What is spherocytosis?

What is Spherocytosis

Spherocytosis (hereditary spherocytosis) is a genetic red blood cell membrane disorder caused by defects in membrane proteins that result in loss of the normal biconcave disc shape, leading to spherical cells that are trapped and destroyed in the spleen, causing hemolytic anemia. 1

Pathophysiology

The fundamental defect in spherocytosis involves mutations in genes encoding membrane skeletal proteins that anchor the lipid bilayer to the cytoskeleton 1:

• Primary protein defects include ankyrin, band 3 (AE1), beta spectrin, alpha spectrin, or protein 4.2 1
• These defects weaken the interaction between the spectrin-actin meshwork and integral membrane proteins 2
• Loss of membrane surface area occurs without proportional loss of cell volume, forcing cells into a spherical shape 1
• The spherical shape reduces deformability and mechanical resistance of the plasma membrane 2, 3

The spleen is the primary site of red cell destruction - abnormal spherocytes cannot navigate the narrow splenic sinusoids due to their reduced flexibility and are sequestered and destroyed by splenic macrophages 1. This splenic trapping is the main determinant of hemolysis in hereditary spherocytosis 4.

Clinical Presentation

The clinical spectrum is highly variable 5:

• Asymptomatic carriers with compensated hemolysis 1
• Mild to moderate disease with well-compensated hemolytic anemia (most common presentation) 1
• Severe forms requiring transfusions in early childhood 5

Key Clinical Features

• Hemolytic anemia with variable severity 1
• Jaundice from unconjugated hyperbilirubinemia 1
• Splenomegaly develops due to chronic red cell sequestration 1
• Pigment gallstones occur with increasing frequency related to patient age, uncommon before age 10 years 3

Complications

• Hemolytic crises (increased hemolysis) 1
• Aplastic crises (typically triggered by parvovirus B19 infection) 1
• Cholelithiasis from chronic hyperbilirubinemia 3, 1
• Risk of traumatic splenic rupture when splenomegaly is present 3

Diagnosis

Diagnosis relies on clinical findings, family history, and laboratory testing 5:

Laboratory Findings

• Complete blood count showing anemia with elevated reticulocyte count 5
• Peripheral blood smear demonstrating spherocytes (though the fraction may be small since defective cells are continuously removed) 2
• Increased osmotic fragility - spherocytes lyse more readily in hypotonic solutions 2

Specific Diagnostic Tests

• EMA (eosin-5-maleimide binding) test - preferential diagnostic test 5
• AGLT (Acidified Glycerol Lysis Time) - alternative specific test 5
• Osmotic stress testing using stopped-flow light scattering can quantify altered osmotic properties 2

Genetic Testing

• Many isolated mutations have been identified in membrane protein genes 1
• No common hereditary spherocytosis-associated mutations exist, making genetic screening challenging 1
• Specific protein deficiencies (ankyrin deficiency, band 3 deficiency) can be identified 2

Inheritance Pattern

Hereditary spherocytosis is most commonly inherited in an autosomal dominant pattern, though recessive forms exist 3. It is the most common inherited anemia in individuals of northern European ancestry 1.

Treatment Considerations

Splenectomy is the definitive treatment that eliminates the primary site of red cell destruction 3, 4:

• Removes anemia and hyperbilirubinemia in most patients 3
• Lowers reticulocyte count to nearly normal levels 4
• Spherocytosis persists after splenectomy, but hemolysis is alleviated 3
• Patients with recessively inherited spherocytosis are exceptions - they benefit from splenectomy but anemia is not completely corrected 3

Timing and Approach

• Delay splenectomy until after age 6 years when possible to reduce risk of overwhelming post-splenectomy sepsis 3
• Identify and remove accessory spleens at time of surgery 3
• Perform cholecystectomy if gallstones are present 3
• Partial splenectomy is an alternative that aims to retain splenic immunologic function while decreasing hemolysis 5

Important Caveat

Splenectomy should only be undertaken after careful assessment of risks versus benefits 1. It is sometimes erroneously recommended for young children with mild clinical phenotypes who may not require intervention 4.