Vitamin Biomarkers: RBC Folate

Optimal Takeaways

Folate is an essential B vitamin with multiple metabolic roles. These include red and white blood cell production, DNA synthesis, and one-carbon metabolism, which helps activate several important compounds, including hormones, carnitine, and phosphatidylcholine. Low RBC folate may be due to insufficient folate or vitamin B12, which is required to uptake folate into the cell.

A high RBC folate can be seen with recent blood transfusions.

Standard Range: 280.00 – 1504 ng/mL (634.48 – 3408.06 nmol/L)

The ODX Range: 500 - 1504 ng/mL (1133 – 3408.06 nmol/L)

Low RBC folate is associated with neural tube defects (Crider 2014, WHO 2015, Chen 2019), overt folate insufficiency, malabsorption, malnutrition, cancer, pregnancy, alcoholism, hemolytic anemia, megaloblastic anemia, vitamin B12 deficiency (Pagana 2021), MTHFR 677 genotype TT, birth defects including oral clefts, congenital heart defects, restricted growth, low birth weight, and premature birth (Chen 2019), and hyperhomocysteinemia (Chan 2013).

High RBC folate may be seen with a recent transfusion (Pagana 2021) or prolonged high-dose supplementation.

Overview

Measuring red blood cell (RBC) folate is the best way to evaluate folate tissue levels. While serum folate reflects recent intake, RBC folate reflects intake over the lifespan of the RBC, as well as folate storage in the liver (Chen 2019). Low RBC folate may be due to overt folate insufficiency, or it can be due to a primary vitamin B12 deficiency, as B12 is required for cellular uptake of folate. It is important to evaluate folate and B12 together and provide targeted nutrition support accordingly (Pagana 2021). RBC folate, serum folate, and homocysteine levels should be part of a comprehensive assessment of folate status (Ohrvik 2011).

Red blood cell folate below 400 ng/mL (906.40 nmol/L) indicates insufficiency with progressively increased risk of folate depletion, hyperhomocysteinemia, hypersegmented neutrophils, impaired erythropoiesis, and megaloblastic anemia (Pfeiffer 2012). The minimum RBC folate threshold for preventing megaloblastic anemia is 135 ng/mL (305 nmol/L) (Chen 2019).

Red blood cell folate is a better indicator of long-term folate status than serum folate, which can fluctuate with intake and cellular uptake. The accumulation of folate in RBCs occurs only at the time of erythropoiesis. Therefore, levels respond slowly due to the 120-day lifespan of the RBC. According to the World Health Organization, RBC folate should be kept above 400 ng/mL (906 nmol/L) in pregnant women to reduce neural tube defects significantly (WHO 2015).

Research demonstrates neural tube defects (NTDs) as RBC folate increases. Data from two prospective population-based trials confirmed the need to maintain optimal RBC folate levels, especially early in pregnancy at 28 days gestation when the neural tube closes. Researchers found that a serum RBC folate above 440 ng/mL (1000 nmol/L) was associated with the lowest incidence of NTDs, while the highest incidence of NTDs was associated with RBC folate of 220.65 ng/mL (500 nmol/L) (Crider 2014). A 10-fold decrease in NTDs was observed with a 4-fold increase in RBC folate from 132.39 to 529.57 ng/mL (from 300 to 1200 nmol/L) in a population-based randomized trial of folic acid supplementation (Chen 2019).

Although food fortification with synthetic folic acid has reduced the incidence of NTDs, an excess can have adverse consequences (Naderi 2018). Elevations in unmetabolized folic acid inhibit folate, B12, and homocysteine metabolism. Therefore, the preferred form of supplemental folate is 5-MTHF (da Silva 2014). Supplementation or fortification with 5-MTHF results in significantly higher RBC folate than supplementation with synthetic folic acid (Scaglione 2014).

References

Chan, Yen-Ming et al. “Folate.” Advances in nutrition (Bethesda, Md.) vol. 4,1 123-5. 1 Jan. 2013, doi:10.3945/an.112.003392

Chen, Meng-Yu et al. “Defining the plasma folate concentration associated with the red blood cell folate concentration threshold for optimal neural tube defects prevention: a population-based, randomized trial of folic acid supplementation.” The American journal of clinical nutrition vol. 109,5 (2019): 1452-1461. doi:10.1093/ajcn/nqz027

Crider, Krista S et al. “Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model.” BMJ (Clinical research ed.) vol. 349 g4554. 29 Jul. 2014, doi:10.1136/bmj.g4554

da Silva, Robin P et al. “Novel insights on interactions between folate and lipid metabolism.” BioFactors (Oxford, England) vol. 40,3 (2014): 277-83. doi:10.1002/biof.1154

Naderi, Nassim, and James D House. “Recent Developments in Folate Nutrition.” Advances in food and nutrition research vol. 83 (2018): 195-213. doi:10.1016/bs.afnr.2017.12.006

Ohrvik, Veronica E, and Cornelia M Witthoft. “Human folate bioavailability.” Nutrients vol. 3,4 (2011): 475-90. doi:10.3390/nu3040475

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Pfeiffer, Christine M et al. “Estimation of trends in serum and RBC folate in the U.S. population from pre- to postfortification using assay-adjusted data from the NHANES 1988-2010.” The Journal of nutrition vol. 142,5 (2012): 886-93. doi:10.3945/jn.111.156919

Scaglione, Francesco, and Giscardo Panzavolta. “Folate, folic acid and 5-methyltetrahydrofolate are not the same thing.” Xenobiotica; the fate of foreign compounds in biological systems vol. 44,5 (2014): 480-8. doi:10.3109/00498254.2013.845705

Sobczyńska-Malefora, Agata, and Dominic J Harrington. “Laboratory assessment of folate (vitamin B9) status.” Journal of clinical pathology vol. 71,11 (2018): 949-956. doi:10.1136/jclinpath-2018-205048

World Health Organization. Serum and red blood cell folate concentrations for assessing folate status in populations. No. WHO/NMH/NHD/EPG/15.01. World Health Organization, 2015.