Megaloblastic anemias result most often from deficiencies of vitamin B₁₂ 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 Sidebar 1: Anemias Caused by Deficient Erythropoiesis: Nonmegaloblastic Macrocytosis). Megaloblasts are large nucleated RBC precursors with noncondensed chromatin. Megaloblastosis precedes macrocytic anemia.

Sidebar 1
Nonmegaloblastic Macrocytosis
Macrocytosis in Liver Disease Most macrocytic (ie, MCV >100 fL/cell) anemias are megaloblastic. Nonmegaloblastic macrocytosis occurs in various clinical states, not all of which are understood. Anemia commonly occurs in patients with macrocytosis but usually results from mechanisms independent of macrocytosis. Macrocytosis due to excess RBC membrane occurs in patients with chronic liver disease when cholesterol esterification is defective. Macrocytosis with an MCV of about 100 to 105 fL/cell can occur with chronic alcohol use in the absence of folate deficiency. Mild macrocytosis can occur in aplastic anemia, especially as recovery occurs. Macrocytosis is also common in myelodysplasia. Because RBC membrane molding occurs in the spleen after cell release from the marrow, RBCs may be slightly macrocytic after splenectomy, although these changes are not associated with anemia. Nonmegaloblastic macrocytosis is suspected in patients with macrocytic anemias when testing excludes vitamin B12 and folate deficiencies. The macro-ovalocytes on peripheral smear and the increased RBC distribution width that are typical of classic megaloblastic anemia may be absent. If nonmegaloblastic macrocytosis is unexplained clinically (eg, by the presence of aplastic anemia, chronic liver disease, or alcohol use) or if myelodysplasia is suspected, bone marrow examination and cytogenetic analysis are done to exclude myelodysplasia. In nonmegaloblastic macrocytosis, the marrow is not megaloblastic, but in myelodysplasia and advanced liver disease there are megaloblastoid RBC precursors with dense nuclear chromatin that differ from the usual fine fibrillar pattern in megaloblastic anemias.

Etiology

The most common cause of megaloblastic states is deficiency or defective utilization of vitamin B₁₂ (see Vitamin Deficiency, Dependency, and Toxicity: Vitamin B12 Deficiency) or folate (see Vitamin Deficiency, Dependency, and Toxicity: 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.

Oval Macrocytes and Hypersegmented Neutrophils in Vitamin B12 Deficiency

Symptoms and Signs

Anemia develops insidiously and may not cause symptoms until it is severe. Deficiencies of vitamin B₁₂ 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 B₁₂ 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 B₁₂ and folate levels are required (see Vitamin Deficiency, Dependency, and Toxicity: Treatment and see Vitamin Deficiency, Dependency, and Toxicity: Treatment).

Treatment depends on the cause. For treatment of folate and vitamin B₁₂ deficiencies, see see Vitamin Deficiency, Dependency, and Toxicity: Treatment and see Vitamin Deficiency, Dependency, and Toxicity: Treatment. Drugs causing megaloblastic states may need to be eliminated or given in reduced doses.

Last full review/revision June 2008 by Alan E. Lichtin, MD