Hereditary spherocytosis overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2]

Overview

Hereditary spherocytosis is a genetically transmitted form of hemolysis, characterized by hemolytic anemia, jaundice and splenomegaly. It was first described by Vanlair and Masius in 1871, where they described chronically icteric patients who had no bile in urine, no evidence of liver disease and often splenomegaly and family history of jaundice. Hereditary spherocytosis is classified in 05 subtypes on the basis of underlying protein defect including; ankyrin1, spectrin beta chain (erythrocytic), spectrin alpha chain (erythrocytic1), band 3 and protein 4.2. The defects in hereditary spherocytosis lie in the cell membrane. The cell membrane proteins essential for the integrity of cell membrane structure includes; spectrin, ankyrin, band 3 and protein 4.1 and 4.2, and their deficiency can produce varying degree of severity of the disease. it should be differentiated from autoimmune hemolysis, congenital dyserythropoietic anemia type II, thermal injury and hemoglobinopathies. Hereditary spherocytosis can present at any age, having a positive family history is an important risk factor for the disease. Mean corpuscular hemoglobin concentration (MCHC) and erythrocyte distribution width (RDW) tests can be used for the screening of hereditary spherocytosis. Complications of the disease include; jaundice, kernicterus, pigment gallstones, splenomegaly, hemolytic, aplastic and megaloblastic crises. It can present with yellowing of skin, fatigue, irritability, shortness of breath or it can be asymptomatic altogether. Physical examination findings include scleral icterus, jaundice and splenomegaly. Laboratory testing includes CBC, MCHC, blood smear, hemolysis testing and coombs test. There is no specific medical therapy for the hereditary spherocytosis, however surveillance is needed to help detect and manage the complications. Folic acid supplementation, blood transfusions and erythropoietin may also be tried. Splenectomy is very effective in reducing the hemolysis. Partial splenectomies are tried in children to control hemolysis and preserve splenic function as well. Administration of vaccines (pneumococcal, hemophilus influenzae, meningococcal and influenza), antibiotics (penicillin) and folic acid should be prescribed for postsplenectomy patients.

Historical Perspective

The hereditary spherocytosis was first described in 1871 by Vanlair and Masius, where they described chronically icteric patients who had no bile in the urine, no evidence of liver disease and often splenomegaly and family history of jaundice. It is the commonest cause of inherited chronic hemolysis in the northern europe and north america.

Classification

The hereditary spherocytosis classified into 05 subtypes on the basis of underlying protein defect including; ankyrin 1, spectrin beta chain (erythrocytic), spectrin alpha chain (erythrocytic 1), band 3 and protein 4.2. It is also classified on the basis of clinical severity into mild, moderate and severe subtypes.

Pathophysiology

The defects in hereditary spherocytosis lie in the cell membrane. The proteins essential for integrity of cell membrane structure lie immediately under the lipid bilayer, horizental alpha & beta spectrin molecules form heterodimers with linkage to vertical elements including ankyrin, proteins 4.1 & 4.2 and band 3 (transmembrane protein). The shorter the lifespan of red blood cells, the worse the clinical effects. Spectrin protein is a tetramer composed of alpha & beta dimers, its deficiency is most frequently seen in hereditary spherocytosis. Spectrin deficiency can result from impaired synthesis of spectrin or from qualitative or quantitative defects in other proteins that integrate proteins into red blood cells. Ankyrin is the principal binding site for spectrin on red blood cell membrane, its deficiency leading to decreased incorporation of spectrin, leading to proportional decrease in spectrin content as well despite normal synthesis of spectrin. Band 3 deficiency is seen in 10-20% of patients with mild to moderate autosomal dominant hereditary spherocytosis and is considerably greater in older red blood cells. Protein 4.2 (Pallidin) deficiency leads to abnormal red blood cell morphology including spherocytes, elliptocytes or sphero-ovalocytes, it is relatively common in japan. Red blood cell antibodies may also have a pathogenic role in red blood cell opsonization and removal by spleen.

Causes

Hereditary spherocytosis is caused by a variety of genetic mutations. The 05 genes associated with hereditary spherocytosis include; alpha spectrin (SPTA1), beta spectrin (SPTB), ankyrin (ANK1), band 3 (SLC4A1) and protein 4.2 (EPB42). Mutations in one or more of these genes can cause membrane protein deficiency leading to hereditary spherocytosis.

Differentiating Hereditary spherocytosis overview from Other Diseases

Hereditary spherocytosis usually presents with hemolysis, therefore should be differentiated from other diseases including; autoimmune hemolysis, thermal injury, clostridial septicemia, wilson disease, hemoglobinopathies, hereditary stomatocytosis, congenital dyserythropoietic anemia type II, infantile pyknocytosis and hemolytic disease of fetus and newborn (HDFN).

Epidemiology and Demographics

Hereditary spherocytosis can present at any age with any presentation from hydrops fetalis inutero through diagnosis in the ninth decade of life, and is reported worldwide in all racial and ethnic groups. It is most common inherited anemia in northern european ancestry and north america. The reported incidence is 1 in 2000 births. Approximately 25% of all hereditary spherocytosis is autosomal recessive. It is most often diagnosed in childhood or early adulthood.

Risk Factors

There are no clearly identified risk factors for the hereditary spherocytosis, but having a positive family history is an important risk factor for the disease.

Screening

The combination of two tests; mean corpuscular hemoglobin concentration (MCHC) and erythrocyte distribution width are an excellent screening tests for hereditary spherocytosis. For young patients with the disease, a full family history, complete blood count (CBC), reticulocyte count and examination of peripheral blood smear on each parent and sibling is required to determine whether the spherocytic mutation is dominant or recessive. For individuals of childbearing age with hereditary spherocytosis, review of familial mutation and its mode of transmission is useful for discussions of likelihood of disease in children.

Natural History, Complications, and Prognosis

Hereditary spherocytosis can present at any age with any severity, ranging from hydrops fetalis in utero through diagnosis in the ninth decade of life, with variable clinical course depending upon the severity of disease. Majority of affected individuals have mild or moderate hemolysis and known family history, making the diagnosis and treatment relatively easy. Complications include; jaundice, kernicterus, pigment gallstones, hemolytic, aplastic and megaloblastic crises, splenomegaly and leukemia. The prognosis is usually good with early diagnosis, regular followup and management. Patients with mild disease may develop symptoms only with environmental triggers. Many patients who undergo splenectomy are able to maintain normal hemoglobin levels, however patients with severe hereditary spherocytosis may remain anemic postsplenectomy and require regular blood transfusions. Postsplenectomy patients are at increased risk of life threatening infections (sepsis), therefore require vaccinations and antibiotics.

Diagnosis

The diagnosis of hereditary spherocytosis can be based on physical examination, complete blood count (CBC), reticulocyte count, medical history and specific tests including eosin-5-maleimide binding (EMA) test and acidified glycerol lysis time (AGLT) test. The diagnosis can be made at any age. EMA binding test has high sensitivity and specificity for the hereditary spherocytosis. Other tests include; osmotic fragility (OF) test, pink test and ektacytometry. Gel electrophoresis analysis of erythrocyte membranes is the method of choice for diagnosis of atypical cases.

History and Symptoms

The hereditary spherocytosis is a familial hemolytic disorder with increased heterogeneity. Clinical features range from asymptomatic to fulminant hemolytic anemia. History and symptoms of hereditary spherocytosis include; yellowing of skin, fatigue, irritability, weakness, shortness of breath, anemia, hemolysis, thrombocytopenia and hyperbilirubinemia. Pigment gallstones may be found in young children, but incidence of gallstones increases markedly with age, however jaundice is more prominent in newborns.

Physical Examination

The physical examination findings in hereditary spherocytosis include; scleral icterus, jaundice, splenomegaly. Right upper quadrant abdominal pain may be elicited if gallbladder disease is present.

Laboratory Findings

The initial laboratory testing for hereditary spherocytosis include; complete blood count (CBC), mean corpuscular hemoglobin concentration (MCHC), blood smear review, hemolysis testing and coombs testing. All individuals suspected of having hereditary spherocytosis based on family history, neonatal jaundice or other findings should have a complete blood count (CBC), reticulocyte count and RBC indices done. Confirmatory tests for hereditary spherocytosis includes EMA binding test, osmotic fragility test, glycerol lysis test, cryohemolysis and plasma membrane electrophoresis.

Imaging Findings

There are chest X-ray, CT scan or MRI findings associated with hereditary spherocytosis.

Other Diagnostic Studies:

There are no other diagnostic studies associated with hereditary spherocytosis.

Treatment

Medical Therapy

There is no specific medical therapy for the hereditary spherocytosis, as the diagnosis is made, surveillance is needed to help detect and manage any complications. A routine annual review is usually sufficient to detect any complications. Folic acid supplementation is not always required, but is used as a routine for children with severe hemolysis and in pregnancy regardless of severity of disease. Blood transfusion may also be required in severely affected infants and may be needed during aplastic crisis or pregnancy. However, erythropoietin (EPO) may be helpful in reducing the need for transfusion in some infants.

Surgery

Generally, the treatment of hereditary spherocytosis involves presplenectomy care, splenectomy and management of postsplenectomy complications. Splenectomy is very effective in reducing hemolysis, leading to significant prolongation of red blood cell lifespan. Partial splenectomies can be used in pediatric patients as it controls hemolysis and preserves splenic function. Patients having concomitant gallstones are likely to benefit from combined splenectomy and cholecystectomy in terms of life expectancy. Post splenectomy complications may include; infections & sepsis caused by encapsulated organisms (streptococcus pneumoniae, neisseria meningitidis, haemophilus influenza), deep venous thrombosis (DVT), pulmonary emboli and portal vein thrombosis.

Prevention

There is no primary prevention available for the hereditary spherocytosis, however administration of vaccines including pneumococcal, hemophilus influenzae, meningococcal and influenza should be given two to three weeks before splenectomy. Folic acid supplementation as well as oral penicillin is also suggested for postsplenectomy patients untill reaching adulthood.