A complete picture of the various serum folate forms after the introduction of folic acid fortification of foods is now possible with the advent of liquid-chromatography tandem-mass-spectrometry. That technology made it possible to measure unmethylated folic acid (UMFA), 5-methyltetrahydrofolate (5-methyl-THF), tetrahydrofolate (THF), 5-formyltetrahydrofolate (5-formyl-THF), 5,10-methenyltetrahydrofolate (5,10-methenyl-THF), and an oxidation product of 5-methyl-THF (MeFox). The initial analyses from NHANES samples were impacted by technical issues, including calibration bias. Fazili and colleagues published a report detailing the serum folate forms measured from NHANES 2011-2016 in the April 2020 issue of The Journal of Nutrition.

Fasting samples from subjects (n = 10,070) at least 1 year of age and older were used for analyses. Geometric means of 5-methyl-THF, UMFA, nonmethyl folates (sum of THF, 5-formyl-THF, 5,10-methenyl-THF), total folate (sum of all), and MeFox were calculated.

Age, sex, and race (Hispanic origin) were associated with most folate forms, even after adjusting for demographic factors. MeFox increased with age but was lower for non-Hispanic blacks, non-Hispanic Asians, and Hispanics. U-shaped age patterns were observed for 5-methyl-THF, UMFA, and nonmethyl folate. Subjects with chronic kidney disease had higher UMFA and MeFox concentrations. Higher levels of UMFA were typically observed in supplement users and older individuals. These data led the authors to conclude that there must be biological and/or genetic influences on folate metabolism since there were differing folate forms based on demographic, physiologic, and lifestyle characteristics.

In a commentary on this article, Miller describes the fact that elevated UMFA is present because of high exposure to folic acid, and that renal clearance is critical in its elimination as those with chronic kidney disease have higher concentrations. Although the Fazili study did not take into consideration common genetic polymorphisms that impact folate metabolism, Miller thinks it does establish the utility of the newer analytical techniques, and it elaborates on the confounding factors that must be considered in future studies.

References Fazili Z, Sternberg MR, Potischman N, Wang C-Y, Storandt RJ, Yeung L, Yamini S, Gahche JJ, Juan WY, Qi YP, Paladugula N, Gabey G, Pfeiffer CM. Demographic, physiologic, and lifestyle characteristics observed with serum total folate differ among folate forms: Cross-sectional data from fasting samples in the NHANES 2011-2016. Journal of Nutrition, DOI: https://doi.org/10.1093/jn/nxz278.

Commentary provided by Miller JW. Factors associated with different forms of folate in human serum: The folate folio continues to grow. Journal of Nutrition, DOI: https://doi.org/10.1093/jn/nxaa046.

Images credit: canva.com