Is Folic Acid Good for Everyone?

Oxford Project to Investigate Memory and Ageing, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.
American Journal of Clinical Nutrition (Impact Factor: 6.77). 04/2008; 87(3):517-33.
Source: PubMed


Fortification of food with folic acid to reduce the number of neural tube defects was introduced 10 y ago in North America. Many countries are considering whether to adopt this policy. When fortification is introduced, several hundred thousand people are exposed to an increased intake of folic acid for each neural tube defect pregnancy that is prevented. Are the benefits to the few outweighed by possible harm to some of the many exposed? In animals, a folic acid-rich diet can influence DNA and histone methylation, which leads to phenotypic changes in subsequent generations. In humans, increased folic acid intake leads to elevated blood concentrations of naturally occurring folates and of unmetabolized folic acid. High blood concentrations of folic acid may be related to decreased natural killer cell cytotoxicity, and high folate status may reduce the response to antifolate drugs used against malaria, rheumatoid arthritis, psoriasis, and cancer. In the elderly, a combination of high folate levels and low vitamin B-12 status may be associated with an increased risk of cognitive impairment and anemia and, in pregnant women, with an increased risk of insulin resistance and obesity in their children. Folate has a dual effect on cancer, protecting against cancer initiation but facilitating progression and growth of preneoplastic cells and subclinical cancers, which are common in the population. Thus, a high folic acid intake may be harmful for some people. Nations considering fortification should be cautious and stimulate further research to identify the effects, good and bad, caused by a high intake of folic acid from fortified food or dietary supplements. Only then can authorities develop the right strategies for the population as a whole.

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Available from: Helga Refsum, Mar 29, 2014
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    • "Folate/FA deficiency is linked to anemia, atherosclerosis, NTDs, adverse pregnancy outcomes, psychiatric disorders, and cancers (Bailey et al., 2003; Brito et al., 2012; Giovannucci, 2002; Reynolds, 2014), but FA intervention trials in humans are inconsistent and are not completely supportive of protective effects of FA supplementation except in the case of NTDs (Bønaa et al., 2006; Clarke et al., 2010; Lonn et al., 2006). Therefore, it has been questioned whether extra folic acid through food fortification is really beneficial to the majority of the population (Smith et al., 2008). Foods were fortified in the United States beginning in 1996 after the FDA approved fortification of grains at a dose of 140 ug FA/100 g of food to place approximately 100 ug FA more into the average adult diet (Table 1) (Hoyo et al., 2011a). "
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    ABSTRACT: Epigenetic mechanisms are now recognized to play roles in disease etiology. Several diseases increasing in frequency are associated with altered DNA methylation. DNA methylation is accomplished through metabolism of methyl donors such as folate, vitamin B12, methionine, betaine (trimethylglycine), and choline. Increased intake of these compounds correlates with decreased neural tube defects, although this mechanism is not well understood. Consumption of these methyl donor pathway components has increased in recent years due to fortification of grains and high supplemental levels of these compounds (e.g. vitamins, energy drinks). Additionally, people with mutations in one of the enzymes that assists in the methyl donor pathway (5-MTHFR) are directed to consume higher amounts of methyl donors to compensate. Recent evidence suggests that high levels of methyl donor intake may also have detrimental effects. Individualized medicine may be necessary to determine the appropriate amounts of methyl donors to be consumed, particularly in women of child bearing age. Copyright © 2015. Published by Elsevier Ltd.
    Progress in Biophysics and Molecular Biology 04/2015; 118(1-2). DOI:10.1016/j.pbiomolbio.2015.03.007 · 2.27 Impact Factor
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    • "Hyperhomocysteinemia is prevented with serum folate level of Z 4.0 ng/mL, thus accounting for some sources using a level of 4.0 ng/mL or greater as normal [7] [13] [16] [17]. However, even using the prevention of elevated serum level of homocysteine may require a serum folate level of about 7.0 ng/mL for an optimal effect [18] [19] [20]. "
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    ABSTRACT: Objective: Assess the need for folate testing, frequency of corrective action, and determine reference level for serum folate. Methods: Serum folate levels in 5313 samples from 4448 patients, and clinical data were reviewed for patient characteristics and for (a) evidence of corrective action in patients with serum folate values <5.5 ng/mL, and (b) differences in patients with serum folate levels <5.5 ng/mL and patients with levels >25.7 ng/mL. Results: The prevalence of serum folate levels, in patients, <3.0, <4.0, <5.5, <7.0 and <13.0 ng/mL was 0.58%, 1.55%, 4.9%, 9.98% and 43.21% respectively. Patients with serum folate levels <5.5 ng/mL had lower serum albumin and hemoglobin. In 64% of patients with serum folate >25.7 ng/mL the sample was collected after supplementation with folic acid. Of the 128 patients with serum folate <5.5 ng/mL documentation of supplementation was present in only 38.9%. Conclusions: Serum folate levels are below the current "normal" level of 3.0 ng/mL in a larger proportion of tertiary care patients than that reported for ambulatory patients. In patients with folate deficiency, corrective action is lacking in >60% of the patients. Since serum folate levels ≥13.0 ng/mL are needed for optimal prevention of neural tube defects in the embryo/fetus, we propose that normal serum folate level should be designated to be ≥ 13.0 ng/mL.
    04/2015; 1(1):35-41. DOI:10.1016/j.plabm.2015.03.005
    • "available methyl groups and worsening the impact on non-proliferating cells of the nervous system (Scott and Weir, 1998; Smith et al., 2008). "
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    ABSTRACT: Folate is a vitamin that plays a role as a cofactor and coenzyme in many essential reactions. These reactions are interrelated and any change in folate homeostasis could affect other reactions. With food fortified with folic acid, and use of multivitamin, unmetabolized folic acid (UMFA) has been detected in blood circulation, particularly among older adults. This has raised concern about the potential harmful effect of high folic acid intake and UMFA on health conditions such as cognitive dysfunction and cancer. To examine what is known about folate metabolism and the release of circulating UMFA, the Key Events Dose-Response Framework (KEDRF) was used to review each of the major key events, dose-response characteristics and homeostatic mechanisms of folate metabolism. The intestine, liver and kidneys each play essential roles in regulating body folate homeostasis. But the determining event in folate metabolism leading to the release of UMFA in circulation appears to be the saturation of dihydrofolate reductase in the liver. However, at each of the key events in folate metabolism, limited information is available on threshold, homeostatic regulation and intracellular effects of folic acid. More studies are needed to fill in the knowledge gaps for quantitatively characterizing the dose-effect relationship especially in light of the call for extending folate fortification to other foods.
    Critical Reviews in Food Science and Nutrition 02/2015; DOI:10.1080/10408398.2013.807221 · 5.18 Impact Factor
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