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. 2022 Dec 1:537:96-104.
doi: 10.1016/j.cca.2022.09.019. Epub 2022 Oct 17.

The establishment of LC-MS/MS assays-specific reference intervals for serum folates and its application in evaluating FA-supplemented folate deficiency patients: Appeals for a suitable and individualized supplementation

Zhenni Liu  1 , Lizi Jin  1 , Jiangtao Zhang  2 , Weiyan Zhou  1 , Jie Zeng  2 , Tianjiao Zhang  1 , Chuanbao Zhang  3
Affiliations

The establishment of LC-MS/MS assays-specific reference intervals for serum folates and its application in evaluating FA-supplemented folate deficiency patients: Appeals for a suitable and individualized supplementation

Zhenni Liu et al. Clin Chim Acta. .

Abstract

Background: Little known about folates status in folate deficiency patients. This study aims to establish liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay-specific reference intervals (RIs) for serum 5-Methyltetrahydrofolate (5MeTHF), folic acid (FA), 5-Formyltetrahydrofolate (5FoTHF), and total folate (TFOL), and investigate the folates status in FA-supplemented folate deficient patients.

Methods: Sera from 120 reference subjects were selected and measured. An LC-MS/MS method for serum 5MeTHF, FA, and 5FoTHF was employed. RIs were derived based on the CLSI C28-A3. Serum folate levels of 38 FA-supplemented folate deficiency patients were analyzed.

Results: RIs (median) for 5MeTHF, FA, 5FoTHF, and TFOL were 3.83-62.33 nmol/L (12.27 nmol/L), 0.30-0.92 nmol/L (0.49 nmol/L), <0.73 nmol/L (0.00 nmol/L), and 4.17-63.47 nmol/L (12.66 nmol/L), respectively. Approximately 53 % (20/38), 74 % (28/38), and 63 % (24/38) of patients presented high levels of 5MeTHF, FA, and TFOL, respectively, which far exceeded the upper reference limit (URL) of the corresponding RIs. A half (18/38) of patients showed simultaneously higher 5MeTHF and FA levels which were beyond the URLs of RIs. Near one-third (11/38) of patients exhibited extremely high FA levels which exceeded the 100-fold URL of RIs. The highest levels can be 539 nmol/L for FA, 364 nmol/L for 5MeTHF, and 686 nmol/L for TFOL.

Conclusions: LC-MS/MS assay-specific RIs were established for folates vitamers without age or gender partitioning. Abnormally high levels of unmetabolized FA and 5MeTHF were observed in quite a few FA-supplemented patients. Considering the adverse risks caused by folates excess, we appeal for a justifiable and individualized FA supplementation. We also recommend establishing LC-MS/MS assay-specific RIs for routine monitoring of folates status.

Keywords: Folate deficiency; Folic acid; Fortification; Liquid chromatography-tandem mass spectrometry; Neural tube defects; Reference interval.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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