Sickle-cell disease
Encyclopedia
Sickle-cell disease or sickle-cell anaemia (or anemia, SCA) or drepanocytosis, is an autosomal
recessive genetic blood disorder with overdominance
, characterized by red blood cell
s that assume an abnormal, rigid, sickle
shape. Sickling decreases the cells' flexibility and results in a risk of various complications. The sickling occurs because of a mutation
in the haemoglobin
gene
. Life expectancy is shortened, with studies reporting an average life expectancy of 42 in males and 48 in females.
Sickle-cell disease, usually presenting in childhood, occurs more commonly in people (or their descendants) from parts of tropical and sub-tropical regions where malaria
is or was common. One-third of all indigenous
inhabitants of Sub-Saharan Africa
carry the gene, because in areas where malaria is common, there is a fitness
benefit in carrying only a single sickle-cell gene (sickle cell trait
). Those with only one of the two alleles of the sickle-cell disease, while not totally resistant, are more tolerant to the infection and thus show less severe symptoms when infected.
The prevalence
of 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 1 out of 500 African-American children born will have sickle-cell anaemia.
Sickle-cell anaemia is the name of a specific form of sickle-cell disease in which there is homozygosity for the mutation that causes HbS. Sickle-cell anaemia is also referred to as "HbSS", "SS disease", "haemoglobin S" or permutations thereof. In heterozygous people, who have only one sickle gene and one normal adult haemoglobin gene, it is referred to as "HbAS" or "sickle cell trait". Other, rarer forms of sickle-cell disease include sickle-haemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/β+) and sickle beta-zero-thalassaemia (HbS/β0). These other forms of sickle-cell disease are compound heterozygous states in which the person has only one copy of the mutation that causes HbS and one copy of another abnormal haemoglobin allele
.
The term disease is applied, because the inherited abnormality causes a pathological condition that can lead to death and severe complications. Not all inherited variants of haemoglobin are detrimental, a concept known as genetic polymorphism.
, aplastic crisis, sequestration crisis, haemolytic crisis and others. Most episodes of sickle cell crises last between five and seven days.
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.
is frequently affected. It is usually infarcted
before the end of childhood in individuals suffering from sickle-cell anaemia. This autosplenectomy
increases the risk of infection from encapsulated organisms; preventive antibiotics and vaccinations are recommended for those with such asplenia
.
, 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.
, presenting as early as six months of age, and may occur in children with sickle trait. The crisis can last up to a month. 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. It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.
) is almost always asymptomatic, and the only usual significant manifestation is the renal concentrating defect presenting with isosthenuria
.
in the β-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 β-globin gene is found on chromosome 11, (Robbin's Pathology). The association of two wild-type α-globin subunits with two mutant β-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 β-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, 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 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. Healthy red blood cells typically live 90–120 days, but sickle cells only survive 10–20 days.
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.
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. 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.
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
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
. 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 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 so-called 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.
and cystic fibrosis
.
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.
, 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. 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 (Île-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-Côte d'Azur
at nearly 42% and the lowest number is in Brittany
at 4.40%.
, especially in Qatif City.
reveals haemoglobin levels in the range of 6–8 g/dL with a high reticulocyte
count (as the bone marrow compensates for the destruction of sickle cells by producing more red blood cells). In other forms of sickle-cell disease, Hb levels tend to be higher. A blood film
may show features of hyposplenism (target cells and Howell-Jolly bodies
).
Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite
. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test". A mixture of haemoglobin S (Hb S) in a reducing solution (such as sodium dithionite
) gives a turbid appearance, whereas normal Hb gives a clear solution.
Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis
on which the various types of haemoglobin move at varying speeds. Sickle-cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography
(HPLC). Genetic testing
is rarely performed, as other investigations are highly specific for HbS and HbC.
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.
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.
s; pain management requires opioid
administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac
or naproxen
). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia
(PCA) devices are commonly used in this setting. Diphenhydramine
is also an effective agent that is frequently prescribed by doctors in order to help control any itching associated with the use of opioids.
, 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.
, 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.
s 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. 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.
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. 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.
The disease was named "sickle-cell anemia" by Verne Mason
in 1922, then a medical resident at Johns Hopkins Hospital
. 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. Also, the practice of using tar soap to cover blemishes caused by sickle-cell sores was prevalent in the black community.
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
".
Autosome
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. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive genetic blood disorder with overdominance
Overdominance
Overdominance is a condition in genetics where the phenotype of the heterozygote lies outside of the phenotypical range of both homozygote parents. Overdominance can also be described as heterozygote advantage, wherein heterozygous individuals have a higher fitness than homozygous individuals.An...
, characterized by red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s that assume an abnormal, rigid, sickle
Sickle
A sickle is a hand-held agricultural tool with a variously curved blade typically used for harvesting grain crops or cutting succulent forage chiefly for feeding livestock . Sickles have also been used as weapons, either in their original form or in various derivations.The diversity of sickles that...
shape. Sickling decreases the cells' flexibility and results in a risk of various complications. The sickling occurs because of a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in the haemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Life expectancy is shortened, with studies reporting an average life expectancy of 42 in males and 48 in females.
Sickle-cell disease, usually presenting in childhood, occurs more commonly in people (or their descendants) from parts of tropical and sub-tropical regions where malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
is or was common. One-third of all indigenous
Indigenous peoples
Indigenous peoples are ethnic groups that are defined as indigenous according to one of the various definitions of the term, there is no universally accepted definition but most of which carry connotations of being the "original inhabitants" of a territory....
inhabitants of Sub-Saharan Africa
Sub-Saharan Africa
Sub-Saharan Africa as a geographical term refers to the area of the African continent which lies south of the Sahara. A political definition of Sub-Saharan Africa, instead, covers all African countries which are fully or partially located south of the Sahara...
carry the gene, because in areas where malaria is common, there is a fitness
Physical fitness
Physical fitness comprises two related concepts: general fitness , and specific fitness...
benefit in carrying only a single sickle-cell gene (sickle cell trait
Sickle cell trait
Sickle cell trait describes a condition in which a person has one abnormal allele of the hemoglobin beta gene , but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele...
). Those with only one of the two alleles of the sickle-cell disease, while not totally resistant, are more tolerant to the infection and thus show less severe symptoms when infected.
The prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of the disease in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
is approximately 1 in 5,000, mostly affecting Americans of Sub-Saharan African descent, according to the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
. In the United States, about 1 out of 500 African-American children born will have sickle-cell anaemia.
Sickle-cell anaemia is the name of a specific form of sickle-cell disease in which there is homozygosity for the mutation that causes HbS. Sickle-cell anaemia is also referred to as "HbSS", "SS disease", "haemoglobin S" or permutations thereof. In heterozygous people, who have only one sickle gene and one normal adult haemoglobin gene, it is referred to as "HbAS" or "sickle cell trait". Other, rarer forms of sickle-cell disease include sickle-haemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/β+) and sickle beta-zero-thalassaemia (HbS/β0). These other forms of sickle-cell disease are compound heterozygous states in which the person has only one copy of the mutation that causes HbS and one copy of another abnormal haemoglobin allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
.
The term disease is applied, because the inherited abnormality causes a pathological condition that can lead to death and severe complications. Not all inherited variants of haemoglobin are detrimental, a concept known as genetic polymorphism.
Signs and symptoms
Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.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 crisisVaso-occlusive crisis
A vaso-occlusive crisis is a common painful complication of sickle cell anemia in adolescents and adults. It is a form of sickle cell crisis. It occurs when the circulation of blood vessels is obstructed by sickled red blood cells, causing ischemic injuries...
, aplastic crisis, sequestration crisis, haemolytic crisis and others. Most episodes of sickle cell crises last between five and seven days.
Vaso-occlusive crisis
The vaso-occlusive crisisVaso-occlusive crisis
A vaso-occlusive crisis is a common painful complication of sickle cell anemia in adolescents and adults. It is a form of sickle cell crisis. It occurs when the circulation of blood vessels is obstructed by sickled red blood cells, causing ischemic injuries...
is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ, resulting in ischaemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
, pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
, necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
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
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
or naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia
Patient-controlled analgesia
Patient-controlled analgesia is any method of allowing a person in pain to administer their own pain relief. The infusion is programmable by the prescriber...
(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
Diphenhydramine
Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
is sometimes effective for the itching associated with the opioid use. Incentive spirometry
Incentive spirometer
An incentive spirometer is a medical device used to help patients improve the functioning of their lungs. It is provided to patients who have had any surgery that might jeopardize respiratory function, particularly surgery to the lungs themselves, but also commonly to patients recovering from...
, a technique to encourage deep breathing to minimise the development of atelectasis
Atelectasis
Atelectasis is defined as the collapse or closure of alveoli resulting in reduced or absent gas exchange. It may affect part or all of one lung. It is a condition where the alveoli are deflated, as distinct from pulmonary consolidation.It is a very common finding in chest x-rays and other...
, is recommended.
Splenic sequestration crisis
Because of its narrow vessels and function in clearing defective red blood cells, the spleenSpleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
is frequently affected. It is usually infarcted
Infarction
In medicine, infarction refers to tissue death that is caused by a local lack of oxygen due to obstruction of the tissue's blood supply. The resulting lesion is referred to as an infarct.-Causes:...
before the end of childhood in individuals suffering from sickle-cell anaemia. This autosplenectomy
Autosplenectomy
An autosplenectomy occurs when a disease damages the spleen to such an extent that it ends up shrunk.-Consequences:...
increases the risk of infection from encapsulated organisms; preventive antibiotics and vaccinations are recommended for those with such asplenia
Asplenia
Asplenia refers to the absence of normal spleen function and is associated with some serious infection risks. Hyposplenism is used to describe reduced splenic functioning, but not as severely affected as with asplenism.-Congenital:...
.
- 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 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.
Aplastic crisis
Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pallorPallor
Pallor is a reduced amount of oxyhaemoglobin in skin or mucous membrane, a pale color which can be caused by illness, emotional shock or stress, stimulant use, lack of exposure to sunlight, anaemia or genetics....
, tachycardia, and fatigue. This crisis is triggered by parvovirus B19
Parvovirus B19
The B19 virus, generally referred to as parvovirus B19 or sometimes erythrovirus B19, was the first known human virus in the family of parvoviruses, genus erythrovirus...
, which directly affects erythropoiesis
Erythropoiesis
Erythropoiesis is the process by which red blood cells are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin...
(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
Reticulocyte
Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...
counts drop dramatically during the disease (causing reticulocytopenia
Reticulocytopenia
Reticulocytopenia, or "aplastic crisis", is the medical term for an abnormal decrease of reticulocytes in the body. Reticulocytopenia can originate from congenital hemolytic anemia, especially when exacerbated by Parvovirus B19 infection...
), 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 co-existent G6PD deficiency. Management is supportive, sometimes with blood transfusions.Other
One of the earliest clinical manifestations is dactylitisDactylitis
Dactylitis or sausage digit is inflammation of an entire digit , and can be painful.The word dactyl comes from the Greek word "daktylos" meaning "finger"...
, presenting as early as six months of age, and may occur in children with sickle trait. The crisis can last up to a month. Another recognised type of sickle crisis is the acute chest syndrome
Acute chest syndrome
The acute chest syndrome is a noninfectious vaso-occlusive crisis of the pulmonary vasculature commonly seen in patients with sickle cell anemia.It is characterized by a new infiltrate on a chest x-ray.-Cause:...
, a condition characterised by fever, chest pain, difficulty breathing, and pulmonary infiltrate on a chest X-ray
Chest X-ray
In medicine, a chest radiograph, commonly called a chest X-ray , is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures...
. 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.
Complications
Sickle-cell anaemia can lead to various complications, including:- Overwhelming post-(auto)splenectomy infectionOverwhelming post-splenectomy infectionAn overwhelming post-splenectomy infection is a rare but rapidly fatal infection occurring in individuals following removal of the spleen...
(OPSI), which is due to functional asplenia, caused by encapsulated organisms such as Streptococcus pneumoniaeStreptococcus pneumoniaeStreptococcus pneumoniae, or pneumococcus, is Gram-positive, alpha-hemolytic, aerotolerant anaerobic member of the genus Streptococcus. A significant human pathogenic bacterium, S...
and Haemophilus influenzaeHaemophilus influenzaeHaemophilus influenzae, formerly called Pfeiffer's bacillus or Bacillus influenzae, Gram-negative, rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the Pasteurellaceae family, it is generally aerobic, but can grow as a facultative anaerobe. H...
. Daily penicillinPenicillinPenicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
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. - StrokeStrokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, which can result from a progressive narrowing of blood vessels, preventing oxygen from reaching the brainHuman brainThe human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
. Cerebral infarction occurs in children and cerebral haemorrhage in adults. - Silent strokeSilent strokeA silent stroke is a stroke that does not have any outward symptoms, and the patient is typically unaware they have suffered a stroke. Despite not causing identifiable symptoms a silent stroke still causes damage to the brain, and places the patient at increased risk for both transient ischemic...
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 10–15% of children with sickle cell disease suffer strokes, with silent strokes predominating in the younger patients. - Cholelithiasis (gallstones) and cholecystitisCholecystitis-Signs and symptoms:Cholecystitis usually presents as a pain in the right upper quadrant. This is known as biliary colic. This is initially intermittent, but later usually presents as a constant, severe pain. During the initial stages, the pain may be felt in an area totally separate from the site...
, which may result from excessive bilirubinBilirubinBilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
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.
- Decreased immune reactionsImmune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
due to hyposplenism (malfunctioning of the spleen). - PriapismPriapismPriapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
and infarctionInfarctionIn medicine, infarction refers to tissue death that is caused by a local lack of oxygen due to obstruction of the tissue's blood supply. The resulting lesion is referred to as an infarct.-Causes:...
of the penisPenisThe penis is a biological feature of male animals including both vertebrates and invertebrates...
. - OsteomyelitisOsteomyelitisOsteomyelitis simply means an infection of the bone or bone marrow...
(bacterial bone infection); the most common cause of osteomyelitis in sickle cell disease is SalmonellaSalmonellaSalmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...
(especially the non-typical serotypes Salmonella typhimurium, Salmonella enteritidis, Salmonella choleraesuis and Salmonella paratyphi B), followed by Staphylococcus aureusStaphylococcus aureusStaphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
and Gram-negative enteric bacilli perhaps because intravascular sickling of the bowel leads to patchy ischaemic infarction. - OpioidOpioidAn opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
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 necrosisRenal papillary necrosisRenal papillary necrosis is a form of nephropathy involving the necrosis of the renal papilla, which is supplied by the vasa recta.-Causes:Analgesic nephropathy is a cause of renal papillary necrosis. The damage is cumulative and most patients of renal papillary necrosis would have ingested at...
in the kidneys. - Leg ulcers.
- In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages and retinal detachments, resulting in blindness. Regular annual eye checks are recommended.
- During pregnancy, intrauterine growth retardation, spontaneous abortionAbortionAbortion is defined as the termination of pregnancy by the removal or expulsion from the uterus of a fetus or embryo prior to viability. An abortion can occur spontaneously, in which case it is usually called a miscarriage, or it can be purposely induced...
, and pre-eclampsiaPre-eclampsiaPre-eclampsia or preeclampsia is a medical condition in which hypertension arises in pregnancy in association with significant amounts of protein in the urine....
. - Chronic pain: Even in the absence of acute vaso-occlusive pain, many patients have chronic pain that is not reported.
- Pulmonary hypertensionPulmonary hypertensionIn medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
(increased pressure on the pulmonary arteryPulmonary arteryThe pulmonary arteries carry deoxygenated blood from the heart to the lungs. They are the only arteries that carry deoxygenated blood....
), leading to strain on the right ventricleRight ventricleThe right ventricle is one of four chambers in the human heart. It receives deoxygenated blood from the right atrium via the tricuspid valve, and pumps it into the pulmonary artery via the pulmonary valve and pulmonary trunk....
and a risk of heart failure; typical symptoms are shortness of breath, decreased exercise tolerance and episodes of syncopeSyncope (medicine)Syncope , the medical term for fainting, is precisely defined as a transient loss of consciousness and postural tone characterized by rapid onset, short duration, and spontaneous recovery due to global cerebral hypoperfusion that most often results from hypotension.Many forms of syncope are...
. - Chronic renal failureRenal failureRenal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
due to Sickle cell nephropathySickle cell nephropathySickle cell nephropathy is a type of nephropathy associated with sickle cell disease, it causes renal complications as a result of sickling of red blood cells in the microvasculature...
—manifests itself with hypertensionHypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
(high blood pressure), proteinuriaProteinuriaProteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
(protein loss in the urine), haematuriaHematuriaIn medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
(loss of red blood cells in urine) and worsened anaemia. If it progresses to end-stage renal failure, it carries a poor prognosis.
Heterozygotes
The heterozygous form (sickle cell traitSickle cell trait
Sickle cell trait describes a condition in which a person has one abnormal allele of the hemoglobin beta gene , but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele...
) is almost always asymptomatic, and the only usual significant manifestation is the renal concentrating defect presenting with isosthenuria
Isosthenuria
Isosthenuria refers to the excretion of urine whose specific gravity is neither greater nor less than that of protein-free plasma, typically 1.008-1.012....
.
Pathophysiology
Sickle-cell anaemia is caused by a point mutationPoint mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...
in the β-globin chain of haemoglobin, causing the hydrophilic amino acid glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
to be replaced with the hydrophobic amino acid valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
at the sixth position. The β-globin gene is found on chromosome 11, (Robbin's Pathology). The association of two wild-type α-globin subunits with two mutant β-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 β-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, 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
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
, the destruction of the red cells inside the spleen, because of their misshape. Although the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically live 90–120 days, but sickle cells only survive 10–20 days.
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.
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 Saudi-Asian. 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.In people heterozygous for HgbS (carriers
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
of sickling haemoglobin), the polymerisation problems are minor, because the normal allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
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
Doughnut
A doughnut or donut is a fried dough food and is popular in many countries and prepared in various forms as a sweet snack that can be homemade or purchased in bakeries, supermarkets, food stalls, and franchised specialty outlets...
-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries
Capillary
Capillaries are the smallest of a body's blood vessels and are parts of the microcirculation. They are only 1 cell thick. These microvessels, measuring 5-10 μm in diameter, connect arterioles and venules, and enable the exchange of water, oxygen, carbon dioxide, and many other nutrient and waste...
. Carriers have symptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
. Under normal circumstances, these painful crises occur about 0.8 times per year per patient. 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.
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of a single nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
(see single-nucleotide polymorphism - SNP) (A to T) of the β-globin gene, which results in glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
being substituted by valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
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
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of a single nucleotide, from a GAG to GTG codon mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
, becoming a GUG codon by transcription. This is normally a benign mutation, causing no apparent effects on the secondary
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
, tertiary
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
, or quaternary structure
Quaternary structure
In biochemistry, quaternary structure is the arrangement of multiple folded protein or coiling protein molecules in a multi-subunit complex.-Description and examples:...
of haemoglobin in conditions of normal oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
concentration. What it does allow for, under conditions of low oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
concentration, is the polymerization
Polymerization
In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form three-dimensional networks or polymer chains...
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
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
responsible for sickle-cell anaemia is autosomal
Autosome
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. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
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
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
. 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
Sickle cell trait
Sickle cell trait describes a condition in which a person has one abnormal allele of the hemoglobin beta gene , but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele...
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
Fitness (biology)
Fitness 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...
than either of the homozygotes. This is known as heterozygote advantage
Heterozygote advantage
A heterozygote advantage describes the case in which the heterozygote genotype has a higher relative fitness than either the homozygote dominant or homozygote recessive genotype. The specific case of heterozygote advantage is due to a single locus known as overdominance...
.
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
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
, the Mediterranean, India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
and the Middle East
Middle East
The Middle East is a region that encompasses Western Asia and Northern Africa. It is often used as a synonym for Near East, in opposition to Far 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 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
Plasmodium
Plasmodium is a genus of parasitic protists. Infection by these organisms is known as malaria. The genus Plasmodium was described in 1885 by Ettore Marchiafava and Angelo Celli. Currently over 200 species of this genus are recognized and new species continue to be described.Of the over 200 known...
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
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, where there is no endemic malaria, the prevalence of sickle-cell anaemia among blacks is lower (about 0.25%) than in West Africa
West Africa
West Africa or Western Africa is the westernmost region of the African continent. Geopolitically, the UN definition of Western Africa includes the following 16 countries and an area of approximately 5 million square km:-Flags of 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 so-called African American community of the USA
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
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.
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.Epidemiology
The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, 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 haemophiliaHaemophilia
Haemophilia is a group of hereditary genetic disorders that impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken. Haemophilia A is the most common form of the disorder, present in about 1 in 5,000–10,000 male births...
and cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
.
Africa
Three quarters of sickle-cell cases occur in Africa. A recent WHOWorld Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
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.
France
In EuropeEurope
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
, the highest prevalence of the disease has been observed in France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
. As a result of population growth in African-Caribbean regions of overseas France
Overseas departments and territories of France
The French Overseas Departments and Territories consist broadly of French-administered territories outside of the European continent. These territories have varying legal status and different levels of autonomy, although all have representation in the Parliament of France , and consequently the...
, and now immigration essentially from North
North Africa
North Africa or Northern Africa is the northernmost region of the African continent, linked by the Sahara to Sub-Saharan Africa. Geopolitically, the United Nations definition of Northern Africa includes eight countries or territories; Algeria, Egypt, Libya, Morocco, South Sudan, Sudan, Tunisia, and...
and sub-Saharan Africa
Sub-Saharan Africa
Sub-Saharan Africa as a geographical term refers to the area of the African continent which lies south of the Sahara. A political definition of Sub-Saharan Africa, instead, covers all African countries which are fully or partially located south of the Sahara...
to mainland France, sickle cell disease has become a major health problem in France. 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
Phenylketonuria
Phenylketonuria is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase , rendering it nonfunctional. This enzyme is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine...
(1/10,862), congenital hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
(1/3,132), congenital adrenal hyperplasia (1/19,008) and cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
(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 (Île-de-France
Île-de-France (région)
Île-de-France is the wealthiest and most populated of the twenty-two administrative regions of France, composed mostly of the Paris metropolitan area....
) 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-Côte d'Azur
Provence-Alpes-Côte d'Azur
Provence-Alpes-Côte d'Azur or PACA is one of the 27 regions of France.It is made up of:* the former French province of Provence* the former papal territory of Avignon, known as Comtat Venaissin...
at nearly 42% and the lowest number is in Brittany
Brittany
Brittany is a cultural and administrative region in the north-west of France. Previously a kingdom and then a duchy, Brittany was united to the Kingdom of France in 1532 as a province. Brittany has also been referred to as Less, Lesser or Little Britain...
at 4.40%.
Middle East
About 6,000 children are born annually with SCD, at least 50% of these in Saudi ArabiaSaudi Arabia
The Kingdom of Saudi Arabia , commonly known in British English as Saudi Arabia and in Arabic as as-Sa‘ūdiyyah , is the largest state in Western Asia by land area, constituting the bulk of the Arabian Peninsula, and the second-largest in the Arab World...
, especially in Qatif City.
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.Diagnosis
In HbSS, the full blood countComplete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
reveals haemoglobin levels in the range of 6–8 g/dL with a high reticulocyte
Reticulocyte
Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...
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
Blood film
A blood film or peripheral blood smear is a thin layer of blood smeared on a microscope slide and then stained in such a way to allow the various blood cells to be examined microscopically...
may show features of hyposplenism (target cells and Howell-Jolly bodies
Howell-Jolly body
Howell-Jolly bodies are histopathological findings of basophilic nuclear remnants in circulating erythrocytes. During maturation in the bone marrow erythrocytes normally expel their nuclei, but in some cases a small portion of DNA remains....
).
Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite
Sodium metabisulfite
Sodium metabisulfite or sodium pyrosulfite is an inorganic compound of chemical formula Na2S2O5. The substance is sometimes referred to as disodium...
. 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
Sodium dithionite
Sodium dithionite is a white crystalline powder with a weak sulfurous odor. It is a sodium salt of dithionous acid. Although it is stable under most conditions, it will decompose in hot water and in acid solutions...
) 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
Gel electrophoresis
Gel electrophoresis is a method used in clinical chemistry to separate proteins by charge and or size and in biochemistry and molecular biology to separate a mixed population of DNA and RNA fragments by length, to estimate the size of DNA and RNA fragments or to separate proteins by charge...
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
High-performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...
(HPLC). Genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
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
Occult
The word occult comes from the Latin word occultus , referring to "knowledge of the hidden". In the medical sense it is used to refer to a structure or process that is hidden, e.g...
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
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
before they have a child. A test to see if an unborn child has the disease takes either a blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
sample from the fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
or a sample of amniotic fluid
Amniotic fluid
Amniotic fluid or liquor amnii is the nourishing and protecting liquid contained by the amniotic sac of a pregnant woman.- Development 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.
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.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.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 analgesicAnalgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
s; pain management requires opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
or naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia
Patient-controlled analgesia
Patient-controlled analgesia is any method of allowing a person in pain to administer their own pain relief. The infusion is programmable by the prescriber...
(PCA) devices are commonly used in this setting. Diphenhydramine
Diphenhydramine
Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
is also an effective agent that is frequently prescribed by doctors in order to help control any 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 wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome), oxygen supplementation for hypoxiaHypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
, and close observation. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
or exchange transfusion
Exchange transfusion
An exchange transfusion is a medical treatment in which apheresis is used to remove one person's red blood cells or platelets and replace them with transfused blood products...
is indicated. The latter involves the exchange of a significant portion of the patients red cell mass for normal red cells, which decreases the percent of haemoglobin S in the patient's blood.
Hydroxyurea
The first approved drug for the causative treatment of sickle-cell anaemia, hydroxyureaHydroxyurea
Hydroxycarbamide or hydroxyurea is an antineoplastic drug, first synthesized in 1869, used in myeloproliferative disorders, specifically polycythemia vera and essential thrombocythemia...
, 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
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
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.
Transfusion therapy
Blood transfusionBlood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
s 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. In children prophylactic chronic red blood cell (RBC) transfusion therapy
Transfusion therapy (Sickle-cell disease)
Transfusion therapy for sickle-cell disease entails the use of blood tranfusions in the management of acute cases of sickle cell disease and as a prophylaxis to prevent complications by decreasing the number of red blood cells that can sickle by adding normal red blood cells...
has been shown to be efficacious to a certain extent in reducing the risk of first stroke or silent stroke when transcranial Doppler
Transcranial doppler
Transcranial Doppler is a test that measures the velocity of blood flow through the brain's blood vessels. Used to help in the diagnosis of emboli, stenosis, vasospasm from a subarachnoid hemorrhage , and other problems, this relatively quick and inexpensive test is growing in popularity in the...
(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.
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 (1861–1954), whose intern Ernest Edward Irons (1877–1959) found "peculiar elongated and sickle-shaped" cells in the blood of Walter Clement Noel, a 20-year-old first-year dental student from Grenada, after Noel was 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". Noel completed his studies and returned to the capital of Grenada (St. George's) to practice dentistry
Dentistry
Dentistry is the branch of medicine that is involved in the study, diagnosis, prevention, and treatment of diseases, disorders and conditions of the oral cavity, maxillofacial area and the adjacent and associated structures and their impact on the human body. Dentistry is widely considered...
. He died of pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
in 1916 and is buried in the Catholic cemetery at Sauteurs
Sauteurs
Sauteurs is a Fishing Town in the Saint Patrick Parish, Grenada and is the sixth largest in Grenada, with a population of about 1,300. It is located in the far north of that island overlooking Sauteurs Bay...
in the north of Grenada. 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.
The disease was named "sickle-cell anemia" by Verne Mason
Verne Mason
Verne Rheem Mason was an eminent internist and associate of Howard Hughes. Mason was chairman of the Howard Hughes Medical Institute's medical advisory committee.-Early years:...
in 1922, then a medical resident at Johns Hopkins Hospital
Johns Hopkins Hospital
The Johns Hopkins Hospital is the teaching hospital and biomedical research facility of Johns Hopkins University School of Medicine, located in Baltimore, Maryland . It was founded using money from a bequest by philanthropist Johns Hopkins...
. 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
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
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. Also, the practice of using tar soap to cover blemishes caused by sickle-cell sores was prevalent in the black community.
Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
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
History of molecular biology
The history of molecular biology begins in the 1930s with the convergence of various, previously distinct biological disciplines: biochemistry, genetics, microbiology, and virology...
, and it was published in their paper "Sickle Cell Anemia, a Molecular Disease
Sickle Cell Anemia, a Molecular Disease
"Sickle Cell Anemia, a Molecular Disease" is a 1949 scientific paper by Linus Pauling, Harvey A. Itano, Seymour J. Singer and Ibert C. Wells that established sickle-cell anemia as a genetic disease in which affected individuals have a different form of the metalloprotein hemoglobin in their blood...
".
See also
- Haematopoietic ulcerHematopoietic ulcerHematopoietic ulcers are those occurring with sickle cell anemia, Cooley anemia, congenital hemolytic anemia, polycythemia vera, thrombocytopenic purpura, macroglobulinemia, and cryoglobulinemia....
- African admixture in Europe