Hereditary Spherocytosis: Diagnosis and Management
Diagnostic Approach
For patients with unexplained hemolytic anemia (anemia, jaundice, splenomegaly, elevated reticulocytes), hereditary spherocytosis should be diagnosed using the EMA dye-binding test combined with flow cytometric osmotic fragility testing (FOFT), which together achieve 100% sensitivity. 1
Initial Clinical Assessment
- Key clinical features to identify: anemia (present in 88% of cases), jaundice (96%), splenomegaly (92%), and cholelithiasis (54%) 2
- Family history: present in approximately 60% of cases, but absence does not exclude diagnosis 2
- Physical examination: specifically assess for splenomegaly and jaundice 2
Laboratory Evaluation
Essential initial tests:
- Complete blood count showing normocytic to microcytic anemia 2
- Reticulocyte count (elevated, indicating hemolysis) 2
- Peripheral blood smear demonstrating spherocytes 3, 2
- Markers of hemolysis: elevated lactate dehydrogenase, bilirubin (particularly indirect), and decreased haptoglobin 2
Confirmatory Diagnostic Testing
The American Society of Hematology recommends combining FOFT with EMA dye-binding test for optimal diagnostic accuracy, achieving 100% sensitivity. 1 This combination significantly outperforms conventional osmotic fragility testing, which has important limitations.
Key advantages of modern flow cytometric methods:
- FOFT has 96.6% sensitivity and 98.63% specificity, far superior to conventional osmotic fragility testing 1
- Using extended 300-second analysis time provides 90% sensitivity in pediatric populations 1
- EMA dye-binding test detects membrane protein deficiencies directly 4, 5
Important pitfalls with conventional osmotic fragility testing:
- Can be normal or altered in pyruvate kinase deficiency and other red cell enzyme deficiencies, rendering it non-diagnostic 1
- Reticulocytosis falsely normalizes results, as young red cells resist osmotic stress 1
- Recent blood transfusions interfere with interpretation 1
Genetic Testing
When diagnosis remains uncertain after flow cytometry or in atypical presentations, genetic testing should be performed to identify mutations in HS pathogenic genes. 2
Most common genetic mutations in order of frequency:
- SPTB mutations (most common, approximately 48% of cases) 2
- ANK1 mutations (second most common, approximately 16% of cases) 2
- SPTA1, SLC4A1, and EPB42 mutations (less common) 3, 2
Genetic testing is particularly valuable for:
- Patients without family history (40% of cases) 2
- Atypical presentations with negative or equivocal flow cytometry 3
- Patients with severe disease requiring early intervention 3
- Family screening and genetic counseling 2
Treatment Strategies
Mild Disease (Hemoglobin >10 g/dL, Reticulocytes <6%)
Patients with mild hereditary spherocytosis do not require splenectomy and can be managed conservatively without folate supplementation. 6
- Monitor annually for complications (cholelithiasis, worsening anemia) 6
- No routine folate supplementation needed 6
- Counsel about increased hemolysis risk during infections 6
Moderate to Severe Disease (Hemoglobin <10 g/dL, Reticulocytes >6%, Transfusion-Dependent)
Splenectomy is the standard treatment for moderate and severe hereditary spherocytosis, resulting in qualitative resolution of anemia and reduction of transfusion requirements. 4
Splenectomy timing and approach:
- Perform after age 6 years to minimize infection risk 6
- Laparoscopic approach preferred (shorter hospital stay, less pain) 6
- Ensure appropriate pre-operative counseling about lifelong infection risk 6
Pre-splenectomy vaccination (mandatory):
- Pneumococcal vaccine (PCV13 followed by PPSV23)
- Meningococcal vaccine (MenACWY and MenB)
- Haemophilus influenzae type b vaccine
- Annual influenza vaccination 6
Partial Splenectomy Consideration
Partial splenectomy may be considered as an alternative to total splenectomy to retain splenic immunologic function while decreasing hemolysis rate. 4
Advantages:
Disadvantages:
- Long-term outcomes less well-established than total splenectomy 4
- Risk of recurrent hemolysis requiring completion splenectomy 4
- ANK1 mutation carriers have higher splenectomy rates and may be less suitable for partial procedures 2
Post-Splenectomy Management
Following splenectomy:
- Lifelong antibiotic prophylaxis (penicillin V 250-500 mg daily or equivalent) for at least 2 years, longer in high-risk patients 6
- Immediate medical attention for fever >38.5°C 6
- Annual influenza vaccination 6
- Patient education about overwhelming post-splenectomy infection risk 6
Special Considerations
Patients with Severe Jaundice
In patients with hereditary spherocytosis and disproportionately severe jaundice, test for UGT1A1 gene mutations (Gilbert syndrome), as decreased enzyme activity significantly elevates total bilirubin levels. 2 The presence of UGT1A1 mutations occurs in approximately 21% of HS patients and leads to significantly higher bilirubin levels 2.
Transfusion-Dependent Patients
Patients requiring monthly transfusions since infancy develop secondary hemochromatosis and require:
- Iron chelation therapy 3
- Monitoring for transfusion-related complications including alloantibody formation 3
- Expedited consideration for splenectomy (even before age 6 in severe cases) 3
Cholelithiasis Management
Cholelithiasis occurs in 54% of HS patients and should be managed with cholecystectomy at the time of splenectomy when present. 2 Screen for gallstones with abdominal ultrasound before splenectomy 2.