Hereditary spherocytosis

Hereditary spherocytosis (HS) is the most common congenital hemolytic disorder among individuals of northern European descent. In most cases, it is an autosomal dominant disease that is caused by red blood cell (RBC) membrane protein defects, which render the RBCs more vulnerable to osmotic stress and hemolysis. Clinical presentation ranges from mild HS, which is generally asymptomatic, to severe HS, which can already present in utero with hydrops fetalis. Moderate HS, which is the most common form, usually presents in infancy or childhood with the classic triad of anemia, jaundice, and splenomegaly. Diagnosis is established based on family history, typical laboratory findings (e.g., elevated mean corpuscular hemoglobin concentration and RBC distribution width), and tests (e.g., eosin-5-maleimide binding test, osmotic fragility test). Treatment depends on the severity of the disease and involves acute measures (e.g., red blood cell transfusions, phototherapy), medication (e.g., folate supplementation), and splenectomy. HS patients are also at risk for complications such as hemolytic and aplastic crises, megaloblastic anemia, and gallstone formation.

• Incidence: 1/5000 in the US ^[1]
• Most common inherited hemolytic disease among individuals of Northern European descent

Epidemiological data refers to the US, unless otherwise specified.

• Congenital RBC membrane protein defect
• Inheritance pattern
  • Autosomal dominant (∼ 75% of cases)
  • Autosomal recessive (∼ 25% of cases)
  • Family history often positive for relatives who required splenectomy and/or developed cholelithiasis at a young age
• Frequently affected proteins
  • Spectrin
  • Ankyrin
  • Band 3
  • Protein 4.2

Genetic mutation → defects in RBC membrane proteins (especially spectrin and/or ankyrin) responsible for tying the inner membrane skeleton with the outer lipid bilayer → continuous loss of lipid bilayer components → decreased surface area of RBCs in relation to volume → sphere-shaped RBCs with decreased membrane stability → inability to change form while going through narrowed vessels →

• Entrapment within splenic vasculature → splenomegaly
• Destruction via splenic macrophages → extravascular hemolysis

• Presentation is variable.
  • Mild HS (20–30% of cases): often asymptomatic
  • Moderate HS (60–75% of cases): onset of symptoms in infancy or childhood
  • Severe HS (5% of cases): onset of symptoms in newborns or even in utero (hydrops fetalis)
• Anemia and pallor
• Jaundice (due to ↑ unconjugated bilirubin)
• Splenomegaly with left upper quadrant pain
• Black pigment gallstones; (made of calcium bilirubinate), may lead to cholecystitis

References:^[2][3]

• Laboratory findings
  • Normocytic anemia: mean cell volume (MCV) within normal range (80-100 fL) or slightly decreased
  • Increased mean corpuscular hemoglobin concentration (MCHC) ^[4]
  • ↑ Red blood cell distribution width (↑ RDW)
  • ↑ Reticulocytes (normal range: 0.5%–1.5% of total RBC count)
  • Findings of hemolytic anemia
    • ↑ Unconjugated bilirubin
    • ↓ Haptoglobin
    • ↑ LDH
• Laboratory tests
  • Eosin-5-maleimide binding test (EMA binding test)
    • Test of choice, as results are readily available (within two hours)
    • Decreased binding between dye (eosin-5-maleimide) and RBC membrane proteins
    • Binding is quantified using flow cytometry, which shows decreased mean fluorescence
  • Other tests may be performed in addition to the EMA binding test.
    • Negative Coombs test: to exclude autoimmune hemolytic anemia (positive Coombs test), since spherocytosis is seen in both
    • Positive osmotic fragility test
      • Measures the ability of RBCs to resist hemolysis when exposed to different degrees of salt dilution (e.g., RBCs swell and eventually lyse when incubated in hypotonic saline due to water influx)
      • Whether or not RBCs lyse depends on their surface area to volume ratio. This ratio is decreased in patients with HS, so their RBCs are more fragile and more vulnerable to osmotic stress.
    • Acidified glycerol lysis test
      • Red blood cells are incubated in a hypotonic solution, to which glycerol is added.
      • The test is positive if the patient's spherocytes lyse more quickly than normal RBCs.
      • Has a greater sensitivity than the classic osmotic fragility test.
• Blood smear
  • Characteristic spherocytes (small round cells without central pallor)
  • Potentially anisocytosis
• Ultrasound: to evaluate gallbladder complications (see cholelithiasis, cholecystitis, and cholangitis)

References:^[5]

• Non-surgical treatments
  • Phototherapy and/or exchange transfusions may be necessary in neonates (e.g., to avoid kernicterus).
  • Blood transfusions may be required in cases of aplastic or hemolytic crisis (see “Complications” below).
  • Folate supplementation to maintain erythropoiesis
• Splenectomy
  • Sole definitive treatment
  • Prior to the procedure, vaccinate against Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitidis (see asplenia).

• Hemolytic crisis: esp. as a result of viral infection
• Aplastic crisis: following infection with parvovirus B19 (erythema infectiosum); characterized by a low reticulocyte count (< 0.1% of total RBC count)
• Megaloblastic anemia: folate and vitamin B12 deficiency may develop due to chronic hemolysis and high RBC turnover
• Megaloblastic crisis: due to folate deficiency (although uncommon in developed countries, it might still be seen among pregnant women)
• Other
  • Bilirubinate gallstone formation, possibly leading to cholecystitis, cholangitis, and pancreatitis
  • Growth retardation and skeletal abnormalities due to bone marrow expansion

References:^[5]

We list the most important complications. The selection is not exhaustive.