Folate Deficiency

Background

• Folate refers to a family of water-soluble vitamins that are naturally present in food (especially dark-green leafy vegetables, legumes, and certain fruits); folic acid is a synthetic, stable, oxidized form of folate used in supplements and fortified foods.
• The incidence of folate deficiency has declined with increasing fortification of foods, which began in 1998 in the United States and Canada in an effort to reduce the incidence of neural tube defects.
• Mechanisms of folate deficiency include:
  • reduced intake, for example, due to poor diet, or alcohol use disorder
  • malabsorption, for example, due to alcohol use disorder, gastrointestinal diseases (especially celiac disease, Crohn disease, and, tropical sprue in developing countries), and drugs
  • drug-induced interference with folate metabolism, for example, folate analogs, trimethoprim, and pyrimethamine
  • increased requirements, for example, due to pregnancy and lactation, neoplastic diseases, dialysis, or drugs
• Folates are essential cofactors in 1-carbon metabolism. They accept or donate single carbons in a network of inter-connected metabolic pathways including de novo synthesis of purine nucleotides, generation of deoxythymidylate, and methylation reactions of DNA, RNA, and protein. Vitamin B12 is required as a cofactor for the conversion of 5-methyl tetrahydrofolate (THF) to biologically active THF.
• Patients may be asymptomatic, or may present with symptoms of anemia, pancytopenia, neurological impairment, or neural tube defects (in newborns).
• Differential diagnosis includes:
  • other megaloblastic causes of macrocytosis (for example, vitamin B12 deficiency, abuse/recreational use of nitrous oxide, inborn errors of metabolism, thiamin responsive megaloblastic anemia, and drugs, specifically purine and pyrimidine nucleoside analogs that block DNA synthesis)
  • nonmegaloblastic causes of macrocytosis (such as increased reticulocytes due to hemolytic anemia or treatment with erythropoietin, alcohol use disorder, liver disease, myelodysplastic syndrome (MDS), aplastic anemia, Fanconi anemia, Diamond-Blackfan anemia, and hypothyroidism)

Evaluation

• Suspect folate deficiency in patients with unexplained anemia of macrocytosis, especially those at high risk including those with alcohol use disorder, suspected malabsorptive diseases that may cause dietary deficiency, conditions associated with high demand for folate (especially pregnancy and perinatal period), or history of medications known to affect serum folate level.
• For patients with strong clinical suspicion of folate deficiency:
  • Perform complete blood count and peripheral blood smear.
  • Measure the serum folate level. A serum folate level < 3 mcg/L (7 nmol/L) indicates folate deficiency (Strong recommendation).
  • Evaluate for an underlying or coexistent vitamin B12 deficiency (Strong recommendation).
  • Measure other biomarkers of megaloblastic anemia (lactic dehydrogenase, bilirubin, iron studies).
  • Consider red blood cell folate if there is a strong clinical suspicion of folate deficiency in patients with a normal serum folate level and if vitamin B12 deficiency is ruled out (Weak recommendation).
  • Consider measuring plasma homocysteine to confirm a suspected folate deficiency in selected cases. Plasma levels > 15 mcmol/L may indicate a folate deficiency but should be assessed relative to local ranges.

Management

• In patients with folate deficiency and megaloblastic anemia (Strong recommendation):
  • who are not pregnant, give folic acid 5,000 mcg/day for 4 months
  • who are pregnant, give folic acid 5,000 mcg/day until term if pregnant
  • who have a malabsorptive disorder, give folic acid up to 15,000 mcg/day for 4 months
• Prophylactic folic acid supplementation:
  • In patients with chronic hemolytic states and renal dialysis, offer folic acid 5,000 mcg/day - 5,000 mcg/week, depending on diet and hemolytic rate (Strong recommendation).
  • For women who are pregnant or considering pregnancy, offer prophylactic folic acid (Strong recommendation). 400 mcg/day is the most commonly recommended dose, but higher doses may be appropriate for specific patients.
• Monitor response to treatment. A complete blood count 10-14 days after starting treatment should show increased hemoglobin and decreased mean corpuscular volume. A full hematologic response should occur within 8 weeks.