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Folic acid: the good, the bad and the ugly
Mandatory fortification has changed the health landscape in a number of ways.
How often do you prescribe folic acid and in what doses? You should certainly not be seeing much in the way of folate-deficient megaloblastic anemia these days, not with folic acid fortification. We are approaching the 10th anniversary since the introduction of mandatory fortification of the U.S. diet with folic acid, so perhaps now is a good time to look back and take stock. Has folic acid fortification paid off, and how do we do the balance sheets? Basically, this is a public health question, but there is more to it for prescribing physicians, including hematologists and oncologists.
In addition to the increase in folate that we are now all consuming from fortified cereals and grains in our diets, there is also the use of supplemental folic acid. Whether from over-the-counter supplements that by law cannot contain more than 400 mcg folic acid per tablet, breakfast cereals that are supplemented with folic acid or from prescription vitamin cocktails with as much as 2,500 mcg in them, vast amounts of folic acid are being consumed by a sizeable number of people in the United States. Perhaps you or a physician in your practice is using a folic acid–containing preparation to treat hyperhomocysteinemia? Is the use of supplemental folic acid beneficial or harmful?
Writing in Hem/Onc Today in January of 2006, I concluded that the jury was still out on the use of vitamin supplements to lower homocysteine for vascular disease risk reduction. Recently published data introduces new evidence in the case relating to cancer risk, but before we declare a mistrial, let us review what has come up.
The folate–cancer connection
Folate has been recognized as important in cancer since the pioneering observations from the Farber and Burchenal groups almost 60 years ago when they demonstrated the efficacy of folic acid antagonists (the “antifols”) in the treatment of human and animal leukemias as well as the detailed and elegant studies that followed from Hitchings and others in the Wellcome group for their work on antimetabolites for which they received the Nobel Prize in Physiology and Medicine 20 years ago.
Simply put, the story runs as follows: Folate is required for DNA synthesis and repair in dividing cells. Cancer cells are generally rapidly dividing and therefore in need of reduced folates for thymidine synthesis and DNA replication. Block the enzyme dihydrofolate reductase with a folic acid analogue like methotrexate and proliferation of the tumor population is arrested. These antifols are cell-cycle specific, hitting cells during S-phase. Conclusion: blocking folate or limiting its supply interdicts cancer growth. But that is not all. Defective DNA occurring in folate-deficient megaloblastic anemia that leads to DNA strand breaks are repaired by folate. The same holds true for potentially precancerous mutations. In other words, folate may also serve to protect against the development of cancer.
These apparently contradictory effects of folate — feeding an established cancer yet protecting against its development in the first place – are further compounded by another effect of folate, its role in methylation. Folate is one of several compounds that are required for making
s-adenosyl methionine, which plays a key role in methylation of several molecules, including cytosine bases in DNA. The cytosines in the promoter region of genes regulates whether the genes are unmethylated or methylated. Hypermethylation of tumor suppressor genes would promote cancer, just as hypomethylation of oncogenes might promote tumorigenesis.
Just how these two folate-dependent mechanisms influence cancer risk is uncertain, but two recent studies provide troubling evidence that folate supply may indeed have a profound bearing on cancer risk and cancer rates. In the first, a large randomized clinical trail by the Polyp Prevention Study Group to assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas, patients receiving
1 mg daily folic acid had a higher risk for having three or more adenomas and for at least one advanced lesion as well as a significantly higher incidence of non-colorectal cancer.
More disturbing still is epidemiological evidence that comes through analysis of North American health statistics by the Tufts group. They report that the downward trend in colorectal cancer incidence that both the United States and Canada had enjoyed during the decade that preceded the introduction of folic acid fortification in both countries was abruptly reversed and has continued to exceed the pre-1996/1997 levels by four to six additional cases per 100,000 individuals annually. This translates to an excess of 15,000 new cases of colorectal cancer in the United States each year.
On the good news front, to offset this possible negative effect of folic acid fortification is other epidemiological evidence from CDC data that shows that the rate of decline in fatal strokes is greater since fortification in Canada and the United States. This has not occurred during the same time in England and Wales where fortification has not yet been introduced.
How to weigh a decrease in fatal stroke incidence against an increased number of colon cancers in the population? More data will be necessary before concluding whether, on balance, we are better off with fortification than we were. One thing is clear: to add more folic acid still to the food supply, as some have proposed, would be ill-advised at this time. Furthermore, the case is compelling to exercise prudent caution in prescribing long-term folic acid supplements. H/Ot