Detectable Unmetabolized Folic Acid and Elevated Folate Concentrations in Folic Acid-Supplemented Canadian Children With Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a variant (rs344) in the HBB gene encoding the β-globin subunit of hemoglobin. Chronic hemolytic anemia and increased erythropoiesis and RBC turnover in individuals with SCD can result in increased needs for folate and other B-vitamins. We assessed B-vitamin status, and the distribution of folate forms, including unmetabolized folic acid (UMFA), in Canadian children with SCD supplemented with 1 mg/d folic acid (current routine practice). Non-fasted serum and plasma samples were analyzed for concentrations of folate, and vitamins B-2, B-6, and B-12. Eleven individuals (45% male; SCD type: HbSS n = 8, HbSC n = 2, HbSβ0-Thal n = 1), with a median (IQR) age of 14 (7, 18) years, were included. Total folate concentrations were 3–27 times above the deficiency cut-off (10 nmol/L), and 64% of children had elevated folate levels (>45.3 nmol/L). UMFA (>0.23 nmol/L) was detected in all children, and 36% of participants had elevated levels of UMFA (>5.4 nmol/L). All children were vitamin B-12 sufficient (>150 pmol/L), and the majority (55%) had sufficient B-6 status (>30 nmol/L). Among this sample of Canadian children with SCD, there was limited evidence of B-vitamin deficiencies, but UMFA was detectable in all children.

High Dietary Folic Acid Intake Is Associated with Genomic Instability in Peripheral Lymphocytes of Healthy Adults

“…Results from the NHANES 1999–2000 study revealed that 23% of the population and 43% of all children had elevated serum folates [ 62 ]. Unsurprisingly, UMFA was detected in most samples collected from US children, adolescent, and adults [ 11 , 33 , 34 , 35 ]. Controversially, UMFA can impair folate metabolism by inhibiting DHFR and MTHFR, potentially leading to a functional folate deficiency [ 39 , 40 ].…”

“…This process of activation is slow and rate limiting in humans causing FA to appear in the blood as unmetabolized FA (UMFA) and persisting in circulation for 12 h after fasting indicating poor handling by human tissues [ 31 , 32 ]. Reports from the United States reveal that UMFA is present in the majority of analyzed population samples [ 11 , 33 , 34 , 35 ]. Daily intake of FA exceeding 200 µg is positively correlated with chronically elevated UMFA levels in a dose dependent manner [ 11 , 18 , 33 ].…”

Emerging Role of Folate-Mediated One Carbon Metabolism in Leukemia: A Review

“…Due to its stability, greater bioavailability, and oxidized form, folic acid is frequently found in dietary supplements and foods fortified with folate. While naturally occurring folate is commonly found in foods such as leafy green vegetables, oranges, beans, and legumes (Williams et al, 2021). The biological effects of folate are carried out by tetrahydrofolate and other derivatives.…”