Hereditary Spherocytosis 

Updated: Feb 18, 2021
Author: Gus Gonzalez, MD; Chief Editor: Emmanuel C Besa, MD 

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, 2]  It is also one of the most common causes of hemolytic anemia due to membrane defect. 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[3, 4] :

  • 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.[5]

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.[6] 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.[7, 8]

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.[9]

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.[10]

 

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.

Approximately 25% 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.

Epidemiology

HS is the most common hereditary hemolytic anemia in people of northern European descent.[11] 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.[12]

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.

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.[13]

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.[13]

 

Presentation

History

As in other chronic hemolytic states, the signs and symptoms of hereditary spherocytosis (HS) include mild pallor, intermittent jaundice, and splenomegaly. However, signs and symptoms are highly variable. Anemia or hyperbilirubinemia may be of such magnitude as to require exchange transfusion in the neonatal period. The disorder also may escape clinical recognition altogether. Anemia usually is mild to moderate, but is sometimes very severe and sometimes not present.

A classification based on severity of anemia and hemolysis has been developed, as follows[4] :

  • Hereditary spherocytosis trait - Normal hemoglbin and reticulocyte count
  • Mild HS - Hemoglobin 11 - 15 g/dL; reticulocyes 3-6 %; bilirubin 1-2 mg/dL (20-30% of cases)
  • Moderate HS - Hemoglobin 8-12 g/dL: reticulocytes > 6%; bilirubin > 2 mg/dL (60-75% of cases)
  • Severe HS - Hemoglobin 6-8 g/dL; reticulocytes >10%; bilirubin > 3 mg/dL (5% of cases)

Newborns with HS may have a normal hemoglobin level at birth, followed by severe anemia that typically develops between 3 weeks of age and the first year of life. Children diagnosed early in life usually have a severe form of HS that results in their early presentation. Jaundice is likely to be most prominent in newborns. The magnitude of hyperbilirubinemia may be such that exchange transfusion is required. Approximately 30-50% of adults with HS had a history of jaundice during the first week of life. Recognition of HS as a potential cause of neonatal anemia and hyperbilirubinemia and prompt institution of treatment may reduce the risk of bilirubin-induced neurologic dysfunction in these patients.[14]

Beyond the neonatal period, jaundice rarely is intense. Icterus is intermittent and may be triggered by fatigue, cold exposure, emotional distress, or pregnancy. An increase in scleral icterus and a darker urine color commonly are observed in children with nonspecific viral infections. Adults who remain undiagnosed usually have a very mild form, and their HS remains undetected until challenged by an environmental stressor.

Gallstones of the pigment type, resulting from excess unconjugated bilirubin in bile, may be found in very young children, but the incidence of gallstones increases markedly with age. In patients with mild HS, cholelithiasis may be the first sign of an underlying red cell disorder.

A family history of HS may be present, or the patient may report a history of a family member having had a splenectomy or cholecystectomy before the fourth decade of life. A history of family members with cholelithiasis in the second or third decade of life is also a clue to the possible presence of HS.

Physical Examination

Splenomegaly is the rule in HS. Palpable spleens have been detected in more than 75% of affected subjects. The liver is normal in size and function.

Other important clues are jaundice and upper right abdominal pain indicative of gallbladder disease. This is especially important if the patient has a family history of gallbladder disease. Any patient who presents with profound and sudden anemia and reticulocytopenia with the aforementioned physical findings also should have HS in the differential diagnosis.

 

DDx

Diagnostic Considerations

Hereditary spherocytosis (HS) can be caused by any of several genetic anomalies, which have different patterns of inheritance and produce disease with a range of severity. Thus, the clinical and laboratory features of HS can vary widely.

Moderate HS is the most common form, accounting for 60-75% of all HS cases. Patients present with mild-to-moderate anemia, modest splenomegaly, and intermittent jaundice. In most cases, the pattern of transmission is autosomal dominant, although recessive inheritance also is observed.

Mild HS occurs in 20-30% of cases of autosomal dominant HS. Anemia generally is not present because the bone marrow is able to fully compensate for the persistent destruction of red cells. Little or no splenomegaly occurs. These patients usually are asymptomatic. They often are not diagnosed until later in life, when they experience hemolytic or aplastic episodes triggered by infection or other stresses. The condition may be identified only through family surveys.

Severe HS occurs in approximately 5% of all patients with HS. Severe hemolytic anemia that requires red cell transfusions and an incomplete response to splenectomy characterize severe HS. The pattern of inheritance is recessive. The parents of affected patients have no signs of HS or have only a mild increase in the reticulocyte count, a few spherocytes on peripheral blood smear, a minimally abnormal incubated osmotic fragility test result, or an abnormal spectrin content detected when sensitive techniques are used.

Gilbert syndrome

HS may occasionally be mistaken for Gilbert syndrome, a hereditary disorder in which reduced conjugation of bilirubin in the liver results in jaundice. Although patients with Gilbert syndrome may be asymptomatic, most have nonspecific symptoms such as abdominal cramps, fatigue, and malaise. Laboratory studies may reveal unconjugated hyperbilirubinemia. In contrast to HS, patients with Gilbert syndrome have normal results on reticulocyte count and blood smear.

Hereditary xerocytosis (HX)

Hereditary xerocytosis (HX), also known as dehydrated hereditary stomatocytosis (DHS), is a rare autosomal dominant congenital hemolytic anemia characterized by erythrocyte dehydration with presentation of various degrees of hemolytic anemia. Over 80% of cases are caused by missense mutations in the PIEZO1 gene. In a subset of HX patients, mutations in the gene coding for calcium-activated potassium channel (KCNN4) have been identified.[15]

The severity of chronic anemia varies; transient perinatal edema and hydrops fetalis may be present. Laboratory findings include spherocytes on the peripheral blood smear, elevated reticulocyte count, and slightly increased MCHC and red cell mean corpuscular volume (MCV). Genetic testing may be required to confirm the diagnosis. Differentiating HX from HS is important because splenectomy is not beneficial in patients with HX and increases the risk for venous thrombosis.[15]

Hemolytic disease of the fetus and newborn

Patients with this disorder, which is also called neonatal alloimmune hemolytic anemia, may present with jaundice and anemia requiring aggressive support. They may have spherocytosis. This disorder is transient and resolves once maternal antibodies are cleared.

Differential Diagnoses

 

Workup

Approach Considerations

The principal laboratory studies used in the diagnosis of hereditary spherocytosis (HS) include the following:

  • Complete blood cell count
  • Reticulocyte count
  • Mean corpuscular hemoglobin concentration (MCHC)
  • Peripheral blood smear
  • Lactate dehydrogenase (LDH) level
  • Haptoglobin
  • Fractionated bilirubin
  • Combs testing
  • Flow cytometry using the eosin-5'-maleimide (EMA) binding test [16]

Osmotic gradient ektacytometry, although recognized as the reference technique for diagnosis of red blood cell (RBC) membrane disorders, has rarely been used in clinical practice because of its limited availability. However, a new generation of ektacytometers has been developed that may result in broader use of this technique.[17] This technique does not differentiate between HS and autoimmune hemolytic anemia (AIHA), but it distinguishes HS from other hereditary membrane  disorders.[18]

The classic laboratory features of HS include the following[3, 4] :

  • Mild to moderate anemia
  • Reticulocytosis
  • Increased MCHC
  • Spherocytes on the peripheral blood smear
  • Hyperbilirubinemia

RBC morphology in HS is distinctive yet not diagnostic. Anisocytosis is prominent, and the smaller cells are spherocytes. Unlike the spherocytes associated with immune hemolytic disease and thermal injury, HS spherocytes are fairly uniform in size and density. Spherocytes are characterized by the following:

  • Lack of central pallor
  • Decreased mean corpuscular diameter
  • Increased density.

Spherocytic RBCs are not specific to HS. Autoimmune hemolytic anemia also may produce spherocytosis, but this disorder usually can be excluded by negative findings on a direct antiglobulin test.

An increased MCHC is a characteristic feature of RBCs cells in HS. MCHC values greater than the upper limit of normal (35-36%) are common. This increased MCHC is a result of mild cellular dehydration. The mean cell volume (MCV) in patients with HS actually is low, presumably because of membrane loss and cell dehydration.

The most sensitive test for HS is incubated osmotic fragility testing (OFT), which is performed after incubating RBCs for 18-24 hours under sterile conditions at 37°C. OFT with RBCs that have not been incubated may demonstrate hemolysis of HS cells in some patients but is not reliable. This is especially true of newborns, as fetal RBCs are generally more resistant to osmotic hemolysis. Incubated OFT results usually are abnormal. Sample stability is critical for OFT and blood specimens should not be refrigerated for more than 2 days prior to testing.[19]

Although OFT has traditionally been used for diagnosis of HS, it is labor intensive and time-consuming to perform. Instead, current guidelines recommend the use of flow cytometry to screen for HS.[20]  

Other laboratory tests used to diagnose HS include the autohemolysis test and the glycerol lysis test. These rarely are used and offer no advantage over OFT.

Further characterization of the specific membrane lesion by looking for abnormalities in spectrin, ankyrin, pallidin, or band 3 is possible. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) can detect the defective protein in most cases; this may be useful for distinguishing HS from other hematologic disorders that may mimic it, such as congenital dyserythropoietic anemia type II.[21]  However, these studies are not routinely performed and are available only in select research laboratories.

Osmotic gradient ektacytometry is the reference technique for diagnosis of RBC membrane disorders. In this technique, a laser-diffraction viscometer (ektacytometer) measures the deformability of erythrocytes as a continuous function of the osmolality of the medium in which they are suspended. Osmotic gradient ektacytometry distinguishes HS from other hereditary membrane pathologies but does not differentiate HS from autoimmune hemolytic anemia.[22]

Other tests are indicated in patients who have experienced an aplastic crisis. Testing for herpes simplex virus, parvovirus B19, and infectious mononucleosis may help identify an infectious etiology for the aplastic crisis. Vitamin B12 and folate levels should be measured to determine the nutritional stores during recovery from an aplastic crisis.

If the diagnosis is being made late in life, patients must have an evaluation of their iron status, especially if they have received frequent blood transfusions (eg, because of multiple hemolytic episodes or an inaccurate diagnosis) or prolonged oral iron supplementation for anemia. This evaluation includes measurement of iron stores and serum ferritin levels. Liver dysfunction or cardiac problems may be present in patients with severe iron overload.

Cholecystitis and cholelithiasis are common complications of HS. If the patient presents with signs and symptoms of hemolysis in addition to right upper abdominal quadrant pain, fever, and leukocytosis, an ultrasound of the biliary tree should be performed.

If an aplastic crisis is suggested, further evaluation of white blood cells and platelets should be pursued. This may require a bone marrow aspiration and biopsy to rule out aplasia or megaloblastosis. Obtaining bone marrow aspirate for testing rarely is necessary except in cases of aplastic or megaloblastic crisis. Test results help evaluate marrow function and the development of the lineage.

 

Treatment

Approach Considerations

Neonates with severe hyperbilirubinemia caused by hereditary spherocytosis (HS) are at risk for kernicterus. These infants should be treated with phototherapy and/or exchange transfusion as clinically indicated.

Aplastic crises occasionally can cause the hemoglobin level to fall because of ongoing destruction of spherocytes that is not balanced by new red blood cell (RBC) production. RBC transfusions often are necessary in these cases.

Folic acid is required to sustain erythropoiesis. Patients with HS are instructed to take supplementary folic acid for life in order to prevent a megaloblastic crisis. During the first 6 years of life, if patients have compensated anemia, are growing well, and can keep up with their peers in most activities, limiting folic acid supplementation to 1 mg/d is prudent.

Splenectomy is the definitive treatment for HS.[4] Except in the unusual autosomal recessive variant of HS, splenectomy usually eliminates hemolysis and the associated signs and symptoms.[5] Interestinagly, splenectomy does little to correct the cytoskeletal membrane defects of HS; an atomic force microscopy study by Li et al found that after splenectomy, erythrocytes were larger but still spheroidal-shaped, with a disorganized membrane ultrastructure and reduced surface particle size.[23]

Splenectomy may fail to control HS because of any of the following:

  • An accessory spleen
  • Accidental autotransplantation of splenic tissue into the peritoneum during surgery
  • Another hemolytic disorder
  • Splenosis

Indications for splenectomy are not always clear.[24] Little doubt exists that patients with more severe anemia (hemoglobin level < 8 g/dL) and symptoms and complications of HS should undergo splenectomy. By the same token, splenectomy can be deferred safely in patients with mild uncomplicated HS (hemoglobin level > 11 g/dL). No good studies have been performed that provide a basis for clinical judgments in patients with moderate asymptomatic HS (hemoglobin level 8-11 g/dL).

Children who are candidates for splenectomy include those with severe HS requiring RBC transfusions and those with moderate HS who manifest growth failure or other signs and symptoms of anemia. Splenectomy for children with HS should not be performed until the child is older than 6 years, to reduce the risk of infections with encapsulated bacteria.

An interesting alternative approach in pediatric patients has been the use of partial splenectomy to retain splenic immunologic function while at the same time reducing the rate of hemolysis.[25] This appears to both control hemolysis and preserve splenic function.

RBC survival improves significantly after splenectomy but does not become absolutely normal. The mean corpuscular volume (MCV) usually falls, but the mean corpuscular hemoglobin concentration (MCHC) does not change significantly.

In children with HS who underwent total or partial splenectomy, a review found that the hemoglobin concentration increased from 10.1 ± 1.8 g/dL at baseline to 12.8 ± 1.6 g/dL at 52 weeks postoperatively. In addition, splenectomry resulted in a decrease in reticulocyte counts and bilirubin levels as well as control of symptoms.[26]

Other postsplenectomy blood changes include the following:

  • Increased hemoglobin level
  • Decreased reticulocyte count
  • Leukocytosis
  • Thrombocytosis

On the peripheral blood smear, spherocytes continue to appear. Expected changes on peripheral blood smears include the appearance of Howell-Jolly inclusion bodies and target cells. Absence of Howell-Jolly bodies on the peripheral blood smear in splenectomized patients may indicate the presence of functional splenic activity.

Fatal sepsis caused by capsulated organisms (eg, Streptococcus pneumoniae, Haemophilus influenzae) is a recognized complication in children who have had a splenectomy. The estimated rate of mortality from sepsis in these children is approximately 200 times greater than that expected in the general population. Although most septic episodes have been observed in children whose spleens were removed in the first years of life, older children and adults also are susceptible.

Vaccination against pneumococcus and H influenzae must be administered to patients prior to splenectomy and, indeed, probably to all patients with severe HS. If a partial splenectomy is performed, splenic function is preserved and vaccinations may be delayed until after surgery; however, the long-term data are not well established.

Bilirubin gallstones are found in approximately 50% of patients with HS and frequently are present in patients with very mild disease. Therefore, periodic ultrasonic evaluation of the gallbladder should be performed.

If surveillance ultrasound examinations reveal gallstones, performing a prophylactic laparoscopic cholecystectomy seems reasonable. This procedure helps prevent significant biliary tract disease and, in some patients with mild HS, helps avoid the need for splenectomy. In patients with bilirubin stones who are candidates for splenectomy, a simultaneous cholecystectomy may eliminate future complications and the need for a second operative procedure.

Splenectomy

Generally, the treatment of HS involves presplenectomy care, splenectomy, and management of postsplenectomy complications. In pediatric cases, splenectomy ideally should not be performed until a child is older than 6 years because of the increased incidence of postsplenectomy infections with encapsulated organisms such as S pneumoniae and H influenzae in young children. Partial splenectomies are increasingly used in pediatric patients, as this approach appears to both control hemolysis and preserve splenic function.

European guidelines on splenectomy for HS note that a laparoscopic approach is currently considered the gold standard for removal of a normal-sized or slightly enlarged spleen and is preferred to open splenectomy, but it should be performed only by experienced surgeons. In children undergoing splenectomy, the gallbladder should be removed concomitantly if the patient has symptomatic gallstones . The study group could not come to consensus on the use of partial splenectomy.[27]

In a study of 79 patients who underwent subtotal splenectomy (85-95% removal), with mean follow-up of approximately 11 years (range, 3-23 years), Pincez et al reported that the benefits varied according to disease severity. In children younger than 6 years with severe disease, the procedure reduces the transfusion rate and increases the hemoglobin to a level compatible with normal growth and activity. Half of those patients will not require total splenectomy; the other half will require it at an age when it will be much safer.[28]

In a study that included 12 patients who underwent subtotal splenectomy at a mean age of 6.5 years, Rosman et al reported that in three children, the procedure was unsuccessful because no functional splenic remnant remained after 6 months; four children required secondary splenectomy for hematologic recurrence after a median of 5 years; and in the remaining five patients, a functional splenic remnant was present for at least 5.5 years.[29]

In patients with intermediate HS, subtotal splenectomy avoids the long-term risk of infections and vascular events associated with total splenectomy. However, it comes with the cost of persistence of a lower but persistent hemolytic state.[28]

A retrospective review by Abdullah et al of splenectomy for HS in over 1650 children found that the morbidity and mortality are low, and that performance of concurrent cholecystectomy and/or appendectomy is safe. In addition, Abdullah et al found that of 13 potentially avoidable complications identified as pediatric quality indicators by the Agency for Healthcare Research and Quality (AHRQ), none occurred in more than 1% of the splenectomized children.[5]

Consultations

If the diagnosis of HS is unclear after routine testing or the patient has severe episodes of hemolysis, consultation with a hematologist is warranted because the patient may have a variant of HS or more than one hemolytic disease. A hematologist also may provide treatment advice regarding iron overload for patients who have an extensive transfusion history or for those who have been receiving prolonged oral iron supplementation.

Patients with HS who have recurring episodes of severe hemolysis should be evaluated by a surgeon for possible splenectomy, because splenectomy provides the greatest chance for control of their disease. A partial splenectomy can be considered if a surgeon experienced in this procedure is available. Another reason for consulting a surgeon is for the complications of gallstone formation and for the prevention of gallstones in those patients with continued hemolysis.

Long-term Monitoring

Lifelong folic acid supplementation is recommended for patients with HS because of their chronic hemolysis. This is especially true for those who have not undergone splenectomy. After splenectomy, all patients should have immunizations updated as needed, especially those covering encapsulated organisms. Vaccination against S pneumonia and H influenzae is of particular importance.

 

Guidelines

Guidelines Summary

The British Society for Haematology (BSH) has published guidelines, most recently updated in 2011, for the diagnosis and treatment of hereditary spherocytosis (HS).[4]

Diagnostic recommendations from the BSH include the following:

  • In patients with a family history of HS who have typical clinical features and laboratory findings (ie, spherocytes, raised mean corpuscular hemoglobin concentration [MCHC], increased reticulocyte count), no additional tests are required to establish the diagnosis of HS.
  • If the diagnosis is equivocal, a screening test with high predictive value for HS is helpful. The recommended screening tests are the cryohemolysis test and EMA (eosin-5-maleimide) binding.
  • If the screening tests produce an equivocal or borderline result (see below), gel electrophoresis of erythrocyte membranes is the method of choice for confirming the diagnosis. Gel electrophoresis can identify atypical cases involving red blood cell (RBC) membrane and cytoskeleton abnormalities caused by spectrin genes, ankyrin gene, and the SCLC4A1 gene. Its main drawback is a lack of sensitivity for very mild or asymptomatic "carrier" HS.
  • Diagnosis of HS does not require molecular analysis of the affected genes.

The use of sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS‐PAGE) is recommended in the following circumstances:

  • When the clinical phenotype is more severe than predicted from the RBC morphology.
  • When the RBC morphology is more severe than predicted from parental blood films, in cases where one parent is known to have HS.
  • If the diagnosis is not clear prior to splenectomy and the patient might have an abnormality in Na +/K + permeability (as is found in hereditary stomatocytosis). When the morphology and RBC indices are typical for HS, there should be no doubt, but in more subtle cases (eg, when mean corpuscular volume [MCV] is >100 fl), clarification is essential, as splenectomy may not be appropriate in patients with the rare overhydrated and dehydrated hereditary stomatocytosis.

Treatment recommendations from the BSH include the following:

  • The laparoscopic approach to splenectomy is recommended, but requires appropriately trained surgeons and suitable equipment.
  • Partial splenectomy may be beneficial but needs further follow-up studies.
  • In children undergoing splenectomy, the gallbladder should be removed concomitantly if there are symptomatic gallstones. If stones are an incidental finding in a patient without symptoms, the value of cholecystectomy remains controversial. If the gallbladder is left in place, including cases in which a cholecystostomy with stone extraction is done, close follow‐up using ultrasound is necessary.
  • In children who require cholecystectomy for symptoms from gallstones, the use of concurrent splenectomy is controversial. Splenectomy in this setting may decrease future risk of common bile duct stones, but is associated with a risk of post‐splenectomy sepsis.
  • When splenectomy is indicated, ideally it should be done after the age of 6 years.
  • There is no indication for extended thrombosis prophylaxis after splenectomy in patients with HS. Adults should receive customary perioperative thromboprophylaxis.
  • Splenectomy should be avoided in patients with some forms of hereditary stomatocytosis, due to an increased risk of venous thromboembolism.
 

Medication

Medication Summary

The goals of pharmacotherapy for hereditary spherocytosis are to reduce morbidity and prevent complications. Folic acid supplementation is indicated to prevent megaloblastic crisis.

Vitamins

Class Summary

These agents are essential for normal DNA synthesis.

Folic acid (Folvite)

Important water-soluble cofactor for enzymes used in production of RBCs.

 

Questions & Answers

Overview

What is hereditary spherocytosis (HS)?

What is the pathophysiology of hereditary spherocytosis (HS)?

What is the role of spectrin deficiency in the pathophysiology of hereditary spherocytosis (HS)?

What is the role of ankyrin defects in the pathophysiology of hereditary spherocytosis (HS)?

What is the role of band-3 deficiency in the pathophysiology of hereditary spherocytosis (HS)?

What is the role of protein 4.2 deficiency in the pathophysiology of hereditary spherocytosis (HS)?

What is the role of aquaporin-1 in the pathophysiology of hereditary spherocytosis (HS)?

What is the role of red blood cell antibodies in the pathophysiology of hereditary spherocytosis (HS)?

What causes hereditary spherocytosis (HS)?

What is the prevalence of hereditary spherocytosis (HS)?

What is the morbidity associated with hereditary spherocytosis (HS)?

What is the prognosis of hereditary spherocytosis (HS)?

Presentation

Which clinical history findings are characteristic of hereditary spherocytosis (HS)?

Which physical findings are characteristic of hereditary spherocytosis (HS)?

DDX

What are the types of hereditary spherocytosis (HS)?

How is Gilbert syndrome differentiated from hereditary spherocytosis (HS)?

How is hereditary spherocytosis (HS) differentiated from hereditary xerocytosis (HX)?

What are the differential diagnoses for Hereditary Spherocytosis?

Workup

Which lab studies are performed in the workup of hereditary spherocytosis (HS)?

What is the role of osmotic gradient ektacytometry in the workup of hereditary spherocytosis (HS)?

Which lab results are characteristic of hereditary spherocytosis (HS)?

What is the role of RBC morphology in the diagnosis of hereditary spherocytosis (HS)?

What is the role of an incubated osmotic fragility test in the diagnosis of hereditary spherocytosis (HS)?

What is the role of SDS-PAGE in the workup of hereditary spherocytosis (HS)?

What is the reference technique for the diagnosis of hereditary spherocytosis (HS)?

Which lab tests are performed following an aplastic crisis due to hereditary spherocytosis (HS)?

When is iron status assessed in the workup of hereditary spherocytosis (HS)?

When is ultrasonography indicated in the workup of hereditary spherocytosis (HS)?

When is bone marrow biopsy indicated in the workup of hereditary spherocytosis (HS)?

Treatment

How is hereditary spherocytosis (HS) treated?

What are indications for splenectomy in the treatment of hereditary spherocytosis (HS)?

What is the role of partial splenectomy in the treatment of hereditary spherocytosis (HS)?

What is the efficacy of splenectomy in the treatment of hereditary spherocytosis (HS)?

What are the postsplenectomy blood changes in patients with hereditary spherocytosis (HS)?

What is a possible fatal complication of splenectomy for the treatment of hereditary spherocytosis (HS)?

What is the role of vaccination in the treatment of hereditary spherocytosis (HS)?

What how are gallstones managed in hereditary spherocytosis (HS)?

What is the role of splenectomy in the treatment of hereditary spherocytosis (HS)?

Which specialist consultations are beneficial to patients with hereditary spherocytosis (HS)?

What is included in long-term monitoring of hereditary spherocytosis (HS)?

Medications

What is the goal of drug treatment for hereditary spherocytosis (HS)?

Which medications in the drug class Vitamins are used in the treatment of Hereditary Spherocytosis?