Introduction
Sickle Cell Anemia or Sickle Cell Disease is an inherited blood ailment. Those suffering from Sickle Cell Disease have abnormal S/ sickle hemoglobin in the red blood cells. Hemoglobin is the protein in the blood that aids in carrying oxygen throughout the body. The ailment takes its appellation from the shape of the red blood cells of a person affected by Sickle Cell Disease, which have the shape of a sickle. They are stiff and adhesive rather than a disk like normal cells. The misshapen cells tend to get trapped in the small blood vessels hindering the movement of blood and oxygen to the many areas of one’s body. This causes pain and organ damage. Hemoglobin molecules are comprised of an alpha and a beta. People with Sickle Cell Disease have an aberration occurring in a gene in their chromosomes 11 and 16. ("Sickle Cell Disease.") Chromosome 11 is the “gene that codes for the beta subunit of the hemoglobin protein” ("Sickle Cell Disease.") This causes the particles in the hemoglobin not to manifest accurately.
History
Sickle Cell Disease was first acknowledged in 1910 after a dental student became ill with respiratory issues (Herrick 1063). Subsequent testing revealed that the patient’s red blood cells were sickle shaped. However, Herrick was unable to determine at the time, whether the patient’s red blood cells were causing his illness or if they were symptomatic of another disease. (Herrick 1063). Within the next fifteen years there would be several more cases. It was then suggested by Gillespie and Hahn that anoxia could be the cause of the sickle shaped red blood cells. They prove their theory by demonstrating how carbon dioxide could cause sickling by saturating a suspended cell with carbon dioxide. (Hahn 233). Afterwards Waugh and Scriver would further prove the idea laid out by Hahn and Gillespie by encouraging intravenous inertia in a finger using a rubber band. In doing this experiment they were able to demonstrate that hypoxia that was stasis-induced increased the number of sickle cells from 15% to 95% (Steinberg 53). Then in 1945 Linus Pauling began to theorize that the disease may have come as a result of an anomaly in the molecular structure of the hemoglobin molecule (Pauling 132-135). This theory would be validated by 1949 when Pauling could demonstrate his argument by showing how the different migration of the sickle shaped cells versus normal red blood cells using gel electrophoresis (Pauling, et al. 545). Also in 1949 it would be discovered that the disease could be inherited as an autosomal recessive disorder. (Neel 65)
Normal Hemoglobin
The hemoglobin of humans is found in a cluster on chromosomes 11 and 16. They are shown to function in a regulatory manner and are the tetramers of two pairs of -like and -like globin chains. Both fetal and adult hemoglobin consists of “Hb A, (Hb A2, or chains (Hb F, whereas in the embryo, -like chains—termed (Hb Portland, or —and and chains form Hb Gower 2 “(Makani, et al. 3). The hemoglobin of a developing fetus is restricted to the yolk sac and after birth the synthesis of the hemoglobin in primarily in the liver. During fetal development, the main type of hemoglobin is HB-F and when a child that is affected with sickle cell disease is born there is a change from fetal to adult expression of the hemoglobin gene. This occurs around six months of age. However, many people still produce small amounts of HB-F hemoglobin along with the HB-A hemoglobin they are now producing. (Makani, et al. 3-4)
Genetics of the Disease
Pauling’s studies showed that SCD was a result of a imperfection on the molecular structure of the hemoglobin molecule and later in the same year it would be found that the disease was autosomal recessive. Then several years later it would be determined by Ingram and others that the disease is caused by a “glutamine-to-valine substitution at the sixth residue of the β-globin polypeptide” (Ingram 408). Then in the 2000’s the globin genes of humans were cloned and the DNA sequence was determined. The globin gene clusters were also identified and organized, which helped to give geneticists insight into how they were expressed within the body (Stamatoyannopoulos 265-67). It was discovered during this time that the hemoglobin in a person’s body is a tetrameric molecule consisting of two pairs of matching polypeptide subunits, each housing a different pair of genes. These are “the human α-like globin genes (ζ, α1, and α2) which are situated on chromosome 16, and the β-like globin genes (ε, Gγ, Aγ, δ, and β) are positioned on chromosome 11 (Bank 435-443). The transcription of the globin gene causes mRNA precursors to be expressed in the nucleus. Theses precursors are processed into mature globin mRNAs in the cytoplasm. It is during this process that the inner machinations of the cell, including ribosomes and enzymes produce globin which then combine with heme to form the normal human hemoglobin. The primary hemoglobin in fetal life is fetal hemoglobin (HbF, α2γ2), while the main hemoglobin in adult life is hemoglobin A (HbA, α2β2). The fetal hemoglobin is the primary hemoglobin as Hemoglobin A2 (HbA) is expressed in less than 2% of hemoglobin (Bank 435-443). During fetal development, the main type of hemoglobin is Hb F (α2γ2). In the postnatal period this is replaced by Hb A (α2β2). Hb A2 (α2δ2). After a person switches from HB-F to HB-A they begin to show symptoms of sickle cell disease. (Bank 435-443)
The chromosomal grouping of the α- and β-globin gene clusters and the genes of the β-globin gene cluster (ε, Gγ, Aγ, δ, and β) are present on chromosome 11 in the same order in which they are manifested during fetal growth. The genes that are on chromosome 16 are also shown to remain in the same order that they were during fetal development. This is shown by the fact that the β–locus control region (β–LCR) is a major regulatory element that is located far upstream of the genes of the cluster that are needed for higher levels of expression that are associated with the genes of α-globin gene cluster (ζ, α1, and α2). There is also the β–locus control region (β–LCR), which is a main regulatory element. The genes making up the cluster are necessary to maintain the high level of expression of those genes. The α-globin gene cluster (ζ, α1, and α2) are present on chromosome 16, also in the same order in which they are expressed during fetal growth. Another element that is upstream is HS-40. HS-40 is a key regulatory element that is essential for high level of expression. During fetal growth, Hb F (α2γ2) is the principal type of hemoglobin. After the child that has sickle cell trait is born hemoglobin switching takes place. Hemoglobin switching is a process that causes the HB-F hemoglobin to be replaced by HB-A hemoglobin as a result of the γ-globin gene expression being silenced along with the mutual activation of adult β-globin gene expression. (Bank 1440-1473)
A child who is born with SCD does not have anemia at birth, but after their bodies have switched to the adult hemoglobin by six months, they begin to exhibit signs of the disease. One of these signs is chronic hemolytic anemia. This is something that they will suffer from throughout their lives. They may often have severe episodes of “anemic crises”. There are also hyperhemolysis crises, which are a sudden fall in steady state hemoglobin accompanied by increased reticulocytosis and exaggerated hyperbilirubinemia (Makani, et al. 5-7). Besides the anemia that is caused by chronic hemolysis there are a couple other types of anemia that can happen. These are acute splenic sequestration, which is when there is a fast inception of trapping red blood cells in the spleen, it is characterized by an unexpected growth in the size of the spleen. The growth is at least 2 cm below the left costal margin. This is along with a reduction in hemoglobin or hematocrit by 20%. This is a major cause of death amongst SCD sufferers. (Makani, et al. 5-7). The other type is caused by infections, viral and bacterial illnesses. Gall bladder disease is likely to be caused by the high amounts of bilirubin in the blood as a result of chronic hemolysis. (Makani, et al. 5-7)
One can determine the frequency of sickle cell disease by estimating the number of affected children at birth. To do this there must be accurate registration and diagnosis at birth. Another method is to look at the occurrence of the heterozygous states (HbAS) to gauge the probable birth rate of SCD by the gene rate and Hardy-Weinberg equation (Makani, et al. 5-7). There are about 300,000 children are born annually with SCD internationally. Countries such as the United States, the United Kingdom, and Jamaica have a SCD population that is documented at birth, but this only accounts for 1percent of the international population of SCD sufferers. The majority of which are located in Sub-Saharan Africa. (Makani, et al. 8)
Symptoms
The indicators of sickle cell typically do not show themselves prior to an infant becoming 4 months old. These symptoms include: (1) Anemia which is caused by the extreme fragility of the sickle cells. This delicateness causes them to effortlessly break down and die. Normal blood cells exist for about some 120 days, sickle cell only lives approximately 20 days before dying and having to be replenished ("Sickle Cell Disease."). This means that there are insufficient red blood cells, which makes it problematic for the person to receive a satisfactory amount of oxygen to their person. This causes continuing enervation. (2) Deferred development is instigated by an absence of strong red blood cells. Red blood cells are critical in providing an individual’s body oxygen and nutrients that it requires to grow. (3) Hand- foot syndrome is the swelling of the hands and feet triggered by the sickle shaped cell, preventing blood flow from the hands and feet. Hand-foot syndrome is one of the initial indicators of Sickle Cell Disease. (4) Infections produced by sickle cells harming the spleen. The function of the spleen is to combat infections, the impairment of the spleen as a result of sickle cell can increase a person’s susceptibility to infections. Doctors habitually treat this by providing individuals with sickle cell a stringent regimen of vaccines and antibiotics. (5) Pain which is referred to as crises is a main symptom of sickle cell anemia. The pain is a result of the sickled cells hindering the movement of blood passing through the tiny blood vessels in one’s torso, lungs and skeleton. The pain can last for a couple hours to a several weeks. It is normal for many people to be hospitalized during this period. This pain can comprise of acute splenic pain and priapism, which is prolonged and painful erections (6) Vision problems are caused by sickle cells obstructing the miniscule blood vessels in the individual’s eye, causing damage to the retina (Makani, et al. 10-16) ("Sickle Cell Disease.")
Causes
Sickle Cell Disease is instigated by an alteration on the 11 and 16 chromosomes that results in stiff, gummy hemoglobin. Hemoglobin consists of iron and it allows red blood cells to transport oxygen to every part of the body. When an individual has Sickle Cell Disease the rigid, sticky cells stop the body from getting the oxygen it requires. The alteration that causes the disease is a hereditary autosomal recessive disorder. Both parents must carry either the trait or the disease for it to be inherited. Therefore, if both parents of a child have Sickle Cell Disease, their child will have the disease. If only one parent has Sickle Cell Disease and the other parent has Sickle Cell Trait the children born to them have a fifty percent chance of inheriting Sickle Cell Disease along with a fifty percent chance of inheriting Sickle Cell Trait. Finally, if the two parents have Sickle Cell Trait, there is a twenty-five percent chance that their child will either be unaffected or have Sickle Cell Disease. There is also a fifty percent chance that their child will be a carrier of the disease. A carrier has a normal and faulty gene, but they do not have the indicators or signs that relate to the disease. They can, however pass it down to their offspring.
Dangers and Difficulties
Sickle Cell Disease can produce a myriad of difficulties owing to the deficiency of oxygen caused by insufficient blood flow ("Sickle Cell Disease."). These problems consist of: (1) Acute Chest Syndrome, a life-threatening problem that results in fever, trouble breathing and chest discomfort. Acute Chest Syndrome tends to be instigated by either sickle cells obstructing the blood vessels in an individual’s lungs or by a lung contagion. (2) Blindness is triggered by the miniscule blood vessels in the eyes becoming congested by sickle cells. Sooner or later this impairment could lead to perpetual loss of sight. (3) Gallstones are caused by elevated amounts of bilirubin. Bilirubin is a matter that is formed throughout the breakdown of the red blood cells. The breakdown of red blood cells transpires at a more considerably advanced frequency for people with Sickle Cell Disease than for individuals without. (4) Organ damage is caused by blood being unable to flow unobstructed to the organs. Depriving the organs of oxygen, causing harm to the nerve cells and organs, which can be fatal. (5) Priapism or long lasting erections are caused by blockages of the blood vessels in the penis. This can cause impotence. (6) Pulmonary hypertension can cause exhaustion and shortness of breath because of high blood pressure in the lungs and has the potential to result in death. (7) There are also open sores on the legs, and (8) Strokes which are caused by sickle cells hindering the movement of blood to an individual’s brain. ("Sickle Cell Disease.")
Treatment
The progress in finding a cure for Sickle Cell Disease has been very slow since the mutation was discovered on the 6th position of the hemoglobin (Ingram 792-94), where it had replaced the glutamine acid with Valine in 1956 as well as the discovery that the disease was an inherited molecular disorder (Ingram 2-5). In 1980 Hebbel and others discovered that sickle cells were stickier than normal cells and that this did not just apply to their relationship with other sickle cells, but to all red blood cells, such as platelets and leukocytes (Hebbel, et al. 154-160). This can increase the negative effect of the sickle cells in a person’s body. Even though SCD was discovered over 70 years-ago, there has been little improvement in the life expectancy of people suffering from the disease. Most of the improvements that have been made only came about in the last thirty years. In the 1980’s prophylactic penicillin V was introduced (Konotey-Ahulu 1205-1206) and in 1998 hydroxyurea began to be used as a vital part of treatment (Al-Salem 330-334) along with blood transfusions. One of the way that the disease could finally be cured is through gene replacement therapy, in which the affected gene would be replaced with a healthy one. Currently the closest that the medical field has gotten to this is allogeneic hematopoietic stem cell transplantation. This procedure is not available to all SCD sufferers because there are not enough donors.
Should a doctor find that a child is at high risk for a stroke in the future they can treat them with blood transfusions throughout their lives. It is vital that children with Sickle Cell Disease to be vaccinated. Vaccination helps to decrease the chances of the child obtaining a dangerous contagion. There are medications that help to combat the effects of Sickle Cell Disease such as (1) antibiotics which are used to fight the infections that can affect SCD sufferers (2) over the counter medication that is used to relieve the pain suffered during a crisis (3) Hydroxyurea, this is a drug that limits the frequency of a crises. However, Hydroxyurea has several side effects, including increasing a person’s risk of infections and long term use may cause tumours and/ or leukaemia. Many SCD patients need oxygen treatments which can assist a person in breathing correctly when they are in a crisis or having acute chest syndrome. Sickle cell patients take daily doses of folic acid, to create new red blood cells. Finally, they are counselled to circumvent strenuous activity, to drink plenty of water and to get an adequate amount of rest ("Sickle Cell Disease.").
Conclusion
Finally, sickle cell anemia is formulated by an alteration to both chromosome 11 and 16 that causes the blood cells to manifest themselves in a sickle shape instead of a rounded shape. The sickled cells are also unyielding and adhesive. The resulting obstruction prevents oxygen from getting to various parts of the body. A person’s body must be able to obtain a certain amount of oxygen to the cells and extremities to operate at its optimum level. To do this cells need to be able to obtain a continuous stream of oxygen. When an individual is incapable of obtaining a satisfactory amount of oxygen, their cells commence dying. Countless people with Sickle Cell Anemia lack oxygen causing acute agony known as Crises. Crises tend to happen without notice and can necessitate the need for the individual to stay in the hospital so the individual can obtain treatment. Eventually the recurrent deficiency in oxygen can cause irretrievable damage to the organs resulting in the need for an organ transplant.
The life expectancy of a one with sickle cell has increase since the 1970’s when most people in the United States with Sickle Cell Disease only lived until they were 14 years old. The current life expectancy of people with Sickle Cell Disease is between 40-60 years due to numerous medical advances in the past thirty years ("Sickle Cell Disease."). These advances include providing children with Penicillin prophylaxis, which prevents children from getting pneumococcal sepsis (Konotey-Ahulu 1205-1206)
Still, despite the increase in the lifespan of a person who has sickle cell disease, it is not analogous to those of people without the disease, who live on average about 73 years. The odds of dying from the disease are worse for people who are unable to get treatment because they cannot afford them or the treatments do the country does not have access to them. Many children who have sickle cell disease die in early childhood in countries such as Nigeria, where 90 percent of children with the disease die. This number is in the process of decreasing and it is expected to be at 50 percent in the next twenty years. (Makani, et al. 11). In the United States, only 85.6 percent live until they reach adulthood compared to 84 percent and Jamaica. Currently, 99 percent of sufferers live to the age of 16 in the United Kingdom. (Makani, et al. 11)
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