Spherocytosis

Hereditary Spherocytosis

Hereditary spherocytosis is the most common inherited anemia in persons of northern European descent. In 75 percent of cases, the condition is inherited in an autosomal dominant fashion. Patients usually present with splenomegaly, jaundice and anemia. A deficiency of the cytoskeletal protein spectrin is believed to underlie this hemolytic state. Affected individuals display a tendency to form pigmented (bilirubin) gallstones. Splenectomy may be essentially curative in the majority of patients. Hereditary spherocytosis (also known as congenital hemolytic jaundice) is an inherited hemolytic anemia characterized by defective erythrocyte membranes. The biconcavity seen in normal red blood cells is lost, and splenic trapping with hemolysis results. The precise cellular defect associated with hereditary spherocytosis is unknown but is believed to involve diminished bioavailability of spectrin, one of the protein building blocks of the erythrocyte "cytoskeleton."

Splenectomy is commonly recommended for patients with hereditary spherocytosis. This operation may be essentially curative in patients with the autosomal dominant form of the disease. In those with the autosomal recessive or sporadic hereditary form, however, anemia may be profound and persistent.

Prevalence

Hereditary spherocytosis occurs in all races[1] and is the most common inherited anemia among persons of northern European ancestry.[1,2] Its incidence in the United States has been estimated at 220 cases per million population.[3]

Clinical Features

The classic features of hereditary spherocytosis include anemia, splenomegaly and jaundice.[1,4,5] Clinical signs and symptoms fluctuate with the degree of hemolysis.[6] Anemia is usually mild to moderate and, in healthy patients, may be insignificant. Asymptomatic splenomegaly is often the presenting sign in children. Overall, splenic enlargement is seen in over 80 percent of patients. At surgery, the spleen may be six times its normal size. Acholuric jaundice[4] (jaundice without urinary bilirubin) and chronic leg ulcers[1] may also be present.

Hereditary spherocytosis is usually diagnosed in childhood, and hyperbilirubinemia in infancy may be the first manifestation. However, in a patient with a compensated anemia and no other signs or symptoms, the disorder may not be diagnosed until old age, if at all. Friedman and associates[5] described five patients in the seventh through ninth decades of life who were found to have hereditary spherocytosis. All patients were asymptomatic, and no further therapy was recommended.

Like other individuals with hemolytic disorders, patients with hereditary spherocytosis show an increased propensity to develop pigmented (bilirubin) gallstones.[6] This type of stone is not uncommon, even in children.[7] Reported prevalence rates for cholelithiasis in patients with hereditary spherocytosis range from 10 to 55 percent.[8,9]

Aplastic and hemolytic crises cause considerable morbidity in patients with this disorder. Aplastic crises are most frequently precipitated by infection, and affected individuals have decreased hemoglobin, reticulocytopenia and, often, transient thrombocytopenia and leukopenia. Recovery usually requires five to ten days and is heralded by normoblastemia and an increased reticulocyte count. Direct viral infection of the erythropoietic cells has been suggested as the cause of these crises.[10] More indolent aplastic crises may occur secondary to folic acid deficiency.[11] Hemolytic crises, while less common than aplastic crises in these patients, are the result of increased red blood cell hemolysis and are also usually secondary to infection.[1]

Laboratory Features

The anemia associated with hereditary spherocytosis tends to be mild. On microscopic examination, red blood cells appear spherical and diminished in size, leading to the term "microspherocyte." The mean corpuscular volume (MCV) is normal to slightly decreased, and the mean corpuscular hemoglobin concentration (MCHC) is usually elevated.[1] The reticulocyte count is also elevated.[4] Thrombocytopenia is not uncommon and will often remit after splenectomy is performed.[8]

Not surprisingly, serum bilirubin (indirect),[6] fecal urobilinogen[1] and serum iron[4] are all increased. Because the hemolysis associated with hereditary spherocytosis occurs in the spleen and not intravascularly, hemoglobinemia is not seen. Haptoglobin levels, however, are decreased.[1]

Bone marrow examination reveals a compensatory erythroblastic hyperplasia. Extramedullary hematopoiesis may occasionally be seen.[1]

Pathophysiology

Accelerated and premature destruction of erythrocytes in the spleen underlies the anemia seen in patients with hereditary spherocytosis. Red blood cells traversing the splenic cords need to have a smooth biconcave form and adequate surface area to undergo deformation.[1] The erythrocytes of patients with hereditary spherocytosis have a markedly diminished ratio of surface area to volume, which causes the spherical shape.[12] Since the spherical cells cannot deform properly in the splenic cords, particularly in the decreased pH of the spleen, hemolysis ensues.[13]

The red blood cell defect responsible for this reduction in surface area has not been identified. Abnormal membrane fluidity has been proposed as a causative factor,[1] as has excessive accumulation of intracellular calcium.[14] Recent evidence, however, implicates an improperly formed cytoskeleton.

Within the erythrocyte is an elastic cytoskeleton that firmly attaches to the lipid membrane[6] and serves to control the shape and deformability of the cell.[15] Included in this latticework are a number of interconnected polypeptides, including spectrin, actin and protein 4.1. These molecules in turn attach to the cell membrane by means of two other proteins, ankyrin and protein 3.[16]

Various mechanisms involving these proteins have been proposed as the cause of the cellular defect in hereditary spherocytosis. Sawyer and coworkers[17] speculated that protein 4.1 interacts improperly with the actin/spectrin macromolecule. Coetzer and associates[18] reported decreased cellular ankyrin levels in two patients with hereditary spherocytosis. Several authors[2,18] have noted decreased spectrin concentrations in affected erythrocytes. In this situation, the underlying cytoskeleton is improperly equipped to fully support the red blood cell membrane. Small areas of the lipid bilayer are lost, and the cell gradually assumes a spherical shape.[6] In the autosomal dominant form of hereditary spherocytosis, a modest degree of spectrin deficiency (5 to 20 percent) has been noted.[19] Agre and colleagues[2] have suggested that spectrin radioimmunoassays may help define both the inheritance pattern and the possible response to splenectomy in patients with hereditary spherocytosis.

Genetics

In the majority of patients, hereditary spherocytosis is inherited in an autosomal dominant fashion.[1,3,4,6,20] However, in approximately 25 percent of patients, no family member has the disease and the family history is negative.[2,6] Previously, such patients have been thought to represent a spontaneous genetic mutation,[6,20,21] incomplete penetrance[22] or a recessively transmitted mutation.[23] Several reports have described patients with an autosomal recessive pattern of inheritance.[6,24] Their anemia was profound, and splenectomy did not provide complete relief.

Recently, Kitatani and colleagues[25] reported on a young boy with multiple congenital anomalies and hereditary spherocytosis. His parents were normal, and the child's karyotype demonstrated a deletion of the short arm of chromosome 8. These authors have proposed that the gene responsible for spherocytosis is located on that chromosome.

Diagnosis

Hereditary spherocytosis should be considered in patients exhibiting splenomegaly, anemia and jaundice. Microscopically, red blood cells demonstrate microspherocytosis and an elevated MCHC (Figure 1). A negative direct Coombs' test must be obtained to rule out immune causes of hemolytic anemia.[5]

The traditional test for hereditary spherocytosis is the osmotic fragility test.[1] When suspended in varying concentrations of saline, erythrocytes from affected patients demonstrate increased fragility compared with normal red cells. Affected cells become spherical and hemolyze more rapidly at high sodium levels. The test will be positive if more than 1 to 2 percent of cells are affected.

In patients with a negative osmotic fragility test and with microspherocytes on a blood smear, it is often helpful to obtain an incubated fragility test or an autohemolysis test. In the former test, whole blood is incubated under sterile conditions at 37 [degrees] C (98.6 [degrees] F), and cell lysis is evaluated after 24 hours. The autohemolysis test measures spontaneous hemolysis of red cells incubated for 48 hours at 37 [degrees] C. Neonates with hereditary spherocytosis may occasionally have normal hemoglobin levels and reticulocyte counts. In these children, the autohemolysis test is particular helpful in making the diagnosis.[26]

Differential Diagnosis

Hereditary spherocytosis is only one of a number of hemolytic anemias (Table 1). The finding of spherocytes on a routine blood smear does not automatically signify hereditary spherocytosis or an erythrocyte membrane defect. Spherocytosis may be seen in patients with hypersplenism secondary to chronic infections or cirrhosis and in neonates with sepsis or ABO incompatibility.[27] Ingestion of oxidant drugs may have a direct toxic effect on red blood cells.[1]

Treatment

The treatment of patients with hereditary spherocytosis usually involves splenectomy.[4,6] Hereditary spherocytosis is the most frequent hematologic disorder for which this operation is performed, and most patients benefit greatly from it.[4] After splenectomy, the spherocytosis may remain, but erythrocyte destruction usually ceases.[1] Since removal of the spleen in young children is associated with an increased incidence of overwhelming infection,[4] it is recommended that the operation be delayed, if possible, until the patient is at least six years of age.[6] Some children with hereditary spherocytosis (particularly those with an autosomal recessive mode of inheritance) may have recurrent hemolytic crises and severe anemia. In these patients, splenectomy may be required at a younger age.[4]

Removal of the spleen in elderly patients carries a greater likelihood of postoperative complications and long-term risk of sepsis.[28] Therefore, splenectomy is not routinely recommended, except in symptomatic patients.[5]

Patients who have undergone splenectomy have a greater incidence of infection by encapsulated microorganisms. Polyvalent pneumococcal vaccine should be administered, preferably before surgery, to all patients over two years of age.[1,4]

The continuous hemolysis in hereditary spherocytosis leads to the development of pigmented (bilirubin) gallstones in more than 40 percent of patients over ten years of age.[4] Therefore, an oral cholecystogram or abdominal sonogram is recommended before splenectomy in patients over age ten.[6,9] If multiple stones are found on removal of the gallbladder, an intraoperative cholangiogram should be performed. Preoperative cholecystography is probably not indicated in children under age ten. However, at splenectomy, the gallbladder must be palpated and removed if stones are found.[4]

Follow-up and Prognosis

Splenectomy is largely curative in the majority of patients with hereditary spherocytosis. Patients whose anemia has been corrected may experience increased energy and a sense of well-being.[6] In addition, a normal life span can be anticipated.[1] However, in patients with an autosomal recessive inheritance of the disease and in those with profound anemia, splenectomy may not return the hematocrit to normal.[6] Pigmented gallstones still form in some individuals despite removal of the spleen.[4]

Some patients may seem to benefit from splenectomy but later experience a relapse. One study[6] showed that a high percentage of patients with hereditary spherocytosis have accessory splenic tissue. If all such tissue is not removed at splenectomy, hemolytic anemia may recur.[6,29]

Various preventive measures may benefit patients who have undergone splenectomy. Davidson and associates[10] have recommended the administration of human immunoglobulin to patients at risk of aplastic anemia secondary to infection. If folic acid deficiency is present, supplementation may be required.[1]

Final Comment

Few hereditary disorders can be easily managed or cured with medical or surgical intervention. However, in the autosomal dominant form of hereditary spherocytosis, the clinical manifestations may be largely eradicated by splenectomy. Diagnosis of this disorder during childhood is not difficult and allows patients to avoid the consequences of a longstanding hemolytic anemia, notably pigmented gallstone formation. [Tabular Data Omitted] [Figure 1 Omitted]

REFERENCES [1]Jandl JH, Cooper RA. Erythrocyte disorders--anemias due to increased destruction of erythrocytes with abnormal shape and normal hemoglobin (membrane defects?). In: Williams WJ, ed. Hematology. 3d ed. New York: McGraw Hill, 1983;547-53. [2]Agre P, Asimos A, Casella JF, McMillan C. Inheritance pattern and clinical response to splenectomy as a reflection of erythrocyte spectrin deficiency in hereditary spherocytosis. N Engl J Med 1986;315:1579-83. [3]Morton NE, MacKinney AA, Kosower N, Schilling RF, Gray MP. Genetics of spherocytosis. Am J Hum Genet 1962;14:170-84. [4]Rutkow IM. Twenty years of splenectomy for hereditary spherocytosis. Arch Surg 1981;116:306-8. [5]Friedman EW, Williams JC, Van Hook L. Hereditary spherocytosis in the elderly. Am J Med 1988;84(3 Pt 1):513-6. [6]Croom RD 3d, McMillan CW, Orringer EP, Sheldon GF. Hereditary spherocytosis. Recent experience and current concepts of pathophysiology. Ann Surg 1986;203:34-9. [7]Gairdner D. Association of gall-stones with acholuric jaundice in children. Arch Dis Childhood 1939;14:109-20. [8]Krueger HC, Burgert EO Jr. Hereditary spherocytosis in 100 children. Mayo Clinic Proc 1966;41:821-30. [9]Lawrie GM, Ham JM. The surgical treatment of hereditary spherocytosis. Surg Gynecol Obstet 1974;139:208-10. [10]Davidson RJ, Brown T, Wiseman D. Human parvovirus infection and aplastic crisis in hereditary spherocytosis. J Infect 1984;9:298-300. [11]Jandl JH, Greenberg MS. Bone-marrow failure due to relative nutritional deficiency in Cooley's hemolytic anemia: painful "erythropoietic crises" in response to folic acid. N Engl J Med 1959;260:461-8. [12]Castle WB, Daland GA. Susceptibility of erythrocytes to hypotonic hemolysis as a function of discoidal form. Am J Physiol 1937;120:371-83. [13]Murphy JR. The influence of pH and temperature on some physical properties of normal erythrocytes and erythrocytes from patients with hereditary spherocytosis. J Lab Clin Med 1967;69:758-75. [14]Feig SA, Guidotti G. Relative deficiency of [Ca.sup.2+] -dependent adenosine triphosphatase activity of red cell membranes in hereditary spherocytosis. Biochem Biophys Res Commun 1974;58:487-94. [15]Branton D, Cohen CM, Tyler J. Interaction of cytoskeletal proteins on the human erythrocyte membrane. Cell 1981;24:24-32. [16]Lux S, Shohet SB. The erythrocyte membrane skeleton: biochemistry. Hosp Pract [Off] 1984;19:77-83. [17]Sawyer WH, Hill JS, Howlett GJ, Wiley JS. Hereditary spherocytosis of man. Defective cytoskeletal interactions in the erythrocyte membrane. Biochem J 1983;211:349-56. [18]Coetzer TL, Lawler J, Liu SC, et al. Partial ankyrin and spectrin deficiency in severe, a typical hereditary spherocytosis. N Engl J Med 1988;318:230-4. [19]Agre P, Casella JF, Zinkham WH, McMillan C, Bennett V. Partial deficiency of erythrocyte spectrin in hereditary spherocytosis. Nature 1985;314(6009):380-3. [20]Stevens RF, Evans DI. Congenital spherocytosis is often not hereditary. Clin Pediatr [Phila] 1981;20:47-9. [21]Bellingham AJ, Prankerd TA. Hereditary spherocytosis. Clin Haematol 1975;4:139-44. [22]MacKinney AA. Hereditary spherocytosis; clinical family studies. Arch Intern Med 1965;116:257-65. [23]Valentine WN. Hereditary spherocytosis revisited. West J Med 1978;128:35-45. [24]Agre P, Orringer EP, Bennett V. Deficient red-cell spectrin in severe, recessively inherited spherocytosis. N Engl J Med 1982;306:1155-61. [25]Kitatani M, Chiyo H, Ozaki M, Shike S, Miwa S. Localization of the spherocytosis gene to chromosome segment 8p11.22 [right arrow] 8p21.1. Hum Genet 1988;78:94-5. [26]Schroter W, Kahsnitz E. Diagnosis of hereditary spherocytosis in newborn infants. J Pediatr 1983;103:460-3. [27]Trucco JI, Brown AK. Neonatal manifestations of hereditary spherocytosis. Am J Dis Child 1967;113:263-70. [28]Weed RI. Hereditary spherocytosis. A review. Arch Intern Med 1975;135:1316-23. [29]Bart JB, Appel MF. Recurrent hemolytic anemia secondary to accessory spleens. South Med J 1978;71:608-9.

ALAN S. BOYD, M.D. is currently a research fellow in the Department of Dermatology at Texas Tech University Health Sciences Center, Lubbock. He was formerly the Simmons Clinical Research Fellow at the Baylor Psoriasis Center, Baylor University Medical Center, Dallas. Dr. Boyd graduated from the University of Texas Medical School, Houston, and served an internship at the McLennan County Family Practice Program in Waco, Tex.

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