This is a collection of inherited disorders which manifest as spherical-shaped erythrocytes (spherocytes) on the peripheral blood smear.¹

Pathogenesis

Clinical severity varies (depending on the mutation), from asymptomatic to a life-threatening haemolytic anaemia, but all mutations alter the cell membrane, causing loss of membrane surface area and reduced deformability of the cell. These abnormal red cells are then selectively retained and destroyed in the spleen, which reduces red cell life and produces the haemolytic anaemia.

Defects in several membrane proteins may be involved (e.g. alpha-spectrin, beta-spectrin, ankyrin, protein 4.2). The most common defect in a European population is a combined spectrin and ankyrin deficiency, found in 40-65% of patients (usually autosomal dominant). Isolated beta-spectrin defects account for about 15-30%, are usually only mild or moderately severe, autosomal dominant and do not require transfusion.^1,2 Isolated alpha-spectrin defects occur in 5% and are usually severe, displaying autosomal recessive inheritance. Other mutations producing defects in other membrane proteins (e.g. protein 4.2) can occur and are more common in Japan.

Epidemiology

it affects about 1 in 2,000 in Europe and North America.¹ Both dominant and recessive forms exist, and a significant number may be new mutations without prior family history.

Presentation

Patients may present at any age with haemolytic anaemia, jaundice (either from haemolysis or gallstones) and splenomegaly. Always ask about any family history of anaemia:¹

• 20-30% of patients have mild disease with an increased red cell turnover compensated with adequate replacement. They are neither symptomatic nor anaemic, but may have mild splenomegaly, slight reticulocytosis and minimal spherocytes visible.
• 60-70% of patients have moderate disease and half of these present in childhood with anaemia.
• Neonates with severe hereditary disease do not always present at birth with anaemia, but haemoglobin may fall dramatically over the first few weeks of life and may be severe enough to require exchange transfusion.³ Amongst neonates of northern European descent with significant hyperbilirubinaemia, hereditary spherocytosis (HS) may be an under-recognised cause.⁴

Differential diagnosis

Other causes of spherocytes in peripheral blood film include:

• Autoimmune, microangiopathic or macroangiopathic haemolytic anaemias.
• Haemolytic transfusion reactions.
• Thermal injury, antioxidant injury or snake envenoming.
• Liver disease.
• Clostridial septicaemia.
• Heinz body anaemia.
• Zinc toxicity.
• Severe hypophosphataemia.
• Hypersplenism.
• ABO incompatibility (neonates).

Investigations

• FBC and blood film including reticulocyte count. Spherocytes and reticulocytosis are seen on peripheral blood film. FBC shows raised mean corpuscular haemoglobin concentration (MCHC) and increased red cell distribution width.
• Liver function tests (indicative of haemolysis) increased unconjugated bilirubin, lactate dehydrogenase and urinary and faecal urobilinogen with reduced haptoglobin levels.
• Direct antiglobulin test is usually negative in hereditary spherocytosis (HS) but is positive in autoimmune haemolytic anaemia.
• Osmotic fragility test - incubated osmotic fragility test is thought to be the gold standard in the diagnosis of HS in a patient with direct antiglobulin test-negative, spherocytic haemolytic anaemia, particularly one of northern European descent or someone with a positive family history of undiagnosed anaemia. However, about 20% of mild cases of HS are missed and it is unreliable in patients with small numbers of spherocytes, or those who have recently had a blood transfusion.
• Osmotic gradient ektacytometry is used to differentiate HS from hereditary stomatocytosis but is available only in specialised laboratories.

Management

• Once the diagnosis and baseline severity are established, it is not necessary to perform repeated blood tests unless there is an additional clinical indication (e.g. intercurrent infection, pallor, an increase in jaundice).⁵ A routine annual review is usually sufficient.
• An open door policy for potential complications such as parvovirus infection, or abdominal pain (which may trigger investigation for gallstones) is good practice. Mild cases do not usually require folate supplements or splenectomy.³
• Steroid therapy may be effective in augmenting haemoglobin levels during haemolytic crises in patients with moderate disease and will result in the patient requiring fewer transfusions.⁶
• More severely affected individuals are usually given folate supplementation, and may benefit from splenectomy (usually performed after the age of 6).³ Partial splenectomy may also be beneficial.⁷
• There needs to be a full discussion on the dangers and benefits of splenectomy, and such patients will need lifelong prophylaxis post-splenectomy (see separate article Splenectomy, Hyposplenism and Asplenia).

Complications

• Gallstones and gallbladder disease. Co-existent Gilbert's syndrome gives 4 x increased risk of gallstones. The increased risk is abolished by splenectomy.
• Haemolytic, aplastic and megaloblastic crises:
  • Rapid haemolysis can be triggered by viral infections and produce jaundice, anaemia and occasionally abdominal pain and tender splenomegaly. Supportive treatment is usually all that is needed.
  • Aplastic crises (aplastic anaemia) can follow viral bone marrow suppression and can be life-threatening. They are most commonly caused by parvovirus infection (B19) and usually last 10-14 days.¹
  • Megaloblastic crises are rare and due to folate deficiency.

Prognosis

3-5% of patients have severe hereditary disease requiring regular transfusions.

Prevention

Genetic testing and family tracing are available. Relatives who are carriers of the gene may show a persistent reticulocytosis. The incubated osmotic fragility test is the most sensitive way of identifying them.

Document references

1. Perrotta S, Gallagher PG, Mohandas N; Hereditary spherocytosis. Lancet. 2008 Oct 18;372(9647):1411-26. [abstract]
2. Spectrin, Beta, Erythrocytic; SPTB, Online Mendelian Inheritance in Man (OMIM)
3. Guidelines for the Diagnosis and Management of Hereditary Spherocytosis, British Committee for Standards in Haematology (2004)
4. Christensen RD, Henry E; Hereditary spherocytosis in neonates with hyperbilirubinemia. Pediatrics. 2010 Jan;125(1):120-5. Epub 2009 Nov 30. [abstract]
5. Bolton-Maggs PH; Hereditary spherocytosis; new guidelines. Arch Dis Child. 2004 Sep;89(9):809-12.
6. Ballin A, Waisbourd-Zinman O, Saab H, et al; Steroid therapy may be effective in augmenting hemoglobin levels during hemolytic Pediatr Blood Cancer. 2011 Apr 7. doi: 10.1002/pbc.22844. [abstract]
7. Tracy ET, Rice HE; Partial splenectomy for hereditary spherocytosis. Pediatr Clin North Am. 2008 Apr;55(2):503-19, x. [abstract]

Internet and further reading

• Gonzalez G et al; Spherocytosis, Hereditary, Medscape, Aug 2009

Acknowledgements