What is sickle cell disease?

Causes and Symptoms

Sickle cell disease is a genetic disorder of hemoglobin, which gives the red color to blood. The hemoglobin
molecule is made up of two pairs of globin polypeptide chains (two α chains and two β chains) and four heme molecules containing iron. Normal hemoglobin (hemoglobin A) is a remarkable protein that changes the biophysical configuration of its amino acid chains so that it can deliver oxygen safely to the tissues without oxidizing iron. Oxygen removal occurs during each cycle of blood flow from the lungs to the tissues. Sickle hemoglobin has a single amino acid substitution of valine for glutamic acid at the sixth position from the end of the β chain. Sickle hemoglobin has the unfortunate propensity to condense as rods in red blood cells when the oxygen is removed during the normal circulation of the blood. These rods distort the cells, making them stiff and rigid and unable to transverse the smaller blood vessels rapidly. The result is vasocclusion (obstruction) of the small and medium-sized blood vessels, damaging the endothelial inner lining of the blood vessel and thereby resulting in tissue necrosis (ischemia).

The most common genotypes of sickle cell disease are sickle cell anemia, or homozygous sickle cell disease (SS disease); sickle cell hemoglobin C disease (SC disease); sickle cell β0
thalassemia (Sβ0
thalassemia); and sickle cell β0 thalassemia (Sβ0 thalassemia). Less common genotypes include sickle cell hemoglobin E disease (SE disease), sickle cell hemoglobin D Los Angeles (SD Los Angeles), and sickle cell hemoglobin O Arab (SO Arab). In addition to these conditions, more than four hundred other abnormal human hemoglobins can combine with sickle hemoglobin. This genetic heterogeneity accounts for the wide spectrum of clinical severity in patients with sickle cell disease, with some forms essentially asymptomatic, such as Hb SE or S deer lodge.

Sickle cell anemia
(SS disease) is the most common and the most severe form of sickle cell disease. It results from the inheritance of the sickle cell gene from both parents. Its hallmark clinical manifestations are anemia and severe episodes of pain; similar but less frequent manifestations are seen with other forms of sickle cell disease. In sickle cell anemia, anemia is caused by the rapid destruction of the red blood cells as they circulate because of a shortened peripheral survival time of less than 30 days (normal is 120 days).

Acute painful episodes—particularly in the older child, adolescent, or adult—are characteristic of sickle cell anemia. Sickle cell crisis often begins with pain in the abdomen or extremities and joints. Painful sickle crisis in the young child is usually precipitated by an acute fever, with excruciatingly tender swelling of the hands and feet (dactylitis) caused by small infarctions of the small growing bones of the hands and feet. Approximately 25 percent of SS patients have endless and repeated painful episodes throughout life requiring frequent hospital care.

The clinical course of sickle cell anemia involves intermittent episodes of acute painful illnesses interspersed with periods of clinical quiescence and relative well-being. Commonly occurring acute complications necessitating intensive medical care are septicemia and meningitis during childhood, recurrent sickle cell pain crises, cerebral infarction with stroke, acute chest
syndrome (often termed pneumonia), severe upper respiratory tract infections, gallbladder disease with gallstones, aplastic crisis, hypersplenism with splenic sequestration crisis, bone infarctions, priapism (a painful erection of the penis not associated with sexual desire), and pyelonephritis (infection of the kidney).

An increased incidence of invasive infections caused by the bacteria
Streptococcus pneumoniae is found in children with SS disease who are between the ages of four months and five years; this is thirty to one hundred times that which would be expected in a healthy population of the same race and age. Blood infections in SS infants and young children are associated with a rapid elevation of temperature, often to 104 degrees Fahrenheit, and the patient becomes even more anemic. In the untreated patient, death occurs within eight to twelve hours.

Chronic major organ failure in SS disease is the direct consequence of irreversible and ongoing damage to the endothelial lining of the small blood vessels as a result of sickle cells (sickle vasculopathy). Vascular damage begins years before the overt clinical symptoms are apparent. The spleen is the first organ to be destroyed, usually by five years of age. During childhood (three to ten years of age), 10 percent of children with this disease will have strokes
, with resulting severe brain damage. Strokes cause paralysis and weakness of the extremities and difficulties in learning. This devastating complication in young children often makes functioning in school or living as self-sustaining adults difficult. Brain
infarction can be accurately identified using computed tomography (CT) brain scans, magnetic resonance imaging (MRI), positron emission tomography (PET), and other diagnostic procedures. Sickle
vasculopathy eventually culminates in young adulthood as end-stage kidney failure (glomerulosclerosis), sickle chronic restrictive lung disease, intracranial hemorrhages and brain damage, retinopathy with blindness, disabling leg ulcers, and painful generalized osteonecrosis of many of the bones of the body. Specialized medical care is required for the diagnosis and management of these permanent incurable complications.

Treatment and Therapy

Most acute complications of SS disease can be treated successfully so that the patient can attend school, be involved in social activities, and have a pleasant childhood and adolescence. Intensive care units with sophisticated monitoring equipment that are dedicated to infants and young children can manage and maintain the vital function of patients during severe illness episodes.

The institution of appropriate immunization programs for children with sickle cell anemia has substantially decreased their mortality and morbidity throughout the world. The importance of preventing the usual childhood infectious diseases such as hepatitis, whooping cough (pertussis), red measles (rubeola), rubella (German measles), diphtheria, tetanus, mumps, poliomyelitis, and Hemophilus influenzae
septicemia allows 90 percent of these children to reach adulthood. The use of prophylactic antibiotics such as penicillin during young childhood (four months to five years) decreases the incidence of invasive pneumococcal blood infections. However, a recent ominous increase has been seen in penicillin resistance to pneumococcal serotype-specific strains, making prophylactic antibiotic prevention less effective. Salmonella contamination of chicken is still a major source of septicemia and salmonella
osteomyelitis (bone infection).

Over time, children with sickle cell disease and their families begin to recognize the things that may precipitate a painful sickle cell crisis. Severe episodes require hospitalization and analgesic treatment, often with narcotic agents in addition to intravenous fluids.

Perspective and Prospects

Sickle cell anemia is the prototypical molecular disease. The causative gene modifying the chemical structure of the hemoglobin β chain (βA to βS)—replacing the amino acid glutamic acid with valine—originated in Africa. The disorder was transmitted to the United States, Arabia, Europe, and South and Central America as part of the slave trade. At that time, healthy persons carrying the sickle gene, who are said to have sickle cell trait, survived the rigors of a slave ship. As persons carrying the sickle cell trait migrated throughout the North and South American continents and Europe, genetic drift occurred, accounting for the 15 percent of patients with the various forms of sickle cell disease who are not phenotypically African in appearance.

Improvements in acute medical care during childhood and in the social and environmental situation for patients, as factors taken together, have made it possible for most children with sickle cell anemia and other forms of sickle cell disease to survive childhood. In the United States, Great Britain, and most European countries, umbilical cord blood diagnosis or peripheral blood sampling of newborns can diagnose the disorder at birth. This allows the children to be provided with responsive, knowledgeable medical care and complete immunizations early in life.

The current focus of clinical investigations is prevention of the tissue destruction induced by the repeated endothelial damage caused when sickle cells obstruct blood vessels. Such prevention requires lifelong medical treatment. Drugs that can modify the rate of hemoglobin polymerization (precipitation) in the red blood cells include hydroxyurea, cytosine arabinoside, 5-azosididine, and other agents that increase the amount of fetal hemoglobin in red blood cells. By increasing the fetal hemoglobin, the rate of polymerization of hemoglobin S is modified so that there is less propensity for insoluble rods to be formed. The membranes of red blood cells become more flexible, allowing the cells to traverse the microvasculature and thereby decreasing the damage to blood vessels. Adhesion molecules (such as VCAM-1) act to provide the glue that binds the damaged sickle cell to the inner lining of the blood vessel, inducing permanent endothelial damage. An intensive search is underway to identify blocking agents for these adhesion molecules that can prevent the blood vessel occlusion.

Bone marrow transplantation

with normal bone marrow (normal red blood cell precursors) from a donor with identical human leukocyte antigens (HLAs) is the only cure now available for sickle cell anemia. Bone marrow
transplantation is limited by the paucity of HLA-compatible sibling donors who do not have sickle cell anemia.

Gene therapy holds the promise of a cure but has not been successfully developed for use in patients with sickle cell anemia. The advantage of gene therapy is that no HLA-compatible donor is required.

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