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Folate (Folic Acid) 

  • Author: Rugheed Ghadban, MD; Chief Editor: Eric B Staros, MD  more...
 
Updated: Dec 11, 2013
 

Reference Range

Testing the folate level, which is also known as folic acid and vitamin B9, is primarily used in the diagnosis of megaloblastic anemia.

The reference range of the plasma folate level varies by age, as follows[1] :

  • Adults: 2-20 ng/mL, or 4.5-45.3 nmol/L
  • Children: 5-21 ng/mL, or 11.3-47.6 nmol/L
  • Infants: 14-51 ng/mL, or 31.7-115.5 nmol/L

The reference range of the red blood cell (RBC) folate level also varies by age, as follows[1] :

  • Adults: 140-628 ng/mL, or 317-1422 nmol/L
  • Children: Over 160 ng/mL, or over 362 nmol/L
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Interpretation

The plasma folate level is very sensitive to dietary changes; it reflects the short-term balance of folate[2, 3] and can decline after few days of fasting, even when folate stores are normal. Conversely, the plasma folate level can be restored to normal with one folate-rich meal.

The RBC folate level is less affected by recent dietary changes; it reflects tissue folate adequacy better than the plasma folate level, since it reflects a time-averaged value of folate. However, measuring the RBC folate level is not entirely free of limitations.[4] Results may be reported as falsely low, especially in pregnancy and alcoholism,[5] as well as in vitamin B-12 deficiency. Cellular uptake of folate requires vitamin B-12, so vitamin B-12 deficiency can decrease RBC folate levels and increase the plasma folate levels.

A plasma folic acid level of more than 4 ng/mL can rule out folate deficiency.

In the absence of recent anorexia or fasting, a plasma folic acid level of less than 2 ng/mL is diagnostic of folate deficiency.

In the following cases, additional tests are indicated for accurate diagnosis, including RBC folate, methylmalonic acid, and homocysteine[4] :

  • Plasma folic acid level of 2-4 ng/mL
  • Plasma folic acid level of less than 2 ng/mL in the presence of recent anorexia or fasting
  • Suspected combined folate and vitamin B-12 deficiency

Causes of folate deficiency include the following[5] :

The following are causes of increased folate levels[5] :

  • Blind loop syndrome
  • Vegetarian diet
  • Vitamin B-12 deficiency (vitamin B-12 deficiency can cause increased plasma and decreased RBC folate levels, as it causes decreased cellular uptake)
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Collection and Panels

Plasma folate test[1, 7]

Specimen type: Venous blood

Container: Red-top tube or serum-separator tube

Collection method: Venipuncture

Specimen volume: 10 mL

Collection instructions: Test should be performed after 8-hour fast; avoid vitamin B12 injection before test

Other instructions: Avoid agitation of the tube or light exposure to avoid hemolysis, as it can cause falsely elevated plasma level; the sample should be refrigerated; if it will not be tested within 24 hours, it needs to be frozen to -10°C

RBC folate test[1, 7]

Specimen type: Venous blood

Container: EDTA anticoagulant

Collection method: Venipuncture

Specimen volume: 5 mL

Collection instructions: Test should be performed after 8-hour fast; avoid vitamin B12 injection before test

Other instructions: A hematocrit determination is also required; the sample should be refrigerated; if it will not be tested within 24 hours, it needs to be frozen to -10°C

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Background

Description

Folate is also known as folic acid and vitamin B-9. Its molecular formula is C19 H19 N7 O6.

Folic acid itself is not biologically active, but its biological importance is due to tetrahydrofolate and other derivatives after its conversion from dihydrofolic acid in the liver.

Folate is found in food in polyglutamyl forms; different types of food contain different numbers of glutamic. The polyglutamyl form of folate is hydrolyzed to a monoglutamyl form (the absorbable form) by the enzyme folate conjugase, which is found mainly in the brush border of the intestinal mucosal cells. This enzyme is also found within cells.[8]

Dihydrofolate is then reduced in the liver by the enzyme dihydrofolate reductase to tetrahydrofolate, which is essential for de novo purine and thymidylate synthesis in the cells as a part of synthesis and repair of DNA .

Folate is usually found in the following foods[9] :

  • Meats: Liver, chicken, kidney, egg yolk
  • Legumes: Dried beans, lentils, soya products, almonds, nuts
  • Starches: Whole-grain breads, wheat flour, potatoes
  • Fruit and vegetables: Spinach, beetroot, Brussel sprouts, broccoli, cabbage, asparagus, banana, oranges, peaches

Normal folate requirements are about 200-400 µg/day. The requirement in pregnant and lactating individuals increases to 500-800 µg/day.

Healthy individuals have about 500-20000 µg of folate stored, mainly in the liver.

Indications/Applications:

The main indication for folate testing is in the workup of megaloblastic anemia and hypersegmented neutrophils.

Screening for folic acid deficiency is performed by checking the serum folic acid level. RBC levels are not recommended as a screening test, but rather as a diagnostic test when serum levels are not diagnostic as mentioned above.[10]

Pregnancy is not an indication for routine folate screening, although it is an indication for prophylactic folate supplementation.

Folate deficiency is treated with folic acid supplementation and management of the underlying cause.

Considerations

The main presentation of folate deficiency is megaloblastic anemia without neurologic changes, in contrast to vitamin B-12 deficiency, in which neurologic changes may be observed.

Folic acid can partially reverse some of the hematologic abnormalities of vitamin B-12 deficiency but not the neurologic manifestation. Thus, megaloblastic anemia is not treated with folic acid until vitamin B-12 deficiency is excluded.

Folate deficiency can also cause congenital neural tube defects, the incidence of which is reduced by the administration of folic acid supplements in pregnant women.

The fact that folic acid is required for synthesis and repair of DNA makes it a target for many cancer medications.

Folate deficiency may increase methotrexate toxicity.

Studies have failed to find a statistically significant cancer risk due to folic acid supplements.[11, 12]

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Contributor Information and Disclosures
Author

Rugheed Ghadban, MD Resident Physician, Department of Internal Medicine, St Louis University Hospital

Rugheed Ghadban, MD is a member of the following medical societies: American Medical Association, National Arab American Medical Association, Syrian American Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Rajaa Almourani, MD Resident Physician, Department of Internal Medicine, St Louis University Hospital

Rajaa Almourani, MD is a member of the following medical societies: National Arab American Medical Association, Syrian American Medical Society

Disclosure: Nothing to disclose.

Chief Editor

Eric B Staros, MD Associate Professor of Pathology, St Louis University School of Medicine; Director of Clinical Laboratories, Director of Cytopathology, Department of Pathology, St Louis University Hospital

Eric B Staros, MD is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology

Disclosure: Nothing to disclose.

References
  1. Fischbach F, Dunning MB. Manual of Laboratory and Diagnostic Tests. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2008.

  2. Green R, Kinsella LJ. Current concepts in the diagnosis of cobalamin deficiency. Neurology. 1995 Aug. 45(8):1435-40. [Medline].

  3. Tefferi A, Pruthi RK. The biochemical basis of cobalamin deficiency. Mayo Clin Proc. 1994 Feb. 69(2):181-6. [Medline].

  4. Antony AC. Megaloblastic anemias. Hoffman R, Benz EJ, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 4th ed. New York, NY: Churchill-Livingstone; 2005.

  5. Dsai SP. Clinician’s Guide to Laboratory Medicine. 3rd ed. Lexicomp; 2009.

  6. Pruthi RK, Tefferi A. Pernicious anemia revisited. Mayo Clin Proc. 1994 Feb. 69(2):144-50. [Medline].

  7. Chernecky CC, Berger BJ. Laboratory Tests and Diagnostic Procedures. 6th ed. Philadelphia, Pa: WB Saunders; 2012.

  8. FAO Corporate Document Repository. Chapter 4. Folate and Folic Acid. Available at http://www.fao.org/DOCREP/004/Y2809E/y2809e0a.htm. Accessed: August 27, 2012.

  9. KwaZulu-Natal Department of Health. Foods Rich in Folic Acid and Vitamin B-12. Available at http://www.kznhealth.gov.za/nutrition/food6.htm. Accessed: August 27, 2012.

  10. Galloway M, Rushworth L. Red cell or serum folate? Results from the National Pathology Alliance benchmarking review. J Clin Pathol. 2003 Dec. 56(12):924-6. [Medline]. [Full Text].

  11. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med. 2010 Oct 11. 170(18):1622-31. [Medline].

  12. Weinstein SJ, Hartman TJ, Stolzenberg-Solomon R, et al. Null association between prostate cancer and serum folate, vitamin B(6), vitamin B(12), and homocysteine. Cancer Epidemiol Biomarkers Prev. 2003 Nov. 12(11 Pt 1):1271-2. [Medline].

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