The A to Z of Testing for Folate Deficiency

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Folic Acid is an important nutrient in our diets.  During the 1990s when the relationship between folic acid deficiency and neural tube defects was demonstrated, the FDA required the addition of folic acid supplements to certain foods.   Today we monitor pregnant patients for folate deficiency and, when detected, supplemental folate is prescribed.  The other medical condition in which folate stores commonly are evaluated are patients presenting with a macrocytic anemia. 


Serum Folate vs. Red Blood Cell Folate Levels

Periodically there is discussion as to which test is better to determine folate levels:  serum folate or red blood cell folate. Dietary sources contribute approximately 20% of the body folate with the remainder synthesized and generated by intestinal microorganisms.    Approximately 90+ per cent of body folate is located in red blood cells and the other 10% is present in serum.  Because the level of folate is higher in red blood cells than serum, many take the position that the RBC folate levels are a better measure of this analyte.  The additional argument is made that the serum folate will represent the recent dietary intake and will show fluctuation while the RBC folate is more stable giving a better estimate in “true” folate levels.  However, the answer is not that simple:

  1. RBC folate analysis demonstrates a greater degree of variation (i.e. decreased precision with increased coefficient of variation) because of the pre-treatment lysing of the red blood cells in processing a blood sample for analysis that may not always be done in a uniform manner.
  2. Furthermore, the RBC folate is more hands-on and time consuming to perform. It is not efficient to perform RBC folate at near patient sites, whereas the serum folate is more readily performed at the point of care and results are available in a shorter time.
  3. Multiple studies have demonstrated that overall RBC and serum folate testing provide equivalent data and RBC testing is unnecessary. Furthermore, studies have established that there is no need to perform both types of testing on a given patient.

In light of the demonstration of the essential equivalency of the two tests, the recommendations is to perform just a serum folate level when testing for folic acid deficiency.


Vitamin B12 and Folate Testing

Because vitamin B12 deficiency can also cause megaloblastic anemia and because in some instances increasing exogenous folic acid may correct the hematologic morphologic change in B12 deficiency but not halt the progression of neurologic disease, when faced with a patient with a macrocytic anemia both vitamin B 12 and folic acid determinations should be measured at the same time.


Other Testing to Differentiate Folic Acid from Vitamin B12 Deficiency

In distinguishing between a folic acid and a vitamin B12 deficiency, testing for homocysteine and methylmalonuc acid (MMA) levels may be performed.  In folate deficiency, homocysteine levels are elevated and MMA levels are normal. 


Final Thoughts

In your laboratory, if you find certain practitioners are ordering RBC folate more commonly than serum folate, it might prove helpful to discuss their reasoning behind the RBC folate ordering.  If the test is being performed for screening for a deficiency, you might suggest that the results of the two tests are comparable and result turn-around-time could be improved and laboratory efficiency enhanced by ordering the serum analysis.  We owe it to our clients to provide them with testing and utilization advice if we are going to provide a quality service.


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About the author

Dr. John Daly

John T. Daly, M.D. received his MD degree at Weill Cornell University Medical College, performed his internship and residency in Anatomic and Clinical pathology at Duke University Medical Center and a residency in Forensic Pathology at the Office of the Chief Medical Examiner in Chapel Hill, N.C. He is board certified in anatomic, clinical and forensic pathology. Through the course of his career, Dr. Daly has had extensive experience directing and advising laboratories of all sizes including physician office practices, Federal Health Clinics, surgical centers, Community Hospitals and the integrated academic health system clinical laboratories of Duke Medicine. He retired as Director of Laboratories of Duke Medicine, and continues his affiliation as a member of the emeritus staff.


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