Folate-Nutritional Requirements

The most satisfactory way of determining the daily requirement of a particular nutrient is to devise a diet which is complete except for the nutrient being studied and to feed it to healthy volunteers together with graded supplements of the nutrient in question. The supplement which just finis to produce clinical change when fed over a period of some weeks represents the minimum daily requirement, lliis is easily done with animals, provided a suitable diet can be devised, but there are problems when using humans for this type of study because it may be necessary to take the diet for many weeks or months before clinical signs of a deficiency occur. 

In 1962, a physician (H14) placed himself on a diet which, when assayed, was found to provide only 5 pg of folate daily. Up to that time no diet had been devised that contained so little folate, and it was made possible only by boiling each 100 g portion of all those constituents that contained more than a trace of the vitamin for 10 minutes in two liters of water. Tlie water was then discarded and the procedure repeated twice (H15). On this diet early megaloblastic change was noted after 137 days. The serum level of the vitamin fell after 14 days followed by the appearance of hypersegmented neutrophils. Formiminoglutamic acid then appeared in the urine and shortly before the megaloblastic change occurred the red cell folate fell. This experiment provided important information on body stores and the sequence of events in folate deficiency. While the diet was not completely free of folate, its content had been carefully measured and was very small. It was calcu- 

In a follow-up experiment three volunteers were placed on this same very-low-folate diet and supplemented with 25, 50, and 100 p.g of folate daily (H17). After 1 month there was a fall in the serum folate level from 10.3 to 

2 (jLg/liter in the volunteer receiving the 25 p.g supplement, while in the two subjects receiving the 50 and 100 p,g supplements the serum folate level remained essentially the same. These results served to confirm that the minimum daily requirement was approximately 50 pg. 

Although it appears that there are folate-synthesizing organisms in the human gut, the folate that they produce does not appear to contribute significantly to the host s folate nutrition. As a consequence man is wholly dependent on food as a source of the vitamin. 

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J. R. Bertino, P. F. Nixon, and A. Nahas, Mechanism of uptake of folate monoglutamates and their metabolism. In Folic Acid Biochemistry and Physiology in Relation to Human Nutrition Requirements, National Academy of Sciences, Washington, D. C. 1977, p. 178. 

Based on folate concentrations in liver biopsy samples, and assuming that the liver contains about half of ail body stores, total body stores of folate are estimated to be between 12 and 28 Kinetic studies that show both fast-turnover and very-slow-turnover folate pools indicate that about 0.5% to 1% of body stores are catabolized or excreted daily,suggesting a minimum daily requirement of between 60 and 280)Llg to replace losses. In calculating nutritional requirement, the concept of dietary folate equivalents (DFE) has been used to adjust for the nearly 50% lower bioavailabihty of food folate compared with supplemental folic acid, such that 1 p.g DFE = 0.6 Llg of folic acid from fortified food = 1 j,g of food folate 0.5 p.g foUc acid supplement taken on an empty stomach. Before the fortification program of cereal grains with folic acid conducted between 1988 and 1994, the median intake of folate from food in the United States was approximately 250p.g/day this figure is expected to increase by about 100 Llg/day after fortification. Recommendations... 

There have been a number of studies on folate nutrition in the elderly and in this article they have been separated from the nutritional folate-deficiency anemias because in the elderly folate deficiency is a special problem. Tlie elderly are particularly prone to folate deficiency because, not only do many have only a moderate to poor diet which may result from poor circumstances or a lack of interest in food, but they appear to utilize the vitamin less efficiently. As a result they may have an increased requirement. 

C4. Cooper, B. A., Physiology of absorption of mono utamyl folates from the gastrointestinal tract. In Folic Acid Biochemistry and Physiology in Relation to Human Nutrition Requirement (C. E. Butterworth, ed.)p. 188. Nad. Acad. Sci., Washington, D.C.,... 

Beck, J. T. and Ullman, B. (1990) Nutritional requirements of wild-type and folate transport-deficient Leishmania donovani for pterins and folates. Mol. Biochem. Parasitol. 43 221-230. 

Considerable uncertainty and controversy exists concerning the folate requirement for humans. Hie review of data concerning the human folate requirement by the Food and Nutrition Board (1989) suggests that the daily maintenance requirement is 100-200 fig of avaUable folic acid equivalents. The 1989 RDAs were reduced to 200 and 180 fig for adult men and women, respectively, from the previous RDA of 400 on the basis of such evidence (Food and Nutrition Board, 1989). Similarly, the Canadian RDA for folate was set at 3 /ig/kg body wt or 210 fig for a 70-kg individual. These lower RDAs may be inadequate for certain population groups, however (Sauberlich, 1990 Bailey, 1992 McPartlin etai, 1 3). It is currently difficult or impossible to predict the quantitative effect on folate nutritional status of factors such as (a) changes in folate intake, (b) differences in folate bioavailability, (c) effects of pregnancy and lactation on folate requirements, and (d) pharmaceuticals with antifolate properties. In addition, the development of mathematical models would improve our ability to evaluate methods of nutritional status assessment for this vitamin. 

FAO/WHO (Food and Agriculture Organization/World Health Organization) (1988) Requirements of Vitamin A, Iron, Folate and Vitamin B12. Joint Expert Consultation Report. FAO Food and Nutrition Series 23, FAO, Rome. 

A further problem with studies in patients maintained on long-term total parenteral nutrition is that they are not normal healthy subjects - there is some good medical reason for their treatment Furthermore, they will have little or no enterohepatic recirculation of vitamins, and hence may have considerably higher requirements than normal there is considerable enterohepatic circulation of folate (Section 10.2.1) and vitamin B12 (Section 10.7.1). 

Bailey LB and Gregory JF, 3rd (1999) Folate metabolism and requirements. Journal of Nutrition 129,779-82. 

The effect of nitrous oxide on vitamin B12 and folate metabolism can cause megaloblastic bone marrow changes, the period required depending on the patient s nutritional status (32). 

It is estimated that the minimum daily requirement of folate is 5 micrograms/kg. Liver stores are about 160 micrograms in premature children, and 220 micrograms in full-term infants. Infants who require parenteral nutrition will rapidly become folate deficient unless fohc acid is included in the regimen. Since many multivitamin supplements do not contain folic acid, its inclusion should be ensured by the addition of folic or folinic acid. 

The data in Table 9.2 concern a study in rats. The animals were raised on nutritionally complete diets or vitamin Bi2-deficient diets for 3 months. Then urine was collected over the course of a day and used for analysis of metabolites related to folate and vitamin B12 (FIGLU and methylmalonic acid). The data show that B12 deficiency induces a dramatic increase in urinary FIGLU. Rats do not require a... 

Reference Intakes for folate have been reported (Food and Nutrition Board 1998) (Table 44.2). The high frequency of folate deficiency has led the Food and Drug Administration in the United States to require folic acid fortification of all enriched cereals and grain products since January 1998. Folate deficiency is a major public health concern both northern and southern countries, and affects both industrialized and non-industrialized nations. In non-industrialized countries, it is particularly accentuated by poverty, limited access to food resources, and infectious diseases (Change and Abdennebi-Najar, 2011). 

Although folate deficiency is one of the common parameters of PCM, only rarely has it been singled out in clinical studies of nutritional effects on immunity. It is worth mentioning that the effect of infection on folate requirements in infants and adults remains to be established. The stress of infection superimposed on low reserves, inadequate nutrition, vitamin loss through diarrhea, vomiting, etc., and increased cell turnover could well render the... 

Food and Agriculture Organization (FAO), Requirements of Vitamin A, Iron, Folate, Vitamin B12. Report of a Joint FAO/WHO Expert Consultation, FAO Food Nutrition Series No. 23, Food Agriculture Organization, Rome, 1988, p. 107. 

Food, Agriculture OrganizationAVorld Health Organization (1989) Requirements of vitamin A, iron, folate, and vitamin Bj2. Report of a joint FAOAVHO Expert Committee. FAO Food and Nutrition Series 23, Rome Food and Nutrition Board, Institute of Medicine (USA) (1997) Dietary reference intakes. Nutr Rev 55 319-326... 

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