Hereditary Spherocytosis

Hereditary spherocytosis (HS) is the most common type of hereditary hemolytic anemia. The condition is caused by a cytoskeletal protein deficiency in the RBC membrane. This results in loss of membrane stability and deformability of the RBC, giving the cell its spherical shape (spherocyte). These cells are predisposed to splenic degradation, leading to hemolysis. Examination may show jaundice and splenomegaly, while laboratory tests are consistent with hemolytic anemia and increased hemoglobin concentration. Among multiple confirmatory tests for HS, the eosin-5’-maleimide (EMA) binding test is preferred. The only definitive treatment for HS is splenectomy.

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Epidemiology and Etiology

Epidemiology

  • The most common type of hereditary hemolytic anemia due to red cell membrane defect
  • Common in those of northern European descent, affecting 1 in 3,000 individuals
  • United States: 1.4% of the population may be silent carriers of hereditary spherocytosis (HS)

Etiology

  • Majority of cases are autosomal dominant with variable penetrance
  • Involves the RBC cell membrane, which has 3 main components:
    • Lipid bilayer
    • Membrane proteins (band 3 is 1 of them)
    • Cytoskeletal network, of which spectrin is the most abundant protein

In HS, gene mutations lead to cytoskeletal protein deficiency:

  • Spectrin deficiency
    • Spectrin, a protein comprising α and β heterodimers, keeps the cell shape and elasticity.
    • Genes: 
      • SPTA1 encodes for α heterodimers (autosomal recessive mutations).
      • SPTB1 encodes for β heterodimers (autosomal dominant mutations).
    • Deficiency can be from:
      • Other defective membrane proteins that bind spectrin (even in ANK1 mutation causing ankyrin defect, there is spectrin deficiency due to loss of ankyrin attachment sites)
      • Impaired spectrin synthesis from SPTA1/SPTB1 mutation
    • Degree of spectrin deficiency correlates with the severity of spherocytosis.
  • Ankyrin deficiency
    • Anchors transmembrane proteins to the skeleton through spectrin, band 3, and protein 4.2
    • Encoded by ANK1 gene (autosomal dominant mutation)
    • Mutation of ANK1 causes combined ankyrin and spectrin deficiency (see above), which is found in 75% of  autosomal dominant HS patients.
  • Band 3 
    • Encoded by SLC4A1 gene (autosomal dominant mutation)
    • Mutations can present with distal renal tubule acidosis.
  • Protein 4.2 
    • Regulates binding of band 3 to ankyrin
    • Encoded by EPB42 gene (mutations mostly autosomal recessive)
    • Mutations commonly found in Japan
Hereditary spherocytosis

Major proteins of the RBC membrane

Image by Lecturio.

Pathophysiology

  • Normal biconcave RBCs circulate repeatedly through narrow channels → requires extensive reversible deformation
  • Defective cytoskeletal proteins → interrupt the vertical structure (spectrin-actin interaction) → disrupted cohesion of the inner membrane skeleton and the outer lipid bilayer → loss of surface area and stability of the RBC → spherocytes
  • Spherocytes are prone to hemolysis:
    • Abnormal RBCs without cellular deformability → trapped by the spleen → successively destroyed by macrophages
    • Low pH, low glucose, and high free radicals in the splenic environment lead to more membrane damage.

Clinical Presentation

General features

  • Anemia: pallor, tachycardia, fatigue, shortness of breath, transfusion dependency
  • Extravascular hemolysis causing bilirubin 
    • Recurrent jaundice 
    • Hemoglobinuria
    • Gallstones (+/- pain in right upper quadrant) 
    • Splenomegaly

Categories

Four clinical categories have been established based on hemoglobin (Hb), reticulocyte (retic) count, and bilirubin (bili) level.

  1. HS trait: 
    • No anemia, normal reticulocyte count, asymptomatic
  2. Mild HS: 
    • Hb 11–15 g/dL, retic 3-6%, bili 1–2 mg/dL
    • 20%–30% of cases
  3. Moderate HS: 
    • Hb 8–12 g/dL, retic > 6%, bili > 2 mg/dL
    • 60%–75% of cases
  4. Severe HS
    • Hb 6–8 g/dL, retic > 10%, bili > 3%
    • 5% of cases
Jaundice eye

Scleral icterus: The 1st clinical sign of bilirubin deposition in the body

Image: “Jaundice eye new” by CDC/Dr. Thomas F. Sellers/Emory University. License: Public Domain

Diagnosis

History and physical exam

  • Check for family history of HS, gallstones
  • Jaundice or splenomegaly (currently present or in history)

Initial tests

  • CBC
    • Anemia (↓ hemoglobin)
    • Normal to mildly MCV (mean corpuscular volume)
    • MCHC (mean corpuscular hemoglobin concentration) 
      • ≥ 36 g/dL
      • Most common finding in neonates 
      • Often the most useful parameter for spherocytosis
  • Peripheral blood smear
    • Spherocytes: lack of central pallor, increased density (not specific to HS)
    • Abnormal RBC shapes
    • Polychromatophilia (affinity for multiple stains)
  • Hemolysis work-up:
    • lactate dehydrogenase (LDH)
    • reticulocytes 
    • indirect/unconjugated bilirubin
    • ↓ haptoglobin

Confirmatory tests

  • Eosin-5’-maleimide (EMA) binding test
    • Most reliable test
    • Eosin-based fluorescent dye binds to cell membrane protein (band 3) in RBC 
    • ↓ fluorescence intensity in HS
    • Advantages: high specificity and sensitivity, short turnaround time, minimal amount of blood used (5 µL)
    • Mild HS may come out false negative.
  • Osmotic fragility test 
    • Positive in hereditary spherocytosis 
    • RBCs placed in serial solutions of saline; Spherocytes, with low surface-to-volume area, hemolyze in hypoosmotic solutions.
    • Labor-intensive, takes 18–24 hours
    • Low sensitivity in detecting mild HS and newborn HS 
  • Acidified glycerol lysis test (AGLT): 
    • Modified osmotic fragility test using glycerol solution
    • “Pink test”: a modified AGLT
    • Comparable sensitivity with EMA test
    • Combination of EMA test with AGLT identifies all patients with HS.
  • Molecular analysis for gene mutations 
    • Further characterization of mutation for family members
    • Done if test(s) us equivocal and/or management will be altered (e.g., splenectomy)
Hereditary spherocytosis

Hereditary spherocytosis (HS): peripheral blood smear

The black arrow shows a spherocyte. The white arrow shows a normal RBC (the lack of central pallor is an artifact). Hereditary spherocytosis forms having different membrane defects can show different red cell morphologies.

Image: “Previously undiagnosed HS” by US National Library of Medicine. License: CC BY 4.0

Management and Complications

Management

  • Education about the risks of aplastic crisis and splenic rupture (in those with splenomegaly)
  • Folate supplementation
    • For pregnancy (4–5 mg/day)
    • In moderate to severe HS (1–2 mg/day)
  • Transfusion in aplastic crisis
  • Cholecystectomy for symptomatic gallstones
  • Splenectomy
    • Definitive management for severe hemolysis (> 6 years old to reduce risk of sepsis), especially those requiring recurrent transfusion
    • Immunization for encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitidis) before splenectomy
  • Pediatric cases:
    • Erythropoietin (EPO) can be administered in anemic infants to decrease the need for transfusion.
    • Neonatal jaundice: 
      • Phototherapy
      • Exchange transfusion

Complications

  • Exacerbations of anemia
    • Transient aplastic crisis can be caused by viral or bacterial infections (commonly parvovirus B19).
      • RBC production in bone marrow is suppressed so that it cannot compensate for the peripheral loss of RBCs by chronic hemolysis.
    • Splenomegaly:
      • Noted in 75% of affected patients
      • If augmented by a superimposed cause of splenomegaly, (e.g., infectious mononucleosis, cirrhosis, lymphoma), then increased sequestration (pooling) of RBCs and/or hemolysis may occur.
    • Nutrient deficiencies: Deficiencies in folate, iron, or vitamin B12 may interfere with RBC production.
      • Pregnancy: added stress of increasing RBC mass and expanding plasma volume may worsen anemia, and folic acid and iron deficiencies may occur
    • Pigment (bilirubin) gallstones:
      • Rare before the age of 10
      • Due to hyperbilirubinemia
      • May present as cholecystitis
  • Newborns at risk for kernicterus (neurologic damage from severe hyperbilirubinemia)

Differential Diagnosis

The differential diagnosis includes other causes of hemolysis, most of which will show at least some spherocytes in the peripheral blood.

  • Sickle cell disease: a group of hereditary disorders characterized by abnormal hemoglobin structure leading to polymerization and deformation of RBCs. Patients present in early childhood with chronic hemolytic anemia, chronic pain, and infections. Sickle cell crises are episodes of acute increased hemolysis requiring blood transfusions. Bone marrow transplantation is the only curative treatment.
  • Glucose-6-phosphate dehydrogenase deficiency (G6PD): an X-linked recessive defect that increases the susceptibility of RBCs to oxidative stress, resulting in episodes of hemolytic anemia. Patients present with abdominal pain, jaundice, hemoglobinuria, and enlargement of the spleen. Triggers include consumption of fava beans, drugs (antimalarials, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs)), and infections. Management includes avoidance of triggers. There is no curative treatment.
  • Immune-related hemolysis: caused by cold or warm reactive immunoglobulins that attach to RBCs and destroy the membrane. Many cases are idiopathic; secondary causes include malignancy, infections, and other autoimmune diseases such as SLE. Treatment includes trigger avoidance, immunosuppressants (glucocorticoids, rituximab), and IV immunoglobulins.

References

  1. Bianchi, P. et al. (2012). Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study in 150 patients grouped according to molecular and clinical characteristics. 97(4): 516–523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347664/
  2. Ciepiela,O. (2018). Old and new insights into the diagnosis of hereditary spherocytosis. Ann Transl Med. 6(17): 339. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174190/
  3. Gonzalez, G.; Talavera, F. & Sacher, R. (Eds.). (2018). Hereditary Spherocytosis. Medscape. Retrieved 24 Aug, 2020, from https://emedicine.medscape.com/article/206107
  4. Mentzer, W.; Leung, L. (Ed.); Tirnauer, J. (Ed.). (2019). Hereditary Spherocytosis. Uptodate. Retrieved 24 Aug, 2020, from https://www.uptodate.com/contents/hereditary-spherocytosis
  5. Saavides, P.; Shalev, O.; John, K.; Lux, S.(1993). Combined Spectrin and Ankyrin deficiency is common in autosomal dominant hereditary spherocytosis. Blood.82:2953-2960.
  6. Tole, S., Dhir, P., Pugi, J., et al. (2020). Genotype–phenotype correlation in children with hereditary spherocytosis. Br J Haematol. doi:10.1111/bjh.16750
  7. Perrotta, S., Gallagher, P.G., Mohandas, N. (2008). Hereditary spherocytosis. Lancet 2008; 372: 1411–26
  8. Lynch, E.. (1990). Peripheral Blood Smear. In: Walker, H.K., Hall, W.D., Hurst, J.W. (Eds.). Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 155. Retrieved 16 Oct, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK263/

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