Hereditary spherocytosis overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Hereditary spherocytosis is a genetically-transmitted form of spherocytosis, an auto-hemolytic anemia characterized by the production of red blood cells that are sphere-shaped rather than donut-shaped, and therefore more prone to hemolysis.

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

The differential diagnosis of HS includes a number of other hemolytic anemias with spherocytes on the peripheral blood smear.

1. Infantile pyknocytosis,
2. Congenital dyserythropoietic anemia (CDA)
3. Autoimmune hemolytic anemias:
4. Other inherited hemolytic anemias: hereditary elliptocytosis (HE) and elliptocytosis variants (eg, Southeast Asian ovalocytosis [SAO], hereditary pyropoikilocytosis [HPP], hereditary stomatocytosis (HSt), and hereditary xerocytosis (HX). RBC enzyme disorders include glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase (PK) deficiency, and other rarer metabolic disorders.
5. Hemolytic disease of the fetus and newborn (HDFN):

Epidemiology and Demographics

• HS is seen in all populations but appears to be especially common in people of northern European ancestry.

• In the United States, the incidence of the disorder is approximately one case in 5000 people.
• In northern European, HS affects as many as 1 in 2000 to 1 in 5000 (prevalence, approximately 0.02 to 0.05 percent).

Risk Factors

• The risk factors for this condition have not yet been properly identified.
• However, having a family member with this condition can increase your susceptibility to this disease. The condition is also most common in individuals of North European origin although it has been found to arise in people of all races.

Screening

• It is also important to test newborns of affected parents for HS, as affected newborns may have severe hyperbilirubinemia and anemia. This may be done by a clinician with expertise in hemolytic anemias or by a genetic counselor. It is possible for an individual with no hemolysis, no spherocytes on the blood smear, and a normal reticulocyte count to be a carrier of HS, which may be relevant in certain families.

Natural History, Complications, and Prognosis

Natural History

• Disease severity and age of presentation — HS can present at any age and with any severity, with case reports describing a range of presentations, from hydrops fetalis in utero through diagnosis in the ninth decade of life.

• The majority of affected individuals have mild or moderate hemolysis or hemolytic anemia and a known family history, making diagnosis and treatment relatively straightforward. Individuals with significant severe hemolysis may develop additional complications such as jaundice/hyperbilirubinemia, folate deficiency, or splenomegaly.

Complications

Common complications of hemolysis include neonatal jaundice, splenomegaly, and pigment gallstones.

• Neonatal jaundice — HS may present in the neonatal period with jaundice and hyperbilirubinemia, and the serum bilirubin level may not peak until several days after birth. Some experts have proposed that HS is underdiagnosed as a cause of neonatal jaundice. A requirement for phototherapy and/or exchange transfusion during this period is common.
• Splenomegaly — Splenomegaly is rare in neonates, but can often be seen in older children and adults with HS. Early reports of family studies found palpable spleens in over three-fourths of affected members, but this may reflect a skewed population with the most severe disease. In these studies, the relationship between disease severity and splenic size was not linear.
• Pigment gallstones — Pigment (bilirubin) gallstones are common in individuals with HS and may be the presenting finding in adults. Gallstones are unlikely before the age of 10 years but are seen in as many as half of adults, especially those with more severe hemolysis. Gallstones appear to be more common in individuals with Gilbert syndrome.

Prognosis

• Overall, the long-term outlook for people with hereditary spherocytosis (HS) is usually good with treatment. However, it may depend on the severity of the condition in each person.
• People with very mild HS may not have any signs or symptoms unless an environmental "trigger" causes symptom onset. In many cases, no specific therapy is needed other than monitoring for  and watching for signs and symptoms.[8] Moderately and severely affected people are likely to benefit from splenectomy.
• Most people who undergo splenectomy are able to maintain a normal hemoglobin level.[4] However, people with severe HS may remain anemic post-splenectomy, and may need blood transfusions during an infection.

Diagnosis

Diagnostic Criteria:

1. Newly diagnosed patients with a family history of HS, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular haemoglobin concentration [MCHC], increase in reticulocytes) do not require any additional tests (grade 1 recommendation, grade A evidence).
2.  If the diagnosis is equivocal, a screening test with high predictive value for HS is helpful. The recommended screening tests are the cryohaemolysis test and EMA binding (grade 1 recommendation, grade A evidence). (Confirmation).
3.  Gel electrophoresis analysis of erythrocyte membranes is the method of choice for diagnosis of atypical cases.

History and Symptoms

• As in any 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.
• Symptoms of hereditary spherocytosis include:
  • Yellowing of the skin and eyes (jaundice)
  • Pale coloring (pallor)
  • Fatigue
  • Irritability
  • Shortness of breath
  • Weakness

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.

Laboratory Findings

Initial testing

• CBC and RBC indices – All individuals with suspected HS based on family history, neonatal jaundice, or other findings should have a complete blood count (CBC) with reticulocyte count and red blood cell (RBC) indices. The mean corpuscular hemoglobin concentration (MCHC) is often the most useful parameter for assessing spherocytosis; an MCHC ≥36 g/dL is consistent with spherocytes. A low mean corpuscular volume (MCV) is also helpful in some cases, especially in neonates, but variable degrees of reticulocytosis make the MCV less useful in older children and adults.
• Blood smear review – All individuals with suspected HS should have a blood smear reviewed by an experienced individual. In a peripheral blood smear, the abnormally small red blood cells lacking the central pallor i.e. spherocytes are seen. Other abnormal RBC shapes, and the degree of polychromatophilia, which reflects reticulocytosis.
• Coombs testing – If hemolysis is present, Coombs testing (also called direct antiglobulin testing [DAT]) is usually done to eliminate the possibility of immune-mediated hemolysis, which may be due to hemolytic disease of the fetus and newborn (HDFN) in neonates or autoimmune hemolytic anemia (AIHA) in older children and adults. The results of testing may also be useful to the transfusion service if transfusion is indicated. Coombs testing in HS is negative.

Confirmatory tests

• EMA binding ●Osmotic fragility ●Glycerol lysis ●Cryohemolysis

Imaging Findings:

• There are no particular other imaging findings associated with HS.

Other Diagnostic Studies:

• There are no particular other diagnostic studies associated with HS.

Treatment

Medical Therapy

• As with most inherited hemolytic anemias, treatment is directed at preventing or minimizing complications of chronic hemolysis and anemia. There are no specific treatments directed at the underlying red blood cell (RBC) membrane defect.

• If a neonate is suspected of having HS (eg, based on positive family history and neonatal jaundice), treatment can be initiated for HS without awaiting diagnostic confirmation. This may include therapy for hyperbilirubinemia and, in severe cases, transfusion or even exchange transfusion [83
• The goals of pharmacotherapy for hereditary spherocytosis are to reduce morbidity and prevent complications. Folic acid supplementation is indicated to prevent megaloblastic crisis.

Surgery

• 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.

Prevention

In general, once the diagnosis and baseline severity of HS in a child are established, it is not necessary to perform repeated blood tests unless there is an additional clinical indication (such as intercurrent infection and pallor, or an increase in jaundice). A routine annual review is usually sufficient together with an open door policy for potential complications such as parvovirus infection, or abdominal pain, which may trigger investigation for gallstones.