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Folic Acid | | |
Folic acid, a member of the family of B-Complex vitamins, is the preferred
term for the vitamin present in foods which represents a mixture of
related compounds (folates). Among some of its more crucial functions are
protein and DNA synthesis as well as health red blood cell production.
Because of the vital role that folic acid plays in human development, it
has become widely publicized how additional folic acid should be taken by
pregnant women to avoid birth defects and to ensure proper, health fetal
development. Studies have shown that neuro tube defects (NTD's) can be
reduced by the intake of folic acid before and during pregnacy. Further
studies have demonstrated how folic acid, present in dark green leafy
vegetables, can reduce the risk of cardiovascular disease and cancer.
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| Common Name | | | Folic Acid
| | | Other Names | | | Vitamin B-9, Folate, Pteroylglutamic Acid, Folacin-800 (The Key
Company), FA-8 (Bio Tech Pharmacal).
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| | | Description | | | Folic acid is a water-soluble vitamin of the vitamin B complex family. It
is the parent compound for a large number of derivatives collectively
known as folates. Folate is the generic term used to describe the
compounds that exhibit the biological activity of folic acid; it is the
preferred term for the vitamin present in foods which represents a mixture
of related compounds (folates).
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| | | Daily Requirements | | | The U.S. RDA for folic acid, the value used for nutritional supplement and
food labeling purposes, is 400 micrograms/day.
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| | | Traditional Internal Uses | | | Folic acid works along with vitamin B-12 and vitamin C to help the body
digest and utilize proteins and to synthesize new proteins when they are
needed. It is necessary for the production of red blood cells and for the
synthesis of DNA (which controls heredity and is used to guide the cell in
its daily activities).
Folic acid also helps with tissue growth and
cell function. In addition, it helps to increase appetite when needed and
stimulates the formation of digestive acids.
Synthetic folic acid
supplements may be used in the treatment of disorders associated with
folic acid deficiency and may also be part of the recommended treatment
for certain menstrual problems and leg ulcers.
Most people in the
United States have an adequate dietary intake of folic acid because it is
plentiful in the food supply. However, pregnant women often require
additional supplementation as prescribed by a health care provider.
Adequate folic acid is important for pregnant women because it has been
shown to prevent some kinds of birth defects, including neural tube
defects such as spina bifida. Many foods are now fortified with folic acid
to help prevent these kinds of birth defects.
Women in their
childbearing years should make an effort to consume foods that are good
sources of folic acid. Studies published by the Centers for Disease
Control and Prevention (CDC) suggest that women who receive supplements of
folic acid BEFORE CONCEPTION may reduce the risk for neural tube defects
by 50%. Women who plan to become pregnant may want to discuss taking a
multivitamin with their health care provider.
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| | | Indications | | | Vitiligo
Primary Indications: Tissue Health / Elasticity, Cellular Health, Indigestion, Blood Dyscrasias (Blood Cell Disorders), DNA / RNA, Genome Integrity / Gene Expression, Pregnancy, Birth Defect Prevention, Anemia (Iron Deficiency), Nervous System / Nervous Disorders, Cardiovascular Disorders, Prenatal Development, Folic Acid Deficiency
Secondary Indications: Menstruation Problems, Ulcers, Depression, Cancer / Cancer Prevention
Primary Indications: Appetite (Increased or Decreased)
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| | | Actions | | | Protein Synthesizing
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| | | Pharmacological Summary | | | There is good evidence that folic acid reduces the risk of neural tube
defects, and supplementation is recommended preconceptually and during the
first 12 weeks of pregnancy. There is increasing evidence that folic acid
reduces elevated plasma homocysteine levels, a risk factor for
cardiovascular disease. Epidemiological studies have shown an inverse
relationship between serum folate levels and colon cancer. Poor folate
status has also been demonstrated in some people with depression. However,
controlled trials are required to determine whether supplements can reduce
the risk of cancer and help to treat depression.
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| | | Dietary Sources | | | Natural folates are found in dark green leafy vegetables (spinach, kale,
mustard greens, turnip greens, escarole, chard, arugula, beet greens, bok
choy, dandelion green, mache, radicchio, rapini or broccoli de rabe, Swiss
chard), oranges, lentils, pinto beans, garbanzo beans, asparagus, orange
juice, broccoli, cauliflower, liver and brewer's yeast. The absorption
efficiency of natural folates is approximately 50% that of folic acid.
Interestingly, folate was named because of its presence in green leafy
vegetables (folium is Latin for leaf) and was originally isolated from
four tons of spinach, such was the crudity of isolation techniques more
than seven decades ago.
Additional sources include beans and
legumes, citrus fruits and juices, wheat bran and other whole grains,
poultry, pork, shellfish, liver
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| | | Metabolism | | | Absorption: Absorption of folate takes place mainly in the
jejunum.
Distribution: Folate is stored mainly in the liver.
Enterohepatic recycling is important for maintaining serum
levels.
Elimination: Excretion of folate is largely renal,
but folates may also be eliminated in the faeces (mainly as a result of
folate synthesis by the gut microflora). Folates are also found in breast
milk.
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| | | Scientific Research and Pharmacologicial Actions | | | Pregnancy and Pre-Pregnancy
The risk of neural tube defects
(NTDs) can be reduced by increased folic acid intake during the
periconceptual period.(1-5) Such studies have given rise to
recommendations in several countries that women intending to become
pregnant should consume additional folic acid. The reason for the
beneficial effect of folic acid is unclear. Although it may be a result of
deficiency, a genetic defect in the methylene tetrahydrofolate reductase
(MTHFR) gene, estimated to occur in about 5 to 15% of white populations,
appears to result in an increased requirement for folates and an increased
risk of recurrent early pregnancy loss and NTDs.(6,7) In addition,
elevated levels of plasma homocysteine have been observed in mothers
producing offspring with NTDs,(8) and the possibility that this factor
could have toxic effects on the fetus at the time of neural tube closure
is currently under further investigation.
Cardiovascular
Disease
Marginal folate status is also associated with elevated
plasma homocysteine levels, an emerging risk factor for cardiovascular
disease mortality.(9-11) Mechanisms by which plasma homocysteine may be
associated with increased risk of cardiovascular disease have not been
clearly established, but possibilities include:(12)- Oxidative
damage to the vascular endothelium;
- Inhibition of endothelial
anticoagulant factors, resulting in increased clot
formation;
- Increased platelet aggregation;
- Proliferation
of smooth muscle cells, resulting in increased vulnerability of the
arteries to obstruction.
Homocysteine is derived from dietary
methionine, and it is removed by conversion to cystathionine, cysteine and
pyruvate, or by remethylation to methionine. Rare inborn errors of
metabolism can cause severe elevations in plasma homocysteine levels. One
example is homocystinuria, which occurs as a result of a genetic defect in
the enzyme cystathione beta synthase. Genetic changes in the enzymes
involved in the remethylation pathway, including MTHFR and methionine
synthase, are also associated with increase in plasma homocysteine
concentrations. All such cases are associated with premature vascular
disease, thrombosis and early death.
Such genetic disorders are,
however, rare and cannot account for the raised homocysteine levels
observed in many patients with cardiovascular disease. However, attention
is now being given to the possibility that deficiency of the various
vitamins which act as co-factors for the enzymes involved in homocysteine
metabolism could result in increased homocysteine concentrations. In
particular, folate is required for the normal function of MTHFR, vitamin
B12 for methionine synthase and vitamin B6 for cystathione beta
synthase.
In theory, lack of any one of these three vitamins could
cause hyperhomocysteinaemia, and could therefore increase the risk of
cardiovascular disease. In the Framingham Heart Study,(13) the longest
observed cohort study on vascular disease, it was shown that folic acid,
vitamin B6 and vitamin B12 are determinants of plasma homocysteine levels,
with folic acid showing the strongest association.
The question of
whether increased vitamin intake can reduce cardiovascular risk was
examined in the Nurses' Health Study,(14) which showed that those with the
highest intake of folate had a 31% lower incidence of heart disease than
those with the lowest intake. For vitamin B6, those with the highest
intake had a 33% lower risk of heart disease, while in those with the
highest intake of both folate and vitamin B6 the risk of heart disease was
reduced by 45%. The risk of heart disease was reduced by 24% in those who
regularly used multivitamins.
Another question is whether
homocysteine levels can be lowered with folate and other B vitamins. Folic
acid (250 ęg daily), in addition to usual dietary intakes of folate,
significantly decreased plasma homocysteine concentrations in healthy
young women,(15) and breakfast cereal fortified with folic acid reduced
plasma homocysteine in men and women with coronary artery disease.(16)
Another study has demonstrated that the addition of vitamin B12 to folic
acid supplements or enriched foods (400 ęg folic acid daily) maximises the
reduction of homocysteine.(17) Furthermore, two meta-analyses(18,19)
suggest that administration of folic acid reduces plasma homocysteine
concentrations and that vitamin B12, but not vitamin B6, may have an
additional effect.(19)
Unfortunately, a definitive answer to the
most important question - can reducing homocysteine reduce cardiovascular
disease - does not yet exist due to the lack of published data. However,
more data should be available during the next few years from at least six
studies which are currently underway. These are designed to examine the
role of folate and other B vitamins in reducing cardiovascular
events.
Cancer
Marginal folate status also appears to
be associated with certain cancers,(20) notably colon cancer, although it
is at present unclear as to whether it is folate or some other nutritional
factors that could be involved. Data, including those from two prospective
studies,(21,22) and four case-control studies(23-26) indicate that an
inadequate intake of folate may increase risk of colon cancer. There is
also some evidence - albeit limited - that use of supplements containing
folic acid could reduce the risk of colon cancer.(27,28)
Mental
Disorders
There is an apparent increase in mental disorders
associated with reduced folate status.(29) Recent studies have found that
Alzheimer's disease is associated with low blood levels of folate and
vitamin B12 and elevated homocysteine levels.(30,31) However, whether this
reduced vitamin status is a cause of the disease or occurs as a result of
having the disease, is unknown.
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| | | Research | | | "Folic Acid Boost Could Save 50,000 Lives A Year"
"Folic Acid Now: Before You Know You're Pregnant"
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| | | Precautions / Contraindications | | | Women of childbearing age, pregnant women and nursing mothers should
ensure that their intake of folic acid from nutritional supplements and/or
fortified food is 400 micrograms/day. A number of pre- and postnatal
supplements deliver 1 milligram (1,000 micrograms) daily of folic acid.
Doses higher than 1 milligram/day should only be used by the above groups
if prescribed by their physicians.
The use of folic acid for the
treatment of folate deficiency or for the treatment of any medical
condition requires medical supervision.
The use of folic acid doses
above 1 milligram/day may precipitate or exacerbate the neurological
damage of vitamin B12 deficiency. Those who use folic acid doses above 1
milligram/day should only do so under medical supervision.
Those
with undiagnosed anemia, should exercise caution in the use of
supplementary folic acid. Doses of folic acid greater than 100 micrograms
daily may result in hematologic improvement in those with vitamin B12
deficiency. In pernicious anaemia, folic acid will correct the
haematological abnormalities, but neuropathy may be precipitated. Doses of
folic acid >400 micrograms daily are not recommended until pernicious
anaemia has been ruled out.
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| | | Interaction with Medications | | | Drugs
Anticonvulsants: Requirements for folic
acid may be increased, but concurrent use of folic acid may antagonise the
effects of anticonvulsants; an increase in anticonvulsant dose may be
necessary in patients who receive supplementary folic acid (monitoring
required).
Antibiotics: May interfere with the
microbiological assay for serum and erythrocyte folic acid (falsely low
results).
Colestyramine: May reduce the absorption of
folic acid; patients on prolonged colestyramine therapy should take a
folic acid supplement 1 hour before colestyramine
administration.
Methotrexate: Acts as a folic acid
antagonist; the risk is significant with high dose and/or prolonged use
(folinic acid instead of folic acid should be
used).
Oestrogens (including oral contraceptives):
May reduce blood levels of folic acid.
Pyrimethamine:
Acts as a folic acid antagonist; the risk is significant with high dose
and/or prolonged use; folic acid supplements should be given in
pregnancy.
Sulfasalazine: May reduce the absorption
of folic acid; requirements for folic acid may be
increased.
Trimethoprim: Acts as a folic acid
antagonist; the risk is significant with high dose and/or prolonged
use.
Nutrients
B Vitamins: Adequate
amounts of all B vitamins are required for optimal functioning; deficiency
or excess of one B vitamin may lead to abnormalities in the metabolism of
another.
Zinc: Folic acid may reduce the absorption
of zinc.
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| | | Possible Side Effects | | | Folic acid is generally considered to be safe even in high doses, but it
may lead to convulsions in patients taking anticonvulsants and may also
precipitate neuropathy in pernicious anaemia. Some gastrointestinal
disturbance and altered sleep pattern has been reported at doses of 15 mg
daily. Allergic reactions (shortness of breath, wheezing, fever, erythema,
skin rash, itching) have been reported rarely.
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| | | Deficiency | | | Folate deficiency results in reduction of DNA synthesis and hence in
reduction of cell division. While DNA synthesis occurs in all dividing
cells, deficiency is most easily seen in tissues with high rates of cell
turnover such as erythrocytes (red blood cells). The main clinical
observation associated with folate deficiency is, therefore, megaloblastic
anaemia.
The main causes of folate deficiency are as
follows:
Decreased dietary intake. This occurs in people eating
inadequate diets, such as some elderly people, those on low incomes, and
alcoholics who substitute alcoholic drinks for good sources of
nutrition.
Decreased intestinal absorption. Patients with disorders
of malabsorption (e.g. coeliac disease) may suffer folate
deficiency.
Increased requirements. Increased requirement for
folate, and hence an increased risk of deficiency, can occur in pregnancy,
during lactation, in haemolytic anaemia and leukaemia.
Alcoholism.
Chronic alcoholism is a common cause of folate deficiency. This may occur
as a result of poor dietary intake, reduced absorption or increased
excretion by the kidney. The presence of alcoholic liver disease increases
the likelihood of folate deficiency.
Long-term use of certain drugs
(e.g. phenytoin, sulfasalazine) is associated with folate
deficiency.
Signs and symptoms include megaloblastic, macrocytic
anaemia; weakness, tiredness, irritability, forgetfulness, dyspnoea,
anorexia, diarrhoea, weight loss, headache, syncope, palpitations and
glossitis. In babies and young children, growth may be affected.
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| | | Dosage | | | Folic acid is available in the form of tablets.
For prevention of
first occurrence of NTDs in women who are planning a pregnancy, oral, 400
micrograms daily before conception until 12th week of
pregnancy.
For prevention of recurrence of NTDs, oral, 5 mg daily
before conception until 12th week of pregnancy.
For prophylaxis
during pregnancy (after 12th week), oral, 200-500 micrograms
daily.
As a dietary supplement, oral, 100-500 micrograms daily.
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| | | References | | | 1. Laurence KM, James N, Miller MH, et al. Double-blind randomised
controlled trial of folate treatment before conception to prevent
recurrence of neural tube defects. Br Med J 1981; 282: 1509-1511.
2. Smithells RW, Seller MJ, Harris R, et al. Further experience of
vitamin supplementation for prevention of neural tube defect recurrences.
Lancet 1983; 1: 1027-1031.
3. Medical Research Council Vitamin Study Research Group. Prevention of
neural tube defects: Results of the Medical Research Council Vitamin
Study. Lancet 1991; 338: 131-137.
4. Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube
defects by periconceptual vitamin supplementation. N Engl J Med 1992; 327:
1832-1835.
5. Weller MM, Shapiro S, Mitchel AA, et al. Periconceptual folic acid
exposure and risk of occurrent neural tube defects. JAMA 1993; 269:
1257-1261.
6. Molloy AM, Daly S, Mills JL, et al. Thermolabile variant of
5,10-methylenetetrahydrofolate reductase associated with low red cell
folates: Implications for folate intake recommendations. Lancet 1997; 349:
1591-1593.
7. Nelen WLDM, Van der Molen EF, Blom HJ, et al. Recurrent early
pregnancy loss and genetic related disturbances in folate and homocysteine
metabolism. Br J Hosp Med 1997; 58: 511-513.
8. Mills JL, McPartlin P, Kirke PM, et al. Homocysteine metabolism in
pregnancies complicated by neural tube defects. Lancet 1995; 345:
149-151.
9. Alfthan G, Aro A, Gey KF. Plasma homocysteine and
cardiovascular disease mortality. Lancet 1997; 349: 397.
10. Nygard O, Nordrehaug JE, Refsum H, et al. Plasma homocysteine levels
and mortality in patients with coronary artery disease. N Engl J Med 1997;
337: 230-236.
11. Wald NJ, Watt HC, Law MR, et al. Homocysteine and ischaemic heart
disease: Results of a prospective study with implications on prevention.
Arch Intern Med 1998; 158: 862-867.
12. Weir DG, Scott JM. Homocysteine as a risk factor for cardiovascular
and related disease: Nutritional implications. Nutr Res Rev 1998; 11:
311-338.
13. Selhub J, Jacques PF, Wilson PWF, et al. Vitamin status and intake as
primary determinants of homocysteinaemia in an elderly population. JAMA
1993; 270: 2693-2698.
14. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and
supplements in relation to risk of coronary heart disease among women.
JAMA 1998; 279: 359-364.
15. Brouwer IA, van Dusseldorp M, Thomas CMG, et al. Low-dose folic acid
supplementation decreases plasma homocysteine concentrations: A randomized
trial. Am J Clin Nutr 1999; 69: 99-104.
16. Malinow MR, Duell PB, Hess DL, et al. Reduction of plasma homocysteine
levels by breakfast cereal fortified with folic acid in patients with
coronary heart disease. N Engl J Med 1998; 338: 1009-1015.
17. Bronstrup A, Hages M, Prinz-Langenohl R, Pietrzik K. Effects of folic
acid and combinations of folic acid and vitamin B-12 on plasma
homocysteine concentrations in healthy young women. Am J Clin Nutr 1998;
68: 1104-1110.
18. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative
assessment of plasma homocysteine as a risk factor for vascular disease:
probable benefits of increasing folic acid intake. JAMA 1995; 274:
1049-1057.
19. Homocysteine Lowering Trialists' Collaboration. Lowering blood
homocysteine with folic acid based supplements: meta-analysis of
randomised trials. Br Med J 1998; 316: 894-898.
20. Mason JB. Folate status: Effects on carcinogenesis In: Bailey LB, eds.
Folates in Health and Disease. New York: Marcel Dekker, 1995: 361-378.
21. Giovannucci E, Rimm EB, Ascherio A, et al. Alcohol, low methionine,
low folate diets and risk of colon cancer in men. J Natl Cancer Inst 1995;
87: 265-273.
22. Glynn SA, Albanes D, Pietinen P, et al. Colorectal cancer and folate
status: a nested case-control study among male smokers. Cancer Epidemiol
Biomarkers Prev 1996; 5: 487-494.
23. Benito E, Stigglebout A, Bosch FX, et al. Nutritional factors in
colorectal cancer risk: A case-control study in Majorca. Int J Cancer
1991; 49: 161-167.
24. Meyer F, White E. Alcohol and nutrients in relation to colon cancer in
middle-aged adults. Am J Epidemiol 1993; 138: 225-236.
25. Ferraroni M, La Vecchia C, D'Avanzo B, et al. Selected micronutrient
intake and the role of colon cancer. Br J Cancer 1994; 70: 1150-1155.
26. Freudenheim JL, Graham S, Marshall JR, et al. Folate intake and
carcinogenesis of the colon and rectum. Int J Epidemiol 1991; 20:
368-374.
27. White E, Shannon JS, Patterson RE. Relationship between
vitamin and calcium supplement use and colon cancer. Cancer Epidemiol
Biomarkers Prev 1997; 6: 769-774.
28. Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use,
folate and colon cancer in women in the nurses' health study. Ann Intern
Med 1998; 129: 517-524.
29. Bottiglieri ET, Crellin RF, Reynolds EH. Folates and neuropsychiatry
In: Bailey LB, ed. Folates in Health and Disease. New York: Marcel Dekker,
1995: 435-462.
30. Joosten E, Lesaffre E, Riezler R, et al. Is metabolic evidence for
vitamin B12 and folate deficiency more frequent in elderly patients with
Alzheimer's disease? J Gerontol A Biol Sci Med 1997; 52: M76-M79.
31. Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12 and serum
homocysteine levels in confirmed Alzheimer's disease. Arch Neurol 1998;
11: 1449-1455.
Our thanks to the following information
resources: Medicinescomplete.com, and PDRHealth.com.
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These statements have not been evaluated by the Food and Drug Administration (FDA). Products are intended to support general well being and are not intended to treat, diagnose, mitigate, prevent, or cure any condition or disease. If conditions persist, please seek advice from your medical doctor.
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