Macrocytic anemias
Also known as: macrocytic anemia
Macrocytic anemia is anemia in which red blood cells are abnormally large, with a mean corpuscular volume above roughly 100 fL. The major subdivision is megaloblastic, caused by impaired DNA synthesis, versus non-megaloblastic.
Anemias are classified first by MCV. Macrocytic anemia sits at the high end — an MCV above about 100 fL — in contrast to microcytic (below ~80 fL) and normocytic anemias. The next step is deciding whether the marrow shows megaloblastic changes, since that single distinction organizes the entire differential.
Megaloblastic anemia arises when DNA synthesis lags behind cytoplasmic maturation, so the nucleus stays immature while the cell keeps growing. The classic causes are vitamin B12 (cobalamin) deficiency and folate deficiency, both of which impair thymidine synthesis. Peripheral smear shows macro-ovalocytes and hypersegmented neutrophils; the marrow shows large erythroid precursors with open chromatin. Drugs that block folate metabolism — methotrexate, trimethoprim, phenytoin — and orotic aciduria produce the same picture.
Distinguishing B12 from folate deficiency is a recurring exam task. Both raise homocysteine, but only B12 deficiency raises methylmalonic acid, and only B12 deficiency causes neurologic disease, classically subacute combined degeneration of the dorsal columns and lateral corticospinal tracts. Pernicious anemia, an autoimmune loss of intrinsic factor from gastric parietal cells, is the prototypical cause of B12 deficiency; others include terminal ileum disease, gastrectomy, and Diphyllobothrium latum infection. Folate deficiency develops faster because stores last months rather than years, and is seen in alcohol use disorder, poor diet, and pregnancy.
Non-megaloblastic macrocytosis has normal DNA synthesis. Causes include chronic alcohol use, liver disease, hypothyroidism, myelodysplastic syndromes, and reticulocytosis, since reticulocytes are larger than mature red cells. Hypersegmented neutrophils are absent, which is the practical smear clue.
USMLE Step 1 tests macrocytic anemias in hematology and oncology. Expect vignettes that hand you an MCV, a smear description, and a methylmalonic acid or homocysteine level and ask you to name the deficiency or predict the neurologic findings.
Key takeaways
- Macrocytic anemia means an MCV above roughly 100 fL and is divided into megaloblastic and non-megaloblastic causes.
- Megaloblastic anemia reflects impaired DNA synthesis, most often from vitamin B12 or folate deficiency, and shows hypersegmented neutrophils.
- Elevated methylmalonic acid and neurologic deficits point to B12 deficiency; folate deficiency raises homocysteine alone.
- Pernicious anemia is autoimmune loss of intrinsic factor and the classic cause of B12 deficiency.
- Non-megaloblastic macrocytosis occurs with alcohol use, liver disease, hypothyroidism, myelodysplasia, and reticulocytosis.