OVERVIEW: What every practitioner needs to know

Are you sure your patient has Hereditary Spherocytosis and other RBC membrane defects? What are the typical findings for this disease?

The most common hemolytic anemias resulting from defects in the red cell membrane include Hereditary Spherocytosis (HS), Hereditary Elliptocytosis (HE), and Hereditary Pyropoikilocytosis (HPP).

Hereditary Spherocytosis is the most common of the RBC membrane effects. Hereditary Spherocytosis (HS) is a congenital, usually familial, disorder often manifested by hyperbilirubinemia in the newborn. A family history of HS, early splenectomy, or gall bladder disease may be suggestive. Splenomegaly is usually present in 30% of patients. Microspherocytes are present on the smear, and a reticulocytosis is expected.

Hereditary Elliptocytosis (HE) is characterized by the presence of cigar-shaped elliptocytes on the blood smear. Hereditary Pyropoikilocytosis (HPP) represents a subtype of HE. In addition to elliptocytes, HPP red cells are bizarrely shaped with fragmentation or budding; microspherocytes are common as well. Approximately one third of parents or siblings of patients with HPP have typical HE.

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Presenting signs and symptoms of these diseases are usually related to the degree of anemia with evidence of striking poikilocytosis on the peripheral blood smear, splenomegaly, and jaundice. This is a heterogenous group of disorders with regard to clinical severity, all resulting from various mutations in the red cell membrane cytoskeletal proteins.

Hereditary Spherocytosis

While the clinical manifestations may vary widely, the typical presentation of a patient with HS is a combination of a chronic incompletely compensated mild-to-moderate hemolytic anemia with evidence of spherocytosis on the peripheral blood smear, splenomegaly, jaundice, and a positive family history (75% cases).

In children anemia is the most common finding followed by splenomegaly (palpable 75-95%) and jaundice.

Symptoms of HS may appear in the perinatal period. Neonatal jaundice is common in the first 2 days of life in patients with HS and the hyperbilirubinemia can be severe enough to require exchange transfusion.

Some neonates may be transfusion dependent due to their inability to mount an adequate erythropoietic response, however, transfusion dependence is unusual.

Mild, moderate, moderately severe, and severe forms of HS have been defined based on hemoglobin, reticulocyte count, and bilirubin levels.

Hereditary Eliptocytosis or Pyropoikilocytosis

Clinical severity in patients with HE is highly variable among different kindreds. While the clinical presentation may vary from asymptomatic carriers to severe life-threatening anemia, the majority of patients with HE are asymptomatic with a hemoglobin greater than 12gm/dl, reticulocyte count less than 4%, and are diagnosed incidentally. HE patients with chronic hemolysis may experience moderate to severe anemia and hemoglobin levels ranging from 9-12 gm/dl; blood smear morphology shows the typical elliptocytes, poikilocytes, and very small microspherocytes. These patients may develop bilirubinate gallstones.

HPP is typically characterized by a moderate to severe hemolytic anemia and splenomegaly; hemoglobin level ranges from 7 to 9 gm/dl, reticulocytosis from 20 to 25%, with marked microcytosis (MCV 25 to 55). Heating pyropoikilocytes to 45 to 47°C causes gross fragmentation, where as normal erythrocytes fragment at 49°C. Thermal instability is not specific for HPP, however, is noted in the majority of patients with phenotypes of HE or HPP.

Patients with HE and HPP generally do well clinically. Occasionally, severe forms of HE or HPP present in the neonatal period with severe hemolytic anemia requiring red cell transfusion, phototherapy, or even exchange transfusion. Usually the hemolysis resolves between 6 and 12 months of age. If severe hemolysis persists, transfusion is palliative and splenectomy is curative with respect to resolution of the anemia, although the erythrocyte abnormality persists.

What other disease/condition shares some of these symptoms?

Hemolytic anemias may be more commonly due to factors external to the red blood cell such as circulating autoantibodies to RBCs in Autoimmune Hemolytic Anemia or ABO incompatibility, or factors intrinsic to the red blood cell such as the enzyme defects G-6-PD deficiency or Pyruvate Kinase deficiency.

In infants with spherocytic hemolytic anemia, ABO incompatibility should be considered. Splenomegaly is uncommon in the newborn period, reticulocytosis is variable, and erythrocytes are more osmotically resistant in ABO incompatibility.

A spherocytic hemolytic anemia can also be due to autoimmune hemolytic anemia (AIHA). This can usually be differentiated from HS by negative family studies and a positive DAT. Classically, AIHA has a higher percentage of microspherocytes seen, but this is variable. The incubated osmotic fragility test detects the presence of microspherocytes, but does not determine the cause. The DAT is negative in HS.

Spherocytic hemolytic anemias also occur in clostridial sepsis, transfusion reactions, thermal burns, and bites from snakes, spiders, bees and wasps – most of which can be differentiated based on the clinical findings.

What caused this disease to develop at this time?

What causes the clinical symptoms of Hereditary Spherocytosis (HS)?

HS is actually a heterogenous group of disorders with regard to both clinical severity and the specific mutations of the genes encoding the cytoskeletal proteins of the red cell membrane. All are characterized by spherical erythrocytes with increased osmotic fragility. The hallmark of the HS erythrocyte is loss of membrane surface area relative to intracellular volume accounting for the spheroidal shape, decreased deformability, and shortened lifespan of 20 to 30 days. Splenic trapping of the non-deformable spherocytes leads to splenic conditioning where further membrane damage amplifies the cycle of membrane injury and ultimately leads to ingestion of RBCs by the monocyte-macrophage system resulting in chronic anemia.

The spheroidal shape of the erythrocyte is attributable to a deficiency or dysfunction of one of the several membrane proteins making up the red cell cytoskeleton. The cytoskeleton is a spectrin-based network of proteins lying horizontal just beneath the lipid bi-layer. The spectrin network has vertical linkage to the lipid bi-layer through Glycophorin C, ankyrin, proteins 4.1 and 4.2, and band 3. Combined deficiencies of spectrin and ankyrin is most commonly found, followed in order of frequency by band 3 deficiency, isolated spectrin deficiency, and protein 4.2 deficiency. Each kindred typically has a different mutation accounting for the considerable variation in clinical severity between different families.

The typical defect in HE and HPP erythrocytes is an abnormality in red cell cytoskeletal proteins including alpha and beta spectrin, protein 4.1 and glycophorin C.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Initial laboratory studies should include a CBC with attention to red cell morphology, a reticulocyte count, serum bilirubin, and a direct antiglobulin test (DAT). A mild to moderate anemia with hemoglobin ranging from 9-12 gm/dl is most commonly encountered. An elevated reticulocyte count is usual. The DAT is negative in HS, HE and HPP.

Red cell morphology may be strikingly abnormal with numerous spherocytes, elliptocytes, or more bizarre shaped red cells with fragmentation and budding characteristic of HPP.

While red cell morphology is variable, typically HS patients will have easily identifiable spherocytes lacking a central pallor, and polychromasia reflecting the reticulocytosis on the blood smear. Mean corpuscular hemoglobin concentration (MCHC) is increased (35-38%) in approximately 50% of patients. Mean corpuscular volume (MCV) is usually normal except in cases of severe HS when the MCV may be mildly decreased.

An incubated Osmotic Fragility test (at 37°C for 24 hours) is considered the standard test in diagnosing HS. Spherocytes have increased fragility at higher than normal saline concentrations. Limitation of the osmotic fragility test is poor sensitivity in the mild form of HS. Increased RBC osmotic fragility may also be seen in other conditions where spherocytes are present. Therefore, it is important that autoimmune hemolytic anemia caused by warm (IgG) or cold (IgM) autoantibody is excluded. In neonates, ABO incompatibility must also be considered. The DAT should be positive in autoimmune hemolysis and in ABO incompatibility.

Diagnosis of HS in the neonate may be difficult for several reasons. Splenomegaly is infrequent, reticulocytosis is variable, spherocytes are commonly seen on neonatal blood smears without disease, and neonatal blood cells are more osmotically resistant rendering the Osmotic Fragility Test less reliable for diagnosis in neonates. Therefore, testing should be postponed until the child is at least 6 months of age or older, unless the need for diagnosis is urgent.

Specialized testing is available for difficult cases but is not routinely performed. Examples include structural and functional studies of erythrocyte membrane proteins, use of an ektacytometer to study membrane rigidity and fragility, cDNA and genomic DNA analysis to obtain a molecular diagnosis.

If you are able to confirm that the patient has Hereditary Spherocytosis, what treatment should be initiated?

Red cell transfusion is only indicated if the patient is clinically unstable due to severe anemia and/or a rapid fall in the red cell mass is observed. Red cell transfusions may be necessary during an aplastic or hemolytic crisis. Transfusions are also sometimes considered during the first year or two of life if the hemolytic anemia is severe and not well compensated.

Attention to iron and folate status in the growing child is also important and may require supplementation, as patients with many forms of chronic hemolytic anemia can become deficient.

Splenectomy may be indicated for patients with clinically severe hemolytic anemia. Splenectomy is very effective in reducing hemolysis, alleviating anemia in the majority of patients, and reducing or eliminating the need for red cell transfusions. Erythrocyte lifespan nearly normalizes and the incidence of cholelithiasis decreases.

Who should undergo splenectomy?

Splenectomy is no longer routine, although in the past it was common for patients to routinely undergoing splenectomy at age 5. The risks of splenectomy are primarily from pneumococcal sepsis. A reasonable approach is to consider splenectomy in the minority of patients with severe HS and in patients with significant signs/symptoms such as growth failure, skeletal changes, leg ulcers, extramedullary hematopoiesis tumors, or repetitive hemolytic crisis requiring increased transfusional support.

Whether patients with moderate HS and compensated asymptomatic anemia should undergo splenectomy is controversial. When splenectomy is warranted, laproscopic splenectomy has become the method of choice in many centers.

What are the adverse effects associated with each treatment option?

Splenectomy carries with it an increased risk of life threatening sepsis from polysaccharide encapsulated bacterial organisms, especially Steptococcus pneumonia. This risk has been reduced by deferring splenectomy until 5-9 years of age (if possible) together with vaccination against S. pneumoniae (with both Prevnar and Pneumovax), Haemophilus influenza B, and N. Meningititis. When possible, those vaccines should be administered several weeks before splenectomy to ensure optimal antibody response and protection. Antibiotic prophylaxis with penicillin post splenectomy is also recommended.

The optimal duration of prophylactic antibiotic therapy post splenectomy is unknown. Recommendations range from at least 5 years post-splenectomy to lifetime.

What are the possible outcomes of Hereditary Spherocytosis?

Chronic hemolysis may lead to formation of bilirubinate gallstones, which are the most common complication of HS. Gallstones are reported in up to half of HS patients and noted in at least 5% of children less than 10 years of age. Once the spleen is removed, patients no longer develop pigment stones.

Hemolytic, aplastic, and megoloblastic crises may also complicate the clinical course of HS patients. Hemolytic crisis typically are associated with viral illness seen in children and are characterized by jaundice, increased splenic size, a drop in hemoglobin, and reticiulocytosis. Severe crisis may necessitate red cell transfusion. Aplastic crisis occurs following virally induced bone marrow suppression, classically from Parvovirus B19, and typically lasts 10-14 days. Laboratory features include a drop in hemoglobin associated with a reticulocytopenia.

Parvovirus infections may also be associated with a mild neutropenia, thrombocytopenia, or pancytopenia. In patients with severe HS, the anemia may be profound, necessitating transfusion support. Megaloblastic crisis may occur in those patients with increased folate demands such as in pregnancy, during growth spurts, or in patients recovering from an aplastic crisis. Appropriate folate supplementation should be prescribed.

Once diagnosis of HS is established, a child should be followed regularly in clinic. Typically, an annual visit is sufficient once a patient’s baseline has been established. At each visit general health, growth, spleen size, exercise tolerance, and general quality of life should be addressed. Information regarding signs/symptoms of both the hemolytic and aplastic crises should be obtained. Ultrasound examination for biliary stones may be performed from the age of 5 years, every 3 to 5 years or as clinically indicated.

What causes this disease and how frequent is it?

HS occurs in all ethnic and racial groups. It is the most common cause of inherited hemolytic anemia in individuals of Northern European ancestry; the incidence is approximately one in 2500 individuals in the United States and England. Males and females are affected equally. Inheritance is usually autosomal dominant (75%).

Inheritance is autosomal dominant in HE and is frequent among the black population. HPP predominantly affects the black population as well, and inheritance is either autosomal recessive or represents double heterozygosity for two spectrin mutations.

Other clinical manifestations that might help with diagnosis and management

HS should be considered in the individual with early cholelythiasis without other obvious cause. In addition, a clinical picture of mild splenomegaly with intermittent mild jaundice should raise HS as an underlying cause. Aplastic crisis (anemia with profound reticulocytopenia), possibly with mild splenomagaly, can be a first presentation of HS. The differential diagnosis for this situation would include Transient Erythroblastopenia of Childhood (TEC) and potentially AIHA.

Are additional laboratory studies available; even some that are not widely available?

Specialized testing is available for difficult cases but is not routinely performed. Examples include structural and functional studies of erythrocyte membrane proteins, use of an ektacytometer to study membrane rigidity and fragility, cDNA and genomic DNA analysis to obtain a molecular diagnosis.

What is the evidence?

Gallagher, P.G., Prchal, J.T, Kaushansky, K, Lichtman, M.A, Kipps, T.J, Seligsohn, U. “The Red Blood Cell Membrane and Its Disorders: Hereditary Spherocytosis, Elliptocytosis, and Related Diseases”. Williams Hematology.

Bolton-Maggs, P.H.B, Stevens, R.F, Dodd, N.J, Lamont, G, Tittensor, P, King, M.J. “on behalf of the General Haematology Task Force of the British Committee for Standards in Haematology. Guidelines for the diagnosis and management of hereditary spherocytosis”. British Journal of Haematology. vol. 126. pp. 455-74.

Bolton-Maggs, P.H.B. “Hereditary spherocytosis; new guidelines”. . pp. 809-12.

Eber, Stefan, Lux, Samuel E. “Hereditary Spherocytosis – Defects in Proteins That Connect the Membrane Skeleton to the Lipid Bilayer”. Seminars in Hematology. vol. Vol. 41. 2001. pp. 118-41.

Perrotta, Silverio, Gallagher, Patrick G, Mohandas, Narla. “Hereditary spherocytosis”. www.thelancet.com. vol. Vol 372. October 18, 2008. pp. 1411-26.