Folate Deficiency

Also see Anemia: General Considerations.

Definition, Etiology, Pathogenesis Top

Folate deficiency leads to abnormalities of DNA synthesis, resulting in megaloblastic anemia. Minimum daily dietary folate requirements in adults are 0.1 to 0.15 mg (0.6 mg in pregnant women and 0.5 mg in breastfeeding women). The main sources of folate are green vegetables, citrus fruits, nuts, yeast, and animal products (liver). The body stores of folate cover up to a 4-month requirement. After being absorbed in the gastrointestinal (GI) tract, folate is converted to tetrahydrofolate; the conversion occurs only in the presence of cobalamin (vitamin B12). In many nations dietary folate supplementation has completely eliminated this disorder.

Causes of folate deficiency:

1) Inadequate dietary intake: Low consumption of fresh foods or foods boiled for a short time only (boiling for >15 minutes causes the degradation of folate), in particular of green vegetables, and total parenteral nutrition without folate supplementation.

2) Inadequate absorption: Crohn disease.

3) Chronic liver disease (mainly cirrhosis).

4) Drugs: Phenytoin, sulfasalazine, folate antagonists (methotrexate, trimethoprim).

5) Alcohol dependency.

6) Zinc deficiency.

7) Increased folate demand: Chronic hemolysis, pregnancy, breastfeeding, inflammatory conditions, malignancy.

8) Increased folate loss: Renal replacement therapy, chronic hemolytic anemia.

Clinical Features Top

Clinical features are the same as in cobalamin deficiency (see Cobalamin Deficiency) except for nervous system manifestations and jaundice. Focal cutaneous and mucosal hyperpigmentation (the former particularly on the dorsal areas of fingers) also may be observed. Folate deficiency may cause infertility.

DiagnosisTop

Diagnostic Tests

1. Complete blood count (CBC): As in cobalamin deficiency.

2. Biochemical studies: Decreased plasma (or red blood cell [RBC]) folate levels, features of moderate hemolysis (elevated serum lactate dehydrogenase levels, decreased haptoglobin levels, minor increases in unconjugated bilirubin levels), increased serum iron levels.

3. Bone marrow biopsy: As in cobalamin deficiency.

Diagnostic Criteria

Reduced folate levels. RBC folate may be more reliable than serum folate.

Differential Diagnosis

Cobalamin deficiency, other types of anemia associated with dyserythropoiesis (sideroblastic anemia, myelodysplastic syndromes), other conditions associated with RBC macrocytosis (alcohol dependency, cirrhosis, purine inhibitors [methotrexate, mercaptopurine, cyclophosphamide, zidovudine, trimethoprim, hydroxyurea], hypothyroidism, reticulocytosis).

Treatment Top

1. Treatment of the underlying condition.

2. A diet rich in high-folate food (see Definition, Etiology, Pathogenesis, above).

3. Oral folic acid 0.8 to 1.2 mg/d (up to 5 mg/d in patients with malabsorption) for 1 to 4 months, until the normalization of hematologic parameters or as long as the cause of folate deficiency persists. The effectiveness of treatment is evidenced by a rapid increase in reticulocyte counts on days 4 to 7 of treatment. In the early stages of treatment, hypokalemia may occur. Starting folate treatment alone in a patient with coexisting cobalamin deficiency may cause an acute onset of neurologic manifestations (or their worsening, if already present).

4. A common practice is to give folate in patients with an expected increased need, for example, those with hemolytic anemia or those with a recovering marrow after a bleeding event; the evidence for this is weak.