eMedicine Specialties > Hematology > Uncommon RBC Membrane Disorders
Elliptocytosis, Hereditary
Updated: May 24, 2006
Introduction
Background
Hereditary elliptocytosis (HE) encompasses inherited disorders of erythrocytes that have the common feature of elliptical RBCs on morphologic examination and shortened RBC survival. These disorders are clinically, genetically, and biochemically heterogeneous.
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. 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.
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 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.
Although normal RBCs can regain their discoid shape because of their elastic recoil after they pass through the microcirculation, the RBCs in HE fail to regain their normal discoid shape. This failure 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. 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).
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.
Frequency
United States
HE has a prevalence of 250-500 cases per million population.
International
HE has worldwide distribution, but the incidence is considerably higher in areas endemic for malaria than in nonendemic areas because of relative resistance of elliptocytes against malaria. 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.
Mortality/Morbidity
Most patients with the common form of HE are asymptomatic. Only 5-20% develop uncompensated hemolysis with anemia. Other findings consistent with chronic hemolysis are splenomegaly, pigmented gallstones, leg ulcers, and elevated reticulocyte counts.
Race
Although no racial or ethnic group is spared, some variants of HE occur more frequently in certain ethnic populations than in others. For example, the incidence of stomatocytic elliptocytosis among Malayan aborigines is 30%. HE with neonatal poikilocytosis occurs almost exclusively in African American families, but spherocytic elliptocytosis most commonly affects individuals of European descent.
Sex
Because HE is an autosomal disorder, the distribution between the sexes is equal.
Age
HE is a congenital disease. However, other acquired disorders, such as myelofibrosis and myelophthisic anemias, may affect the degree of hemolysis.
Clinical
History
Hereditary elliptocytosis (HE) is a heterogeneous group of disorders that shares the common feature of generally having more than 25% elliptical RBCs. Because specific molecular lesions are not necessarily correlated with clinical manifestations, a morphologic classification has been devised. The 3 commonly identified morphologic variants include 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 subcategories of typical HE (mild HE), a silent carrier state, HPP, and 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, particularly among homozygotes and those with HPP. In otherwise asymptomatic patients, hemolysis may occasionally increase because of intercurrent infections (eg, hepatitis, infectious mononucleosis, and 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 the 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 people 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.
- This form is most commonly observed in individuals of European descent, particularly Italians.
- It is often associated with clinically apparent mild to moderate hemolysis, with a peripheral smear showing both spherocytes and elliptocytes but no poikilocytes.
- Unlike HPP, which is generally an autosomal recessive disorder, spherocytic elliptocytosis is an autosomal dominant disorder.
- 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.
- It is usually associated with mild or no hemolysis.
- On peripheral smears, RBCs show a characteristic morphology with 1 or 2 transverse slits across the body of oval-shaped RBCs.
- The mode of transmission is autosomal dominant. Only heterozygous conditions are reported, and the homozygous state is thought to be lethal in utero.
- SAO is also unique among elliptocytes in that the membrane structure of the RBCs is characterized by rigid stability rather than instability.
- SAO is associated with renal tubular acidosis.
- Of note, SAO confers resistance against Plasmodium falciparum infection likely because of alterations in band 3, which is one of the malaria receptors.
Physical
Most patients are asymptomatic and do not have any obvious physical signs. Patients with clinically significant hemolysis have splenomegaly, pallor, scleral icterus, and (in rare cases) leg ulcers.
Causes
HE is an inherited disease with an autosomal dominant pattern, with the exception of HPP, which is generally autosomal recessive. A number of genetic mutations described in HE ultimately result in qualitative and quantitative cytoskeletal abnormalities.
Differential Diagnoses
| Glucose-6-Phosphate Dehydrogenase
Deficiency | Myeloproliferative Disease |
| Iron Deficiency Anemia | Pyruvate Kinase Deficiency |
| Megaloblastic Anemia | Sickle Cell Anemia |
| Myelodysplastic Syndrome | Spherocytosis, Hereditary |
Workup
Laboratory Studies
- Microscopic examination of peripheral smears 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.
- 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 hereditary elliptocytosis (HE). Elliptocytes in patients with severe iron deficient 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.
- Patients with HPP have an increased number of microspherocytes, whereas patients with stomatocytic elliptocytosis have distinctive, rounded elliptocytes bisected by a bar of hemoglobin, as described previously.
- Pseudoelliptocytosis is a common artifact of peripheral smear preparation, in which the blood cells appear stretched and lined up in parallel; this finding is in contrast to true elliptocytosis in which the cells are oriented in different directions.
- Laboratory studies may show evidence of hemolysis, such as low haptoglobin levels; a high reticulocyte count; and elevated concentrations of lactic dehydrogenase (LDH), indirect bilirubin, and urinary bilinogen. It is important to emphasize that the percentage of elliptocytes observed is not correlated to the severity of hemolysis.
- Results of osmotic fragility test are within reference ranges in typical HE, but values are increased in spherocytic HE and HPP.
- When tested for thermal stability, normal RBCs can withstand temperatures up to 49°C, but RBCs associated with HPP denature at 45-46°C.
- If necessary, specialized laboratories can identify the underlying skeletal defects by quantifying membrane proteins, studying spectrin function, and performing molecular studies. Only rarely are such studies indicated.
Imaging Studies
- Imaging studies are not needed in the diagnosis of HE, but can reveal findings consistent with chronic hemolysis, such as splenomegaly and gallstones.
Histologic Findings
Elliptocytes are observed on peripheral blood smears.
Treatment
Medical Care
Most patients with hereditary elliptocytosis (HE) do not require medical treatment. 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, the pneumococcal, meningococcal, and Haemophilus influenzae vaccines should be administered before surgery.
Consultations
- Consultation with a general surgeon is indicated if considering splenectomy 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.
Diet
A diet with adequate folic acid (green leafy vegetables) or folic acid supplements is advisable to prevent folate deficiency.
Medication
No specific medical therapy is indicated for this disease, especially because most patients with HE are asymptomatic. For patients with clinically significant hemolysis, splenectomy markedly improves the hemolytic anemia.
Follow-up
Prognosis
- Most patients with hereditary elliptocytosis (HE) are asymptomatic.
- Even those with clinically significant hemolysis have an excellent prognosis after splenectomy.
Patient Education
- Patients should be informed about the autosomal dominant inheritance of the major types of HE.
- In addition, despite the asymptomatic nature of the disease, family members can be encouraged to be screened for HE.
Miscellaneous
Medicolegal Pitfalls
- Failure to diagnose the disease in a patient with clinically significant hemolysis can be the greatest pitfall. Simple peripheral smear in the appropriate clinical setting, along with thorough history taking and physical examination, can guide the clinician in the right direction.
- In the converse, attributing hemolysis to HE, when the patient has a de novo hemolytic process superimposed on a chronic, clinically insignificant HE state, is another pitfall.
References
Delaunay J. Genetic disorders of the red cell membrane. Crit Rev Oncol Hematol. Jun 1995;19(2):79-110. [Medline].
Delaunay J. Molecular basis of red cell membrane disorders. Acta Haematol. 2002;108(4):210-8. [Medline].
Gallagher PG, Romana M, Wong C, Forget BG. Genetic basis of the polymorphisms of the alphaI domain of spectrin. Am J Hematol. Oct 1997;56(2):107-11. [Medline].
Gallagher PG. Hereditary elliptocytosis: spectrin and protein 4.1R. Semin Hematol. Apr 2004;41(2):142-64.
Nicolas G, Pedroni S, Fournier C, et al. Spectrin self-association site: characterization and study of beta- spectrin mutations associated with hereditary elliptocytosis. Biochem J. May 15 1998;332(pt 1):81-9. [Medline].
Palek J, Jarolim P. Clinical expression and laboratory detection of red blood cell membrane protein mutations. Semin Hematol. Oct 1993;30(4):249-83. [Medline].
Silveira P, Cynober T, Dhermy D, et al. Red blood cell abnormalities in hereditary elliptocytosis and their relevance to variable clinical expression. Am J Clin Pathol. Oct 1997;108(4):391-9. [Medline].
Keywords
hereditary elliptocytosis, HE, elliptical red cells, Southeast Asian ovalocytosis, SAO, hereditary pyropoikilocytosis, HPP, elliptocytes, hemolytic anemia, folate deficiency, splenectomy
Contributor Information and Disclosures
Author
Daniel J Kim, MD, Staff Physician, Department of Medicine, Olive View - UCLA Medical Center
Daniel J Kim, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Medical Association, California Medical Association, Christian Medical & Dental Society, and Society of General Internal Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Leland D Powell, MD, PhD, Associate Clinical Professor of Medicine, David Geffen School of Medicine at UCLA; Consulting Staff, Department of Medicine, Olive View-UCLA Medical Center
Disclosure: Nothing to disclose.
Medical Editor
Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Clinical Oncology, and American Society of Hematology
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Marcel E Conrad, MD, BS is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwestern Oncology Group
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Chief Editor
Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
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