Folate for therapy

Folate is a B vitamin which is needed for DNA synthesis, replication and repair. It is found in leafy green vegetables.

Folic acid supplementation in pregnancy reduces the risks of neural tube defects. In the general population, supplements have no clear benefit in reducing the risk of cardiovascular disease or dementia.

There is conflicting evidence about cancer prevention. Some studies suggest folic acid supplements increase the risk of malignancy.

Routine folic acid supplementation in patients receiving low-dose methotrexate for rheumatic diseases reduces the risk of some adverse effects.

Folate is vitamin B₉. It was named after the Latin word folium (leaf) and it was first isolated from spinach in 1941. Folate-rich foods include green leafy vegetables (broccoli, spinach, salad greens), chickpeas, nuts, orange juice and some fruits. Many foods are fortified with folic acid including some breakfast cereals, bread and products containing wheat flour.

The active form of folate is tetrahydrofolate. This has a role in the synthesis, replication and repair of DNA. A deficiency of folate can lead to megaloblastic anaemia.

Synthetic folate used as a supplement differs from the main naturally occurring folate. In its oxidised state folic acid has a significantly higher bioavailability. A dose of more than 200 microgram saturates normal intestinal absorptive mechanisms. Raised total folate and unmetabolised folate in the serum may interfere with the regulatory functions of natural folates by competing for binding with enzymes, carrier proteins and binding proteins.¹

Taking supplements around the time of conception reduces the risks of neural tube defects. As the neural tube is closed by embryonic day 26, folic acid supplementation needs to begin one month before conception and be maintained for at least three months after. The Australian Government recommendation is that all pregnant women take a folic acid supplement of at least 400 microgram/day and aim for a dietary intake of 600 microgram. Australian wheat flour is fortified to 120 microgram/100 g of bread (about three slices).²

Supplementation has also been purported to prevent some types of cancer, cardiovascular disease and dementia. More recently there has been concern that folic acid supplements may increase the risk of some cancers.

In 1969 a connection between homocysteine and cardiovascular disease was proposed. Patients with homocystinuria, an inherited enzyme deficiency, leading to elevated plasma concentrations of homocysteine, were noted to develop severe cardiovascular disease in their early twenties. It was speculated that high homocysteine concentrations could contribute to atherosclerosis.

Homocysteine elevation also occurs in people with diets deficient in folate, vitamin B₆ or B₁₂ . Regardless of the cause, supplementation with folate, vitamin B₆ or B₁₂ can lower plasma homocysteine. In patients with homocystinuria, lowering homocysteine reduced the risk of cardiovascular events.³

Folic acid supplementation reduces homocysteine concentrations typically by 25% in those with hyperhomocysteinaemia. Maximum responses are seen with 800 microgram/day over six weeks. Higher doses do not result in further significant lowering.⁴

Randomised controlled trials in people without homocystinuria are inconclusive regarding the benefit of folic acid supplementation. There was no significant evidence of change in the risk of cardiovascular events, stroke or all-cause mortality in those with a history of cardiovascular disease.3 Lowering homocysteine does not confer a secondary prevention benefit, but some studies show a primary prevention benefit for stroke.⁵ The benefit of folic acid supplementation in cardiovascular disease in patients with rheumatoid arthritis is unknown.⁶

The effect of folic acid supplements on cognitive impairment is uncertain. Higher concentrations of homocysteine have been associated with worse function across a number of cognitive domains7 and a study of 818 patients aged 50 to 70 years with hyperhomocysteinaemia found improvement in cognitive tests in those taking supplements.⁸ However, the role of folic acid in lowering homocysteine for the primary prevention of dementia is not established. A study in the USA after the introduction of fortification found an association between increased cognitive decline and increased folic acid intakes (greater than 400 microgram/day).⁹ In a Cochrane review of eight trials there was no evidence that folic acid improved the cognitive function of unselected elderly people with or without dementia.¹⁰

Although folic acid supplementation had been considered safe, there has been increasing concern that it may raise the risk of cancer. In Norway, where food is not fortified with folic acid, two randomised controlled trials found an increased incidence of cancer among patients taking supplements for secondary prevention of cardiovascular events. The Norwegian Vitamin Trial (NORVIT) and Western Norway B Vitamin Intervention Trial (WENBIT) included 6837 Norwegians taking supplementary folic acid 800 microgram/day, vitamin B₁₂ and vitamin B₆ in various combinations. In those taking folic acid for a median of 39 months, with a further 38 months of post-trial follow-up, there was an increase in cancer incidence (hazard ratio 1.2) and mortality (hazard ratio 1.38). The predominant cancer was lung cancer.¹¹

Other observational studies have shown source-specific effects, with dietary folate being protective while folic acid supplements were harmful or without effect in relation to cancer risk.¹² A Swedish study found the risk of pancreatic cancer was reduced by diets rich in folate, but not by supplements.¹³

The dose and timing of folic acid supplementation relative to the development of premalignant lesions may be important, but the mechanism by which supplementation may promote cancer development is unknown.¹⁴ After a review of the risk, the UK Scientific Advisory Committee on Nutrition considered that, despite uncertainties, the mandatory fortification of flour was supported, with controls to limit excessive folic acid intake.¹⁵

There is no evidence that folic acid supplementation reduces the risk of colorectal, breast or prostate cancer. Some reported studies suggest an increased risk of breast, prostate, colorectal and endometrial cancer with folic acid supplementation.

Breast cancer

An observational study found that folic acid supplementation of at least 400 microgram/day led to a 20% increased risk of breast cancer.¹⁶ However, the Women’s Antioxidant and Folic Acid Cardiovascular study found no association with breast cancer.¹⁷ Similarly, another study found no association with breast cancer when folic acid supplementation was 200 microgram/day or less.¹⁸

Colorectal cancer

A randomised controlled trial for the prevention of colorectal cancer in genetically predisposed patients found folic acid 1 mg/day for six years did not prevent recurrence of colorectal adenoma. However it reported a 67% increased risk of advanced lesions with malignant potential and a twofold increased risk of having three adenomas.¹⁹

An intake below 200 microgram daily is recommended in those with a history of colorectal adenomas and those more than 50 years old, due to the increased risk of developing colorectal cancer after this age.¹⁵

Prostate cancer

There has been a meta-analysis of 10 randomised controlled trials of oral folic acid supplementation of at least 400 microgram/day. This showed a small but significant increase in prostate cancer compared with controls.¹²

Methotrexate is a cornerstone of disease-modifying antirheumatic drug therapy for rheumatoid arthritis. It is an analogue of folic acid and thus classed as an antimetabolite. Methotrexate inhibits dihydrofolate reductase (which converts dihydrofolate to tetrahydrofolate), but the mechanism of action in rheumatoid arthritis is unclear.

On average, 30% of patients cease methotrexate within one year due to adverse effects and 60% experience mild adverse effects.²⁰ Gastrointestinal intolerance and transaminase elevation are the main reasons for dose reduction or cessation. The risk factors for methotrexate toxicity include alcohol use, obesity (≥ 8% hepatotoxicity with body mass index 20–25; ≥ 20% hepatotoxicity with body mass index 30–35), older age and folate deficient status.

Concurrent folic acid supplementation reduces elevations of hepatic transaminases, gastrointestinal intolerance and stomatitis, and may increase the maximum tolerated dose of methotrexate.²¹ Supplementation does not appear to have a protective effect on the development of cytopenia or liver disease, such as cirrhosis.

Folinic acid is a metabolically active reduced form of folate that bypasses dihydrofolate reductase.²⁰ It is a stronger methotrexate antagonist than folic acid, as folic acid must be enzymatically converted to a fully reduced form. However it seems to have no greater effect than folic acid in the prevention of methotrexate-related adverse effects. As folinic acid may reduce the effectiveness of methotrexate and is more expensive, its routine use is not recommended.²² It has an important role in the treatment of methotrexate overdose and acute bone marrow toxicity, due to its faster action and independence of dihydrofolate reductase.

Studies have shown no reduced efficacy of methotrexate with a folate:methotrexate dose ratio of 3:1, that is, the dose of folate can be at least three times that of methotrexate before there is any effect on efficacy. For a once-weekly dose of 15 mg methotrexate, up to 45 mg of folic acid could be prescribed concurrently if required. There is no difference in benefit between folic acid 1 mg/day or 5 mg/week during methotrexate therapy.²³

Recommendations for the use of folic acid with methotrexate are varied. Patients with a normal mean corpuscular volume and no adverse effects from methotrexate may not require prophylactic folic acid.²⁴ If the red blood cell folate is low, 1 mg/day folic acid is recommended (except on the day of the methotrexate dose to avoid competing for absorption). When the red blood cell folate is persistently low the folic acid dose should be gradually escalated up to a maximum folate:methotrexate ratio of 3:1. The British Society for Rheumatology²⁵ recommends a single weekly dose of folic acid 5 mg the morning following the day of the methotrexate dose. A consensus statement from 751 rheumatologists from 17 countries in 2008 recommended at least 5 mg/week of folic acid during methotrexate therapy.²²

It is unknown if patients with rheumatoid arthritis who take folic acid supplements have increased rates of cancer. Theoretically, they may incur a higher risk of cancer because of the doses of folic acid prescribed concurrently with methotrexate.

The role of folic acid supplementation when methotrexate is used in juvenile idiopathic arthritis and psoriatic arthritis is uncertain. Folic acid supplementation in patients with psoriasis possibly reduces the efficacy of methotrexate.²⁶

Supplementation with folic acid has a clear role to correct folate deficiency and in the prevention of neural tube defects. Prophylactic folic acid is recommended with low-dose methotrexate for rheumatic diseases, to reduce the risk of some adverse effects.

The routine use of more than 5 mg/week folic acid exceeds many formal recommendations. The harm versus benefit of higher doses is unclear. There is a limited benefit in vascular disease and a possible increase in malignancy.

Conflict of interest: none declared

Acknowledgement: Professor R Woodbaker, School of Medicine, University of Tasmania, for his assistance and suggestions in reviewing the article.

The following statements are either true or false.

1. Folic acid supplements increase the efficacy of methotrexate
2. To reduce fetal neural tube defects, folic acid supplements should be started before conception.

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