Hereditary spherocytosis

Hereditary spherocytosis results from mutations in the proteins that anchor the red cell membrane to its underlying cytoskeleton — most often ankyrin, along with spectrin, band 3, and protein 4.2. Without a stable anchor, the membrane sheds in small fragments. Losing surface area while retaining volume forces the cell from a biconcave disc into a sphere, which cannot deform enough to squeeze through the splenic cords. Most cases are inherited in an autosomal dominant pattern.

The clinical picture follows from splenic destruction of those cells: anemia, jaundice from unconjugated hyperbilirubinemia, splenomegaly, and pigmented gallstones. Laboratory findings include spherocytes without central pallor on the peripheral smear, an elevated mean corpuscular hemoglobin concentration (MCHC), increased red cell distribution width, and reticulocytosis. A negative direct Coombs test separates hereditary spherocytosis from autoimmune hemolytic anemia, which also produces spherocytes. Diagnosis is confirmed with the eosin-5-maleimide binding test, with the osmotic fragility test as the classic alternative.

Complications reflect the strain of ongoing hemolysis. Parvovirus B19 infection halts erythroid production and can precipitate an aplastic crisis in a patient whose marrow was already working at capacity. Management ranges from folate supplementation and transfusion in mild disease to splenectomy in severe cases; splenectomy stops the hemolysis but leaves spherocytes and Howell-Jolly bodies on the smear and requires encapsulated organism vaccination beforehand.

Hereditary spherocytosis is a recurring USMLE Step 1 topic in hematology and oncology. High-yield points are the membrane protein defect, the elevated MCHC, the negative Coombs test that rules out an immune cause, the eosin-5-maleimide and osmotic fragility studies, and the parvovirus B19 aplastic crisis association.