HaematologyTier 2Disease (DEADMAN)

Hereditary spherocytosis

Description

Inherited defect of the red cell membrane vertical linkage (cytoskeleton to lipid bilayer)
- -> membrane loss -> sphere with reduced surface-area-to-volume ratio -> rigid, undeformable
- -> trapped and destroyed in the splenic cords = extravascular haemolysis
Commonest inherited haemolytic anaemia in people of northern European ancestry

Severity spectrum

Related membrane disorders: hereditary elliptocytosis (horizontal linkage, usually asymptomatic), hereditary pyropoikilocytosis, South-East Asian ovalocytosis, hereditary stomatocytosis (splenectomy contraindicated - high thrombosis risk)

~1 in 2,000-5,000 in northern European populations
~75% autosomal dominant; the remainder recessive or de novo (a negative family history does not exclude it)
M = F
Presents at any age - neonatal jaundice through to incidental adult diagnosis

Genes - all vertical linkage proteins

Mechanism

Defective anchoring -> vesiculation and loss of lipid bilayer
-> dec surface area, inc MCHC (cellular dehydration), loss of deformability
-> retained in splenic red pulp -> further membrane conditioning -> destroyed by splenic macrophages
- The spleen is both the site of destruction and the amplifier - hence the effect of splenectomy
Chronic haemolysis -> inc unconjugated bilirubin -> pigment gallstones, folate consumption, compensatory reticulocytosis

Clinical

Anaemia + jaundice + splenomegaly - the classic triad
Neonate: jaundice and anaemia, often needing phototherapy or exchange transfusion
Adults: asymptomatic through to pallor, fatigue, exercise intolerance
Pigment gallstones - may present as the first manifestation, even in the first decade
Leg ulcers (uncommon)

Crises

Laboratory

Anaemia, reticulocytosis, inc unconjugated bilirubin, inc LDH, dec haptoglobin
inc MCHC (>360 g/L) - reflects cellular dehydration; almost unique to HS among common anaemias
inc RDW; MCV normal or low despite reticulocytosis
Film: spherocytes - dense, small, no central pallor + polychromasia
*DAT negative - the key test*

Confirmatory tests

EMA (eosin-5-maleimide) binding by flow cytometry - binds band 3; reduced fluorescence. Now the first-line confirmatory test
Cryohaemolysis test - the other recommended screen
The osmotic fragility test is insensitive (misses ~20%) and non-specific - superseded
Equivocal results -> SDS-PAGE gel electrophoresis of membrane proteins, or genetic testing
*No confirmatory test needed* if there is a positive family history plus typical features (spherocytes, inc MCHC, reticulocytosis)

Differential for spherocytes on film

Autoimmune haemolytic anaemia - *DAT positive*
Haemolytic disease of the newborn, especially ABO incompatibility - DAT positive
Clostridial sepsis, severe burns, Wilson disease, hypophosphataemia, transfusion reaction, snake bite

A. All patients

Folic acid - lifelong in moderate/severe disease (high red cell turnover)
Monitor Hb, reticulocytes, bilirubin; abdominal ultrasound for gallstones every few years
Genetic counselling and testing of first-degree relatives

B. Neonates

Observe closely for jaundice - phototherapy, occasionally exchange transfusion
Anaemia often needs transfusion in the first months (physiological nadir plus haemolysis), then improves

C. Transfusion

D. Splenectomy - effective but no longer routine

Abolishes most haemolysis (the cells remain spherocytic but survive)
Indicated for:
- Severe disease (transfusion dependence, growth failure)
- Moderate disease with symptomatic anaemia, poor growth or persistent fatigue
- Symptomatic gallstones - do cholecystectomy at the same operation
*Defer until at least age 6* (ideally later) - overwhelming post-splenectomy infection risk is highest in young children
*Do not splenectomise mild disease* - the long-term thrombotic, cardiovascular and infective hazards outweigh the benefit
Partial splenectomy is an option in young children - preserves immune function
Before splenectomy
- Vaccinate >=2 weeks pre-operatively: pneumococcal, meningococcal ACWY and B, Hib, annual influenza
- Lifelong penicillin V prophylaxis (at minimum through childhood and the first 2 years post-op)
- Patient alert card, standby antibiotics, urgent medical review for any fever, malaria advice
Cholecystectomy alone (leaving the spleen) is appropriate where gallstones are the only problem

E. Aplastic crisis

Parvovirus B19 - transfuse until reticulocytes recover (2-14 days); isolate from pregnant contacts and immunosuppressed patients

Pigment gallstones and cholecystitis - the commonest complication; risk higher with co-inherited Gilbert syndrome (UGT1A1)
Aplastic crisis with parvovirus B19
Folate deficiency and megaloblastic crisis
Leg ulcers, extramedullary haematopoiesis (severe disease)
Iron overload - co-inherited HFE mutations, and in transfusion-dependent patients
Post-splenectomy: encapsulated organism sepsis, thrombosis, pulmonary hypertension, accelerated atherosclerosis

Most patients have mild, well-compensated disease and a normal life expectancy
Haemolysis is lifelong; anaemia fluctuates with intercurrent illness
Splenectomy: haemolysis largely abolished, Hb normalises, but the membrane defect and spherocytes persist

Complications

Gallstones - up to 50% by adulthood without splenectomy
Aplastic crisis (parvovirus B19) - occasionally profound and life-threatening
Growth failure and delayed puberty in severe untreated disease
Overwhelming post-splenectomy infection - lifetime risk ~1-5%, mortality up to 50%
- The risk never goes away - counsel repeatedly
Post-splenectomy thrombosis and pulmonary hypertension

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