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Megaloblastic Macrocytic Anemias


Evan M. Braunstein

, MD, PhD, Johns Hopkins School of Medicine

Last full review/revision Mar 2020| Content last modified Mar 2020
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Megaloblastic anemias result most often from deficiencies of vitamin B12 and folate. Ineffective hematopoiesis affects all cell lines but particularly red blood cells. Diagnosis is usually based on a complete blood count and peripheral smear, which usually shows a macrocytic anemia with anisocytosis and poikilocytosis, large oval red blood cells (macro-ovalocytes), Howell-Jolly bodies (residual fragments of the nucleus), hypersegmented neutrophils, and reticulocytopenia. Treatment is directed at the underlying disorder.

Megaloblasts are large nucleated red blood cell (RBC) precursors with noncondensed chromatin due to impaired DNA synthesis. Macrocytes are enlarged RBCs (ie, mean corpuscular volume [MCV] > 100 fL/cell). Macrocytic RBCs occur in a variety of clinical circumstances, many unrelated to megaloblastic maturation.

Nonmegaloblastic macrocytosis

Macrocytic (ie, MCV >100 fL/cell) anemias due to vitamin B12 deficiency or folate deficiency are megaloblastic. Nonmegaloblastic macrocytosis occurs in various clinical states, not all of which are understood. Anemia can occur in patients with macrocytosis due to mechanisms independent of the 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 (eg, in a hemolytic anemia) can cause macrocytosis.

Nonmegaloblastic macrocytosis is suspected in patients with macrocytic anemias when testing excludes vitamin B12 deficiency or folate deficiency. The large oval RBCs (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 may be done. 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). Pernicious anemia can develop even in the absence of old age. Other common causes are malabsorption due to gastritis, gastric bypass, or tapeworm infection. Dietary deficiency is rare but can occur in patients eating a vegan diet.

Common causes of folate deficiency include celiac disease and chronic alcohol use.

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. Macro-ovalocytes enter the circulation. Hypersegmentation of polymorphonuclear neutrophils is common. Howell-Jolly bodies (residual fragments of the nucleus) are usually present. If iron deficiency or impaired iron utilization is present simultaneously, macrocytosis may not develop.

Symptoms and Signs

Megaloblastic anemia develops insidiously and may not cause symptoms until anemia is severe. Gastrointestinal manifestations are common, including diarrhea, glossitis, and anorexia. Neurologic manifestations, including peripheral neuropathy and gait instability, are unique to B12 deficiency and can be permanent if prolonged. Paresthesias can be the presenting manifestation of B12 deficiency, even before (or in the absence of) anemia.


  • Complete blood count (CBC), RBC indices, reticulocyte count, and peripheral smear

  • B12 and folate levels

Megaloblastic anemia is suspected in anemic patients with macrocytic indices. It should also be considered in patients with risk factors who have unexplained paresthesias and/or a high RBC distribution width (RDW). 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 (variation in RBC size), and poikilocytosis (variation in RBC shape).

The RDW is high. Howell-Jolly bodies 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. Although iron deficiency can mask macrocytosis, Howell-Jolly bodies and granulocyte hypersegmentation should still be present.

Serum B12 and folate levels should be measured. A B12 level < 200 pg/mL (< 147.6 pmol/L) or folate level < 2 ng/mL (< 4.53 nmol/L) is generally diagnostic of deficiency. B12 levels between 200 to 300 pg/mL (147.6 to 221.3 pmol/L) are nondiagnostic.

When vitamin B12 levels are not diagnostic, both a methylmalonic acid (MMA) and homocysteine (HCY) level should be checked. Serum levels of both MMA and HCY are elevated in B12 deficiency, while only HCY is elevated in folate deficiency. Renal insufficiency elevates the MMA level.

If vitamin B12 deficiency is confirmed, testing for the presence of autoantibodies to intrinsic factor should be done.

Testing is done to determine the cause of a vitamin 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.

Treatment of folate deficiency and vitamin B12 deficiency are discussed elsewhere. Drugs causing megaloblastic states may need to be eliminated or given in reduced doses.

The etiology of any vitamin deficiency should also be treated.

Key Points

  • Megaloblasts are large nucleated red blood cell precursors with noncondensed chromatin.

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

  • Do complete blood count, red blood cell 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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