127 Sickle-Cell Anemia

Sickle-cell disease is an inherited disorder resulting from an abnormality in the structure of a protein in the red blood cell called hemoglobin. It represents a spectrum of disorders ranging from the full-blown form, sickle-cell anemia, to the carrier state called sickle-cell trait.

Sickle-cell trait occurs when the individual is het­erozygous for the sickle-cell gene and results in red blood cell concentrations of the abnormal hemoglobin (hemoglobin S) of less than 50 percent. It generally does not result in serious illness although this gener­alization has recently been disputed. In addition to sickle-cell trait, several sickle-cell syndromes occur when hemoglobin S is present in a heterozygous state with other hemoglobin variants - some with similar properties. Common examples of these include hemo­globin C and hemoglobin E.

Distribution and Incidence

Sickle-cell anemia is found in as many as 4 percent of Africans and in 1 percent of black Americans (1 per 500). Upward of 40 percent of Africans carry the sickle-cell trait as compared to 9 percent of black Americans. In some Mediterranean cultures the trait is also present. It is now generally believed that the sickle-cell gene mutation occurred independently in several areas of Africa. Therefore, its presence across several different peoples is easily explained.

Hemoglobin S is transmitted as an autosomal re­cessive gene. So if both parents have sickle-cell trait, the chances are 1 in 4 that any child born to them will have hemoglobin SS and thus sickle-cell ane­mia; 1 in 4 that it will have hemoglobin AA and be normal; and 2 in 4 that it will have hemoglobin AS and have the sickle-cell trait.

The pattern of death in persons who have sickle­cell anemia is bimodal, with the first peak occurring in childhood and the second occurring among people in their late 30s. Deaths during childhood are re­lated to infectious causes, whereas those during adulthood are due to organ failure from repeated tissue destruction.

Etiology

Hemoglobin is responsible for carrying oxygen in the bloodstream and is found inside the red blood cell. It is a protein made up of four chains called globins and four iron groups called heme. Each globin chain is composed of a series of building blocks called amino acids that in turn are built from the genetic material known as deoxyribonucleic acid (DNA). The structure of a particular piece of DNA determines the structure of a particular protein. In the case of sickle-cell anemia the structure of the DNA molecule is changed through a single genetic mutation and results in a change in the amino acid composition of the protein chain. This change is a substitution of valine for glutamic acid in the sixth position of the amino end of the molecule. This sim­ple substitution causes marked changes in the solu­bility and interactive properties of hemoglobin. Un­der appropriate conditions, this results in a dramatic conformational change in the red cell from a flexible biconcaved disk to an inflexible sickled cell.

Sickling results from a low oxygen state and tends to occur in the acidotic and hypertonic milieu of small blood vessels. It is a two-step process. Initially, small Submicroscopic aggregates of hemoglobin form, fol­lowed by rapid polymer formation into long tubular helical fibers that twist the red cell into the sickle shape. This fiber formation is reversible and results from noncovalent chemical bonds between hemoglo­bin molecules.

Sickling is also accompanied by a dynamic process at the cell membrane. Ion fluxes that occur normally at the membrane become disrupted during sickling, and a rapid influx of calcium occurs. This calcium is later pumped out of the cell by an energy-dependent mechanism utilizing an intercellular energy source known as adenosine triphosphate (ATP).

Functionally, hemoglobin S has a lower affinity for oxygen especially at low hydrogen-ion concentra­tions and increased tonicity. This results in early release of oxygen and the inability to oxygenate tissues adequately. In the sickled form, these cells have significant difficulty traversing the small vas- Culatnre of the capillary bed. Vascular occlusion and destruction of tissues result. The life-span of a single cell is also decreased from 120 to 60 days and is manifested as a hemolytic anemia. This condition results from a combination of acquired membrane abnormalities from recurrent sickling and destruc­tion of irreversibly sickled cells. There is also in­creased incidence of infection owing to gradual de­struction of the spleen and alterations in the im­mune system.

The presence of other forms of hemoglobin can modify the ability of hemoglobin S to form fibrils. One such hemoglobin is fetal hemoglobin. Hemoglo­bin F is normally present at birth in large concentra­tions. After birth its production is decreased and is replaced with adult hemoglobin (hemoglobin A), such that by 6 months of life the individual has hemoglobin in adult percentages. In some individu­als, however, hemoglobin F persists in abnormally high levels. This persistence of hemoglobin F alters the final hemoglobin concentration in the red blood cell and reduces the percentage of hemoglobin S in patients with sickle-cell disease. Hemoglobin F is a poor participant in hemoglobin S fibril formation and thus inhibits sickling. Clinically this results in a milder form of the disease and in some patients produces an asymptomatic state.

Clinical Manifestations

Sickle-cell disease can be diagnosed prenatally by a procedure known as amniocentesis. After birth the diagnosis is generally made by hemoglobin electro­phoresis using cord or peripheral blood. Early diag­nosis is now encouraged because of the benefits of new preventive therapies for infection.

Sickle-cell anemia is characterized clinically by a chronic hemolytic anemia and recurrent states called crises. These crisis states are further divided into three types: pain, sequestration, and aplastic.

Pain crisis is the most common and occurs on the average of three times a year. It first presents after 6 months of life when the level of fetal hemoglobin has decreased to a low level. At this age the first signs are often a painful inflammation of the bones of the hands or feet, known as the hand-foot syndrome. Older patients generally develop a recurrent syn­drome of joint, back, abdominal, or long-bone pain, which may last for approximately 7 days. Other seri­ous manifestations of vascular occlusion include strokes, heart attacks, leg ulcers, priapism, and pul­monary infarcts.

Splenic sequestration occurs when a large portion of the red cell mass becomes trapped in the spleen, resulting in acute shock. With age, recurrent vascu­lar occlusion of small blood vessels in the spleen results in functional destruction of this organ. Be­cause the spleen is required for destruction of cer­tain types of bacteria, patients with sickle-cell ane­mia are at increased risk of bacterial infections.

In rare instances, the blood-forming bone marrow becomes exhausted or suppressed for short periods of time, resulting in an acute reduction in red blood cells. This is known as red cell aplasia. This is a temporary condition but one that may require blood transfusions until the bone marrow recovers.

By contrast, sickle-cell trait occurs when individu­als’ genes carry only one hemoglobin S gene. These persons are phenotypically normal in most respects, although sickling has occasionally been reported to occur in these individuals at high altitudes or low oxygen tension, resulting in splenic infarction.

Various other hemoglobins have been shown to sickle in a manner similar to hemoglobin S. Careful chemical analysis is required to differentiate these from sickle hemoglobin.

History and Geography

Sickle-cell anemia has been traced back to at least 1670, where it was noted to be present in the Krobo tribe in Ghana. This disorder was first described clinically by James B. Herrick, a Chicago physician, in 1910. During the 10 years following Herrick’s report, three cases of sickle-cell anemia were re­ported. Thirteen years later, J. G. Huck reported a series of 14 patients and first noted the reversibility of sickling. In 1939 J. Bibb and L. W. Diggs described irreversibly sickled cells, and in 1946 M. Sherman demonstrated that hemoglobin S has an ordered structure. This finding encouraged Linus Pauling to investigate the physical chemistry of hemoglobin S by electrophoresis. On the basis of his findings he reasoned that the genetic basis of sickling was due to a single gene. V. M. Ingram, using peptide mapping techniques, then demonstrated that the condition resulted from a single amino acid substitution of valine for glutamic acid. M. Murayama noted that this change resulted in the loss of two negative charges and postulated that noncovalent interac­tions took place, resulting in hemoglobin stacking. In 1949 A. B. Raper noted the high incidence of sickle-cell trait in areas endemic for malaria and suggested that the trait protected against infesta­tion. But it was not until 1954 that geneticist A.

Further analysis of this observation showed that this gene change was the result of a genetic princi­ple known as balanced polymorphism. Generally a gene such as the sickle-cell gene, which results in severe morbidity and mortality, dies out in a popula­tion unless certain conditions result in a more favor­able survival. Such is the case with the sickle-cell gene. Africa and the Mediterranean are areas en­demic for the parasitePlasmodiumfalciparum, which causes a malignant form of malaria. But when per­sons with sickle-cell hemoglobin are infected with malaria, the infected cells tend to sickle and are selectively destroyed by the body’s immune system. Therefore, the sickle-cell gene promotes survival in persons infected with a disease that is potentially fatal and, paradoxically, prolongs survival. In parts of the world such as the United States where P. falciparum is no longer endemic, the sickle-cell gene becomes the sole determinant of morbidity and does not prolong life. This explains why the fre­quency of the sickle-cell gene has decreased in much of the Americas.

Georges C. Benjamin

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