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Megaloblastic Macrocytic Anemias


Gloria F. Gerber

, MD, Johns Hopkins School of Medicine, Division of Hematology

Reviewed/Revised Jun 2023
Topic Resources

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). Macrocytic RBCs occur in a variety of clinical circumstances, many unrelated to megaloblastic maturation.

Nonmegaloblastic macrocytosis

Macrocytosis due to excess RBC membrane occurs in patients with chronic liver disease when cholesterol esterification is defective. Macrocytosis with mean corpuscular volume of about 100 to 105 fL can occur with chronic alcohol use in the absence of folate deficiency. Mild macrocytosis can occur in aplastic anemia Aplastic Anemia Aplastic anemia is a disorder of the hematopoietic stem cell that results in a loss of blood cell precursors, hypoplasia or aplasia of bone marrow, and cytopenias in two or more cell lines ... read more Aplastic Anemia , especially as recovery occurs. Macrocytosis is also common in myelodysplasia Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more . 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 chronic liver disease or alcohol use) or if myelodysplasia Myelodysplasia and Iron-Transport Deficiency Anemia In myelodysplastic syndrome, anemia is commonly prominent. The anemia is usually normocytic or macrocytic, and a dimorphic (large and small) population of circulating cells can be present. ... read more 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.

Etiology of Megaloblastic Macrocytic 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 Autoimmune Metaplastic Atrophic Gastritis Autoimmune metaplastic atrophic gastritis is an inherited autoimmune disease that attacks parietal cells, resulting in hypochlorhydria and decreased production of intrinsic factor. Consequences... read more Autoimmune Metaplastic Atrophic Gastritis ). Pernicious anemia can develop even in the absence of old age. Other common causes are malabsorption due to gastritis Overview of Gastritis Gastritis is inflammation of the gastric mucosa caused by any of several conditions, including infection (Helicobacter pylori), drugs (nonsteroidal anti-inflammatory drugs, alcohol),... read more Overview of Gastritis , gastric bypass Roux-en-Y gastric bypass (RYGB) surgery Metabolic and bariatric surgery is the surgical alteration of the stomach, intestine, or both to cause weight loss in patients with obesity-related metabolic disorders and their sequellae. In... read more , Crohn disease Crohn Disease Crohn disease is a chronic transmural inflammatory bowel disease that usually affects the distal ileum and colon but may occur in any part of the gastrointestinal tract. Symptoms include diarrhea... read more Crohn Disease , or tapeworm infection Overview of Tapeworm Infections Tapeworms (cestodes) are flat, parasitic worms. The four main intestinal cestode pathogens of humans are Taenia saginata ( beef tapeworm) Taenia solium ( pork tapeworm) Hymenolepis... read more . Dietary deficiency is rare but can occur in patients eating a vegan diet.

Other causes of megaloblastosis include medications (generally antineoplastics such as hydroxyurea, or immunosuppressants) that interfere with DNA synthesis and rare metabolic disorders (eg, hereditary orotic aciduria). Copper deficiency Copper Deficiency Copper is a component of many body proteins; almost all of the body’s copper is bound to copper proteins. Copper deficiency may be acquired or inherited. (See also Overview of Mineral Deficiency... read more can cause megaloblastic changes in some cases and may manifest as macrocytic, normocytic, or even microcytic anemia.

Pathophysiology of Megaloblastic Macrocytic Anemias

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 Overview of Leukopenias Leukopenia is a reduction in the circulating white blood cell (WBC) count to < 4000/mcL (9/L). It is usually the consequence of a reduced number of circulating neutrophils, although... read more and thrombocytopenia Overview of Platelet Disorders Platelets are circulating cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes... read more Overview of Platelet Disorders 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 of Megaloblastic Macrocytic Anemias

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 vitamin 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.

Diagnosis of Megaloblastic Macrocytic Anemias

  • 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 Peripheral smear Anemia is a decrease in the number of red blood cells (RBCs) as measured by the red cell count, the hematocrit, or the red cell hemoglobin content. In men, anemia is defined as any of the following... read more Peripheral smear . When fully developed, the anemia is macrocytic, with mean corpuscular volume > 100 fL 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), folate level < 2 ng/mL (< 4.53 nmol/L), or RBC folate level < 150 ng/mL (< 340 nmol/L) is generally diagnostic of deficiency. Vitamin B12 levels between 200 and 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 methylmalonic acid and homocysteine are elevated in vitamin B12 deficiency, while only homocysteine is elevated in folate deficiency. Renal insufficiency elevates the methylmalonic acid level.

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

Evaluation to determine the cause of the vitamin deficiency should also be done.

Treatment of Megaloblastic Macrocytic Anemias

  • Appropriate vitamin supplementation

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

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.

Drugs Mentioned In This Article

Drug Name Select Trade
DROXIA, HYDREA, Mylocel, Siklos
No brand name available
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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