Hereditary Elliptocytosis

Etiology

The elastic deformability of RBCs is primarily influenced by the cytoskeleton proteins located beneath the cell membrane. The 5 interconnected proteins crucial to this process are spectrin, ankyrin, protein 4.2, band 3 protein, and glycophorin C. Any genetic abnormalities affecting these proteins can alter their structure and function, resulting in abnormal RBCs and compromised deformability.

Most hereditary elliptocytosis cases are due to genetic defects impacting α-spectrin, β-spectrin, protein 4.1, band 3, and rarely glycophorin C.[3] These genetic alterations include single base substitution, insertions, deletions, or changes in mRNA processing. The genes associated with these mutations include SPTA1 for α-spectrin, SPTB for β-spectrin, and EPB41 for protein 4.1. Among these, SPTA1 mutation is the most prevalent in hereditary elliptocytosis, occurring in 65% of cases, followed by mutations in SPTB (30%) and EPB41 (5%).

Hereditary elliptocytosis typically follows an autosomal dominant inheritance pattern, except HPP, which is inherited in an autosomal recessive manner.[4][5] An α-spectrin mutation characterizes HPP juxtaposed in a transformation noted as α-LELY.[6][7]

Epidemiology

The prevalence of hereditary elliptocytosis remains uncertain, given that many individuals with mild symptoms often go undiagnosed. The estimated prevalence ranges from 1 in 2000 to 1 in 4000 globally. Hereditary elliptocytosis is most commonly observed in populations of African, Southeast Asian, or Mediterranean descent. In West Africa, the prevalence can be as high as 1% to 2%, making it approximately 10 times more frequent in this region compared to Europe and the US.[8] 

Less than 10% of individuals with hereditary elliptocytosis exhibit the more severe variant known as HPP. The geographical distribution of hereditary elliptocytosis aligns with malaria-endemic areas, suggesting that malaria may have played a role in driving the expansion of the gene mutation associated with this condition.

Specific hereditary elliptocytosis variants, such as SAO, are particularly prevalent in populations from Malaysia, Papua New Guinea, Indonesia, and the Philippines, with estimated prevalence rates ranging from 5% to 25%. On the other hand, SE is more commonly observed in individuals of European descent.[9]

Pathophysiology

The normal RBC membrane comprises a lipid bilayer and cytoskeleton proteins crucial for maintaining membrane integrity and surface area. These cytoskeleton proteins include spectrin (composed of α and β heterodimers), ankyrin, protein 4.1, protein 4.2, band 3, and glycophorin C. Genetic alterations affecting α-spectrin, β-spectrin, protein 4.1, band 3, and rarely glycophorin C result in defects in RBC membrane stability and deformability during their passage through the microcirculation.

Consequently, RBCs struggle to regain their normal biconcave shape due to the loss of elastic recoil, resulting in a fixed morphology of elliptocytes in peripheral blood. These elliptocytes become entrapped and eliminated by the spleen, resulting in the premature destruction of the RBCs (<120 days) and prominent intravascular hemolysis, a predominant feature in hereditary elliptocytosis. The severity of anemia directly correlates with the degree of reduction in RBC membrane stability.[10][11] 

Individuals heterozygous for an elliptocytic variant typically remain asymptomatic. In contrast, those who are homozygous or compound heterozygous for hereditary elliptocytosis variants may experience mild-to-severe anemia.

The membranes in HPP are reportedly uniquely susceptible to thermal stressors, exhibiting unique instability. In HPP, the α-spectrin cannot associate in dimeric form with the β-spectrin, disrupting the membrane cytoskeleton. This disturbance leads to a membrane elasticity loss, making it prone to hemolysis. 

HPP is typically biallelic, unlike the monoallelic inheritance pattern observed in hereditary elliptocytosis. Individuals with HPP carry either a homozygous or compound heterozygous mutation, contributing to phenotypic heterogenicity.[3][7][12] The clinical polymorphism observed in HPP reflects the genetic variations underlying the condition.

History and Physical

Most cases of hereditary elliptocytosis are asymptomatic and may be incidentally discovered during the investigation of anemia. However, some individuals may exhibit symptoms such as fatigue or reduced exercise tolerance due to anemia. It is essential to focus on anemia within family members, as hereditary elliptocytosis may be misdiagnosed as another condition like iron deficiency anemia. Rarely, hereditary elliptocytosis may present as neonatal jaundice.

Long-standing hemolytic anemia associated with hereditary elliptocytosis can result in splenomegaly, characterized by early satiety, left upper quadrant abdominal pain, and abdominal discomfort. Patients with HPP may display frontal bossing, while chronic hemolysis can lead to leg ulcers. The presentation varies among the different subtypes of hereditary elliptocytosis, each of which is described below.

Common hereditary elliptocytosis represents the most prevalent form of hereditary elliptocytosis, and patients are typically asymptomatic. Neonates with this condition may experience transient hemolysis, which typically resolves within the first year of life. In cases of severe hemolytic anemia and jaundice in neonates, transfusion and phototherapy may be necessary. The defining characteristic of common hereditary elliptocytosis is the presence of elliptical-shaped RBCs in the peripheral blood smear, constituting anywhere from 15% to 100% of the total RBCs. The peripheral blood smear may also observe spherocytes, stomatocytes, and poikilocytes (fragmented cells).

HPP stands out as the most severe form of hereditary elliptocytosis, predominantly affecting African-American neonates. These infants typically present with neonatal jaundice and persistent hemolytic anemia throughout their lives. The peripheral blood smear in HPP reveals poikilocytes and spherocytes with rare elliptocytes. Microspherocytes are present, with a mean corpuscular volume (MCV) of 30 to 50 gL. In some cases, the cellular morphology may resemble those of thermal burn patients, displaying microspherocytes and erythrocyte fragments.[13] 

Neonates affected by HPP often experience complications related to hemolysis, like splenomegaly and the formation of pigment gallstones, necessitating interventions like transfusion and splenectomy. Additionally, the profound hemolysis in neonates with HPP may lead to challenges such as an increased risk of severe anemia, emphasizing the importance of prompt and targeted medical interventions.

SAO, also called stomatocytosis elliptocytosis, is predominantly observed in regions endemic to malaria. This condition is characterized by mild or no hemolysis and provides resistance against Plasmodium falciparum infection. The peripheral blood smear of individuals with SAO exhibits stomatocytes, ovalocytes, and macro-ovalocytes. The underlying cause of this entity is a deletion within the SLC441 gene that encodes erythrocyte band 3.[14]

SE is frequently observed in individuals of Italian descent and is associated with mild to moderate hemolysis. Distinguishing between HS and hereditary elliptocytosis using ektacytometry can be effective, but challenges may arise in the presence of HPP. The intricate pattern of ektacytometry and morphological features of HPP may pose difficulties for differentiation. In such cases, genetic analysis can provide valuable assistance [7]. 

Physical examination findings in hereditary elliptocytosis include pallor in individuals undergoing hemolysis and observable signs such as splenomegaly. Additionally, right upper quadrant pain may be present in patients with gallstones related to hemolysis.[15][16]

Evaluation

The evaluation of hereditary elliptocytosis is initiated with a comprehensive assessment, including a complete blood count (CBC) revealing normocytic normochromic anemia. A peripheral blood smear is essential, typically demonstrating elliptocytes in 15% to 100% of RBCs, along with other variations, such as spherocytes, stomatocytes, poikilocytes, ovalocytes, and macro-ovalocytes. Testing for hemolysis reveals features of extravascular hemolysis characterized by an elevated reticulocyte count, increased lactate dehydrogenase, indirect bilirubin, and decreased haptoglobin level. The predominance of elliptocytes does not consistently correlate with the severity of hemolysis. Polychromasia is expected with hemolysis and reticulocytosis. 

For a more detailed analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) can quantify protein 4.1 and spectrin. Additionally, morphologic and genetic studies are completed by ektacytometry, which reveals characteristic responses of the erythrocyte membrane to laser diffraction and biomechanical stressors.[17] 

In cases where splenomegaly is suspected, ultrasonography is the preferred and cost-effective diagnostic tool. Computed tomography (CT) and magnetic resonance imaging (MRI) may also be utilized for further investigation. 

Treatment / Management

Asymptomatic individuals without hemolysis do not require treatment or regular follow-up. The priority is to educate the patient about the nature of the disease and ensure proper documentation in the patient's records to prevent unnecessary testing. 

Individuals experiencing intermittent hemolysis or anemia may necessitate blood transfusions when symptomatic or when their hemoglobin level falls below the age-specific threshold. Splenectomy is considered for patients facing severe, life-threatening anemia or requiring regular blood transfusions. However, vaccination against pneumococcus, meningococcus, and Haemophilus influenza is mandatory before surgery due to the associated heightened risk of infection with encapsulated organisms.

Differential Diagnosis

The differential diagnosis of hereditary elliptocytosis includes various conditions:

• Hereditary spherocytosis
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Thalassemia: Coinheritanced with hereditary elliptocytosis may present as a non-transfusion-dependent patient with marked poikilocytosis and fragmented cells.[7]
• Pyruvate kinase deficiency
• Hereditary stomatocytosis/xerocytosis
• Iron deficiency anemia
• Megaloblastic anemia
• Sickle cell anemia
• Myelofibrosis
• Myelodysplastic syndrome, although rare, acquired elliptocytosis can arise in a myelodysplastic setting.[18][19] The most common genetic defect of HE/MDS is del20q.[18] 

Prognosis

Most patients with hereditary elliptocytosis are asymptomatic, and only a small percentage (5%-20%) experience uncompensated hemolysis leading to anemia. Even among those with severe hemolysis who undergo treatment with splenectomy, the prognosis is generally favorable, emphasizing the overall benign course of the condition.

Complications

Complications associated with hereditary elliptocytosis include:

• Megaloblastic anemia may result from folate and Vitamin B12 deficiency due to chronic hemolysis. The deficiency may arise from nutritional factors, functional issues related to significant erythrocyte production, or a combination.[20] Supplementation with vitamin B12 or folate can help alleviate this issue. 

• Pigment gallstones: May lead to complications such as cholangitis, cholecystitis, and pancreatitis.

• Splenomegaly: Patients may experience functional and moderate splenomegaly similar to many hemolytic anemias.[21]

• Renal tubular acidosis: Associated with SAO, wherein familial distal renal tubular acidosis is associated with this specific subtype.[22].

• Leg ulcers: Typically form around the medial malleoli, which are thought to occur in hemolytic anemias due to stasis.[23]

• Growth retardation and skeletal abnormalities: May develop due to marrow expansion.[24]