About the Condition

Description/definition:

Hereditary spherocytosis (HS) belongs to the group of congenital hemolytic anemias resulting from plasma membrane protein deficiency. It is the most common inherited red blood cell plasma membrane disorder in Northern Europe and Northern America.

Prevalence is about 1 in every 2000 individuals.

75% of HS cases are dominantly inherited, 25% of the cases are non-dominant including autosomal recessive and de novo events that are mostly related to haploinsufficient mutations.

Disease severity is highly variable. Clinical spectrum ranges from symptom-free carriers to patients affected by severe hemolysis.

Pathophysiology:

Hereditary spherocytosis (HS) results from heterogeneous alterations in one of five genes that encode red blood cell membrane proteins involved in vertical associations that link the membrane cytoskeleton to the lipid bilayer:

  • Ankyrin-1 (ANK1 gene)
  • Erythrocytic ⍺- and b-spectrin chains (SPTA1 and SPTB genes)
  • Erythrocyte membrane protein band 4.2 (EPB42 gene)
  • Band 3 anion transport protein (SLC4A1 gene)
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In HS, deficiency in a membrane protein results in the disruption of the vertical linkages between the phospholipid bilayer and the membrane skeleton and assembly of an intrinsically unstable membrane leading to:

  • Increased cell sphericity (altered surface-to-volume ratio, primarily related to loss of membrane surface area).
  • Reduced cellular deformability.
  • Sequestration of the non-deformable spherocytes in the spleen .
  • Phagocytosis by the splenic macrophages, leading to reduced lifespan of the erythrocyte and anemia.

The decreased surface area is a feature of both the reticulocytes and mature red cells in HS.

Clinical presentation:

The clinical presentation of hereditary spherocytosis (HS) is highly variable and ranges from intrauterine demise to very mild anemia or fully compensated hemolysis.

Most affected individuals have mild or moderate hemolysis or hemolytic anemia and a known family history.

Classification of hereditary spherocytosis (HS) according to clinical severity:

% CasesHb (g/dL)Retics (%)Bili (mg/dL)
HS trait N/ANormalNormalNormal
Mild HS20-30%11-153-61-2
Mod HS 60-75%8-12> 6> 2
Severe HS5%6-8> 10> 3
Mod, moderate; Hb, hemoglobin; retics, reticulocytes; bili, bilirubin

Presentation in older children and adults includes:

  • Incidental finding of:
    • Hemolysis
    • Hemolytic anemia
    • Spherocytes on the blood smear
  • Symptoms of:
    • Anemia
    • Splenomegaly
    • Pigment gallstones
    • Jaundice

Exacerbtaions of anemia may occur with:

  • Infections
  • Splenomegaly – spleen is the site of sequestration and phagocytosis of the poorly deformable HS red cells
  • Nutrient deficiencies
  • Pregnancy

Complications of hemolysis may include:

  • Neonatal jaundice
  • Splenomegaly
  • Pigment gallstones
  • Extramedullary hematopoiesis
  • Growth delay
  • Iron overload
  • Leg ulcers
  • Priapism
  • Gout

Diagnosis:

Suspect diagnosis of hereditary spherocytosis in a patient with:

  • Coombs-negative (non-immune) hemolytic anemia.
  • Presence of  spherocytes on the peripheral blood smear.
  • Increased mean corpuscular hemoglobin concentration (MCHC).
  • A positive family history for HS.

Confirm diagnosis using one of:

  • EMA binding:
    • EMA (eosin-5-maleimide) is an eosin-based fluorescent dye that binds to RBC membrane proteins, especially band 3 and Rh-related proteins.
    • The mean fluorescence of EMA-labeled RBCs from individuals with HS is lower than controls, and this reduction in fluorescence can be detected in a flow cytometry-based assay.
    • High sensitivity (93%-96%) and specificity (93%-99%).
    • Rapid turnaround time (approximately two hours).
  • Osmotic fragility test:
    •  If EMA binding is not available.
    • In this assay, fresh RBCs are incubated in hypotonic buffered salt solutions of various osmolarities, and the fraction of hemoglobin released (due to hemolysis) is measured.
    • Spherocytes have increased sensitivity to hemolysis  due to their reduced surface area to volume ratio.
    • Relatively low sensitivity and specificity.
  • Osmotic gradient ektacytometry:
    • An alternative assay that generates a profile of osmotically induced RBC shape change (deformability) across an osmotic gradient.
    • Not routinely available.
  • Other tests such as:
    • Glycerol lysis
    • Cryohemolysis

Treatment:

Treatment is supportive and directed at preventing or minimizing complications of chronic hemolysis and anemia.

Transfusions:

  • The need for transfusions should be based on comprehensive clinical judgment regarding quality of life, growth, and symptoms and not on hemoglobin level alone.
  • Individuals with an aplastic crisis due to parvovirus infection or other bone marrow insult may require transfusions if they have a decreasing hemoglobin level without a robust reticulocytosis.

Folic acid supplementation:

  • Especially important during hemolytic crises, pregnancy, and in childhood during growth and development.

Splenectomy:

  • For those with relatively severe hemolysis, splenectomy is effective at improving anemia. Ideally, this is delayed until the individual is older than six years to reduce the likelihood of sepsis due to absent splenic function. Simultaneous cholecystectomy can be performed if gallstones are also present.
  • Indications include:
    • Children with HS who remain transfusion-dependent or severely symptomatic from anemia after one year of age.
    • Those with severe hemolysis and/or greater symptoms (eg, abdominal symptoms related to splenomegaly, distress related to jaundice).

Iron chelation:

  • Ideally use to prevent iron accumulation
  • Initiate chelation (e.g., DFO) if ≥ 1 of:
    • ≥ 10-20 transfusions
    • Serum ferritin > 1,000 ng/mL

Hematopoietic stem cell transplant or gene therapy

Allogeneic hematopoietic cell transplantation (HCT) is not used in HS due to an unfavorable risk-benefit ratio.

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