Hereditary Spherocytosis

Risk factors

• Family history of hemolytic anemia, jaundice, splenomegaly, early gallstones, or splenectomy
• Northern European ancestry
• Consanguinity (recessive forms)

Pathophysiology

Mutations in genes encoding vertical membrane-cytoskeleton anchor proteins (ANK1, SPTB, SPTA1, SLC4A1, EPB42) weaken the connection between the lipid bilayer and underlying spectrin network. Surface area is lost via microvesiculation, generating dense spherical cells with reduced surface-to-volume ratio. These rigid spherocytes cannot traverse splenic sinusoids and are removed by splenic macrophages.

Clinical presentation

Differential diagnosis

• Autoimmune hemolytic anemia (warm AIHA) — Spherocytes on smear PLUS positive direct antiglobulin (Coombs) test; no family history; often new-onset
• G6PD deficiency — Episodic hemolysis triggered by oxidants/infection; bite cells and Heinz bodies; X-linked
• Hereditary elliptocytosis — Elliptocytes (>25%) on smear; usually mild; horizontal cytoskeletal defect
• Pyruvate kinase deficiency — Chronic non-spherocytic hemolysis; echinocytes; low PK enzyme activity
• Microangiopathic hemolytic anemia (TTP/HUS, DIC) — Schistocytes, thrombocytopenia, end-organ injury; negative family history
• Gilbert syndrome — Isolated unconjugated hyperbilirubinemia without anemia, reticulocytosis, or hemolysis markers

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[Hemolytic anemia<br/>+ spherocytes on smear] --> B{Direct Coombs?}
  B -->|Positive| C[Warm AIHA]
  B -->|Negative| D[EMA binding<br/>flow cytometry]
  D -->|Decreased| E[Hereditary<br/>Spherocytosis]
  E --> F{Severity}
  F -->|Mild| G[Observation<br/>+ folate]
  F -->|Moderate| H[Folate<br/>± splenectomy]
  F -->|Severe| I[Vaccinate then<br/>total splenectomy]
  I --> J[Lifelong PCN<br/>prophylaxis if young]

Treatment

Complications

• Pigment (bilirubin) gallstones — often by adolescence
• Aplastic crisis from parvovirus B19 — abrupt drop in hemoglobin with reticulocytopenia
• Hemolytic crisis triggered by infection
• Megaloblastic crisis from folate deficiency
• Post-splenectomy: overwhelming post-splenectomy infection (OPSI), venous thromboembolism, pulmonary hypertension (late)
• Iron overload in transfusion-dependent patients

PANCE pearls

• Elevated MCHC is a useful screening clue — few conditions raise it.
• EMA binding flow cytometry has largely replaced osmotic fragility as the test of choice.
• Splenectomy resolves anemia and jaundice but does NOT correct the underlying membrane defect — spherocytes persist on smear.
• Parvovirus B19 wipes out the reticulocyte response; suspect aplastic crisis when hemoglobin falls and reticulocyte count is paradoxically low.
• Vaccinate (pneumococcal, meningococcal, Hib) at least 2 weeks before elective splenectomy.

References

• British Society for Haematology — Bolton-Maggs PHB et al. Guidelines for the diagnosis and management of hereditary spherocytosis — 2011 update. Br J Haematol 2012.
• ASH Education Program — Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet 2008; 372:1411-26.