Investigation of suspected folate deficiency
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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.(1)
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.(3) 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, forminotransferase deficiency, 5,10-methylenetetrahydrofolate reductase deficiency, and tetrahydrofolate methyltransferase deficiency)
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
> or =4.0 mcg/L
<4.0 mcg/L suggests folate deficiency
Serum folate is a relatively nonspecific test.(3) 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.
Results <4 mcg/L are suggestive of folate deficiency. The cutoff is based on consensus and was derived from the US NHANES III data.(4)
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.
Additional testing with homocysteine and methylmalonic acid (MMA) determinations may help distinguish between B12 and folate deficiency states. In folate deficiency, homocysteine levels are elevated and MMA levels are normal. In vitamin B12 deficiency, both homocysteine levels and MMA levels are elevated.
See Pernicious Anemia Testing Cascade in Special Instructions.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
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.
Folates other than N-(5)-methyltetrahydrofolate and folic acid antagonists (such as methotrexate) may, under some circumstances, be present in serum and will also be measured by this method.
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.
Some patients who have been exposed to animal antigens, either in the environment or as part of treatment or imaging procedures, may have circulating anti-animal antibodies present. These antibodies may interfere with the assay reagents to produce unreliable results.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Fairbanks VF, Klee GG: Biochemical aspects of hematology. In Tietz Textbook of Clinical Chemistry. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 1999, pp 1690-1698
2. George L, Mills JL, Johansson AL, et al: Plasma folate levels and risk of spontaneous abortion. JAMA 2002 October 16;288:1867-1873
3. Klee GG: Cobalamin and folate evaluation: measurement of methylmalonic acid and homocysteine vs vitamin B12 and folate. Clin Chem 2000 August;46(8 Pt 2):1277-1283
4. Benoist BD: Conclusions of a WHO Technical Consultation on folate and vitamin B12 deficiencies. Food and Nutrition Bulletin 2008(volume 29, number 2) S238-S244