Clinical and Interpretive

The term folate refers to all derivatives of folic acid. For practical purposes, serum folate is almost entirely in the form of N-(5)-methyl tetrahydrofolate. Approximately 20% of the folate absorbed daily is derived from dietary sources; the remainder is synthesized by intestinal microorganisms. Serum folate levels typically fall within a few days after dietary folate intake is reduced and may be low in the presence of normal tissue stores. RBC folate levels are less subject to short-term dietary changes.

Significant folate deficiency is characteristically associated with macrocytosis and megaloblastic anemia. Lower than normal serum folate also has been reported in patients with neuropsychiatric disorders, in pregnant women whose fetuses have neural tube defects, and in women who have recently had spontaneous abortions. Folate deficiency is most commonly due to insufficient dietary intake and is most frequently encountered in pregnant women or in alcoholics.

Other causes of low serum folate concentration include:
-Excessive utilization (eg, liver disease, hemolytic disorders, and malignancies)
-Rare inborn errors of metabolism (eg, dihydrofolate reductase deficiency, formiminotransferase deficiency, 5,10-methylenetetrahydrofolate reductase deficiency, and tetrahydrofolate methyltransferase deficiency)

Serum folate is a relatively nonspecific test. Low serum folate levels may be seen in the absence of deficiency and normal levels may be seen in patients with macrocytic anemia, dementia, neuropsychiatric disorders, and pregnancy disorders. Evaluation of macrocytic anemias commonly requires measurement of the serum concentration of both vitamin B12 and folate; ideally they should be measured at the same point in time.

Serum folate measurement is preferred over RBC folate measurement due to considerable analytic variability (coefficient of variation: CV) of assays. Both results give the same interpretation (internal Mayo study) therefore RBC folate quantitation is not recommended. Additional serum testing with homocysteine and methylmalonic acid (MMA) determinations may help distinguish between vitamin B12 and folate deficiency states. In folate deficiency, homocysteine levels are elevated and MMA levels are normal. In vitamin B12 deficiency, the analytic variability (CV) of both serum and RBC folate assays is considerable. Homocysteine and MMA levels are alternate determinates of folate deficiency.

Patients with combined deficiency of folate and iron may not demonstrate the erythrocyte macrocytosis that is typical of folate deficiency anemia. In these patients, however, the red cell distribution width (RDW) will typically be elevated.

Nonfasting specimens yield falsely elevated results. Recent folic acid administration or dietary folate intake could result in normal or elevated values and possibly mask an underlying folate deficiency.