megaloblastic

Megaloblastic refers to a state in the bone marrow and peripheral blood characterized by impaired DNA synthesis, which leads to enlarged, immature erythroid precursors called megaloblasts. This results in macrocytic anemia and a range of hematologic abnormalities. The term is most often used to describe megaloblastic anemia, but can also describe the cellular changes observed in marrow.

Pathophysiology centers on deficient thymidine synthesis in the DNA of rapidly dividing cells. This is most commonly caused by deficiencies of vitamin B12 (cobalamin) or folate, both of which are essential cofactors in nucleotide biosynthesis. The nucleus lags behind cytoplasmic development, producing megaloblasts with large, immature nuclei and open chromatin. Peripheral blood typically shows macrocytosis with oval or round macrocytes and hypersegmented neutrophils. In some conditions, reticulocytopenia accompanies anemia despite increased red cell turnover.

Causes of megaloblastic changes include nutritional deficiencies (vitamin B12 deficiency from pernicious anemia, malabsorption, vegan diets; folate deficiency from poor intake, alcoholism, pregnancy, malabsorption), and drug-induced impairment of folate or B12 metabolism (methotrexate, trimethoprim-sulfamethoxazole, phenytoin, certain chemotherapies). Less commonly, secondary megaloblastic changes can occur with other disorders affecting DNA synthesis.

Clinical features reflect the anemia and, in B12 deficiency, may include neurologic symptoms such as paresthesias, gait disturbances, and cognitive changes; folate deficiency alone typically lacks neurologic signs. Diagnosis relies on laboratory findings: macrocytic anemia with anisocytosis and hypersegmented neutrophils, low reticulocyte count, low serum B12 or folate, and elevated methylmalonic acid (specific for B12 deficiency) and/or homocysteine. Management involves treating the underlying deficiency, with B12 replacement (often parenteral) for B12 deficiency and folate for folate deficiency; therapy should address possible combined deficiencies and monitor response.