Sickle-cell disease

Sickle-cell disease

Sickle-cell disease, or sickle-cell anaemia (or drepanocytosis), is a life-long blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various complications. The sickling occurs because of a mutation in the hemoglobin gene. Life expectancy is shortened, with studies reporting an average life expectancy of 42 and 48 years for males and females, respectively.[1]

Sickle-cell disease, usually presenting in childhood, occurs more commonly in people (or their descendants) from parts of tropical and sub-tropical regions where malaria is or was common. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the gene[2], because in areas where malaria is common, there is a survival value in carrying only a single sickle-cell gene (sickle cell trait).[3] Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria plasmodium is halted by the sickling of the cells which it infests.
The prevalence of the disease in the United States is approximately 1 in 5,000, mostly affecting African Americans, according to the National Institutes of Health.[4]

Classification

Sickle-cell anaemia is the name of a specific form of sickle-cell disease in which there is homozygosity for the mutation that causes HbS. Sickle-cell anaemia is also referred to as "HbSS", "SS disease", "haemoglobin S" or permutations thereof. In heterozygous people, who have only one sickle gene and one normal adult hemoglobin gene, it is referred to as "HbAS" or "sickle cell trait". Other, rarer forms of sickle-cell disease include sickle-haemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/β+) and sickle beta-zero-thalassaemia (HbS/β0). These other forms of sickle-cell disease are compound heterozygous states in which the person has only one copy of the mutation that causes HbS and one copy of another abnormal haemoglobin allele.

The term disease is applied, because the inherited abnormality causes a pathological condition that can lead to death and severe complications. Not all inherited variants of haemoglobin are detrimental, a concept known as genetic polymorphism.

In the US sickle-cell anemia usually occurs in African Americans, but sometimes occurs in Latino Americans. In the United States, about one in five hundred black births, and about one in 36,000 Hispanic births, have sickle-cell anemia.[5]

Signs and symptoms

Sickle-cell disease symptoms may lead to various acute and chronic complications, several of which are potentially lethal.

Vaso-occlusive crisis

The vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ, resulting in ischemia, pain, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration and analgesics; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is sometimes effective for the itching associated with the opioid use. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected. It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anaemia. This autosplenectomy increases the risk of infection from encapsulated organisms;[6][7] preventive antibiotics and vaccinations are recommended for those with such asplenia.

One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle trait.[8] The crisis can last up to a month.[9] Another recognised type of sickle crisis is the acute chest syndrome, a condition characterised by fever, chest pain, difficulty breathing, and pulmonary infiltrate on a chest X-ray. Given that pneumonia and sickling in the lung can both produce these symptoms, the patient is treated for both conditions.[citation needed] It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.

Most episodes of sickle cell crises last between five and seven days.[10]

Other sickle-cell crises

Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pallor, tachycardia, and fatigue. This crisis is triggered by parvovirus B19, which directly affects erythropoiesis (production of red blood cells). Parvovirus infection nearly completely prevents red blood cell production for two to three days. In normal individuals, this is of little consequence, but the shortened red cell life of sickle-cell patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the disease, and the rapid turnover of red cells leads to the drop in hemoglobin. Most patients can be managed supportively; some need blood transfusion.
Splenic sequestration crises are acute, painful enlargements of the spleen. The abdomen becomes bloated and very hard. Management is supportive, sometimes with blood transfusion.
Hemolytic crises are acute accelerated drops in hemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with co-existent G6PD deficiency. Management is supportive, sometimes with blood transfusions.

Complications

Sickle-cell anaemia can lead to various complications, including:

Overwhelming post-(auto)splenectomy infection (OPSI), which is due to functional asplenia, caused by encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae. Daily penicillin prophylaxis is the most commonly used treatment during childhood, with some haematologists continuing treatment indefinitely. Patients benefit today from routine vaccination for H. influenzae, S. pneumoniae, and Neisseria meningitidis.
Stroke, which can result from a progressive vascular narrowing of blood vessels, preventing oxygen from reaching the brain. Cerebral infarction occurs in children, and cerebral hemorrhage in adults.
Cholelithiasis (gallstones) and cholecystitis, which may result from excessive bilirubin production and precipitation due to prolonged haemolysis.
Jaundice, yellowing of the skin, may occur due to the inability of the liver to effectively remove bilirubin from the filtering of damaged red blood cells out of the blood supply as well as blocks in the organ's blood supply.[11][12]
Avascular necrosis (aseptic bone necrosis) of the hip and other major joints, which may occur as a result of ischemia.
Decreased immune reactions due to hyposplenism (malfunctioning of the spleen).
Priapism and infarction of the penis.
Osteomyelitis (bacterial bone infection), which is most frequently caused by Salmonella in individuals with sickle-cell disease, whereas Staphylococcus is the most common causative organism in the general population.
Opioid tolerance, which can occur as a normal, physiologic response to the therapeutic use of opiates. Addiction to opiates occurs no more commonly among individuals with sickle-cell disease than among other individuals treated with opiates for other reasons.
Acute papillary necrosis in the kidneys.
Leg ulcers.
In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages and retinal detachments, resulting in blindness. Regular annual eye checks are recommended.
During pregnancy, intrauterine growth retardation, spontaneous abortion, and pre-eclampsia.
Chronic pain: Even in the absence of acute vaso-occlusive pain, many patients have chronic pain that is not reported[13].
Pulmonary hypertension (increased pressure on the pulmonary artery), leading to strain on the right ventricle and a risk of heart failure; typical symptoms are shortness of breath, decreased exercise tolerance and episodes of syncope[14].
Chronic renal failure—manifests itself with hypertension (high blood pressure), proteinuria (protein loss in the urine), hematuria (loss of red blood cells in urine) and worsened anaemia. If it progresses to end-stage renal failure, it carries a poor prognosis.[15]

Sickle-Cell Disease Diagnosis

In HbSS, the full blood count reveals haemoglobin levels in the range of 6–8 g/dL with a high reticulocyte count (as the bone marrow compensates for the destruction of sickle cells by producing more red blood cells). In other forms of sickle-cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (target cells and Howell-Jolly bodies).

Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test". A mixture of haemoglobin S (Hb S) in a reducing solution (such as sodium dithionite) gives a turbid appearance, whereas normal Hb gives a clear solution.

Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds. Sickle-cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography (HPLC). Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.[16]

An acute sickle-cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an occult urinary tract infection, and chest X-ray to look for occult pneumonia should be routinely performed.[17]

Sickle-cell disease Treatment

Cyanate: Dietary cyanate, from foods containing cyanide derivatives, has been used as a treatment for sickle- cell anemia.[25] In the laboratory, cyanate and thiocyanate irreversibly inhibit sickling of red blood cells drawn from sickle cell anemia patients.[26] However, the cyanate would have to be administered to the patient for a lifetime, as each new red blood cell created must be prevented from sickling at the time of creation. Cyanate also would be expelled via the urea of a patient every cycle of treatment. Also see nicosan.
Painful (vaso-occlusive) crisis: Most people with sickle-cell disease have intensely painful episodes called vaso-occlusive crises. The frequency, severity, and duration of these crises, however, vary tremendously. Painful crises are treated symptomatically with analgesics; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is also an effective agent that is frequently prescribed by doctors in order to help control any itching associated with the use of opioids.
Folic acid and penicillin: Children born with sickle-cell disease will undergo close observation by the pediatrician and will require management by a hematologist to assure they remain healthy. These patients will take a 1 mg dose of folic acid daily for life. From birth to five years of age, they will also have to take penicillin daily due to the immature immune system that makes them more prone to early childhood illnesses.
Acute chest crisis: Management is similar to vaso-occlusive crisis, with the addition of antibiotics (usually a quinolone or macrolide, since wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome),[27] oxygen supplementation for hypoxia, and close observation. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves the exchange of a significant portion of the patients red cell mass for normal red cells, which decreases the percent of haemoglobin S in the patient's blood.
Hydroxyurea: The first approved drug for the causative treatment of sickle-cell anaemia, hydroxyurea, was shown to decrease the number and severity of attacks in a study in 1995 (Charache et al.)[28] and shown to possibly increase survival time in a study in 2003 (Steinberg et al.).[29] This is achieved, in part, by reactivating fetal haemoglobin production in place of the haemoglobin S that causes sickle-cell anaemia. Hydroxyurea had previously been used as a chemotherapy agent, and there is some concern that long-term use may be harmful, but this risk has been shown to be either absent or very small and it is likely that the benefits outweigh the risks.[30]
Bone marrow transplants: Bone marrow transplants have proven to be effective in children.[31]
Future treatments: Various approaches are being sought for preventing sickling episodes as well as for the complications of sickle-cell disease. Other ways to modify hemoglobin switching are being investigated, including the use of phytochemicals such as nicosan. Gene therapy is under investigation.

Another treatment being investigated is Senicapoc.[32]

Sickle-cell disease
Campylobacter Infections Pneumonia Carcinoid Tumors Spleen Diseases Bacterial vaginosis Toxoplasmosis Meningococcal Disease Vaginal Diseases Stomach cancer Ingrown Nail Giardiasis Cardiogenic shock Scoliosis Chronic Diarrhea Urinary Tract And Bladder Infections Aortic Stenosis Mitral Valve Prolapse Colorectal cancer Liver cancer Yersinia Enterocolitica Kaposi's Sarcoma Leukemia, Adult Acute Shigellosis Sickle-cell disease Adenoviridae Coming Soon	Sickle-cell disease Sickle-cell disease, or sickle-cell anaemia (or drepanocytosis), is a life-long blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various complications. The sickling occurs because of a mutation in the hemoglobin gene. Life expectancy is shortened, with studies reporting an average life expectancy of 42 and 48 years for males and females, respectively.[1] Sickle-cell disease, usually presenting in childhood, occurs more commonly in people (or their descendants) from parts of tropical and sub-tropical regions where malaria is or was common. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the gene[2], because in areas where malaria is common, there is a survival value in carrying only a single sickle-cell gene (sickle cell trait).[3] Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria plasmodium is halted by the sickling of the cells which it infests. The prevalence of the disease in the United States is approximately 1 in 5,000, mostly affecting African Americans, according to the National Institutes of Health.[4] Classification Sickle-cell anaemia is the name of a specific form of sickle-cell disease in which there is homozygosity for the mutation that causes HbS. Sickle-cell anaemia is also referred to as "HbSS", "SS disease", "haemoglobin S" or permutations thereof. In heterozygous people, who have only one sickle gene and one normal adult hemoglobin gene, it is referred to as "HbAS" or "sickle cell trait". Other, rarer forms of sickle-cell disease include sickle-haemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/β+) and sickle beta-zero-thalassaemia (HbS/β0). These other forms of sickle-cell disease are compound heterozygous states in which the person has only one copy of the mutation that causes HbS and one copy of another abnormal haemoglobin allele. The term disease is applied, because the inherited abnormality causes a pathological condition that can lead to death and severe complications. Not all inherited variants of haemoglobin are detrimental, a concept known as genetic polymorphism. In the US sickle-cell anemia usually occurs in African Americans, but sometimes occurs in Latino Americans. In the United States, about one in five hundred black births, and about one in 36,000 Hispanic births, have sickle-cell anemia.[5] Signs and symptoms Sickle-cell disease symptoms may lead to various acute and chronic complications, several of which are potentially lethal. Vaso-occlusive crisis The vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ, resulting in ischemia, pain, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration and analgesics; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is sometimes effective for the itching associated with the opioid use. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended. Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected. It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anaemia. This autosplenectomy increases the risk of infection from encapsulated organisms;[6][7] preventive antibiotics and vaccinations are recommended for those with such asplenia. One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle trait.[8] The crisis can last up to a month.[9] Another recognised type of sickle crisis is the acute chest syndrome, a condition characterised by fever, chest pain, difficulty breathing, and pulmonary infiltrate on a chest X-ray. Given that pneumonia and sickling in the lung can both produce these symptoms, the patient is treated for both conditions.[citation needed] It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery. Most episodes of sickle cell crises last between five and seven days.[10] Other sickle-cell crises Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pallor, tachycardia, and fatigue. This crisis is triggered by parvovirus B19, which directly affects erythropoiesis (production of red blood cells). Parvovirus infection nearly completely prevents red blood cell production for two to three days. In normal individuals, this is of little consequence, but the shortened red cell life of sickle-cell patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the disease, and the rapid turnover of red cells leads to the drop in hemoglobin. Most patients can be managed supportively; some need blood transfusion. Splenic sequestration crises are acute, painful enlargements of the spleen. The abdomen becomes bloated and very hard. Management is supportive, sometimes with blood transfusion. Hemolytic crises are acute accelerated drops in hemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with co-existent G6PD deficiency. Management is supportive, sometimes with blood transfusions. Complications Sickle-cell anaemia can lead to various complications, including: Overwhelming post-(auto)splenectomy infection (OPSI), which is due to functional asplenia, caused by encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae. Daily penicillin prophylaxis is the most commonly used treatment during childhood, with some haematologists continuing treatment indefinitely. Patients benefit today from routine vaccination for H. influenzae, S. pneumoniae, and Neisseria meningitidis. Stroke, which can result from a progressive vascular narrowing of blood vessels, preventing oxygen from reaching the brain. Cerebral infarction occurs in children, and cerebral hemorrhage in adults. Cholelithiasis (gallstones) and cholecystitis, which may result from excessive bilirubin production and precipitation due to prolonged haemolysis. Jaundice, yellowing of the skin, may occur due to the inability of the liver to effectively remove bilirubin from the filtering of damaged red blood cells out of the blood supply as well as blocks in the organ's blood supply.[11][12] Avascular necrosis (aseptic bone necrosis) of the hip and other major joints, which may occur as a result of ischemia. Decreased immune reactions due to hyposplenism (malfunctioning of the spleen). Priapism and infarction of the penis. Osteomyelitis (bacterial bone infection), which is most frequently caused by Salmonella in individuals with sickle-cell disease, whereas Staphylococcus is the most common causative organism in the general population. Opioid tolerance, which can occur as a normal, physiologic response to the therapeutic use of opiates. Addiction to opiates occurs no more commonly among individuals with sickle-cell disease than among other individuals treated with opiates for other reasons. Acute papillary necrosis in the kidneys. Leg ulcers. In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages and retinal detachments, resulting in blindness. Regular annual eye checks are recommended. During pregnancy, intrauterine growth retardation, spontaneous abortion, and pre-eclampsia. Chronic pain: Even in the absence of acute vaso-occlusive pain, many patients have chronic pain that is not reported[13]. Pulmonary hypertension (increased pressure on the pulmonary artery), leading to strain on the right ventricle and a risk of heart failure; typical symptoms are shortness of breath, decreased exercise tolerance and episodes of syncope[14]. Chronic renal failure—manifests itself with hypertension (high blood pressure), proteinuria (protein loss in the urine), hematuria (loss of red blood cells in urine) and worsened anaemia. If it progresses to end-stage renal failure, it carries a poor prognosis.[15] Sickle-Cell Disease Diagnosis In HbSS, the full blood count reveals haemoglobin levels in the range of 6–8 g/dL with a high reticulocyte count (as the bone marrow compensates for the destruction of sickle cells by producing more red blood cells). In other forms of sickle-cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (target cells and Howell-Jolly bodies). Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test". A mixture of haemoglobin S (Hb S) in a reducing solution (such as sodium dithionite) gives a turbid appearance, whereas normal Hb gives a clear solution. Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds. Sickle-cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography (HPLC). Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.[16] An acute sickle-cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an occult urinary tract infection, and chest X-ray to look for occult pneumonia should be routinely performed.[17] Sickle-cell disease Treatment Cyanate: Dietary cyanate, from foods containing cyanide derivatives, has been used as a treatment for sickle- cell anemia.[25] In the laboratory, cyanate and thiocyanate irreversibly inhibit sickling of red blood cells drawn from sickle cell anemia patients.[26] However, the cyanate would have to be administered to the patient for a lifetime, as each new red blood cell created must be prevented from sickling at the time of creation. Cyanate also would be expelled via the urea of a patient every cycle of treatment. Also see nicosan. Painful (vaso-occlusive) crisis: Most people with sickle-cell disease have intensely painful episodes called vaso-occlusive crises. The frequency, severity, and duration of these crises, however, vary tremendously. Painful crises are treated symptomatically with analgesics; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is also an effective agent that is frequently prescribed by doctors in order to help control any itching associated with the use of opioids. Folic acid and penicillin: Children born with sickle-cell disease will undergo close observation by the pediatrician and will require management by a hematologist to assure they remain healthy. These patients will take a 1 mg dose of folic acid daily for life. From birth to five years of age, they will also have to take penicillin daily due to the immature immune system that makes them more prone to early childhood illnesses. Acute chest crisis: Management is similar to vaso-occlusive crisis, with the addition of antibiotics (usually a quinolone or macrolide, since wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome),[27] oxygen supplementation for hypoxia, and close observation. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves the exchange of a significant portion of the patients red cell mass for normal red cells, which decreases the percent of haemoglobin S in the patient's blood. Hydroxyurea: The first approved drug for the causative treatment of sickle-cell anaemia, hydroxyurea, was shown to decrease the number and severity of attacks in a study in 1995 (Charache et al.)[28] and shown to possibly increase survival time in a study in 2003 (Steinberg et al.).[29] This is achieved, in part, by reactivating fetal haemoglobin production in place of the haemoglobin S that causes sickle-cell anaemia. Hydroxyurea had previously been used as a chemotherapy agent, and there is some concern that long-term use may be harmful, but this risk has been shown to be either absent or very small and it is likely that the benefits outweigh the risks.[30] Bone marrow transplants: Bone marrow transplants have proven to be effective in children.[31] Future treatments: Various approaches are being sought for preventing sickling episodes as well as for the complications of sickle-cell disease. Other ways to modify hemoglobin switching are being investigated, including the use of phytochemicals such as nicosan. Gene therapy is under investigation. Another treatment being investigated is Senicapoc.[32]
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