INTRODUCTION — Hereditary elliptocytosis (HE), also called hereditary ovalocytosis, is a heterogeneous group of inherited red blood cell (RBC) disorders characterized by the presence of elongated, oval, or 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 common HE, hereditary pyropoikilocytosis (HPP), Southeast Asian ovalocytosis (SAO), and spherocytic elliptocytosis (SE).

Separate topic reviews present more general discussions regarding the approach to the patient with anemia or hemolytic anemia, as well as other inherited RBC membrane/cytoskeletal disorders such as hereditary spherocytosis (HS) and hereditary stomatocytosis (HSt):

●General approach and hemolytic anemias (child) – (see "Approach to the child with anemia" and "Overview of hemolytic anemias in children")

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

●HS – (see "Hereditary spherocytosis")

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

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 is linked to the membrane via specialized protein attachments to the lipid bilayer. The following interconnected proteins are involved in the coupling of the cytoskeleton to the membrane (figure 1):

●Spectrin (the most abundant RBC cytoskeletal protein, composed of alpha-beta heterodimers)

●Ankyrin

●Protein 4.2 (also called band 4.2; previously called pallidin)

●Protein 4.1 (also called band 4.1)

●Band 3 protein (also called AE1 [anion exchange protein 1])

●Glycophorin C

Genetic variation affecting the abundance, structure, and/or function of these proteins can cause abnormalities of RBC shape and reduced deformability [1]. Elliptocytosis is one such shape change, which can be conferred by abnormalities in spectrin, protein 4.1, or band 3. (See 'Gene variants' below.)

The elliptical shape of elliptocytes (picture 1) appears to develop during the normal aging of RBCs 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 [2].

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 [1]. Unaffected RBCs undergo elastic recoil after they emerge from narrow capillaries and regain the normal biconcave disc shape, but RBCs from individuals with HE appear to lack some of the normal connections between cytoskeletal and membrane components 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 in HE do not necessarily shorten the lifespan of an RBC. This is illustrated by the observation of a normal lifespan of RBCs from individuals with Southeast Asian ovalocytosis (SAO; caused by abnormalities of band 3), despite the oval shape of these cells and their increased membrane rigidity [2]. As a result, people with SAO generally do not have hemolysis or anemia. (See 'Findings in specific syndromes' below.)

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

Gene variants

Overview of genotypes — Most cases of HE are due to disease-causing variants affecting α-spectrin (alpha-spectrin), β-spectrin (beta-spectrin), or protein 4.1 [3]. These include single base substitutions, insertions, deletions, and/or changes that affect mRNA processing [4,5]. Variants in alpha-spectrin and beta-spectrin are most common, accounting for approximately 65 and 30 percent of cases, respectively (see 'Spectrin variants' below). Variants affecting protein 4.1 account for approximately 5 percent, and variants affecting glycophorin C have also been reported.

●Common HE – Most forms of HE are transmitted in an autosomal dominant pattern; affected individuals are heterozygous for a disease-causing variant. Expressivity can be variable (the phenotype can be more or less severe in different individuals with the same genotype) (see "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Variable expressivity'). Heterozygotes are usually asymptomatic with mild or no hemolysis, although a small percentage may have more severe disease with chronic or intermittent hemolysis. (See 'Spectrin variants' below.)

●Hemolytic HE or HPP – Homozygotes or compound heterozygotes often have severe, symptomatic hemolytic anemia, which may be designated as hemolytic HE or hereditary pyropoikilocytosis (HPP), depending on the RBC morphology. HPP is often caused by homozygous or compound heterozygous variants affecting spectrin protein structure [5]. In other HPP cases, heterozygosity for a spectrin variant may occur in combination with a low expression allele (a variant that severely reduces production of the normal spectrin protein) [5]. (See 'Spectrin variants' below.)

●SAO – SAO is due to a characteristic deletion in band 3. SAO is transmitted in an autosomal dominant pattern. (See 'Band 3 variants' below.)

Spectrin variants — Spectrin is a heterotetramer formed by the head-to-head self-association of two αβ (alpha-beta) dimers (α2β2) [4]. 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, organization, 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 [6,7].

●Alpha-spectrin – The majority of alpha-spectrin variants are single nucleotide substitutions that cause changes in helix C of one of the repeating polypeptide units near the amino-terminal end of the alpha-spectrin polypeptide; these affect dimer-dimer self-association and thus interfere with tetramer formation [8,9]. These variants can be identified because they often alter the normal 80 kD alpha-I tryptic fragment from this region upon tryptic digestion of the protein, creating smaller polypeptide fragments (typical sizes: 78, 74, 65, or 46 to 50 kD) [4,10-12]. Variants have also been described that affect the alpha-II tryptic fragment, which is adjacent to the alpha-I 80 kD fragment [4,13,14]. A more distal mutation, located between the alpha-3 and alpha-4 spectrin repeats, limits tetramer formation by stabilizing the closed dimer conformation [15]. There are also several abnormally truncated (shortened) alpha-spectrins caused by alterations in introns that lead to exon skipping [16-20].

Most individuals with disease-causing alpha-spectrin variants are heterozygotes and have common HE, often with little to no hemolysis (see 'Clinical syndromes' below). Some individuals may have more severe hemolytic anemia or an HPP phenotype, especially when they are homozygous or compound heterozygous for a disease-causing mutation or when they are compound heterozygous for a disease-causing mutation and an alpha-spectrin variant that reduces production of normal alpha-spectrin, resulting in a high ratio of abnormal to normal alpha-spectrin [4,5,15,18,21-24].

●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 [25]. 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) [25-27]. The reduced expression appears to be due to the partial exon skipping, which confers increased vulnerability to proteolysis. It can be convenient to consider the alpha-spectrin LELY mutation to be acting in a way similar to alpha thalassemia with a single alpha globin gene affected, in both cases giving rise to a condition that is clinically silent on its own but that can exacerbate other anemias (such as HE) that depend on normal levels of alpha-spectrin production. When inherited in trans with an HE disease-causing mutation, alpha-spectrin LELY causes a more severe disease phenotype because it reduces levels of the normal alpha-spectrin protein. 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 [28]. When inherited on its own (without an HE variant, which occurs in 20 to 30 percent of the general population), alpha-spectrin LELY does not cause disease or abnormal RBCs. Other low-expression alleles have also been reported that reduce mRNA synthesis or increase proteolysis (LEPRA [low-expression allele Prague], Bicetre, St. Louis) [29,30].

●Beta-spectrin – Disease-causing beta-spectrin variant typically cause abnormalities at the distal (carboxyl-terminal) end of the protein and affect dimer-dimer association. Several single nucleotide substitutions lead to production of full-length beta-spectrin polypeptides with altered function. These variants also lead to greater exposure of the alpha-I-74 cleavage site in alpha-spectrin and increase the ratio of the I-74 to I-80 fragments upon tryptic digestion of alpha-spectrin. Heterozygosity for these variants is clinically silent or produces a mild phenotype, but homozygosity can cause severe or even lethal disease [10,12,31-33]. Other variants that truncate (shorten) the beta-spectrin polypeptide have also been demonstrated to interfere with dimer-dimer association [34-38]. Low-abundance beta-spectrins may give rise to spectrin deficiency as well as altered dimer-dimer associations, sometimes causing spherocytic elliptocytosis [34,36,38] (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 [39].

Protein 4.1 variants — Protein 4.1 binds to the spectrin-actin cytoskeleton via a 10 kD internal domain and contributes to membrane stability via its spectrin-actin binding [40,41]. (See "Red blood cell membrane: Structure, organization, and dynamics", section on 'Protein 4.1'.)

Disease-causing variants in protein 4.1 account for approximately 5 percent of HE cases [6,7]. Variants that lead to deficiency of the protein and structural abnormalities have been described. As an example, analysis of nine related French families with HE revealed a single codon deletion that causes loss of a single amino acid (lysine) residue in protein 4.1, resulting in a partial protein 4.1 deficiency [42]. Heterozygotes tend to have elliptocytosis without hemolysis or anemia, whereas homozygotes for disease-causing variants in protein 4.1 tend to have a severe HPP phenotype [43]. (See 'Clinical syndromes' below.)

Band 3 variants — Band 3 (also called erythrocyte membrane protein band 3 [EMPB3], solute carrier family 4 anion exchanger member 1 [SLC4A1], or anion exchange protein 1 [AE1]) is an integral membrane protein that constitutes approximately one-fourth of total RBC membrane proteins. Its functions are twofold: exchanging bicarbonate for chloride ions across the RBC membrane and linking the membrane lipid bilayer to the underlying cytoskeleton. (See "Red blood cell membrane: Structure, organization, and dynamics", section on 'Band 3'.)

A specific band 3 variant (a 27 base pair deletion) causes SAO (see 'Southeast Asian ovalocytosis (SAO)' below). This deletion creates an in-frame removal of nine amino acids (codons 400 to 408) at the junction of the membrane-spanning domain and the cytoplasmic tail of band 3 on its cytosolic surface [44-46]. The abnormal band 3 protein fails to undergo proper glycosylation. It has defective anion transport properties, markedly reduced lateral mobility within the membrane, and increased oligomerization, in turn leading to increased membrane rigidity [44,47-49]. The SAO variant appears to be linked to an additional single base pair substitution (the band 3 Memphis variant, which leads to a substitution of glutamic acid for lysine at codon 56) [50]. Band 3 Memphis is also seen in individuals without the SAO deletion and is thought to be a disease marker rather than a pathogenic variant.

Homozygosity for the SAO band 3 deletion is thought to be lethal in utero [51]. One individual homozygous for the SAO variant was diagnosed with hydrops fetalis due to severe anemia at 22 weeks of gestation and has required continuous transfusion support [52].

Other band 3 variants (but not the SAO band 3 deletion by itself) can cause hereditary spherocytosis or a renal tubular acidosis [53]. These other conditions are discussed separately (See "Hereditary spherocytosis" and "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance", section on 'Distal (type 1) RTA'.)

The Diego blood group is based on the band 3 protein. (See "Red blood cell antigens and antibodies", section on 'Diego blood group system'.)

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

Absence of glycophorin C causes elliptocytosis without hemolysis; this is thought to be due to partial deficiency of protein 4.1 and/or p55, another RBC membrane protein that binds to glycophorins [54,55].

Glycophorin C is the basis for the Gerbich blood group antigen, and absence of the antigen (the Leach phenotype) has been used to identify individuals with glycophorin C deficiency. (See "Red blood cell antigens and antibodies", section on 'Gerbich blood group system'.)

Mechanism of hemolysis — As noted above, 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 [2,22,23]. 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 [2,7]. 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 [56,57].

The hemolysis 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 (see 'Testing for hemolysis' below), as well as the benefit of splenectomy in individuals with severe chronic hemolytic anemia due to HE. (See '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 [58,59]. These changes have been hypothesized to occur as a consequence of the high concentrations of fetal hemoglobin (HbF) in neonatal RBCs. HbF 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 [59]. 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 HbF 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 [6]. 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 [60]. In areas such as West Africa, prevalences of HE as high as 1 to 2 percent have been suggested [7,61,62]. In RBCs with elliptocytosis and various spectrin variants from West Africa, in vitro cell culture studies have shown resistant to invasion by Plasmodium falciparum parasites, and growth of the parasite was inhibited [62]. (See 'Spectrin variants' above.)

Southeast Asian ovalocytosis (SAO) is seen in parts of Southeast Asia, including Malaysia, New Guinea, Indonesia, and the Philippines. In the Melanesian population of Papua New Guinea, as many as 12 to 30 percent of individuals may be affected [63]. These distribution patterns suggest that exposure to malaria may have driven expansion of the gene mutations, as discussed separately. (See "Protection against malaria by abnormalities in red cell surface antigens and cytoskeletal proteins", section on 'Red cells with cytoskeletal abnormalities'.)

CLINICAL SYNDROMES

Overview of clinical features — The clinical presentation of HE is highly variable, ranging from clinically silent/asymptomatic, in which elliptocytosis is an incidental finding on the blood smear, to severe hemolytic anemia. 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. Anemia can develop or worsen if the individual develops concomitant iron deficiency or deficiency of vitamin B12 or folate. Severe hemolysis is usually a consequence of homozygosity or compound heterozygosity for one or more disease variants or one disease variant and one low-expression allele of α-spectrin (alpha-spectrin). (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 [6]. 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'.)

Subtypes of HE include:

●Common HE

●Hereditary pyropoikilocytosis (HPP)

●Southeast Asian ovalocytosis (SAO)

●Spherocytic elliptocytosis

Some of these syndromes have specific genotype-phenotype relationships (heterozygosity for spectrin or protein 4.1 mutations in common HE; homozygosity or compound heterozygosity for spectrin or protein 4.1 mutations in HPP; specific band 3 deletion in SAO), but others do not. 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 (table 1).

Abnormal RBC morphologies — The hallmark of common HE is the presence of elliptical (oval)-shaped red blood cells (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 (eg, <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. In SAO the ovalocytes are stomatocytic with one or two transverse bars (picture 5).

The mean corpuscular volume (MCV) is normal in most cases of common HE and SAO, low in more severe forms of common HE, and extremely low in HPP (30 to 50 fL) [6].

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 2). (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 2), although SAO and common HE typically have minimal or no hemolysis outside of the neonatal period [6,7]. Spherocytic elliptocytosis is associated with mild to moderate hemolysis; approximately 10 percent of individuals with common HE have moderate to severe hemolytic anemia (referred to as "hemolytic HE"); and HPP is generally characterized by severe hemolytic anemia [5,7].

In any patient, the severity of hemolysis and whether it is chronic or intermittent depends on the specific mutation(s), genetic modifiers, and external factors. Individuals who are homozygous or compound heterozygous for HE mutations are more likely to have chronic hemolysis [64-67]. As noted above, the severity of hemolysis or anemia does not correlate with the percentage of elliptocytes on the blood smear [6]. (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 [68,69]

●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

Common HE — Common HE is usually asymptomatic in heterozygotes, with no or only minimal signs of hemolysis outside of the neonatal period. Some neonates with common HE have transient neonatal hemolysis with abnormal RBC morphologies that may include poikilocytes, spherocytes, fragmentation, and extreme microcytosis, which subsequently resolves during infancy; the mechanism is discussed above (see 'Mechanism of hemolysis' above). Many individuals with common 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 mutation that, in others, underlies common HE but for poorly understood reasons do not exhibit the RBC morphologic changes typical of HE. Nevertheless, their mutation, if inherited alone or in combination with another HE mutation, may lead to clinical HE in their children.

Approximately 10 percent of individuals with common HE have more severe hemolysis, referred to as hemolytic HE. This may be due to homozygosity or compound heterozygosity for an HE mutation, heterozygosity for an HE mutation in combination with a low-expression alpha-spectrin allele (see 'Gene variants' above), or another genetic or environmental modifier.

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, spherocytes, fragmentation, and extreme microcytosis (MCV 30 to 50 fL) (picture 4). Elliptocytes are uncommon in HPP.

HPP often presents with neonatal jaundice from hemolytic anemia during the neonatal period that continues throughout life. 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.)

A case of HPP with milder clinical symptoms has been reported [74].

Southeast Asian ovalocytosis (SAO) — SAO (also called Melanesian ovalocytosis) is characterized by a specific RBC morphology often described as stomatocytic elliptocytosis. On the blood smear, these cells appear as stomatocytes (RBCs containing either a longitudinal slit or one or two transverse ridges), ovalocytes, and macro-ovalocytes with one or more transverse slits (picture 5) [75]. Hemolysis and anemia are usually absent or mild, although some neonates with SAO have transient neonatal hemolysis. In two series of individuals with genetically documented SAO (85 individuals in total), approximately one-half had neonatal hyperbilirubinemia that resolved in early childhood [76,77].

Hereditary spherocytic elliptocytosis (HSE) — A form of HE referred to as hereditary spherocytic elliptocytosis (HSE) has been described in various case reports, but it is not clear whether this is a separate entity, as many of the reports predated molecular analysis [78]. The clearest description of the molecular basis for HSE is that of two family members with HSE who inherited a mutation that caused truncated beta-spectrin and as a result were not only deficient in spectrin, a feature of hereditary spherocytosis (HS), but also exhibited reduced spectrin tetramer formation, a feature of HE [38,57,79].

DIAGNOSTIC EVALUATION — HE or a related variant such as hereditary pyropoikilocytosis (HPP) or Southeast Asian ovalocytosis (SAO) is suspected in an individual with elliptocytes, poikilocytes, or stomatocytes on the peripheral blood smear (picture 1), especially if there is African, Mediterranean, or Southeast Asian ancestry. The presence of elliptocytes may be an incidental finding or may be noted during the evaluation of hemolytic anemia or testing in family members of an affected individual.

History and examination — The family history should focus on anemia in family members. 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.

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 (eg, early satiety, abdominal fullness) or to gallstones (eg, 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".)

CBC and blood smear — All individuals with suspected HE should have a complete blood count (CBC) with differential and red blood cell (RBC) indices, as well as review of the peripheral blood smear by an individual familiar with RBC morphology. This will already have been done in the majority of cases, but the CBC and differential may be repeated and an additional blood smear reviewed if the original blood smear is no longer available.

The CBC and RBC indices in HE may show a normocytic, normochromic anemia (normal mean corpuscular volume [MCV] and mean corpuscular hemoglobin concentration [MCHC]), or the hemoglobin level may be normal [6].

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, fragmentation, or stomatocytosis, depending upon the HE syndrome (table 1).

Morphologic features are helpful in distinguishing among the HE syndromes:

●Stomatocytic elliptocytes (picture 5) are typical of SAO.

●Profound microcytosis (MCV 30 to 50 fL), high MCHC, and/or abundant microspherocytes with RBC fragmentation (picture 4) are consistent with HPP or severe (hemolytic) HE.

It should be noted that 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.

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. (See 'Differential diagnosis' below.)

If the findings on the history, physical examination, CBC, and blood smear are consistent with HE or SAO, the diagnosis can be considered to be confirmed (see 'Diagnostic confirmation' below). Additional laboratory testing for hemolysis is appropriate because it may impact management. (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 2):

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

●Lactate dehydrogenase (LDH) and indirect bilirubin

●Haptoglobin

●Direct antiglobulin (Coombs) test

In some cases, the Coombs test may be omitted in the evaluation for HE (eg, in a patient from a family with known HE who has obvious elliptocytosis on the blood smear). The Coombs test is negative in HE (ie, there is no anti-RBC antibody involved), with the caveat that some individuals may have evidence of an antibody to RBCs as an incidental finding.

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 level. However, the absence of these findings does not eliminate the possibility of HE since many individuals with HE do not have 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). Thus, 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.

Osmotic fragility testing was used routinely to diagnose hereditary hemolytic anemias before other biochemical and genetic tests became available. This test is not required for the diagnosis of HE, but it may be helpful in selected cases in which there is diagnostic uncertainty such as suspected hereditary spherocytic elliptocytosis (HSE). This test may require a specialized laboratory. If osmotic fragility testing is performed, it may be normal in individuals with common HE who do not have significant hemolysis; it may show increased fragility in individuals with HPP or hemolytic HE or spherocytic HE; and it may show normal to decreased fragility in individuals with SAO. It is worth noting that individuals with HE may have other conditions that alter osmotic fragility testing. An example of this was illustrated in a case report that described falsely normalized osmotic fragility in an individual with SAO and beta thalassemia trait [80].

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

Diagnostic confirmation — Fundamentally, HE is a morphologic diagnosis made by review of the peripheral blood smear. We consider the diagnosis of an HE syndrome (HE, SAO, or HPP) to be confirmed in an individual who has ovalocytes or elliptocytes on the peripheral blood smear without another explanation. Typically, at least 15 percent of the RBCs show the abnormal morphology, although there may be exceptions (eg, a recent episode of severe hemolysis). The extent of evaluation required to exclude other causes depends on the individual and the RBC morphology. In a young healthy person with a known family history, it may not be necessary to do other testing with the possible exception of testing for 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 and family studies 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 hereditary spherocytic elliptocytosis (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 HSE and HS, as well as differentiation among other HE subtypes, may be facilitated by osmotic fragility tests, a search for elliptocytes in family members, and, in some cases, genetic testing (eg, suspected SAO). (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 (eg, inadequate diet, negative family history for HE, positive family history for thalassemia) or those with anemia and a blood smear that has typical findings such as microcytosis 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 and 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 deformability and hydration of an RBC population [59,67]. OGE is effective in confirming the diagnosis when RBC morphology does not provide a clear diagnosis. OGE is also helpful in distinguishing HE from hereditary spherocytosis (HS) and hereditary xerocytosis, as illustrated in the figure (figure 3). OGE can also measure the mechanical stability of RBC ghosts, which has been shown to be abnormal in individuals with HPP [59,67].

A flow cytometry test using eosin-5-maleimide (EMA) binding has been evaluated as a possible ancillary test for HPP [81]. This test is more often used in evaluating HS (figure 3). Patients with HPP or SAO often have similar results as those seen in HS. Results of EMA binding are variable (and therefore less helpful) in common HE [82]. (See "Hereditary spherocytosis", section on 'Confirmatory tests'.)

Genetic testing — Genetic testing is not required for diagnosis or therapy in most cases but may be helpful in selected individuals for whom there is diagnostic uncertainty and/or a role for family testing, genetic counseling, or prenatal diagnosis.

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 due to homozygosity or compound heterozygosity.

Next generation sequencing, exome sequencing, and whole genome sequencing are increasingly available for the diagnosis of challenging cases [83,84]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Testing for known variants such as the SAO band 3 deletion or the low-expression α-spectrin allele (alpha-spectrin LELY [low-expression allele Lyon]) is easier 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 "Tools for genetics and genomics: Polymerase chain reaction".)

If sequencing is requested, certain academic laboratories have a special interest or ability to perform this testing and 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

●Yale University Blood Disease Reference Laboratory

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

•Phone – (203) 737-1349

●Mayo Clinic Mayo Medical Laboratories

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

•Phone – (800) 533-1710

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

Commercial gene panels may also be available.

Prenatal diagnosis has been reported using analysis of the properties of RBCs from a fetus in a family in which both parents were heterozygous for an HE variant [85].

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 it is considered helpful to distinguish among the various HE syndromes, or when there is a reason to differentiate between HE and other possible inherited RBC disorders such as hereditary spherocytosis (HS) or hereditary xerocytosis (HX). (See 'Differential diagnosis' below.)

Analysis of cytoskeletal proteins is usually limited to specialized research laboratories and may include one or more of the following [2]:

●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 4.1) abnormally large cytoskeletal proteins

●Nondenaturing acrylamide gel electrophoresis of spectrin extracted from RBC membrane ghosts, which can detect defective 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 4) 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 hemoglobinopathy in which reduced production of alpha globin or beta globin chains leads to their precipitation, 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 mutations affecting the RBC cytoskeleton lead to production of spherocytes (RBCs that lack central pallor) and hemolytic anemia due to membrane instability. Like HE, HS is characterized by gene variants affecting cytoskeletal components, including spectrin and band 3, and 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 3). Confusion may arise when encountering a case of hereditary spherocytic elliptocytosis (HSE), a rare condition that shares features of both HS and HE. The presence of numerous elliptocytes in the blood of a patient with otherwise typical HS suggests a diagnosis of HSE. (See "Hereditary spherocytosis" and 'Hereditary spherocytic elliptocytosis (HSE)' above.)

●Hereditary xerocytosis – Hereditary xerocytosis (HX; also referred to as dehydrated hereditary stomatocytosis [dehydrated HSt]) is a rare inherited RBC disorder in which gene variants affecting RBC membrane transport channels lead to reduced RBC water content, producing stomatocytes on the blood smear and hemolytic anemia. Like individuals with Southeast Asian ovalocytosis (SAO), those with HX have a family history of hemolytic anemia and stomatocytic-appearing cells on the blood smear, although the appearance of stomatocytes differs from stomatocytic elliptocytes. Like SAO, some cases of HX are caused by gene variants affecting band 3; however, the characteristic band 3 deletion is specific to SAO. Unlike SAO, target cells are a dominant feature of HX. Osmotic fragility is not helpful as it is decreased in both HX and SAO, but osmotic gradient ektacytometry may be useful. Additional laboratory test results specific to HX are discussed separately. (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)

●Iron deficiency or iron deficiency anemia – Iron deficiency and iron deficiency anemia are acquired conditions in which insufficient iron is present for the production of hemoglobin. Like those with HE, individuals with iron deficiency may have abnormal RBC morphologies and anemia. Unlike HE, iron deficiency anemia is microcytic and hypochromic without elliptocytes, and in iron deficiency the iron studies show low serum ferritin and low 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 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, or secondary to another condition. 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) [86]. (See "Clinical manifestations and diagnosis 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 cases of HE are asymptomatic and require no specific therapy or follow-up care. Routine monitoring is not necessary. The emergence of a new, unrelated disease that may impact the hemoglobin level might call for repeating the complete blood count (CBC) (see 'Individuals 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 the patient's medical record in order to prevent unnecessary testing or delays in care. Awareness of the diagnosis may also be helpful in family planning (eg, if a child has inherited the disorder or if there is consanguinity and concern about having a child with homozygosity for a disease-causing variant).

Individuals 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 red blood cell transfusion in the adult"). 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 transfusional iron overload. (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 hemolytic anemia 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, although 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 [87-90]. This is consistent with our experience and with the mechanism of extravascular hemolysis involving reticuloendothelial macrophages (of which the spleen is a primary site).

When hemolysis is severe or the resulting anemia is life-threatening, splenectomy may lessen anemia and/or eliminate the need for regular RBC transfusions. We sometimes use 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, in which splenectomy is routine for individuals with chronic hemolysis, in HE the decision requires more thought. Given the paucity of definitive information and the relative rarity of HE, decisions must be individualized, 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 six years if possible, and we provide pre-splenectomy vaccinations and education regarding when to use prophylactic antibiotics and when to seek medical attention for possible infections. This subject is 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".)

Splenectomy may also increase the risk for thromboembolic disease, although the likelihood of complications in individuals with HE relative to other disorders is not known [91]. 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 [90]. In a series of 41 patients with HE who were evaluated at a national referral center in France, five who had hereditary pyropoikilocytosis (HPP) with severe hemolytic anemia were referred for subtotal splenectomy [92]. Of the three who were available for follow-up, all had a reduced transfusion requirement, but the response was transient. One required repeat subtotal splenectomy and one underwent total splenectomy six years later for continued hemolysis. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Partial splenectomy'.)

Family testing and prenatal counseling — It is reasonable to perform prenatal 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 or Southeast Asian ovalocytosis (SAO) 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 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 other family members become the primary tools for distinguishing the various elliptocytic syndromes. Folic acid supplementation is used for individuals with chronic hemolysis, and counseling about the risks of an affected child may be an appropriate component of prenatal care.

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; also called hereditary ovalocytosis) is a heterogeneous group of inherited red blood cell (RBC) disorders in which genetic alterations that affect spectrin, protein 4.1, band 3, 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 5 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 abnormalities in red cell surface antigens and cytoskeletal proteins".)

●Clinical features – The clinical presentation of HE is highly variable, which is partly, but not completely, genotype-dependent. Subtypes of HE include common HE, hereditary pyropoikilocytosis (HPP), Southeast Asian ovalocytosis (SAO), and spherocytic elliptocytosis. The major clinical differences in these syndromes are in the RBC morphology and severity of hemolysis (table 1). (See 'Clinical syndromes' above.)

●Evaluation – HE may be suspected in an individual with unexplained hemolytic anemia or a family member 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 and RBC indices, as well as review of the peripheral blood smear by an individual familiar with RBC morphology. Testing for hemolysis is appropriate if >15 percent elliptocytes or other characteristic HE morphologies are present or if the patient has anemia. (See 'Diagnostic evaluation' above.)

●Confirmatory testing – We consider the diagnosis of an HE syndrome (HE, SAO, or HPP) to be confirmed in an individual who has ovalocytes or elliptocytes on the peripheral blood smear without another explanation. Specialized testing (eg, testing for iron deficiency and/or thalassemia, analysis of RBC proteins, ektacytometry, genetic testing) is not required for diagnosis but may be helpful in challenging cases or those with implications for family testing, preconception counseling, or prenatal testing. (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 stomatocytosis, and hereditary spherocytosis (figure 4), as well as acquired conditions that produce similar-appearing RBC morphologies (eg, iron deficiency, myelofibrosis, myelodysplasia). The figure shows differences between HE and HS on ektacytometry (figure 3). (See 'Differential diagnosis' above.)

●Treatment – Most cases of HE are asymptomatic and require no specific therapy or follow-up care. 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 (eg, 1 mg daily). Occasional transfusions are used for some cases 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 should have appropriate prophylaxis and education to address the increased risks of infection and thromboembolic disease. (See 'Management' above and "Elective (diagnostic or therapeutic) splenectomy".)

●Other considerations – It is reasonable to perform prenatal counseling in couples at risk for having a severely 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 family members; folate supplementation is appropriate for individuals with hemolysis. (See 'Family testing and prenatal counseling' above and 'Pregnancy' above and 'Resource-limited settings' above.)

ACKNOWLEDGMENTS — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.