Hereditary Spherocytosis

Hereditary Spherocytosis is a topic covered in the Select 5-Minute Pediatrics Topics.

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Basics

Description

  • Hemolytic anemia with shortened RBC survival due to selective destruction of RBCs in the spleen secondary to an inherent defect of the RBC membrane.
  • Pathophysiologically related to hereditary elliptocytosis and hereditary ovalocytosis
  • Membrane loss is gradual; it results in spherocytosis, which results in increased osmotic fragility.
  • Severity related to degree of membrane loss
    • Mild (20% of patients)
      • Hemoglobin near normal
      • Slight reticulocytosis (<6%)
      • Compensated hemolysis, mild splenomegaly
      • Often not diagnosed until adulthood due to gallstones
    • Moderate (60% of patients)
      • Hemoglobin 8–10 mg/dL
      • Reticulocytes generally >8%
      • >50% patients have splenomegaly.
    • Moderately severe (10%)
      • Hemoglobin 6–8 mg/dL
      • Reticulocytes >15%
      • Intermittent transfusions
    • Severe (3–5%)
      • Life-threatening anemia requiring regular transfusions
      • Almost always recessive

Epidemiology

Most common in people of Northern European extraction (∼1:3,000)

Risk Factors

Genetics

  • ∼75% of cases are inherited in an autosomal dominant pattern.
  • The other 25% are autosomal recessive forms, dominant disease with reduced penetrance, or new mutations.

Pathophysiology

  • The most common abnormality is a deficiency of ankyrin and subsequent decrease in spectrin, 2 major proteins of the erythrocyte membrane skeleton (50–60% Northern European decent; 5–10% Japan).
    • Spectrin deficiency alone accounts for 20% of HS.
    • Mutations in other erythrocyte surface proteins also occur, including the following:
      • Beta-spectrin (typically mild to moderately severe), alpha-spectrin (severe HS)
      • Band 3 (15–20% generally mild to moderately severe)
      • Protein 4.2 (<5% HS, recessive and results in almost complete absence)
      • Rh antigen (<10% mild to moderate hemolytic anemia)
  • The membrane skeletal defect causes RBC membrane fragility, resulting in membrane loss.
  • The sequelae are as follows:
    • Loss of cell surface area relative to volume (spherocytosis) causes a decrease in cellular deformability.
    • The spleen detains and “conditions” the nondeformable spherocytic RBC.
    • Conditioning of cells involves depletion of adenosine 5′-triphosphate (ATP), increased glycolysis, increased influx and efflux of sodium, and loss of membrane lipid.
  • Ultimately, these events lead to premature RBC destruction.

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Basics

Description

  • Hemolytic anemia with shortened RBC survival due to selective destruction of RBCs in the spleen secondary to an inherent defect of the RBC membrane.
  • Pathophysiologically related to hereditary elliptocytosis and hereditary ovalocytosis
  • Membrane loss is gradual; it results in spherocytosis, which results in increased osmotic fragility.
  • Severity related to degree of membrane loss
    • Mild (20% of patients)
      • Hemoglobin near normal
      • Slight reticulocytosis (<6%)
      • Compensated hemolysis, mild splenomegaly
      • Often not diagnosed until adulthood due to gallstones
    • Moderate (60% of patients)
      • Hemoglobin 8–10 mg/dL
      • Reticulocytes generally >8%
      • >50% patients have splenomegaly.
    • Moderately severe (10%)
      • Hemoglobin 6–8 mg/dL
      • Reticulocytes >15%
      • Intermittent transfusions
    • Severe (3–5%)
      • Life-threatening anemia requiring regular transfusions
      • Almost always recessive

Epidemiology

Most common in people of Northern European extraction (∼1:3,000)

Risk Factors

Genetics

  • ∼75% of cases are inherited in an autosomal dominant pattern.
  • The other 25% are autosomal recessive forms, dominant disease with reduced penetrance, or new mutations.

Pathophysiology

  • The most common abnormality is a deficiency of ankyrin and subsequent decrease in spectrin, 2 major proteins of the erythrocyte membrane skeleton (50–60% Northern European decent; 5–10% Japan).
    • Spectrin deficiency alone accounts for 20% of HS.
    • Mutations in other erythrocyte surface proteins also occur, including the following:
      • Beta-spectrin (typically mild to moderately severe), alpha-spectrin (severe HS)
      • Band 3 (15–20% generally mild to moderately severe)
      • Protein 4.2 (<5% HS, recessive and results in almost complete absence)
      • Rh antigen (<10% mild to moderate hemolytic anemia)
  • The membrane skeletal defect causes RBC membrane fragility, resulting in membrane loss.
  • The sequelae are as follows:
    • Loss of cell surface area relative to volume (spherocytosis) causes a decrease in cellular deformability.
    • The spleen detains and “conditions” the nondeformable spherocytic RBC.
    • Conditioning of cells involves depletion of adenosine 5′-triphosphate (ATP), increased glycolysis, increased influx and efflux of sodium, and loss of membrane lipid.
  • Ultimately, these events lead to premature RBC destruction.

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