An inherited disorder of red blood cells characterized by lifelong anemia and recurrent painful episodes. The sickle cell mutation is caused by a single nucleotide effecting a change in the β-globin gene, resulting in the substitution of valine for glutamic acid as the sixth amino acid of β-globin. The short circulatory survival of red blood cells that contain sickle cell hemoglobin S results in anemia, and their abnormal rigidity contributes to painful obstruction of small blood vessels. See also Anemia; Genetic code;
The sickle cell gene is found most commonly among individuals of African ancestry, but also has a significant incidence in Mediterranean, Middle Eastern, and Asian Indian populations. Inheritance of one sickle gene and one normal β-globin allele results in a simple heterozygous condition known as sickle cell trait. This benign carrier condition is associated with a normal life expectancy, and it does not cause either anemia or recurrent pain. The large amounts of hemoglobin A within sickle-cell-trait red blood cells protect against the deleterious effects of hemoglobin S. The inheritance of homozygous sickle cell anemia results in sufficiently high intracellular concentration of sickle cell hemoglobin S to cause clinical disease. See also Human genetics.
The property of sickle cell hemoglobin S responsible for clinical disease is its insolubility when deoxygenated. Oxygenated sickle cell hemoglobin S is as soluble as oxygenated normal hemoglobin, but when it is deoxygenated it aggregates and forms an insoluble polymer. Polymerization of sickle cell hemoglobin within deoxygenated sickle cells reversibly reduces cellular deformability and distorts cells to the sickle shape (see illustration). Sickle cells usually return from the venous circulation to the arterial, where the hemoglobin is reoxygenated and the cells unsickle. Persistent cycles of sickling and unsickling result in the generation of dehydrated, very dense sickle cells; these are irreversibly sickled cells that are incapable of resuming a normal shape when reoxygenated. As a result of the poor deformability of individual sickle red blood cells, sickle cell blood has high viscosity. The impaired rheologic properties of sickle blood are compounded by abnormal adherence of sickle red cells to endothelial cells lining the blood vessels.
Scanning electron micrograph of a deoxygenated sickle red blood cell. (Electron micrograph by Dr. James White)
The short-lived nature of sickle red blood cells results in lifelong chronic hemolytic anemia with which accelerated red blood cell production cannot keep pace. The increased turnover of red blood cells results in elevated levels of hemoglobin degradation and bilirubin production by the liver and in very frequent formation of gallstones. Vasoocclusive complications of sickle cell disease include the episodic painful crises and both chronic and acute organ dysfunction. Average life expectancy is in the fifth decade. One disease manifestation that is particularly problematic in young children is susceptibility to infections.
The standard method of diagnosing sickle cell syndromes is hemoglobin electrophoresis. There are a variety of diagnostic tests based on deoxyribonucleic acid (DNA). These DNA-based diagnostic methods are particularly useful for prenatal diagnosis of sickle cell disease. See also Deoxyribonucleic acid (DNA); Electrophoresis; Prenatal diagnosis.
Despite the profound understanding of sickle cell disease, treatment of painful episodes often consists of only symptomatic therapy, including analgesics for pain, antibiotics for infections, and transfusions for episodes of severe anemia. Genetic counseling and prenatal diagnosis remain important therapeutic approaches. See also Blood; Genetic engineering.
