Hereditary Spherocytosis

Updated: Nov 20, 2017
  • Author: Gus Gonzalez, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Practice Essentials

Hereditary spherocytosis (HS) is a familial hemolytic disorder associated with a variety of mutations that lead to defects in red blood cell (RBC) membrane proteins. [1]  The morphologic hallmark of HS is the microspherocyte, which is caused by loss of RBC membrane surface area and has abnormal osmotic fragility in vitro. Investigation of HS has afforded important insights into the structure and function of cell membranes and the role of the spleen in maintaining RBC integrity.

Clinically, HS shows marked heterogeneity, ranging from an asymptomatic condition to fulminant hemolytic anemia. Patients with severe cases may present as neonates, while those with mild HS may not come to medical attention until adulthood, when an environmental stressor uncovers their disorder. The major complications of HS are aplastic or megaloblastic crisis, hemolytic crisis, and cholecystitis and cholelithiasis.

The classic laboratory features of HS include the following [2, 3] :

  • Mild to moderate anemia
  • Reticulocytosis
  • Increased mean corpuscular hemoglobin concentration (MCHC)
  • Spherocytes on the peripheral blood smear
  • Hyperbilirubinemia
  • Abnormal results on the incubated osmotic fragility test

Splenectomy is the standard treatment for patients with clinically severe HS, but can be deferred safely in patients with mild uncomplicated HS (hemoglobin level >11 g/dL). Splenectomy usually results in full control of HS, except in the unusual autosomal recessive variant of the disorder. [4]

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Pathophysiology

In HS, intrinsic defects in erythrocyte membrane proteins result in RBC cytoskeleton instability. Loss of erythrocyte surface area leads to the production of spherical RBCs (spherocytes), which are culled rapidly from the circulation by the spleen. Hemolysis primarily is 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

Spectrin deficiency

Spectrin deficiency is the most common defect in HS. The biochemical nature and the degree of spectrin deficiency are reported to correlate with the extent of spherocytosis, the degree of abnormality on osmotic fragility test results, and the severity of hemolysis.

Spectrin deficiency can result from impaired synthesis of spectrin or from quantitative or qualitative deficiencies of other proteins that integrate spectrin into the red cell membrane. In the absence of those binding proteins, free spectrin is degraded, leading to spectrin deficiency.

The spectrin protein is a tetramer made up of alpha-beta dimers. Mutations of alpha-spectrin are associated with recessive forms of HS, whereas mutations of beta-spectrin occur in autosomal dominant forms of HS. [5, 6]

Synthesis of alpha-spectrin is threefold greater than that of beta-spectrin. The excess alpha chains normally are degraded. Heterozygotes for alpha-spectrin defects produce sufficient normal alpha-spectrin to balance normal beta-spectrin production. Defects of beta-spectrin are more likely to be expressed in the heterozygous state because synthesis of beta-spectrin is the rate-limiting factor.

Red cell membranes isolated from individuals with autosomal recessive HS have only 40-50% of the normal amount of spectrin (relative to band protein 3). In the autosomal dominant form of HS, red cell spectrin levels range from 60-80% of normal.

Approximately 50% of patients with severe recessive HS have a point mutation at codon (969) that results in an amino acid substitution (alanine [Ala]/aspartic acid [Asp]) at the corresponding site in the alpha-spectrin protein. This leads to a defective binding of spectrin to protein 4.1. Mutations involving the alpha-spectrin beta-spectrin gene also occur, each resulting in spectrin deficiency.

Several other beta-spectrin mutations have been identified. Some of these mutations result in impaired beta-spectrin synthesis. Others produce unstable beta-spectrins or abnormal beta-spectrins that do not bind to ankyrin and undergo proteolytic degradation.

Ankyrin defects

HS is described in patients with translocation of chromosome 8 or deletion of the short arm of chromosome 8, where the ankyrin gene is located. Patients with HS and deletion of chromosome 8 have a decrease in red cell ankyrin content.

Ankyrin is the principal binding site for spectrin on the red cell membrane. Studies of cytoskeletal protein assembly in reticulocytes indicate that ankyrin deficiency leads to decreased incorporation of spectrin. In HS caused by ankyrin deficiency, a proportional decrease in spectrin content occurs, although spectrin synthesis is normal. Of particular interest, 75-80% of patients with autosomal dominant HS have combined spectrin and ankyrin deficiency and the two proteins are diminished equally.

Band 3 deficiency

Band 3 deficiency has been recognized in 10-20% of patients with mild-to-moderate autosomal dominant HS. These patients also have a proportionate decrease in protein 4.2 content on the erythrocyte membrane. In some individuals with HS who are deficient in band 3, the deficiency is considerably greater in older RBCs. This suggests that band 3 protein is unstable.

Protein 4.2 (pallidin) deficiency

Hereditary hemolytic anemia has been described in patients with a complete deficiency of protein 4.2. RBC morphology in these cases is characterized by spherocytes, elliptocytes, or sphero-ovalocytes.

Deficiency of protein 4.2 in HS is relatively common in Japan. One mutation that appears to be common in the Japanese population (resulting in protein 4.2 Nippon) is associated in the homozygous state with a red cell morphology described as spherocytic, ovalocytic, and elliptocytic. Another mutant protein 4.2 (protein 4.2 Lisboa) is caused by a deletion that results in a complete absence of protein 4.2. This is associated with a typical HS phenotype.

Aquaporin-1

In addition to abnormal levels of proteins affected by mutations, patients with HS may demonstrate aberrant distribution of other proteins in erythrocytes. Crisp et al found reduced expression of the water channel protein aquaporin-1 (AQP1) in the membranes of erythrocytes from patients with HS, compared with normal controls. The AQP1 content in erythrocyte membranes correlated with the clinical severity of HS. [7]

Red blood cell antibodies

Using a mitogen-stimulated direct antiglobulin test, Zaninoni and colleagues found RBC antibodies in 61% of patients with HS. Patients with RBC-bound IgG of more than 250 ng/mL (the positive threshold of autoimmune hemolytic anemia) had increased numbers of spherocytes and mainly had spectrin deficiency. These researchers concluded that the more evident hemolytic pattern in patients with RBC autoantibodies suggests that these antibodies have a pathogenic role in RBC opsonization and removal by the spleen. [8]

 

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Etiology

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.

Twenty-five percent of all newly diagnosed patients do not demonstrate a dominant inheritance pattern. Parents of these patients do not have clinical or hematologic abnormalities. Some of these sporadic cases may result from new mutations.

An autosomal recessive mode of inheritance also occurs, as indicated by descriptions of families in which apparently healthy parents have had more than one affected child. Recessive inheritance may account for 20-25% of all HS cases. It manifests only in individuals who are homozygous or compound heterozygous and often is associated with severe hemolytic anemia.

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Epidemiology

HS is the most common hereditary hemolytic anemia in people of northern European descent. [9] In the United States, the incidence of the disorder is approximately one case in 5000 people. However, this figure probably is an underestimate. Given that approximately 25% of all HS is autosomal recessive, calculations indicate that 1.4% of the US population might be silent carriers of HS.

Although HS is encountered worldwide, its prevalence in other groups has not been established clearly. One systematic review estimated that the overall prevalence of HS in China is 1.27 cases per 100,000 population in males and 1.49 cases per 100,000 population in females. [10]

Mortality/Morbidity

Anemia or hyperbilirubinemia may be of such magnitude as to require exchange transfusion in the neonatal period. Anemia usually is mild to moderate; however, sometimes it is very severe and sometimes it is not present. Splenomegaly is the rule, and palpable spleens have been detected in more than 75% of affected subjects. Severe hemolytic anemia requires red cell transfusions.

In chronic congenital hemolytic anemia (ie, HS), long periods of asymptomatic disease depend on a fragile equilibrium in which the excessive destruction of cells is balanced by accelerated erythropoiesis. Disruption of this equilibrium can lead to rapid and dramatic falls in blood hemoglobin levels, producing an aplastic crisis. Most, if not all, aplastic crises are caused by infection with type B19 human parvovirus (HPV).

In some cases, an abrupt increase in the rate of red cell destruction may occur, possibly because of increased splenic activity (hemolytic crisis). Another type of crisis develops when erythropoiesis to compensate for hemolysis is impaired by folate deficiency (megaloblastic crisis), to which patients with chronic hemolysis appear to be particularly prone. The onset of megaloblastic crises tends to be more gradual than that of aplastic or hemolytic crises and is unrelated to complicating infections.

In patients with mild HS, cholelithiasis may be the first sign of an underlying red cell disorder. Cholelithiasis is common in HS. Gallstones of the pigment type (caused by bilirubin) may be found in very young children, but the incidence of gallstones increases markedly with age.

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Prognosis

Patients with very mild HS may remain unaffected by their disorder unless challenged by an environmental stressor. In patients who undergo splenectomy, RBC survival improves dramatically, and most are able to maintain a normal hemoglobin level.

A Dutch study in 132 children and adolescents with HS, of whom 48 had undergone splenectomy, concluded that these patients overall have a strong ability to cope with HS. However, their health-related quality of life scores were lower than those of their peers, with fatigue and patients' perceived social acceptance and parents' perceived vulnerability appearing as important determinants. [11]

Patients with HS who have not undergone splenectomy are often thought to have an increased risk of blunt splenic injury from trauma because of splenomegaly. However, review of a population-based database by Hsiao and colleagues showed that the rate of blunt splenic injury in the HS patient population appears not to differ significantly from the rate in the general population. [11]

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