Hereditary Spherocytosis
Definition
Hereditary spherocytosis is an inherited haemolytic anaemia, caused by defects in RBC membrane proteins (most commonly ankyrin-1, spectrin).
Aetiology and Pathophysiology
Most common inheritance pattern: autosomal dominant (~75%) [Ref]
- Most common (~50%): ankyrin-1 (ANK1 gene)
- Beta-spectrin (SPTB)
- Band 3 protein / anion exchanger 1 (SLC4A1)
Defects in the RBC membrane impairs membrane integrity, as a result: [Ref]
- Reduced membrane surface area → less deformable spherocytes (spherical shape – instead of the normal biconcave shape)
- Spherocytes are unable to transverse the splenic microvasculature efficiently → trapped and prematurely destroyed in the spleen → extravascular haemolysis → splenomegaly (from chronic haemolysis)
Clinical Features
Clinical presentation is highly variable, ranging from asymptomatic to severe, transfusion-dependent anaemia.
Typical features: [Ref]
- Anaemia (e.g. fatigue, weakness, pallor)
- Jaundice (usually intermittent)
- Splenomegaly (from chronic extravascular haemolysis)
- ↑ Risk of gallstones (most common complication)
In the neonatal period, hereditary spherocytosis commonly causes neonatal jaundice (pathological) and may require phototherapy and/or exchange transfusion.
Complications
There are 3 key acute complications, which are seen in both hereditary spherocytosis and sickle cell disease. [Ref]
Note that sequestration crisis is LESS common in hereditary spherocytosis, the main acute complications are haemolytic and aplastic crisis. Haemolytic crises are the most common.
| Feature | Haemolytic crisis | Aplastic crisis | Sequestration crisis |
|---|---|---|---|
| Definition | Acute increase in red cell destruction | Temporary failure of red cell production | Acute pooling of blood in the spleen |
| Main mechanism | Accelerated haemolysis | Bone marrow suppression | Splenic trapping of RBCs |
| Triggers | Infection, stress | Parvovirus B19 (classic) | Mainly sickle cell disease (children) |
| Key diagnostic clues |
|
|
|
| Mainstay of management |
|
|
|
Investigation and Diagnosis
Laboratory Tests
Hereditary spherocytosis causes a non-immune mediated, haemolytic anaemia: [Ref]
- -ve Direct Coombs test (supports non-immune mediated)
- Non-specific haemolysis marker
- ↓ Haemoglobin
- Normal mean corpuscular volume and normal mean corpuscular haemoglobin (normocytic, normochromic anaemia)
- ↓ Haptoglobin
- ↑ Reticulocyte
- ↑ Unconjugated bilirubin
- ↑ LDH
- Red cell indices
- ↑ Mean corpuscular haemoglobin concentration (due to the smaller surface area of spherocytes)
- ↑ Red cell distribution width (due to mixed population of normal RBCs and spherocytes)
Peripheral Blood Smear
Hallmark finding: spherocytes [Ref]
- Small, dense spherical red cells
- Lack central pallor
Further Tests
Test of choice: EMA binding test (by flow cytometry) [Ref]
- Test results are available within hours
- Supportive finding: reduced binding between EMA (the dye) and RBC membrane proteins
Osmotic fragility test (↑ osmotic fragility supports hereditary spherocytosis) is an old test and is no longer recommended. [Ref]
It has a poor sensitivity because about 20% of mild cases of hereditary spherocytosis are missed.
Management
ALL patients:
- Folate supplementation (to support erythropoiesis)
- Blood transfusion as needed (in haemolytic / aplastic crisis)
Definitive management: splenectomy [Ref]
- Splenectomy cure almost all patients with hereditary spherocytosis, by eliminating anaemia and hyperbilirubinemia
- Risks and benefits should be assessed carefully before splenectomy is done
The main complications associated with splenectomy are:
- ↑ Risk of infection (esp. encapsulated bacteria)
- Due to the very high risk of post-splenectomy infection in infancy and early childhood, splenectomy should be delayed until 6-9 y/o if possible
- Appropriate vaccinations should be given 2 weeks before elective splenectomy
- Thromboembolic complications (due to persistent thrombocytosis and altered platelet function)
- DVT
- PE
- Stroke and ischaemic heart disease
See the Hyposplenism article for more information.