Folate deficiency

Folate (vitamin B₉) is an essential coenzyme that enables critical biochemical reactions. Dietary sources include naturally folate-rich foods such as leafy green vegetables, fruit and liver, but also supplements and fortified foods. Malnutrition and excessive alcohol use are the most common causes of deficiency. Folate deficiency causes impaired DNA synthesis, which leads to megaloblastic anemia. The clinical picture of anemia is similar to that of vitamin B₁₂ deficiency, although folate deficiency is generally not associated with neurological manifestations. Diagnosis is based on laboratory findings such as macrocytosis, hyperhomocysteinemia, and normal levels of methylmalonic acid. Therapy consists of oral supplementation.

• Folate ; : coenzyme in single-carbon transfers and methylation reactions → DNA synthesis and amino acid metabolism ^[1]
  • Active form: tetrahydrofolate (THF), obtained after reduction of folate by dihydrofolate reductase
  • Sources
    • Leafy green vegetables , fruits, and liver
    • Fortified foods (e.g., bread, flour, and cereal)
  • Absorption: in the jejunum
  • Storage: liver (stores folate for up to three months, after which time signs and symptoms of deficiency begin to appear)

Folate deficiency is the most common vitamin deficiency in the US.

• Malnutrition
  • Insufficient intake, malnutrition (e.g., “tea and toast” diet)
  • Chronic alcohol use
• Malabsorption
  • Small bowel disease (e.g., tropical sprue, celiac disease, inflammatory bowel disease)
  • Surgical resection of the small intestine
• Increased requirement
  • Pregnancy/lactation
  • Severe hemolytic anemia
• Drug-related ^[2]
  • Methotrexate
  • Antiepileptic drugs (e.g., phenytoin)
  • Sulfonamides
  • Trimethoprim

Decreased folate levels leads to decreased levels of tetrahydrofolate. This, in term, leads to the following effects:

• ↓ DNA synthesis → megaloblastic erythropoiesis → megaloblastic anemia (and ↓ in other cell lines)
• ↓ Methionine and ↑ homocysteine → endothelial damage → ↑ risk of cardiovascular disease and thromboembolic events
• During fetal development: nucleotide synthesis impairment → neural tube defects
• Aberrant DNA methylation → ↑ risk of cancer ^[3][4]

• Signs of anemia (e.g., fatigue, pallor)
• Glossitis
• Maternal deficiency: fetal spina bifida/anencephaly

Unlike vitamin B₁₂ deficiency, folate deficiency does not result in neurological symptoms.

• Macrocytic, megaloblastic anemia: ↑ MCV (> 100 μm³)
• ↑ Homocysteine
• Methylmalonic acid (MMA) is normal (unlike in vitamin B₁₂ deficiency, where MMA is ↑)
• Hypersegmented polymorphonuclear cells (PMNs)
• Folate serum levels are not reliable

If folate deficiency is suspected, always exclude the possibility of vitamin B12 deficiency.

• Oral folate supplementation for four months or until hematologic recovery takes place
• Nutritional counseling to increase folate intake

Because of the risk of neural tube defects, it is recommended that women planning to become pregnant initiate folate supplementation before conception.