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Folate


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Qian Sun, Ph.D.

Last author update: 14 April 2025
Last staff update: 14 April 2025

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PubMed Search: Folate deficiency

Qian Sun, Ph.D.
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Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Diagrams / tables | Pathophysiology | Clinical features | Test indications | Laboratory | Comparison studies of platforms or methodologies | Practice question #1 | Practice answer #1 | Practice question #2 | Practice answer #2
Cite this page: Sun Q. Folate. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/chemistryfolate.html. Accessed April 29th, 2025.
Definition / general
  • Folate, also known as vitamin B9, is essential for red blood cell formation, healthy cell growth and function and proper development of embryos and fetuses
  • Low serum folate levels can occur in patients with inadequate dietary intake, malabsorption syndromes, hemolytic disorders or those taking certain medications
Essential features
  • Folate is found in many foods, including dark green leafy vegetables, beans, nuts, oranges, lemons, bananas and melons as well as fortified foods such as cereals and pasta
  • Balanced diet usually provides enough folate except in women who are planning to become pregnant, are pregnant or are breastfeeding; for these women, folic acid (synthetic form of folate) supplementation is recommended
  • Folate deficiency is characteristically associated with macrocytic anemia; evaluation of macrocytic anemia commonly requires simultaneous measurement of vitamin B12 and folate
Terminology
  • Folate deficiency
  • Macrocytic anemia
  • Neural tube defects
ICD coding
  • ICD-10
    • D52 - folate deficiency anemia
    • E53.8 - deficiency of other specified B group vitamins (including folate)
    • D53.9 - macrocytic anemia
    • Q05.9 - spina bifida, unspecified
Diagrams / tables

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Folic acid metabolism

Folic acid metabolism

Pathophysiology
  • Absorption of folate mainly occurs in the jejunum; once it is absorbed, folate is stored in the liver, blood and body tissues (Arch Intern Med 1999;159:1289)
  • Predominant form of folate in serum is L-5 methyl tetrahydrofolate (THF)
    • It enters the cells by binding to megalin, a folate receptor
    • Once inside the cells, folate takes part in a number of biologic processes such as DNA synthesis (Curr Opin Hematol 2006;13:119)
  • Biochemical pathway involving folate is shown in the above figure; folate functions as a 1 carbon source for DNA methylation and synthesis (Adv Nutr 2012;3:21)
  • Vitamin B12 deficiency can lead to folate deficiency by trapping an increased proportion of folate as THF (Mayo Clin Proc 1994;69:181)
  • Folate and vitamin B12 are required for the formation and proliferation of red blood cells (Annu Rev Nutr 2004;24:105)
    • Severe deficiency of either folate or vitamin B12 will cause megaloblastic changes, which will result in isolated anemia or other cytopenias
  • Body stores of folate are relatively small (5 - 10 mg) in adults; if dietary intake is not sufficient, it may take weeks to months to develop folate deficiency
  • Folate deficiency is the main cause of neural tube defects; since the neural plate formation takes place during the first month of pregnancy, supplementation should start at least 1 month before conception and continues through the first 3 months of pregnancy (JAMA 2023;330:454)
  • Certain medications can interfere with folate metabolism and cause folate deficiency; those include methotrexate, phenytoin, valproate, trimethoprim and pyrimethamine (Drugs 1985;30:145, Sci Rep 2021;11:4393)
Clinical features
  • Symptoms of folate deficiency anemia include fatigue, heart palpitations, pale skin, shortness of breath and dizziness
  • Patients with folate deficiency anemia would have decreased hemoglobin and hematocrit, mean corpuscular volume (MCV) > 100 in complete blood count (CBC) and macrocytic red blood cells or megaloblasts on peripheral smear
  • Neural tube defects are among the most common congenital malformations and are birth defects of the brain, spinal cord and overlying tissues (JAMA 2023;330:454)
  • Some of the most common forms of neural tube defects include
    • Anencephaly: cranial portion of the neural tube fails to close
    • Encephalocele: protrusion of the brain tissue
    • Spina bifida: a group of conditions that vary in severity, including myelomeningocele (protrusion of spinal cord and meninges), meningocele (protrusion of meninges) and spina bifida occulta (spinal defects without protrusion)
  • Folic acid fortification programs have been implemented in ~80 countries to reduce neural tube defects (J Med Screen 2022;29:138)
  • Hypersegmentation of neutrophil nuclei on peripheral blood smear due to disrupted DNA synthesis
  • Hypersegmented neutrophils have 6 or more nuclear lobes, whereas normal neutrophils have 3 - 5 lobes; in addition to megaloblastic anemia due to vitamin B12 or folic acid deficiency, other causes of hypersegmented neutrophils include myelodysplastic syndromes, rare congenital conditions and certain medications
Test indications
  • Patient populations with a high risk of folate deficiency include patients who underwent bariatric surgery or suffer from chronic hemolytic anemia, chronic alcohol use, malnutrition and conditions with high cell turnover
  • Patients who have been diagnosed with or show symptoms of megaloblastic anemia
Laboratory
  • Serum folate measurement is more commonly offered compared to red blood cell folate for assessing folate deficiency; fewer laboratories now offer red blood cell folate tests because they are more costly, require pretreatment steps and have higher analytical variation (Clin Chem Lab Med 2013;51:555)
    • Red blood cell folate tends to be less subject to short term dietary changes because serum folate levels tend to fall within a few days of reduced dietary intake when the folate tissue stores may still be normal
  • Nonfasting samples may yield falsely increased results
  • Hemolysis significantly increases folate concentrations due to the high folate content in red blood cells
  • Both vitamin B12 and folate deficiency can cause megaloblastic anemia
    • It is recommended to perform the 2 tests at the same time
    • To differentiate between the deficiencies of vitamin B12 and folate, serum homocysteine and methylmalonic acid (MMA) levels can be tested
    • Vitamin B12 promotes the metabolism of MMA for energy production and in conjunction with folic acid, helps to convert homocysteine to methionne
    • In patients with vitamin B12 deficiency, elevations of both homocysteine and MMA are seen
    • In patients with folate deficiency, only homocysteine concentration is typically elevated while MMA is normal (Arch Intern Med 1999;159:1289)
Comparison studies of platforms or methodologies
Practice question #1
Which of the following statements is true about serum folate testing?

  1. Folate deficiency may be seen in patients who are taking methotrexate
  2. Folate tests should be done for patients diagnosed with microcytic anemia
  3. Hemolysis does not significantly affect folate test results
  4. Red blood cell folate test is simpler to perform and provides lower analytical variation compared with serum folate test
Practice answer #1
A. Folate deficiency may be seen in patients who are taking methotrexate. Low serum folate concentrations may be seen in patients who take certain medications such as methotrexate. Answer B is incorrect because folate tests should be done in patients with macrocytic anemia. Answer C is incorrect because hemolysis significantly increases folate test results. Answer D is incorrect because red blood cell folate tests show higher analytical variation compared with serum folate tests due to pretreatment steps.

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Reference: Folate
Practice question #2
Both vitamin B12 and folate deficiency can cause megaloblastic anemia. To differentiate between the deficiency of vitamin B12 and folate, homocysteine and methylmalonic acid (MMA) may be tested. Which of the following results suggest folate deficiency?

  1. Both homocysteine and MMA are elevated
  2. Homocysteine concentration is decreased, MMA is normal
  3. Homocysteine concentration is elevated, MMA is normal
  4. MMA concentration is decreased, homocysteine is normal
  5. MMA concentration is elevated, homocysteine is normal
Practice answer #2
C. Homocysteine concentration is elevated, MMA is normal. In patients with vitamin B12 deficiency, elevations of both metabolites should be seen. In patients with folate deficiency, only homocysteine concentration should be elevated. Answer A is incorrect because elevated MMA is specific to vitamin B12 deficiency and is not seen in folate deficiency. Answer B is incorrect because this result does not fit with either folate or vitamin B12 deficiency. Deficiencies in these vitamins typically cause elevated homocysteine levels, not decreased levels. Answer D is incorrect because decreased MMA is not associated with either folate or vitamin B12 deficiency. Folate deficiency leads to elevated homocysteine. Answer E is incorrect because this result is indicative of vitamin B12 deficiency, as elevated MMA is specific to this condition. Folate deficiency does not affect MMA levels and typically causes elevated homocysteine levels.

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Reference: Folate
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