Sickle Cell Anemia - DescriptionSickle cell disease is a generic term for a group of genetic disorders characterized by the predominance of hemoglobin S (Hb S). These disorders include sickle cell anemia, the sickle beta thalassemia syndromes, and hemoglobinopathies in which Hb S is in association with another abnormal hemoglobin that not only can participate in the formation of hemoglobin polymers but also is present in sufficient concentration to enable the red cells to sickle. Examples of the latter disorders include hemoglobin SC disease, hemoglobin SD disease, and hemoglobin S O Arab disease. The sickle cell disorders are found in people of African, Mediterranean, Indian, and Middle Eastern heritage. In the United States, these disorders are most commonly observed in African Americans and Hispanics from the Caribbean, Central America, and parts of South America.
Sickle cell disorders are best classified by genotype. The type of hemoglobin produced is determined by the two beta globin genes located on chromosome 11 and the four alpha globin genes located on chromosome 16. Individuals who are homozygous for the sickle beta globin gene (b S ) have sickle cell anemia (SS disease). Individuals with sickle beta thalassemia have a b S gene and a gene for beta thalassemia. If no beta globin is produced by the beta thalassemia gene, the individual has Sb o thalassemia (Sb o thal). If some normal beta globin is produced by the thalassemia gene, the individual has Sb + thalassemia (Sb + thal). In the case of hemoglobin (SC disease), the individual has two abnormal beta globin genes, b S and b C , and makes two abnormal hemoglobins, Hb S and Hb C. Because the alpha globin genes are located on a different chromosome from the beta genes, a patient with sickle cell anemia can independently inherit an alpha globin gene abnormality. A common condition in people of African descent that has clinical significance for patients with a sickle cell disorder is the deletion of two of the four alpha globin genes, resulting in alpha thalassemia trait.
In contrast to these diseases is sickle cell trait. Individuals with sickle cell trait (Hb AS) have a normal beta globin gene (bA) and a bS globin gene, resulting in the production of both normal hemoglobin A and hemoglobin S, with a predominance of Hb A. Their red blood cells sickle only under unusual circumstances such as marked hypoxia and the hyperosmolar environment of the renal medulla (resulting in hyposthenuria).
There are two cardinal pathophysiologic features of sickle cell disorders: chronic hemolytic anemia and vasoocclusion (which results in ischemic tissue injury). Hemolytic anemia may be related to repeated cycles of sickling and unsickling, which interact to produce irreversible red cell membrane changes, red cell dehydration, and erythrocyte destruction. Tissue injury is usually produced by hypoxia secondary to the obstruction of blood vessels by an accumulation of sickled erythrocytes. The organs at greatest risk are those with venous sinuses where blood flow is slow and oxygen tension and pH are low (spleen and bone marrow) or those with a limited terminal arterial blood supply (eye, head of the femur and humerus). The lung, as the recipient of deoxygenated sickle cells that escape from the spleen or bone marrow, may be at special risk for vasoocclusion and infarction. No tissue or organ is spared from this injury. Symptoms of the hypoxic injury may be either acute (e.g., painful events, acute chest syndrome) or insidious in onset (e.g., aseptic necrosis of the hips, sickle cell retinopathy). The effects of acute and chronic tissue injury may ultimately result in failure of organs like the kidney, particularly as the patient ages.
An additional and less recognized problem is that sickle cell patients live under considerable psychosocial stress. Not only do they experience stresses common to other painful chronic illnesses, but they must also cope with the unpredictable nature of their illness. The recurrent and unpredictable nature of the disease can adversely affect both school and work attendance and has the potential of reducing the patients sense of self-esteem.
Appropriate counseling and management requires definitive diagnosis. The diagnosis of sickle cell disease is primarily based on hemoglobin electrophoresis. In those instances where Hb S is found in association with another abnormal hemoglobin such as Hb C, the diagnosis can be made by electrophoresis alone. In those instances, however, when the electrophoresis reveals only Hb S, Hb F (fetal hemoglobin), and Hb A 2 , there can be difficulty in distinguishing between sickle cell anemia and some of the sickle beta thalassemia syndromes, including Sb o thal and sickle cell trait, in association with hereditary persistence of fetal hemoglobin (S HPFH). It is important that distinctions be made because these disorders differ markedly in their clinical expression. For example, symptoms of patients with Hb Sb o thal are similar to those of Hb SS; patients with Hb Sb + thal have less associated symptoms, and those with Hb S HPFH are asymptomatic and not anemic.
Patients with SS or Sb o thal disease or S HPFH all have similar electrophoretic patterns. Mean corpuscular volume (MCV) is definitely decreased in thalassemia syndromes and is somewhat decreased in S HPFH. Measurement of Hb A 2 and Hb F may help in distinguishing between these conditions. In general, Hb A 2 levels are elevated above 3.5 percent in Sb o thal and are low in patients with S HPFH. Hb F levels are generally higher in the sickle beta thalassemic disorders than in SS disease, although there is considerable overlap between these diagnostic groups. In those instances where S HPFH is suspected, measurement of Hb F in the parents and/or siblings can be valuable.
The diagnosis of sickle cell disease cannot and must not be made from either a sickle cell preparation or solubility test because neither of these tests will reliably distinguish sickle cell trait from sickle cell disease. The diagnosis of a specific sickle cell disorder can be readily established through an analysis of the alpha and beta globin gene complex by using techniques of molecular biology; however, these are not usually required. The clinician should rely on the clinical history, blood counts, peripheral blood smear, hemoglobin electrophoresis with measurement of the minor hemoglobins A 2 and F, and, when available, family studies that include hemoglobin electrophoresis and measurement of Hb A 2 and Hb F.
Table 1 summarizes the relationships between the clinical severity, blood counts, peripheral smear, Hb A 2 levels, and Hb S levels for the more common sickle cell disorders.
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