Hereditary spherocytosis

Definition

Hereditary spherocytosis is an inherited red cell membrane disorder. Defects of membrane skeleton proteins produce spherical, poorly deformable red blood cells that are prematurely destroyed in the spleen. The result is a chronic, usually mild to moderate hemolytic anemia with jaundice and splenomegaly.

Classification

Clinical severity

• Carriers: no anemia, smear normal or with occasional spherocytes
• Mild form (about 25–30 % of patients): no or only slight anemia, reticulocytes below 6 %
• Moderate form (about 60–70 %): marked anemia, reticulocytes 6 % or more, bilirubin raised
• Severe form (about 10 %) and very severe form (3–5 %): pronounced anemia, reticulocytes above 10 %, microspherocytes and poikilocytosis

Occurrence & epidemiology

The prevalence in Germany is estimated at about 1:2,500 to 1:5,000. In people of northern or central European origin, hereditary spherocytosis is by far the most common inherited hemolytic anemia, although it counts as a rare disease.

Aetiopathogenesis

The cause is mutations in the genes for ankyrin-1 (about 40–65 % in central Europe), band 3 (20–35 %), β-spectrin (15–30 %), α-spectrin and protein 4.2 (each below 5 %). Most forms are inherited in an autosomal dominant manner with variable penetrance; some cases are due to new mutations or – less often – recessive inheritance. Many mutations are specific to a family.

The disturbed link between the membrane skeleton and the lipid bilayer leads to progressive loss of membrane surface relative to cell contents. The spherical cells are too rigid to pass through the splenic microcirculation and are destroyed there (intrasplenic, extravascular hemolysis).

Clinical features

The spectrum ranges from severe courses in childhood to asymptomatic adults diagnosed incidentally. The picture is often similar within a family, but generations may be skipped because of variable penetrance.

• anemia (Coombs-negative), jaundice with raised indirect bilirubin
• splenomegaly almost always, sometimes hepatomegaly
• cholelithiasis (pigment stones) common, sometimes the first sign
• aplastic crisis, mostly after primary parvovirus B19 infection: marked fall in Hb due to a temporary arrest of erythropoiesis; not infrequently the first manifestation in a previously mild course
• hemolytic crises with intercurrent infections
• megaloblastic crisis in folate deficiency
• rarely after decades extramedullary hematopoiesis (paravertebral masses), secondary iron overload, in older patients leg ulcers

Histology

Blood smear

Small, dense, round red cells without central pallor (spherocytes) are typical, together with polychromasia and anisocytosis. In mild forms and in adults the picture may be uncharacteristic, with few or no spherocytes; polychromasia and anisocytosis, however, are almost always present. Spherocytes are also found in warm autoimmune hemolysis.

Diagnosis

• Family history and splenomegaly (examination, ultrasound)
• Blood count: anemia, normal MCV, raised MCHC (above 35 g/dl); the combination of raised MCHC and RDW above 15 % is highly specific
• Signs of hemolysis: reticulocytes raised, indirect bilirubin and LDH raised, haptoglobin reduced to undetectable
• Negative direct Coombs test – distinguishes it from autoimmune hemolysis with spherocytes
• Special tests: acidified glycerol hemolysis test (AGLT; sensitivity 80–95 %, high specificity) and the eosin-5-maleimide binding test by flow cytometry (EMA test; sensitivity 90–95 %, specificity 95–99 %). The combination of both reaches a sensitivity of up to 100 %; classic osmotic fragility with hypotonic saline is considerably less sensitive.
• Ektacytometry, membrane protein analysis and genetic testing in specialised laboratories for unclear cases

Keep learning in the app

Further reading (open access)

1. Onkopedia-Leitlinie (DGHO): Sphärozytose, hereditär (Kugelzellenanämie)
2. MSD Manual Professional: Hereditary Spherocytosis and Hereditary Elliptocytosis

Cross-references