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Megaloblastic Macrocytic Anemias

By Evan M. Braunstein, MD, PhD, Assistant Professor of Medicine, Division of Hematology, Department of Medicine, Johns Hopkins School of Medicine

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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 usually shows a macrocytic anemia with anisocytosis and poikilocytosis, large oval RBCs (macro-ovalocytes), hypersegmented neutrophils, and reticulocytopenia. Treatment is directed at the underlying disorder.

Megaloblasts are large nucleated RBC precursors with noncondensed chromatin. Macrocytes are enlarged RBCs (ie, MCV > 100 fL/cell). Macrocytic RBCs occur in a variety of clinical circumstances, many unrelated to megaloblastosis.

Nonmegaloblastic macrocytosis

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. Reticulocytosis (in a hemolytic anemia, for example) can also cause macrocytosis.

Nonmegaloblastic macrocytosis is suspected in patients with macrocytic anemias when testing excludes vitamin B12, folate deficiencies, and reticulocytosis. 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.


The most common causes of megaloblastic states are

The most common cause of B12 deficiency is pernicious anemia due to impaired intrinsic factor secretion (usually secondary to the presence of autoantibodies—see Autoimmune Metaplastic Atrophic Gastritis). Other common causes are malabsorption due to gastritis, gastric bypass or tapeworm infection. Dietary deficiency is rare.

Common causes of folate deficiency include celiac disease and alcoholism.

Other causes of megaloblastosis include drugs (generally antineoplastics such as hydroxyurea, or immunosuppressants) that interfere with DNA synthesis and rare metabolic disorders (eg, hereditary orotic aciduria).


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. 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.

Symptoms and Signs

Anemia develops insidiously and may not cause symptoms until it is severe. Gastrointestinal manifestations are common, including diarrhea, glossitis, and anorexia. Neurologic manifestations, including peripheral neuropathy, gait instability, and dementia, are unique to B12 deficiency and can be permanent if prolonged.


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

  • B12 and folate levels

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 in the absence of iron deficiency, thalassemia trait, or renal disease. 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.

Serum B12 and folate levels should be measured. A B12 level < 200 pg/mL or folate level < 2 ng/mL is generally diagnostic of deficiency. B12 levels between 200 to 300 pg/mL are nondiagnostic, and in this case, both a methylmalonic acid (MMA) and homocysteine (HCY) level should be checked. Serum levels of MMA and HCY are both elevated in B12 deficiency, while only HCY is elevated in folate deficiency.


  • Appropriate vitamin supplementation

Supplementation with the proper vitamin is required. Always rule out B12 deficiency prior to supplementation with folate. Failure to do so can mask a concomitant B12 deficiency and lead to progression of neurologic complications.

For treatment of folate and vitamin B12 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.

The etiology of any vitamin deficiency should also be investigated and treated.

Key Points

  • Megaloblasts are large nucleated RBC precursors with noncondensed chromatin.

  • The most common causes of megaloblastic, macrocytic anemia are deficiency or defective utilization of vitamin B12 or folate.

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

  • Measure vitamin B12 and folate levels and consider methylmalonic acid and homocysteine testing.

  • Treat the cause of B12 or folate deficiency.

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