This is a collection of inherited disorders which manifest as spherical-shaped erythrocytes (spherocytes) on the peripheral blood smear.
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 (eg, 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, are 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 (eg, protein 4.2) can occur and are more common in Japan.
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:
- 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. Amongst neonates of northern European descent with significant hyperbilirubinaemia, hereditary spherocytosis (HS) may be an under-recognised cause.
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.
- ABO incompatibility (neonates).
Most patients can be diagnosed on the basis of a family history, typical clinical features and laboratory investigations - spherocytes, raised mean corpuscular haemoglobin concentration (MCHC), and an increase in reticulocytes. They do not require any additional tests.
- FBC and blood film including reticulocyte count. Spherocytes and reticulocytosis are seen on peripheral blood film. FBC shows raised MCHC and increased red cell distribution width.
- LFTs (indicative of haemolysis), increased unconjugated bilirubin, lactate dehydrogenase and urinary and faecal urobilinogen with reduced haptoglobin levels.
- Direct antiglobulin test - is usually negative in HS but is positive in autoimmune haemolytic anaemia.
- Osmotic fragility test - is unreliable and is no longer recommended.
- Osmotic gradient ektacytometry - is used to differentiate HS from hereditary stomatocytosis but is available only in specialised laboratories.
If the diagnosis is equivocal, a screening test is helpful. The recommended screening tests are the cryohaemolysis test and EMA binding.SDS-polyacrylamide gel electrophoresis of erythrocyte membrane proteins is carried out to confirm the diagnosis of atypical hereditary spherocytosis.
- Once the diagnosis and baseline severity are established, it is not necessary to perform repeated blood tests unless there is an additional clinical indication (eg, intercurrent infection, pallor, an increase in jaundice). 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.
- 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.
- Moderate-to-severely affected individuals are usually given folate supplementation and offered splenectomy:
- Splenectomy eliminates anaemia and hyperbilirubinaemia and lowers the high reticulocyte number to nearly normal levels.
- Treatment of hereditary spherocytosis with splenectomy is curative in most patients but increased recognition of the long-term risks of splenectomy has led to re-evaluation of the role of splenectomy.
- A laparoscopic approach should be used if a suitably trained surgeon is available, This is usually performed after the age of 6 years. Partial splenectomy may also be beneficial.
- If children are having a splenectomy, the gallbladder should be removed at the same time if there are symptomatic gallstones. However, if children are having cholecystectomy (for symptoms of gallstones), concurrent splenectomy is controversial, as it is associated with a risk of post-splenectomy sepsis.
- Partial splenic embolisation may be considered.
Splenectomy should be avoided in patients with some forms of hereditary stomatocytosis, due to an increased risk of venous thromboembolism. There should 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.
- 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 infection with parvovirus B19 and usually last 10-14 days.
- Megaloblastic crises are rare and due to folate deficiency.
3-5% of patients have severe disease that requires regular blood transfusions.
Genetic testing and family tracing are available.Relatives who are carriers of the gene may show a persistent reticulocytosis.
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