, malabsorption syndrome such a celiac disease, and inflammatory bowel disease, some medications including methotrexate and phenytoin, and states of increased requirements such as hemolysis, dermatitis and pregnancy.


Red blood cell folate levels reflect tissue stores.


Red blood cell folate may remain normal for 3 to 4 months in the absence of dietary folate.


Because folic acid around the time of conception reduces the risk of neural tube defects in children, there is mandatory fortification of flour with folio acid in several countries.


Three forms of folate are commonly used:folic acid, five-methyltetrahydrofolate (5-MTHF), and folinic acid.


Folic acid requires 4 step transformation in the intestines and liver to become l- methylfolate, a biologically active form of folate that can cross the blood brain barrier and activate enzymes that synthesize dopamine, norepinephrine, and serotonin.


Recommended dose 400 micrograms of folic acid per day to begin prior to pregnancy is recognized and continued through its early stages.


The USPSTF recommends that all persons planning to or who could become pregnant take a daily supplement containing 0.4 to 0.8 mg of folic acid.


Once pregnancy is present it is too late for folic acid to be neuroprotective.


Folic acid supplementation is recommended to be taken by women planning to become pregnant starting one month before conception.


Evidence exists that maternal colic acid supplementation during pregnancy may be associated reduced reduced risk of other neurodevelopmental diseases in children.


A Norwegian study of 38,954 children revealed that maternal intake of folic acid supplements from four weeks before to eight weeks after the start of pregnancy was associated with a lower risk of severe language delay at age 3 years and also associated reduced risk of autism spectrum disorders in children. (Roth C et al, Suren P et al).


A California study of autism spectrum disorders revealed that maternal intake of colic acid and prenatal vitamins three months prior to pregnancy and the first month of pregnancy was associated with a lower risk of autism spectrum disease in the offspring,


Decreased levels associated with increased cardiovascular risk.


Supplementation reduces elevated homocysteine levels.


Use does not increase miscarriage rate in pregnancy.


Daily requirement of folate is about 150microgm.


Mandated that flour and other grain products must be

fortified at a minimal level of 0.14 mg of folic acid per 100 g of cereal grain.

Sonce  the  implementation  of mandatory fortification of all green products in the US folate deficiency has become rare.

Functions associated a coenzyme in single carbon transfers in metabolism of amino acids and nucleic acids.


The most stable oxidized form of folate.


Is the form used in vitamins and fortified foods.


Food folates, naturally occurring folates, are pteroylpolyglutamates.


Food folate has a nearly 50% lower bioavailability compared to synthetic folic acid.


Periconceptional multivitamin supplementation can prevent major birth defects aside from neural tube defects with a 47% reduction in such defects including orofacial clefts and congenital heart defects.


Deficiency related to inadequate dietary intake of B vitamins.


Oral contraceptives, anticonvulsants alcohol and tobacco can lead to folate deficiency.


Folate deficiency has been associated with depression and may impair the response to antidepressants and may contribute to relapse of depression.


Impaired absorption associated with jejunal disease, atrophic gastritis, short bowel syndrome, pregnancy, emotional stress and oxidative stress.


Can be associated with diseases with rapid proliferative growth rate such as leukemia or lymphoma which may deplete the body’s supply.


Bacterial overgrowth in the bowel may lead to lowered levels as bacteria compete for the body’s folate.


Various inborn errors of metabolism may prevent the body from breaking down folate, or cause transport errors preventing the molecule from crossing cell membranes.


Genetic polymorphisms exist such as methylenetetrahydrofolate reductase polymorphism that can affect the body’s ability to metabolize folate resulting in deficiency of MTHF.


The mandatory folic acid fortification of foods implemented in 1998 has resulted in increased circulating folate concentrations and decreased plasma total homocysteine concentrations and is associated with an accelerated decline in stroke mortality in the U.S. compared to areas where fortification is not mandatory.


FA supplementation by women in early pregnancy is associated with a reduced risk of severe language delay in children at age 3 years (Roth C et al).


In the above study maternal use of supplements containing folic acid from four weeks before to eight weeks after conception was associated with a substantial reduced risk of severe language delay in children at age 3 years.

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