Folate deficiency

Folate deficiency is most commonly caused by malnutrition, e.g., in individuals with insufficient dietary intake or alcohol use disorder. Patients typically present with signs of anemia (e.g., fatigue). Initial laboratory studies show macrocytic anemia, circulating megaloblasts, and, in some cases, pancytopenia. Low fasting serum folate levels confirm the diagnosis, but sensitivity is limited; if levels are normal, RBC folate or plasma homocysteine testing should be performed. Treatment of folate deficiency consists of oral folate replacement and increasing dietary intake of folate-rich foods, e.g., leafy green vegetables, fruits, and fortified foods.

• 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)

• Malnutrition
  • Insufficient intake (e.g., “tea and toast” diet)
  • Alcohol use disorder
• Malabsorption
  • Small bowel disease (e.g., tropical sprue, celiac disease, inflammatory bowel disease)
  • Surgical procedures (e.g., resection of the small intestine, gastric bypass)
• Increased requirement
  • Pregnancy or lactation
  • Severe hemolytic anemia
  • Exfoliative skin disease (e.g., eczema) ^[2][3]
• Medication-related ^[4]
  • Methotrexate
  • Antiepileptic drugs (e.g., phenytoin)
  • Sulfonamides
  • Trimethoprim

Decreased folate levels lead 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 ^[5][6]

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

Unlike vitamin B₁₂ deficiency, folate deficiency does not typically cause neurological symptoms; rarely, neuropsychiatric conditions (e.g., cognitive impairment, depression) or peripheral neuropathy can occur. ^[7][8]

Initial studies ^[3]

• Evaluate CBC and morphology.
  • CBC: macrocytic anemia (MCV > 100 μm³)
  • Peripheral blood smear: oval macrocytes, circulating megaloblasts; , and hypersegmented neutrophils
• Rule out vitamin B₁₂ deficiency.
  • Vitamin B₁₂ level
  • Methylmalonic acid (MMA): normal in folate deficiency ^[9]

In folate deficiency, MMA is normal; in vitamin B₁₂ deficiency, MMA is elevated.

Diagnostic confirmation ^[2][3]

• Fasting serum folate level (first line): < 3 ng/dL (limited sensitivity) ^[2][3][10]
• If folate level is normal, obtain either:
  • Plasma homocysteine: ↑ (sensitive, but not specific)
  • RBC folate: ↓

Additional evaluation

Consider further assessment based on the suspected underlying cause.

• Assessment of nutritional status
• Diagnostics for malabsorption
• Diagnostics for celiac disease
• Diagnostics for alcohol use disorder

• Initiate folate replacement in patients with confirmed folate deficiency. ^[2][3]
  • Folic acid
  • Duration of treatment depends on the underlying cause.
• Encourage consumption of folate-rich foods, e.g., leafy green vegetables, fruits, and fortified foods.
• Manage the underlying condition.
• See also “Folic acid supplementation in pregnancy.”

In combined vitamin B₁₂ and folate deficiency, folate replacement without vitamin B₁₂ may exacerbate neurological symptoms. Rule out vitamin B₁₂ deficiency before starting folate replacement. ^[11]

Folic acid supplementation is recommended for all individuals planning or capable of pregnancy because of the risk of neural tube defects due to maternal folate deficiency. ^[12]