Key Facts

Hereditary spherocytosis (HS) is the most common inherited haemolytic anaemia in Northern European populations. It is caused by defects in red cell membrane skeleton proteins.

Epidemiology

• Prevalence: ~1 in 2,000–5,000 in Northern Europeans
• Autosomal dominant in ~75%; autosomal recessive or de novo in ~25%

Aetiology

• Mutations in genes encoding membrane skeleton proteins:
  • Ankyrin (ANK1): most common (~40%)
  • Band 3 (SLC4A1): ~25%
  • Spectrin (α or β): ~20%
  • Protein 4.2: ~5%

Pathophysiology

• Defective membrane cytoskeleton → loss of membrane surface area → spherical RBCs
• Spherocytes are rigid, less deformable
• Trapped in splenic sinusoids → phagocytosed by splenic macrophages → extravascular haemolysis
• Reduced RBC lifespan (10–30 days vs normal 120 days)

Typical Presentation

• Neonatal jaundice: may be severe; prolonged
• Childhood: anaemia, jaundice, splenomegaly
• Variable severity:
  • Mild (~20–30%): compensated haemolysis, normal Hb, mild reticulocytosis
  • Moderate (~60–70%): mild-moderate anaemia, intermittent jaundice
  • Severe (~5–10%): transfusion-dependent

Complications

• Pigment gallstones: unconjugated bilirubin stones (~50% by adulthood)
• Aplastic crisis: parvovirus B19 → temporary RBC aplasia → rapid Hb drop
• Megaloblastic crisis: folate depletion from chronic haemolysis
• Haemolytic crisis: concurrent infection → increased haemolysis

Red Flags

• Severe neonatal jaundice (kernicterus risk)
• Sudden fall in Hb (aplastic crisis — check reticulocyte count)
• Symptomatic gallstones

Bloods

• FBC: anaemia (variable severity); raised MCHC (>360 g/L — classically associated)
• Reticulocyte count: raised (compensatory; often 5–20%)
• Blood film: spherocytes (small, round, no central pallor), polychromasia
• DAT (Coombs test): NEGATIVE (essential to exclude AIHA)
• LDH, bilirubin (unconjugated): raised (haemolysis)
• Haptoglobin: low

Special Tests

• EMA binding test (flow cytometry): reduced eosin-5-maleimide binding to band 3 on RBCs — gold standard screening test (replaced osmotic fragility)
• Osmotic fragility test: increased (spherocytes lyse at higher NaCl concentrations) — historical; less commonly used now
• SDS-PAGE: membrane protein analysis (specialist)
• Genetic testing: definitive
• USS abdomen: gallstones

Conservative

• Folic acid 5mg daily: prevent megaloblastic crisis
• Monitoring: regular FBC, reticulocyte count, bilirubin, ferritin
• Transfusion: for aplastic crises or severe chronic anaemia

Splenectomy

• Curative for haemolysis (spherocytes no longer destroyed in spleen; anaemia resolves)
• Indications: moderate-severe HS with symptomatic anaemia, growth failure, recurrent gallstones
• Timing: defer until >6 years (infection risk higher in younger children)
• Partial (subtotal) splenectomy: option in children (maintains some splenic function)
• Pre-splenectomy: vaccinations (pneumococcal, meningococcal ACWY + B, Hib, influenza) ≥2 weeks before
• Post-splenectomy: lifelong penicillin V 250–500mg BD; carry alert card; prompt medical attention for fever

Cholecystectomy

• If symptomatic gallstones; may be done at same time as splenectomy

Referral Criteria

• Haematology: all confirmed HS
• Surgery: splenectomy consideration
• Neonatology: severe neonatal jaundice

• Mild HS: normal lifespan; no treatment needed
• Moderate HS: well-managed with folic acid ± splenectomy; normal lifespan after splenectomy
• Severe HS: transfusion-dependent until splenectomy
• Post-splenectomy: excellent haematological outcomes; lifelong OPSI risk (~1–5% lifetime risk, ~50% mortality if occurs)
• Parvovirus B19 aplastic crisis: transient (1–2 weeks); may need transfusion support

Severity Classification