What is hereditary spherocytosis?

Hereditary Spherocytosis: A Comprehensive Overview

Hereditary spherocytosis (HS) is a genetic disorder characterized by abnormally shaped red blood cells (spherocytes) that leads to hemolytic anemia, with clinical manifestations ranging from asymptomatic to severe forms requiring transfusions in early childhood.

Pathophysiology

Hereditary spherocytosis results from defects in the red blood cell membrane proteins that affect the structural integrity of erythrocytes:

• Caused by mutations in genes encoding red blood cell membrane proteins (primarily ANK1, SPTB, SLC4A1, EPB42, and SPTA1) 1
• These mutations lead to deficiency or dysfunction of membrane skeleton proteins, particularly spectrin 2
• The compromised membrane skeleton results in:
  • Loss of normal biconcave shape
  • Formation of spherical red blood cells (spherocytes)
  • Reduced deformability and flexibility
  • Premature destruction in the spleen

Epidemiology

• Most common non-immune hemolytic anemia among people of Northern European ancestry 3
• Prevalence of approximately 1 in 2000, though milder forms may be more common 3
• Inheritance pattern:
  • 75% autosomal dominant
  • 25% autosomal recessive or de novo mutations 3

Clinical Presentation

The clinical spectrum varies widely based on disease severity:

• Mild forms: Often asymptomatic or with minimal anemia
• Moderate forms: Intermittent jaundice, mild to moderate anemia, fatigue
• Severe forms: Significant anemia requiring transfusions, pronounced jaundice, growth retardation

Common manifestations include:

• Hemolytic anemia
• Jaundice
• Splenomegaly
• Fatigue and exercise intolerance
• Increased risk of gallstones (pigment gallstones due to chronic hemolysis) 2
• Aplastic crises (particularly during infections)

Complications may include:

• Cholelithiasis (gallstones) - risk increases with age 2
• Hemolytic crises (often triggered by infections)
• Aplastic crises (typically associated with parvovirus B19 infection)
• Folate deficiency due to increased erythropoiesis

Diagnosis

Diagnosis is based on:

1. Clinical features: Family history, physical examination (jaundice, splenomegaly)
2. Laboratory tests:
   • Complete blood count: Anemia, increased MCHC, normal MCV or microcytosis
   • Peripheral blood smear: Presence of spherocytes
   • Reticulocyte count: Elevated (reflecting increased erythropoiesis)
   • Bilirubin: Elevated (predominantly unconjugated)
   • Specific diagnostic tests:
     • EMA binding test (eosin-5'-maleimide binding test) - preferred test 4
     • Acidified Glycerol Lysis Time (AGLT) 4
     • Osmotic fragility test
3. Genetic testing: Identification of mutations in genes associated with HS 1

Treatment

Treatment depends on disease severity and is aimed at reducing hemolysis and managing complications:

1. Supportive care:

   • Folic acid supplementation
   • Blood transfusions when necessary
   • Avoidance of oxidative stressors

2. Surgical management:

   • Splenectomy: Indicated in moderate to severe forms of HS 4
     • Total splenectomy: Traditional approach but carries lifelong risk of overwhelming post-splenectomy infection
     • Partial splenectomy: Alternative approach that preserves some immune function while reducing hemolysis 4
   • Timing: Generally delayed until after 6 years of age to reduce risk of overwhelming post-splenectomy sepsis 2
   • Cholecystectomy: Should be performed at the time of splenectomy if gallstones are present 2

3. Post-splenectomy management:

   • Vaccination against encapsulated organisms
   • Prophylactic antibiotics (especially in children)
   • Monitoring for complications

Outcomes

• Splenectomy typically results in clinical resolution of anemia in most patients 2
• Spherocytosis persists after splenectomy, but hemolysis is significantly reduced
• Patients with recessively inherited HS may have persistent mild anemia even after splenectomy 2
• Long-term outcomes are generally favorable with appropriate management
• Regular monitoring for late complications is recommended

Special Considerations

• Children: Delay splenectomy until after age 6 when possible to reduce infection risk
• Pregnancy: May require increased monitoring and supportive care
• Accessory spleens: Important to identify and remove during splenectomy to prevent recurrence of hemolysis 2

Proper diagnosis and management of hereditary spherocytosis significantly improves quality of life and reduces morbidity associated with chronic hemolysis and its complications.