sickle cell anemia

鎌状赤血球症

WordNet

1. a congenital form of anemia occurring mostly in blacks; characterized by abnormal blood cells having a crescent shape (同)sickle-cell anaemia, sickle-cell disease, crescent-cell anemia, crescent-cell anaemia, drepanocytic anemia, drepanocytic anaemia
2. deeply affected by a strong feeling; "sat completely still, sick with envy"; "she was sick with longing"
3. people who are sick; "they devote their lives to caring for the sick"
4. small room in which a monk or nun lives (同)cubicle
5. a device that delivers an electric current as the result of a chemical reaction (同)electric cell
6. a room where a prisoner is kept (同)jail cell, prison cell
7. (biology) the basic structural and functional unit of all organisms; they may exist as independent units of life (as in monads) or may form colonies or tissues as in higher plants and animals
8. any small compartment; "the cells of a honeycomb"
9. a small unit serving as part of or as the nucleus of a larger political movement (同)cadre
10. an edge tool for cutting grass or crops; has a curved blade and a short handle (同)reaping_hook, reap hook
11. a deficiency of red blood cells (同)anaemia
12. a lack of vitality (同)anaemia
13. genus of terrestrial or lithophytic ferns having pinnatifid fronds; chiefly of tropical America (同)genus Anemia

PrepTutorEJDIC

1. (人が)『病気の』;(部屋などが)病人の[ための];(顔色などが)病気を示す(思わせる) / 《名詞的に》《the ~;複数扱い》病人 / 《補語にのみ用いて》《おもに英》(…で)むかついて,吐き気を催して,気分が悪い《+『at(『with』,『from』+『名』(do『ing』)》 / 《補語にのみ用いて》(…に)『うんざりして』,あきあきして,いや気がさして;(…に)しゃくにさわって,腹が立って《+『of』+『名』(do『ing』)》 / 《補語にのみ用いて》(…に)『がっかりして』,落胆して《+『at』(『about』)+『名』(do『ing』)》 / 《補語にのみ用いて》(…を)熱望して,こがれて《+『for』+『名』》 / 病的な,異常心理の;気味の悪い
2. (刑務所の)『独房』;(修道院の)小さい独居室 / (ミツバチの)みつ房,巣穴 / 小さい部屋 / 『細胞』 / 電池 / 花粉室 / (共産党などの)細胞
3. (麦刈り用の三日月形の)小がま

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/10/01 23:08:47」(JST)

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Sickle-cell disease
sickle cell disorder
Figure (A) shows normal red blood cells flowing freely through veins. The inset shows a cross section of a normal red blood cell with normal hemoglobin. Figure B shows abnormal, sickled red blood cells sticking at the branching point in a vein. The inset image shows a cross-section of a sickle cell with long polymerized sickle hemoglobin (HbS) strands stretching and distorting the cell shape.
Classification and external resources
Specialty	Hematology
ICD-10	D57
ICD-9-CM	282.6
OMIM	603903
DiseasesDB	12069
MedlinePlus	000527
eMedicine	med/2126 oph/490 ped/2096 emerg/26 emerg/406
MeSH	C15.378.071.141.150.150
GeneReviews	Sickle-cell disease
Orphanet	232

Sickle-cell disease (SCD) is a group of genetically passed down blood disorders. The most common type is known as sickle-cell anaemia (SCA). It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to a rigid, sickle-like shape under certain circumstances. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain ("sickle-cell crisis"), anemia, bacterial infections, and stroke. Long term pain may develop as people get older. The average life expectancy in the developed world is 40 to 60 years.

Sickle-cell disease occurs when a person inherits two abnormal copies of the haemoglobin gene, one from each parent. Several subtypes exist, depending on the exact mutation in each haemoglobin gene. An attack can be set off by temperature changes, stress, dehydration, and high altitude. A person with a single abnormal copy does not usually have symptoms and is said to have sickle-cell trait. Such people are also referred to as carriers. Diagnosis is by a blood test and some countries test all babies at birth for the disease. Diagnosis is also possible during pregnancy.

The care of people with sickle-cell disease may include infection prevention with vaccination and antibiotics, high fluid intake, folic acid supplementation, and pain medication. Other measures may include blood transfusion, and the medication hydroxycarbamide (hydroxyurea). A small proportion of people can be cured by a transplant of bone marrow cells.

As of 2013 about 3.2 million people have sickle-cell disease while an additional 43 million have sickle-cell trait. About 80% of sickle-cell disease cases are believed to occur in sub-Saharan Africa. It also occurs relatively frequently in parts of India, the Arabian peninsula, and among people of African origin living in other parts of the world. In 2013, it resulted in 176,000 deaths, up from 113,000 deaths in 1990. The condition was first described in the medical literature by the American physician James B. Herrick in 1910. In 1949 the genetic transmission was determined by E. A. Beet and J. V. Neel. In 1954 the protective effect against malaria of sickle-cell trait was described.

Signs and symptoms

Sickle-cell anemia.

Sickle-cells in human blood: both normal red blood cells and sickle-shaped cells are present.

Normal blood cells next to a sickle-blood cell, colored scanning electron microscope image

Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.

Sickle-cell crisis

The terms "sickle-cell crisis" or "sickling crisis" may be used to describe several independent acute conditions occurring in patients with SCD. SCD results in anemia and crises that could be of many types including the vaso-occlusive crisis, aplastic crisis, sequestration crisis, haemolytic crisis, and others. Most episodes of sickle-cell crises last between five and seven days. "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."

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 ischaemia, pain, necrosis, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration, analgesics, and blood transfusion; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac or naproxen. For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis or lungs are considered an emergency and treated with red-blood cell transfusions. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.

Splenic sequestration crisis

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 anemia. This spleen damage increases the risk of infection from encapsulated organisms; preventive antibiotics and vaccinations are recommended for those lacking proper spleen function.

Splenic sequestration crises are acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells and resulting in a precipitous fall in hemoglobin levels with the potential for hypovolemic shock. Sequestration crises are considered an emergency. If not treated, patients may die within 1–2 hours due to circulatory failure. Management is supportive, sometimes with blood transfusion. These crises are transient, they continue for 3–4 hours and may last for one day.

Acute chest syndrome

Acute chest syndrome (ACS) is defined by at least two of the following signs or symptoms: chest pain, fever, pulmonary infiltrate or focal abnormality, respiratory symptoms, or hypoxemia. It is the second-most common complication and it accounts for about 25% of deaths in patients with SCD, majority of cases present with vaso-occlusive crises then they develop ACS. Nevertheless, about 80% of patients have vaso-occlusive crises during ACS.

Aplastic crisis

Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pale appearance, fast heart rate, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them. Parvovirus infection almost 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 SCD patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the disease (causing reticulocytopenia), and the rapid turnover of red cells leads to the drop in haemoglobin. This crisis takes 4 days to one week to disappear. Most patients can be managed supportively; some need blood transfusion.

Haemolytic crisis

Haemolytic crises are acute accelerated drops in haemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with coexistent G6PD deficiency. Management is supportive, sometimes with blood transfusions.

Other

One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle-cell trait. The crisis can last up to a month. Another recognised type of sickle crisis, acute chest syndrome, is 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. It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery. Hematopoietic ulcers may also occur.

Genetics

Sickle-cell disease is inherited in the autosomal recessive pattern.

Distribution of the sickle-cell trait shown in pink and purple

Historical distribution of malaria (no longer endemic in Europe) shown in green

Modern distribution of malaria

Normally, humans have haemoglobin A, which consists of two alpha and two beta chains, haemoglobin A2, which consists of two alpha and two delta chains, and haemoglobin F, consisting of two alpha and two gamma chains in their bodies. Of these, haemoglobin F dominates until about 6 weeks of age. Afterwards, haemoglobin A dominates throughout life.

Sickle-cell conditions have an autosomal recessive pattern of inheritance from parents. The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from her or his parents. If one parent has sickle-cell anaemia and the other has sickle-cell trait, then the child has a 50% chance of having sickle-cell disease and a 50% chance of having sickle-cell trait. When both parents have sickle-cell trait, a child has a 25% chance of sickle-cell disease, 25% do not carry any sickle-cell alleles, and 50% have the heterozygous condition.

Sickle-cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis. These variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. Their clinical importance is because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.

In people heterozygous for HgbS (carriers of sickling haemoglobin), the polymerisation problems are minor, because the normal allele is able to produce over 50% of the haemoglobin. In people homozygous for HgbS, the presence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth doughnut-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers have symptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated. The sickle-cell disease occurs when the sixth amino acid, glutamic acid, is replaced by valine to change its structure and function; as such, sickle-cell anemia is also known as E6V. Valine is hydrophobic, causing the haemoglobin to collapse on itself occasionally. The structure is not changed otherwise. When enough haemoglobin collapses on itself the red blood cells become sickle-shaped.

The gene defect is a known mutation of a single nucleotide (see single-nucleotide polymorphism - SNP) (A to T) of the β-globin gene, which results in glutamic acid (E/Glu) being substituted by valine (V/Val) at position 6. Note, historic numbering put this glutamic acid residue at position 6 due to skipping the methionine (M/Met) start codon in protein amino acid position numbering. Current nomenclature calls for counting the methionine as the first amino acid, resulting in the glutamic acid residue falling at position 7. Many references still refer to position 6 and both should likely be referenced for clarity. Haemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. The genetic disorder is due to the mutation of a single nucleotide, from a GAG to GTG codon on the coding strand, which is transcribed from the template strand into a GUG codon. Based on genetic code, GAG codon translates to glutamic acid (E/Glu) while GUG codon translates to valine (V/Val) amino acid at position 6. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structures of haemoglobin in conditions of normal oxygen concentration. What it does allow for, under conditions of low oxygen concentration, is the polymerization of the HbS itself. The deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices. The hydrophobic side chain of the valine residue at position 6 of the beta chain in haemoglobin is able to associate with the hydrophobic patch, causing haemoglobin S molecules to aggregate and form fibrous precipitates.

HBB gene (responsible for sickle-cell anaemia) is located on the short (p) arm of chromosome 11 at position 15.5

The allele responsible for sickle-cell anaemia can be found on the short arm of chromosome 11, more specifically 11p15.5. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier or heterozygote. Heterozygotes are still able to contract malaria, but their symptoms are generally less severe.

Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India, and the Middle East. Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.

The malaria parasite has a complex lifecycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the Plasmodium parasite unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle-cell trait (selection for the heterozygote).

In the USA, with no endemic malaria, the prevalence of sickle-cell anaemia among African Americans is lower (about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle-cell mutation is purely disadvantageous, and tends to decline in the affected population by natural selection, and now artificially through prenatal genetic screening. However, the African American community descends from a significant admixture of several African and non-African ethnic groups, and also represents the descendants of survivors of slavery and the slave trade. Thus, a lower degree of endogamy and, particularly, abnormally high health-selective pressure through slavery may be the most plausible explanations for the lower prevalence of sickle-cell anaemia (and, possibly, other genetic diseases) among African Americans compared to West Africans. Another factor that limits the spread of sickle-cell genes in North America is the absence of cultural proclivities to polygamy, which allows affected males to continue to seek unaffected children with multiple partners.

Pathophysiology

Scanning electron micrograph showing a mixture of red blood cells, some with round normal morphology, some with mild sickling showing elongation and bending

The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease. Normal red blood cells are quite elastic, which allows the cells to deform to pass through capillaries. In sickle-cell disease, low oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.

The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days.

Diagnosis

In HbSS, the complete 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 sickled 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. Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.

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.

People who are known carriers of the disease often undergo genetic counseling before they have a child. A test to see if an unborn child has the disease takes either a blood sample from the fetus or a sample of amniotic fluid. Since taking a blood sample from a fetus has greater risks, the latter test is usually used. Neonatal screening provides not only a method of early detection for individuals with sickle-cell disease, but also allows for identification of the groups of people that carry the sickle cell trait.

Management

Folic acid and penicillin

Folic acid daily for life is recommended. From birth to five years of age, penicillin daily due to the immature immune system that makes them more prone to early childhood illnesses is also recommended.

Malaria prevention

The protective effect of sickle-cell trait does not apply to people with sickle cell disease; in fact, they are more vulnerable to malaria, since the most common cause of painful crises in malarial countries is infection with malaria. It has therefore been recommended that people with sickle-cell disease living in malarial countries should receive anti-malarial chemoprophylaxis for life.

Vaso-occlusive crisis

Most people with sickle-cell disease have intensely painful episodes called vaso-occlusive crises. However, the frequency, severity, and duration of these crises vary tremendously. Painful crises are treated symptomatically with pain medications; 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 doctors frequently prescribe to help control itching associated with the use of opioids.

Acute chest crisis

Management is similar to vaso-occlusive crisis, with the addition of antibiotics (usually a quinolone or macrolide, since cell wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome), 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. The patient with suspected acute chest syndrome should be admitted to the hospital with worsening A-a gradient an indication for ICU admission.

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.) and shown to possibly increase survival time in a study in 2003 (Steinberg et al.). 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.

Blood transfusion

Blood transfusions are often used in the management of sickle-cell disease in acute cases and to prevent complications by decreasing the number of red blood cells (RBC) that can sickle by adding normal red blood cells. In children preventative red blood cell (RBC) transfusion therapy has been shown to reduce the risk of first stroke or silent stroke when transcranial Doppler (TCD) ultrasonography shows abnormal cerebral blood flow. In those who have sustained a prior stroke event it also reduces the risk of recurrent stroke and additional silent strokes.

Bone marrow transplant

Bone marrow transplants have proven effective in children. Bone marrow transplants are the only known cure for SCD. However, bone marrow transplants are difficult to obtain because of the specific HLA typing necessary. Ideally, a close relative (allogeneic) would donate the bone marrow necessary for transplantation.

Prognosis

About 90% of people survive to age 20, and close to 50% survive beyond the fifth decade. In 2001, according to one study performed in Jamaica, the estimated mean survival for people with sickle-cell was 53 years old for men and 58 years old for women with homozygous SCD. The specific life expectancy in much of the developing world is unknown.

Complications

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

• Increased risk of severe bacterial infections due to loss of functioning spleen tissue (and comparable to the risk of infections after having the spleen removed surgically). These infections are typically 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 S. pneumoniae.
• Stroke, which can result from a progressive narrowing of blood vessels, prevents oxygen from reaching the brain. Cerebral infarction occurs in children and cerebral haemorrhage in adults.
• Silent stroke causes no immediate symptoms, but is associated with damage to the brain. Silent stroke is probably five times as common as symptomatic stroke. About 10–15% of children with SCD suffer strokes, with silent strokes predominating in the younger patients.
• Cholelithiasis (gallstones) and cholecystitis may result from excessive bilirubin production and precipitation due to prolonged haemolysis.
• Avascular necrosis (aseptic bone necrosis) of the hip and other major joints may occur as a result of ischaemia.
• Decreased immune reactions due to hyposplenism (malfunctioning of the spleen)
• Priapism and infarction of the penis
• Osteomyelitis (bacterial bone infection), the most common cause of osteomyelitis in SCD is Salmonella (especially the atypical serotypes Salmonella typhimurium, Salmonella enteritidis, Salmonella choleraesuis and Salmonella paratyphi B), followed by Staphylococcus aureus and Gram-negative enteric bacilli perhaps because intravascular sickling of the bowel leads to patchy ischaemic infarction.
• Opioid tolerance 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 can result 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 unreported chronic pain.
• Pulmonary hypertension (increased pressure on the pulmonary artery) can lead 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. 21% of children and 30% of adults have evidence of pulmonary hypertension when tested; this is associated with reduced walking distance and increased mortality.
• Chronic kidney failure due to sickle-cell nephropathy manifests itself with hypertension, protein loss in the urine, loss of red blood cells in urine and worsened anaemia. If it progresses to end-stage renal failure, it carries a poor prognosis.

Epidemiology

The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India and the Middle-East. Migration of substantial populations from these high prevalence areas to low prevalence countries in Europe has dramatically increased in recent decades and in some European countries sickle-cell disease has now overtaken more familiar genetic conditions such as haemophilia and cystic fibrosis. In 2013 it resulted in 176,000 deaths due to SCD up from 113,000 deaths in 1990.

Sickle-cell disease occurs more commonly among people whose ancestors lived in tropical and sub-tropical sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single sickle-cell allele (trait) confers a selective advantage—in other words, being a heterozygote is advantageous. Specifically, humans with one of the two alleles of sickle-cell disease show less severe symptoms when infected with malaria.

Africa

Three quarters of sickle-cell cases occur in Africa. A recent WHO report estimated that around 2% of newborns in Nigeria were affected by sickle cell anaemia, giving a total of 150,000 affected children born every year in Nigeria alone. The carrier frequency ranges between 10% and 40% across equatorial Africa, decreasing to 1–2% on the north African coast and <1% in South Africa. There have been studies in Africa that show a significant decrease in infant mortality rate, ages 2–16 months, because of the sickle-cell trait. This happened in predominant areas of malarial cases.

United States

The number of people with the disease in the United States is approximately 1 in 5,000, mostly affecting Americans of Sub-Saharan African descent, according to the National Institutes of Health. In the United States, about one out of 500 African-American children and one in every 36,000 Hispanic-American children have sickle-cell anaemia. It is estimated that sickle-cell disease affects 90,000 Americans. Most infants with SCD born in the United States are now identified by routine neonatal screening. Forty-four states along with the District of Columbia, Puerto Rico and the Virgin Islands currently provide universal neonatal screening for SCD. Sickle cell trait occurs among about 1:13 African-Americans and 1:100 Hispanic-Americans. It is estimated that 2.5 million Americans are heterozygous carriers for the sickle-cell trait.

France

As a result of population growth in African-Caribbean regions of overseas France and immigration from North and sub-Saharan Africa to mainland France, sickle-cell disease has become a major health problem in France. SCD has become the most common genetic disease in the country, with an overall birth prevalence of 1/2,415 in mainland France, ahead of phenylketonuria (1/10,862), congenital hypothyroidism (1/3,132), congenital adrenal hyperplasia (1/19,008) and cystic fibrosis (1/5,014) for the same reference period. In 2010, 31.5% of all newborns in mainland France (253,466 out of 805,958) were screened for SCD (this percentage was 19% in 2000). 341 newborns with SCD and 8,744 heterozygous carriers were found representing 1.1% of all newborns in mainland France. The Paris metropolitan district (Île-de-France) is the region that accounts for the largest number of newborns screened for SCD (60% in 2010). The second largest number of at-risk is in Provence-Alpes-Côte d'Azur at nearly 43.2% and the lowest number is in Brittany at 5.5%.

United Kingdom

In the United Kingdom (UK) it is thought that between 12,000 and 15,000 people have sickle cell disease with an estimate of 250,000 carriers of the condition in England alone. As the number of carriers is only estimated, all newborn babies in the UK receive a routine blood test to screen for the condition. Due to many adults in high risk groups not knowing if they are carriers, pregnant women and both partners in a couple are offered screening so they can get counselling if they have the sickle cell trait. In addition blood donors from those in high risk groups are also screened to confirm whether they are carriers and whether their blood filters properly. Donors who are found to be carriers are then informed and their blood, while often used for those of the same ethnic group, is not used for those with sickle cell disease who require a blood transfusion.

Middle East

In Saudi Arabia about 4.2% of the population carry the sickle-cell trait and 0.26% have sickle-cell disease. The highest prevalence is in the Eastern province where approximately 17% of the population carry the gene and 1.2% have sickle-cell disease. In 2005 in Saudi Arabia a mandatory pre-marital test including HB electrophoresis was launched and aimed to decrease the incidence of SCD and thalassemia.

In Bahrain a study published in 1998 that covered about 56,000 people in hospitals in Bahrain found that 2% of newborns have sickle cell disease, 18% of the surveyed people have the sickle cell trait, and 24% were carriers of the gene mutation causing the disease. The country began screening of all pregnant women in 1992 and newborns started being tested if the mother was a carrier. In 2004, a law was passed requiring couples planning to get married to undergo free premarital counseling. These programs were accompanied by public education campaigns.

India and Nepal

Sickle-cell disease is common in ethnic groups of central India who share a genetic linkage with African communities, where the prevalence has ranged from 9.4 to 22.2% in endemic areas of Madhya Pradesh, Rajasthan and Chhattisgarh. It is also endemic among Tharu people of Nepal and India; however, they have a sevenfold lower incidence of malaria despite living in a malaria infested zone.

Caribbean Islands

In Jamaica, 10% of the population carries the sickle-cell gene, making it the most prevalent genetic disorder in the country.

History

The first modern report of sickle-cell disease may have been in 1846, where the autopsy of an executed runaway slave was discussed; the key findings was the absence of the spleen. There were also reports amongst African slaves in the United States exhibiting resistance to malaria but being prone to leg ulcers. The abnormal characteristics of the red blood cells, which later lent their name to the condition, was first described by Ernest E. Irons (1877–1959), intern to the Chicago cardiologist and professor of medicine James B. Herrick (1861–1954), in 1910. Irons saw "peculiar elongated and sickle-shaped" cells in the blood of a man named Walter Clement Noel, a 20-year-old first-year dental student from Grenada. Noel had been admitted to the Chicago Presbyterian Hospital in December 1904 suffering from anaemia. Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" but completed his studies and returned to the capital of Grenada (St. George's) to practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada. Shortly after the report by Herrick, another case appeared in the Virginia Medical Semi-Monthly with the same title, "Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia." This article is based on a patient admitted to the University of Virginia Hospital on November 15, 1910. In the later description by Verne Mason in 1922, the name "sickle cell anemia" is first used. Childhood problems related to sickle cells disease were not reported until the 1930s, despite the fact that this cannot have been uncommon in African-American populations.

The Memphis physician Lemuel Diggs, a prolific researcher into sickle cell disease, first introduced the distinction between sickle cell disease and trait in 1933, although it took until 1949 until the genetic characteristics were elucidated by James V. Neel and E.A. Beet. 1949 was the year when Linus Pauling described the unusual chemical behaviour of haemoglobin S, and attributed this to an abnormality in the molecule itself. The actual molecular change in HbS was described in the late 1950s BY Vernon Ingram. The late 1940s and early 1950s saw further understanding in the link between malaria and sickle cell disease. In 1954, the introduction of haemoglobin electrophoresis allowed the discovery of particular subtypes, such as HbSC disease.

Large scale natural history studies and further intervention studies were introduced in the 1970s and 1980s, leading to the more widespread use of prophylaxis against pneumococcal infections amongst other interventions. Bill Cosby's Emmy-winning 1972 TV movie, To All My Friends on Shore, depicted the story of the parents of a child suffering from sickle-cell disease. The 1990s saw the development of hydroxycarbamide, and reports of cure through bone marrow transplantation appeared in 2007.

Some old texts refer to it as drepanocytosis.

Research

See also: List of sickle-cell disease researchers

Umbilical cord blood transplant

In December 1998, researchers from Emory University conducted an experimental bone marrow transplant procedure on a group of 22 children under 16 years old. One of those patients, 12-year-old Keone Penn, was apparently the first person to be cured of sickle-cell disease through this method. The stem cells were sourced from a donor unrelated to Penn. A 2007 Georgia Senate bill proposing the collection and donation of stem cell material, the "Saving the Cure Act", was nicknamed "Keone's Law" in his honor.

By mid-2007 a similar set of clinical trials in Baltimore had also cured several adults.

Gene therapy

In 2001 it was reported that sickle-cell disease had been successfully treated in mice using gene therapy. The researchers used a viral vector to make the mice—which have essentially the same defect that causes human sickle cell disease—express production of fetal hemoglobin (HbF), which an individual normally ceases to produce shortly after birth. In humans, using hydroxyurea to stimulate production of HbF has been known to temporarily alleviate sickle cell disease symptoms. The researchers demonstrated that this gene therapy method is a more permanent way to increase therapeutic HbF production.

Phase 1 clinical trials of gene therapy for sickle cell disease in humans were started in 2014. The clinical trials will assess the safety and initial evidence for efficacy of an autologous transplant of lentiviral vector modified bone marrow for adults with severe sickle cell disease. As of 2014, however, no randomized controlled trials have been reported.

References

Further reading

Library resources about Sickle-cell disease

Resources in your library Resources in other libraries

• Brown, Robert T., ed. (2006). Comprehensive handbook of childhood cancer and sickle cell disease: a biopsychosocial approach. Oxford University Press. ISBN 978-0-19-516985-0. 
• Hill, Shirley A. (2003). Managing Sickle Cell Disease in Low-Income Families. Temple University Press. ISBN 978-1-59213-195-2. 
• Serjeant, Graham R.; Beryl E. (2001). Sickle Cell Disease. Oxford University Press. ISBN 978-0-19-263036-0. 
• Tapper, Melbourne (1999). In the blood: sickle cell anemia and the politics of race. University of Pennsylvania Press. ISBN 978-0-8122-3471-8. 

External links

• Sickle cell at DMOZ
• Sickle Cell Anaemia OER Project

UpToDate Contents

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• 1. 鎌状赤血球症の臨床症状の概要 overview of the clinical manifestations of sickle cell disease
• 2. 鎌状赤血球症を伴う成人における急性胸部症候群 acute chest syndrome in adults with sickle cell disease
• 3. 鎌状赤血球症を有する小児に対する定期的な包括的ケア routine comprehensive care for children with sickle cell disease
• 4. 鎌状赤血球症のマネージメントの概要 overview of the management of sickle cell disease
• 5. 鎌状赤血球症候群の診断 diagnosis of sickle cell syndromes

English Journal

• Fetal Hemoglobin in Tunisian Sickle Cell Disease Patient: Relationship with Polymorphic Sequences Cis to the β-Globin Gene.

• Moumni I1, Ben Mustapha M1, Ben Mansour I1, Zoraï A1, Douzi K1, Sassi S1, Chaouachi D1, Mellouli F2, Bejaoui M2, Abbes S1.
• Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion.Indian J Hematol Blood Transfus.2016 Mar;32(1):114-9. doi: 10.1007/s12288-015-0504-7. Epub 2015 Jan 23.
• Fetal hemoglobin (HbF) plays a dominant role in ameliorating morbidity and mortality of hemoglobinopathies. We evaluated the effects of polymorphic markers within the β-globin gene cluster to identify the genetic mechanics that influence HbF on Tunisian sickling patients (n = 242). Haplotype anal
• PMID 26855518

• The Effect of Hydroxyurea Therapy in Bahraini Sickle Cell Disease Patients.

• Shome DK1, Al Ajmi A2, Radhi AA3, Mansoor EJ3, Majed KS3.
• Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion.Indian J Hematol Blood Transfus.2016 Mar;32(1):104-9. doi: 10.1007/s12288-015-0529-y. Epub 2015 Mar 18.
• Hydroxyurea (HU) is used as a disease-modifying agent in sickle cell disease (SCD). Its beneficial effects have been ascribed to inhibition of the sickling process through increase of fetal hemoglobin (HbF) levels and influence on multiple factors affecting adhesion of erythrocytes to vascular endot
• PMID 26855516

• Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia.

• Estepp JH1, Melloni C2, Thornburg CD3, Wiczling P4, Rogers Z5, Rothman JA6, Green NS7, Liem R8, Brandow AM9, Crary SE10, Howard TH11, Morris MH12, Lewandowski A13, Garg U14, Jusko WJ15, Neville KA16; Best Pharmaceuticals for Children Act-Pediatric Trials Network Administrative Core Committee*.
• Journal of clinical pharmacology.J Clin Pharmacol.2016 Mar;56(3):298-306. doi: 10.1002/jcph.598. Epub 2015 Oct 15.
• Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended
• PMID 26201504

Japanese Journal

• Arterial blood pressure in adult Nigerians with sickle cell anemia

• OGUANOBI N. I.,ONWUBERE B. J. C.,IBEGBULAM O. G.,IKE S. O.,ANISIUBA B. C.,EJIM E. C.,AGWU O.
• Journal of cardiology 56(3), 326-331, 2010-11-15
• NAID 10028189679

• 5-Hydroxymethyl-2-furfural, a clinical trials agent for sickle cell anemia, and its mono/di-glucosides from classically processed steamed Rehmanniae Radix

• LIN An-Shen,QIAN Keduo,USAMI Yoshihide,LIN Li,ITOKAWA Hideji,HSU Charleson,MORRIS-NATSCHKE Susan L.,LEE Kuo-Hsiung
• Journal of natural medicines 62(2), 164-167, 2008-05-20
• NAID 10024189679

• Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin

• HANNA J
• Science 318, 1920-1923, 2007
• NAID 80017959513

Related Links

• What Is Sickle Cell Disease? - NHLBI, NIH

The term sickle cell disease (SCD) describes a group of inherited red blood cell disorders. People with SCD have abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in their red blood cells. Hemoglobin is a protein in red ...

• About Sickle Cell Disease

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Related Pictures

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★リンクテーブル★

リンク元	「貧血」「Streptococcus pneumoniae」「常染色体劣性遺伝病」「鎌状赤血球症」「SCA」
関連記事	「sick」「sickle」「sickle cell」「cell」

「貧血」

　　[★]

英

anemia

同

貧血症

関

慢性疾患による貧血 anemia of chronic disease ACD

• 血液08, 症候 091215I

定義(2007前期生理学プリント、WHOの貧血判定基準)

• 下記表のHb,Htに達しない場合を貧血とする

	Hb(g/dl)	Ht(%)
男性	13	39
女性	12	36
高齢者・乳幼児・妊婦	11	33

ヘモグロビンと貧血症状

• 8 g/dl　：急性貧血で症状が出る
• 7 g/dl　：慢性貧血で症状が出る
• 5 g/dl　：心雑音
• 3 g/dl　：生命の危険

臨床検査

• 貧血を疑ったらMCV(平均赤血球容量)を測定する。

一つの赤血球の平均の大きさが分かる

• MCHC(平均赤血球ヘモグロビン濃度)は赤血球に含まれるヘモグロビンの濃度が検査できる

臨床検査に基づく分類

• MCV(平均赤血球容量)により３つに分類できる

1. 正球性貧血
2. 小球性貧血
3. 大球性貧血

• MCHC(平均赤血球ヘモグロビン濃度)により以下の２つに分類できる

1. 低色素性貧血
2. 正色素性貧血

貧血の鑑別 (文献不明)

MCV	赤血球の大きさ	網状赤血球数	腎障害	診断	治療
≦80	小球性貧血			鉄欠乏性貧血	鉄剤
80-100	正球性貧血	減少, 正常	あり	腎性貧血	エリスロポエチン
			なし	再生不良性貧血	コロニー刺激因子
		増加		溶血性貧血	グルココルチコイド
≧101	大球性貧血			巨赤芽球性貧血	ビタミンB12, 葉酸

スクリーニングによる貧血の鑑別 (OLM.80)

• Fe↓、UIBC↑、フェリチン↓：鉄欠乏性貧血、慢性出血、慢性体内溶血。体内での鉄の絶対量が不足
• Fe↓、UIBC↓、フェリチン↑：慢性感染症、慢性炎症。細網系では鉄が増加しているが(フェリチン↑)、末梢に鉄を放出できず(Fe↓)、トランスフェリンも減少している(UIBC↓)

身体所見

• 胸部聴診：収縮期機能性雑音　　←　　どこで聴取される？高心拍出量状態だから心基部か？あるいは心尖部？(100D012)

USMLE

• Q book p.292 25

sickle cell anemia	microcytic anemia
beta thalassemia	microcytic anemia
Heinz body anemia	normocytic anemia
hereditary spherocytosis	normocytic anemia
pernicious anemia	macrocytic anemia

貧血と低酸素血症

• 貧血とは血液中のヘモグロビン濃度が低下した状態であり、一方、低酸素血症は単位体積あたりの酸素分圧が低下してる状態である。PaO2低下すなわちSpO2の低下に相当すると考えてみよう。貧血ではヘモグロビン濃度は少なくても、その少ないヘモグロビンの各々は十分に酸素化されるため、SpO2は低下しない。ただし、ヘモグロビンの絶対量が少ないために、末梢組織に届ける酸素の量が少なくなるだけなのである。(cf. 101B071)

臨床

• MCVで検査項目を絞っていくが、病態が複雑な場合はMCVによる絞り込みが意味をなさないことがある。commonな貧血から除外していく。

• 1. 血算、網状赤血球、フェリチン、鉄、UIBC、葉酸、ビタミンB12
• 2. 銅、亜鉛
• 3. 赤沈、血液像
• 4. 抗核抗体、抗dsDNA抗体、ハプトグロビン、免疫電気泳動(血液)、蛋白分画、IgG,IgA,IgM、C3c、C4、CH50、エリスロポエチン
• 5. 抗SS-A抗体、抗Sm抗体、ループスアンチコアグラント、抗カルジオ抗体、抗CLGPI抗体、抗RNA抗体、PR3-ANCA、MPO-ANCA、直接クームス検査
• 6. リンパ球サブセット、PNH(CD55,CD59)

「Streptococcus pneumoniae」

　　[★]

ラ

Streptococcus pneumoniae

同

肺炎球菌、肺炎レンサ球菌、肺炎連鎖球菌、肺炎双球菌、ストレプトコッカス・ニューモニエ

関

連鎖球菌

• first aid step1 2006 p.134,138

細菌学

• グラム陽性球菌
• 西洋槍(ランセット)型の双球菌
• α溶血性。ランスフィールド分類には分類されない
• オプトヒン感受性
• 自己融解 autolysis ←　培養しすぎに注意
• 中心部の陥凹した集落
• 莢膜多糖体を有する　←　抗食菌作用(C3bの付着に抵抗する)
• IgA proteaseを分泌
• 健常人の5-250%の気道に存在するが莢膜がない弱毒の株

感染症

• 肺炎球菌感染症

• 肺炎(大葉性肺炎)

• 慢性気道感染症の急性増悪

• 中耳炎、心内膜炎、関節炎、腹膜炎、軟部組織の炎症(SMB.248)
• 髄膜炎(化膿性髄膜炎)
• 敗血症：sickle cell anemia, splenectomy

易感染性宿主

• 2歳以下の乳幼児や老人で重症化しやすい
• 脾臓を受けた患者、急性骨髄性白血病、骨髄移植、HIV感染症で発症しやすい

most common cause of:

MOPS are Most OPtochin Sensitive

• meningitis 髄膜炎
• otitis media 中耳炎
• pneumonia 肺炎
• sinusitis 副鼻腔炎

診断

• 臨床像から疑い、胸部X線、喀痰のグラム染色、尿中抗原を行う。グラム染色と尿中抗原が陽性であれば特異的な治療を開始する。 (IRE.1010)
• (経験的治療の前に？)診断及び感受性検査のために喀痰培養、血液培養検査を行う。

参考

• 光顕像

• http://www.fujita-hu.ac.jp/~kimigaai/byouri/syourei/syourei21.htm
• http://www.kamimutsukawa.com/vaccine.html
• http://fp-the-ambiguous.blogspot.com/2008/02/blog-post.html

USMLE

• Q book p.192 29

「常染色体劣性遺伝病」

　　[★]

英

autosomal recessive disease, autosomal recessive disorder

同

常染色体劣性遺伝疾患

関

遺伝病、常染色体優性遺伝病

autosomal-recessive diseases(first aid step　1 p.108)

• 嚢胞線維症 cystic fibrosis
• 白皮症 albinism
• α1アンチトリプシン欠損症 α1-antitrypsin deficiency
• フェニルケトン尿症 phenylketonuria
• サラセミア thalassemias
• 鎌状赤血球貧血 sickle cell anemia
• グリコーゲン貯蔵病 glycogen storage disease
• ムコ多糖症(ハンター症候群以外) mucopolysaccharidoses (except Hunter's syndrome)
• スフィンゴリピドーシス(ファブリー病以外) sphingolipidoses (except Fabry's disease)
• 幼児型嚢胞腎 infant polycystic kidney disease
• ヘモクロマトーシス hemochromatosis

「鎌状赤血球症」

　　[★]

英

sickle cell disease, SCD

同

鎌状赤血球貧血 sickle cell anemia、鎌状赤血球性貧血、鎌形赤血球症。ヘモグロビンS症 hemoglobin S disease

関

ヘモグロビンS、HbSC症

治療

• 葉酸：有効らしい。　←　葉酸は慢性溶血性貧血に対してルーチンに投与される。これは骨髄での需要が高まる(DNA合成の亢進)ため、と思われる。しかし、鎌状赤血球症に対するビタミンB12投与は前向きRCTにおいて有効性が示されなかった(WCH.1385 PMID 6347243)。

「SCA」

　　[★]

• 脊髄小脳変性症 spinocerebellar degeneration=脊髄小脳失調症 spinocerebellar ataxia
• 鎌状赤血球性貧血 sickle cell anemia
• 上小脳動脈 superior cerebellar artery
• 選択的腹腔動脈造影 selective celiac angiography
• 鎖骨下動脈 subclavian artery
• 心臓突然死 心臓突然死 sudden cardiac arrest 突然の心臓停止

「sick」

　　[★]

• 病気の

関

ail、ailment、disease、ill、illness、sickness

　 　 　

「sickle」

　　[★]

• adj.

• 鎌状の

関

falciform

　 　

「sickle cell」

　　[★] 鎌状赤血球

同

sickle cells

「cell」

　　[★] 細胞