Folic Acid

Definition

Folic acid is a water-soluable vitamin belonging to the B-complex group of vitamins. These vitamins help the body break down complex carbohydrates into simple sugars to be used for energy. Excess B vitamins are excreted from the body rather than stored for later use. This is why sufficient daily intake of folic acid is necessary.

Description

Folic acid is also known as folate, or folacin. It is one of the nutrients most often found to be deficient in the Western diet, and there is evidence that deficiency is a problem on a worldwide scale. Folic acid is found in leafy green vegetables, beans, peas and lentils, liver, beets, brussel sprouts, poultry, nutritional yeast, tuna, wheat germ, mushrooms, oranges, asparagus, broccoli, spinach, bananas, strawberries, and cantaloupes. In 1998, the U.S. Food and Drug Administration (FDA) required food manufacturers to add folic acid to enriched bread and grain products to boost intake and to help prevent neural tube defects (NTD).

Purpose

Folic acid works together with vitamin B₁₂ and vitamin C to metabolize protein in the body. It is important for the formation of red and white blood cells. It is necessary for the proper differentiation and growth of cells and for the development of the fetus. It is also used to form the nucleic acid of DNA and RNA. It increases the appetite and stimulates the production of stomach acid for digestion and it aids in maintaining a healthy liver. A deficiency of folic acid may lead to anemia, in which there is decreased production of red blood cells. This reduces the amounts of oxygen and nutrients that are able to get to the tissues. Symptoms may include fatigue, reduced secretion of digestive acids, confusion, and forgetfulness. During pregnancy, a folic acid deficiency may lead to preeclampsia, premature birth, and increased bleeding after birth.

People who are at high risk of strokes and heart disease may greatly benefit by taking folic acid supplements. An elevated blood level of the amino acid homocysteine has been identified as a risk factor for some of these diseases. High levels of homocysteine have also been found to contribute to problems with osteoporosis. Folic acid, together with vitamins B₆ and B₁₂, helps break down homocysteine, and may help reverse the problems associated with elevated levels.

Pregnant women have an increased need for folic acid, both for themselves and their child. Folic acid is necessary for the proper growth and development of the fetus. Adequate intake of folic acid is vital for the prevention of several types of birth defects, particularly NTDs. The neural tube of the embryo develops into the brain, spinal cord, spinal column, and the skull. If this tube forms incompletely during the first few months of pregnancy a serious, and often fatal, defect results in spina bifida or anencephaly. Folic acid, taken from one year to one month before conception through the first four months of pregnancy, can reduce the risk of NTDs by 50-70%. It also helps prevent a cleft lip and palate.

Research shows that folic acid can be used to successfully treat cervical dysplasia, a condition diagnosed by a Pap smear, of having abnormal cells in the cervix. This condition is considered to be a possible precursor to cervical cancer, and is diagnosed as an abnormal Pap smear. Daily consumption of 1,000 mcg of folic acid for three or more months has resulted in improved cervical cells upon repeat Pap smears.

Studies suggest that long-term use of folic acid supplements may also help prevent lung and colon cancer. Researchers have also found that alcoholics who have low folic acid levels face a greatly increased possibility of developing colon cancer.

Preparations

To correct a folic acid deficiency, supplements are taken in addition to food. Since the functioning of the B vitamins is interrelated, it is generally recommended that the appropriate dose of B-complex vitamins be taken in place of single B vitamin supplements. The Recommended Dietary Allowances (RDA) for folate is 400 mcg per day for adults, 600 mcg per day for pregnant women, and 500 mcg for nursing women. Medicinal dosages of up to 1,000-2,000 mcg per day may be prescribed.

Precautions

Folic acid is not stable. It is easily destroyed by exposure to light, air, water, and cooking. Therefore, the supplement should be stored in a dark container in a cold, dry place, such as a refrigerator. Many medications interfere with the body's absorption and use of folic acid. This includes sulfa drugs, sleeping pills, estrogen, anti-convulsants, birth control pills, antacids, quinine, and some antibiotics. Using large amounts of folic acid (e.g., over 5,000 mcg per day) can mask a vitamin B₁₂ deficiency and thereby risk of irreversible nerve damage.

Side effects

At levels of 5,000 mcg or less, folic acid is generally safe for use. Side effects are uncommon. However, large doses may cause nausea, decreased appetite, bloating, gas, decreased ability to concentrate, and insomnia. Large doses may also decrease the effects of phenytoin (Dilantin), a seizure medication.

Interactions

As with all B-complex vitamins, it is best to take folic acid with the other B vitamins. Vitamin C is important to the absorption and functioning of folic acid in the body.

Resources

ORGANIZATIONS

Centers for Disease Control and Prevention. 1600 Clifton Rd., NE, Atlanta, GA 30333. (800) 311-3435, (404) 639-3311. 〈http://www.cdc.gov〉.

OTHER

Adams, Suzanne L. The Art of Cytology: Folic Acid/ B-12 Deficiency. [email protected]. 〈http://www.concentric.net/∼Suza2/page22.htm〉.

"Folic Acid: Coming to A Grocery Store Near You." 〈http://www.mayohealth.org/mayo/9710/htm/folic.htm〉.

"Folic Acid." 〈http://www.cybervitamins.com/folicacid.htm〉.

"Folic acid (oral/injectible)." Dr. Koop.com.Inc. 700 N. Mopac, Suite 400, Austin, TX 48731. 〈http://www.drkoop.com/hcr/drugstore/pharmacy/leaflets/english/d00241a1.asp〉.

Pregnancy and Nutrition Update. 〈http://www.mayohealth.org/mayo/9601/htm/pregvit.htm〉.

KEY TERMS

Homocysteine— An amino aid involved in the breakdown and absorption of protein in the body.

Preeclampsia— A serious disorder of late pregnancy in which the blood pressure rises, there is a large amount of retained fluids, and the kidneys become less effective and excrete proteins directly into the urine.

Raynaud's disease— A symptom of various underlying conditions affecting blood circulation in the fingers and toes and causing them to be sensitive to cold.

Recommended Dietary Allowance (RDA)— Guidelines for the amounts of vitamins and minerals necessary for proper health and nutrition established by the National Academy of Sciences in 1989.

Water-soluble vitamins— Vitamins that are not stored in the body and are easily excreted. They must, therefore, be consumed regularly as foods or supplements to maintain health.

Folic acid

Definition

Folic acid is the synthetic (man-made) form of the B-vitamin, folate. A water-soluble, B-complex vitamin, folic acid—also called folacin, pteroylglutamic acid, or vitamin B₉—is found in fortified foods and supplements.

Description

Folate serves many important functions in the body and is essential to maintaining good health.

Functions

The body needs folate to manufacture deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), which are building blocks of cells. For this reason, adequate folate intake is particularly important during pregnancy and in infancy. Folate has a well-documented role in preventing birth defects of the brain and spinal cord (neural tube defects).

Adults as well as children need folate to make normal red blood cells and prevent a type of anemia (a blood disorder characterized by a decrease in red blood cells and measured by a decrease in hemoglobin, the oxygen-carrying portion of the blood) called megaloblastic or pernicious anemia. This disorder is characterized by malformed and underdeveloped red blood cells.

Folate is also needed to metabolize and maintain normal levels of homocysteine (an amino acid) in the blood. When the body is deficient in folate, homocysteine accumulates. Elevated blood levels of homocysteine have been linked to an increased risk of heart disease, stroke , and even osteoporosis . Taking folic acid may be a preventive measure against these disorders.

Folic acid may decrease the risk of certain cancers such as colon, breast, cervical, throat and mouth, and lung cancer by preventing DNA changes that may lead to cancer . Other conditions affecting seniors, such as depression , dementia, and Alzheimer's disease, may be alleviated by maintaining adequate folate levels. A number of studies have shown that the elderly may get physical as well as mental benefits—including memory improvement—by taking folic acid supplements.

In conjunction with vitamins B₁₂ and C, folate works to break down and use proteins and convert complex carbohydrates into simple sugars the body can use for energy. Folate also stimulates the appetite and produces hydrochloric acid in the digestive tract.

Folic acid deficiencies

According to the National Institutes of Health (NIH), folate is one of the vitamins most often found to be deficient in the Western diet . To increase the average daily folate intake and to prevent birth defects of the brain and spinal cord, in 1998, the U.S. Food and Drug Administration (FDA) required food manufacturers to add folic acid to enriched bread and grain products such as pastas and cereals.

Among the elderly, folate deficiency is caused by a variety of factors, including insufficient intake of folate-rich foods or supplements, poor absorption or metabolism, taking certain medications, excessive alcohol consumption, and stress . Individuals with medical conditions such as liver disease or who are on renal (kidney) dialysis may also have folate deficiency.

Symptoms of severe folate deficiency include headaches , weakness, diarrhea , forgetfulness, fatigue, depression, weight loss , a red and sore tongue, or bone fractures. Because these conditions may be caused by a wide variety of disorders, a blood test is required to confirm folate deficiency.

Recommended dosage

According to the Institute of Medicine (IOM), the U.S. Recommended Dietary Allowance (RDA) for males and females 1–3 years of age is 150 micrograms (mcg) per day; for ages 4–8, 200 mcg per day; and for ages 9–13, 300 mcg per day. The RDA is 400 mcg per day for males and females aged 14 years and older; 500 mcg per day for breastfeeding adult women; and 600 mcg per day for pregnant adult women.

Folic acid upper limits

As a water-soluble vitamin, excess folate is excreted from the body and must be replenished daily. Ingesting large amounts of folate from whole foods has not been linked to any adverse health risks. The risk of toxicity from ingesting excessive amounts of folic acid from fortified foods or supplements is low, according to the Office of Dietary Supplements , which is part of the NIH.

The IOM has established a tolerable upper intake level (UL) for folic acid (there is no UL for folate in whole foods) from fortified foods or supplements for ages one and above. For males and females ages 1–3, the UL is 300 mcg per day; ages 4–8, 400 mcg per day; ages 9–13, 600 mcg per day; ages 14–18, 800 mcg per day, and for those 19 years and older, the UL is 1,000 mcg per day. Folate intake above these levels over a long period of time may increase the risk of adverse health effects such as nerve or kidney damage, especially in the elderly.

Dietary sources of folate

Some of the richest dietary sources of folate include:

• Breakfast cereals (folic-acid fortified) (3/4 cup)—100–400 mcg
• Beef liver (3 oz)—185 mcg
• Black-eyed peas (1/2 cup)—105 mcg
• Spinach, cooked (1/2 cup)—100 mcg

QUESTIONS TO ASK YOUR PHARMACIST

• Will folic acid supplements interact adversely with any of my prescription medications?
• If I take folic acid supplements, how much vitamin B₁₂ will I need to take to avoid a vitamin B₁₂ deficiency?

Other good food sources of folate include dark leafy vegetables; asparagus; lima beans; chickpeas; lentils; soybeans; fruits such as oranges, cantaloupes, and bananas; kidney meat; brewer's yeast; and nuts.

Taking folic acid in the form of supplements or fortified foods is preferred over whole food sources for several reasons. The folate in food is unstable, and preparation and cooking may lead to a loss of potency. Also, it is difficult to calculate the amount of folate ingested from natural dietary sources. Finally, the folate in food is less bioavailable (less able to be absorbed and used by the body) than folic acid in supplements. Folic acid supplements, like some other vitamins, are affected by heat and light and may lose potency when stored for long periods of time. It is necessary to check the expiration date prior to using the supplement.

Precautions

Some evidence suggests that ultraviolet radiation may deplete the body's stores of folate, especially in individuals with fair skin. Spending excessive amounts of time in the sun should be avoided.

It is important for older adults to be aware of the relationship between folic acid and vitamin B ₁₂. Folate and vitamin B₁₂ deficiencies may cause anemia. If an individual takes large amounts of folic acid, the anemia may improve, but a vitamin B₁₂ deficiency may go undetected. High folate levels may then worsen the nerve damage caused by a B₁₂ deficiency. Before ingesting a supplement containing folic acid or folic-acid fortified foods, seniors should make sure they are ingesting no more than 1,000 mcg of folic acid daily. They should also be sure to take the recommended amount of vitamin B₁₂ in addition to their folic acid.

Although multivitamins typically contain a balanced amount of B vitamins, the RDA for vitamin B₁₂ is 2.4 mcg daily for those 19 years of age and older. People 50 years of age or older who are undergoing medical treatments such as chemotherapy or dialysis or who are taking certain medications for rheumatoid arthritis or psoriasis (an immune-system disorder), should consult with their physician before taking supplements containing folic acid. Vitamin B₁₂ levels in these individuals should be monitored.

Side effects

Although side effects are rare, very high amounts of folic acid taken over long periods of time may lead to formation of folic acid crystals in the kidney or cause severe neurologic (nerve) problems. Symptoms such as decreased appetite, nausea, gas, abdominal bloating, or insomnia may occur in doses exceeding 1,500 mcg per day.

Interactions

Folic acid may interact adversely with other vitamins as well as some prescription medications.

Vitamin interactions

Intake of supplemental folic acid should not exceed 1,000 mcg to prevent folic acid from triggering symptoms of vitamin B₁₂ deficiency. It is important to take folic acid with other B-complex vitamins instead taking of folic acid alone.

Prescription medication interactions

Some medications that interfere with folate absorption or utilization include:

• antibiotics (such as tetracycline)
• anticonvulsant medications (such as dilantin, phenytoin, and primidone)
• barbiturates (sedatives)
• metformin (to control blood sugar in type 2 diabetes)
• methotrexate (to treat cancer and immune-system disorders such as rheumatoid arthritis and psoriasis)
• sulfasalazine (to control inflammation in disorders such as Crohn's disease and ulcerative colitis)
• triamterere (a diuretic)

It is important for seniors with any serious illness to seek medical advice before initiating or continuing folic acid supplementation. Folic acid may interact adversely with chemotherapy.

Caregiver concerns

If administering folic acid to the elderly, caregivers should be sure to administer a sufficient amount of vitamin B₁₂ in addition to the folic acid to avoid B₁₂ deficiency. If an elderly person has any major illness, such as pernicious anemia, cancer, or diabetes, or is taking prescribed medication, folic acid may cause serious side effects or interfere with treatment. Caregivers should check with the individual's physician before initiating or continuing folic acid supplementation.

KEY TERMS

Bioavailability —The portion of a substance that reaches the general circulation and is transported to the target tissue.

Homocysteine —An amino acid in the blood.

Water-soluble vitamin —A vitamin not stored in the body; it must be replaced every day.

Resources

BOOKS

Balch, Phyllis A. Prescription for Nutritional Healing: A Practical A-to-Z Reference to Drug-Free Remedies Using Vitamins, Minerals, Herbs and Food Supplements. New York: Penguin Group, 2006.

Hathcock, John N. Vitamin and Mineral Safety. 2nd ed. Washington, DC: Council for Responsible Nutrition, 2004.

Perlmutter, David. The Better Brain Book. New York: Penguin Group, 2005.

PERIODICALS

McCully, K. S. “Homocysteine, Vitamins, and Vascular Disease Prevention.” American Journal of Clinical Nutrition 86, no. 5 (November 2007): 1563S–8S.

Wang, X., et al. “Efficacy of Folic Acid Supplementation in Stroke Prevention: A Meta-analysis.” Lancet 369, no. 9576 (June 2, 2007): 1876–1882.

Yi, Kim. “Folic Acid Fortification and Supplementation—Good for Some But Not So Good for Others.” Nutrition Reviews 65, no. 11 (November 2007): 504–511.

OTHER

Dietary Supplement Fact Sheet: Folate. National Institutes of Health, Office of Dietary Supplements. August 22, 2005 [cited April 12, 2008]. http://ods.od.nih.gov/factsheets/folate.asp.

“Folic Acid: Boost for your Brain?” Publications: Science in the Spotlight. Spring 2007 [cited April 12, 2008]. Alliance for Aging Research. http://agingresearch.org/content/article/detail/1351/.

Homocysteine, Folic Acid and Cardiovascular Disease. American Heart Association. [Cited April 12, 2008]. http://www.americanheart.org/presenter.jhtml?identifier=4677.

Paddock, Catharine. “Folic Acid Increases Mental Agility in the Elderly.” Medical News Today January 19, 2007 [cited April 12, 2008]. http://www.medicalnewstoday.com/articles/61211.php.

ORGANIZATIONS

Alliance for Aging Research, 2021 K Street, NW Suite 305, Washington, DC, 20006, (202) 293-2856, (202) 785 8574, http://agingresearch.org.

American Heart Association (National Center), 7272 Greenville Avenue, Dallas, TX, 75231, (800) 242-872.

Council for Responsible Nutrition, 1828 L Street, NW, Suite 900, Washington, DC, 20036-5114, (202) 776 7929, (202) 204-7980, [email protected], http://www.crnusa.org.

Linus Pauling Institute. Oregon State University, 571 Weniger Hall, Corvallis, Oregon, 97331-6512, (541) 737-5075, (541) 737-5077, [email protected], http://lpi.oregonstate.edu.

Genevieve Slomski PhD

FOLIC ACID

FOLIC ACID. Folic acid is a water-soluble B-vitamin first identified in 1930 by Wills and Mehta as "Wills factor." Wills factor cured the anemias of pregnant women in India, a clinical condition that commonly results from undernutrition. This vitamin was later isolated from spinach leaves and named folic acid (Latin folium, leaf). Unlike most bacteria and yeast, mammals cannot synthesize folate and, therefore, require folate in the diet. This vitamin is present in the body as a family of at least nine structurally related chemical compounds that are collectively referred to as folate. The term folic acid refers to a synthetic form of the vitamin. Folic acid, which is biologically inactive, is found in foods that have been fortified with it. Folic acid is also the form that is present in nutritional supplements. Folic acid can be converted by living cells to a biologically active form called tetrahydrofolate. This active form serves the same biological function as natural folates. The terms "folic acid" and "folate" are therefore often used interchangeably.

Chemical Forms of Folate

The different forms of folate found in the body exist primarily as modified forms of tetrahydrofolate. Each tetrahydrofolate form differs by modification of the selected positions in the molecule that involve the placement of a single carbon unit. Additionally, folate derivatives found in cells contain a glutamate polypeptide tail that consists of two to eight glutamate residues in length. This polyglutamate chain is required for folates to perform their biochemical functions and also to retain folate in the cell. The glutamate chain prevents the molecule from crossing cell membranes.

Dietary Folate

Vegetables are good dietary sources of naturally occurring folate, especially dark green leafy vegetables. Citrus fruits and fresh juices, berries, legumes, liver, and whole grains are other good sources. Most naturally occurring folates are sensitive to degradation by air and heat but are stabilized when bound to proteins present in foods. For this reason, fresh fruits and vegetables are the best sources of dietary folates since many food folates are destroyed during food preparation. Dietary folates contain a polyglutamate chain that must be removed by digestive enzymes in the intestine. These enzymes leave a single glutamate residue on the folate, and the folate is then absorbed by the intestinal cell. Most folates are taken up by the liver, which is the primary storage site for folate. Folates can then be redistributed to other tissues from the liver. Glutamate chains are re-elongated by the body after the absorption of folates with single glutamates.

Overview of Folate Metabolism

Folate serves as a cofactor that delivers single carbon units to particular enzymes that catalyze biochemical reactions. These folate-dependent biochemical reactions are referred to collectively as one-carbon metabolism. Folate functions in both the cytoplasm and mitochondria, the energy-producing units, of mammalian cells. Folate metabolism in mitochondria is responsible for the generation of formate, a source of one-carbon unit. Formate escapes the mitochondria and is a primary source of the single carbon units for one-carbon metabolism in the cytoplasm. One-carbon metabolism in the cytoplasm is required for the synthesis of DNA precursors, and the amino acid methionine from its precursor, homocysteine. Methionine, in turn, is converted to the cofactor S-adenosylmethionine or SAM. SAM serves as an additional source of single carbon units in the form of methyl groups that are required for other metabolic reactions including the methylation of DNA, RNA, and proteins. SAM also is required for the synthesis of phospholipids, neurotransmitters, and many small metabolites.

Folate as a Therapeutic Target

Folate-dependent reactions are fundamental for DNA synthesis and maintenance of DNA integrity. Therefore, folate is required for cell growth and replication. It is not surprising that folate-dependent enzymes have proven to be effective targets for antitumor and antimicrobial drug therapies. These pharmaceutical agents are structurally similar to folate and are referred to as antifolates. Agents including 5-fluorouracil and methotrexate (and related antifolates) bind to folate-dependent enzymes by mimicking the structure of folate but do not serve the same biological function. These agents enter the cell and inhibit folate-dependent reactions associated with DNA synthesis and result in cell death. Antifolates are used in the treatment of many cancers, Crohn's disease, rheumatoid arthritis, lupus, and other autoimmune disorders.

Folate Deficiency and Disease

The most common impairments of folate metabolism result from inadequate folate intake, certain drug therapies, smoking, malabsorption disorders, alcoholism, genetic mutations, and subtle individual genetic variations that occur normally in populations. Additionally, certain dietary factors can interfere with folate absorption in the gut and result in malabsorption of the vitamin. Inadequate folate status has been reported in many population groups including pregnant and lactating women, women twenty to forty-four years of age, adolescents, and the elderly. Folate requirements are greatly increased during pregnancy due to the high demand for folate by the growing fetus and placenta. Folate deficiency can present itself clinically as megaloblastic anemia, a clinical condition associated with enlarged red blood cells due to decreased DNA synthesis. Other clinical symptoms include an inflamed, redlooking tongue, nausea, vomiting, diarrhea, anorexia, hyperpigmentation, and fever. Folate deficiency during pregnancy is highly associated with several congenital defects including spina bifida. Population studies implicate impaired folate metabolism in other pathologies including cardiovascular disease, colon cancer, cervical dysplasia, and pre-eclampsia.

Folate and Homocysteine

One of the first biochemical indicators associated with impaired folate metabolism is increased serum homocysteine (resulting from decreased methionine synthesis). Both folate and vitamin B₁₂ are required for converting homocysteine to methionine. Plasma homocysteine level is a sensitive marker of folate status, but homocysteine can be influenced by other vitamins, including vitamin B₆ and B₁₂ status, as well as age. The relationship between folic acid and homocysteine levels in the body is important because of the association between homocysteine and vascular disease. Elevated plasma homocysteine is now considered an independent risk factor for atherosclerotic vascular disease. The risk of cardiovascular disease rises in proportion to an individual's serum homocysteine concentrations. Some studies also suggest an independent role of folate deficiency in cardiovascular disease. The relationship between homocysteine and disease is not understood, but two mechanisms are the focus of current research. Homocysteine contains a reactive thiol group that can modify proteins and affect their function. Alternatively, homocysteine can also be converted to S -adenosylhomocysteine, which is a potent inhibitor of many methylation reactions that modify DNA proteins and influences gene expression. Either or both of these mechanisms may account for pathologies that are associated with elevated homocysteine in humans.

Dietary Recommendations

In 1998, the National Academy of Sciences released the Dietary Reference Intake (DRI) values for folate that include a recommended dietary allowance (RDA) of 400 micrograms for males and females aged fourteen years and younger. For these individuals, the source of folate is not important. However, it is recommended that women of childbearing age consume an additional 400 micrograms of folic acid per day from fortified foods and/or supplements in addition to the intake of food folate from a varied diet. It is critical that women be folate-sufficient prior to pregnancy, since most birth defects that result from folate deficiency occur before the twenty-ninth day of pregnancy, often before the woman realizes she is pregnant. Maintaining adequate folate status is especially critical for women with a history of bearing children with neural tube defects, to prevent future incidence of birth defects. Pregnant women should consume an additional 600 micrograms of synthetic folate per day in addition to a naturally folate-rich diet. It is not normally recommended that anyone consume more than 1 milligram of folate per day.

The RDA is expressed as dietary folate equivalents (DFEs) because synthetic folic acid is more easily absorbed in the intestine than naturally occurring folate. One microgram of naturally occurring food folate is equivalent to 0.6 microgram of folic acid from fortified foods or supplements consumed with meals and to 0.5 microgram of supplements not consumed with meals. Because of recent federal regulations for food fortification, synthetic folic acid can now be found not only in dietary supplements, but also in enriched grain products (0.43 to 1.4 micrograms of folic acid per pound grain product) such as flour and pasta. Initial results from the fortification program indicate that plasma folate levels have more than doubled among adults who do not use folic acid supplements. The effect of this program on reducing spina bifida and other folate-associated birth defects and pathologies is yet to be determined.

See also Fiber, Dietary ; Vegetables .

BIBLIOGRAPHY

Centers for Disease Control and Prevention. "Knowledge and Use of Folic Acid by Women of Childbearing Age—United States, 1997." Morbidity and Mortality Weekly Report 46, no. 31 (8 August 1997): 721–723.

Centers for Disease Control and Prevention. "Recommendations for the Use of Folic Acid to Reduce the Number of Cases of Spina Bifida and Other Neural Tube Defects." Morbidity and Mortality Weekly Report, 41 no RR–14 (11 September 1992).

Gregory, Jesse F. "The Bioavailability of Folate" In Folate in Health and Disease. Edited by Lynn B. Bailey. New York: M. Dekker, 1995.

Lindenbaum, John, and Robert H. Allen. "Clinical Spectrum and Diagnosis of Folate Deficiency" In Folate in Health and Disease. Edited by Lynn B. Bailey. New York: Marcel Dekker, 1995.

Shane, Barry. "Folate Chemistry and Metabolism." In Folate in Health and Disease. Edited by Lynn B. Bailey. New York: Marcel Dekker, 1995.

Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. "Dietary Reference Intakes: Folate, Other B Vitamins, and Choline." Washington, D.C., National Academy Press (7 April 1998).

Wagner, Conrad. "Biochemical Role of Folate in Cellular Metabolism" In Folate in Health and Disease. Edited by Lynn B. Bailey. New York: M. Dekker, 1995.

Patrick J. Stover

Folic acid

Definition

Folic acid is a water-soluble vitamin belonging to the B-complex group of vitamins . These vitamins help the body break down complex carbohydrates into simple sugars to be used for energy. Excess B vitamins are excreted from the body rather than stored for later use. This is why sufficient daily intake of folic acid is necessary.

Description

Folic acid is also known as folate or folacin. It is one of the nutrients most often found to be deficient in the Western diet. There is evidence that folate deficiency is a worldwide problem. Folic acid is found in leafy green vegetables, beans, peas and lentils, liver, beets, brussel sprouts, poultry, nutritional yeast, tuna, wheat germ, mushrooms, oranges, asparagus, broccoli, spinach, bananas, strawberries, and cantaloupes. In 1998, the U.S. Food and Drug Administration (FDA) required food manufacturers to add folic acid to enriched bread and grain products to boost intake. Pregnant women whose diets are deficient in folic acid have a greater chance of having a baby with neural tube defects (NTD), such as spina bifida .

General use

Folic acid works together with vitamin B₁₂ and vitamin C to metabolize protein in the body. It is important for the formation of red and white blood cells. It is also necessary for the proper differentiation and growth of cells in fetal development. It is also used to form the nucleic acid of DNA and RNA. It increases the appetite and stimulates the production of stomach acid for digestion, and it aids in maintaining a healthy liver. A deficiency of folic acid may lead to anemia, in which there is decreased production of red blood cells. This situation reduces the amounts of oxygen and nutrients that are able to get to the tissues. Symptoms may include fatigue, reduced secretion of digestive acids, confusion, and forgetfulness. During pregnancy, a folic acid deficiency may lead to preeclampsia, premature birth, and increased bleeding after birth.

Pregnant women have an increased need for folic acid, both for themselves and their unborn child. Folic acid is necessary for the proper growth and development of the fetus. Adequate intake of folic acid is vital for the prevention of several types of birth defects, particularly NTDs. The neural tube of the embryo develops into the brain, spinal cord, spinal column, and the skull. If this tube forms incompletely during the first few months of pregnancy, a serious, and often fatal, defect results in spina bifida or anencephaly (formation of the head without the brain). Folic acid, taken from one year to one month before conception through the first four months of pregnancy, can reduce the risk of NTDs by 50 to 70 percent. It also helps prevent cleft lip and palate .

Research shows that folic acid can be used to successfully treat cervical dysplasia. This condition is considered to be a possible precursor to cervical cancer and is diagnosed as an abnormal Pap smear. Daily consumption of 1,000 mcg of folic acid for three or more months has resulted in improved cervical cells upon repeat Pap smears.

Precautions

Folic acid is not stable. It is easily destroyed by exposure to light, air, water, and cooking. Therefore, the supplement should be stored in a dark container in a cold, dry place, such as a refrigerator. Many medications interfere with the body's absorption and use of folic acid. This includes sulfa drugs, sleeping pills, estrogen, anticonvulsants, birth control pills, antacids, quinine, and some antibiotics . Using large amounts of folic acid (e.g., over 5,000 mcg per day) can mask a vitamin B ₁₂ deficiency and thereby risk of irreversible nerve damage.

Side effects

At levels of 5,000 mcg or less, folic acid is generally safe for use. Side effects are uncommon. However, large doses may cause nausea , decreased appetite, bloating, gas, decreased ability to concentrate, and insomnia. Large doses may also decrease the effects of phenytoin (Dilantin), a seizure medication.

Parental concerns

Pregnant women or those thinking of becoming pregnant should ensure that that they get the recommended amount of folic acid daily. As with all B-complex vitamins, it is best to take folic acid with the other B vitamins. Vitamin C is important to the absorption and functioning of folic acid in the body.

KEY TERMS

Homocysteine —A sulfur-containing amino acid.

Preeclampsia —A condition that develops after the twentieth week of pregnancy and results in high blood pressure, fluid retention that doesn't go away, and large amounts of protein in the urine. Without treatment, it can progress to a dangerous condition called eclampsia, in which a woman goes into convulsions.

Recommended Dietary Allowance (RDA) —The Recommended Dietary Allowances (RDAs) are quantities of nutrients in the diet that are required to maintain good health in people. RDAs are established by the Food and Nutrition Board of the National Academy of Sciences, and may be revised every few years. A separate RDA value exists for each nutrient. The RDA values refer to the amount of nutrient expected to maintain good health in people. The actual amounts of each nutrient required to maintain good health in specific individuals differ from person to person.

Water-soluble vitamins —Vitamins that are not stored in the body and are easily excreted. They must, therefore, be consumed regularly as foods or supplements to maintain health.

To correct a folic acid deficiency, supplements are taken in addition to food. Since the functioning of the B vitamins is interrelated, it is generally recommended that the appropriate dose of B-complex vitamins be taken in place of single B vitamin supplements. The Recommended Dietary Allowances (RDA) for folate is 400 mcg per day for adults, 600 mcg per day for pregnant women, and 500 mcg for nursing women. Medicinal dosages of up to 1,000–2,000 mcg per day may be prescribed. Nearly all multivitamin formulations for women include the RDA for folic acid.

Resources

BOOKS

Folic Acid: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References. San Diego, CA: ICON Health Publications, 2004.

Heird, William C. "Nutritional Requirements." In Nelson Textbook of Pediatrics, 17th ed. Edited by Richard E. Behrman, et al. Philadelphia: Saunders, 2003, pp. 153–56.

Rock, Cheryl L. "Nutrition in the Prevention and Treatment of Disease." In Cecil Textbook of Medicine, 22nd ed. Edited by Lee Goldman, et al. Philadelphia: Saunders, 2003, pp. 1308–11.

Russell, Robert M. "Vitamin and Trace Mineral Deficiency and Excess." In Harrison's Principles of Internal Medicine, 15th ed. Edited by Eugene Braunwald et al. New York: McGraw Hill, 2001, pp. 461–69.

PERIODICALS

Allen, L. H. "Folate and vitamin B12 status in the Americas." Nutrition Reviews 62, no. 6, Pt. 2 (2004): 29–33.

Bailey, L. B. "Folate and vitamin B12 recommended intakes and status in the United States." Nutrition Reviews 62, no. 6, Pt. 2 (2004): S14–20.

Baro, L., et al. "The administration of a multivitamin/mineral fortified dairy product improves folate status and reduces plasma homocysteine concentration in women of reproductive age." International Journal of Vitamin and Nutritional Research 74, no. 3 (2004): 234–40.

Rockel, J. E., et al. "Folic acid fortified milk increases red blood cell folate concentration in women of childbearing age." Asia Pacific Journal of Clinical Nutrition 13, supplement (2004): S84–7.

ORGANIZATIONS

American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211–2672. Web site: <www.aafp.org/>.

American Academy of Pediatrics. 141 Northwest Point Boulevard, Elk Grove Village, IL 60007–1098. Web site: <www.aap.org/default.htm>.

American Association of Naturopathic Physicians. 8201 Greensboro Drive, Suite 300, McLean, VA 22102. Web site: <http://naturopathic.org/>.

American Heart Association. National Center, 7272 Greenville Avenue, Dallas, Texas 75231. Web site: <www.americanheart.org/Heart_and_Stroke_A_Z_Guide/heim.html>.

American Medical Association. 515 N. State Street, Chicago, IL 60610. Web site: <www.ama-assn.org/>.

American Osteopathic Association. 142 East Ontario Street, Chicago, IL 60611. Web site: <www.osteopathic.org/>

WEB SITES

"Folate (Folacin, Folic Acid)." Ohio State University Extension Fact Sheet. Available online at <http://ohioline.osu.edu/hyg-fact/5000/5553.html> (accessed November 18, 2004).

"Folic Acid." Centers for Disease Control and Prevention (CDC). Available online at <http://www.cdc.gov/node.do/id/0900f3ec80010af9> (accessed November 18, 2004).

"Folic Acid." March of Dimes. Available online at <www.marchofdimes.com/pnhec/173_769.asp> (accessed November 18, 2004).

L. Fleming Fallon Jr., MD, DrPH

Folic acid

Description

Folic acid is a water-soluable vitamin belonging to the B-complex group of vitamins. These vitamins help the body break down complex carbohydrates into simple sugars that can be readily used for energy. Excess B vitamins are excreted from the body rather than stored for later use. This is why sufficient daily intake of folic acid is necessary.

Folic acid is also known as folate, or folacin. It is one of the nutrients most often found to be deficient in the Western diet, and there is evidence that deficiency is a problem worldwide. Folic acid is found in leafy green vegetables, beans, peas and lentils, liver, beets, Brussels sprouts, poultry, nutritional yeast, tuna, wheat germ , mushrooms, oranges, asparagus, broccoli, spinach, bananas, strawberries, and cantaloupes. In 1998, the U.S. Food and Drug Administration (FDA) required food manufacturers to add folic acid to enriched bread and grain products, to boost intake and to help prevent neural tube defects (NTD) in the fetus during pregnancy .

General use

Folic acid works together with vitamin B₁₂ and vitamin C to metabolize protein. It is important for the formation of red and white blood cells. Folic acid is necessary for the proper differentiation and growth of cells, and for the development of the fetus. It is also used to form the nucleic acid of DNA and RNA. It increases the appetite, stimulates the production of stomach acid for digestion, and aids in maintaining a healthy liver. A folic acid deficiency may lead to megaloblastic anemia , in which there is decreased production of red blood cells, and the cells that are produced are abnormally large. This reduces the amounts of oxygen and nutrients that are able to reach the tissues. Symptoms may include fatigue , reduced secretion of digestive acids, confusion, and forgetfulness. During pregnancy, a folic acid deficiency may lead to preeclampsia, premature birth, and increased bleeding after birth.

People who are at high risk for strokes and heart disease may benefit from folic acid supplements. An elevated blood level of the amino acid homocysteine has been identified as a risk factor for some of these diseases. High levels of homocysteine have also been found to contribute to problems with osteoporosis . Folic acid, together with vitamins B₆ and B₁₂, aids in the breakdown of homocysteine, and may help reverse the problems associated with elevated levels.

Pregnant women have an increased need for folic acid, both for themselves and their unborn child. Folic acid is necessary for the proper growth and development of the fetus. Adequate intake of folic acid is vital for the prevention of several types of birth defects, particularly neural tube defects (NTDs). The neural tube of the embryo develops into the brain, spinal cord, spinal column, and the skull. If this tube forms incompletely during the first few months of pregnancy, a serious—and often fatal—defect such as spina bifida or anencephaly, may occur. Folic acid, taken from one year to one month before conception through the first four months of pregnancy, can reduce the risk of NTDs by 50–70%. It also helps prevent cleft lip and palate.

Research shows that folic acid can be used to successfully treat cervical dysplasia , a condition that is diagnosed by a Pap smear, and consists of abnormal cells in the cervix. This condition is considered to be a possible precursor to cervical cancer . Daily consumption of 1,000 micrograms (mcg) of folic acid for three or more months has resulted in improved cervical cells upon repeat Pap smears.

Studies suggest that long-term use of folic acid supplements may also help prevent lung and colon cancers. Researchers have also found that alcoholics who have low folic acid levels face a greatly increased chance of developing colon cancer.

Preparations

Supplements are taken to correct a folic acid deficiency. Since the functioning of the B vitamins is interrelated, it is generally recommended that the appropriate dose of B-complex vitamins be taken in place of single B vitamin supplements. The Recommended Dietary Allowance (RDA) for folate is 400 mcg per day for adults, 600 mcg per day for pregnant women, and 500 mcg daily for nursing women. Medicinal dosages of up to 1,000 to 2,000 mcg per day may be prescribed.

Precautions

Folic acid is not stable. It is easily destroyed by exposure to light, air, water, and cooking. Therefore, the supplement should be stored inside a dark container in a cold, dry place, such as a refrigerator. Many medications interfere with the body's absorption and ability to use folic acid. These medications include sulfa drugs, sleeping pills, estrogen, anti-convulsants, birth control pills, antacids, quinine, and some antibiotics.

The anemia caused by folic acid deficiency is identical to that caused by lack of vitamin B₁₂. Using large amounts of folic acid (e.g., over 5,000 mcg per day) can mask a vitamin B₁₂ deficiency, since the anemia will improve but the other effects of vitamin B₁₂ deficiency will continue. This can lead to irreversible nerve damage. Therefore, people with megaloblastic anemia should be treated under medical supervision, since regular testing may be required.

Side effects

Folic acid is generally considered safe at levels of 5,000 mcg or less. Side effects are uncommon. However, large doses may cause nausea , decreased appetite, bloating, gas , decreased ability to concentrate, and insomnia . Large doses may also decrease the effects of phenytoin (Dilantin), a seizure medication.

Interactions

As with all B-complex vitamins, it is best to take folic acid with the other B vitamins. Vitamin C is important to the absorption and functioning of folic acid in the body.

Resources

BOOKS

Braverman, Eric R., M.D., Carl C. Pfeiffer, M.D., Ph.D., Ken Blum, Ph.D., and Richard Smayda, D.O. The Healing Nutrients Within. New Canaan, CT: Keats Publishing, 1997.

PERIODICALS

Fallest-Strobl, Patricia, Ph.D., David Koch, James Stein, and Patrick McBride. "Homocysteine: A New Risk Factor for Atherosclerosis." American Family Physician (October 15, 1997): 1607-14.

ORGANIZATIONS

Centers for Disease Control and Prevention. 4770 Buford Highway NE, MSF-45, Atlanta, GA 30341-3724. (888) 232-6789. [email protected]. <http://www.cdc.gov/nceh/programs/cddh/folic/folicfaqs.htm>.

OTHER

Adams, Suzanne L. The Art of Cytology: Folic Acid/B-12 Deficiency [cited June 6, 2004]. <http://www.concentric.net/~Suza2/page22.htm>.

"Folic Acid." Cybervitamins [cited June 6, 2004]. <http://www.cybervitamins.com/folicacid.htm>.

"Folic Acid: Coming to A Grocery Store Near You" [cited June 6, 2004]. <http://www.mayohealth.org/mayo/9710/htm/folic.htm>.

"Folic acid (oral/injectible)." Dr. Koop.com. Inc. 700 N. Mopac, Suite 400, Austin, TX 78731. <http://www.drkoop.com/hcr/drug-store/pharmacy/leaflets/english/d00241a1.asp>.

Pregnancy and Nutrition Update. MayoHealth [cited June 6, 2004]. <http://www.mayohealth.org/mayo/9601/htm/pregvit.htm>.