Hereditary pyropoikilocytosis (hp) is a red cell membrane defect characterized by:

Continuing Education Activity

Hereditary elliptocytosis is a group of inherited heterogenous red blood cell (RBC) membrane disorders characterized by elliptical-shaped RBCs. The presentation of patients varies from asymptomatic to severe hemolysis and should be managed accordingly. This activity illustrates the pathophysiology of hereditary elliptocytosis and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe the pathophysiology of hereditary elliptocytosis.
• Review the appropriate steps in the evaluation of hereditary elliptocytosis.
• Outline the management options for hereditary elliptocytosis.
• Summarize the importance of collaboration and communication amongst the interprofessional team to enhance the care of patients with hereditary elliptocytosis.

Introduction

Hereditary elliptocytosis (HE), also known as hereditary ovalocytosis, is an inherited heterogeneous red blood cell (RBC) disorder, characterized by elongated, oval, or elliptical-shaped red blood cells on the peripheral blood smear. Genetic alterations in alpha spectrin, beta spectrin, protein 4.1, band 3, and rarely glycophorin C result in failure of the elastic recoil property of normal RBCs in peripheral circulation resulting in an elliptical shape. These elliptocytes are trapped and removed by the spleen resulting in hemolytic anemia. Elliptocytosis was first described by Dresbach in 1904, and Hunter firmly established its heritability.

The subtypes of hereditary elliptocytosis include common hereditary elliptocytosis, hereditary pyropoikilocytosis (HPP), Southeast Asian ovalocytosis (SAO), and spherocytic elliptocytosis (SE). These subtypes differ in RBC morphology and the degree of hemolysis.

Most of the cases of hereditary elliptocytosis are asymptomatic and require no treatment. However, symptomatic patients should be managed with blood transfusion and splenectomy.[1][2]

Etiology

The elastic deformability of red blood cells is formed by the cytoskeleton protein located underneath the cell membrane. The five interconnected proteins involved are spectrin, ankyrin, protein 4.2, band 3 protein, and glycophorin C. Any genetic abnormalities affecting this protein can change the structure and function of these proteins leading to abnormal red blood cells and abnormal deformability.

Most cases of hereditary elliptocytosis are due to genetic defects affecting alpha spectrin, beta spectrin, protein 4.1, band 3, and rarely glycophorin C. These changes include single base substitution, insertion, deletions, or mRNA processing changes. The mutation in the gene encoding alpha spectrin is SPTA1, beta spectrin is SPTB, and protein 4.1 is EPB41. In most HE cases, SPTA1 mutation is the most common, occurring in 65%, followed by mutations in SPTB (30%) and EPB41 (5%). Hereditary elliptocytosis is inherited in an autosomal dominant fashion except for hereditary pyropoikilocytosis (HPP), which is inherited in an autosomal recessive pattern.[3][4]

Epidemiology

The true prevalence of hereditary elliptocytosis is not known as many mildly affected people remain undiagnosed. An estimated prevalence has been found to be 1 in 2000 to 1 in 4000 throughout the globe. HE most commonly occurs in African, Southeast Asian, or Mediterranean people. In West Africa, it's prevalence is as high as 1%-2%. Its geographical distribution reflects malaria-endemic areas, and malaria may have driven the expansion of the gene mutation.

Certain variants of HE like Southeast Asian ovalocytosis are very common in people from Malaysia, Papua New Guinea, Indonesia, and the Philippines, where the prevalence is as high as 5% to 25%. Spherocytic elliptocytosis is common in individuals of European descent.[5]

Pathophysiology

The normal RBC membrane is composed of a lipid bilayer with the cytoskeleton proteins that help in maintaining the membrane integrity and surface area. The different cytoskeleton proteins present in the RBC membrane are spectrin (composed of alpha and beta heterodimers), ankyrin, protein 4.1, protein 4.2, band 3, and glycophorin C. Genetic alterations affecting alpha spectrin, beta spectrin, protein 4.1, band 3, and rarely glycophorin C result in defects in RBC membrane stability and deformability as the RBCs pass through the microcirculation. As a result, RBCs fail to regain their normal biconcave shape as they pass through the microcirculation due to loss of elastic recoil resulting in a fixed morphology of elliptocytes in peripheral blood. These elliptocytes are trapped and removed by the spleen resulting in premature destruction of the RBCs (less than 120 days), leading to intravascular hemolysis that is predominant in hereditary elliptocytosis. The severity of anemia is directly related to the extent of the decrease in the RBCs membrane stability.[6][7] Individuals that are heterozygous for an elliptocytic variant are asymptomatic, while individuals that are homozygous or compound heterozygous for HE variants experience mild-to-severe anemia.

History and Physical

Most of the cases of hereditary elliptocytosis are asymptomatic and may be an incidental finding during the workup for anemia, while others may present with symptoms of anemia like fatigue or reduced exercise tolerance. It is important to focus on anemia in family members, as HE may be misdiagnosed as another condition like iron deficiency anemia. Rarely HE may present as neonatal jaundice. Long-standing hemolytic anemia can lead to splenomegaly (early satiety, left upper quadrant abdominal pain, and abdominal discomfort). Frontal bossing may be seen in patients with HPP and leg ulcers in a patient with chronic hemolysis. The presentation is different in the different subtypes of HE, which is described below.

Common hereditary elliptocytosis: This is the most common form of HE, and the patient is generally asymptomatic. Neonates may present with transient hemolysis, which typically resolves within the first year of life. Transfusion and phototherapy may be required if neonates present with severe hemolytic anemia and jaundice. The hallmark of common HE is the presence of elliptical-shaped RBCs in the peripheral blood smear, and their number ranges from 15% to 100%. A few spherocytes, stomatocytes, and poikilocytes (fragmented cells) may be seen.

Hereditary pyropoikilocytosis (HPP): It is the most severe form of HE and most commonly affects African-American neonates that present with neonatal jaundice and hemolytic anemia persisting throughout life. The peripheral blood smear shows poikilocytes and spherocytes with rare elliptocytes. The affected neonates most commonly have complications related to hemolysis like splenomegaly and pigment gallstones that often require transfusion and splenectomy.

Southeast Asian ovalocytosis (SAO): Also known as stomatocytosis elliptocytosis, is most commonly seen in malaria-endemic regions. It is associated with mild or no hemolysis and confers resistance against Plasmodium falciparum infection. The peripheral blood smear shows stomatocytes, ovalocytes, and macro-ovalocytes.

Spherocytic elliptocytosis (SE): Most commonly noted in the Italian people with mild to moderate hemolysis.

Physical examination findings in HE include pallor in patients undergoing hemolysis, splenomegaly, and right upper quadrant pain in patients with a gallstone.[8][9]

Evaluation

The evaluation of HE begins with a complete blood count. Normocytic normochromic anemia can be seen. Additionally, a peripheral blood smear should be done, which typically shows that 15% to 100% of the RBCs are elliptocytes. Other cells that can be seen in different subtypes are spherocytes, stomatocytes, poikilocytes, ovalocytes, and macro-ovalocytes. Testing for hemolysis should be carried out. There is extravascular hemolysis in hereditary elliptocytosis, which is characterized by an increased reticulocyte count, increased lactate dehydrogenase, increased indirect bilirubin, and decreased haptoglobin level. A sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) for quantitation of protein 4.1 and spectrin analysis can be done. Osmotic gradient ektacytometry may be helpful and typically shows a decreased maximum of deformability.[5] If splenomegaly is suspected, ultrasonography is the test of choice due to its accuracy and low cost. Computed tomography (CT) and magnetic resonance imaging (MRI) may also be done.

Treatment / Management

Asymptomatic individuals without hemolysis do not require treatment and follow up. It is of utmost importance that the patient is educated about the nature of the disease, and documentation of the disease in the patient's record has been done to prevent unnecessary testing.

Individuals with intermittent hemolysis or anemia may require blood transfusions when the patient is either symptomatic, or the hemoglobin level drops below the threshold required for their age.

Splenectomy is reserved for the patient with severe anemia that is life-threatening or severe anemia that requires regular blood transfusions. Since splenectomy is associated with increased risk of infection with encapsulated organisms, vaccination against pneumococcus, meningococcus, and Haemophilus influenza is required prior to the surgery.

Differential Diagnosis

The differential diagnosis of hereditary elliptocytosis incudes:

• Hereditary spherocytosis
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Thalassemia
• Pyruvate kinase deficiency
• Hereditary stomatocytosis/xerocytosis
• Iron deficiency anemia
• Megaloblastic anemia
• Sickle cell anemia
• Myelofibrosis
• Myelodysplastic syndrome[10]

Prognosis

Most patients with HE are asymptomatic. Only 5%-20% develop uncompensated hemolysis with anemia. Even patients with severe hemolysis that are treated with splenectomy have a relatively good prognosis.

Complications

The complications of hereditary elliptocytosis include:

• Megaloblastic anemia due to folate and Vitamin B12 deficiency as a result of chronic hemolysis
• Pigment gallstone leading to cholangitis, cholecystitis, and pancreatitis
• Splenomegaly
• Renal tubular acidosis associated with SAO
• Leg ulcer
• Growth retardation and skeletal abnormalities due to marrow expansion[11]

Consultations

• General surgeon: For patients planned to undergo splenectomy
• Genetic counselor: To explain the genetic transmission of the disease

Deterrence and Patient Education

The patient and family members should be educated about the autosomal dominant mode of inheritance of the disease, and family members should be screened for HE. The parents of a severely affected child with hereditary elliptocytosis should be offered prenatal counseling. Patients who have undergone splenectomy require prophylactic vaccination and follow-up to monitor for complications.

Enhancing Healthcare Team Outcomes

Hereditary elliptocytosis presentation is vague and ranges from asymptomatic to severe hemolysis. A high degree of suspicion for hereditary elliptocytosis is needed for a patient with normocytic normochromic anemia and a family history of anemia. An interprofessional team should be involved in the management of the patient diagnosed with hereditary elliptocytosis to improve outcomes.