The terms folic acid and folate are often used interchangeably for this water-soluble B-complex vitamin.
The terms folic acid and folate are often used interchangeably for this water-soluble B-complex vitamin. Folic acid, the most stable form, occurs rarely in foods or the human body, but is the form most often used in vitamin supplements and fortified foods. Naturally occurring folates exist in many chemical forms. Folates are found in foods as well as in metabolically active forms, in the human body (1). In the following discussion forms found in food or the body will be referred to as “folates”, while the form found in supplements or fortified foods will be referred to as “folic acid”.
One-carbon metabolism: The only function of folate coenzymes in the body appears to be mediating the transfer of one-carbon units (2). Folate coenzymes act as acceptors and donors of one-carbon units in a variety of reactions critical to the metabolism of nucleic acids and amino acids (3).
Nucleic acid metabolism:
- Folate coenzymes play a vital role in DNA metabolism through two different pathways.1) The synthesis of
- from its precursors is dependent on folate coenzymes. 2) A folate coenzyme is required for the synthesis of methionine, and methionine is required for the synthesis of S-adenosylmethionine (SAM). SAM is a methyl group (one-carbon unit) donor used in many biological
- reactions, including the methylation of a number of sites within DNA and
- . Methylation of DNA may be important in cancer prevention (see
Amino acid metabolism: Folate coenzymes are required for the metabolism of several important amino acids. The synthesis ofmethionine from homocysteine requires a folate coenzyme as well as a vitamin B-12 dependent enzyme. Thus, folate deficiency can result in decreased synthesis of methionine and a build up of homocysteine. Increased levels of homocysteine may be a risk factor for heart disease, as well as several other chronic diseases (see Disease Prevention).
Vitamin interrelationships: The metabolism of homocysteine, an intermediate in the metabolism of sulphur-containing amino acids, provides an example of the interrelationships among nutrients necessary to optimize physiological function and health. Healthy individuals utilize two different pathways to metabolize homocysteine (see Diagram). One pathway (methionine synthase) results in the synthesis of methionine from homocysteine, and is dependent on a folate coenzyme and a vitamin B-12 dependent enzyme. The other pathway converts homocysteine to another amino acid, cysteine, and requires two vitamin B-6 dependent enzymes. Thus, the amount of homocysteine in the blood is regulated by three vitamins: folic acid, vitamin B-12, and vitamin B-6 (4).
Causes: Folate deficiency occurs in a number of situations. For example, low dietary intake and diminished absorption, as in alcoholism, can result in a decreased supply of folate. Certain conditions like pregnancy or cancer result in increased rates of cell division and metabolism, leading to an increase in the body’s demand for folate (5). Several medications may also contribute to deficiency (see Drug interactions).
Symptoms: Individuals in the early stages of folate deficiency may not show obvious symptoms, but blood levels of homocysteine may increase (seePrevention). Rapidly dividing cells are most vulnerable to the effects of folate deficiency. When the folate supply to the rapidly dividing cells of the bone marrow is inadequate, blood cell division becomes abnormal resulting in fewer but larger red blood cells. This type of anemia is called megaloblastic ormacrocytic anemia, referring to the large immature red blood cells.Neutrophils, a type of white blood cell, become hypersegmented, a change which can be found by examining a blood sample microscopically. Because normal red blood cells have a lifetime in the circulation of approximately four months, it can take months for folate deficient individuals to develop the characteristic megaloblastic anemia. Progression of such an anemia leads to a decreased oxygen carrying capacity of the blood and may ultimately result in symptoms of fatigue, weakness, and shortness of breath (1). It is important to point out that megaloblastic anemia resulting from folate deficiency is identical to the megaloblastic anemia resulting from vitamin B-12 deficiency, and further clinical testing is required to diagnose the true cause of megaloblastic anemia.
Determination of the RDA: Traditionally, the dietary folate requirement was defined as the amount needed to prevent a deficiency, severe enough to cause symptoms like anemia. The most recent RDA (1998) was based primarily on the adequacy of red blood cell folate concentrations at different levels of folate intake, which have been shown to correlate with liver folate stores. Maintenance of normal blood homocysteine levels, an indicator of one-carbon metabolism, was considered only as an ancillary indicator of adequate folate intake. Because pregnancy is associated with a significant increase in cell division and other metabolic processes requiring folate coenzymes, the RDA for pregnant women is considerably higher than for women who are not pregnant (3). However, the prevention of neural tube defects (NTD) was not taken into consideration in setting the RDA for pregnant women. Rather, reducing the risk of NTD was considered in separate recommendation for women capable of becoming pregnant (see Prevention), because the crucial events in the development of the neural tube occur before many women are aware that they are pregnant (6).
Dietary Folate Equivalents (DFE): When the Food and Nutrition Board of the Institute of Medicine set the new dietary recommendation for folate, they introduced a new unit, the Dietary Folate Equivalent (DFE). Use of the DFE reflects the higher bioavailability of synthetic folic acid found in supplements and fortified foods compared to that of naturally occurring food folates (6).
- 1 microgram (mcg) of food folate provides 1 mcg of DFE
- 1 mcg of folic acid taken with meals or as fortified food provides 1.7 mcg of DFE
- 1 mcg of folic acid (supplement) taken on an empty stomach provides 2 mcg of DFE
For example, a serving of food containing 60 mcg of folate would provide 60 mcg of DFE, while a serving of pasta fortified with 60 mcg of folic acid would provide 1.7 x 60 = 102 mcg DFE due to the higher bioavailability of folic acid. A folic acid supplement of 400 mcg taken on an empty stomach would provide 800 mcg of DFE.
|Recommended Dietary Allowance for Folate in Dietary Folate Equivalents (DFE)|
|Life Stage||Age||Males (mcg/day)||Females (mcg/day)|
|Infants||0-6 months||65 (AI)||65 (AI)|
|Infants||7-12 months||80 (AI)||80 (AI)|
|Adults||19-years and older||400||400|
Genetic variation in folate requirements: A common polymorphism or variation in the gene for the enzyme methylene tetrahydrofolate reductase (MTHFR), known as the C677T MTHFR polymorphism, results in a less stable enzyme (7). Depending on the population, 50% may have inherited one copy (C/T) and 5 to 25 % may have inherited two copies (T/T) of the abnormal MTHFR gene. MTHFR plays an important role in maintaining the specific folate coenzyme required to form methionine from homocysteine (see Diagram). When folate intake is low, individuals who are homozygous (T/T) for the abnormal gene have lower levels of the MTHFR enzyme and higher levels of homocysteine in their blood (8). Improved folate nutritional status appears to stabilize the MTHFR enzyme, resulting in improved enzyme levels and lower homocysteine levels. An important unanswered question about folate is whether the present RDA is enough to normalize MTHFR enzyme levels in individuals who are homozygous for the C677T polymorphism, or whether those individuals have a higher folate requirement than the RDA (9).
Neural tube defects:
- Fetal growth and development is characterized by widespread cell division. Adequate folate is critical because of its roles in DNA and RNA synthesis.
- (NTD) result in either
- , which are devastating and sometimes fatal birth defects. The defects occur between the 21
- and 27
- days after conception, a time when many women do not realize they are pregnant (
- ). The risk of NTD in the United States prior to
- of foods with folic acid was estimated to be one per 1000 pregnancies (
- ). Results of randomized trials have demonstrated 60% to 100% reductions in NTD cases when women consumed folic acid supplements in addition to a varied diet during the periconceptional period (about 1 month before and 1 month after conception). The results of these and other studies prompted the U.S. Public Health Service to recommend that all women capable of becoming pregnant consume 400 mcg of folic acid daily to prevent NTD. The recommendation was made to all women of childbearing age, because adequate folic acid must be available very early in pregnancy, and because many pregnancies in the U.S. are unplanned. Despite the effectiveness of folic acid supplementation, it appears that less than half of women who become pregnant follow the recommendation (
- ). In order to decrease births affected by NTD, the FDA implemented legislation in 1998 requiring the fortification of all enriched grain products with folic acid (see
- ). The required level of folic acid fortification in the U.S. was estimated to provide 100 mcg of additional folic acid in the average person’s diet, though it probably provides more than this, due to overuse of folic acid by food manufacturers (
Other pregnancy complications: Adequate folate status may also prevent the occurrence of other types of birth defects, including certain heart defects and limb malformations. However, the support for these findings is not as consistent or clear as support for NTD prevention (10). Low levels of dietary folate during pregnancy have also been associated with increased risk of premature delivery and infant low birth weight. More recently, elevated blood homocysteine levels, considered an indicator of functional folate deficiency, have been associated with increased incidence of miscarriage, as well as pregnancy complications like preeclampsia and placental abruption (12). Thus, it is reasonable to maintain folic acid supplementation throughout pregnancy, even after closure of the neural tube in order to decrease the risk of other problems in pregnancy.
Cardiovascular diseases (heart disease, stroke, and peripheral vascular diseases):
Homocysteine and cardiovascular diseases:
- The results of more than 80 studies indicate that even moderately elevated levels of
- in the blood increase the risk of
- ). An analysis of the observational studies of blood homocysteine and vascular disease indicated that a prolonged decrease in plasma homocysteine level of only 1 micromole/liter resulted in about a 10% risk reduction (
- ). The mechanism by which homocysteine increases the risk of vascular disease remains the subject of a great deal of research, but may involve adverse effects on clotting, arterial
- , and thickening of arterial walls (
- ). Although increased homocysteine levels in the blood have been consistently associated with increased risk of cardiovascular diseases, it is not yet clear whether lowering homocysteine levels will reduce cardiovascular disease risk. Consequently, the American Heart Association recommends screening for elevated total homocysteine levels only in “high risk” individuals, for example those with personal or family history of premature cardiovascular disease, malnutrition or
- , kidney failure,
- , or individuals taking certain medications (nicotinic acid, theophylline, bile acid-binding resins, methotrexate, and L-dopa). Most research indicates that a plasma homocysteine level of < 10 micromoles/liter is associated with a lower risk of cardiovascular disease and a reasonable treatment goal for individuals at high risk (
Folate and homocysteine: Folate-rich diets have been associated with decreased risk of cardiovascular disease. A study that followed 1,980 Finnish men for 10 years found that those who consumed the most dietary folate had only 45% the risk of an acute coronary event when compared with those who consumed the least dietary folate (16). Of the three vitamins that regulate homocysteine levels, folic acid has been shown to have the greatest effect in lowering basal levels of homocysteine in the blood, when there is no coexisting deficiency of vitamin B-12 or vitamin B-6 (see Vitamin interrelationships). Increasing folate intake through folate-rich foods or supplements has been found to lower homocysteine levels. A supplement regimen of 400 mcg of folic acid, 2 mg of vitamin B-6, and 6 mcg of vitamin B-12 has been advocated by the American Heart Association if an initial trial of a folate-rich diet (see Sources) is not successful in adequately lowering homocysteine levels (15). Although increased folic acid intake has been found to decrease homocysteine levels, it is not presently known whether increasing folic acid intake will result in decreased rates of cardiovascular diseases. However, several randomized placebo-controlled trials are presently being conducted to determine whether homocysteine lowering through folic acid supplementation reduces the incidence of cardiovascular diseases. Since the initiation of fortification of the U.S. food supply with folic acid, blood homocysteine levels in the population have declined (9).
Cancer: Cancer is thought to arise from DNA damage in excess of ongoing DNA repair and/or the inappropriate expression of critical genes. Because of the important roles played by folate in DNA and RNA synthesis andmethylation it is possible for folate intake to affect both DNA repair and gene expression. The consumption of at least five servings of fruits and vegetables daily has been consistently associated with a decreased incidence of cancer. Fruits and vegetables are excellent sources of folate, which may play a role in their anti-carcinogenic effect. Observational studies have found diminished folate status to be associated with cancers of the cervix, colon and rectum, lung, esophagus, brain, pancreas, and breast. Intervention trials in humans have been conducted mainly with respect to cervical and colorectal (colon and rectal) cancer. While the results in cervical cancer have been inconsistent (2), randomized intervention trials regarding colorectal cancer have been very promising (17,18).
Colorectal cancer: The role of folate in preventing colorectal cancer provides an example of the complexity of the interactions between genetics and the nutritional environment. In general, observational studies have found relatively low folate intake and high alcohol intake to be associated with increased incidence of colorectal cancer (1,19,20). Alcohol interferes with the absorption and metabolism of folate (5). In aprospective study of more than 45,000 male health professionals, current intake of more than two alcoholic drinks per day doubled the risk of colon cancer. The combination of high alcohol and low folate intake yielded an even greater risk of colon cancer. However, increased alcohol intake in individuals who consumed 650 mcg or more of folate per day was not associated with an increased risk of colon cancer (21). In some studies, individuals who are homozygous for the C677T MTHFR polymorphism (TT) have been found to be at decreased risk for colon cancer when folate intake is adequate. However, when folate intake is low and/or alcohol intake is high individuals with the (T/T) genotype have been found to be at increased risk of colorectal cancer (22, 23).
Breast cancer: A number of prospective studies have found that even moderate alcohol intake is associated with an increased risk of breast cancer in women. Recently, the results of two prospective studies suggested that increased folate intake may reduce the risk of breast cancer in women who regularly consume alcohol (24-26). A very large prospective study of over 88,000 nurses found no relationship between folic acid intake and breast cancer in women who consumed less than one alcoholic drink per day. However, in those women consuming at least one alcoholic drink per day, folic acid intake of at least 600 mcg daily resulted in about half the risk of breast cancer compared with women who consumed less that 300 mcg of folic acid daily (26).
Alzheimer’s disease and cognitive impairment: The role of folate in nucleic acid synthesis and methylation reactions is essential for normal brain function. Over the past decade several investigators have described associations between decreased folate levels and cognitive impairment in the elderly (27). A largecross-sectional study of elderly Canadians found that those individuals with low folate levels were more likely to have dementia, be institutionalized, and be depressed. However, these findings could reflect the poorer nutritional status of institutionalized elderly and individuals with dementia. In the same study, low folate levels were associated with an increased likelihood of short-term memory problems in elderly individuals who did not show signs of dementia (28). In a recent study of 30 elderly nuns, who lived in the same convent, ate the same diet, and had similar lifestyles, researchers found a strong association between decreased blood folate levels and the severity of brain atrophy related toAlzheimer’s disease after their deaths (29). Moderately increased homocysteine levels, as well as decreased folate and vitamin B12 levels have also been associated with Alzheimer’s disease and vascular dementia. Low serum vitamin B12 (< 150 pmol/L) or folate (< 10 nmol/L) levels were associated with a doubling of the risk of developing Alzheimer’s disease in 370 elderly men and women followed over 3 years (30). In a sample of 1,092 men and women without dementia followed for an average for 10 years, those with higher plasma homocysteine levels at baseline had a significantly higher risk of developing Alzheimer’s disease and other types of dementia (31). Those with plasma homocysteine levels greater than 14 micoromoles/liter had nearly double the risk of developing Alzheimer’s disease.
Food sources: Green leafy vegetables (foliage) are rich sources of folate and provide the basis for its name. Citrus fruit juices, legumes, and fortified cereals are also excellent sources of folate (1). A number of folate-rich foods are listed in the table below along with their folate content in micrograms (mcg). For more information on the nutrient content of foods you eat frequently, search theUSDA food composition database.
|Orange juice (from concentrate)||6 ounces||82|
|Spinach (cooked)||1/2 cup||131|
|Asparagus (cooked)||1/2 cup (~ 6 spears)||131|
|Lentils (cooked)||1/2 cup||179|
|Garbanzo beans (cooked)||1/2 cup||141|
|Lima beans (cooked)||1/2 cup||78|
|Bread||1 slice||20 (Folic acid)*|
|Pasta (cooked)||1 cup||60 (Folic acid)*|
|Rice (cooked)||1 cup||60 (Folic acid)*|
|Breakfast cereals (ready to eat)||1 cup||100 (Folic acid)*|
*In order to help prevent neural tube defects the FDA required 1.4 milligrams (mg) of folic acid per kilogram (kg) of grain to be added to refined grain products, which are already enriched with niacin, thiamin, riboflavin, and iron, as of January 1, 1998. The addition of nutrients to foods in order to prevent a nutritional deficiency or restore nutrients lost in processing is known asfortification. It has been estimated that this level of fortification increases dietary intake by an average of 100 mcg folic acid/day (10). For more information on folic acid fortification, review the FDA fact sheet.
Supplements: The principal form of supplementary folate is folic acid. It is available in single ingredient and combination products, such as B-complex vitamins and multivitamins. Doses greater than or equal to 1 mg require a prescription (32).
Toxicity: No adverse effects have been associated with the consumption of excess folate from foods. Concerns regarding safety are limited to synthetic folic acid intake. Deficiency of vitamin B-12, though often undiagnosed, may affect a significant number of people, especially older adults (see Vitamin B-12). One symptom of vitamin B-12 deficiency is megaloblastic anemia, which is indistinguishable from that associated with folate deficiency (seeDeficiency). Large doses of folic acid given to an individual with an undiagnosed vitamin B-12 deficiency could correct megaloblastic anemia without correcting the underlying vitamin B-12 deficiency, leaving the individual at risk of developing irreversible neurologic damage. Most cases of this sort of neurologic progression in vitamin B-12 deficiency have been seen at doses of folic acid of 5,000 mcg (5 mg) and above. In order to be very sure of preventing irreversible neurological damage in B-12 deficient individuals, the Food and Nutrition Board of the Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1,000 mcg (1 mg daily). The board also noted that vitamin B-12 deficiency is very rare in women in their childbearing years, making the consumption of folic acid at or above 1000 mcg/day unlikely to cause problems (1), although there is limited data on the effects of large doses.
|Tolerable Upper Intake Level (UL) for Folic Acid|
|Age Group||UL (mcg/day)|
|Infants 0-12 months||Not possible to establish*|
|Children 1-3 years||300|
|Children 4-8 years||400|
|Children 9-13 years||600|
|Adolescents 14-18 years||800|
|Adults 19 years and older||1,000|
*Source of intake should be from food and formula only.
Drug interactions: When taken in very large therapeutic dosages, for example in the treatment of severe arthritis, nosteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen may interfere with the metabolism of folate. Routine low dose use of NSAIDs has not been found to adversely affect folate status. The anticonvulsant, phenytoin, has been shown to inhibit the intestinal absorption of folate, and several studies have associated decreased folate status with long-term use of the anti-convulsants, phenytoin, phenobarbital, and primidone (33). However, few studies controlled for differences in folate intake between anticonvulsant users and nonusers. Taking folic acid at the same time as the cholesterol-lowering agents, cholestyramine and colestipol, may decrease the absorption of folic acid (32). Methotrexate is a folic acid antagonist used to treat a number of diseases, including rheumatoid arthritis and psoriasis. Some of the side effects of methotrexate are similar to those of severe folate deficiency, and increased dietary folate or supplemental folic acid may decrease side effects without reducing the efficacy of methotrexate. A number of other medications have been shown to have antifolate activity, including trimethoprim (an antibiotic), pyrimethanine (an antimalarial), triamterene (a blood pressure medication), and sulfasalazine (a treatment for ulcerative colitis). Early studies of oral contraceptives (birth control pills) containing high doses of estrogen indicated an adverse effect on folate status, which has not been supported by more recent studies on low dose oral contraceptives, in which dietary folate was controlled (1).
THE LINUS PAULING INSTITUTE RECOMMENDATION
Researchers at the Linus Pauling Institute feel that there exists ample scientific evidence to suggest that adequate folate intake is helpful in lowering the risk of cardiovascular diseases, some forms of cancer, neural tube defects and other poor outcomes of pregnancy, especially in genetically susceptible individuals. The Linus Pauling Institute recommends that adults take a 400 mcg supplement of folic acid daily, in addition to folate and folic acid consumed in the diet. A daily multivitamin-mineral supplement, containing 100 % of the Daily Value (DV) for folic acid will provide 400 mcg of folic acid/day. Even with a larger than average intake of folic acid from fortified foods, it is unlikely that an individual’s daily folic acid intake would regularly exceed the tolerable upper intake level of 1,000 mcg/day established by the Food and Nutrition Board (seeSafety).
Older adults (65 years and older): The recommendation for 400 mcg/day of supplemental folic acid as part of a daily multivitamin/multimineral supplement, in addition to a folate-rich diet, is especially relevant for older adults because blood homocysteine levels tend to increase with age (see Disease Prevention.)
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