Elsevier

Biochimie

Volume 126, July 2016, Pages 71-78
Biochimie

Review
Excessive folic acid intake and relation to adverse health outcome

https://doi.org/10.1016/j.biochi.2016.04.010Get rights and content

Highlights

  • This is a review article which was written in response to the 2015 guidelines from the World Health Organization that: “high folic acid intake has not reliably been shown to be associated with negative health effects”.

  • It describes peer reviewed publication showing that excessive folic acid intake is not always safe.

  • In particular excessive intake of folic acid could have adverse health outcome in elderly with vitamin B12 deficiency, particularly with respect to cognitive function and anemia.

  • Other studies show diverse adverse effects, including lower natural killer cell activity in elderly women, increase in insulin resistance in offspring of mothers from India with high folic acid intake and increase in incident of breast cancer and other cancers in women with polymorphism of the dihydrofolate gene (19 bp deletion).

Abstract

The recent increase in the intake of folic acid by the general public through fortified foods and supplements, has raised safety concern based on early reports of adverse health outcome in elderly with low B12 status who took high doses of folic acid. These safety concerns are contrary to the 2015 WHO statement that “high folic acid intake has not reliably been shown to be associated with negative healeffects”. In the folic acid post-fortification era, we have shown that in elderly participants in NHANES 1999–2002, high plasma folate level is associated with exacerbation of both clinical (anemia and cognitive impairment) and biochemical (high MMA and high Hcy plasma levels) signs of vitamin B12 deficiency. Adverse clinical outcomes in association with high folate intake were also seen among elderly with low plasma B12 levels from the Framingham Original Cohort and in a study from Australia which combined three elderly cohorts. Relation between high folate and adverse biochemical outcomes were also seen in the Sacramento Area Latino Study on Aging (High Hcy, high MMA and lower TC2) and at an outpatient clinic at Yale University where high folate is associated with higher MMA in the elderly but not in the young.

Potential detrimental effects of high folic acid intake may not be limited to the elderly nor to those with B12 deficiency. A study from India linked maternal high RBC folate to increased insulin resistance in offspring. Our study suggested that excessive folic acid intake is associated with lower natural killer cells activity in elderly women. In a recent study we found that the risk for unilateral retinoblastoma in offspring is 4 fold higher in women that are homozygotes for the 19 bp deletion in the DHFR gene and took folic acid supplement during pregnancy. In the elderly this polymorphism is associated with lower memory and executive scores, both being significantly worse in those with high plasma folate. These and other data strongly imply that excessive intake of folic acid is not always safe in certain populations of different age and ethnical/genetic background.

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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