megaloblast

A megaloblast is a markedly enlarged erythroblast in the bone marrow characterized by defective DNA synthesis, leading to asynchronous maturation of the nucleus and cytoplasm. Megaloblasts arise during megaloblastic changes in hematopoiesis and are most often associated with megaloblastic anemia, a disorder typically due to impaired thymidine synthesis from deficiencies of vitamin B12 (cobalamin) or folate.

Pathophysiology and morphology

Megaloblastic changes result from impaired DNA synthesis, causing delayed nuclear maturation while cytoplasmic development proceeds. In the bone marrow, erythroid precursors become large with open, finely clumped chromatin and prominent nucleoli. Peripheral blood may show macrocytosis and oval macrocytes, and neutrophils often appear hypersegmented. The resulting anemia is usually normocytic to macrocytic with a low reticulocyte response.

Causes

Common causes include deficiencies of folate or vitamin B12, which can arise from inadequate intake, malabsorption, or increased requirements. Drugs that disrupt DNA synthesis (such as methotrexate, pyrimethamine, 5-fluorouracil, and certain antiretrovirals), alcoholism, liver disease, and some laboratory or congenital conditions can also produce megaloblastic changes.

Diagnosis

Diagnosis relies on clinical context, complete blood count showing macrocytosis, and peripheral smear findings of macrocytes and hypersegmented neutrophils. Assessments of B12 and folate levels, methylmalonic acid and homocysteine (elevated in deficiency states) aid differentiation. Bone marrow examination can show megaloblastic erythroid precursors; in some cases a direct marrow biopsy confirms the diagnosis when peripheral findings are equivocal.

Treatment

Treatment targets the underlying deficiency: vitamin B12 for deficiency or malabsorption, and folate for folate deficiency. In B12 deficiency, especially with neurologic symptoms, parenteral B12 is preferred. Folate supplementation should not mask untreated B12 deficiency. Most patients improve hematologically with appropriate therapy; neurological symptoms may be irreversible if B12 deficiency is prolonged.