Etiology

Hereditary elliptocytosis is inherited as a dominant disorder. In the rare instances when 2 abnormal alleles are inherited (HPP), the patient exhibits particularly severe hemolytic anemia. Various molecular defects have been described in hereditary elliptocytosis; these produce abnormalities of α- and β-spectrin and defective spectrin heterodimer self-association (see Fig. 452-1). The abnormalities (spectrin mutations) can provide resistance to malarial infection. Such defects in horizontal protein interactions result in gross membrane fragmentation, particularly in homozygous HPP. Less commonly, mutations in protein 4.1 and glycophorin C can produce elliptocytosis.

Clinical Manifestations

Elliptocytosis may be an incidental finding on a blood film examination and might not be associated with clinically significant hemolysis (see Fig. 452-4B). The diagnosis of hereditary elliptocytosis is established by the findings on the blood film, the autosomal dominant inheritance pattern, and the absence of other causes of elliptocytosis, such as deficiencies of iron, folic acid, or vitamin B₁₂. Hemolytic elliptocytosis can produce neonatal jaundice, even though characteristic elliptocytosis might not be evident at that time. The blood of the affected newborn can show bizarre poikilocytes and pyknocytes. Transient augmented fragmentation and hemolysis in the newborn can result from the presence of hemoglobin F that binds poorly to the glycolytic intermediate 2,3-diphosphoglycerate. The increased 2,3-diphosphoglycerate tends to destabilize the spectrin–actin–protein 4.1 complex, leading to membrane instability (see Fig. 452-1).

The usual features of a chronic hemolytic process with elliptocytosis are manifested later as anemia, jaundice, splenomegaly, and osseous changes. Cholelithiasis can occur in later childhood; aplastic crises have been reported. The most severe form is HPP, which is characterized by extreme microcytosis (mean corpuscular volume, 50-60 fL/cell), extraordinary variation in cell size and shape, and primarily microspherocytic rather than elliptocytic cells (see Fig. 452-4C). These patients usually inherit a mutant spectrin from one parent, who has mild or no elliptocytosis, and a partial spectrin deficiency from the other parent, who is hematologically normal.

Ovalocytes, in contrast to elliptocytes, are less elongated and might reflect a condition known as Southeast Asian ovalocytosis (SAO). SAO is associated with an abnormal protein 3, which functions as an anion exchanger. This disorder can produce neonatal hyperbilirubinemia, but it causes little hemolysis later. It might offer protection against Plasmodium falciparum malaria because normal protein 3 is one of the malarial receptors. Protein 3 as an anion exchanger is also expressed in renal tubular cells and can cause distal renal tubular acidosis in association with SAO.

Laboratory Findings

The blood film is the most important test to establish hereditary elliptocytosis (see Fig. 452-4B). The red blood cells (RBCs) show various degrees of elongation and can actually be rod shaped. In hereditary elliptocytosis, other abnormal RBC shapes may be present, depending on the severity of hemolysis. They include microcytes, spherocytes, and other poikilocytes. The reticulocyte percentage reflects the severity of hemolysis; erythroid hyperplasia and indirect hyperbilirubinemia may be present. Increased thermal instability is characteristic of HPP, hence its name. The abnormal spectrin denatures and the cells lyse at 45-46°C instead of the usual 49-50°C. The specific protein abnormality can be established by protein separation and analysis techniques. Molecular defects are defined only in research laboratories.

Treatment

If hereditary elliptocytosis represents a morphologic abnormality on the blood film without evident hemolysis, no treatment is necessary. Patients with chronic hemolysis should receive folic acid, 1 mg daily, to prevent secondary folic acid deficiency. Splenectomy decreases the hemolysis and should be considered if the hemoglobin is <10 g/dL and the reticulocyte count is >10%. The RBCs on the blood film may be more abnormal after splenectomy, even though hemoglobin increases and reticulocytes decrease. The hematologic features of SAO do not require treatment beyond the newborn period.