Sickle cell disease
Risk Factors (Genetics & Inherited Conditions)
Individuals of African, Mediterranean, Middle Eastern, Indian, Central American, and Caribbean ancestry have the greatest chance of having a mutation in the beta globin gene (HBB). Approximately 1 in 12 individuals of African American ancestry have sickle-cell trait, which means approximately 1 in 600 babies born in the United States to African American parents have sickle-cell disease.
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Etiology and Genetics (Genetics & Inherited Conditions)
Sickle-cell disease was the very first example of a genetic disease being traced to its precise origin at the molecular level. The HBB gene, located on chromosome 11, encodes the main type of adult hemoglobin (hemoglobin A). Hemoglobin is the major protein in red blood cells whose properties allow it to bind with oxygen in the lungs and transport it to other parts of the body.
Sickle-cell anemia occurs when there is a single point mutation with one nucleotide (thymine instead of adenine) of the HBB gene. This causes a substitution of amino acids: Glutamic acid in the sixth codon is replaced by valine. The change of amino acids causes an absence in normal hemoglobin A production. Consequently, a structurally abnormal hemoglobin S is produced. For individuals with sickle-cell anemia, the mutation causes the hemoglobin molecules to stick to one another and changes the normally smooth and flexible, donut-shaped appearance of the red blood cell to a characteristic sickled crescent moon shape. This prevents red blood cells from traveling through tiny capillaries, especially under conditions of oxygen deprivation. On average, the life span of red blood cells of healthy individuals is 120 days before they are replaced by new cells. In individuals with sickle-cell disease, the red blood cells have a reduced life span of only 16 days.
Sickle-cell disease is inherited in an autosomal recessive manner. One...
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Symptoms (Genetics & Inherited Conditions)
Individuals with sickle-cell trait typically display no symptoms, although some have been known to become ill under extreme circumstances, such as high altitudes with decreased oxygen supply. Symptoms of sickle-cell disease typically appear about six to twelve months after birth, when the last of fetal hemoglobin(hemoglobin F), a type of hemoglobin that increases the oxygen supply of blood in pregnancy, decreases and hemoglobin S increases. The severity of the illness varies widely among individuals.
Individuals have varying degrees of red cell breakdown, which may cause a decrease in the amount of red blood cells (hemolytic anemia), jaundice, and physical weakness. The change in the red blood cell shape leads to a vaso-occlusive crisis (sickle-cell crisis), which causes a lack of oxygen to be delivered to the body’s tissues. Subsequently, this causes organ dysfunction and may cause significant pain in joints and bones. The organs that are most often involved include the spleen, lungs, brain, kidneys, and genitalia. Individuals typically have an enlarged spleen, and the compromised function predisposes mostly children but also adults to infections. The lungs may have significant life-threatening complications such as damage or changes to the lungs (acute chest syndrome), as well as a constriction of blood supply to the lungs (pulmonary hypertension). Other significant complications include the possibility of a stroke or blindness....
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Screening and Diagnosis (Genetics & Inherited Conditions)
The diagnosis of sickle-cell disease may be made by several different laboratory techniques. High-performance liquid chromatography (HPLC), isoelectric focusing (IEF), hemoglobin electrophoresis, and peripheral blood smear are all available testing options. Almost all cases of sickle-cell disease are diagnosed at birth. All fifty states currently provide newborn screening for sickle-cell disease by one of these methods. Sickledex (sickleprep, solubility test) is an outdated method of testing for sickle-cell disease, as an abnormal test result cannot distinguish sickle-cell trait from an affected individual, nor can it tell if an individual has a different form of sickle-cell disease from hemoglobin S/S. Molecular genetic testing is available to detect mutations in the HBB gene associated with sickle-cell disease. Mutation analysis is typically reserved for when sickle-cell trait is suspected to be inherited with another hemoglobin variant or for purposes of diagnosing a fetus in pregnancy.
Any individual planning a pregnancy or who is currently pregnant that is from the aforementioned ethnic backgrounds should be offered screening for sickle-cell disease. If a pregnancy is found to be at 25 percent risk for sickle-cell disease, then prenatal diagnosis is available. Prenatal diagnosis includes testing options of a chorionic villus sampling (CVS) at ten to twelve weeks of gestation or amniocentesis at approximately...
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Prevention and Outcomes (Genetics & Inherited Conditions)
Despite advancing treatments, there still exists no cure for sickle-cell disease. Stem cell transplantation, whereby an individual receives stem cells from an unaffected individual, has the potential to cure symptoms of sickle-cell disease. Clinical trials with animal models and human cell lines are ongoing. Bone marrow transplantation is similar in theory to stem cell transplantation, but an individual donating bone marrow must be related to the affected individual and be an immunological match. There are significant risks with this procedure that put the individual at risk for developing complications, such as bone marrow rejection, infection, bleeding, and possible death. Therefore, this is currently reserved for a select population of individuals.
It may be possible to prevent the onset of symptoms by proper fluid hydration, avoiding high altitudes with poor oxygenation and climates with extreme temperatures, and taking preventive medications. Penicillin is administered to all children to reduce infections, and vaccinations are also recommended to reduce the chance of other illnesses. A folic acid supplement may also be prescribed.
Current treatments include oral medication and fluid hydration for vaso-occlusive pain and crises. Typical medications that are prescribed for patients to manage their pain crisis at home include acetaminophen or ibuprofen. However, more severe pain crises require hospitalization...
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Further Reading (Genetics & Inherited Conditions)
ACOG Committee on Obstetrics “Hemoglobinopathies in Pregnancy.” Obstetrics and Gynecology 109 (2007): 229-237. Practice recommendations for carrier screening for sickle-cell disease and other blood disorders in or prior to pregnancy. Illustrations for testing algorithm.
MacMillin, M., ed. Ancestry Based Carrier Screening. Chicago: National Society of Genetic Counselors, 2005. A guide for which populations should be offered screening for sickle-cell disease and other genetic disorders. Tables for carrier frequency.
Pack-Mabien, A. “A Primary Care Provider’s Guide to Preventative and Acute Care Management of Adults and Children with Sickle-Cell Disease.” Journal of the American Academy of Nurse Practitioners 21 (2009): 250-257. In-depth coverage for symptoms and management of sickle-cell disease as well as new treatment options.
Serjeant, Graham R., and Beryl E. Serjeant. Sickle Cell Disease. 3d ed. New York: Oxford University Press, 2001. Discusses the biology of sickle-cell disease and the disease’s management. Illustrations, maps, bibliography, index.
Steinberg, Martin H., et al., eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Foreword by H. Franklin Bunn. New York: Cambridge University Press, 2001. Covers the diseases’ molecular and genetic bases, epidemiology and genetic selection, and diagnoses and...
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Web Sites of Interest (Genetics & Inherited Conditions)
American Sickle Cell Anemia Association. www.ascaa.org
Dolan DNA Learning Center, Your Genes Your Health. http://www.ygyh.org
Gene Reviews. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=sickle
Sickle Cell Disease Association of America. www.sicklecelldisease.org
Sickle Cell Information Center. http://www.scinfo.org
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Sickle cell disease
Causes and Symptoms (Magill’s Medical Guide, Sixth Edition)
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-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...
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Treatment and Therapy (Magill’s Medical Guide, Sixth Edition)
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...
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Perspective and Prospects (Magill’s Medical Guide, Sixth Edition)
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...
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For Further Information: (Magill’s Medical Guide, Sixth Edition)
Ballas, S. K. “Sickle Cell Anaemia: Progress in Pathogenesis and Treatment.” Drugs 62 (2002): 1143-1172. A clearly presented review of sickle cell anemia, with available treatment options described.
Edelstein, Stuart J. The Sickled Cell: From Myths to Molecules. Cambridge, Mass.: Harvard University Press, 1986. A historical description of ancient African cultural beliefs and how they correlated to the modern molecular understanding of sickle hemoglobinopathies.
Embury, Stephen H., Robert P. Hebbel, Narla Mohandas, and Martin H. Steinberg, eds. Sickle Cell Disease: Basic Principles and Clinical Practice. New York: Raven Press, 1994. Chapters 26, 30, 35, 38, and 40 offer an in-depth description of the molecular and biochemical nature of sickle hemoglobin and clinical correlations.
O’Malley, Paul D., ed. New Developments in Sickle Cell Disease Research. New York: Nova Science, 2006. Covers a range of topics, from psychobiological reactivity to acute chest syndrome.
Pauling, Linus, H. Itano, S. J. Singer, and I. C. Wells. “Sickle Cell Anemia: A Molecular Disease.” Science 110 (1949): 543-548. The discovery of the electrophoretic mobility of sickle Hb S as compared to normal Hb A defines the first molecular disease to be identified.
Powars, Darleen R. “Management of Cerebral Vasculopathy in Children with Sickle Cell Anaemia.”...
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Sickle cell disease (Encyclopedia of Genetic Disorders)
Sickle cell disease describes a group of inherited blood disorders characterized by chronic anemia, painful events, and various complications due to associated tissue and organ damage.
The most common and well-known type of sickle cell disease is sickle cell anemia, also called SS disease. All types of sickle cell disease are caused by a genetic change in hemoglobin, the oxygen-carrying protein inside the red blood cells. The red blood cells of affected individuals contain a predominance of a structural variant of the usual adult hemoglobin. This variant hemoglobin, called sickle hemoglobin, has a tendency to develop into rod-like structures that alter the shape of the usually flexible red blood cells. The cells take on a shape that resembles the curved blade of the sickle, an agricultural tool. Sickle cells have a shorter life span than normally-shaped red blood cells. This results in chronic anemia characterized by low levels of hemoglobin and decreased numbers of red blood cells. Sickle cells are also less flexible and more sticky than normal red blood cells, and can become trapped in small blood vessels preventing blood flow. This compromises the delivery of oxygen, which can result in pain and damage to associated tissues and...
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Sickle Cell Disease (Encyclopedia of Medicine)
Sickle cell disease describes a group of inherited blood disorders characterized by chronic anemia, painful events, and various complications due to associated tissue and organ damage.
The most common and well-known type of sickle cell disease is sickle cell anemia, also called SS disease. All types of sickle cell disease are caused by a genetic change in hemoglobin, the oxygen-carrying protein inside the red blood cells. The red blood cells of affected individuals contain a predominance of a structural variant of the usual adult hemoglobin. This variant hemoglobin, called sickle hemoglobin, has a tendency to polymerize into rod-like structures that alter the shape of the usually flexible red blood cells. The cells take on a shape that resembles the curved blade of the sickle, an agricultural tool. Sickle cells have a shorter life span than normally-shaped red blood cells. This results in chronic anemia characterized by low levels of hemoglobin and decreased numbers of red blood cells. Sickle cells are also less flexible and more sticky than normal red blood cells, and can become trapped in small blood vessels preventing blood flow. This compromises the delivery of oxygen, which can result in pain and damage to associated tissues and organs. Sickle cell disease presents with marked variability, even within...
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Sickle Cell Anemia (Encyclopedia of Children's Health)
Sickle cell anemia, also called sickle cell disease (SS disease), is an inherited condition caused by having abnormal hemoglobin, the protein that carries oxygen in the blood. People with sickle cell anaemia have sickle hemoglobin (HbS) which is different from the normal hemoglobin (HbA).
Children with sickle cell anemia produce two abnormal hemoglobin proteins (inheriting one from each parent), which makes their red blood cells easily destructible while giving them a sickle-like shape. Since the red blood cells do not have a normal shape, their circulation in the small blood vessels is impaired as well as the function of the abnormal hemoglobin (HbS) which can no longer carry oxygen with maximum efficiency.
Sickle cell anemia is usually inherited from parents who are carriers, who have the sickle cell trait milder form of sickle cell anemia, or one abnormal hemoglobin.
Sickle cell anemia and sickle cell trait are found mainly in people whose families come from Africa, the Caribbean, the Eastern Mediterranean, Middle...
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Sickle Cell Anemia (Encyclopedia of Alternative Medicine)
Sickle cell anemia, which is also known as meniscocytosis or sicklemia, is an inherited blood disorder that arises from a gene mutation. As a result, affected hemoglobin molecules have a tendency to stick to one another, forming abnormal strands of hemoglobin within the red blood cells. The cells that contain these strands become stiff and elongatedickle-shaped.
Because sickle cell anemia is characterized by the rapid loss of red blood cells as they enter the circulation, it is classified as a hemolytic anemia, "hemolytic" referring to the destruction of the cell membrane of red blood cells, resulting in the release of hemoglobin.
Sickle-shaped cells die much more rapidly than normal red blood cells and the body cannot create replacements fast enough. Anemia develops due to the chronic shortage of red blood cells. Further complications arise because sickle cells do not fit well through small blood vessels, and can become trapped. The trapped sickle cells form blockages that prevent oxygenated blood from reaching associated tissues and organs. The damaged tissues and organs cause considerable pain and can lead to serious complications, including stroke and an impaired immune system. Sickle cell anemia primarily affects people with African, Mediterranean, Middle Eastern, and...
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Sickle Cell Disease (Encyclopedia of Nursing & Allied Health)
Sickle cell disease describes a group of inherited blood disorders characterized by chronic anemia, painful events, and various complications due to associated tissue and organ damage.
The most common and well-known type of sickle cell disease is sickle cell anemia, also called SS disease. All types of sickle cell disease are caused by a genetic change in hemoglobin, the oxygen-carrying protein inside the red blood cells. The red blood cells of affected individuals contain a predominance of a structural variant of the usual adult hemoglobin. This variant hemoglobin, called sickle hemoglobin, has a tendency to polymerize into rod-like structures that alter the shape of the usually flexible red blood cells. The cells take on a shape that resembles the curved blade of a sickle, an agricultural tool. Sickle cells have a shorter life span than normally-shaped red blood cells. This results in chronic anemia characterized by low levels of hemoglobin and decreased numbers of red blood cells. Sickle cells are also less flexible and more sticky than normal red blood cells and can become trapped in small blood vessels preventing blood flow. This compromises the delivery of oxygen, which can result in pain and damage to associated tissues and organs. Sickle cell disease presents with marked variability, even within families.
Carriers of the sickle cell gene are said to have sickle cell trait. Unlike sickle cell disease, sickle cell trait does not cause health problems. In fact, sickle cell trait is protective against malaria, a disease caused by blood-borne parasites transmitted through mosquito bites. According to a widely accepted theory, the genetic mutation associated with the sickle cell trait occurred thousands of years ago. Coincidentally, this mutation increased the likelihood that carriers would survive malaria infection. Survivors then passed the mutation on to their offspring, and the trait became established throughout areas where malaria was common. As populations migrated, so did the sickle cell trait. Today, approximately one in 12 African Americans has sickle cell trait.
Worldwide, it has been estimated that one in every 250,000 babies is born with sickle cell disease. Sickle cell disease primarily affects people with African, Mediterranean, Middle Eastern, and Asian Indian ancestry. In the United States, sickle cell disease is most often seen in African Americans, in whom the disease occurs in one out of every 400 births. The disease has been described in individuals from several different ethnic backgrounds and is also seen with increased frequency in Latino Americans, particularly those of Caribbean, Central American, and South American ancestry. Approximately one in every 1,000,400 Latino births are affected.
Humans normally make several types of the oxygen-carrying protein hemoglobin. An individual's stage in development determines whether primarily embryonic, fetal, or adult hemoglobins will be made. All types of hemoglobin are made of three components: heme, alpha (or alpha-like) globin, and beta (or beta-like) globin. Sickle hemoglobin is the result of a genetic change in the beta globin component of normal adult hemoglobin. The beta globin gene is located on chromosome 11. The sickle cell form of the beta globin gene results from the substitution of a single DNA nucleotide, or genetic building-block. The change from adenine to thymine at codon (position) 6 of the beta globin gene leads to insertion of the amino acid valine instead of glutamic acid at this same position in the beta globin protein. As a result of this change, sickle hemoglobin has unique properties in comparison to the usual type of adult hemoglobin.
Most individuals have two normal copies of the beta globin gene, which make normal beta globin that is incorporated into adult hemoglobin. Individuals who have sickle cell trait (called sickle cell carriers) have one normal beta globin gene and one sickle cell gene. These individuals make both the usual adult hemoglobin and sickle hemoglobin in roughly equal proportions, so they do not experience any health problems as a result of having the trait. Although traces of blood in the urine and difficulty in concentrating the urine can occur, neither represents a significant health problem due to sickle cell trait. Of the millions of people with sickle cell trait worldwide, a small handful of individuals have experienced acute symptoms. In these very rare cases, individuals were subject to very severe physical strain.
When both members of a couple are carriers of sickle cell trait, there is a 25% chance in each pregnancy for their baby to inherit two sickle cell genes and have sickle cell anemia, or SS disease. Correspondingly, there is a 50% chance their baby will have sickle cell trait and a 25% chance that the baby will have the usual type of hemoglobin. Other types of sickle cell disease include SC disease, SD disease, and S/beta thalassemia. These conditions are caused by the co-inheritance of the sickle cell gene and another altered beta globin gene. For example, one parent may have sickle cell trait and the other parent may have hemoglobin C trait (another hemoglobin trait that does not cause health problems). For such a couple, there would be a 25% chance of SC disease in each pregnancy.
Causes and symptoms
Normal adult hemoglobin transports oxygen from the lungs to tissues throughout the body. Sickle hemoglobin can also transport oxygen. However, once the oxygen is released, sickle hemoglobin tends to polymerize (line-up) into rigid rods that alter the shape of the red blood cell. Sickling of the red blood cell can be triggered by low oxygen, such as occurs in organs with slow blood flow. It can also be triggered by cold temperatures and dehydration.
Sickle cells have a decreased life span in comparison to normal red blood cells. Normal red blood cells survive for approximately 120 days in the bloodstream; sickle cells last only 102 days. As a result, the bloodstream is chronically short of red blood cells and hemoglobin, and an affected individual develops anemia.
The sickle cells can create other complications. Due to their shape, they do not fit well through small blood vessels. As an aggravating factor, the outside surfaces of sickle cells may have altered chemical properties that increases their stickiness. These sticky sickle cells are more likely to adhere to the inside surfaces of small blood vessels, as well as to other blood cells. As a result of the sickle cells' shape and stickiness, blockages form in small blood vessels. Such blockages prevent oxygenated blood from reaching areas where it is needed, causing pain, as well as organ and tissue damage.
The severity of symptoms cannot be predicted based solely on the genetic inheritance. Some individuals with sickle cell disease may develop problems in infancy that affect their health or be life-threatening. Others may experience only mild symptoms throughout their lives. Individuals may experience varying degrees of health at different stages in the life cycle. For the most part, this clinical variability is unpredictable, and the reasons for the observed variability can not usually be determined. However, certain types of sickle cell disease (i.e., SC disease) tend to result in fewer and less severe symptoms on average than other types of sickle cell disease (i.e., SS disease). Some additional modifying factors are known. For example, elevated levels of fetal hemoglobin in a child or adult can decrease the quantity and severity of some symptoms and complications. Fetal hemoglobin is a normally occurring hemoglobin that usually decreases from over 90% of the total hemoglobin to under 1% during the first year of life. This change is genetically determined, although some individuals may experience elevated levels of fetal hemoglobin due to variation in the genes that control fetal hemoglobin production. Such individuals often experience a reduction in their symptoms and complications due to the ability of fetal hemoglobin to prevent the polymerization of sickle hemoglobin, which leads to sickling of the red blood cell.
There are several symptoms that warrant immediate medical attention, including the following:
- signs of infection (fever above 101°F or 38.3°C, coughs frequently or breathing trouble, unusual crankiness, feeding difficulties)
- signs of severe anemia (pale skin or lips, yellowing of the skin or eyes, very tired, very weak)
- signs indicating possible dehydration (vomiting, diar-rhea, fewer wet diapers)
- other signs (pain or swelling in the abdomen, swollen hands or feet, screams when touched)
The following can be signs of various complications that occur in sickle cell disease.
Infections and effects on the spleen
Children with sickle cell disease who are under age three are particularly prone to life-threatening bacterial infections. Streptococcus pneumoniae is the most common offending bacteria, and invasive infection from this organism leads to death in 15% of cases. The spleen, an organ that helps to fight bacterial infections, is particularly vulnerable to the effects of sickling. Sickle cells can impede blood flow through the spleen, causing organ damage, which usually results in the loss of spleen function by late childhood. The spleen can also become enlarged due to blockages and/or increased activity of the spleen. Rapid enlargement of the spleen may be a sign of another complication called splenic sequestration, which occurs mostly in young children and can be life-threatening. Widespread sickling in the spleen prevents adequate blood flow from the organ, removing increasing volumes of blood from the circulation and leading to accompanying signs of severe anemia.
Painful events, also known as vaso-occlusive events, are a hallmark symptom of sickle cell disease. The frequency and duration of the pain can vary tremendously from person to person and over an individual's life cycle. Painful events are the most common cause of hospitalizations in sickle cell disease. However, only a small proportion of individuals with sickle cell disease experience frequent and severe painful events. Most painful events can be managed at home. Pain results when small blood vessel blockages prevent oxygen from reaching tissues. Pain can affect any area of the body, although the extremities, chest, abdomen, and bones are frequently affected sites. There is some evidence that cold temperatures or infection can trigger a painful event, but most events occur for unknown reasons. The hand-foot syndrome, or dactylitis, is a particular type of painful event. Most common in toddlers, dactylitis results in pain and swelling in the hands and feet and is sometimes accompanied by a fever.
Sickle cells have a high turnover rate, and there is a deficit of red blood cells in the bloodstream. Common symptoms of anemia include fatigue, paleness, and a shortness of breath. A particularly severe form of anemia called aplastic anemia may occur following infection with parvovirus. Parvovirus infection causes extensive destruction of the bone marrow, bringing production of new red blood cells to a halt. Bone marrow production resumes after seven to 10 days. However, given the short lives of sickle cells, even a brief shut-down in red blood cell production can cause a rapid decline in hemoglobin concentrations.
The energy demands of the bone marrow for red blood cell production compete with the demands of a growing body. Children with sickle cell anemia may have delayed growth and reach puberty at a later age than normal. By early adulthood, they catch up on growth and attain normal height. However, their weight typically remains below average.
Children with sickle cell disease have a significantly elevated risk of having a stroke, which can be one of the most serious complications of sickle cell disease. Approximately 11% of individuals with sickle cell disease will have a recognizable stroke by the age of 20. Magnetic resonance imaging (MRI) studies have found that 17% of children with sickle cell anemia have evidence of a previous stroke or clinically 'silent' stroke-like events called transient ischemic attacks. Stroke in sickle cell disease is usually caused by a blockage of a blood vessel. However, approximately one-fourth of the time they may be caused by a hemorrhage (or rupture) of a blood vessel.
Strokes result in compromised delivery of oxygen to an area of the brain. The consequences of stroke can
range from life-threatening, to severe physical or cognitive impairments, to apparent or subtle learning disabilities, to undetectable effects. Common stroke symptoms include weakness or numbness that affects one side of the body, sudden behavioral changes, loss of vision, confusion, loss of speech or the ability to understand spoken words, dizziness, headache, seizures, vomiting, or even coma.
Approximately two-thirds of children who have a stroke will have at least one more. Transfusions have been shown to decrease the incidence of a second stroke. A recent study showed that children at highest risk to experience a first stroke were ten times more likely to stroke if untreated when compared to high-risk children treated with chronic blood transfusion therapy. High-risk children were identified using transcranial Doppler ultrasound technology to detect individuals with increased blood flow speeds due to constricted intracranial blood vessels.
Acute chest syndrome
Acute chest syndrome (ACS) is a leading cause of death for individuals with sickle cell disease, and recurrent attacks can lead to permanent lung damage. Therefore rapid diagnosis and treatment is of great importance. ACS can occur at any age and is similar but distinct from pneumonia. Affected persons may experience fever, cough, chest pain, and shortness of breath. ACS seems to have multiple causes including infection, sickling in the small blood vessels of the lungs, fat embolisms to the lungs, or a combination of factors.
Males with sickle cell anemia may experience priapism, a condition characterized by a persistent and painful erection of the penis. Due to blood vessel blockage by sickle cells, blood is trapped in the tissue of the penis. Priapism may be short in duration or it may be prolonged. Priapism can be triggered by low oxygen (hypoxemia), alcohol consumption, or sexual inter-course. Since priapism can be extremely painful and can result in damage to this tissue (causing impotence), rapid treatment is essential.
The internal environment of the kidney is particular-ly prone to damage from sickle cells. Signs of kidney damage can include blood in the urine, incontinence, and enlarged kidneys. Adults with sickle cell disease often experience insufficient functioning of the kidneys, which can progress to kidney failure in a small percentage of adults with sickle cell disease.
Jaundice and gallstones
Jaundice is indicated by a yellow tone in the skin and eyes, and alone it is not a health concern. Jaundice may occur if bilirubin levels increase, which can occur with high levels of red blood cell destruction. Bilirubin is the final product of hemoglobin degradation, and is typically removed from the bloodstream by the liver. Therefore, jaundice can also be a sign of a poorly functioning liver, which may also be evidenced by an enlarged liver hepatomegaly. Increased bilirubin also leads to increased chance for gallstones in children with sickle cell disease. Treatment, which may include removal of the gall bladder, may be selected if the gallstones start causing symptoms.
The blood vessels that supply oxygen to the retina, the tissue at the back of the eye, may be blocked by sickle cells, leading to a condition called retinopathy. This is one of the only complications that is actually more common in SC disease as compared to SS disease. Retinopathy can be identified through regular ophthalmology evaluations and effectively treated in order to avoid damage to vision.
Avascular necrosis of the hip and shoulder joints, in which bone damage occurs due to compromised blood flow due to sickling, can occur later in childhood. This complication can affect an individual's physical abilities and result in substantial pain.
In the United States, African Americans and Latino Americans have the highest risk of having the disease or trait. Sickle cell is also common among individuals of Mediterranean, Middle Eastern, and Eastern Indian descent. Individuals from these areas of ethnic groups should consider screening for sickle cell disease.
A complete blood count (CBC) will describe several aspects of an individual's blood cells. A person with sickle cell disease will have a lower than normal hemoglobin level, together with other characteristic red blood cell abnormalities. Hemoglobin electrophoresis is a test that can help identify the types and quantities of hemoglobin made by an individual. This test uses an electric field applied across a slab of gel-like material. Hemoglobins migrate through this gel at various rates and go to specific locations, depending on their size, shape, and electrical charge. Although sickle hemoglobin (Hb S) and regular adult hemoglobin (called Hb A) differ by only one amino acid, they can be clearly separated using hemoglobin electrophoresis. Isoelectric focusing and high-performance liquid chromatography (HPLC) use similar principles to separate hemoglobins and can be used instead of or in various combinations with hemoglobin electrophoresis to determine the types of hemoglobin present.
Another test, called the 'sickledex' can help confirm the presence of sickle hemoglobin, although this test cannot provide accurate or reliable diagnosis when used alone. When Hb S is present, but there is an absence or only a trace of Hb A, sickle cell anemia is a likely diagnosis. Additional beta globin DNA test that directly assays the beta globin gene can be performed to help confirm the diagnosis and establish the exact genetic type of sickle cell disease. CBC and hemoglobin electrophoresis are also typically used to diagnosis sickle cell trait and various other types of beta globin traits.
Diagnosis of sickle cell disease can occur under various circumstances. If an individual has symptoms that are suggestive of this diagnosis, the above-described screening tests can be performed followed by DNA testing, if indicated. Screening at birth using HPLC or a related technique offers the opportunity for early intervention. More than 40 states include sickle cell screening as part of the usual battery of blood tests done for newborns. This allows for early identification and treatment. Hemoglobin trait screening is recommended for any individual of a high-risk ethnic background who may be considering having children. When both members of a couple are found to have sickle cell trait, or other related hemoglobin traits, they can receive genetic counseling regarding the risk of sickle cell disease in their future children and various testing options.
Sickle cell disease can be identified before birth through the use of prenatal diagnosis. Chorionic villus sampling (CVS) can be offered as early as 10 weeks of pregnancy and involves removing a sample of the placenta made by the baby and testing the cells. CVS carries a risk of causing a miscarriage that is between 0.5 and 1%.
Amniocentesis is generally offered between 15 and 22 weeks of pregnancy, but can sometimes be offered earlier. Two to three tablespoons of the fluid surrounding a baby are removed. This fluid contains fetal cells that can be tested. Although both tests carry a risk of causing a miscarriage, the risk is not greater than 1%. Pregnant woman and couples may choose prenatal testing in order to prepare for the birth of a baby that may have sickle cell disease. Alternately, knowing the diagnosis during pregnancy allows for the option of pregnancy termination.
Preimplantation genetic diagnosis (PGD) is a relatively new technique that involves in-vitro fertilization followed by genetic testing of one cell from each developing embryo. Only the embryos unaffected by sickle cell disease are transferred back into the uterus. PGD is currently available on a research basis only and is relatively expensive.
There are several practices that are intended to prevent some of the symptoms and complications of sickle cell disease. These include preventative antibiotics, good hydration, immunizations, and access to comprehensive care. Maintaining good health through adequate nutrition, avoiding stresses and infection, and getting proper rest is also important. Following these guidelines usually improves the health of individuals with sickle cell disease.
Infants are typically started on a course of penicillin that extends from infancy to age six. Use of this antibiotic is meant to ward off potentially fatal infections. Infections at any age are treated aggressively with antibiotics. Vaccines for common infections, such as pneumococcal pneumonia, are also recommended.
Pain is one of the primary symptoms of sickle cell anemia, and controlling it is an important concern. The methods necessary for pain control are based on individual factors. Some people can gain adequate pain control through over-the-counter oral painkillers (analgesics). Others individuals or painful events may require stronger methods, which can include administration of narcotics. Alternative therapies may be useful in avoiding or controlling pain, including relaxation, hydration, avoiding extremes of temperature, and the application of local warmth.
Blood transfusions are not usually given on a regular basis but are used to treat individuals with frequent and severe painful events, severe anemia, and other emergencies. In some cases blood transfusions are given as preventive measures, for example to treat spleen enlargement (splenomegaly) or prevent a second stroke (or a first stroke in an individual shown to be at high risk).
Regular blood transfusions have the potential to decrease formation of hemoglobin S, and reduce associated symptoms. However, there are limitations and risks associated with regular blood transfusions, including the risk of blood-borne infection and sensitization to proteins in the transfused blood that can make future transfusions very difficult. Most importantly, chronic blood transfusions can lead to iron overload. The body tends to store excess iron, such as that received through transfusions, in various organs. Over time, this iron storage can cause damage to various tissues and organs, such as the heart and endocrine organs.
Some of this damage can be prevented by the administration of a medication called desferrioxamine that helps the body to eliminate excess iron through the urine. Alternately, some individuals receive a new, non-standard treatment called erythrocytophoresis. This involves the automated removal of sickle cells and is used in conjunction with a reduced number of regular transfusions. This treatment also helps to reduce iron overload.
Emphasis is being placed on developing drugs that treat sickle cell anemia directly. The most promising of these drugs in the beginning of the twenty-first century is hydroxyurea, a drug that was originally designed for anti-cancer treatment. Hydroxyurea has been shown to reduce the frequency of painful crises and acute chest syndrome in adults, and to lessen the need for blood transfusions. Hydroxyurea, and other related medications, seem to work by inducing a higher production of fetal hemoglobin. The major side effects of the drug include decreased production of platelets, red blood cells, and certain white
Amino acid type of molecule used as a building block for protein construction.
Anemia condition in which the level of hemoglobin or the number of red blood cells falls below normal values. Common symptoms include paleness, fatigue, and shortness of breath.
Bilirubin yellow pigment that is the end result of hemoglobin breakdown. Bilirubin is cleared from the blood by action of liver enzymes and excreted from the body.
Bone marrow spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones. Bone marrow is the site of blood cell generation.
Bone marrow transplantation medical procedure in which normal bone marrow is transferred from a healthy donor to an ailing recipient. An illness such as sickle cell anemia that prevents production of normal blood cells may be treated with a bone marrow transplant.
Globinne of the component protein molecules found in hemoglobin. Normal adult hemoglobin has a pair each of alpha-globin and beta-globin molecules.
Hemehe iron-containing molecule in hemoglobin that serves as the site for oxygen binding.
Hemoglobinhe red pigment found within red blood cells that enables them to transport oxygen throughout the body. Hemoglobin is a large molecule composed of five components: a heme molecule and two pairs of globin molecules.
Hemoglobin Aormal adult hemoglobin contains a heme molecule, two alpha-globin molecules, and two beta-globin molecules.
Hemoglobin electrophoresis laboratory test that separates molecules based on their size, shape, or electrical charge.
Hemoglobin Semoglobin that is produced in association with the sickle cell trait. The beta-globin molecules of hemoglobin S are defective.
Hydroxyurea drug that has been shown to induce production of fetal hemoglobin. Fetal hemoglobin has a pair of gamma-globin molecules in place of the typical beta-globins of adult hemoglobin. Higher-than-normal levels of fetal hemoglobin can prevent sickling from occurring.
Impotencehe inability to have a penile erection, which can be due to tissue damage resulting from sickling within the penis (priapism).
Iron overload side effect of frequent transfusions in which the body accumulates abnormally high levels of iron. Iron deposits can form in organs, particularly the heart, and cause life-threatening damage.
Jaundice condition characterized by higher-than-normal levels of bilirubin in the bloodstream and an accompanying yellowing of the skin and eyes.
Mutation change in a gene's DNA. Whether a mutation is harmful is determined by the effect on the product for which the gene codes.
Magnetic resonance imaging type of imaging technique that allows the visualization of internal structures, such as the brain.
Narcotictrong, prescription medication that can be effective in treating sickle cell pain. Narcotics have the potential to be habit-forming if their use is not adequately supervised.
Nucleic acid type of chemical that is used as a component for building DNA. The nucleic acids found in DNA are adenine, thymine, guanine, and cytosine.
Ophthalmologyhe medical specialty of vision and the eye.
Placentahe organ responsible for oxygen and nutrition exchange between a pregnant mother and her developing baby.
Red blood cellemoglobin-containing blood cells that transport oxygen from the lungs to tissues. In the tissues, the red blood cells exchange their oxygen for carbon dioxide, which is brought back to the lungs to be exhaled.
Screeningrocess through which carriers of a trait may be identified within a population.
Sickle cell red blood cell that has assumed a elongated shape due to the presence of hemoglobin S.
blood cells. The effects of long-term hydroxyurea treatment are unknown.
Bone marrow transplantation
Bone marrow transplantation has been shown to cure sickle cell anemia in some cases. This treatment is reserved primarily for severely affected children with a healthy donor whose marrow proteins match those of the recipient, namely a brother or sister who has inherited the same tissue type. Indications for a bone marrow transplant are stroke, recurrent acute chest syndrome, and chronic unrelieved pain.
Bone marrow transplantations tend to be the most successful in children. Adults have a higher rate of transplant rejection and other complications. There is approximately a 10% fatality rate associated with bone marrow transplants performed for sickle cell disease. Survivors face potential long-term complications, such as chronic graft-versus-host disease (an immune-mediated attack by the donor marrow against the recipient's tissues), infertility, and development of some forms of cancer. A relatively recent advance in transplantation involves the use of donor stem cells obtained from cord blood, the blood from the placenta that is otherwise discarded following the birth of a new baby. Cord blood cells, as opposed to fully mature bone marrow cells, appear to be less likely to result in graft-versus-host disease in a recipient. This increases the safety and efficacy of the transplant procedure.
Certain surgical interventions are utilized in the treatment of specific sickle cell-related complications. Removal of a dysfunctional gallbladder (cholecystectomy) or spleen (splenectomy) can often lead to improvements in health. Investigations are currently underway to establish the efficacy of hip coring surgery, in which a portion of affected bone is removed to treat avascular necrosis of the hip. The hope is that this may provide an effective treatment to alleviate some pain and restore function in an affected hip.
As in any lifelong, chronic disease, comprehensive care is important. Assistance in coping with the emotional, social, family-planning, economic, vocational, and other consequences of sickle cell disease can enable affected individuals to better access and benefit from their medical care providers.
Sickle cell disease is characteristically variable between and within affected individuals. Predicting the course of the disorder based solely on genes is not possible. Several factors aside from genetic inheritance determine the prognosis for affected individuals, including the frequency, severity, and nature of specific complications in any given individual. The availability and access of comprehensive medical care also plays an important role in preventing and treating serious, acute complications that cause the majority of sickle cell-related deaths. For those individuals who do not experience such acute events, life-expectancy is probably substantially greater than the average for all people with sickle cell disease. The impact of recent medical advances supports the hypothesis that current life-expectancies may be significantly greater than those estimated in the early 1990s. At that time, individuals with SS disease lived, on average, to their early-to mid-40s, and those with SC disease lived into the upper 50s. With early detection and comprehensive medical care, most people with sickle cell disease enjoy fairly good health throughout most of their lives. Most individuals can be expected to live well into adulthood, enjoying an improved quality of life including the ability to choose a variety of education, career, and family-planning options for themselves.
Health care team roles
Sickle cell disease is often initially identified as a result of a screening test. This may be ordered by a pediatrician, obstetrician or family physician. A phlebotomist or nurse often obtains a sample of blood. A laboratory technician processes the sample. A pathologist or hematologist analyzes the results of a test. A family doctor may return results to individuals who have been tested. A genetic counselor or other person with training in test interpretation and ethics must be available to assist tested persons to accurately assess their options in the future.
Inheritance of sickle cell disease or trait cannot be prevented, but it may be predicted. Screening is recommended for individuals in high-risk populations.
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American Academy of Pediatrics. 141 Northwest Point Boulevard, Elk Grove Village, IL 60007-1098. (847) 434-4000. Fax: (847) 434-8000. <<a href="http://www.aap.org/default.htm">http://www.aap.org/default.htm>. firstname.lastname@example.org.
American Society of Hematology. 1900 M Street NW, Suite 200, Washington, DC 20036. (202) 776-0544. Fax: (202) 776-0545. <<a href="http://www.hematology.org">http://www.hematology.org>. email@example.com.
Sickle Cell Disease Association of America, Inc. 200 Corporate Pointe, Suite 495, Culver City, California 90230-8727. (310) 216-6363 or (310) 215-3722. Fax:(800) 421-8453. <<a href="http://www.sicklecelldisease.org">www.sicklecelldisease.org>. firstname.lastname@example.org.
American Academy of Family Physicians. <<a href="http://www.aafp.org/afp/20000901/1027ph.html">http://www.aafp.org/afp/20000901/1027ph.html> and <<a href="http://www.aafp.org/afp/20000901/1013.html">http://www.aafp.org/afp/20000901/1013.html>.
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L. Fleming Fallon, Jr., MD, DrPH
Sickle Cell Disease (Encyclopedia of Public Health)
The sickle cell diseases are a group of disorders that have in common the propensity of the red blood cells to become deformed when oxygen tension in the blood is lowered, causing anemia, occlusion of blood vessels by misshapen cells, and various associated clinical consequences, including death. In sickle cell disease, a mutation of the beta-globin gene results in the substitution of valine for glutamic acid in the sixth amino acid of the chain, producing a hemoglobin, designated hemoglobin S, that has less solubility than does normal hemoglobin A. Inheriting one gene for hemoglobin S, together with a normal gene, results in the formation of red cells that contain approximately 40 percent of the abnormal hemoglobin and 60 percent of the normal hemoglobin, an essentially harmless state that is designated as sickle cell trait. But if the gene inherited together with the sickle gene is not normal, then the sickle cell disease may develop. The most common hemoglobin that interacts with sickle hemoglobin is hemoglobin C, and the thalassemia (beta-thalassemia) mutation also interacts with the sickle gene by restricting the formation of normal hemoglobin.
The sickle gene, and genes that interact with it, are common in a number of different populations, but the highest gene frequencies are observed in Africa. The gene is also found in southern Europe, the Middle East, and India. A single dose of the sickle gene provides protection against malaria. Since malaria was a major cause of death in Africa, persons who carried the sickle gene had a survival advantage over those who did not. Thus, the number of persons carrying this mutation has tended to increase generation after generation in areas where malaria was a major killer. Among African Americans, approximately 7.8 percent are carriers of the sickle mutation, that is, they have sickle cell trait; while 2.3 percent have hemoglobin C trait (one copy of the hemoglobin C gene); and0.8 percent have thalassemia trait.
Although a single copy of the hemoglobin S gene is quite harmless, if a person inherits two copies of the hemoglobin S genes, he or she will have sickle cell disease. If one hemoglobin S gene and one hemoglobin C gene are inherited, the patient has hemoglobin S-C disease. Coinheritance of the beta-thalassemia and sickle hemoglobin result in sickle cell thalassemia. Patients with these three disorders have a similar clinical disease. Anemia occurs as a result of the rapid destruction of red blood cells. The red cells may have the shape of sickles, hence the term "sickle cell disease." However, the cells may assume may other forms. The misshapen red cells occlude blood vessels and cause pain and even tissue death.
In small children, one of the great problems incident to sickle cell disease is infections. If these are treated promptly, most children with sickle cell disease survive into adult life. One of the most characteristic manifestations of the disease in adults and older children is "pain crises." These occur at regular intervals, often at a time of stress, and may cause frequent hospitalizations and varying degrees of dependence upon pain-killing drugs. As patients with the sickle cell disease grow older they begin to suffer from the results of accumulated damage in small blood vessels all through the body. Dysfunction of the lungs, kidneys, and heart are common. Strokes may occur. Interruption of the blood supply to bones may result in areas of bone death, particularly in the hips.
Although sickle cell disease is a disorder that has been better understood and studied in more detail than most other disorders, treatment is still very unsatisfactory. Prenatal diagnosis can be carried out quite easily and very reliably, and parents are provided with the option of terminating the pregnancy. Antibiotics and immunization programs have drastically reduced the mortality rate among young children. Transfusion of red blood cells improves the flow properties of blood and may ameliorate the symptoms. Hydroxyurea has been administered to increase the amount of fetal hemoglobin, a hemoglobin that does not interact with sickle hemoglobin. This treatment has met with some success.
The disease is cured by bone marrow transplantation, a procedure with a relatively high risk, even in those patients in whom a match can be found. Ultimately the disease may be treated by putting a normal beta-globin gene into a stem cell of the patient, and then transplanting that patient with his or her own transduced cells, but there are many barriers to implementing such a strategy. Because stem cells do not divide often, they are relatively resistant to many gene-transfer methods. It is not enough to put a normal globin gene in the cell; the abnormal globin gene needs to be inactivated. There is also a tendency for normal human cells to shut off the function of foreign genes that are implanted in them. It is likely that these technical obstacles to gene therapy will be overcome eventually, and that the treatment of this group of diseases will give better results in the future.
(SEE ALSO: Genes; Genetic Disorders; Hemoglobin; Hemoglobinopathies; Malaria; Medical Genetics)