Folic Acid - Health Issues

Health issues

[edit]Human reproduction

Adequate folate intake during the periconception period, the time right before and just after a woman becomes pregnant, helps protect against a number of congenital malformations, including neural tube defects (which are the most notable birth defects that occur from folate deficiency).^[35] Neural tube defects produce malformations of the spine, skull, and brain including spina bifida and anencephaly. The risk of neural tube defects is significantly reduced when supplemental folic acid is consumed in addition to a healthy diet prior to and during the first month following conception.^[36][37] Supplementation with folic acid has also been shown to reduce the risk of congenital heart defects, cleft lips,^[38] limb defects, and urinary tract anomalies.^[39] Folate deficiency during pregnancy may also increase the risk of preterm delivery, infant low birth weight and fetal growth retardation, as well as increasing homocysteine level in the blood, which may lead to spontaneous abortion and pregnancy complications, such as placental abruption and pre-eclampsia.^[40] Women who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risk of serious birth defects.^[41] Taking 400 micrograms of synthetic folic acid daily from fortified foods and/or supplements has been suggested. The RDA for folate equivalents for pregnant women is 600–800 micrograms, twice the normal RDA of 400 micrograms for women who are not pregnant.^[42] The mechanisms and reasons why folic acid prevents birth defects is unknown.^[43] It is hypothesized that the insulin-like growth factor 2 gene is differentially methylated and these changes in IGF2 result in improved intrauterine growth and development.^[43] Approximately 85% of women in an urban Irish study reported using folic acid supplements before they become pregnant, but only 18% used enough folic acid supplements to meet the current folic acid requirements due, reportedly, to socio-economic challenges.^[44] Folic acid supplements may also protect the fetus against disease when the mother is battling a disease or taking medications or smoking during pregnancy.^[45]

Folic acid may also reduce chromosomal defects in sperm.^[46] A benefit is indicated even for more than 700 mcg folate per day, which, though below the tolerable upper intake levels of 1,000 µg/day, was 1.8 times the recommended dietary allowance.^[46]

[edit]Heart disease

An estimated 13,500 deaths occur annually due to folate deficiency's effect on coronary artery disease and the risk of ischemic heart disease, and stroke has been reduced by 15% since folate fortification regulations were enforced.^[47] Adequate concentrations of folate, vitamin B₁₂, or vitamin B₆ may decrease the circulating level of homocysteine, an amino acid normally found in blood. There is evidence an elevated homocysteine level is an independent risk factor for heart disease and stroke.^[48] The evidence suggests high levels of homocysteine may damage coronary arteries or make it easier for blood platelets to clump together and form a clot.^[49] However, there is currently no evidence available to suggest lowering homocysteine with vitamins will reduce risk of heart disease. The NORVIT trial suggests folic acid supplementation may do more harm than good.^[50]

As of 2006, studies have shown giving folic acid to reduce levels of homocysteine does not result in clinical benefit. One of these studies suggests folic acid in combination with B₁₂ may even increase some cardiovascular risks.^[51][52][53]

However, a 2005 study found 5 mg of folate daily over a three-week period reduced pulse pressure by 4.7 mmHg compared with a placebo, and concluded^[54] folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension.

Also, as a result of new research, "heart experts" at Johns Hopkins Medical Center reported in March 2008^[55] in favour of therapeutic folate, although they cautioned that it is premature for people to begin to self-medicate by taking high doses of folic acid."

Hyperhomocysteinemia is a predictor of cardiovascular disease and hypertension among children and folic acid is a safe and effective supplement because it reduces serum homocysteine levels as well as systolic and diastolic blood pressure, thus preventing cardiovascular disease in children.^[56]

Folic acid supplements may improve the integrity of the vascular endothelium.^[57] Folic acid supplements consumed before and during pregnancy may reduce the risk of heart defects in infants,^[58] and may reduce the risk for children to develop metabolic syndrome.^[59] Thet may, however, worsen the outcomes in patients with cardiovascular disease such as angina and myocardial infarction.^[60]

[edit]Stroke

Folic acid appears to reduce the risk of stroke. The reviews indicate the risk of stroke appears to be reduced only in some individuals, but a definite recommendation regarding supplementation beyond the current RDA has not been established for stroke prevention.^[61] Observed stroke reduction is consistent with the reduction in pulse pressure produced by folate supplementation of 5 mg per day, since hypertension is a key risk factor for stroke. Folic supplements are inexpensive and relatively safe to use, which is why stroke or hyperhomocysteinemia patients are encouraged to consume daily B vitamins including folic acid.^[62]

[edit]Cancer

Folate deficiency decreases intracellular S-adenosylmethionine (SAM), which inhibits cytosine methylation in DNA, activates proto-oncogenes, induces malignant transformations, causes DNA precursor imbalances, misincorporates uracil into DNA, and promotes chromosome breakage; all of these mechanisms increase the risk of prostate cancer development.^[63]

The association between folate and cancer appears to be complex and mixed.^[64] There are theoretical reasons that folate may help prevent cancer,^[65] and a meta-analysis published in 2010 failed to find a statistically significant cancer risk due to folic acid treatments,^[66] but a 1995 study found supplementationincreases rates of cancer.^[11]

Some investigations have proposed good levels of folic acid may be related to lower risk of esophageal, stomach, and ovarian cancers, but the benefits of folic acid against cancer may depend on when it is taken and on individual conditions. In addition, folic acid may not be helpful, and could even be damaging, in people already suffering from cancer or from a precancerous condition. Likewise, it has been suggested excess folate may promote tumor initiation.^[67] Folate has shown to play a dual role in cancer development;low folate intake protects against early carcinogenesis, and high folate intake promotes advanced carcinogenesis.^[68] Therefore, public health recommendations should be careful not to encourage too much folate intake.^[68]

Diets high in folate are associated with decreased risk of colorectal cancer; some studies show the association is stronger for folate from foods alone than for folate from foods and supplements,^[69] while other studies find that folate from supplements is more effective due to greater bioavailability.^[70] A 2007 randomized clinical trial found folate supplements did not reduce the risk of colorectal adenomas, and in fact increase the presence of advanced lesions and adenoma multiplicity.^[71] Colorectal cancer is the most studied type of cancer in relation to folate and one carbon metabolism. For example, folic acid supplement intake increased advanced colorectal cancer development by 67% in a 14-year European research study involving 520,000 men.^[72]

A 2006 prospective study of 81,922 Swedish adults found diets great in folate from foods, but not from supplements, were associated with a reduced risk of pancreatic cancer.^[73]

Most epidemiologic studies suggest diets high in folate are associated with decreased risk of breast cancer, but results are not uniformly consistent. One broad cancer screening trial reported a potential harmful effect of much folate intake on breast cancer risk, suggesting routine folate supplementation should not be recommended as a breast cancer preventive,^[74] but a 2007 Swedish prospective study found much folate intake was associated with a lower incidence of postmenopausal breast cancer.^[75] A 2008 study has shown no significant effect of folic acid on overall risk of total invasive cancer or breast cancer among women.^[76]Folate intake may not have any effect on the risk of breast cancer but may have an effect for women who consume at least 15 g/d of alcohol.^[77] Folate intake of more than 300 µg/d may reduce the risk of breast cancer in women who consume alcohol.^[77]

Most research studies associate high dietary folate intake with a reduced risk of prostate cancer;^[72]however, in men, folic acid supplementation appears to double the risk of prostate cancer.^[78] Recently, aclinical trial showed daily supplementation of 1 mg of folic acid increased the risk of prostate cancer, whiledietary and plasma folate levels among vitamin nonusers actually decreased the risk of prostate cancer.^[26]A Finnish study consisting of 29,133 older male smokers observed prostate cancer risk had no relationship with serum folate levels.^[7]

The reason high levels of folic acid may increase cancer is because of its role in nucleotide synthesis (proliferating neoplastic cells need this and folate receptors are increased in cancers).^[26] Folate's role inDNA methylation is important in prostate cancer.^[26] Unmetabolized folic acid is associated with a reduction in natural killer cell cytotoxicity, which reduces the immune system's ability to defend against malignant cells.^[26] However, the study also showed dietary baseline intake of folate may have an inverse relationship to prostate cancer occurrence.

Although the relationship between folate and prostate cancer is not yet clear, suicide gene studies show a target vector for folate to prostate and nasopharyngeal cancer cells.^[79] Growth of tumor cells is significantly inhibited when a folate-linked nanoparticle is injected intratumorally.^[79] The mechanism might be the interference of transfection and communication failures of intracellular gap junctions.^[79]

The cancer drug methotrexate is designed to inhibit the metabolism of folic acid. Folic acid may interact unexpectedly with the cancer drug fluorouracil. The exact mechanism of interaction is unknown.^[80]

The low dihydrofolate reductase activity in the liver of humans compared to other animals and so the low conversion of folic acid into its active derivatives might be due to the control of this enzyme by transcription factors, such as E2F-1 involved in cell proliferation. It has been suggested "the low level of DHFR, and the other proteins under the control of E2F-1, in humans may have evolved to hinder the development of cancer. If this is the case, other animals with slow tissue turnover rates, possibly related to long life span, might also have low DHFR activity."^[6]

Folic acid supplements prevent mistakes (inserting uracils into the DNA, for example) from occurring during DNA replication and repair.^[81] This is a proposed mechanism for folic acid's protection against colorectal cancer.^[81]

Folic acid supplements stimulate the PI3k/Akt signaling cascade, which leads to improved cell survival, but this could be beneficial or harmful for the body because cancer cells may use this pathway to survive.^[82]Folic acid may also reduce the levels of PTEN (a tumor suppressor gene), making this relationship even more controversial.^[82]

Additionally, low amounts of folate may increase lung cancer risk, as evidenced in an epidemiological study that have suggested a relationship between low folate status and lung cancer. One such study suggested that folic acid combined with vitamin B12 reduced evidence of atypical bronchial squamous metaplasia in smokers.^{[citation needed]}

[edit]Antifolates

Folate is important for cells and tissues that rapidly divide.^[25] Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. The antifolate methotrexate is a drug often used to treat cancer because it inhibits the production of the active form of THF from the inactive dihydrofolate (DHF). However, methotrexate can be toxic,^[83][84]