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Megaloblastic Macrocytic Anemias

by Alan E. Lichtin, MD

Megaloblastic anemias result most often from deficiencies of vitamin B 12 and folate. Ineffective hematopoiesis affects all cell lines but particularly RBCs. Diagnosis is usually based on a CBC and peripheral smear, which may show a macrocytic anemia with anisocytosis and poikilocytosis, large oval RBCs (macro-ovalocytes), hypersegmented neutrophils, and reticulocytopenia. Treatment is directed at the underlying disorder.

Macrocytes are enlarged RBCs (ie, MCV > 100 fL/cell). Macrocytic RBCs occur in a variety of clinical circumstances, many unrelated to the megaloblastosis and the resultant anemia. Macrocytosis may be due to megaloblasts or other enlarged RBCs (see Nonmegaloblastic Macrocytosis). Megaloblasts are large nucleated RBC precursors with noncondensed chromatin. Megaloblastosis precedes macrocytic anemia.

Etiology

The most common cause of megaloblastic states is deficiency or defective utilization of vitamin B 12 (see Vitamin B 12 Deficiency) or folate (see Folate Deficiency). Other causes include drugs (generally antineoplastics or immunosuppressants) that interfere with DNA synthesis and rare metabolic disorders (eg, hereditary orotic aciduria); some cases are of unknown etiology.

Pathophysiology

Megaloblastic states result from defective DNA synthesis. RNA synthesis continues, resulting in a large cell with a large nucleus. All cell lines have dyspoiesis, in which cytoplasmic maturity is greater than nuclear maturity; this dyspoiesis produces megaloblasts in the marrow before they appear in the peripheral blood. Dyspoiesis results in intramedullary cell death, making erythropoiesis ineffective and causing indirect hyperbilirubinemia and hyperuricemia. Because dyspoiesis affects all cell lines, reticulocytopenia and, during later stages, leukopenia and thrombocytopenia develop. Large, oval RBCs (macro-ovalocytes) enter the circulation. Hypersegmentation of polymorphonuclear neutrophils is common; the mechanism of their production is unknown.

Symptoms and Signs

Anemia develops insidiously and may not cause symptoms until it is severe. Deficiencies of vitamin B 12 may cause neurologic manifestations, including peripheral neuropathy, dementia, and subacute combined degeneration. Folate deficiency may also cause diarrhea and glossitis. Many patients with folate deficiency appear wasted, particularly with temporal wasting.

Diagnosis

  • CBC, RBC indices, reticulocyte count, and peripheral smear

  • Sometimes bone marrow examination

Megaloblastic anemia is suspected in anemic patients with macrocytic indices. Diagnosis is usually based on peripheral smear. When fully developed, the anemia is macrocytic, with MCV > 100 fL/cell. The smear shows macro-ovalocytosis, anisocytosis, and poikilocytosis. The RBC distribution width (RDW) is high. Howell-Jolly bodies (residual fragments of the nucleus) are common. Reticulocytopenia is present. Hypersegmentation of the granulocytes develops early; neutropenia develops later. Thrombocytopenia is often present in severe cases, and platelets may be bizarre in size and shape. If the diagnosis is questionable, a bone marrow examination may be needed.

Treatment

Before treatment, the cause must be identified. Deficiency of vitamin B 12 or folate is suspected if megaloblastic anemia is recognized; these disorders are indistinguishable on the basis of peripheral blood and bone marrow findings, so vitamin B 12 and folate levels are required ( Folate Deficiency : Treatment and see Vitamin B 12 Deficiency : Treatment).

Treatment depends on the cause. For treatment of folate and vitamin B 12 deficiencies, see Folate Deficiency : Treatment and see Vitamin B 12 Deficiency : Treatment. Drugs causing megaloblastic states may need to be eliminated or given in reduced doses.

Key Points

  • Macrocytes are enlarged RBCs (ie, MCV > 100 fL/cell); megaloblasts are large nucleated RBC precursors with noncondensed chromatin.

  • Megaloblastosis precedes macrocytic anemia.

  • The most common causes of megaloblastic, macrocytic anemia are deficiency or defective utilization of vitamin B 12 or folate.

  • Do CBC, RBC indices, reticulocyte count, and peripheral smear; do vitamin B 12 and folate levels in patients with characteristic findings.

  • Treat the cause.

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