Folic acid causes higher prevalence of detectable unmetabolized folic acid in serum than B-complex: a randomized trial

Obeid, Rima; Kirsch, Sarah; Dilmann, Sarah; Klein, Cosima; Eckert, Rudolf; Geisel, Jürgen; Herrmann, Wolfgang

doi:10.1007/s00394-015-0916-z

Cited by 21 publications

(14 citation statements)

References 38 publications

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“…The recommended daily intake for adults is 0.4 mg with a recommended tolerable upper intake level of 1 mg (16). However, there are groups in the population that are consuming 4–5 mg/day, primarily due to the increased use of vitamin supplements (17,18). Concerns have emerged about the possible consequences of high folic acid intake; these concerns include increased growth of sub-clinical tumors, the possibility of masking B 12 deficiency and impaired immune function (16,19).…”

Section: Introductionmentioning

confidence: 99%

High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring

et al. 2017

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Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C > T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex. Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid.

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Section: Introductionmentioning

confidence: 99%

High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring

et al. 2017

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“…Furthermore, adults age 20–59 years were 2 times less likely to have UMFA concentrations >1 nmol/L compared to participants ≥60 years of age [36]. Though our model explored only a few variables of interest, we found sex and dietary folic acid intake to be independent variables that explain UMFA concentrations ≥ 0.55 nmol/L.…”

Section: Discussionmentioning

confidence: 96%

“…The investigators gave the participants either a daily supplement of folic acid or folic acid plus cyanocobalamin and pyridoxine. After supplementation, participants who received the B-complex had lower postintervention serum UMFA concentrations and prevalence of UMFA ≥0.21 nmol/L, compared to the folic acid group, suggesting that vitamins B6 and B12 are needed to efficiently metabolize folic acid and natural folate [36]. …”

Section: Discussionmentioning

confidence: 99%

Association between Serum Unmetabolized Folic Acid Concentrations and Folic Acid from Fortified Foods

Palchetti

Paniz

Carli

et al. 2017

Journal of the American College of Nutrition

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Objective To investigate the association between serum unmetabolized folic acid (UMFA) concentrations and folic acid from fortified foods and nutrients known as dietary methyl-group donors (folate, methionine, choline, betaine and vitamins B2, B6 and B12) in participants exposed to mandatory fortification of wheat and maize flours with folic acid. Methods Cross-sectional study carried out with 144 healthy Brazilian participants, both sexes, supplement nonusers. Serum folate, UMFA, vitamin B12 and total plasma homocysteine (tHcy) were biochemically measured. Dietary intake was assessed by 2 non-consecutive 24-hour dietary recalls (24-HRs) and deattenuated energy-adjusted nutrient data were used for statistical analysis. Results Ninety eight (68.1%) participants were women. Median (interquartile range) age was 35.5 (28.0–52.0) years. Elevated serum folate concentrations (>45 nmol/L) were found in 17 (11.8%), while folate deficiency (<7 nmol/L) in 10 (6.9%) participants. No one had vitamin B12 deficiency (<148 pmol/L). An elevated serum UMFA concentration was defined as > 1 nmol/L (90th percentile). UMFA concentrations were positively correlated with folic acid intake and negatively correlated to choline, methionine and vitamin B6 intakes. Participants in the lowest quartile of UMFA concentrations had lower dietary intake of total folate (DFEs) and folic acid, and higher dietary intake of methionine, choline and vitamin B6 than participants in the highest quartile of UMFA. Folic acid intake (OR [95% CI] D 1.02 [1.01–1.04)] and being a male (OR [95% CI] = 0.40 [0.19–0.87) were associated with increased and reduced odds for UMFA concentrations > 0.55 nmol/L (median values), respectively. Conclusion UMFA concentrations were directly influenced by folic acid intake from fortified foods in a healthy convenience sample of adult Brazilians exposed to mandatory flour fortification with folic acid.

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“…Furthermore, unmetabolized free folic acid is found in serum samples from nearly all people who consume folic acid-containing foods (Pfeiffer et al, 2015). The amount of free serum folic acid increases with greater consumption of folic acid (Palchetti et al, 2017), but appears to be partially dependent on other nutrient statuses (Obeid et al, 2016;Palchetti et al, 2017). Variation exists in the dihydrofolate reductase enzyme and individuals with decreased enzyme activity are at higher risk of high blood concentrations of free folic acid (Bailey & Ayling, 2009).…”

Section: Toxicitymentioning

confidence: 99%

Global Concerns with B Vitamin Statuses: Biofortification, Fortification, Hidden Hunger, Interactions, and Toxicity

Titcomb

Tanumihardjo

2019

Comp Rev Food Sci Food Safe

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The prevalence of undernutrition due to insufficient energy intake has been reduced by nearly 50% since 1990. This reduction is largely attributed to improved yields of staple crops, such as wheat, rice, and maize; however, these improvements did little for micronutrient deficiencies that affect an estimated two billion people worldwide. Starchy staple crops are energy dense but are often lacking in one or more B vitamins, making resource‐constrained people who consume monotonous diets comprised predominantly of these staples at risk for developing deficiency. B vitamin deficiencies occur due to a poor overall nondiversified diet and rarely occur alone. Many B vitamins are essential cofactors involved in the metabolism of other nutrients, including other B vitamins, whereby the deficiency of one B vitamin affects the metabolism and status measurements of another. Food fortification efforts have nearly eradicated diseases of extreme B vitamin deficiency, such as beriberi from thiamin deficiency and pellagra from niacin deficiency. However, subclinical deficiency, sometimes referred to as hidden hunger, is still common especially in low‐income countries. Most dietary B vitamins, due to their water‐soluble nature, are not a concern for excessive intakes, but synthetic forms used for fortification and supplements sometimes can have adverse effects when consumed in high amounts. Biofortified crops offer a long‐term sustainable method to increase the amount of dietary B vitamins for people who rely on staple crops for most of their caloric intake. Efforts have been made to improve B vitamin content of crops, especially for thiamin, vitamin B6, and folate, but none have undergone human feeding trials; therefore, more research is needed to provide sustainable and scalable solutions in many parts of the world.

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Folic acid causes higher prevalence of detectable unmetabolized folic acid in serum than B-complex: a randomized trial

Cited by 21 publications

References 38 publications

High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring

High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring

Association between Serum Unmetabolized Folic Acid Concentrations and Folic Acid from Fortified Foods

Global Concerns with B Vitamin Statuses: Biofortification, Fortification, Hidden Hunger, Interactions, and Toxicity

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