Folic Acid Revisited

A reader of my health tips inquired about Folic Acid last week. I went through my archives for him and sent him this:

TUESDAY, NOVEMBER 17, 2009
Folic Acid = Increased Risk of Cancer, Death

Patients with heart disease in Norway, a country with no fortification of foods with folic acid, had an associated increased risk of cancer and death from any cause if they had received treatment with folic acid and vitamin B12, according to a study in the November 18 issue of JAMA.

Posted by Jonathan Kantrowitz at 2:19 PM 0 comments


Health Benefits, Consequences of Folic Acid Dependent on Circumstances



For the past several decades, evidence has shown that greater dietary intake of the B-vitamin, folate, offers protection against the development of certain common cancers and reduces neural tube defects in newborns, opening new avenues for public health interventions that have a great impact on health. However, folate’s central role as an essential factor in DNA synthesis also means that abundant availability of the vitamin can enhance the development of pre-cancerous and cancerous tumors. Further, the intake of folic acid that results from consuming foods that are voluntarily fortified (e.g.: ready-to-eat cereals) in combination with the additional intake received from mandatory fortification of flour means that supplementary intake of folic acid is unnecessary for many segments of the population, and may even present a risk. Nevertheless, the issue is a complicated one since women of child-bearing age seem to benefit from supplemental folic acid in regard to its protection against birth defects. In the April issue of the journal Nutrition Reviews, two new articles by Omar Dary, Ph.D., and Joel B. Mason, M.D., assess the conditions under which folic acid can be beneficial and harmful and contribute to guidelines for the healthful intake of folic acid as a complement to dietary folate.



The consequences of inadequate folate intake remain prevalent in many countries, even in industrial countries where specific interventions of folic acid have not been implemented. Moreover, there continues to be some concern—which, to date, lacks compelling scientific evidence—that the synthetic form of the vitamin, folic acid, might have adverse effects that do not exist with natural sources of folate.



Under most circumstances, adequate intake of folate appears to assume the role of a protective agent against cancer, most notably colorectal cancer. However, in select circumstances in which an individual who harbors a pre-cancerous or cancerous tumor consumes too much folic acid, the additional amounts of folate may instead facilitate the promotion of cancer. In countries in which the fortification of flour with folic acid is working well, additional supplementation in the form of vitamin pills can lead to excessive intakes of the vitamin, which can then have undesirable adverse effects.



Thus, folate appears to assume different guises depending on the circumstances. The level of intake of this micronutrient that is safe for one person may be potentially harmful to another.



“These effects of folate on the risk of developing cancer have created a global dilemma in the efforts to institute nationwide folic acid fortification programs around the world,” Mason notes.



Most individuals in the U.S. population are now folate-replete, so one consideration would be to reduce the doses of the vitamin that are present in most over-the-counter supplements. Many people receive sufficient amounts of folate through their diet.



Now that the supply of folic acid in the diet is much larger than it was prior to mandatory fortification, food policies may need to be adjusted to the current knowledge and the new circumstances.



“The design of cogent public health policies that effectively optimize health for many while presenting no or minimal risk to others, must often occur in the absence of complete information,” Mason concludes. “However, we are nevertheless obliged to deliberate with as much of an in-depth understanding as the existing science allows.”



Folic Acid Fortification May Be Linked to Increased Colon Cancer Risk



The rate of colorectal cancer in Chile may have increased since that country began fortifying wheat flour with folic acid, reports a study in the European Journal of Gastroenterology & Hepatology. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health, a leading provider of information and business intelligence for students, professionals, and institutions in medicine, nursing, allied health, pharmacy and the pharmaceutical industry.

"Our data provide new evidence that a folate fortification program could be associated with an additional risk of colon cancer," according to the new report by Dr. Sandra Hirsch and colleagues of University of Chile, Santiago.

Possible Increase in Colon Cancer after Start of Folic Acid Fortification

The researchers analyzed changes in colon cancer rates since the Chilean government introduced a mandatory program of folic acid fortification of wheat flour in 2000. Several countries have implemented similar policies in recent years, with the goal of preventing spina bifida and other neural tube defects. In Chile, the rate of neural tube defects decreased by 40 percent in the first year after the start of folic acid fortification. __The researchers compared hospital discharge data on colon cancer rates in Chile in four-year periods before and after folic acid fortification: 1992-96 versus 2001-04. Although no causative relationship can be proven, the data suggested a significant "temporal relationship" between folic acid supplementation and colorectal cancer. Reported cases of colon cancer increased by 162 percent in people aged 45 to 64 and by 190 percent in people aged 65 to 79.

After adjustment for other factors, discharge diagnoses of colon cancer in these age groups were two to three times more frequent after the start of folic acid fortification. Most other diseases showed no consistent pattern of changes. There was a small increase in breast cancer, which may have been related to early detection and universal treatment programs for breast cancer.

Evidence Is Weaker than Similar Changes Reported in U.S. and Canada

Chile is the third country to report an apparent increase in colorectal cancer after introducing a national folic acid fortification program. A 2007 paper suggested increases in colorectal cancer after folic acid fortification was introduced in the United States and Canada in the mid-1990s. Chile uses a higher "dose" of folic acid than the two North American countries. Folic acid fortification has not yet been introduced in Europe.

There are other possible explanations for the rise in colon cancer in Chile, including increases in obesity and other risk factors.

Another important limitation of the study was the use of hospital discharge data to identify cases of colon cancer. "Discharge rates are influenced by health care politics, increasing access to healthcare for new strata of the population with increased cancer risk, and so forth," comments Dr. Reinhold Stockbrugger, one of the editors of The European Journal of Gastroenterology & Hepatology. "This study provides only a weak, indirect indication of a causal relationship between folate enrichment and colorectal cancer, though similar to that reported in the U.S. and Canada."


Folic Acid Supplements Linked To Higher Risk Of Prostate Cancer

A study led by researchers at the University of Southern California (USC) found that men who took a daily folic acid supplement of 1 mg daily had more than twice the risk of prostate cancer compared with men who took a placebo.

The finding came from a secondary analysis of the Aspirin/Folate Polyp Prevention Study (AFPP), a placebo-controlled randomized trial to determine the impact of aspirin and folic acid on colon polyps in men and women who were at high risk for the disease. The results appear in the March 10 online issue of the Journal of the National Cancer Institute.

Folic acid (folate) is a B vitamin found in many vegetables, beans, fruits and whole grains. While evidence of its ability to reduce neural tube defects in infants while taken by the mother before or during pregnancy has been well documented, its effects on other conditions are unclear.

“We know that adequate folate levels are important in the prevention of several cancer types, cardiovascular and neurological diseases,” says lead author Jane Figueiredo, Ph.D., assistant professor of preventive medicine at the Keck School of Medicine of USC. “However, little has been known about its role in prostate cancer. Our objective was to investigate the relationship between folic acid supplements and dietary folate and risk of prostate cancer.”

The AFPP study was conducted between 1994 and 2006 and found that aspirin reduced the risk of colon polyps while folic acid had a negative effect and increased the risk of advanced and multiple polyps. The first analysis did not address the impact of folic acid supplements on prostate cancer risk. Previous observational studies have been inconsistent. Some studies suggest that increased folate in the diet or in supplements might actually lower the risk of prostate cancer, and others have suggested no effect or even a potential harmful effect.

In the secondary analysis, researchers looked at prostate cancer incidence among 643 men who were randomly assigned to 1 mg daily folic acid supplements or placebo in the AFPP study and who enrolled in an extended follow-up study. The estimated prostate cancer risk was 9.7 percent at 10 years in men assigned to folate, compared with 3.3 percent in men assigned to placebo.

By contrast, dietary folate intake and plasma folate showed a trend toward reduced risk of prostate cancer, although the difference did not reach statistical significance. It remains unclear why dietary and circulating folate among non-multivitamin users may be inversely associated with risk, Figueiredo says.

“The synthetic form of folate, folic acid, found in supplements, is more bioavailable compared to folate from dietary sources and we know the amount of folate available is critical,” she says. “Adequate levels of folate may be beneficial, but too much folate is unlikely to be beneficial.”

Alternatively, these results may be due to chance, and replication by other studies is needed, she notes.

“These findings highlight the potentially complex role of folate in prostate cancer. The possibility of different effects from folic acid-containing supplements versus natural sources of folate definitely merits further investigation.”

Folic Acid Linked to Increased Cancer Rate

Two recent commentaries appearing in the November issue of Nutrition Reviews find that the introduction of flour fortified with folic acid into common foods was followed by an increase in colon cancer diagnoses in the U.S. and Canada. The two new review articles address these recent findings and provide an overview of the existing evidence on folic acid fortification and the associated policy issues.

For nearly a decade, folic acid, a chemical form of a common B vitamin (folate), has been added to wheat flour and other grain products in the U.S. and Canada. This public health measure was enacted after evidence was discovered linking folic acid with a reduced rate of a specific birth defect that affected the development of the spinal cord and central nervous system. During the same period, however, rates of colorectal cancer in the U.S. inexplicably began rising, even as regular colonoscopy check-ups became more common. In Canada, where folic acid supplementation was introduced a bit later, the same trend has been observed.

Dr. Solomons, author of one of the review commentaries, “Food Fortification with Folic Acid: Has the Other Shoe Dropped?” advises that a careful reconsideration of the fortification program is needed. “One size of dietary folic acid exposure does not fit all. It can be beneficial to some and detrimental to others at the same time,” comments Solomons.

Since the risk-benefit value of fortification varies according to age, Solomons suggests a reevaluation of the manner in which folic acid to prevent birth defects is delivered to the public. Among other things, targeting women of reproductive age while reducing folic acid levels in foods for which fortification is optional (such as ready-to-eat cereals and commercial drinks), would be worthy of consideration, in the opinion of Solomons.

As a result of noted birth defect reduction, 42 countries have implemented some form of mandatory folic acid fortification. The two commentaries stress the need to carefully consider and balance the risks and benefits associated with introducing such a program.

“Folic acid supplementation wields a double-edged sword,” remarks Dr. Young-In Kim, author of “Folic Acid Fortification and Supplementation—Good for Some but Not So Good for Others,” the other commentary review published in the November issue. According to Kim, “It may be beneficial or harmful, depending on the timing of intervention.” Exposure to high intakes of folic acid in early life and young adulthood may provide life-long protection from the tendency for cancer formation in different organs, such as the large intestines, whereas such exposures later in life, when cell damage has occurred, can spur on the advance of the tumor.