Bio-availability of Folic Acid and Food Folate

Differences in bio-availability of folic acid and food folate

The RNIs suggested food folate as the source of dietary folate

because most societies in developing countries consume folate from naturally occurring sources. As discussed in the introduction, natural folates are found in a conjugated form in food, which reduces its bio-availability by perhaps as much as 50 percent. In addition, natural folates are much less stable. If chemically pure folic acid (pteroyl monoglutamate) is used to provide part of the RNI, by way of fortification or supplementation, the total dietary folate, which contains conjugated forms (pteroyl polyglutamates), could be reduced by an appropriate amount. On average the conjugated folate in natural foods is considered to be only half as available as synthetic folic acid. For example, the recommendation of usual mixed forms of folate in the diet is 400 μg/day, but 100 μg of this given as pure folic acid would be considered to be equivalent to 200 μg of dietary mixed folate. Hence, only an additional 200 μg of dietary folate would be needed.

The FAO/WHO expert group agreed with the findings of the Food and Nutrition Board of the US National Academy of Sciences: 

"Since folic acid taken with food is 85 percent bio available but food folate is only about 50 percent bio-available, folic acid taken with food is 85/50 (i.e., 1.7) times more available. Thus, if a mixture of synthetic folic acid plus food folate has been fed, dietary folate equivalents (DFEs) are calculated as follows to determine the EAR:

μg of DFE provided = [μg of food folate + (1.7 x μg of synthetic folic acid)] To be comparable to food folate, only half as much folic acid is needed if taken on an empty stomach, i.e., 1 μg of DFE = 1 μg of food folate = 0.5 μg of folic acid taken on an empty stomach = 0.6 μg of folic acid with meals.

The experts from the National Academy of Sciences went on to say that the required estimates for the dietary folate equivalents could be lowered if future research indicates that food folate is more than 50 percent bio-available. 

Neural tube defects

It is now agreed that a supplement of 400 μg of folic acid taken near the time of conception will prevent most neural tube defects (NTDs). The recommendation to prevent recurrence in women with a previous NTD birth remains 4.0 mg/day because of the high increase in risk in such cases and because that was the amount used in the most definitive trial. Because of the poorer bio-availability and stability of food folate, a diet based on food folate will not be optimum in prevention. 

One study determined that risk of NTD is 10-fold higher in people with poor folate status than in those with high normal folate status. A further study suggests that an extra 200 μg/day or possibly 100 μg/day if taken habitually in fortified food would prevent most if not all of folate-preventable NTDs. Ideally, an extra 400 μg/day should be provided because this is the amount used in various intervention trials and can be achieved by supplementation. 

This amount could not be introduced by way of fortification, because exposure to high intakes of folic acid by people consuming a large intake of flour would run the risk of preventing the diagnosis of pernicious anaemia in the elderly. It is likely that depending on the staple chosen it would be possible to increase intake in most women by 100 μg/day without causing too high an exposure in other groups. It is suggested that this amount, although not optimal, will prevent most NTDs.

Cardiovascular disease

Plasma homo-cysteine concentration, if only moderately elevated, is an independent risk factor for cardiovascular disease and stroke. Increased risk was associated with values higher than 11 μmol/l, which is well within what is the normal range (5–15 μmol/l) of plasma homo-cysteine levels. In addition, even in populations that are apparently normal and consuming diets adequate in folate, there is a range of elevation of plasma homocysteine that could be lowered by an extra 100 or 200 μg/day of folic acid. Largescale intervention trials regarding the significance of interrelationships among folate levels, plasma homo-cysteine levels, and cardiovascular disease have not been completed and therefore it would be premature to introduce public health measures in this area.

Colorectal cancer

Evidence suggests a link between colorectal cancer and dietary folate intake and folate status. One study reported that women who take multivitamin supplements containing folic acid for prolonged periods have a significantly reduced risk of colorectal cancer. However, the scientific evidence is not sufficiently clear for recommending increased folate intake in populations at risk for colorectal cancer.

Upper limit

There is no evidence that it is possible to consume sufficient natural folate to pose a risk of toxicity. However, this clearly does not apply to folic acid given in supplements or fortified foods. The main concern is the masking of the diagnosis of pernicious anaemia, because high levels of folic acid correct the anaemia, allowing the neuropathy to progress undiagnosed to where it may become irreversible even upon treatment with vitamin B12. Consumption of large amounts of folic acid might also pose other less well-defined risks. Certainly, consumption of milligram amounts of folic acid would be undesirable. Savage and Lindenbaum suggest that even at levels of the RNI there is a decreased opportunity to diagnose pernicious anaemia through its presentation via the anaemia.

The US National Academy of Sciences, after reviewing literature, has suggested an upper level of 1000 μg. Thus, 400 μg/day of folic acid, in addition to dietary folate, would seem safe. There is probably no great risk of toxicity at a range between 400 and 1000 μg of folic acid per day with the exception of some increased difficulty in diagnosing pernicious anaemia resulting from the masking of the anaemia.

References:

Gregory, J.F. 1997. Bio-availability of folate. Eur. J. Clin. Nutr., 51: 554-559.

Wald, N.J., Watt, H.C., Law, M.R., Weir, D.G., McPartlin, J. & Scott, J.M. 1998. Homo-cysteine and ischaemic heart disease: results of a prospective study with implications on prevention. Arch. Internal Med., 158: 862-867.

Sauberlich, H. 1995. Folate status in the US Population groups. Folate in Health and Disease. Lynn Bailey editor p. 171-194 Marcel Dekker, New York.

Scott, J.M., Kirke, P., Molloy, A.M., Daly, L. & Weir, D. 1994. The role of folate in the prevention of neural tube defects Proc. Nutr. Soc., 53: 631-636.

Daly, L.E., Kirke, P.M., Molloy, A., Weir, D.G. & Scott, J.M. 1995. Folate levels and neural tube defects. Implications for prevention. JAMA, 274: 1698-1702.

National Academy of Sciences. 1998. Dietary Reference Intakes: Folate, other B Vitamins and Choline. Wasington, D.C., National Academy Press.

UK Dept of Health. 1992. Folic Acid and the Prevention of Neural Tube Defects. Report from an Expert Advisory Group. H.M. Stationary Office

Centers for Disease Control. 1992. Recommendations for the use of folic acid to reduce

the number of cases of spina bifida and other neural tube defects. MMWR, 41: 1-7.(No.

RR-14).

MRC Vitamin Study Research Group. 1991. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet, 338: 131-137.

Daly, S., Mills J.L, Molloy, A.M., Conley, M.L., Lee, Y.J., Kirke, P.N., Weir, D.G. & Scott, J.M. 1997. Minimum effective dose of folic acid for food fortification to prevent

neural tube defects. Lancet 350: 1666-1669.

Scott, J.M. & Weir , D.G. 1996. Homo-cysteine and cardiovascular disease. Q. J. Med., 89: 561-563

Boushey, C.J. Beresford S.A., Omenn, G.S. & Motulsky A.G. 1995. A quantitative assessment of plasma homo-cysteine as a risk factor for vascular disease. JAMA, 274: 1049-1057.

Perry, I.J., Refsum, H., Morrise, R.W., Ebrahim, S.B., Ueland, P.M. & Shaper, A.C. 1995. Prospective study of serum total homo-cysteine concentrations and risk of stroke in a middle aged British men. Lancet, 346: 1395-1398.

Refsum, H., Ueland, P.M., Bygard, M.D. & Vollset, S.E. 1998. Homo-cysteine and Cardiovascular Disease. Annu. Rev. Med., 49: 31-62.

Giovannucci E., Stampfer M.J., Colditz G.A., Hunter D.J., Fuchs C., Rosen B.A., Speitzer F.F. & Willett W.C. 1998. Multivitamin use, folate and colorectal cancer in women in the Nurses’ Health Study. Ann. Internal Med., 129: 517-524.

Mason, J.B. 1995. Folate status: Effect on carcinogenesis. In: Bailey L.B. editor Folate in Health and Disease. p. 361-378. New York, Marcel Dekker,

Kim, Y.I., Fowaz, K., Knox, T., Lee, Y., Norton, R., Arora, S. Paiva, L. & Mason, J.B. 1998. Colonic mucosal concentrations of folate correlate well with blood measurements of folate in persons with colorectal polyps. Am. J. Clin. Nutr., 68: 866-872.

Weir Donald G. & Scott John M. 1999. Vitamin B12 “Cobalamin’ In: Modern Nutrition in Health and Disease, editors: Maurice A.Shils, James A.Olson, Moshe Shike,A, Catharine Ross. Ninth Edition, p. 477-458. Philadelphia, Lippincott Williams and Wilkins.

Savage, D.G. & Lindenbaum, J. 1995 Neurological complications of acquired cobalamin deficiency : clinical aspects. In: Baillieres Clin Haematol. Megaloblastic Anaemia Editor S.M. Wickramasinghe vol. 8, p. 657-678. London, Bailliere Tindall.