Megaloblastic change
the picture
Large oval RBCs, hypersegmented neutrophils (≥ 5 lobes); can cause pancytopenia.
Thymidine synthesis ↓ → nucleus matures slower than cytoplasm; ineffective erythropoiesis
↑ LDH and indirect bilirubin from marrow cell death
Poor diet (alcohol, elderly), ↑ demand (pregnancy, hemolysis), drugs (methotrexate, trimethoprim, phenytoin). Stores last ~3–4 months.
Absorbed in jejunum
↑ homocysteine, normal MMA, no neuro signs; pregnancy → neural tube defects
Pernicious anemia (most common), gastrectomy, strict vegan diet, ileal resection or Crohn, fish tapeworm, pancreatic insufficiency, metformin, long PPI use, nitrous oxide.
Needs acid + intrinsic factor; absorbed in terminal ileum; stores last years
↑ homocysteine and ↑ MMA
Subacute combined degeneration: dorsal columns, lateral corticospinal tracts, spinocerebellar tracts; peripheral neuropathy; dementia.
MMA buildup → abnormal myelin fatty acids
Can occur without anemia; folate masks the anemia, not the neuropathy
Pernicious anemia
autoimmune
Antibodies to parietal cells and intrinsic factor → atrophic gastritis of body and fundus.
Achlorhydria → ↑ gastrin
Risk of gastric adenocarcinoma and carcinoid; other autoimmunity · IM B12
Orotic aciduria
rare, inherited
UMP synthase defect → pyrimidine synthesis fails.
Megaloblastic anemia that does not respond to B12 or folate; orotic acid in urine; no hyperammonemia
Treat with uridine
Methotrexate (DHFR), hydroxyurea, 5-FU, zidovudine, trimethoprim.
Block DNA synthesis directly
Leucovorin rescues methotrexate toxicity
Nonmegaloblastic
no hypersegs
Alcohol, liver disease, hypothyroidism, reticulocytosis, MDS, Diamond-Blackfan anemia.
Membrane lipid changes or immature/abnormal precursors
Diamond-Blackfan: infant red cell aplasia, thumb anomalies, ↑ HbF