Folic Acid Deficiency's Role Expands Beyond Birth Defects

Nutritionists once associated low levels of folic acid-a B vitamin found in fruits and leafy green vegetables-primarily with birth defects. But in recent years, epidemiological studies have established more correlations between folate deficiency and heart disease, cancer, and brain damage. Now, researchers are discovering mechanisms that may explain how folate deficiency contributes to these health problems. BRAIN CONNECTION: Berkeley's Bruce Ames thinks chromosome breaks caused by folate deficiency could cause brain damage. One study out of the University of California, Berkeley, shows that a low-folate diet can cause nicks in genes, resulting in chromosome breaks (B.C. Blount et al., Proceedings of the National Academy of Sciences, 94:3290-5, 1997). Those chromosome breaks could contribute to cancer and other diseases. When the cell lacks enough folate to synthesize thymine, its biochemical precursor, uracil, builds up in the cell's DNA instead. Then the cell's repair mechanisms remove the uracil, resulting in nicks. "When you have two opposing nicks in the DNA, the chromosome falls apart," says Bruce N. Ames, a professor of biochemistry and molecular biology at UC-Berkeley who co- authored the study. About 10 percent of the United States population (and about 50 percent of its poor minority population) does not receive enough folates-worrisome because even light deficiencies can cause genetic damage. The UC-Berkeley study also shows that increasing folate in the diet prevents this cellular damage. "Folate deficiency is going to be a great cause of cancer in the United States," predicts Ames. He also thinks that broken chromosomes could lead to brain damage and affect cognitive function, although the evidence is less clear. "B12 deficiency, which also appears to cause uracil misincorporation into DNA, seems to knock out glial cells surrounding nerves in the periphery." EARLY EVIDENCE: FDA's James MacGregor found evidence of genetic damage linked to folate deficiency in one subject in 1988. The relationship between folate deficiency and cellular damage arose accidentally. In 1988, James T. MacGregor, now the director of the Food and Drug Administration's (FDA's) Center for Drug Evaluation and Research, stumbled upon it while studying cellular division. He used pieces of chromosomes left over as a marker for the process. One subject's blood cells contained an abundance of the micronuclei. "We were quite surprised to find this one individual who had 15 times as much as everyone else." MacGregor and colleagues followed that subject for a year and found that the elevated level of micronuclei was due to a moderate folate deficiency. When the subject received folate supplements, the number of micronuclei found in his blood soon decreased (R.B. Everson et al., Journal of the National Cancer Institute, 80:525-9, 1988). MacGregor has a new study in press with a population of 22 that should strengthen the argument that a poor diet can result in genetic damage. "The effects on genetic damage could be way bigger than people thought." However, scientists need to better understand the biochemical reactions that lead to genetic damage, and they need to conduct randomized clinical trials. Other questions remain, as well. BROKEN CHROMOSOMES: CDC fellow Benjamin Blount showed that a low folate diet can cause nicks in genes. The same biochemical processes resulting in birth defects like spina bifida may also be responsible for other diseases, says Benjamin C. Blount, a visiting fellow at the Centers for Disease Control and Prevention's (CDC's) National Center for Environmental Health in Atlanta. "It could be that the birth defect mechanism is the same as the one for cancer, or it could be totally different." Blount also wonders how the folic cofactor involved in cancer differs from ones associated with heart disease. Low folate levels could contribute to one but not the other in the same subject. The reason for this discrepancy remains unknown. However, one answer could lie in variances in individual genetic makeup. "By studying people with different inborn errors in metabolism, we'll be able to study these subtle differences," he says. GENETIC VARIATION: Harvard's Eric Rimm is searching for ways in which genetic variations may affect folate levels and diseases related to them. Eric B. Rimm, an associate professor of epidemiology at the Harvard School of Public Health, agrees that genetic variation may affect folate levels and diseases related to them. He and a team of Harvard colleagues are searching for that link. They also want to establish a more conclusive cause-and-effect relationship between folate deficiency and both cancer and heart disease. "Right now, there really aren't any published reports linking folic acid directly," Rimm says. The search for direct links of folate deficiency to cancer, heart disease, and brain damage could be complicated by the elemental role folate plays in the body's numerous biochemical reactions. "Folate provides a chemical building block, an essential chemical necessary for the body's basic biochemical needs," explains Meir J. Stampfer, a professor of epidemiology at the Harvard School of Public Health. Because folic acid comes into play early in metabolism and bonds many other chemicals together, it may be difficult to discern just how its absence may add to one disease but not another. VITAMIN TRIALS: Randomized trials may establish stronger links between folate deficiency and disease, maintains Harvard's Meir Stampfer. Stampfer has helped establish epidemiological evidence linking folate deficiency to both heart disease (L. Chasen et al., Journal of the American College of Nutrition, 15:136-43, 1996) and colon cancer (J. Chen et al., Cancer Research, 56:4862-4, 1996). But he acknowledges the need for clinical randomized trials to more definitively establish a cause-and-effect relationship. Scientists may not have to wait long. Stampfer and his Harvard colleagues have begun work on such studies, including a randomized trial of vitamin therapy in people who have survived a nondisabling stroke. In particular, the study will examine the role of folates in preventing recurrences. Stampfer predicts that other research groups are taking on the same sorts of problems and results should begin to emerge in the next several years. "These randomized trials are going to be very strong," he comments. "There's going to be a flood of new data. It's going to enhance our ability to reduce the risk of these diseases." HEART LINK: Southern Illinois University's Carol Boushey conducted a meta-analysis linking folate deficiency to heart disease. Carol J. Boushey, an associate professor in the department of animal science, food and nutrition at Southern Illinois University, agrees that clinical randomized trials will provide more understanding about how folate deficiency is related to diseases. But she says enough epidemiological data have accumulated to convince her of the link between folate deficiency and heart disease. Boushey and colleagues conducted a meta-analysis of 27 studies relating increased homocysteine with arteriosclerotic vascular diseases and 11 studies of folic acid deficiency's effects on homocysteine. She found that, as in other studies, higher folic acid intake reduces homocysteine (C.J. Boushey et al., JAMA-Journal of the American Medical Association, 274:1049-57, 1995; Hot Papers, The Scientist, Sept. 15, 1997, page 12). None of the studies she examined directly related folate deficiency with heart disease. However, increased homocysteine levels have been repeatedly linked to heart disease. "I believe the association is there," Boushey says. "I'm comfortable promoting a high-folate diet. But many individuals are skeptical until you do the randomized trials." POOR RATIONALE: Katherine Tucker of Tufts University says the assumption that folic acid masks symptoms of B12 deficiency doesn't warrant a low RDA. Although scientists lack a definitive answer on how folate deficiency leads to heart disease, they are beginning to get some ideas, according to Katherine L. Tucker, an associate professor of epidemiology at the Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center at Tufts University. Folic acid lowers blood levels of homocysteine, an amino acid, that, in high levels, has been associated with heart disease, hypertension, and stroke. "When there's a deficiency, the homocysteine cannot move to the next step and clear. So it accumulates in the blood," Tucker states. She says that accumulation may contribute to the narrowing of the arterial walls by somehow making them more susceptible to plaque buildup. Tucker has seen this buildup and subsequent narrowing in ultrasounds of folate-deficient individuals participating in the longitudinal Framingham Heart Study. That study, initiated in 1948, continues to establish risk factors for heart disease. An analysis of questionnaires of 747 subjects in that study who were also tested for folate showed that those with the lowest folate intake had the highest homocysteine levels. As evidence linking folate deficiency to disease and genetic damage builds, scientists are questioning the federal government's decision in 1987 to lower the recommended daily allowance of folic acid from 400 µg per person to 200 µg. The Dietary Reference Committee has been actively discussing the RDA of folates and other B vitamins, confirms Carol Suitor, senior program officer with the Institute of Medicine's Food and Nutrition Board. She predicts that the committee will make its recommendations public in April 1998. FOLIC BOOSTER: To prevent birth defects, CDC's Godfrey Oakley promotes increasing the minimum RDA. Research by Tucker and her colleagues challenges the rationale that led to the folate RDA reduction-that higher levels of folic acid mask anemia in the elderly population, an early stage of B12 deficiency (K.L. Tucker et al., JAMA, 276:1879-85, 1996). Without that warning and subsequent action, the argument goes, B12 deficiency can cause progressively worse neurological problems, including dementia. However, Tucker says that anemia may not be the best indicator for B12 deficiency. Therefore, the benefits of increasing daily folic acid intake greatly outweigh the risks. Godfrey P. Oakley, Jr., director of the division of birth defects and developmental disabilities at CDC, favors bumping the folate RDA back up to 400 µg. If Boushey's conclusions are correct, that decision could prevent about 50,000 yearly deaths due to heart attack in the U.S. "That's more people than who would die in automobile crashes," Oakley says. He calls the move from an RDA of 400 µg to 200 µg of folate a day "an absolute disaster" and wouldn't be surprised if that decision were reversed when the Dietary Reference Committee makes its April announcement. In the meantime, FDA's move to fortify every 100 grams of flour with 140 µg of folic acid by the end of 1998 will automatically put more folate into people's diets. Oakley advocates women take more than 400 µg of folic acid a day because diseases with the strongest link to folic acid deficiency-neural tube defects such as spinal bifida-are passed on during the earliest months of pregnancy. In 1993, 2,400 children were born with neural tube defects. Oakley estimates that folic acid supplementation of 700 µg a day would eliminate 75 percent of neural tube defects. UNEVEN ABSORPTION: Maryland's Stephen Hoag notes that some folic acid supplements are not absorbed effectively. While most researchers in the field support fortification, a recent study shows that some supplements may be more effective than others. Stephen Hoag, an assistant professor at the University of Maryland School of Pharmacy, and colleagues tested nine multivitamins and found that six failed to release the industry-standard 75 percent of their folic acid within one hour (S. Hoag et al., Journal of the American Pharmaceutical Association, NS37:397-400, July/August 1997). FOR MORE INFORMATION: National Center for Environmental Health Mailstop F17 4770 Beauford Hwy. Atlanta, Ga. 30341 (770) 488-7030 Fax: (770) 488-7197 http://www.cdc.gov/nceh Food and Drug Administration Center for Drug Evaluation and Research 5600 Fishers Lane Rockville, Md. 20857 (301) 594-6779 Fax: (301) 594-6197 http://www.fda.gov/cedr/ "We're not quite sure why they failed," says Hoag. He suspects that the poor performers were absorbed into the body too far along in the digestive process. "If you can present a drug high in the small intestine, then it's pretty readily absorbed." However, variable absorption rates can be thwarted by taking the vitamins on a full stomach. Doing so slows the supplement's journey through the body, giving it more time to break down. Scientists agree that the recent research has fundamentally changed the way they look at vitamins in a relatively short period. Until the late 1980s, people associated vitamins mostly with growth, according to MacGregor. Then, the research shifted to the role of vitamins and birth defects. The newest wave of research linking vitamin deficiency with genetic damage is just beginning to take hold, but MacGregor thinks it perhaps has the strongest implications. Blount agrees. "When I first started in this field in 1989, there was still a lot of questions about birth defects." Now that the correlations between folic deficiency and birth defects have been established, more scientists are searching for an understanding of why it exists. "We do not know how the folate is working," says John Lloyd, director of developmental biology at Jefferson Medical College in Wilmington, Del. "It could be that these mothers are actually methionine-deficient. Or it could be that they are Vitamin B12-deficient. They are all viable hypotheses at the moment." Lloyd echoes other scientists who say pinpointing the cause may be difficult because of the folic acid's intricate chemical interactions with other chemicals. Folic acid promotes homocysteine to methionine, but that conversion depends on B12. "Perhaps it will be experimental work on animals that will help sort this out," Lloyd says. While scientists continue to unravel the biochemical reactions and government agencies debate the merits of changing the RDA and supplementation level, most scientists agree that the U.S. diet could be improved to deliver folic acid naturally. "We don't eat enough fresh fruit and vegetables," Stampfer says. "We eat too much fast food and junk food-food that doesn't have these vitamins." l (The Scientist, Vol:11, #20, pg 10-11, October 13, 1997)

Folic Acid Deficiency's Role Expands Beyond Birth Defects

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