Megaloblastic Anemia: Diagnosis and Treatment

Diagnosis

The complete hematologic picture includes:

• Large bone marrow precursor cells of neutrophils and erythrocytes (macro–ovalocytes) with an elevated mean corpuscular volume (MCV). Note: An elevated MCV may not be present if iron deficiency is concurrent.
• Hypersegmented neutrophil nuclei (6 lobes or greater or several 5–lobed cells).
• A complete blood count showing anemia. Severe anemia is possible with occasional hemoglobin values less than 5.0 g/dL.
• Normal or depressed reticulocyte counts.
• Marked lactate dehydrogenase (LDH) elevation (in the thousands) due to ineffective red blood cell production.
• Thrombocytopenia and neutropenia.

Bone marrow biopsy is usually not necessary for diagnosis, but typically shows megaloblastosis and hypercellularity with erythroid and myeloid hyperplasia.

Additional tests must be conducted to distinguish between folate and vitamin B₁₂ deficiencies, because the hematologic indices revealed by blood smear review and bone marrow aspirate are similar for both deficiency types.
Serum B₁₂ and folate and/or red blood cell folate concentration should be measured. Serum folate can be acutely elevated after a folate–rich meal, whereas red blood cell folate more accurately measures actual stores.

If the serum B₁₂ and folate results are not diagnostic, additional testing can be performed. Note that serum folate and vitamin B₁₂ assays may be rendered unreliable by pregnancy, alcohol intake, acute nutrition change, or medication use. In these instances, additional tests may aid diagnosis.

Serum methylmalonic acid is elevated in vitamin B₁₂ deficiency and is usually normal in folate deficiency.

Deficiency of vitamin B₁₂ or folate will elevate homocysteine.

Treatment

Identification of the underlying cause of vitamin B₁₂ or folate deficiency is necessary to ensure adequate long–term treatment.

Vitamin B₁₂

Vitamin B₁₂ injections (1000 µg) are usually given daily for 1 week, then weekly for 4 weeks, and then monthly until hematologic indices have stabilized. Patients with continued risk of deficiency should remain on monthly injections. Oral B₁₂ (1000–2000 µg/day) may be substituted in highly compliant patients. At high intakes, the vitamin enters the body through diffusion. Vitamin B₁₂ sublingual preparations and a nasal gel are also available for maintenance therapy when compliance is ensured.

Folate

Oral folate (1 mg) taken daily for several months usually corrects the deficiency.
Doses up to 5 mg may be used, if indicated.

Concomitant B₁₂ deficiency must be ruled out, as folate supplementation can mask the hematologic signs of B₁₂ deficiency, leading to irreversible neurological injury if not treated. This masking is more likely to occur in patients routinely prescribed folate for other medical reasons (eg, sickle cell anemia).²