Pernicious anemia

Pernicious anemia is an autoimmune cause of vitamin B12 (cobalamin) deficiency. Autoantibodies attack gastric parietal cells and intrinsic factor itself. Because parietal cells produce intrinsic factor — the protein that binds B12 so it can be absorbed in the terminal ileum — their destruction leaves dietary B12 unabsorbable, and body stores are gradually depleted.

The result is a megaloblastic, macrocytic anemia: B12 is required for DNA synthesis, so red cell precursors grow without dividing properly, producing large cells (elevated MCV) and hypersegmented neutrophils on the peripheral smear. The associated autoimmune gastritis causes achlorhydria and can raise gastrin levels, and long-standing disease increases the risk of gastric cancer.

What distinguishes B12 deficiency from folate deficiency — which produces an identical-looking anemia — is the neurologic involvement. B12 is also a cofactor for methylmalonyl-CoA mutase, so deficiency elevates methylmalonic acid and damages the dorsal columns and lateral corticospinal tracts (subacute combined degeneration), causing loss of vibration and position sense, ataxia, and spasticity. Folate deficiency raises homocysteine but leaves methylmalonic acid normal and spares the nervous system.

USMLE Step 1 tests pernicious anemia heavily within the anemia framework: recognize the macrocytic anemia with hypersegmented neutrophils, tie it to anti-intrinsic factor or anti-parietal cell antibodies, use methylmalonic acid to separate B12 from folate deficiency, and remember that treating B12 deficiency with folate alone corrects the anemia but not the neurologic damage.