Sickle Cell Crisis Overview

Sickle cell disease is the most common of the hereditary blood disorders.It occursalmost exclusively among black Americans and black Africans. Sickle cell disease in black Americans occurs in 3 of every 1,000 (or about 1 in 375) live births. Estimates indicate that the severe form of sickle cell disease affectsmore than 50,000 black Americans. The first account of what was then called sickle cell anemia in the medical literature was in 1910. James B. Herrick, a Chicago physician, described the symptoms of a 20-year-old black male student from the West Indies. The man had reported "shortness of breath, palpitations, and episodes of icterus [yellow eyes]. He had an anemia." Dr. Herrick described the patient's blood smear as showing "thin, sickle-shaped and crescent-shaped red cells." Red blood cells deliver oxygen to working or active tissues. In the lungs, hemoglobin (the molecule in the red blood cell) takes on oxygen and, at the same time, releases carbon dioxide. This process is called oxygenation. At the tissue level, this activity is reversed. The same hemoglobin molecule releases oxygen and takes on carbon dioxide. This process is calleddeoxygenation. In sickle cell disease, certain red blood cells become crescent-shaped (the sickle cell Dr. Herrick described). These abnormal red blood cells, carrying an abnormal hemoglobin known as hemoglobin S, are fragile. A person who hassickle cell disease can become more likely to get infections because the damaged cells eventually clog the spleen. A severe attack, known as sickle cell crisis, can cause pain because blood vessels can become blocked or the defective red blood cells can damage organs in the body. The words homozygous, heterozygous, and hemizygous are used to describe the genotype of a diploid organism at a single locus on the DNA. Homozygous describes a genotype consisting of two identical alleles at a given locus, heterozygous describes a genotype consisting of two different alleles at a locus, hemizygous describes a genotype consisting of only a single copy of a particular gene in an otherwise diploid organism, and nullizygous refers to an otherwise diploid organism in which both copies of the gene are missing.

Sickle Cell Crisis Causes

Sickle cell disease results from mutation, or change, of certain types of hemoglobin chains in red blood cells (the beta hemoglobin chains). The changes in the building of normal hemoglobin result in the abnormal hemoglobin of sickle cell disease. These mutated molecules do not have the smooth motion needed for oxygenation and deoxygenation. When the oxygen concentration in the blood is reduced, the red blood cell assumes the characteristic sickle shape. This causes the red blood cell to be stiff and rigid, and stops the smooth passage of the red blood cells through the narrow blood vessels. It does not take much imagination to see sharp-end "sickled" red cells stacking up in narrow blood vessels known as capillaries. When this happens, red blood cells are not able to carry oxygen to tissues, and tissue cell injury or death occurs. Someone with sickle cell disease would be experiencing pain with this process-the sickle cell crisis.

Sickle Cell Crisis Symptoms

The sites most often affected by the blocking or stacking action of sickled cells are found in the lungs, liver, bone, muscles, brain, spleen, penis, eyes, and kidneys.

The immune system of a person with sickled cellsdramatically weakens. People with sickle cells arehighly susceptible to infections from certain forms of bacteria. Some of the most common infections are from flu viruses, pneumonia, and salmonella (a type of bacteria). Severe pain is the most common of sickle cell disease emergencies (acute sickle cellcrises). A personmay not know what brought on the pain, but one or more of the following situations may have contributed to the start of the painful sickle crisis:

Dehydration Infection Fever Hypoxia (decrease in oxygen to body tissue) Bleeding Cold exposure Drug and alcohol use Pregnancy and stress

Fourpatterns of an acute sickle cell crisis are now recognizable. They are based on the part of the body where the crisis occurs.

Bone crisis: An acute or sudden pain in a bone can occur, usually in an arm or leg. The area may be tender. Common bones involved include the large bones in the arm or leg: the humerus, tibia, and femur. The same bone may be affected repeatedly in future episodes of bone crisis. Acute chest syndrome: Sudden acute chest pain with coughing up of blood can occur. Low-grade fevers can be present. The person is usually short of breath. If a cough is present, it often is nonproductive.Acute chest syndrome is common in a young person with sickle cell disease. Chronic (long-term) sickle cell lung disease develops with time because the acute and subacute lung crisis leads to scarred lungs and other problems. Abdominal crisis: The pain associated with the abdominal crisis of sickle cell disease is constant and sudden. It becomes unrelenting. The pain may or maynot be localized to any one area of the abdomen. Nausea, vomiting, and diarrhea may or may not occur. Joint crisis: Acute and painful joint crisis may develop without a significant traumatic history. Its focus iseither ina single jointor in multiple joints. Often the connecting bony parts of the joint are painful. Range of motion is often restricted because of the pain.

Many other organ systems are often injured orimpaired.

Central nervous system: Two-thirds of all strokes in people with sickle cell disease occur in children, at an average age of8 years. About 10% of people with sickle cell disease have strokes or other brain bleeding when younger than 8-10 years. As the population ages, the incidence of these events also increases. Repeat strokes occur in two-thirds of all survivors within 3 years of the first stroke. Blood clots affect the large vessels in the brain. Bleeding may occur in the small vessels damaged by sickle cell disease.

Eyes: The effectofsickle cell disease on the eyes comes from the increased viscosity, or "sludging," of blood and the narrowness of the eye's blood vessels. Retinopathy (disease of the retina in the eye) is common and causes problems with vision. Retinal detachment is frequent. Hyphemas, bleeding in the eye, occur at the same rate as the general population, but complications are more common because of the increased sickling effect that the waterlikefluid in the eye promotes. Kidneys: Some amount of kidney damage occurs in nearly every person with sickle cell disease. Genitals: Priapism (a constant erection of the penis) is common. It affects about 40% of all men with sickle cell disease. Severe episodes are a frequent cause of impotency. Infections: People with sickle cell disease have weakened immune systems and are at increased risk for developing infection, especially in the lungs, kidneys, bones, and central nervous system. Blood problems: People with sickle cell disease can develop anemia-a reduction in the number of red blood cells. Symptoms of anemia are shortness of breath (oxygen is not getting to tissues), lightheadedness, and fatigue.

When to Seek Medical Care

If certain conditions develop in a person withsickle cell disease, the personmust contact a physician. If the physicianis not quickly available or cannot see the person right away, the person with sickle cell diseasemay choose to go to a hospital's emergency department. Contact the physicianin the followingcases:

Many people with sickle-cell disease have pain with enough frequency that they need to take pain medications at home. If the pain is unrelieved by the medication, or the pain is significantly different fromprevious episodes, contact the health care provider. Ifexperiencing nausea, vomiting, and diarrhea;losing a lot of fluid; and having inabilityto drink and keep it down, the person with sickle cell disease isin danger of becoming dehydrated. This is a serious concern with sickle cell disease. The physicianor the hospital may provideIV fluids to replace the lost fluids. It is important to control infection. If it appears that a person with sickle cell disease isgetting an infection, even ifusing antibiotics to prevent infection,contact the physician immediately.

A sickle cell crisis can often be managed efficiently and quickly in a hospital's emergency department with fluids and pain medicines. A person with sickle cell disease shouldnot delay going to the hospital. Delay can only make the condition worse and might requirehospitalizationfor treatment. Go to a hospital's emergency department if these conditions develop:

Uncontrollable pain even with the use of narcotics Continued loss of fluid leading to dehydration (ifvomiting) Uncontrollable fever Chest pain or shortness of breath Severe abdominal pain

Exams and Tests

The health care providerwill take the complete medical history of a person with sickle cell disease. Thishistory should includewhetherany infections are present. The health care provider will ask about other problems that are common starters of sickle cell crisis. These problems would be a lack of oxygen in the tissue, bleeding, dehydration, alcohol and drug use, pregnancy, and other concerns.

During a physical exam, the physician will check the nervous system, lungs, bones, eyes, and abdomen, in particular. The physician will perform blood and urine tests. If indicated, the physician may have a CT scan of the head taken and perform a spinal tap to check for problems in the spinal fluid and brain.

If the physician suspects sickle cell disease in an adult, or more commonly a child not previously diagnosed with this disease, attention will first be paid to getting a family history of sickle cell disease. The physician then performs a blood test to diagnose the disease.

Sickle Cell Crisis Treatment Self-Care at Home

Even tiny changes in the red blood cells can begin a cascade of symptoms leading to a sickle cell crisis. Therefore, home care, even when a person iscareful about drinking plenty of fluids and avoiding infection, is difficult. The best home care is understanding the illness and knowing when and where to seek immediate medical care.

Medications

Sickle cell pain crisis

o o o

Pain medications, often narcotics, will be given. IV fluids are an important part of therapy.

Infection: If the physician diagnoses or suspects a bacterial infection, antibiotics are prescribed. Anemia: If there is a significant decrease in the red blood cell count, a red blood cell transfusion may be needed.

Other Therapy

Chronic therapy: New developments in regularly scheduled transfusion therapy have shown promise in decreasing the following:
o o o o o

Symptoms of acute chest syndrome Incidence of stroke Severity of pain crises

Bone marrow transplantation holds promise for a very small percentage of people with sickle cell disease. Discuss this with the physician.

Follow-up
Considering the many body systems involved and the likelihood that sickle cell crisis will occur time and time again, strong consideration should be given to follow-up with a hematologist (a physician with a specialty in treating blood disorders). Most uncomplicated cases of sickle cell crisis can be treated in community emergency departments. People with this condition can be safely sent home when their pain is under control and their dehydration is eliminated. A short observational period in the emergency department helps to prevent acute relapse and admission for pain and rehydration. Outpatient treatmentcenterson the control of infection, reduction of pain, and prevention of dehydration. The use of narcotics is often necessary and should not be limited for fear of turning someone with sickle cell disease into a drug addict.

[edit] Homozygous
A cell is said to be homozygous for a particular gene when identical alleles of the gene are present on both homologous chromosomes.[2] The cell or organism in question is called a homozygote. True breeding organisms are always homozygous for the traits that are to be held constant. An individual that is homozygous dominant for a particular trait carries two copies of the allele that codes for the dominant trait. This allele, often called the "dominant allele", is normally represented by a capital letter (such as "P" for the dominant allele producing purple flowers in pea plants). When an organism is homozygous dominant for a particular trait, the genotype is represented by a doubling of the symbol for that trait, such as "PP". An individual that is homozygous recessive for a particular trait carries two copies of the allele that codes for the recessive trait. This allele, often called the "recessive allele", is usually represented by the lowercase form of the letter used for the corresponding dominant trait (such as, with reference to the example above, "p" for the recessive allele producing white flowers in pea plants). The genotype of an organism that is homozygous recessive for a particular trait is represented by a doubling of the appropriate letter, such as "pp".

[edit] Heterozygous
A diploid organism is heterozygous at a gene locus when its cells contain two different alleles of a gene.[3] Heterozygous genotypes are represented by a capital letter (representing the dominant allele) and a lowercase letter (representing the recessive allele), such as "Rr" or "Ss". The capital letter is usually written first. If the trait in question is determined by simple (complete) dominance, a heterozygote will express only the trait coded by the dominant allele and the trait coded by the recessive allele will not be present. In more complex dominance schemes the results of heterozygosity can be more complex.

[edit] Hemizygous
A chromosome in a diploid organism is hemizygous when only one copy is present.[2] The cell or organism is called a hemizygote. Hemizygosity is observed when one copy of a gene is deleted, or in the heterogametic sex when a gene is located on a sex chromosome. For organisms in which the male is heterogametic, such as humans, almost all X-linked genes are hemizygous in males with normal chromosomes because they have only

one X chromosome and few of the same genes are on the Y chromosome. In a more extreme example, male honeybees (known as drones) are completely hemizygous organisms. They develop from unfertilized eggs and their entire genome is haploid, unlike female honeybees, which are diploid. Transgenic mice generated through exogenous DNA microinjection of an embryo's pronucleus are also hemizygous, and can later be bred to homozygosity to reduce the need to confirm genotype of each litter.[clarification needed]

[edit] Nullizygous
A nullizygous organism carries two mutant alleles for the same gene. The mutant alleles are both complete lossof-function or 'null' alleles, so homozygous null and nullizygous are synonymous.[2] The mutant cell or organism is called a nullizygote.

[edit] Autozygous and allozygous

Zygosity may also refer to the origin(s) of the alleles in a genotype. When the two alleles at a locus originate from a common ancestor by way of nonrandom mating (inbreeding), the genotype is said to be autozygous. This is also known as being "identical by descent", or IBD. When the two alleles come (at least to the extent that the descent can be traced) from completely different sources, as is the case in most normal, random mating, the genotype is called allozygous. This is known as being "identical by state", or IBS. Because the alleles of autozygous genotypes come from the same source, they are always homozygous, but allozygous genotypes may be homozygous too. All heterozygous genotypes are, by definition, allozygous because they contain two completely different alleles. Hemizygous and nullizygous genotypes do not contain enough alleles to allow for comparison of sources, so this classification is irrelevant for them. Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.

[edit] Sickle cell crisis

The term "sickle cell crisis" is used to describe several independent acute conditions occurring in patients with sickle cell disease. Sickle cell disease results in anaemia and crisis 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.[6]
[edit] 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 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. Vaso-occlusive crisis involving organs such as the penis or lungs are considered an emergency and treated with red-blood cell transfusions. 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.[citation needed]

[edit] Splenic sequestration crisis

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected[citation needed]. 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;[7][8] preventive antibiotics and vaccinations are recommended for those with such asplenia.

Splenic sequestration crises: are acute, painful enlargements of the spleen. The sinusoids and gates would open at the same time resulting in sudden pooling of the blood into the spleen and circulatory defect leading to sudden hypovolaemia. The abdomen becomes bloated and very hard. Splenic sequestration crises is considered an emergency. If not treated, patients may die within 12 hours due to circulatory failure. Management is supportive, sometimes with blood transfusion. These crises are transient, they continue for 34 hours and may last for one day.

[edit] Aplastic crisis

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) by invading the red cell precursors and multiplying in them and destroying them. 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 (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.
[edit] 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 co-existent G6PD deficiency. Management is supportive, sometimes with blood transfusions.
[edit] Other

One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle trait.[9] The crisis can last up to a month.[10] 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, bonemarrow embolisation, or possibly by atelectasis, opiate administration, or surgery.

[edit] 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 narrowing of blood vessels, preventing oxygen from reaching the brain. Cerebral infarction occurs in children and cerebral haemorrhage in adults.

Silent stroke is a stroke that causes no immediate symptoms but is associated with damage to the brain. Silent stroke is probably five times as common as symptomatic stroke. Approximately 1015% of children with sickle cell disease suffer strokes, with silent strokes predominating in the younger patients.[11][12] Cholelithiasis (gallstones) and cholecystitis, which may result from excessive bilirubin production and precipitation due to prolonged haemolysis. Avascular necrosis (aseptic bone necrosis) of the hip and other major joints, which may occur as a result of ischaemia.[13] Decreased immune reactions due to hyposplenism (malfunctioning of the spleen).[14] Priapism and infarction of the penis.[15] Osteomyelitis (bacterial bone infection); the most common cause of osteomyelitis in sickle cell disease is Salmonella (especially the non-typical 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.[16] 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.[17] In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages and retinal detachments, resulting in blindness.[18] 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.[19] 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.[20] Chronic renal failure due to Sickle cell nephropathymanifests itself with hypertension (high blood pressure), proteinuria (protein loss in the urine), haematuria (loss of red blood cells in urine) and worsened anaemia. If it progresses to end-stage renal failure, it carries a poor prognosis.[21]

[edit] Heterozygotes
The heterozygous form (sickle cell trait) is almost always asymptomatic, and the only usual significant manifestation is the renal concentrating defect presenting with isosthenuria.

[edit] Pathophysiology
Sickle-cell anaemia is caused by a point mutation in the -globin chain of haemoglobin, causing the hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position. The globin gene is found on chromosome 11, (Robbin's Pathology). The association of two wild-type -globin subunits with two mutant -globin subunits forms haemoglobin S (HbS). Under low-oxygen conditions (being at high altitude, for example), the absence of a polar amino acid at position six of the -globin chain promotes the non-covalent polymerisation (aggregation) of haemoglobin, which distorts red blood cells into a sickle shape and decreases their elasticity. 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, lowoxygen 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 inside the spleen, because of their misshape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction.[22] Healthy red blood cells typically live 90120 days, but sickle cells only survive 1020 days.[23] 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 A makes up around 96-97% of the normal haemoglobin in humans.

[edit] Genetics
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 SaudiAsian. Their clinical importance springs from the fact that some of them are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.[24] 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. Under normal circumstances, these painful crises occur about 0.8 times per year per patient.[citation needed] The sickle-cell disease occurs when the seventh amino acid (if the initial methionine is counted), glutamic acid, is replaced by valine to change its structure and function. Valine is hydrophobic, causing the haemoglobin to collapse in on itself occasionally. The structure is not changed otherwise. When enough haemoglobin collapses in on itself the red blood cells become sickle-shaped.

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

The gene defect is a known mutation of a single nucleotide (see single-nucleotide polymorphism - SNP) (A to T) of the -globin gene, which results in glutamic acid being substituted by valine at position 6. 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 mutation, becoming a GUG codon by transcription. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structure 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 residues of the valine at position 6 of the beta chain in haemoglobin are able to associate with the hydrophobic patch, causing haemoglobin S molecules to aggregate and form fibrous precipitates. The allele responsible for sickle-cell anaemia is autosomal recessive and can be found on the short arm of chromosome 11. A person that receives the defective gene from both father and mother develops the disease; a person that receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier. If two parents who are carriers have a child, there is a 1-in-4 chance of their child developing the disease and a 1-in-2 chance of their child's being just a carrier. Since the gene is incompletely recessive, carriers can produce a few sickled red blood cells, not enough to cause symptoms, but enough to give resistance to malaria. Because of this, heterozygotes have a higher fitness than either of the homozygotes. This is known as heterozygote advantage. 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.[25] Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.[26] The malaria parasite has a complex life cycle 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 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, where there is no endemic malaria, the prevalence of sickle-cell anaemia among blacks 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 will tend to be selected out of the affected population. However, the socalled African American community of the USA is known to be the result of significant admixture between several African and non-African ethnic groups, and also represents the descendants of survivors of the 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 Afro-Americans compared to Sub-Saharan African people. Another factor limiting 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.[27]

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

[edit] Inheritance
Sickle-cell conditions are inherited from parents in much the same way as blood type, hair color and texture, eye colour, and other physical traits. The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from his parents. If one parent has sickle-cell anaemia (SS) and the other has sickle-cell trait (AS), there is a 50% chance of a child's having sickle-cell disease (SS) and a 50% chance of a child's having sickle-cell trait (AS). When both parents have sickle-cell trait (AS), a child has a 25% chance (1 of 4) of sickle-cell disease (SS), as shown in the diagram.

[edit] Epidemiology
The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, India and the Middle-East.[28] 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.[29]

[edit] 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.[30]

[edit] Europe
[edit] France

In Europe, the highest prevalence of the disease has been observed in France. As a result of population growth in African-Caribbean regions of overseas France, and now immigration essentially from North and sub-Saharan Africa to mainland France, sickle cell disease has become a major health problem in France.[31] SCD has become the most common genetic disease in this 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 2007, 28.45% of all newborns in mainland France had at least one parent originated from a region defined "at risk" (mainly Africa and Overseas departments and territories of France) and were screened for SCD. The Paris metropolitan district (le-de-France) is the region that accounts for the largest number of people at presumably higher risk of SCD. Indeed, nearly 56% of all newborns in this area in 2007 had at least one parent originated from a region defined as "at-risk" and were screened for SCD. The second largest number of at-risk is in Provence-Alpes-Cte d'Azur at nearly 42% and the lowest number is in Brittany at 4.40%.[32]
[edit] United Kingdom

In United Kingdom, more than 200 babies are born annually with SCD.

[edit] Middle East

About 6,000 children are born annually with SCD, at least 50% of these in Saudi Arabia, especially in Qatif City.

[edit] India
Sickle cell disease is prevalent in many parts of India, where the prevalence has ranged from 9.4 to 22.2% in endemic areas.[33]

[edit] Diagnosis
In HbSS, the full blood count reveals haemoglobin levels in the range of 68 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 formscan 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.[34] 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.[35] 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. After the mutation responsible for this disease was discovered in 1979, the U.S. Air Force required black applicants to test for the mutation. It dismissed 143 applicants because they were carriers, even though none of them had the condition. It eventually withdrew the requirement, but only after a trainee filed a lawsuit.[36]

[edit] Management

[edit] Folic acid and penicillin

Children born with sickle-cell disease will undergo close observation by the paediatrician and will require management by a haematologist 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.

[edit] Malaria chemoprophylaxis

The protective effect of sickle cell trait does not apply to people with sickle cell disease; in fact, they are uniquely 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.[37]

[edit] 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; patientcontrolled 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.

[edit] 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),[38] 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.

[edit] 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.)[39] and shown to possibly increase survival time in a study in 2003 (Steinberg et al.).[40] 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.[41]

[edit] Transfusion therapy

Blood transfusions are often used in the management of sickle cell disease in acute cases and to prevent complications by decreasing the the number of red blood cells (RBC) that can sickle by adding normal red blood cells.[42] In children prophylactic chronic red blood cell (RBC) transfusion therapy has been shown to be

efficacious to a certain extent in reducing the risk of first stroke or silent stroke when transcranial Doppler (TCD) ultrasonography shows abnormal increased cerebral blood flow velocities. In those who have sustained a prior stoke event it also reduces the risk of recurrent stroke and additional silent strokes.[43][44]

[edit] Bone marrow transplants

Bone marrow transplants have proven to be effective in children.[45]

[edit] History
This collection of clinical findings was unknown until the explanation of the sickle cells in 1910 by the Chicago cardiologist and professor of medicine James B. Herrick (18611954), whose intern Ernest Edward Irons (18771959) found "peculiar elongated and sickle-shaped" cells in the blood of Walter Clement Noel, a 20year-old first-year dental student from Grenada, after Noel was admitted to the Chicago Presbyterian Hospital in December 1904 suffering from anaemia.[46] Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks". Noel 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.[47] Herrick's published account included illustrations, but the earliest available slide showing sickle cells is that of a 1918 autopsy from a soldier with sickle trait, initially reviewed only 92 years later.[48] The disease was named "sickle-cell anemia" by Verne Mason in 1922, then a medical resident at Johns Hopkins Hospital.[49] However, some elements of the disease had been recognized earlier: A paper in the Southern Journal of Medical Pharmacology in 1846 described the absence of a spleen in the autopsy of a runaway slave. The African medical literature reported this condition in the 1870s, when it was known locally as ogbanjes ("children who come and go") because of the very high infant mortality rate caused by this condition. A history of the condition tracked reports back to 1670 in one Ghanaian family.[50] Also, the practice of using tar soap to cover blemishes caused by sickle-cell sores was prevalent in the black community.[citation needed] Linus Pauling and colleagues were the first, in 1949, to demonstrate that sickle-cell disease occurs as a result of an abnormality in the haemoglobin molecule. This was the first time a genetic disease was linked to a mutation of a specific protein, a milestone in the history of molecular biology, and it was published in their paper "Sickle Cell Anemia, a Molecular Disease".

An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females.[1] For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y. So, humans have 23 pairs of chromosomes.

Human chromosomes

Female (XX)

Male (XY)

There are two copies of each autosome (chromosomes 1-22) in both females and males. The sex chromosomes are different: There are two copies of the X-chromosome in females, but males have a single X-chromosome and a Y-chromosome.

In genetics, the term "recessive gene" refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele) and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father. If a genetic trait is recessive, a person needs to inherit two copies of the gene for the trait to be expressed. Thus, both parents have to be carriers of a recessive trait in order for a child to express that trait. If both parents are carriers, there is a 25% chance with each child to show the recessive trait. Thus if the parents are closely related (in-breeding) the probability of both having inherited the same gene is increased and as a result the probability of the children showing the recessive trait is increased as well. The term "recessive gene" is part of the laws of Mendelian inheritance created by Gregor Mendel. Examples of recessive genes in Mendel's famous pea plant experiments include those that determine the color and shape of seed pods, and plant height. Autosomal recessive or autorecessive is a mode of inheritance of genetic traits located on the autosomes (the 22 non-sex determining chromosomes).

In opposition to autosomal dominant trait, a recessive trait only becomes phenotypically apparent when two copies of a gene (two alleles) are present. In other words, the subject is homozygous for the trait. Recessive genes will also show a horizontal inheritance on a pedigree chart. The frequency of the carrier state can be calculated by the Hardy-Weinberg formula: p2 + 2pq + q2 = 1 (p is the frequency of one pair of alleles, and q = 1 p is the frequency of the other pair of alleles.)

Recessive genetic disorders occur when both parents are carriers and each contributes an allele to the embryo. As both parents are heterozygous for the disorder, the chance of two disease alleles being inherited by one of their offspring is 25% (in autosomal dominant traits this is higher). 50% of the children (or 2/3 of the remaining ones) are carriers. When one of the parents is homozygous, the trait will only show in his/her offspring if the other parent is also a carrier. In that case, the chance of disease in the offspring is 50%. Fitness (often denoted w in population genetics models) is a central idea in evolutionary theory. It can be defined either with respect to a genotype or to a phenotype in a given environment. In either case, it describes the ability to both survive and reproduce, and is equal to the average contribution to the gene pool of the next generation that is made by an average individual of the specified genotype or phenotype. If differences between alleles at a given gene affect fitness, then the frequencies of the alleles will change over generations; the alleles with higher fitness become more common. This process is called natural selection. An individual's fitness is manifested through its phenotype. The phenotype is affected by the developmental environment as well as by genes, and the fitness of a given phenotype can be different in different environments. The fitnesses of different individuals with the same genotype are therefore not necessarily equal. However, since the fitness of the genotype is an averaged quantity, it will reflect the reproductive outcomes of all individuals with that genotype in a given environment or set of environments. Inclusive fitness differs from individual fitness by including the ability of an allele in one individual to promote the survival and/or reproduction of other individuals that share that allele, in preference to individuals with a different allele. One mechanism of inclusive fitness is kin selection.

Fitness is often defined as a propensity or probability, rather than the actual number of offspring. For example, according to Maynard Smith, "Fitness is a property, not of an individual, but of a class of individuals for example homozygous for allele A at a particular locus. Thus the phrase expected number of offspring means the average number, not the number produced by some one individual. If the first human infant with a gene for levitation were struck by lightning in its pram, this would not prove the new genotype to have low fitness, but only that the particular child was unlucky." [1] Equivalently, "the fitness of the individual - having an array x of phenotypes - is the probability, s(x), that the individual will be included among the group selected as parents of the next generation."[2]

[edit] Measures of fitness

There are two commonly used measures of fitness; absolute fitness and relative fitness.

[edit] Absolute fitness

Absolute fitness (wabs) of a genotype is defined as the ratio between the number of individuals with that genotype after selection to those before selection. It is calculated for a single generation and may be calculated from absolute numbers or from frequencies. When the fitness is larger than 1.0, the genotype increases in frequency; a ratio smaller than 1.0 indicates a decrease in frequency.

Absolute fitness for a genotype can also be calculated as the product of the proportion surviving times the average fecundity.

[edit] Relative fitness

Relative fitness is quantified as the average number of surviving progeny of a particular genotype compared with average number of surviving progeny of competing genotypes after a single generation, i.e. one genotype is normalized at w = 1 and the fitnesses of other genotypes are measured with respect to that genotype. Relative fitness can therefore take any nonnegative value, including 0. The two concepts are related, as can be seen by dividing each by the mean fitness, which is weighted by genotype frequencies.

Because fitness is a coefficient, and a variable may be multiplied by it several times, biologists may work with "log fitness" (particularly so before the advent of computers). By taking the logarithm of fitness each term may be added rather than multiplied.
Dominance in genetics is a relationship between two variant forms (alleles) of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms (A & B), three combinations of alleles (genotypes) are possible: AA, AB, and BB. If AA and BB individuals (homozygotes) show different forms of the trait (phenotype), and AB individuals (heterozygotes) show the same phenotype as AA individuals, then allele A is said to dominate or be dominant to allele B, and B is said to be recessive to A. If instead AB has the same phenotype as BB, B is dominant to A.

Most familiar plants, like peas, and familiar animals, like fruit flies and humans, have paired chromosomes, and are described as diploid. One chromosome of each pair is contributed by each parent: one by the female parent in her ovum, and one by the male parent in his sperm, which are joined at fertilization. The ovum and sperm cells have only one copy of each chromosome and are described as haploid. Production of haploid gametes occurs through a process called meiosis.

[edit] Chromosomes, genes, and alleles

Each chromosome of a matching pair is structurally similar to the other, and each member of a homologous pair has the same genetic material arranged in the same order and physical locations (loci, singular locus). The genetic material in each chromosome comprises a series of discrete genes that influence various traits. Thus, each gene also has a corresponding homologue, which may exist in different forms: the variant forms are called alleles. The alleles at the same locus on the two homologous chromosomes may be identical or different. In popular usage, "gene" and "allele" are often used interchangeably. This produces misunderstandings. Properly, "gene" refers to a hereditary unit, ordinarily at a fixed position on a chromosome, that influences a particular trait. Genes are now understood to comprise DNA. "Allele" refers to any of the many particular forms of a gene that may be present in a population of individuals from a particular species, at a particular locus. E.g., it is inaccurate to say "This pea plant has a pair of wrinkled genes", and it is more accurate to say, "This plant has two 'w' alleles for the 'Seed Shape' gene, and will produce wrinkled peas." Consider also the example of blood type in humans. Near the long arm of chromosome nine appears a gene that determines whether an individual will be blood type, A, B, or O. There are three different alleles that could be present at this locus, but only two can be present in any individual, one inherited from their mother and one from their father.[1]

[edit] Homozygous, heterozygous

If two alleles of a given gene are identical, the organism is called a homozygote and is homozygous with respect to that gene; if instead the two alleles are different, the organism is a heterozygote and is heterozygous. The genetic makeup of an organism, either at a single locus or over all its genes collectively, is called the genotype. The genotype of an organism directly or indirectly affects its molecular, physical,and other traits, which individually or collectively are called the phenotype. At heterozygous gene loci, the two alleles interact to produce the phenotype. The simplest form of allele interaction is the one described by Mendel, now called Mendelian, in which the appearance/phenotype caused by one allele is apparent, called dominant, and the appearance/phenotype caused by the other allele is not apparent, called recessive. In the simplest case, the phenotypic effect of one allele completely masks the other in heterozygous combination; that is, the phenotype produced by the two alleles in heterozygous combination is identical to that produced by one of the two homozygous genotypes. The allele that masks the other is said to be dominant to the latter, and the alternative allele is said to be recessive to the former.[2]

[edit] Which trait is dominant?

The terms dominant and recessive refer to the interaction of alleles in producing the phenotype of the heterozygote. If there are two alternative phenotypes, by definition the phenotype exhibited by the heterozygote is called "dominant" and the "hidden" phenotype is called "recessive". The key concept of dominance is that the heterozygote is phenotypically identical to one of the two homozygotes. That trait corresponding to the dominant allele may then be called the "dominant" trait. Dominance is a genotypic relationship between alleles, as manifested in the phenotype. It is unrelated to the nature of the phenotype itself, e.g., whether it is regarded as normal or abnormal, standard or nonstandard, healthy or diseased, stronger or weaker, or more or less extreme. It is also important to distinguish between the

"round" gene locus, the "round" allele at that locus, and the "round" phenotype it produces. It is inaccurate to say that "the round gene dominates the wrinkled gene" or that "round peas dominate wrinkled peas."