Hereditary elliptocytosis and related disorders

INTRODUCTION — Hereditary elliptocytosis (HE) is a heterogeneous group of inherited red blood cell (RBC) disorders characterized by the presence of elongated, elliptically-shaped RBCs on the peripheral blood smear. Hemolytic anemia in these disorders ranges from absent to life-threatening.

This topic review will discuss the genetics, pathogenesis, clinical features, diagnosis, and management of HE syndromes, including HE, hereditary pyropoikilocytosis (HPP), and spherocytic elliptocytosis/pyropoikilocytosis (SE/SPP).

Separate topic reviews present general discussions of the approach to the patient with anemia or hemolytic anemia, as well as other inherited RBC membrane (cytoskeletal and hydration) disorders such as hereditary spherocytosis (HS), hereditary stomatocytosis (HSt), and Southeast Asian ovalocytosis (SAO):

●General approach (child) – (See "Approach to the child with anemia".)

●Hemolytic anemias (child) – (See "Overview of hemolytic anemias in children".)

●General approach (adult) – (See "Diagnostic approach to anemia in adults" and "Diagnosis of hemolytic anemia in adults".)

●Hemolytic anemias (adult) – (See "Diagnosis of hemolytic anemia in adults".)

●HS – (See "Hereditary spherocytosis".)

●HSt – (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)

●SAO – (See "Southeast Asian ovalocytosis (SAO)".)

PATHOGENESIS

Cytoskeletal proteins that control RBC shape — The elastic deformability of red blood cells (RBCs) is maintained by a cytoskeleton located underneath the cell membrane that acts as a horizontal scaffold (figure 1); the scaffold is linked to the lipid bilayer via specialized vertically positioned protein complexes [1].

●Horizontal cytoskeleton – The cytoskeleton is formed by alpha- and beta-spectrin heterodimers joining head-to-head in the spectrin tetramerization domain, with their tails bound to the junctional complexes formed by several proteins including central actin oligomers and protein 4.1R, which enable the actin-spectrin association [2]. Each junctional complex forms the corner of a triangle, with the spectrin heterotetramer forming each side. These triangles then assemble in the hexagonal network of the RBC cytoskeleton.

●Transmembrane protein complexes – Transmembrane complexes are formed by band 3 anchored via ankyrin and band 4.2 (also called protein 4.2) to the spectrin cytoskeleton, providing a vertical linkage with the lipid bilayer. Band 3 also binds to protein 4.1R at the junctional complexes, along with several transmembrane proteins including glycophorin C.

Genes that encode these proteins are discussed below. (See 'Gene variants' below.)

The elliptical shape of elliptocytes (picture 1) appears to develop during their normal aging in the circulation (rather than during RBC production in the bone marrow), since RBC precursor cells in the HE syndromes are round and do not exhibit morphologic abnormalities [3].

The mechanism is thought to involve repeated episodes of deformation that occur as RBCs pass through narrow capillary beds; these episodes of deformation cause permanent changes in the cytoskeleton of affected cells [4]. Unaffected RBCs undergo elastic recoil after they emerge from narrow capillaries and regain their normal biconcave disc shape, but RBCs from individuals with HE appear to lack some of the normal connections within the horizontal cytoskeleton and may form new contacts that cause the cell to retain an elliptocytic shape. In severe cases membrane is lost, leading to more severe alterations in shape and/or membrane fragmentation, producing spherocytes or poikilocytes (picture 2). (See 'Abnormal RBC morphologies' below.)

The morphologic changes and decreased deformability of RBCs in HE do not necessarily shorten their lifespan, as frequently observed in many cases of dominantly inherited (heterozygous) HE. Nevertheless, even patients with HE are at risk for increased hemolysis as neonates or during an illness causing hyperplasia of the reticuloendothelial system, such as viral hepatitis, infectious mononucleosis, or malaria [5-8].

Additional information about the properties of the RBC cytoskeleton is presented separately. (See "Red blood cell membrane: Structure and dynamics".)

Gene variants

Overview of genotypes — HE and related disorders are caused by pathogenic variants in the following genes:

●SPTA1, coding for α-spectrin (alpha-spectrin)

●SPTB, coding for β-spectrin (beta-spectrin)

●EPB41, coding for protein 4.1R

●GYPC, coding for glycophorin C

These variants affect the structure of alpha- or beta-spectrin incorporated in the RBC cytoskeleton, or the structure and/or quantity of protein 4.1R, or they cause complete absence of glycophorin C, which leads to partial deficiency of protein 4.1R [2,6]. The result is an altered structure of the horizontal RBC cytoskeleton, impairing membrane deformability and allowing a permanent elliptical deformation of the RBC under shear stress [4].

Most cases of HE are due to pathogenic variants affecting α-spectrin (alpha-spectrin), β-spectrin (beta-spectrin), or protein 4.1R [9]. These include single base substitutions, insertions, deletions, and/or changes that affect mRNA processing [5,6,10,11]. Variants in alpha-spectrin and beta-spectrin are most common, accounting for approximately 65 and 30 percent of cases, respectively. (See 'Spectrin variants (SPTA1 and SPTB genes)' below.)

Variants affecting protein 4.1R account for approximately 5 percent of cases. Rare biallelic GYPC pathogenic variants causing complete deficiency of glycophorin C (Leach phenotype) have also been reported to cause HE because they result in concurrent partial deficiency of protein 4.1R [12]. (See 'Protein 4.1R variants (EPB41 gene)' below and 'Glycophorin C variants (GYPC gene)' below.)

●Hereditary elliptocytosis (HE) – HE is transmitted in an autosomal dominant pattern; affected individuals are heterozygous for a pathogenic variant in EPB41 or an HE-causing variant in SPTA1, SPTB. The HE variants affect the "quality" of the protein, in contrast with HS-causing variants, which affect the quantity of spectrin chains incorporated into the RBC cytoskeleton.

Heterozygous individuals are at risk for increased hemolysis as neonates and are usually asymptomatic with mild or no hemolysis after infancy [8]. They may be diagnosed either because of review of a blood smear obtained for another cause or during evaluation for incidentally discovered splenomegaly. They are also at risk of hemolysis at times of an illness causing hyperplasia of the reticuloendothelial system, such as viral hepatitis, infectious mononucleosis, or malaria [6-8]. (See 'Spectrin variants (SPTA1 and SPTB genes)' below.)

●Hereditary pyropoikilocytosis (HPP) – Homozygous or compound heterozygous individuals often have severe, symptomatic hemolytic anemia, with RBC morphology characterized by anisopoikilocytosis, with elliptocytes and fragmented RBCs, a morphology resembling that seen in patients with thermal burns, giving to this disease the name HPP.

Severe HPP is typically caused by homozygous or compound heterozygous HE-causing variants of SPTA1 or SPTB or a combination of SPTA1 and SPTB alleles affecting spectrin protein structure [5,6,9]. Homozygous variants of EPB41 causing an apparently complete deficiency of protein 4.1R have also been reported to cause HPP [13,14].

Much more common is infantile HPP, in which hemolysis improves after infancy. These cases are due to heterozygosity for an HE-causing SPTA1 variant in trans to a low expression SPTA1 allele (an intronic variant that severely reduces production of the normal spectrin protein) [2,5,6]. (See 'Spectrin variants (SPTA1 and SPTB genes)' below.)

Spectrin variants (SPTA1 and SPTB genes) — Spectrin is a heterotetramer formed by the head-to-head self-association of two αβ (alpha-beta) dimers (α2β2) [11]. Alpha chains are normally produced in excess of beta chains, but the proportion of alpha to beta chains in the final spectrin molecule is equivalent. Thus, the quantity of beta chains synthesized is thought to determine the total quantity of spectrin that will ultimately be assembled on the RBC membrane. (See "Red blood cell membrane: Structure and dynamics", section on 'Spectrin'.)

Variants affecting the alpha-spectrin gene are the most common cause of HE, accounting for approximately two-thirds of cases (figure 2); variants affecting beta-spectrin account for another 30 percent [15,16]. The location of these variants relative to the alpha-beta spectrin interface is illustrated in the figure (figure 3).

●Alpha-spectrin – The majority of SPTA1 variants causative for HE and HPP are single nucleotide substitutions that translate to amino acid changes in the C helix, part of the α0 repeat of alpha-spectrin (near its amino-terminal end). The C helix participates in the spectrin tetramerization domain along with two helices from the β17 repeat of β-spectrin; missense mutations in this domain affect dimer-dimer self-association and thus interfere with tetramer formation [17,18]. These variants were first identified at the protein level, with extensive work two to three decades before next generation sequencing (NGS) technology made genetic diagnosis widely available for clinical diagnosis.

At the protein level, alpha-spectrin from patients with HE was found to have altered the normal 80 kD alpha-I tryptic fragment produced from the region upon tryptic digestion of the protein, creating smaller polypeptide fragments (typical sizes: 78, 74, 65, or 46 to 50 kD) [1,11,19,20]. Variants have also been described that affect the alpha-II tryptic fragment, which is adjacent to the alpha-I 80 kD fragment [11,21,22]. A more distal mutation, located between the alpha-3 and alpha-4 spectrin repeats, limits tetramer formation by stabilizing the closed dimer conformation [23]. There are also several abnormally truncated (shortened) alpha-spectrins caused by alterations in introns that lead to exon skipping [24-28].

Amino-terminal variants in SPTA1 causing HE are fairly common in populations that originate from areas where malaria was or is endemic, implicating a survival advantage in individuals with HE exposed to malaria [2,29].

•Genotype-phenotype correlations

-Most individuals with disease-causing SPTA1 variants are heterozygous for the variant and have common HE, often with little to no hemolysis. (See 'Hereditary elliptocytosis' below.)

-Individuals homozygous or compound heterozygous for an HE-causing SPTA1 variant have more severe hemolytic anemia with an HPP phenotype [30]. (See 'Hereditary pyropoikilocytosis (HPP)' below.)

-Individuals who are compound heterozygous for an HE-causing SPTA1 variant and a variant that reduces production of normal alpha-spectrin, resulting in a high ratio of abnormal-to-normal alpha-spectrin, typically present in the neonatal period with infantile HPP [5,6,23,26,31-34]. This generally improves after one to two years to common HE.

●Low expression alpha-spectrin alleles – The most common low-expression alpha-spectrin allele is alpha-spectrin LELY (Low-Expression allele LYon), named for the city in France where it was characterized [35]. The allele has two base substitutions (a single base change in exon 40 and a single base change in intron 45 that causes partial skipping of exon 46) [35-37]. The reduced expression appears to be due to the partial exon skipping, which confers increased vulnerability to proteolysis.

It may be helpful for understanding the low expression alleles to consider the similarities between alpha-spectrin and alpha-globin, both being critical for the survival of RBCs and for life in general. The alpha globin gene has been duplicated to allow for a single alpha globin gene deletion to be asymptomatic. Similarly, alpha-spectrin is expressed normally in excess; therefore, monoallelic low-expression variants such as α-LELY are clinically silent on their own. However, when inherited in trans to an HE-causing variant, α-LELY or other low expression variants lead to more severe disease phenotypes because they reduce the level of the normal alpha-spectrin protein available to be incorporated in the RBC cytoskeleton.

When inherited in cis with an HE disease variant (on the same allele as the disease variant), the clinical consequences of the variant may be ameliorated because the level of the abnormal spectrin is reduced [38]. When inherited on its own without an HE variant, which occurs in 20 to 30 percent of the general population (minor allele frequency [MAF] of 0.255 in the gnomAD database), alpha-spectrin LELY does not cause disease or abnormal RBCs. Other low-expression alleles have also been reported to reduce mRNA synthesis or increase proteolysis (LEPRA [Low-Expression allele PRAgue], Bicetre, St. Louis) [39,40].

●Beta-spectrin – Disease-causing STPB variants typically cause abnormalities at the distal (carboxyl-terminal) end of the protein, which is the one participating in the spectrin tetramerization domain along with the amino-terminal end of α-spectrin, therefore affecting dimer-dimer association. Several single nucleotide substitutions lead to production of full-length beta-spectrin polypeptides with altered function, as depicted in the figure (figure 3). Heterozygosity for these variants produces a mild or non-hemolytic HE phenotype, while homozygosity can cause severe HPP and even lethal hydrops fetalis without transfusion support in utero [1,20,41-43].

Other variants that truncate (shorten) the beta-spectrin polypeptide have also been demonstrated to interfere with dimer-dimer association [44-48]. Such variants may give rise to spectrin deficiency as well as altered dimer-dimer associations, a combination of quantitative (spherocytosis) with a qualitative (elliptocytosis) RBC membrane disorder, leading to spherocytic elliptocytosis [44,46,48]. (See 'Hereditary spherocytic elliptocytosis (HSE)' below.)

A beta-spectrin variant that produces an abnormally long polypeptide has been described as causing a mild clinical phenotype in heterozygotes [49].

Protein 4.1R variants (EPB41 gene) — Protein 4.1R binds to the spectrin-actin cytoskeleton via a 10 kD internal domain and contributes to membrane stability via its spectrin-actin binding [50,51]. (See "Red blood cell membrane: Structure and dynamics", section on 'Protein 4.1'.)

Disease-causing variants in EPB41, which encodes protein 4.1R, account for approximately 5 percent of HE cases [15,16]. EPB41 pathogenic variants have been described to cause deficiency of the protein, due to nonsense, frameshift, large deletions, or splicing mutations [5,52,53]. Other variants can cause structural abnormalities, such as due to a small deletion (p.Lys448del) and defective incorporation of the protein 4.1R in the cytoskeleton [54]. Individuals who have heterozygous pathogenic variants in EPB41 tend to have elliptocytosis without hemolysis or anemia, whereas individuals who are homozygous for EPB41 pathogenic variants tend to have a severe HPP phenotype [13]. (See 'Clinical syndromes' below.)

Glycophorin C variants (GYPC gene) — Glycophorin C, encoded by GPYC, is an integral RBC membrane protein that binds to protein 4.1R and regulates its abundance in the membrane. (See "Red blood cell membrane: Structure and dynamics", section on 'Glycophorins'.)

Absence of glycophorin C causes elliptocytosis without hemolysis; this is thought to be due to partial deficiency of protein 4.1R and/or p55, another RBC membrane protein that binds to glycophorins [55,56].

Glycophorin C is the basis for the Gerbich blood group antigen, and complete absence of the antigen, named the Leach phenotype, characterizes individuals with elliptocytosis due to glycophorin C deficiency, in rare families with homozygous GYPC exon 3 and 4 deletions or frameshift variants [57]. (See "Red blood cell antigens and antibodies", section on 'Gerbich blood group system'.)

Mechanism of hemolysis — The elliptical shape of RBCs in HE does not necessarily shorten the lifespan of the RBC. Rather, the weakening of cytoskeletal interactions involving spectrin, protein 4.1, and other proteins (either by alterations in protein abundance or structure) causes diminished mechanical stability of the membrane in some cases of HE [3,32,33]. Reduced membrane stability can lead to fragmentation, hemolysis, and production of microcytic or spherocytic RBCs, with the severity of hemolysis correlated to the amount of membrane loss [3,16]. (See 'Cytoskeletal proteins that control RBC shape' above.)

RBCs in HPP and some cases of common HE are susceptible to additional budding and fragmentation upon heating to 46°C, whereas normal RBCs are unaffected at temperatures below 50°C [58,59].

When hemolysis occurs, it appears to be predominantly extravascular (mediated by reticuloendothelial cells of the spleen, liver, and bone marrow) rather than intravascular. This explains the typical laboratory findings consistent with extravascular hemolysis, as well as the improved hemoglobin after splenectomy in individuals with severe chronic hemolytic anemia due to HE. (See 'Testing for hemolysis' below and 'Role of splenectomy' below.)

Transient hemolytic anemia with more striking morphologic abnormalities (schistocytes, fragments, budding forms, and microcytes) has been reported in neonates with some of the more severe HE syndromes [60,61]. This includes cases of infantile HPP where heterozygosity for an HE-causing SPTA1 variant occurs in trans to a low expression allele (such as alpha-LELY) that reduces production of the normal spectrin protein [3,6,10]. (See 'Spectrin variants (SPTA1 and SPTB genes)' above.)

Based on the natural history of the disease in such cases of infantile HPP, RBC morphology improves to typical elliptocytosis, and the transfusion requirement typically resolves after infancy.

Infantile HPP has been hypothesized to be aggravated by the high concentrations of fetal hemoglobin (Hb F) in neonatal RBCs. Hb F does not bind 2,3-diphosphoglycerate (DPG), and, as a result, large amounts of free 2,3-DPG are available to interact with and destabilize the RBC cytoskeleton [61].

Excess 2,3-DPG does not appear to have a discernible effect on RBC shape or survival in infants without HE. However, in RBCs with a weakened cytoskeleton, 2,3-DPG is thought to decrease mechanical stability, producing poikilocytosis and hemolytic anemia. As Hb F levels decline over the first few months of life, the contribution of 2,3-DPG to the hemolytic process wanes, hemolysis disappears, and poikilocytes are replaced by the elliptocytes that are characteristic of common HE. Transient hemolysis and/or anemia may also be precipitated by intercurrent illnesses or infections in older children and adults. (See 'Hemolysis, splenomegaly, gallstones' below.)

EPIDEMIOLOGY — HE is relatively common in some parts of the world, although the true prevalence of HE is unknown because many mildly affected individuals are likely to remain undiagnosed [15]. Prevalence has been estimated at approximately 1 in 2000 to 1 in 4000 (0.05 to 0.025 percent) worldwide.

HE is most common in individuals of African, Mediterranean, or Southeast Asian descent, paralleling the distribution of malaria [29]. In areas such as West Africa, prevalence of HE as high as 1 to 2 percent has been suggested [16,62,63]. In RBCs with elliptocytosis and various spectrin variants from West Africa, in vitro cell culture studies have shown resistance to invasion by Plasmodium falciparum parasites, and growth of the parasite was inhibited [63]. (See 'Spectrin variants (SPTA1 and SPTB genes)' above.)

This distribution pattern in addition to the in vitro studies of resistance of HE cells to Plasmodium falciparum support the hypothesis that malaria has driven expansion of these variants, as discussed separately. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Evolutionary selection pressure from malaria'.)

CLINICAL SYNDROMES

Overview of clinical features — The clinical presentation of the HE syndromes is highly variable, ranging from clinically silent/asymptomatic, in which elliptocytosis is an incidental finding on the blood smear, to severe hemolytic anemia. The table compares these features across the different syndromes (figure 4).

Causes of this variability include the specific genes affected and the specific variant(s) within those genes, as well as whether the individual has inherited an HE variant from one parent or both.

Severe hemolysis is usually a consequence of homozygosity or compound heterozygosity for one or more disease variants in SPTA1, SPTB, or EPB41, a combination of SPTA1 and SPTB alleles affecting spectrin protein structure, or one SPTA1 disease variant and one low-expression SPTA1 allele in trans [6,10,17,20,21]. (See 'Gene variants' above.)

Variability is also seen in different family members with the same disease variant, as well as in the same individual at different ages [15]. Genetic modifiers and other factors are thought to be responsible for this variability among individuals with the same HE genotype. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)

Anemia can develop or worsen if the individual develops concomitant iron deficiency or deficiency of vitamin B12 or folate.

Subtypes of HE with the corresponding genotype-phenotype correlation are the following:

●Common HE – Typically this is characterized by mild or no hemolysis at baseline, although increased hemolysis may be noted in the neonatal period and during an illness causing hyperplasia of the reticuloendothelial system, such as viral hepatitis, infectious mononucleosis, or malaria [5-8]. Common HE is due to:

•Heterozygous "qualitative" SPTA1 or SPTB variants

•Heterozygous "qualitative" or "quantitative" EPB41 variants

•Homozygous GYPC variants (rare)

●Hereditary pyropoikilocytosis (HPP)

•Chronic hemolytic anemia of variable severity is due to homozygosity or compound heterozygosity for HE-causing variants of SPTA1 or SPTB or a combination of SPTA1 and SPTB alleles affecting spectrin protein structure [6,10,17].

•Rare, severe cases are due to homozygous variants of EPB41, causing an apparently complete deficiency of protein 4.1R [20,21].

•Infantile HPP is typically caused by compound heterozygosity for an SPTA1 HE variant in trans to alpha-LELY, the most common low expression SPTA1 allele, where the intronic variant c.6531-12C>T reduces production of the normal spectrin protein [2,3,6,10].

●Hereditary spherocytic elliptocytosis or pyropoikilocytosis (HSE/PP)

•With chronic mild to severe hemolysis, red blood cell (RBC) morphology on the blood smear resembling pyropoikilocytosis with fragmented cells and elliptocytes (but spherocytes are also notable), and an ektacytometry typical of hereditary spherocytosis (HS). (See 'EMA binding and ektacytometry' below.)

•Compound heterozygous SPTA1 or SPTB pathogenic variants that result both in spectrin deficiency (a feature of HS) as well as defective spectrin tetramer formation (a feature of HE/HPP) [26,48,59,64].

The major clinical differences in these syndromes are in the RBC morphology and severity of hemolysis, as discussed in the following sections and summarized in the table (figure 4).

Abnormal RBC morphologies — The hallmark of common HE is the presence of elliptical (oval-shaped) RBCs on the peripheral blood smear (picture 1), which can be numerous or less apparent, ranging from up to 100 percent of cells at one extreme to approximately 15 percent of RBCs at the other. Generally, a smaller proportion of elliptocytes (<15 percent) is not characteristic of HE.

Other morphologies such as spherocytes, stomatocytes, and/or fragmented cells (poikilocytes) may be seen (picture 3). These morphologies are also readily apparent on scanning electron microscopy (picture 2). In HPP, there are numerous poikilocytes, RBC fragments, microspherocytes, and microelliptocytes (picture 4). In spherocytic elliptocytosis, the elliptocytes are more spherocytic and RBC fragments are absent.

The mean corpuscular volume (MCV) is low or low-normal in most cases of common HE, and frequently extremely low in HPP (30 to 50 fL) [15].

The hemoglobin and hematocrit are normal in the absence of hemolysis (or in the presence of compensated hemolysis) and low if hemolysis is more significant or if the capacity of the bone marrow to respond is impaired, as may occur during an infection (table 1). (See 'Hemolysis, splenomegaly, gallstones' below.)

Hemolysis, splenomegaly, gallstones — Hemolysis may be present in any of the HE syndromes, with laboratory findings as listed in the table (table 1), although common HE typically has minimal or no hemolysis outside of the neonatal period [15,16]. Spherocytic elliptocytosis is associated with mild to moderate hemolysis; HPP is generally characterized by moderate to severe hemolytic anemia, which in the case of infantile HPP improves with time [6,16].

In any patient, the severity of hemolysis and whether it is chronic or intermittent depends on the specific gene variant(s), genetic modifiers, and external factors. Individuals who are homozygous or compound heterozygous for HE pathogenic variants are more likely to have chronic hemolysis [65-68]. The severity of hemolysis or anemia does not correlate with the percentage of elliptocytes on the blood smear [15]. (See 'Mechanism of hemolysis' above.)

Anemia may occur when hemolysis is severe and/or when bone marrow capacity to increase production of RBCs is impaired, such as in the following circumstances:

●During the neonatal period when fetal hemoglobin levels are high (see 'Mechanism of hemolysis' above).

●During acute infections, which may increase the stress on RBCs and/or suppress the bone marrow [7,69].

●During pregnancy [70].

●In the setting of other hemolytic conditions (eg, thrombotic microangiopathy, liver dysfunction, prosthetic heart valve) [71-73].

Individuals with chronic hemolysis may have associated findings such as jaundice (including neonatal jaundice), splenomegaly, or pigment gallstones.

Findings in specific syndromes

Hereditary elliptocytosis — HE, which is almost always a heterozygous (autosomal dominant [AD]) condition, is typically asymptomatic with no or only minimal signs of hemolysis outside of the neonatal period.

Some individuals with HE may have history of transient neonatal hemolysis and neonatal hyperbilirubinemia, with abnormal RBC morphologies that may include poikilocytes, spherocytes, fragmentation, and extreme microcytosis, which subsequently resolves during infancy; these individuals may have infantile HPP due to a SPTA1 HE pathogenic variant in trans to the low expression allele alpha-LELY, or potentially they may have other aggravating factors during the neonatal period. (See 'Mechanism of hemolysis' above.)

Many individuals with HE only come to medical attention when a high percentage of elliptocytes (typically ≥15 percent, often as high as 90 percent) is noted on the peripheral blood smear. A few individuals, termed silent carriers, inherit a variant that, in others, underlies HE but for poorly understood reasons do not exhibit the RBC morphologic changes typical of HE. Nevertheless, their variant, if inherited alone or in combination with another HE variant, may lead to clinical HE in their relatives.

Approximately 10 percent of individuals with presumed HE have more severe hemolysis, referred to as hemolytic HE. These patients may have compound heterozygosity for an HE variant plus a deep-intronic low-expression alpha-spectrin allele, not yet discovered and therefore not evaluated for in available next-generation sequencing panels (see 'Gene variants' above), or another genetic or environmental modifier of a single HE pathogenic variant.

Hereditary pyropoikilocytosis (HPP) — HPP, generally the most severe type of HE, is thus named because the RBC morphology resembles that seen in patients with thermal burns. RBC abnormalities on the peripheral blood smear include poikilocytes, elliptocytes, spherocytes, and fragmentation leading to significant microcytosis (picture 4).

HPP often presents with neonatal jaundice from hemolytic anemia during the neonatal period that continues throughout life [74]. Hydrops fetalis can occur [30].

Individuals with HPP often have complications of hemolysis, including splenomegaly and/or pigment gallstones, and they may require frequent transfusions and/or splenectomy. (See 'Hemolysis, splenomegaly, gallstones' above and 'Management' below.)

Hereditary spherocytic elliptocytosis (HSE) — A form of HE referred to as HSE has been described in various case reports.

The initial reports predated molecular analysis [75]; however, subsequent reports have revealed that the molecular basis for HSE is compound heterozygosity for SPTA1 or SPTB pathogenic variants that result both in spectrin deficiency (a feature of HS) as well as abnormal spectrin tetramer formation (a feature of HE/HPP) [26,48,59].

DIAGNOSTIC EVALUATION — HE or a related variant such as hereditary pyropoikilocytosis (HPP) is suspected in an individual with elliptocytes, poikilocytes, and fragmented cells on the peripheral blood smear (picture 1). The presence of elliptocytes may be an incidental finding or may be noted during the evaluation of hemolytic anemia or testing in relatives of an affected individual.

History and examination — The patient history may include neonatal jaundice and/or symptoms attributable to anemia such as fatigue or decreased exercise tolerance; however, such findings may be absent. Individuals with longstanding hemolytic anemia may have a history of symptoms attributable to splenomegaly (early satiety, abdominal fullness) or to gallstones (right upper quadrant pain).

Findings on examination associated with chronic hemolysis may include splenomegaly, gallbladder tenderness, and leg ulcers. Frontal bossing may be seen in severely anemic patients with HPP. (See "Diagnosis of hemolytic anemia in adults" and "Overview of hemolytic anemias in children".)

The family history should focus on anemia, splenomegaly, gallstones, or need for early cholecystectomy in relatives. In some cases, the diagnosis of HE may not have been established, or the anemia may have been mischaracterized as being due to another condition such as iron deficiency.

CBC, reticulocyte count, and blood smear — All individuals with suspected HE should have a complete blood count (CBC) with differential, red blood cell (RBC) indices, and reticulocyte count, as well as review of the peripheral blood smear by an individual familiar with RBC morphology.

●CBC – The CBC and RBC indices in HE may show a mildly microcytic or normocytic, normochromic anemia (low or low-normal mean corpuscular volume [MCV] and mean corpuscular hemoglobin concentration [MCHC]), or the hemoglobin may be normal [15].

Macrocytosis, white blood cell (WBC) abnormalities, and platelet abnormalities are not characteristic of HE, and the presence of one or more of these findings suggests an alternative (or additional) diagnosis.

●Reticulocyte count – Hemolysis is associated with increased reticulocytosis. Absence of reticulocytosis, especially if other findings of hemolysis are present, suggests a concomitant cause of anemia. (See 'Testing for hemolysis' below and "Diagnosis of hemolytic anemia in adults", section on 'Hemolysis without reticulocytosis'.)

●Blood smear – On the blood smear, elliptocytes appear as oval, elongated, thin, rod- or cigar-shaped RBCs (picture 1 and picture 3). The percentage of elliptocytes is variable, ranging from 15 to 100 percent of RBCs. Additional RBC morphologies may include variable degrees of spherocytosis and fragmentation, depending upon the HE syndrome (figure 4).

Profound anisopoikilocytosis, frequent microcytes, microspherocytes and/or fragmented RBCs, and high MCHC (picture 3 and picture 4) are consistent with HPP or severe (hemolytic) HE; the latter may actually be HPP not yet clarified genetically.

Individuals without HE may have a small percentage of elliptical RBCs on the blood smear (typically <5 percent). In the absence of hemolysis, these individuals do not require additional evaluation or testing and should not be labeled as having HE.

If the findings on the history, physical examination, CBC, and blood smear are consistent with HE, the diagnosis can be considered to be confirmed. (See 'Diagnostic confirmation' below.)

Additional laboratory testing for hemolysis and genetic diagnosis is appropriate because it may impact management, prognosis, and genetic counseling. (See 'Testing for hemolysis' below and 'Management' below.)

Testing for hemolysis — Testing for hemolysis is appropriate if >15 percent elliptocytes or other characteristic HE morphologies are present, regardless of the hemoglobin level. This is because some individuals may have compensated hemolysis with a high reticulocyte count that is able to maintain the hemoglobin in the normal range.

Standard hemolysis testing includes the following (table 1):

●Reticulocyte count (absolute count is preferred over reticulocyte percentage)

●Lactate dehydrogenase (LDH), indirect bilirubin, and aspartate transaminase>alanine transaminase (AST>ALT)

●Haptoglobin (test is indicated after six months of age; haptoglobin value in early infancy is normally decreased due to decreased production of the protein from the neonatal liver)

●Direct antiglobulin (Coombs) test

The Coombs test is negative in HE or HPP (no anti-RBC antibodies are involved), except in the rare cases where a hereditary hemolytic anemia is complicated by an autoimmune hemolytic anemia.

Evidence of hemolysis (increases in the reticulocyte count, LDH, and/or indirect bilirubin; decreased haptoglobin) is consistent with a more severe form of HE, independent of the hemoglobin. However, the absence of these findings does not eliminate the possibility of common HE since most individuals with common HE do not have chronic hemolysis. If hemolysis is present, the severity and chronicity of hemolysis has implications for management that are discussed below. (See 'Management' below.)

When present, hemolysis in HE is predominantly extravascular (in the reticuloendothelial macrophages of the spleen, liver, and bone marrow). (See 'Mechanism of hemolysis' above.)

Findings of marked intravascular hemolysis such as pink serum, hemoglobinemia, or hemoglobinuria are not consistent with HE and suggest an alternate diagnosis such as a transfusion reaction or cold agglutinin disease. (See "Hemolytic transfusion reactions" and "Cold agglutinin disease".)

Osmotic fragility testing was used routinely to diagnose hereditary hemolytic anemias before other phenotypic and genetic tests became available. This test is not helpful for the diagnosis of HE, since in most cases of HE and related disorders, except for the cases of hereditary spherocytic elliptocytosis (HSE), osmotic fragility is not increased. Osmotic fragility testing may require a specialized reference laboratory. It is worth noting that individuals with hereditary RBC membrane disorders may have other conditions that alter the results of osmotic fragility testing. For example, beta thalassemia trait causes decreased osmotic fragility, and patients with an RBC membrane disorder expected to have increased osmotic fragility may have an apparently normal result if they have concurrent beta thalassemia trait [76].

Testing for hemolysis is often appropriate in other individuals with unexplained anemia (with diagnoses other than HE), as discussed separately. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)

Diagnostic confirmation — The diagnosis of an HE syndrome (HE, HPP, or HSE) is frequently initiated by review of the peripheral blood smear revealing at least 15 percent of the RBCs as elliptocytes.

The extent of evaluation required to confirm the diagnosis and/or exclude other causes depends on the individual and the RBC morphology. When there is no indication of chronic hemolysis and no further intervention is needed, it may not be necessary to do other testing. However, when there is chronic hemolysis, evaluation for subclinical iron overload is indicated, a potential complication for any chronic hemolytic condition.

Moreover, other potential causes for elliptocytes and/or significant poikilocytosis in a patient presenting with those findings on the blood smear may need to be considered, such as iron deficiency and/or thalassemia. In other cases (eg, negative family history, RBC morphologies other than typical elliptocytes), additional testing is used. (See 'Additional testing in selected cases' below.)

In resource-limited areas, examination of RBC morphology on the blood smear by a knowledgeable individual coupled with a CBC, reticulocyte count, and family history will usually produce an adequate diagnosis.

Differentiation of the various subtypes of HE may have implications for management, especially if hemolysis is present and the possibility of HSE versus hereditary spherocytosis (HS) is being considered. This is because HS is routinely treated with splenectomy, whereas HSE is only treated with splenectomy if hemolysis is quite severe. (See 'Role of splenectomy' below.)

Distinction between HE/HPP, HSE and HS, as well as differentiation from other causes of hereditary hemolytic anemia, may be facilitated by a search for elliptocytes in family members, osmotic fragility, ektacytometry or EMA flow cytometry testing, and, in some cases, genetic testing. (See 'Genetic testing' below.)

Additional testing in selected cases

Eliminate possibility of iron deficiency and/or thalassemia — In selected cases, it may be useful to eliminate the possibility of iron deficiency and/or thalassemia before considering the diagnosis of HE to be confirmed. Examples include individuals with a personal or family history that suggests one of these other disorders (inadequate diet, negative family history for HE, positive family history for thalassemia) or those with anemia and a blood smear that has typical findings of hypochromic/microcytic or target cells. (See "Microcytosis/Microcytic anemia".)

●Individuals found to have iron deficiency should be treated appropriately with iron replacement followed by re-evaluation of the CBC, blood smear, and iron studies to determine whether any abnormalities persist. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Iron deficiency in infants and children <12 years: Treatment" and "Treatment of iron deficiency anemia in adults".)

●Individuals found to have thalassemia should be managed as indicated for their disease phenotype. (See "Diagnosis of thalassemia (adults and children)" and "Management of thalassemia".)

Rarely, it may be possible for an individual to have two RBC disorders, such as HE and one of these other conditions. In such cases, hematology consultation is appropriate.

EMA binding and ektacytometry — Osmotic gradient ektacytometry (OGE) measures the osmotic fragility, deformability, and hydration status of the RBC population [61,68]. OGE is effective in confirming the diagnosis when RBC morphology does not provide a clear diagnosis. OGE is also helpful in distinguishing HE from HS and hereditary xerocytosis [3,17,27], as illustrated in the figure (figure 5). OGE can also measure the mechanical stability of RBC ghosts, which has been shown to be abnormal in individuals with HPP [61,68].

A flow cytometry test using eosin-5-maleimide (EMA) binding that detects decreased band 3 on the membrane as a surrogate test for membrane loss has been evaluated as a possible ancillary test for HPP [77]. This test is more often used as a screening test for HS (figure 5). Patients with HPP often have similar results as those seen in HS. Results of EMA binding are variable (and therefore less helpful) in common HE [78]. (See "Hereditary spherocytosis", section on 'Confirmatory tests'.)

Genetic testing — Genetic testing is not necessary for diagnosis in common, non-hemolytic HE cases, when no therapeutic intervention is planned, but it may be helpful in selected individuals for whom there is diagnostic uncertainty and/or a role for testing relatives, genetic counseling, or reproductive testing and counseling.

If both parents carry an HE variant, their children have a 50 percent chance of being heterozygous for one of the variants and a 25 percent chance of being severely affected with HPP presenting as chronic hereditary hemolytic anemia due to homozygosity or compound heterozygosity.

Next generation sequencing (NGS) of a panel of genes known to be associated with RBC membrane disorders or a more inclusive panel of genes associated with hereditary hemolytic anemias, whole exome sequencing (WES), and whole genome sequencing (WGS) are increasingly available for the diagnosis of challenging cases [79,80]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Targeted testing for known variants identified in relatives with disease is easier and less expensive than gene sequencing, because testing can be done using polymerase chain reaction (PCR) to amplify the relevant portion of the relevant gene. (See 'Gene variants' above and "Polymerase chain reaction (PCR)".)

If sequencing is requested, a number of commercial laboratories can perform CLIA-certified NGS panels for diagnostics. In addition, certain academic laboratories have a special interest in these disorders and have the ability to perform this testing. They may be contacted for further discussions. Examples include:

●Cincinnati Children's Molecular Genetics Laboratory

•Website – https://www.cincinnatichildrens.org/service/d/diagnostic-labs/molecular-genetics

•Phone – (513) 636-4474

●Mayo Clinic Mayo Medical Laboratories

•Website – https://news.mayocliniclabs.com/hematology/

•Phone – (800) 533-1710

•Email – [email protected] (United States) or [email protected] (international)

●Yale University Blood Disease Reference Laboratory (research testing only)

•Website – https://medicine.yale.edu/pathology/clinical/mdx/

•Phone – (203) 737-1349

Commercial gene panels are also available, including one sponsored by a pharmaceutical company and provided after informed consent from the patient/family/caregivers [81].

Prenatal diagnosis has been reported as early as 1987, at that time using analysis of the properties of RBCs from a fetus in a family in which both parents were heterozygous for an HE variant [82]. Prenatal diagnosis can now be pursued with genetic testing of fetal DNA obtained by amniocentesis or chorionic villus sampling (CVS).

Analysis of RBC proteins — Analysis of red blood cell (RBC) membrane proteins is not required for diagnosis but may be helpful in challenging cases, when clinically available OGE (see 'EMA binding and ektacytometry' above) and genetic sequencing do not provide a clear diagnosis of a patient's red cell membrane disorder. (See 'Differential diagnosis' below.)

Analysis of cytoskeletal proteins is usually limited to specialized research laboratories and may include one or more of the following [3]:

●Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), which will show deficiency of a specific protein or proteins, abnormally shorted (truncated) versions, or (in the case of protein 4.1R) abnormally large cytoskeletal proteins.

●Nondenaturing acrylamide gel electrophoresis of spectrin extracted from RBC membrane ghosts, which can detect abnormal spectrin tetramer formation.

●Tryptic peptide mapping by two-dimensional gel electrophoresis of digested spectrin, to define the likely site of a spectrin mutation.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of HE includes other inherited (figure 6) and acquired conditions that may be associated with the presence of elliptocytes (typically ≥15 percent of red blood cells [RBCs]) on the peripheral blood smear.

●Thalassemia – Thalassemia is an inherited hemoglobin disorder in which reduced production of alpha globin or beta globin chains leads to the precipitation of its counterpart chain remaining in excess, causing hemolysis in the bone marrow and peripheral blood. Like HE, thalassemia is common in malaria-endemic regions of the world, the family history is often positive, and the blood smear shows abnormal RBC morphologies.

Like hereditary pyropoikilocytosis (HPP), hemoglobin H disease (a severe form of alpha thalassemia) can have microcytosis, fragmented RBCs, spherocytes, and reticulocytosis. Unlike HE, the main finding in the thalassemias is hypochromic, microcytic RBCs, teardrop-shaped RBCs, target cells, and basophilic stippling in RBCs. Unlike HE, thalassemia results in an abnormal hemoglobin analysis and globin gene abnormalities on DNA testing. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Patient with suspected thalassemia' and "Diagnosis of thalassemia (adults and children)", section on 'Laboratory testing'.)

●Hereditary spherocytosis – Hereditary spherocytosis (HS) is an inherited RBC disorder in which pathogenic variants in SPTA1, SPTB, ANK1, SLC4A1, or EPB42 cause a decrease in the quantity of the corresponding proteins (spectrin, ankyrin, band 3) in the RBC cytoskeleton. This can lead to production of spherocytes (RBCs that lack central pallor) and hemolytic anemia due to membrane instability.

Like HE, in HS there is often a family history of hemolytic anemia. Unlike HE, HS is characterized by abundant spherocytes without RBC fragments or severe microcytosis; elliptocytes are not present in HS (figure 5). Confusion may arise when encountering a case of hereditary spherocytic elliptocytosis or pyropoikilocytosis (HSE/HSPP), a rare condition that shares features of both HS and HE/HPP. The presence of numerous elliptocytes and fragmented cells in the blood of a patient with HS findings in ektacytometry, as well as residual hemolysis after splenectomy for presumed HS, suggests a diagnosis of HSE/HSPP [26]. (See "Hereditary spherocytosis" and 'Hereditary spherocytic elliptocytosis (HSE)' above.)

●Southeast Asian ovalocytosis – Southeast Asian ovalocytosis (SAO; also called Melanesian ovalocytosis) is most frequently seen in individuals from parts of Southeast Asia, including Malaysia, New Guinea, Indonesia, and the Philippines.

Like HE, in SAO, the cells have an oval or elliptocytic shape on the blood smear. Unlike HE, the gene involved is different, the RBCs in SAO often have one or more central slits, and clinical features differ; as an example, hemolytic anemia typically is not seen after three years of age in individuals with SAO. (See "Southeast Asian ovalocytosis (SAO)".)

●Hereditary stomatocytosis/xerocytosis – Dehydrated hereditary stomatocytosis [dehydrated HSt]), also referred to as hereditary xerocytosis (HX), is a rare inherited RBC disorder in which gene variants affecting RBC membrane transport channels (PIEZO1 and Gardos channel, encoded by the genes PIEZO1 and KCNN4, respectively) lead to reduced RBC water content because of intracellular K⁺ leak, producing stomatocytes on the blood smear and hemolytic anemia (or, most frequently, well-compensated hemolysis). Osmotic gradient ektacytometry gives a characteristic curve. Dehydrated HSt is frequently associated with iron overload even with no blood transfusions; a tendency for cardiac iron overload has been reported. Splenectomy is contraindicated in these patients because it predisposes to life-threatening thrombotic events and it does not improve the hemolysis. Additional details are discussed separately. (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)

●Iron deficiency anemia (IDA) – IDA is an acquired condition in which insufficient iron is present for the production of hemoglobin.

Like those with HE, individuals with IDA may have abnormal RBC morphologies along with the anemia, including elliptocytes. Unlike HE, IDA is microcytic and hypochromic, and in IDA the iron studies show low serum ferritin, high serum transferrin or total iron binding capacity (TIBC), and low transferrin or transferrin saturation (TSAT). In some cases of suspected HE, it may be prudent to eliminate the possibility of iron deficiency before proceeding to more specialized testing. (See 'Eliminate possibility of iron deficiency and/or thalassemia' above and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Findings on CBC'.)

●Myelofibrosis – Myelofibrosis is typically an acquired condition in which the bone marrow has increased reticulin fiber formation; this may be due to a myeloproliferative neoplasm, such as primary myelofibrosis, essential thrombocytosis, or polycythemia vera, due to acquired or occasionally germline pathogenic variants in MPL, CALR, or JAK2 [34]. Germline pathogenic variants in MPIG6B underlie idiopathic primary myelofibrosis, which may present in early childhood [35].

Like HE, the RBC morphology in myelofibrosis may show oval-shaped cells, and the patient may be anemic. Unlike HE, the cells in myelofibrosis are more teardrop-shaped than elliptical, and in myelofibrosis there are often abnormalities in other cell lines such as leukopenia, thrombocytopenia, leukocytosis, or thrombocythemia. Unlike HE, myelofibrosis is associated with characteristic increased reticulin fibers in the bone marrow. Unlike HE, myelofibrosis usually affects older adults. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Laboratory findings'.)

●Myelodysplastic syndrome – Myelodysplastic syndromes (MDS) are acquired, premalignant bone marrow disorders in which genetic abnormalities affecting hematopoietic stem cells interfere with normal cellular maturation.

Like HE, the RBC morphology in MDS is abnormal, but in MDS there is typically macrocytosis (large cells) rather than elliptocytosis. Unlike HE, MDS can be associated with other cytopenias besides anemia (MDS often causes thrombocytopenia and neutropenia), along with dysplastic changes in one or more cell lines. Acquired elliptocytosis has been described in some patients with MDS, often in association with del(20q) [83]. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Clinical presentation'.)

●Megaloblastic anemia – Megaloblastic anemias are anemias in which nuclear maturation is delayed relative to cytoplasmic maturation in developing hematopoietic cells in the bone marrow. Megaloblastic anemias are most commonly acquired (eg, due to drugs or deficiency of vitamin B12 or folate); inherited megaloblastic anemias may rarely be seen.

Like HE, megaloblastic anemias are characterized by anemia with oval-appearing RBCs on the blood smear. Unlike HE, in megaloblastic anemias the RBCs are macrocytic, there may be leukopenia and/or thrombocytopenia, and abnormal white blood cell (WBC) morphology (hypersegmented nuclei in granulocytes) may be seen. (See "Macrocytosis/Macrocytic anemia", section on 'Megaloblastic anemia'.)

MANAGEMENT

Asymptomatic individuals — Most individuals with HE are asymptomatic and require no specific therapy or follow-up care. Routine monitoring is not necessary.

Nevertheless, individuals with HE are at increased risk for episodic hemolysis with illnesses that cause hyperplasia of the reticuloendothelial system, such as viral hepatitis, infectious mononucleosis, bacterial infections, and malaria [10]. Individuals with episodes of hemolysis require closer medical attention. (See 'Older children or adults with intermittent hemolysis or anemia' below.)

Asymptomatic individuals without hemolysis do not require supplemental folic acid (unless given for another reason such as prenatal supplementation).

It is especially helpful to explain the diagnosis to the patient and document it in their medical record in order to prevent unnecessary testing or delays in care. Awareness of the diagnosis is also helpful in family planning, since an individual with non-hemolytic HE has a significant possibility of having a child with infantile hereditary pyropoikilocytosis (HPP), since the low expression SPTA1 variant alpha-LELY is very common (minor allele frequency in gnomAD, up to 25.5 percent). (See 'Spectrin variants (SPTA1 and SPTB genes)' above.)

Infants with hemolysis — Babies with infantile HPP (due to an HE-causing SPTA1 variant in trans to alpha-LELY) or even common HE are at risk for neonatal hemolysis with severe, fast-increasing hyperbilirubinemia causing increased risk for kernicterus. They will need to be managed for anemia and hyperbilirubinemia. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening" and "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management".)

Older children or adults with intermittent hemolysis or anemia — Intermittent hemolysis may occur in certain settings, such as intercurrent illnesses, and in some cases may be accompanied by clinically significant anemia.

Occasional red blood cell (RBC) transfusions may be required for episodes of symptomatic anemia, which is usually related to intercurrent infection or other medical or surgical conditions. We typically provide transfusions to relieve symptoms and/or if the hemoglobin level drops below a threshold appropriate to the patient's age and health (see "Red blood cell transfusion in infants and children: Indications" and "Indications and hemoglobin thresholds for RBC transfusion in adults"). The intensity of monitoring and duration of therapy are determined by the patient's condition and the duration of the intercurrent illness.

Individuals with chronic hemolysis — Individuals with HE who have low-grade, compensated hemolysis may not require extensive evaluations or treatment once the baseline laboratory values are established and other concomitant causes of anemia such as iron deficiency or vitamin B12 or folate deficiency have been eliminated.

We generally provide supplemental folic acid to individuals with more than a minimal degree of hemolysis in order to prevent folate deficiency, although this practice has not been studied in depth in HE. The typical dose is 1 mg orally per day.

Individuals who are symptomatic from chronic hemolytic anemia may require periodic or regular transfusions. Attention to iron stores and initiation of a chelation regimen is important to prevent complications of iron overload, which can either be due to transfusions and/or increased erythropoiesis with chronic hemolysis. (See "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload' and "Iron chelators: Choice of agent, dosing, and adverse effects".)

Consideration of splenectomy is appropriate in those with chronic hemolytic anemia, as discussed below. (See 'Role of splenectomy' below.)

Chronic hemolysis may also lead to formation of pigment gallstones and symptomatic gallstone disease. We generally reserve gallbladder imaging for those with symptoms or those planning to undergo splenectomy (for whom cholecystectomy might be performed at the same time if gallstones are present). (See "Approach to the management of gallstones" and "Treatment of acute calculous cholecystitis".)

Role of splenectomy — There are no randomized trials or observational studies evaluating the efficacy of splenectomy in HE syndromes with chronic hemolytic anemia, such as HPP due to biallelic pathogenic variants in HE genes and hereditary spherocytic elliptocytosis (HSE).

A limited number of case reports dating from as far back as the 1950s have described improvements in the hemoglobin level following splenectomy in patients with HE who have transfusion-dependent anemia [84-87]. This is consistent with our experience and with the mechanism of extravascular hemolysis involving reticuloendothelial macrophages (of which the spleen is a primary site); however, while anemia and transfusion-requirement may resolve, residual hemolysis is likely to continue in most cases [26,36].

When hemolysis is severe, causing anemia that is life-threatening, splenectomy may lessen anemia and/or eliminate the need for regular RBC transfusions. We consider splenectomy in this setting, with a decision process similar to that for individuals with hereditary spherocytosis (HS), as discussed separately. (See "Hereditary spherocytosis", section on 'Splenectomy'.)

However, unlike HS, where splenectomy typically eliminates chronic hemolysis, in HPP and HSE the decision requires more thought since the residual intravascular hemolysis may predispose to a significant increase in thrombotic complications and potentially increased risk for pulmonary hypertension. Given the paucity of definitive information and the relative rarity of HPP and HSE cases that may require chronic transfusions, decisions must be individualized weighing the risks and benefits for each case, and referral to a hematologist and surgeon with the appropriate experience is warranted.

As with splenectomy for other nonmalignant disorders, splenectomy is associated with surgical risks and an increased risk of infections, especially with encapsulated organisms. Thus, we usually try to delay the procedure until after the age of five years if possible, and we provide pre-splenectomy vaccinations and education regarding the use of prophylactic antibiotics and when to seek medical attention for possible infections. These subjects are discussed in more detail separately. (See "Elective (diagnostic or therapeutic) splenectomy" and "Prevention of infection in patients with impaired splenic function" and "Clinical features, evaluation, and management of fever in patients with impaired splenic function".)

With persistent hemolysis, splenectomy may increase the risk for thromboembolic disease more significantly than in patients with HS. The likelihood of such complications in individuals with HPP or HSE relative to other disorders is not definitively known [88]; we recommend consideration for thromboprophylaxis (typically with aspirin) when residual hemolysis is significant [64]. We educate patients about this risk and about signs of thrombophlebitis and thromboembolism. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Venous thromboembolism'.)

Subtotal splenectomy (resection of 80 to 90 percent of the spleen) is another option that may be used in selected cases with appropriate surgical expertise. Subtotal splenectomy might also be a temporizing measure in selected individuals such as very young children [87]. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Partial splenectomy'.)

In a series of 41 patients with HE who were evaluated at a national referral center in France, five who had HPP with severe hemolytic anemia were referred for subtotal splenectomy [89]. Of the three who were available for follow-up, all had a reduced transfusion requirement, but the response was transient. In a retrospective evaluation of a total of nine patients with HPP who underwent total splenectomy (six after initial subtotal splenectomy was performed), persistent hematologic improvement with transfusion independence was noted in all cases; however, all patients had residual hemolysis [36].

Reproductive counseling — It is appropriate to perform reproductive counseling in couples at risk for having a severely affected child, as follows:

●Heterozygosity of both parents for a common HE variant, which places the child at risk for homozygosity

●HPP in one or both parents

●Consanguinity

●Previous child with clinically significant elliptocytosis with hemolysis and/or anemia

Pregnancy — Limited information is available regarding pregnancy in HE. Isolated case reports indicate that individuals with HE/HPP who have chronic hemolysis may experience an exacerbation of hemolysis throughout pregnancy, requiring RBC transfusion support [70].

Resource-limited settings — In resource-limited settings, evaluation of RBC morphology and evaluation of relatives become the primary tools for distinguishing the various elliptocytic syndromes.

Folic acid supplementation is used for individuals with chronic hemolysis, and reproductive counseling about the risks of an affected child and the need for close monitoring during the neonatal period are appropriate.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Hereditary elliptocytosis (HE) is a heterogeneous group of inherited red blood cell (RBC) disorders in which genetic alterations that affect alpha- or beta-spectrin (figure 3), protein 4.1R, or (rarely) glycophorin C cause circulating RBCs to become elliptical (picture 1); this shape-change occurs in the peripheral circulation after repeated cycles of deformation and failure of elastic recoil (picture 2). In some cases, HE can also cause other RBC morphologies (picture 4 and picture 3) and/or hemolysis, which can range from mild to life-threatening. (See 'Pathogenesis' above.)

●Prevalence – The prevalence of HE is estimated at approximately 1 in 2000 to 1 in 4000 (0.05 to 0.025 percent) worldwide; it is most common in individuals of African, Mediterranean, or Southeast Asian descent, paralleling the distribution of malaria. (See 'Epidemiology' above and "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Evolutionary selection pressure from malaria'.)

●Clinical features – Presentation of HE is highly variable, which is at least partially genotype-dependent. Subtypes of HE include common HE, hereditary pyropoikilocytosis (HPP), and spherocytic elliptocytosis. The major clinical differences in these syndromes are in RBC morphology and severity of hemolysis (figure 4). (See 'Clinical syndromes' above.)

●Evaluation – HE may be suspected in an individual with unexplained hemolytic anemia or relatives of an affected individual, or it may be an incidental finding. All individuals with suspected HE should have a complete blood count (CBC) with differential, RBC indices, and reticulocyte count, as well as review of the blood smear by an individual familiar with RBC morphology. Evaluation and monitoring for hemolysis complications is appropriate if reticulocytosis with or without anemia is present, or if other characteristic HE morphologies in addition to elliptocytes are seen, indicating HPP or hereditary spherocytic elliptocytosis (HSE). (See 'Diagnostic evaluation' above.)

●Confirmatory testing – The diagnosis of an HE syndrome (HE, HPP, or HSE/pyropoikilocytosis [PP]) can be confirmed in an individual who has ovalocytes or elliptocytes on the blood smear without another explanation such as iron deficiency and/or thalassemia. Specialized testing with ektacytometry and/or genetic testing may be helpful in challenging cases or those with implications for testing relatives, or reproductive testing and counseling (figure 5). (See 'Diagnostic confirmation' above and 'Additional testing in selected cases' above.)

●Differential diagnosis – The differential diagnosis of HE includes other inherited RBC disorders such as thalassemia, hereditary spherocytosis (figure 6), Southeast Asian ovalocytosis (SAO) (picture 5), dehydrated hereditary stomatocytosis (HSt), and acquired conditions that produce similar-appearing RBC morphologies (iron deficiency, myelofibrosis, myelodysplasia). The figure shows differences between HE and HS on ektacytometry (figure 5). (See 'Differential diagnosis' above.)

●Treatment – HE is generally asymptomatic and requires no specific therapy or follow-up. It is especially helpful to explain the diagnosis to the patient and document it in the medical record. Individuals with hemolysis are given regular folic acid (typically 1 mg daily). Occasional transfusions are used for some individuals with intermittent hemolysis, and chronic transfusions may be used for those with severe chronic hemolysis. Splenectomy is reserved for selected transfusion-dependent individuals. Individuals considering splenectomy should be evaluated by clinicians with expertise in inherited RBC disorders and the procedure, and they should have appropriate prophylaxis and education to address the increased risks of infection and thromboembolism. (See 'Management' above and "Elective (diagnostic or therapeutic) splenectomy".)

●Other considerations – It is appropriate to perform reproductive counseling in couples at risk for having an affected child. Some individuals may have an exacerbation of hemolysis during pregnancy. In resource-limited settings, diagnosis primarily involves evaluation of the blood smear and relatives. (See 'Reproductive counseling' above and 'Pregnancy' above and 'Resource-limited settings' above.)

ACKNOWLEDGMENTS

UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD, and William C Mentzer, MD, to earlier versions of this and many other topic reviews.