Hereditary Spherocytosis

The commonest inherited red cell membrane disorder in populations of Northern European descent, caused by mutations in genes encoding vertical membrane-cytoskeleton linkage proteins (ankyrin, band 3, spectrin, protein 4.2), resulting in progressive loss of membrane surface area relative to cell volume and formation of spherocytes with reduced deformability, which are prematurely trapped and destroyed in the splenic microcirculation.

Inheritance and severity

Autosomal dominant in roughly 75% of cases (typically milder), with the remainder autosomal recessive or de novo, generally producing more severe disease. Clinical severity ranges from a mild, well-compensated, sometimes asymptomatic trait to severe transfusion-dependent haemolytic anaemia, and correlates broadly with the degree of membrane protein deficiency.

• Variable severity: mild disease may be entirely asymptomatic or discovered incidentally (family screening, unexplained gallstones); severe disease presents in infancy with significant anaemia and jaundice.
• Neonatal jaundice, often the earliest presentation, occasionally requiring phototherapy or exchange transfusion.
• Chronic compensated haemolysis: mild jaundice, splenomegaly (present in the great majority, often the most consistent physical finding), fatigue.
• Pigment gallstones from chronic elevated bilirubin turnover, occurring at a younger age than the general population, and a common reason for presentation in adolescents/young adults.
• Aplastic crisis: transient marked worsening of anaemia with reticulocytopenia, classically triggered by parvovirus B19 infection, which transiently suppresses erythropoiesis --- dangerous in a patient already dependent on high marrow output to compensate for chronic haemolysis.
• Haemolytic crisis with intercurrent infection, causing transient worsening jaundice and anaemia with an appropriate reticulocyte response (distinguishing from aplastic crisis).
• Growth delay in severe undertreated childhood disease; leg ulcers and folate deficiency in longstanding severe cases (rare).

• Full blood count: variable anaemia, elevated mean corpuscular haemoglobin concentration (MCHC) is a characteristic and useful clue (spherocytes have reduced surface-to-volume ratio, concentrating haemoglobin), reticulocytosis.
• Blood film: spherocytes (small, dense, lacking central pallor), though these are not entirely specific and also occur in autoimmune haemolytic anaemia.
• Direct antiglobulin test is negative, the key test distinguishing hereditary spherocytosis from autoimmune haemolytic anaemia (which also produces spherocytes on the film).
• Osmotic fragility test: increased fragility in hypotonic saline, though sensitivity is imperfect, particularly in mild disease or shortly after a transfusion.
• Eosin-5-maleimide (EMA) binding test by flow cytometry is now the preferred diagnostic test, offering better sensitivity and specificity than osmotic fragility.
• Family history and screening of first-degree relatives, given autosomal dominant inheritance in most cases.
• Genetic testing available for atypical or diagnostically uncertain cases.

• Folic acid supplementation for all patients with ongoing haemolysis, given increased erythropoietic demand.
• Mild disease: often requires no specific treatment beyond folic acid and monitoring.
• Splenectomy is highly effective, essentially curing the haemolytic anaemia (spherocytes persist but are no longer preferentially destroyed without a spleen) --- reserved for moderate to severe disease with significant anaemia, growth impairment, symptomatic splenomegaly, or recurrent biliary complications; increasingly deferred until after age 5-6 years where possible given post-splenectomy infection risk in young children, and partial splenectomy is used in some centres to preserve some immune function while reducing haemolysis.
• Pre-splenectomy vaccination (pneumococcal, meningococcal, Haemophilus influenzae type b) at least 2 weeks before surgery, and lifelong penicillin prophylaxis (particularly important in young children) post-splenectomy, with patient education on fever as a medical emergency.
• Cholecystectomy considered concurrently with splenectomy if gallstones are present, or independently for symptomatic cholelithiasis.
• Transfusion support for severe anaemia or during aplastic crisis.
• Monitor for and manage aplastic crises (parvovirus B19) with supportive transfusion until marrow recovery, typically 1-2 weeks.
• Genetic counselling given autosomal dominant inheritance in the majority.