Hereditary Elliptocytosis 

Updated: Nov 06, 2019
Author: Daniel J Kim, MD, MS; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Hereditary elliptocytosis (HE) is a group of disorders of the red blood cell (RBC) membrane that are characterized by elliptical-shaped erythrocytes (elliptocytes; see the image below) and shortened RBC survival. Unlike normal RBCs, which repeatedly and momentarily assume an elliptical shape to negotiate through capillaries but then regain their biconcave discoid shape after they pass through the microcirculation, the RBCs in HE lack the elastic recoil necessary for returning to the discoid shape and eventually assume the fixed characteristic morphology of elliptocytes, with a decreased surface-to-volume ratio. These elliptocytes are not as deformable as normal RBCs and are eventually trapped and removed by the spleen; this manifests as hemolytic anemia.[1, 2, 3]

Hereditary elliptocytosis: Peripheral blood smear Hereditary elliptocytosis: Peripheral blood smear reveals cigar-shaped erythrocytes (elliptocytes). Courtesy of Jean A. Shafer, BS, MA, Assistant Professor of Hematology and Pathology at the University of Rochester School of Medicine and Dentistry.

HE is due to defects in either the structure or quantity of the cytoskeletal proteins responsible for maintaining the biconcave morphology of RBCs. Mutations in either alpha- and beta-spectrin are most commonly responsible, but mutations in other cytoskeletal proteins (band 4.1 and glycophorin) are also described.[4]  Most of these disorders are clinically silent, with only some forms associated with clinically significant hemolysis.

The mode of inheritance is autosomal dominant, except for hereditary pyropoikilocytosis (HPP), which is autosomal recessive. Instances of spontaneous mutations are rare.

In most cases, HE causes no symptoms and requires no therapy. For patients with clinically significant hemolytic anemia, splenectomy provides marked improvement. See Treatment.

 

 

Pathophysiology

HE results from defects in the protein scaffolding of the erythrocyte membrane, which decrease the deformability and resilience of the RBCs. Normal RBCs are 7 microns in diameter and assume the shape of a biconcave disk with central pallor. They are rugged cells and can survive in the circulation for 120 days as they repeatedly and momentarily assume an elliptical shape to negotiate through capillaries as small as 2-3 microns in diameter.

After passing through the microcirculation, normal RBCs can regain their discoid shape because of their elastic recoil; however, the RBCs in HE fail to do so. This failure to regain their discoid shape eventually produces the fixed characteristic morphology of elliptocytes with a decreased surface-to-volume ratio. These elliptocytes are not as deformable as normal RBCs and are eventually trapped and removed by the spleen. This process of premature destruction (ie, cells surviving < 120 d) is the basis of the extravascular hemolysis that clinically defines these disorders.

The RBC membrane is composed of a fragile lipid bilayer stretched over a flexible protein cytoskeleton. Spectrin is the major component of this scaffold and consists of 2 chains, alpha and beta, which are encoded by separate genes and which are twisted together to form an elongated heterodimer. At the head region, the heterodimers associate to form tetramers. At the distal end, they bind to other cytoskeletal proteins, namely actin and protein 4.1. These proteins, in turn, anchor the scaffold to the lipid bilayer by linking to the transmembrane proteins band 3, glycophorin A, and glycophorin C.

Mutations in either of the spectrins, glycophorin C, or band 4.1 account for most cases of HE.[5] Different point mutations are described in various families and account for some the clinical variability of this disorder. Mutations affecting the level (but not the structure) of glycophorin C (Leach phenotype) are also described. These mutations collectively result in defective assembly of the protein scaffolding on the inner aspect of the RBC membrane. The most common group of mutations affect alpha- or beta-spectrin and result in defects in the formation of the spectrin heterodimer or in the association of the heterodimer with the lipid anchoring complex (formed by actin, band 3, protein 4.1 and glycophorin C).[6]

Taken together, all of these defects result in defects in membrane stability and deformability as the RBCs pass through the microcirculation. The spleen removes the damaged erythrocytes, diminishing erythrocyte survival. Therefore, as with other chronic hemolytic disorders, clinical sequelae of HE may include splenomegaly and a propensity to develop gallstones, along with a variable degree of anemia.

Etiology

Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are heterogeneous red blood cell (RBC) membrane disorders that result from mutations in the genes encoding α-spectrin (SPTA1), β-spectrin (SPTB), or protein 4.1R (EPB41). HE is caused by monoallelic (heterozygous) mutations and inherited in an autosomal dominant fashion, while HPP has an autosomal recessive inheritance and is typically caused by biallelic (homozygous or compound heterozygous) mutations.[7]  [8]

Mutations in SPTA1 are the most common, occurring in 65% of HE cases, followed by mutations in SPTB (30%) and EPB41 (5%).[5]   The clinical phenotypses and associated genes in all RBC membrane disorders are summarized in Table 1. below.

Table 1. RBC Membrane Disorders [5, 1] (Open Table in a new window)

Phenotype Gene Inheritance
Disorders with RBC membrane structural defect
HE Type 1 EPB41 AD
HE Type 2 SPTA1 AD
HE Type 3 SPTB  AD
HPP SPTA1 AR
SAO SLC4A1 AD
HS Type 1 ANK1 AD/AR
HS Type 2 SPTB AD
HS Type 3 SPTA1 AR
HS Type 4 SLC4A1 AD
HS Type 5 EPB42 AR
Disorders with altered RBC membrane permeability
DHS 1 PIEZO1 AD
DHS 2 KCNN4 AD
OHS RHAG AD
CHC ABCB6 AD
FP SLC4A1 AD

AD: Autosomal dominant; AR:  Autosomal recessive

CHC:  cryohydrocytosis; DHS: dehydrated herediatry stomatocytosis;

FP: familial pseudohyperkalemia HE: hereditary elliptocytosis;

HPP: hereditary pyropoikilocytosis; HS: hereditary spherocytosis; 

OHS: overhydrated herediatry stomatocytosis SAO: Southeast Asian ovalocytosis

 

 

Epidemiology

The worldwide incidence of HE is 1:2000–4000 individuals, but it is as high as 1:100 in some African regions endemic for malaria because of relative resistance of elliptocytes against malaria.[1] In equatorial Africa, the incidence is approximately 0.6%; in Malayan aborigines, the incidence is as high as 30%. However, the true incidence is unknown because many patients do not have any symptoms.[9]

Although no racial or ethnic group is spared, some variants of HE occur more frequently in certain ethnic populations than in others. HE with neonatal poikilocytosis occurs almost exclusively in African-American families, but spherocytic elliptocytosis most commonly affects individuals of European descent. Southeast Asian ovalocytosis (SAO) is a very common condition in the aboriginal peoples from Papua New Guinea, Indonesia, Malaysia, the Philippines, and southern Thailand, in areas where malaria is endemic, with prevalence varying between 5% and 25%.[1]  

Because HE is an autosomal disorder, the distribution between the sexes is equal. HE is a congenital disease. However, other acquired disorders, such as myelofibrosis and myelophthisic anemias, may affect the degree of hemolysis.

Prognosis

Most patients with the common form of HE are asymptomatic. Only 5-20% develop uncompensated hemolysis with anemia. Even those with clinically significant hemolysis have an excellent prognosis after splenectomy. Other findings consistent with chronic hemolysis are splenomegaly, pigmented gallstones, leg ulcers, and elevated reticulocyte counts.

 

Patient Education

Patients should be informed about the autosomal dominant inheritance of the major types of HE. Despite the asymptomatic nature of the disease, family members can be encouraged to be screened for HE.

 

Presentation

History

Hereditary elliptocytosis (HE) is a heterogeneous group of disorders that shares the common feature of generally having more than 25% elliptical red blood cells (RBCs). Because specific molecular lesions do not necessarily correlate with clinical manifestations, a morphologic classification has been devised. The three commonly identified morphologic variants are common HE, spherocytic elliptocytosis, and Southeast Asian ovalocytosis (SAO, also known as stomatocytic elliptocytosis). Common HE can be further subcategorized on the basis of clinical features.

Common HE

Common HE is the most prevalent form of HE and includes the following subcategories:

  • Typical HE (mild HE)
  • A silent carrier state
  • Hereditary pyropoikilocytosis (HPP)
  • Neonatal poikilocytosis

In general, symptoms are rare because even when hemolysis is present, most patients have compensated hemolysis. However, patients with clinically significant hemolysis may have symptoms related to anemia; that is particularly true of homozygotes and those with HPP.

In otherwise asymptomatic patients, hemolysis may occasionally increase because of intercurrent infections (eg, hepatitis, infectious mononucleosis, malaria), renal transplant rejection, vitamin B-12 deficiency, or even normal pregnancy. Transfusion support may be necessary during hemolysis.

The most common clinical form of HE is typical HE, also known as mild HE or heterozygous common HE. Patients are asymptomatic, and the disease is incidentally diagnosed because of abnormal results on laboratory tests (ie, peripheral smears). Patients do not have anemia, though all of the peripheral smear may show prominent elliptocytosis.

The silent carrier state in HE is associated with normal peripheral smear and no anemia. Patients are asymptomatic, and the condition is detected by laboratory testing of membrane cytoskeletal properties that is performed during pedigree analysis.

HPP is considered the most severe type of HE and manifests during infancy. Most patients are of African origin, though cases have been reported in individuals of Arabian or Caucasian descent. The name is derived from similarities in the morphology of blood smears of HPP and in those of patients with thermal burns; that is, spherocytes are more abundant than elliptocytes. As opposed to neonatal poikilocytosis, the hemolytic anemia in HPP is lifelong. Parents of patients with HPP may have typical HE, but in general, all first-degree relatives including parents are clinically and hematologically healthy.

In neonatal poikilocytosis, which occurs almost exclusively in African-American families, newborns and infants have severe hemolytic anemia that typically resolves after the first year of life. Transfusions and phototherapy may be required during severe hemolytic anemia and jaundice. The resolution of symptoms after a year helps distinguish neonatal poikilocytosis from HPP.

Spherocytic elliptocytosis

Spherocytic elliptocytosis is also known as spherocytic HE, HE with spherocytosis, or hereditary hemolytic ovalocytosis. Unlike HPP, which is generally an autosomal recessive disorder, spherocytic elliptocytosis is an autosomal dominant disorder. This form is most commonly observed in individuals of European descent, particularly Italians. It is often associated with clinically apparent mild to moderate hemolysis. 

Southeast Asian ovalocytosis

Also known as stomatocytic elliptocytosis, SAO is a variant that commonly occurs in malaria-endemic Southeast Asia—namely, Indonesia, Malaysia, Melanesia, New Guinea, and the Philippines.[1]  The mode of transmission is autosomal dominant. Only heterozygous conditions are reported, and the homozygous state is thought to be lethal in utero. Of note, SAO confers resistance against Plasmodium falciparum infection, likely because of alterations in band 3, which is one of the malaria receptors. SAO is usually associated with mild or no hemolysis but is associated with renal tubular acidosis.

 

 

Physical Examination

Most patients are asymptomatic and do not have any obvious physical signs. findings in patients with clinically significant hemolysis include the following:

  • Splenomegaly
  • Pallor
  • Scleral icterus
  • Leg ulcers (rare)
 

DDx

Diagnostic Considerations

Hereditary elliptocytosis (HE) must be differentiated from hereditary spherocytosis (HS), which is the most common red blood cell (RBC) membranopathy. HS is characterized by the presence of spherical-shaped RBCs on peripheral blood smears and most commonly has autosomal dominant inheritance. SPTB mutations identified in HE affect the tetramerization domain but in HS the mutation effects are distributed between the actin-binding domain and spectrin repeats.[10]  

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of hereditary elliptocytosis (HE) and its more severe form, hereditary pyropoikilocytosis (HPP), relies on identifying abnormal red blood cell (RBC) morphology on peripheral blood smear (elliptocytes, poikilocytosis and fragmented RBCs), and identifying characteristic membrane biomechanical properties using osmotic gradient ektacytometry.[2, 7]

Targeted next-generation gene sequencing can be used to identify or confirm the diagnosis of HE and HPP, especially in severe, transfusion-dependent cases in which the RBC phenotype cannot be evaluated. In addition, identification of the molecular cause allows genotype-phenotype correlations and may assist in discussions of prognosis.[7, 11]  

The major drawback of current next-generation sequencing applications is the difficulty in determining the pathogenicity of the numerous identified variants. One of the ways to overcome this limitation is the simultaneous evaluation of all family members, allowing one to establish the inheritance pattern of the identified variants and thus to understand its pathogenetic role, although functional characterizations are often necessary.[7]

Laboratory Studies

Initial laboratory studies for the diagnosis of hereditary elliptocytosis (HE) include the following[12] :

  • Complete blood cell count (CBC)
  • Peripheral blood smear
  • Direct antiglobulin test (Coombs test)
  • Bilirubin
  • Haptoglobin
  • Reticulocyte count/immature reticulocyte fraction
  • Potassium
  • Lactate dehydrogenase (LDH)

Microscopic examination of peripheral smears in patients with HE reveals that about 25% (sometimes nearly 100%) of cells are characteristically elliptical and often described as cigar-shaped. Some cases have fewer than 25% elliptocytes. Fragmented cells may also be seen. See the image below.

Hereditary elliptocytosis: Peripheral blood smear Hereditary elliptocytosis: Peripheral blood smear reveals cigar-shaped erythrocytes (elliptocytes). Courtesy of Jean A. Shafer, BS, MA, Assistant Professor of Hematology and Pathology at the University of Rochester School of Medicine and Dentistry.

While an overwhelming majority of HE cases are asymptomatic, 10% of patients present with moderate‐to‐severe anemia. Poikilocytes and fragmented red cells in addition to elliptocytes are a feature of red cell morphology in HE patients with moderate–to‐severe anemia.[13]  

Peripheral smear findings in subcategories of HE include the following:

  • Patients with hereditary pyropoikilocytosis (HPP) have an increased number of microspherocytes (see the image below)

  • Patients with stomatocytic elliptocytosis have both spherocytes and elliptocytes but no poikilocytes. RBCs are distinctive, rounded elliptocytes bisected by a bar of hemoglobin

  • Southeast Asian ovalocytosis is unique among elliptocytoses in that the membrane structure of the RBCs is characterized by rigid stability rather than instability. RBCs show a characteristic morphology with one or two transverse slits across the body of oval-shaped RBCs 

Bizarre RBC morphology seen in hereditary pyropoik Bizarre RBC morphology seen in hereditary pyropoikilocytosis. Courtesy of Jean A. Shafer, BS, MA, Assistant Professor of Hematology and Pathology at the University of Rochester School of Medicine and Dentistry.

Elliptocytes can occur in many other conditions (eg, iron deficiency, leukemias, megaloblastic anemias, myeloproliferative diseases, myelodysplastic syndromes) but usually do not reach the proportions observed in patients with HE. Elliptocytes in patients with severe iron deficiency anemia are markedly hypochromic, a finding not associated with any of the HE disorders. Of most importance, patients with HE have a positive family history, whereas patients with other diseases associated with elliptocytes have underlying manifestations of their particular diseases.

Elliptocytosis must be differentiated from pseudoelliptocytosis, which is a common artifact of peripheral smear preparation. In pseudoelliptocytosis, the blood cells appear stretched and lined up in parallel, whereas in true elliptocytosis, the cells are oriented in different directions.

Results of osmotic fragility testing are within reference ranges in typical HE, but values are increased in spherocytic HE and HPP.[14]  When tested for thermal stability, normal RBCs can withstand temperatures up to 49°C, but RBCs associated with HPP denature at 45-46°C.

Laboratory studies may show evidence of hemolysis, such as low haptoglobin levels; a high reticulocyte count; and elevated concentrations of LDH and indirect bilirubin. It is important to emphasize that the percentage of elliptocytes observed does not correlate with the severity of hemolysis.

Although in most cases, the diagnosis of HE can be made without further studies, for further testing, International Council for Standardization in Haematology (ICSH) guidelines recommend sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) for quantitation of protein 4.1 and spectrin analysis (spectrin dimer content and spectrin variant), if those are available; or use of ektacytometry to obtain a deformability index (DI) profile, which shows a characteristic trapezoidal shape in patients with HE.[12, 15]

Imaging studies are not needed in the diagnosis of HE, but can reveal findings consistent with chronic hemolysis, such as splenomegaly and gallstones.

Ektacytometry

Osmotic gradient ektacytometry has been the reference technique for diagnosis of RBC membrane disorders, but its limited availability has severely restricted its use.[16]  Although not readily available, ektacytometry in combination with gene sequencing can help clarify unusual variants.[17]  

An ektacytometer is a laser-diffraction viscometer in which deformability is measured as a continuous function of the osmolality of the suspending medium. The Omin point is the osmolality at which the minimum deformability index is reached and is related to the surface area–to-volume ratio of the cell. The Hyper point is the osmolality at which the minimum deformability index reaches half of its maximum value. The Hyper point is related to the internal viscosity of the cell and to its mechanical properties.[2]

In HE, ektacytometry shows decreased maximum deformability characterized by a trapezoidal curve with normal Omin and Hyper points. In HPP, the maximum deformability is decreased and the Omin and Hyper points are shifted towards the left.[7] In Southeast Asian ovalocytosis, the key finding is lack of deformability of the erythrocytes.[16]

 

Treatment

Approach Considerations

In most cases, hereditary elliptocytosis (HE) causes no symptoms and requires no therapy. For patients with clinically significant hemolytic anemia, splenectomy provides marked improvement. A diet rich in folic acid or folic acid supplementation is recommended to avoid consequences of folate deficiency in a hemolytic state. Other supportive measures, such as blood transfusions, may be indicated if the anemia is severe.

Surgical Care

Because the spleen is the site for erythrocyte destruction, splenectomy markedly improves anemia for patients with clinically significant hemolysis. Splenectomy stops or markedly reduces hemolysis that results from HE but does not correct the underlying membrane defect. As with splenectomy for other indications, pneumococcal, meningococcal, and Haemophilus influenzae vaccines should be administered before surgery.

Consultations

Consultation with a general surgeon is indicated if splenectomy is being considered in a patient with clinically significant uncompensated hemolysis. Consultation with a genetic counselor is helpful to explain the genetic nature and implications of this disease to immediate family members.