Etiology

Hereditary spherocytosis usually is transmitted as an autosomal dominant or, less commonly, as an autosomal recessive disorder. As many as 25% of patients have no previous family history. Of these patients, most represent new mutations, and a few cases result from recessive inheritance or represent nonpaternity. The most common molecular defects are abnormalities of spectrin or ankyrin, which are major components of the cytoskeleton responsible for RBC shape. A recessive defect has been described in α-spectrin. Dominant defects have been described in β-spectrin and protein 3. Dominant and recessive defects have been described in ankyrin (Table 452-1). A deficiency in spectrin, protein 3, or ankyrin results in uncoupling in the “vertical” interactions of the lipid bilayer skeleton and the loss of membrane microvesicles (Figs. 452-1 and 452-2). The loss of membrane surface area without a proportional loss of cell volume causes sphering of the RBCs and an associated increase in cation permeability, cation transport, adenosine triphosphate (ATP) use, and glycolysis. The decreased deformability of the spherocytic RBCs impairs cell passage from the splenic cords to the splenic sinuses, and the spherocytic RBCs are destroyed prematurely in the spleen. Splenectomy markedly improves RBC life span and cures the anemia.

Figure 452-1 A simplified cross-section of the red blood cell (erythrocyte) membrane. The lipid bilayer forms the equator of the cross-section with its polar heads (small circles) turned outward. 4.1 R, protein; 4.2, protein 4.2; LW, Landsteiner-Wiener glycoprotein; Rh, Rhesus polypeptide; RhAG, Rh-associated glycoprotein.

(From Perrotta S, Gallagher PG, Mohandas N: Hereditary spherocytosis, Lancet 372:1411–1426, 2008.)

Figure 452-2 Pathophysiologic effects of hereditary spherocytosis.

(From Perrotta S, Gallagher PG, Mohandas N: Hereditary spherocytosis, Lancet 372:1411–1426, 2008.)

Clinical Manifestations

Hereditary spherocytosis may be a cause of hemolytic disease in the newborn and can manifest as anemia and hyperbilirubinemia sufficiently severe to require phototherapy or exchange transfusions. Hemolysis may be more prominent in the newborn because hemoglobin F binds 2,3-diphosphoglycerate poorly, and the increased level of free 2,3-diphosphoglycerate destabilizes interactions among spectrin, actin, and protein 4.1 in the RBC membrane (see Fig. 452-1).

The severity of symptoms in infants and children is variable. Some patients remain asymptomatic into adulthood, but others have severe anemia with pallor, jaundice, fatigue, and exercise intolerance. Severe cases may be marked by expansion of the diploë of the skull and the medullary region of other bones, but to a lesser extent than in thalassemia major. After infancy, the spleen is usually enlarged, and pigmentary (bilirubin) gallstones can form as early as age 4-5 years. At least 50% of unsplenectomized patients ultimately form gallstones, although they may be asymptomatic.

Because of the high RBC turnover and heightened erythroid marrow activity, children with hereditary spherocytosis are susceptible to aplastic crisis, primarily as a result of parvovirus B19 infection, and to hypoplastic crises associated with various other infections (Fig. 452-3). The erythroid marrow failure can rapidly result in profound anemia (hematocrit <10%), high-output heart failure, hypoxia, cardiovascular collapse, and death. White blood cell and platelet counts can also fall (see Fig. 452-3).

Figure 452-3 Parvovirus-induced aplastic crisis. Progression of the changes in blood count is shown for a patient with hereditary spherocytosis and infection with parvovirus. Note that the fall in baseline reticulocytosis is associated with a rapid fall in hemoglobin. White blood cells (WBC) and platelets are also affected.

(Modified from Nathan DG, Orkin SH, Ginsburg D, et al, editors: Hematology of infancy and childhood, ed 6, Philadelphia, 2003, WB Saunders.)

Long-term complications include gout, myopathy, and spinocerebellar degenerations.

Laboratory Findings

Evidence of hemolysis includes reticulocytosis and indirect hyperbilirubinemia. The hemoglobin level usually is 6-10 g/dL, but it can be in the normal range. The reticulocyte percentage often is increased to 6-20%, with a mean of approximately 10%. The mean corpuscular volume (MCV) is normal, although the mean corpuscular hemoglobin concentration often is increased (36-38 g/dL RBCs). The RBCs on the blood film vary in size and include polychromatophilic reticulocytes and spherocytes (Fig. 452-4). The spherocytes are smaller in diameter and appear hyperchromic on the blood film as a result of the high hemoglobin concentration. The central pallor is less conspicuous than in normal cells. Spherocytes may be the predominant cells or may be relatively sparse, depending on the severity of the disease, but they usually account for >15-20% of the cells when hemolytic anemia is present. Erythroid hyperplasia is evident in the marrow aspirate or biopsy. Marrow expansion may be evident on routine roentgenographic examination. Other evidence of hemolysis can include decreased haptoglobin and the presence of gallstones on ultrasonography.

Figure 452-4 Morphology of abnormal red cells. A, Hereditary spherocytosis. B, Hereditary elliptocytosis. C, Hereditary pyropoikilocytosis. D, Hereditary stomatocytosis. E, Acanthocytosis. F, Fragmentation hemolysis.

The diagnosis of hereditary spherocytosis usually is established clinically from the blood film, which shows many spherocytes and reticulocytes, from the family history, and from splenomegaly. The presence of spherocytes in the blood can be confirmed with an osmotic fragility test (Fig. 452-5). The RBCs are incubated in progressive dilutions of an iso-osmotic buffered salt solution. Exposure to hypotonic saline causes the RBCs to swell, and the spherocytes lyse more readily than biconcave cells in hypotonic solutions. This feature is accentuated by depriving the cells of glucose overnight at 37°C, known as the incubated osmotic fragility test. Unfortunately, this test is not specific for hereditary spherocytosis, and results may be abnormal in immune and other hemolytic anemias. A normal test result also may be found in 10-20% of patients. Other tests, such as the cryohemolysis test, osmotic gradient ektacytometry, and the eocin-5-maleimide test, may be more sensitive but are not readily available. Detection of a population of hyperdense RBCs using a laser-based instrument or a Coulter counter may prove more convenient as an approach to diagnosis.

Figure 452-5 Osmotic fragility of normal red cells and red cells from a patient with hereditary spherocytosis (HS). The accentuation of the osmotic sensitivity, particularly of the HS cells, is shown after incubation overnight without glucose.

(From Reich PR, editor: Hematology: pathophysiologic basis for clinical practice, ed 2, Boston, 1984, Little, Brown, with permission.)

As a research tool, the specific protein abnormality can be established in 80% of these patients by RBC membrane protein analysis using gel electrophoresis and densitometric quantitation. The protein abnormalities are more evident in patients who have had a splenectomy. Studies to define the underlying defects in the cytoskeleton might require assessment of protein synthesis, stability, assembly, and binding to the other membrane proteins. Molecular diagnosis also is possible. Most patients have family-specific private mutations that can be detected by DNA analysis. De novo mutations in the β-spectrin and ankyrin genes have been described in 50% of patients with unaffected parents.

Differential Diagnosis

The major alternative considerations when large numbers of spherocytes are seen on the blood film are isoimmune and autoimmune hemolysis. Isoimmune hemolytic disease of the newborn, particularly due to ABO incompatibility, mimics hereditary spherocytosis. The detection of antibody on an infant’s RBCs using a direct antiglobulin (Coombs) test should establish the diagnosis of immune hemolysis. Autoimmune hemolytic anemias also are characterized by spherocytes, and there may be evidence of previously normal values for hemoglobin, hematocrit, and reticulocyte count. Rare causes of spherocytosis include thermal injury, clostridial septicemia with exotoxemia, and Wilson disease, each of which can manifest as transient hemolytic anemia (see Table 451-1).

Treatment

Because the spherocytes in hereditary spherocytosis are destroyed almost exclusively in the spleen, splenectomy eliminates most of the hemolysis associated with this disorder. After splenectomy, osmotic fragility often improves because of diminished splenic conditioning and less RBC membrane loss; the anemia, reticulocytosis, and hyperbilirubinemia then resolve. Whether all patients with hereditary spherocytosis should undergo splenectomy is controversial. Some do not recommend splenectomy for patients whose hemoglobin values exceed 10 g/dL and whose reticulocyte percentage is <10%. Folic acid, 1 mg daily, should be administered to prevent deficiency and the resultant decrease in erythropoiesis. For patients with more severe anemia and reticulocytosis or those with hypoplastic or aplastic crises, poor growth, or cardiomegaly, splenectomy is recommended after age 5-6 yr to avoid the heightened risk of postsplenectomy sepsis in younger children. Laparoscopic splenectomy decreases the length of hospital stay and has replaced open splenectomy for many patients.

Vaccines (conjugated and/or capsular) for encapsulated organisms, such as pneumococcus, meningococcus, and Haemophilus influenzae type b, should be administered before splenectomy, and prophylactic oral penicillin V (age <5 yr, 125 mg twice daily; age 5 yr through adulthood, 250 mg twice daily) should be administered thereafter. Postsplenectomy thrombocytosis is commonly observed, but it needs no treatment and usually resolves spontaneously. Partial (near total) splenectomy also may be useful in children younger than age 5 yr and can provide some increase in hemoglobin and reduction in the reticulocyte count, with potential maintenance of splenic phagocytic and immune function.