The major conditions in this category are congenital spherocytosis and hereditary elliptocytosis. Also included in this group are the uncommon condition abetalipoproteinemia and the extremely rare hereditary stomatocytosis.

Congenital spherocytosis

Congenital spherocytosis is one of the more common hereditary hemolytic anemias after the hemoglobinopathies and G-6-PD deficiency. Most patients are English or northern European. About 75% of cases manifest an autosomal dominant inheritance pattern, with about 25% apparently being sporadic but in most cases actually having a recessive inheritance pattern.

The basic RBC defect is partial deficiency of a protein called spectrin that forms an important part of the RBC cell membrane cytoskeleton. Patients with the autosomal dominant form are said to have 60%-80% of normal spectrin levels; patients with the recessive form have 30%-70% of normal levels.

Symptoms may develop at any time. Splenomegaly is found in approximately 50% of young children with the disease and in about 80% of older children and adults (literature range 72%-95%). About 50% develop jaundice, which is usually intermittent. Jaundice occurs in a substantial minority of patients in the first 48 hours of life but occasionally may appear after the first week. Gallstones develop in 55%-75% of patients by the time of old age and even during childhood in a few cases.

Hematologic findings. Some degree of ongoing hemolysis is present in more than 90% of cases. However, about 50%-60% of patients are able to compensate by continued bone marrow hyperactivity and do not manifest anemia except during crises. When anemia is present, it is usually mild or moderate, and hemoglobin values are normally more than 8 gm/100 ml. Patients who are symptomatic and thus are diagnosed during childhood tend to have more pronounced anemia than those diagnosed in adulthood. Reticulocyte counts are elevated in approximately 90% of patients, with a mean count of approximately 9%. The MCV and MCH values are within reference range in about 80% of cases; in the remaining 20% these values may be increased or decreased. The MCHC is also more often within reference range, but 20%-50% of affected persons may have an increased value, and an increased MCHC is a finding that suggests the possibility of congenital spherocytosis. Peripheral blood spherocytes are the trademark of congenital spherocytosis. The number of spherocytes varies and in 20%-25% of cases are few in number and frequently not recognized. Spherocytes are not specific for congenital spherocytosis and may be found in ABO transfusion reactions as well as in some patients with widespread malignancy, Clostridium welchii septicemia, severe burns, some autoimmune hemolytic anemias, and after transfusion with relatively old stored blood.

Patients with congenital spherocytosis may experience two different types of crises, which are self-limited episodes in which the anemia becomes significantly worse. The most common type is an increased degree of hemolysis (hemolytic crisis), which is frequently associated with viral infections and in which the decrease in hemoglobin level is usually not severe. The other type is the aplastic crisis, sometimes accompanied by fever and abdominal pain, lasting 6-14 days, in which bone marrow production of WBCs, RBCs, and platelets comes to a halt and during which the hemoglobin level drops to nearly one half previous values. Folic acid deficiency leading to megaloblastic anemia has also been described in congenital spherocytosis.

The spherocytes are not destroyed in the bloodstream but are sequestered, removed, and destroyed in the spleen. Splenomegaly usually is present. Splenectomy satisfactorily cures the patient’s symptoms because increased marrow RBC production can then compensate for the presence of spherocytes, which have a shorter life span than normal RBCs.

Diagnosis of congenital spherocytosis. The most useful diagnostic test in congenital spherocytosis is the osmotic fragility test. Red blood cells are placed in bottles containing decreasing concentrations of sodium chloride (NaCl). When the concentration becomes too dilute, normal RBCs begin to hemolyze. Spherocytes are more susceptible to hemolysis in hypotonic saline than normal RBCs, so that spherocytes begin hemolyzing at concentrations above normal range. This occurs when there are significant degrees of spherocytosis from any cause, not just congenital spherocytosis. Incidentally, target cells are resistant to hemolysis in hypotonic saline and begin to hemolyze at concentrations below those of normal RBCs. Osmotic fragility is not reliable in the newborn unless the blood is incubated at 37°C for 24 hours before testing. Incubation is also necessary in 20%-25% of adults, so that a normal nonincubated osmotic fragility result does not rule out congenital spherocytosis.

In the great majority of patients with congenital spherocytosis, the nonincubated or the incubated osmotic fragility tests yield clear-cut positive results. In a few cases the results are equivocal, and in rare cases they are negative. In these few cases the autohemolysis test may be helpful. Congenital spherocytosis produces a considerable increase in hemolysis under the conditions of the test, which can be corrected to a considerable degree by addition of glucose to the test media. The autohemolysis test was originally proposed as a general screening procedure for genetic hemolytic disorders, but problems with sensitivity and specificity have led some investigators to seriously question its usefulness except when osmotic fragility tests fail to diagnose a case of possible congenital spherocytosis.

Spherocytes are often confused with nonspherocytic small RBCs (microcytic RBCs). A classic spherocyte is smaller than normal RBCs, is round, and does not demonstrate the usual central clear area. (The relatively thin center associated with normal biconcave disk shape is lost as the RBC becomes a sphere.)

Hereditary elliptocytosis (ovalocytosis)

Hereditary elliptocytosis occurs in Europeans and African Americans, it is inherited as a dominant trait. Eighty percent to 90% of affected persons have mild compensated hemolysis either without anemia or with a mild anemia. Reticulocyte counts are usually slightly elevated but are not greatly increased. More than 40% of the RBCs are elliptocytes. These are oval RBCs that look like thick rods when viewed from the side. Normal persons reportedly may have up to 15% elliptocytes. There are several uncommon variants of hereditary elliptocytosis in which hemolysis is more pronounced, and moderate or severe anemia may be present; these include a variant of severe neonatal hemolytic anemia with jaundice in which anisocytosis and poikilocytosis are prominent but elliptocytosis is not. Infants with this variant slowly revert to the more usual mild elliptocytic clinical and hematologic picture by age 6-12 months. There is also a form called hemolytic hereditary elliptocytosis with spherocytosis in which there is mild anemia and another very similar form called homozygous hereditary elliptocytosis in which anemia is severe. Both variants demonstrate spherocytes as well as elliptocytes.

Abetalipoproteinemia (Bassen-Kornsweig syndrome)

Patients with abetalipoproteinemia totally lack chylomicrons, very low-density lipoproteins, and low-density lipoproteins (Chapter 22) and have only high-density lipoproteins in fasting plasma. There is associated fat malabsorption, various neuromuscular abnormalities (especially ataxia), retinitis pigmentosa, and presence of acanthocytes (Chapter 2) constituting 40%-80% of the peripheral blood RBCs. There is mild to moderate anemia with mild to moderate reticulocytosis. A peripheral smear picture similar to abetalipoproteinemia may be present in Zieve’s syndrome (hemolytic anemia with hypertriglyceridemia in alcoholic liver disease).

Congenital stomatocytosis (stomatocytic elliptocytosis)

Congenital stomatocytosis is found in certain Pacific Ocean populations, is inherited as an autosomal recessive trait, consists clinically of mild anemia, and demonstrates slightly elliptocytic stomatocytes on peripheral smear. Stomatocytes are RBCs with the central clear area compressed to a linear rodlike shape. Stomatocytes may also be found in association with alcoholism and liver disease.