ReviewExcessive folic acid intake and relation to adverse health outcome
Introduction
In the guideline entitled “The optimal serum and red blood cell folate concentrations in women of reproductive age for the prevention of neural tube defects”, published in 2015, the World Health Organization (WHO) stated that “high folic acid intake has not reliably been shown to be associated with negative health effects” [1]. In this statement the WHO panel appears to have ignored those studies that were published in peer reviewed journals which have consistently shown that excessive folic acid intake is not always safe particularly as it applies to certain vulnerable segments of the population [2], [3], [4]. The evidence ignored or under-valued by this report is the substance of this review.
Section snippets
What is folic acid?
Folic acid, the fully oxidized and synthetic form of the vitamin folate found in supplements and fortified foods and not naturally in foods was first synthesized in 1945 [5]. It requires post-absorptive reduction to tetrahydrofolate (THF) for its metabolic activation. This reduction, which is required for incorporation of folic acid into body folate pools, is a two-step reaction catalyzed by dihydrofolate reductase (DHFR). The first step of this reaction, the conversion of folic acid to
The history of folic acid use in treatment of pernicious anemia
Excessive folic acid intake is entwined with the history and discovery of pernicious anemia (PA). Pernicious anemia is a disease caused by vitamin B12 deficiency which is primarily manifested as megaloblastic anemia, macrocytosis and neurological symptoms. Megaloblastic anemia and macrocytosis, but not the neurological symptoms, are also present in folate deficiency. This similarity between folate and vitamin B12 deficiencies with respect to hematological symptoms, stems from the participation
Folic acid fortification of grain products for the prevention of neural tube defects (NTD) and the debate on the safety of folic acid
The risks of excessive folic acid intake in the presence of unrecognized vitamin B12 deficiency have been widely accepted in early years, but were questioned and doubted, mainly by advocates of food fortification with folic acid to prevent NTD [14], [15], [16], [17]. The claim was that these case reports are inconsistent and do not amount to statistical significance.
Assessing risks and benefits in the aftermath of folic acid fortification
Folic fortification of grain products in the USA which was officially implemented in 1998 and was associated with a substantial reduction of both spina bifida and anencephaly and possibly reduction of stroke mortality [18], [19]. In the Framingham Offspring Cohort, fortification was associated with the doubling of plasma folate concentrations that practically eliminated the prevalence of folate deficiency [20]. Same increases in plasma folate were seen in the participants of National Health and
Exacerbation of vitamin B12 deficiency by high folate is also expressed biochemically
In mammals vitamin B12 functions as a coenzyme in two reactions. The methylation of homocysteine by 5-MTHF to form methionine, a reaction which is catalyzed by a methyl-cobalamin dependent methionine synthase and, in the isomerization of methylmalonyl-CoA to succinyl-CoA, a reaction which occurs in mitochondria and is catalyzed by MMA-CoA mutase which uses adenosyl-cobalamin as a coenzyme. Vitamin B12 deficiency is associated with elevation of both plasma homocysteine and methylmalonic acid
Separating the individual contributions of high folic acid intake vs low vitamin B12 status to adverse health outcomes
Our studies of the Framingham Heart Study Cohort (n = 549, mean age 74.5 years) have shown that, the annual rates of decline in mini mental exam (MMSE) scores over an 8-year follow up [31] were low in those with normal baseline vitamin B12 (>258 pmol/L) irrespective of supplemental folic acid intake (Fig. 8). Individuals with low baseline plasma vitamin B12 levels (<258 pmol/L), had a higher rate of annual decline when compared to those with normal vitamin B12, and the rate of decline was 2.5
Unmetabolized folic acid
Excessive intake of folic acid in man results in the appearance of unmetabolized folic acid (UMFA) in the circulation [7], [33], [34]. The physiological significance of UMFA in circulation is presently unknown, although it most likely represents excessive intake of folic acid or/and inhibited reduction of folic acid either through inhibition by antifolate agents or because of dihydrofolate reductase (DHFR) polymorphism [35].
Our study of the elderly participants in the1999–2002 NHANES [36],
Evidence from genetic polymorphism
A 19 bp deletion polymorphism in intron 1 of DHFR gene (rs70991108) is common among the US population with 20% homozygosity [38]. It has been implicated in neural tube defects and cancer, but the data have been inconsistent. Our study of the Offspring Framingham Cohort [35] has shown that high (>500 μg/d) folic acid intake is associated with significantly higher circulating UMFA in subjects who were homozygous for this polymorphism when compared to heterozygotes or those without the
Concluding remarks
In 1993 we published a paper showing that if plasma homocysteine is used as an indicator of B vitamin status, then one third of the US population, as represented by the Framingham Study Original Cohort, has insufficient status of folate, vitamin B12 and vitamin B6 [41]. This is in spite of the facts that close to 35% of the population take vitamins supplement. In this respect the food fortification with folic acid for the prevention of NTD, can be regarded as a welcome measure. However the
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