Three of the Bs: Folate, vitamin B6, and Vitamin B12

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The Nutrition Source

Three of the Bs: Folate, Vitamin B6, and Vitamin B12

The Institute of Medicine's recommended intake of folate is 400 micrograms per day. The upper limit of intake for adults is set at 1,000 micrograms per day of folate from fortified food or as a supplement, not including folate from food. People who regularly drink alcohol should make sure to get at least 600 micrograms of folate a day. It is best to achieve that level of intake through a healthy diet; taking a standard multivitamin (which contains 400 micrograms of folic acid) is added insurance. Most people should avoid taking higher doses of folate supplements.

Food sources: Many foods are excellent sources of folate—fruits and vegetables, whole grains, beans, breakfast cereals, and fortified grains and grain products. It's best to avoid foods that are heavily fortified with folic acid.

The Institute of Medicine's recommended intake of vitamin B6 is 1.3 to 1.7 milligrams per day, depending on age and gender. Somewhat higher intakes than that may protect against colon cancer, but more research is needed. (21) Very high-dose vitamin B6 supplements should be avoided, since they could lead to nerve damage; in light of these concerns, the Institute of Medicine set the upper limit for vitamin B6 intake in adults at 100 milligrams per day (an amount that can only be achieved through high dose supplements). (22) Food sources: Good sources of vitamin B6 include fortified cereals, beans, poultry, fish, and some fruits and vegetables.

The Institute of Medicine's recommended intake of vitamin B12 is 2.4 micrograms per day. No upper limit has been set. Food sources: Vitamin B12 is found naturally in animal products (such as fish, poultry, meat, eggs, or dairy); it is also found in fortified breakfast cereals and enriched soy or rice milk.

One of the advances that changed the way we look at vitamins was the discovery that too little folate, one of the eight B vitamins, is linked to birth defects such as spina bifida and anencephaly.

Fifty years ago, no one knew what caused these birth defects, which occur when the early development of tissues that eventually become the spinal cord, the tissues that surround it, or the brain goes awry. More than three decades ago, British researchers found that mothers of children with spina bifida had low vitamin levels. (1) Eventually, two large trials in which women were randomly assigned to take folic acid (the form of folate added to multivitamins or fortified foods) or a placebo showed that getting too little folate increased a woman's chances of having a baby with spina bifida or anencephaly and that getting enough folate could prevent these birth defects. (2, 3)

Timing of folate is critical: For folate to be effective, it must be taken in the first few weeks after conception, often before a woman knows she is pregnant.

Enough folate, at least 400 micrograms a day, isn't always easy to get from food. That's why women of childbearing age are urged to take extra folic acid as a supplement. It's also why the US Food and Drug Administration now requires that folic acid be added to most enriched breads, flour, cornmeal, pastas, rice, and other grain products, along with the iron and other micronutrients that have been added for years. (4)

Since the advent of mandatory folate fortification in 1998, neural tube birth defects have dropped by 20 to 30 percent, and studies have shown that far fewer people have low levels of folate in their blood. (5)

The other exciting discovery about folate and two other B vitamins, vitamin B6 and vitamin B12, is that they may help fight heart disease and some types of cancer. It's too early to tell if there's merely an association between increased intake of folate, vitamin B6, and vitamin B12 and heart disease or cancer, or if high intakes prevent these chronic diseases.

B Vitamins and Heart Disease

In 1968, a Boston pathologist investigated the deaths of two children from massive strokes. Both had inherited conditions that caused them to have extremely high levels of a protein breakdown product in their blood, and both had arteries as clogged with cholesterol as those of a 65-year-old fast-food addict. (6) Putting one and one together, he hypothesized that lower, but still elevated levels of homocysteine would contribute to the artery-clogging process of atherosclerosis. Since then, most—but not all—studies have linked high levels of this breakdown product, called homocysteine, with increased risks of heart disease and stroke. However, linking higher levels of homocysteine with heart disease risk does not necessarily mean that lowering homocysteine levels will lower risk. That requires testing in randomized trials.

Vitamin B-12 Deficiency: Causes and Symptoms

Several factors may cause vitamin B12 deficiency:

Avoiding animal products. People who do not eat any meat, fish, poultry, or dairy products are at risk of becoming deficient in vitamin B12, since B12 is only found naturally in animal products. That's why vegans should make sure to include B12-fortified foods or a B12 supplement in their diets. Lack of intrinsic factor. Vitamin B12 deficiency can also be caused by a lack of "intrinsic factor" (a substance secreted by gastric cells that binds to vitamin B12 and enables its absorption). This can lead to so-called "pernicious anemia," and ultimately to serious neurological damage. Lack of stomach acid. A much more common cause of deficiency, especially in older people, is a lack of stomach acid, because stomach acid is required to liberate vitamin B12 from food. An estimated 10 to 30 percent of adults over the age of 50 have difficulty absorbing vitamin B12 from food. (22) Even people who lack adequate stomach acid can typically absorb vitamin B12 from fortified foods or supplements, however, providing yet another reason to take a multivitamin.

Symptoms of B12 deficiency include memory loss, disorientation, hallucinations, and tingling in the arms and legs. Some people diagnosed with dementia or Alzheimer's disease are actually suffering from the more reversible vitamin B12 deficiency.

Folate, vitamin B6, and vitamin B12 play key roles in recycling homocysteine into methionine, one of the 20 or so building blocks from which the body builds new proteins. Without enough folate, vitamin B6, and vitamin B12, this recycling process becomes inefficient and homocysteine levels increase. Several observational studies show that high levels of homocysteine are associated with increased risks of heart disease and stroke. Increasing intake of folate, vitamin B6, and vitamin B12 decreases homocysteine levels. And some observational studies, including the Nurses' Health Study, show lower risks of cardiovascular disease among people with higher intakes of folate, those who use multivitamin supplements, or those with higher levels of serum folate (the form of folate found in the body).

The first large trial of B vitamins to lower homocysteine and prevent heart disease and stroke ended without finding any benefit. (7) In the Vitamin Intervention for Stroke Prevention trial, 3,680 adults who had had non-disabling strokes took a pill containing high doses of vitamins B6, B12, and folic acid or one containing low doses of these three B vitamins. After two years, second strokes, heart attacks and other coronary heart disease events, and deaths were the same in the two groups. However, in this trial, high levels of homocysteine at baseline were associated with higher risk of cardiovascular disease.

Similar studies in people who had a history of heart disease or were at a very high risk of heart disease—so-called "secondary prevention trials"—have had similarly discouraging results: Taking high doses of the three B vitamins lowered homocysteine levels but did not lead to a reduction in coronary heart events. (8-10) But looking at heart disease as a whole may have obscured a potential benefit of at least one of the B vitamins: A recent analysis of multiple studies suggests that folic acid supplements can reduce the risk of stroke, especially in people who have not already suffered a stroke. (11) Folic acid supplements were most protective in studies that lasted longer than three years or that took place in countries without folic acid

fortification.

Emerging research suggests that for most people, folate may prevent heart disease through other mechanisms besides its role in homocysteine recycling. Several large randomized controlled trials of B vitamins and heart disease have yet to report results; when they do, we may have more definitive answers regarding B vitamins and cardiovascular risk in people who have a history of heart disease. (12-14) But none of these studies will answer the question of whether B vitamins can protect against heart disease in healthy people. To date, no one has conducted a randomized controlled trial of folate supplementation and heart disease in healthy people, probably because it would take decades to yield results and would be very costly. Ultimately, folate supplementation may only reduce the risk of heart disease in people who have lower levels of folate intake,

most likely in countries that do not fortify their food supply with folate; in people who already get enough folate in their diets, very high doses of folate supplements may actually cause harm.

Folate and Cancer

In addition to recycling homocysteine, folate plays a key role in building DNA, the complex compound that forms our genetic blueprint. Observational studies show that people who get higher than average amounts of folate from their diets or folic acid supplements for 15 years or more have lower risks of colon cancer (15) and breast cancer. (16) This could be especially important for those who drink alcohol, since alcohol blocks the absorption of folate and inactivates circulating folate. An interesting observation from the Nurses' Health Study is that higher intake of folate blunts the increased risk of breast cancer seen among women who have more than one alcoholic drink a day. (16) A more recent study from Sweden found that a high folate intake can protect against breast cancer even in women who have only a drink a day or less. (17)

But the relationship between folate and cancer is a complicated one, especially for people at a high risk of colon cancer. (18) Colorectal adenomas, or polyps, are pre-cancerous growths in the large intestine. A recent multiyear trial looked at whether high-dose folic acid supplements could prevent new polyps in people who had a history of polyps. (19) The study found that taking a daily pill with 1,000 micrograms of folic acid offered no protection against new polyps, and, more worrisome, increased the risk of developing multiple or more serious polyps. Keep in mind that this study tested a very high dose of folic acid, more than two times higher than what is found in a standard multivitamin; furthermore, study participants were already at a very

high risk of developing new polyps. This may be another case where timing of folate intake is critical: Getting adequate folate may prevent polyps in people who do not have them, but high dose folate supplements may speed up polyp growth in people who do.

Supplement Studies: Sorting Out the Confusion: How to make sense of the media hype around supplements

When teasing out the relationship between any vitamin supplement and cancer, it is important to remember that cancer cells are essentially our own cells on overdrive, growing and rapidly dividing, and they have a greater need for nutrients than most of our normal cells do. Indeed, one successful chemotherapy agent works as a folate antagonist, since rapidly dividing cells require folate to maintain their fast pace of cell division. So for people who have cancer or precancerous growths, nutritional supplements may be a double-edged sword. If you have cancer, make sure to check with your doctor before beginning any vitamin supplement regimen.

Getting Your Bs from Diet—and a Daily Multivitamin

The definition of a healthy daily intake of B vitamins isn't set in stone, and it is likely to change over the next few years as data from ongoing randomized trials are evaluated. In the U.S., folic acid fortification of food has increased the percentage of adults who have adequate levels of folate in their blood. (20) Yet only a fraction of U.S. adults currently get the recommended daily intake of all B vitamins by diet alone. So use of a multivitamin supplement will become increasingly important.

References

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2. Czeizel AE, Dudas I. Prevention of the first occurrence of neural–tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992; 327:1832–5.

3. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991; 338:131–7.

4. Federal Register. Food Standards: Amendment of Standards of Identity For Enriched Grain Products to Require Addition of Folic Acid. Final rule, 5 March 1996. Food and Drug Administration: Washington, DC, 1996.

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6. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969; 56:111–28.

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12. VITATOPS TSG. The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine–lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis. 2002; 13:120–6.

13. Galan P, de Bree A, Mennen L, et al. Background and rationale of the SU.FOL.OM3 study: double–blind randomized placebo–controlled secondary prevention trial to test the impact of supplementation with folate, vitamin B6 and B12 and/or omega–3 fatty acids on the prevention of recurrent ischemic events in subjects with atherosclerosis in the coronary or cerebral arteries. J Nutr Health Aging. 2003; 7:428–35.

14. MacMahon M, Kirkpatrick C, Cummings CE, et al. A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Nutr Metab Cardiovasc Dis. 2000; 10:195–203.

15. Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med. 1998; 129:517–524.

16. Zhang S, Hunter DJ, Hankinson SE, et al. A prospective study of folate intake and the risk of breast cancer. JAMA. 1999; 281:1632–1637.

17. son U, Sonestedt E, Gullberg B, Olsson H, Wirfalt E. High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmo Diet and Cancer cohort. Am J Clin Nutr. 2007; 86:434–43.

18. Ulrich CM. Folate and cancer prevention: a closer look at a complex picture. Am J Clin Nutr. 2007; 86:271–3.

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21. Wei EK, Giovannucci E, Selhub J, Fuchs CS, Hankinson SE, Ma J. Plasma vitamin B6 and the risk of colorectal cancer and adenoma in women. J Natl Cancer Inst. 2005; 97:684–92.

22. Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press, 1999.