Hereditary spherocytosis overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Hereditary spherocytosis is a genetically-transmitted form of spherocytosis, an auto-hemolytic anemia characterized by the production of red blood cells that are sphere-shaped rather than donut-shaped, and therefore more prone to hemolysis.

Historical Perspective

• Towards the end of the nineteenth century Vanlair and Masius described the case of a young woman who developed icterus, recurrent attacks of left upper quadrant abdominal pain and splenomegaly shortly after giving birth. The stools were not light coloured, but rather deeply pigmented. The patient's mother and sister were also icteric, and the sister's spleenwas enlarged.

Classification

• Hereditary Spherocytosis classified on basis of underlying defect in protein and also on the basis of severity of hemolysis.

Pathophysiology

There is intrinsic defects in erythrocyte membrane proteins that result in RBC cytoskeleton instability. Loss of erythrocyte surface area leads to the spherical shape of RBCs (spherocytes), which are culled rapidly from the circulation by the spleen. Hemolysis mainly confined to the spleen and, therefore, is extravascular. Splenomegaly commonly develops.

The following four abnormalities in RBC membrane proteins have been identified in HS:

• Spectrin deficiency alone
• Combined spectrin and ankyrin deficiency
• Band 3 deficiency
• Protein 4.2 defects

Causes

• HS is caused by a variety of mutations that lead to defects in red blood cell (RBC) membrane proteins. HS usually is transmitted as an autosomal dominant trait, and the identification of the disorder in multiple generations of affected families is the rule. Homozygosity for this dominantly transmitted HS gene has not been identified, which suggests that the homozygous state is incompatible with life.

Epidemiology and Demographics

• HS is seen in all populations but appears to be especially common in people of northern European ancestry.

• In the United States, the incidence of the disorder is approximately one case in 5000 people.
  • In northern European, HS affects as many as 1 in 2000 to 1 in 5000 (prevalence, approximately 0.02 to 0.05 percent).

Risk Factors

• The risk factors for this condition have not yet been properly identified.
• However, having a family member with this condition can increase your susceptibility to this disease. The condition is also most common in individuals of North European origin although it has been found to arise in people of all races.

Screening

• It is also important to test newborns of affected parents for HS, as affected newborns may have severe hyperbilirubinemia and anemia. This may be done by a clinician with expertise in hemolytic anemias or by a genetic counselor. It is possible for an individual with no hemolysis, no spherocytes on the blood smear, and a normal reticulocyte count to be a carrier of HS, which may be relevant in certain families.

Natural History, Complications, and Prognosis

Natural History

• Disease severity and age of presentation — HS can present at any age and with any severity, with case reports describing a range of presentations, from hydrops fetalis in utero through diagnosis in the ninth decade of life.

• The majority of affected individuals have mild or moderate hemolysis or hemolytic anemia and a known family history, making diagnosis and treatment relatively straightforward. Individuals with significant severe hemolysis may develop additional complications such as jaundice/hyperbilirubinemia, folate deficiency, or splenomegaly.

Complications

Common complications of hemolysis include neonatal jaundice, splenomegaly, and pigment gallstones.

• Neonatal jaundice — HS may present in the neonatal period with jaundice and hyperbilirubinemia, and the serum bilirubin level may not peak until several days after birth. Some experts have proposed that HS is underdiagnosed as a cause of neonatal jaundice. A requirement for phototherapy and/or exchange transfusion during this period is common.
• Splenomegaly — Splenomegaly is rare in neonates, but can often be seen in older children and adults with HS. Early reports of family studies found palpable spleens in over three-fourths of affected members, but this may reflect a skewed population with the most severe disease. In these studies, the relationship between disease severity and splenic size was not linear.
• Pigment gallstones — Pigment (bilirubin) gallstones are common in individuals with HS and may be the presenting finding in adults. Gallstones are unlikely before the age of 10 years but are seen in as many as half of adults, especially those with more severe hemolysis. Gallstones appear to be more common in individuals with Gilbert syndrome.