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Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
s. This leads to a rigid, sickle-like shape under certain circumstances. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain (known as a sickle cell crisis),
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
, swelling in the hands and feet, bacterial infections and
stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
. Long-term pain may develop as people get older. The average life expectancy in the developed world is 40 to 60 years. Sickle cell disease occurs when a person inherits two abnormal copies of the β-globin gene (''HBB'') that makes haemoglobin, one from each parent. This gene occurs in chromosome 11. Several subtypes exist, depending on the exact
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
in each haemoglobin gene. An attack can be set off by temperature changes, stress,
dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
, and high altitude. A person with a single abnormal copy does not usually have symptoms and is said to have sickle cell trait. Such people are also referred to as carriers. Diagnosis is by a blood test, and some countries test all babies at birth for the disease. Diagnosis is also possible during pregnancy. The care of people with sickle cell disease may include infection prevention with
vaccination Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulat ...
and
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
s, high fluid intake,
folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing a ...
supplementation, and
pain medication An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). I ...
. Other measures may include
blood transfusion Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
and the medication hydroxycarbamide (hydroxyurea). A small percentage of people can be cured by a transplant of bone marrow cells. , about 4.4 million people have sickle cell disease, while an additional 43 million have sickle cell trait. About 80% of sickle cell disease cases are believed to occur in
Sub-Saharan Africa Sub-Saharan Africa is, geographically, the area and regions of the continent of Africa that lies south of the Sahara. These include West Africa, East Africa, Central Africa, and Southern Africa. Geopolitically, in addition to the List of sov ...
. It also occurs to a lesser degree in parts of
India India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area, the List of countries and dependencies by population, second-most populous ...
,
Southern Europe Southern Europe is the southern region of Europe. It is also known as Mediterranean Europe, as its geography is essentially marked by the Mediterranean Sea. Definitions of Southern Europe include some or all of these countries and regions: Alb ...
, West Asia,
North Africa North Africa, or Northern Africa is a region encompassing the northern portion of the African continent. There is no singularly accepted scope for the region, and it is sometimes defined as stretching from the Atlantic shores of Mauritania in ...
and among people of African origin (sub-Saharan) living in other parts of the world. In 2015, it resulted in about 114,800 deaths. The condition was first described in the medical literature by American physician
James B. Herrick James Bryan Herrick (11 August 1861 in Oak Park, Illinois – 7 March 1954 in Chicago, Illinois) was an American physician and professor of medicine who practiced and taught in Chicago. He is credited with the description of sickle-cell dis ...
in 1910. In 1949, its genetic transmission was determined by E. A. Beet and J. V. Neel. In 1954, the protective effect against
malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. ...
of sickle cell trait was described.


Signs and symptoms

Signs of sickle cell disease usually begin in early childhood. The severity of symptoms can vary from person to person. Sickle cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.


Sickle cell crisis

The terms "sickle cell crisis" or "sickling crisis" may be used to describe several independent acute conditions occurring in patients with SCD, which results in anaemia and crises that could be of many types, including the vaso-occlusive crisis,
aplastic crisis Reticulocytopenia is the medical term for an abnormal decrease of reticulocytes in the body. Reticulocytes are new, immature red blood cells. Causes Reticulocytopenia is usually a result of viral parvovirus B19 infection, which invades and destr ...
, splenic sequestration crisis, haemolytic crisis, and others. Most episodes of sickle cell crises last between five and seven days. "Although infection, dehydration, and
acidosis Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma. The term ''acidemia'' describe ...
(all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."


Vaso-occlusive crisis

The vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ, resulting in
ischaemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
,
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
, necrosis, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration,
analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
s, and
blood transfusion Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
; pain management requires
opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...
drug administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manages on nonsteroidal anti-inflammatory drugs such as diclofenac or naproxen. For more severe crises, most patients require inpatient management for intravenous opioids;
patient-controlled analgesia Patient-controlled analgesia (PCA) is any method of allowing a person in pain to administer their own pain relief. The infusion is programmable by the prescriber. If it is programmed and functioning as intended, the machine is unlikely to deliver ...
devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis or lungs are considered an emergency and treated with red blood cell transfusions. Incentive spirometry, a technique to encourage deep breathing to minimise the development of
atelectasis Atelectasis is the collapse or closure of a lung resulting in reduced or absent gas exchange. It is usually unilateral, affecting part or all of one lung. It is a condition where the alveoli are deflated down to little or no volume, as distinct ...
, is recommended.


Splenic sequestration crisis

The
spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .
is frequently affected in sickle cell disease, as the sickle-shaped red blood cells cause narrowing of blood vessels and reduced function in clearing the defective cells. It is usually infarcted before the end of childhood in individuals with sickle cell anaemia. This spleen damage increases the risk of infection from
encapsulated organisms Encapsulation may refer to: Chemistry * Molecular encapsulation, in chemistry, the confinement of an individual molecule within a larger molecule * Micro-encapsulation, in material science, the coating of microscopic particles with another mater ...
; preventive antibiotics and vaccinations are recommended for those lacking proper spleen function. Splenic sequestration crises are acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells and resulting in a precipitous fall in haemoglobin levels with the potential for hypovolemic shock. Sequestration crises are considered an emergency. If not treated, patients may die within 1–2 hours due to circulatory failure. Management is supportive, sometimes with blood transfusion. These crises are transient; they continue for 3–4 hours and may last for one day.


Acute chest syndrome

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


Aplastic crisis

Aplastic crises are instances of an acute worsening of the patient's baseline anaemia, producing pale appearance,
fast heart rate Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (s ...
, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them. Parvovirus infection almost completely prevents red blood cell production for two to three days. In normal individuals, this is of little consequence, but the shortened red cell life of SCD patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the disease (causing
reticulocytopenia Reticulocytopenia is the medical term for an abnormal decrease of reticulocytes in the body. Reticulocytes are new, immature red blood cells. Causes Reticulocytopenia is usually a result of viral parvovirus B19 infection, which invades and destr ...
), and the rapid turnover of red cells leads to the drop in haemoglobin. This crisis takes 4 to 7 days to disappear. Most patients can be managed supportively; some need a 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 people with coexistent G6PD deficiency.Another influence of hemolytic crises in Sickle Cell Disease is oxidative stress on the erythrocytes, leukocytes, and platelets. When there is not enough red blood cell production in the bone marrow, the oxygen that the body receives, processes, and transports is unbalanced with the body’s antioxidants. There is an imbalance in the oxygen reactive species in the cells, which leads to more production of red blood cells that are not properly oxygenated or formed. Oxidative stress may lead to anemia because of the imbalance of oxygen in the tissue. Management is supportive, sometimes with blood transfusions.


Other

One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle cell trait. The crisis can last up to a month. Given that pneumonia and sickling in the lung can both produce symptoms of acute chest syndrome, the patient is treated for both conditions. It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery. Hematopoietic ulcers may also occur.


Complications

Sickle cell anaemia can lead to various complications, including: * Increased risk of severe bacterial infections is due to loss of functioning spleen tissue (and comparable to the risk of infections after having the spleen removed surgically). These infections are typically caused by encapsulated organisms such as '' Streptococcus pneumoniae'' and ''
Haemophilus influenzae ''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bact ...
''. Daily
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
prophylaxis is the most commonly used treatment during childhood, with some haematologists continuing treatment indefinitely. Patients benefit today from routine vaccination for ''S. pneumoniae''. *
Stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
, which can result from a progressive narrowing of blood vessels, prevents oxygen from reaching the
brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
. Cerebral infarction occurs in children and cerebral haemorrhage in adults. * Silent stroke causes no immediate symptoms, but is associated with damage to the brain. Silent stroke is probably five times as common as symptomatic stroke. About 10–15% of children with SCD have strokes, with silent strokes predominating in the younger patients. *
Cholelithiasis A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of mig ...
(gallstones) and
cholecystitis Cholecystitis is inflammation of the gallbladder. Symptoms include right upper abdominal pain, pain in the right shoulder, nausea, vomiting, and occasionally fever. Often gallbladder attacks (biliary colic) precede acute cholecystitis. The pai ...
may result from excessive
bilirubin Bilirubin (BR) ( Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from t ...
production and precipitation due to prolonged haemolysis. * Avascular necrosis (
aseptic bone necrosis Avascular necrosis (AVN), also called osteonecrosis or bone infarction, is death of bone tissue due to interruption of the blood supply. Early on, there may be no symptoms. Gradually joint pain may develop which may limit the ability to move. Co ...
) of the hip and other major joints may occur as a result of ischaemia. * Decreased immune reactions due to hyposplenism (malfunctioning of the spleen) * Priapism and
infarction Infarction is tissue death ( necrosis) due to inadequate blood supply to the affected area. It may be caused by artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as an infarct (from th ...
of the
penis A penis (plural ''penises'' or ''penes'' () is the primary sexual organ that male animals use to inseminate females (or hermaphrodites) during copulation. Such organs occur in many animals, both vertebrate and invertebrate, but males d ...
* Osteomyelitis (bacterial bone infection), the most common cause of osteomyelitis in SCD is '' Salmonella'' (especially the atypical serotypes ''Salmonella typhimurium, Salmonella enteritidis, Salmonella choleraesuis'', and ''Salmonella paratyphi'' B), followed by ''
Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posit ...
'' and Gram-negative enteric bacilli perhaps because intravascular sickling of the bowel leads to patchy ischaemic infarction. * Acute papillary necrosis in the kidneys * Leg ulcers * In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages, and retinal detachments can result in blindness. Regular annual eye checks are recommended. * During pregnancy,
intrauterine growth restriction Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...
, spontaneous
abortion Abortion is the termination of a pregnancy by removal or expulsion of an embryo or fetus. An abortion that occurs without intervention is known as a miscarriage or "spontaneous abortion"; these occur in approximately 30% to 40% of pre ...
, and
pre-eclampsia Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease ...
* Chronic pain: Even in the absence of acute vaso-occlusive pain, many patients have unreported chronic pain. * Pulmonary hypertension (increased pressure on the pulmonary artery) can lead to strain on the
right ventricle A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the uppe ...
and a risk of
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
; typical symptoms are shortness of breath, decreased exercise tolerance, and episodes of syncope. 21% of children and 30% of adults have evidence of pulmonary hypertension when tested; this is associated with reduced walking distance and increased mortality. *
Cardiomyopathy Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. ...
and left ventricular
diastolic dysfunction Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the l ...
caused by fibrosis or scarring of cardiac tissues. This also contributes to pulmonary hypertension, decreased exercise capacity, and arrhythmias. * Chronic
kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
due to sickle-cell nephropathy manifests itself with
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...
, protein loss in the urine, loss of red blood cells in urine and worsened anaemia. If it progresses to end-stage
kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
, it carries a poor prognosis.


Genetics

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 (HbF), consisting of two alpha and two gamma chains in their bodies. Of these three types, haemoglobin F dominates until about 6 weeks of age. Afterwards, haemoglobin A dominates throughout life. In people diagnosed with sickle cell disease, at least one of the β-globin subunits in haemoglobin A is replaced with what is known as haemoglobin S. In sickle cell anaemia, a common form of sickle cell disease, haemoglobin S replaces both β-globin subunits in the haemoglobin. Sickle cell disease has an autosomal recessive pattern of inheritance from parents. The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from her or his parents. If one parent has sickle cell anaemia and the other has sickle cell trait, then the child has a 50% chance of having sickle cell disease and a 50% chance of having sickle cell trait. When both parents have sickle cell trait, a child has a 25% chance of sickle cell disease; 25% do not carry any sickle cell alleles, and 50% have the heterozygous condition. Sickle cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis. These variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. Their clinical importance is because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease. The gene defect is a single
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
(see
single-nucleotide polymorphism In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently ...
– SNP) (GAG
codon The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
changing to GTG) of the β-globin gene, which results in glutamate (E/Glu) being substituted by
valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...
(V/Val) at position 6 (E6V substitution).Historic numbering put this glutamic acid residue at position 6 due to skipping the methionine (M/Met) start codon in protein amino acid position numbering. Current nomenclature calls for counting the methionine as the first amino acid, resulting in the glutamic acid residue falling at position 7. Many references still refer to position 6 and both should likely be referenced for clarity. Haemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. This is normally a benign mutation, causing no apparent effects on the secondary,
tertiary Tertiary ( ) is a widely used but obsolete term for the geologic period from 66 million to 2.6 million years ago. The period began with the demise of the non-avian dinosaurs in the Cretaceous–Paleogene extinction event, at the start ...
, or quaternary structures of haemoglobin in conditions of normal
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
concentration. However, under low
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
concentration, HbS
polymerizes In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many for ...
and forms fibrous precipitates because the deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices (Phe 85, Leu 88). In people
heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. ...
for HbS ( carriers of sickling haemoglobin), the polymerisation problems are minor because the normal
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chrom ...
can produce half of the haemoglobin. In people
homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
for HbS, the presence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth, doughnut-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers have symptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated. The
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chrom ...
responsible for sickle cell anaemia can be found on the short arm of chromosome 11, more specifically 11p15.5. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a
carrier Carrier may refer to: Entertainment * ''Carrier'' (album), a 2013 album by The Dodos * ''Carrier'' (board game), a South Pacific World War II board game * ''Carrier'' (TV series), a ten-part documentary miniseries that aired on PBS in April 20 ...
or heterozygote. Heterozygotes are still able to contract malaria, but their symptoms are generally less severe. Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as
Africa Africa is the world's second-largest and second-most populous continent, after Asia in both cases. At about 30.3 million km2 (11.7 million square miles) including adjacent islands, it covers 6% of Earth's total surface area ...
, the
Mediterranean The Mediterranean Sea is a sea connected to the Atlantic Ocean, surrounded by the Mediterranean Basin and almost completely enclosed by land: on the north by Western and Southern Europe and Anatolia, on the south by North Africa, and on ...
,
India India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area, the List of countries and dependencies by population, second-most populous ...
, and the
Middle East The Middle East ( ar, الشرق الأوسط, ISO 233: ) is a geopolitical region commonly encompassing Arabian Peninsula, Arabia (including the Arabian Peninsula and Bahrain), Anatolia, Asia Minor (Asian part of Turkey except Hatay Pro ...
. Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases. The malaria parasite has a complex lifecycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the ''
Plasmodium ''Plasmodium'' is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of ''Plasmodium'' species involve development in a blood-feeding insect host which then injects parasites into a ve ...
'' parasite unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle cell traits (selection for the heterozygote). In the United States, with no endemic malaria, the prevalence of sickle cell anaemia among people of African ancestry is lower (about 0.25%) than among people in
West Africa West Africa or Western Africa is the westernmost region of Africa. The United Nations defines Western Africa as the 16 countries of Benin, Burkina Faso, Cape Verde, The Gambia, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Liberia, Mali ...
(about 4.0%) and is falling. Without endemic malaria, the sickle cell mutation is purely disadvantageous and tends to decline in the affected population by
natural selection Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Cha ...
, and now artificially through prenatal genetic screening. However, the African American community descends from a significant admixture of several African and non-African ethnic groups and also represents the descendants of survivors of slavery and the slave trade. Thus, a degree of genetic dilution via crossbreeding with non-African people and high health-selective pressure through slavery (especially the slave trade and the frequently deadly
Middle Passage The Middle Passage was the stage of the Atlantic slave trade in which millions of enslaved Africans were transported to the Americas as part of the triangular slave trade. Ships departed Europe for African markets with manufactured goods (first ...
) may be the most plausible explanations for the lower prevalence of sickle cell anaemia (and, possibly, other genetic diseases) among African Americans compared to West Africans. Another factor that limits the spread of sickle cell genes in North America is the relative absence of
polygamy Crimes Polygamy (from Late Greek (') "state of marriage to many spouses") is the practice of marrying multiple spouses. When a man is married to more than one wife at the same time, sociologists call this polygyny. When a woman is marr ...
. In polygamous societies, affected males may father many children with multiple partners.


Pathophysiology

The loss of red blood cell elasticity is central to the pathophysiology of sickle cell disease. Normal red blood cells are quite elastic and have a biconcave disc shape, 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 Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
. The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days.


Diagnosis

In HbS, the
complete blood count A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and ...
reveals haemoglobin levels in the range of 6–8 g/dl with a high reticulocyte count (as the bone marrow compensates for the destruction of sickled cells by producing more red blood cells). In other forms of sickle cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (
target cells Codocytes, also known as target cells, are red blood cells that have the appearance of a shooting target with a bullseye. In optical microscopy these cells appear to have a dark center (a central, hemoglobinized area) surrounded by a white ring ( ...
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" (also called "sickledex"). A mixture of haemoglobin S (HbS) 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 Hemoglobin C (abbreviated as HbC) is an abnormal hemoglobin in which glutamic acid residue at the 6th position of the β-globin chain is replaced with a lysine residue due to a point mutation in the ''HBB'' gene. People with one copy of the gene ...
with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography. Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC. An acute sickle cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an
occult The occult, in the broadest sense, is a category of esoteric supernatural beliefs and practices which generally fall outside the scope of religion and science, encompassing phenomena involving otherworldly agency, such as magic and mysticism a ...
urinary tract infection, and chest X-ray to look for occult pneumonia should be routinely performed. People who are known carriers of the disease or at risk of having a child with sickle cell anemia may undergo
genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease; t ...
. Genetic counselors work with families to discuss the benefits, limitations, and logistics of genetic testing options as well as the potential impact of testing and test results on the individual. During pregnancy, genetic testing can be done on either a blood sample from the
fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...
or a sample of
amniotic fluid The amniotic fluid is the protective liquid contained by the amniotic sac of a gravid amniote. This fluid serves as a cushion for the growing fetus, but also serves to facilitate the exchange of nutrients, water, and biochemical products between ...
. During the first trimester of pregnancy, chorionic villus sampling (CVS) is also a technique used for SCD prenatal diagnosis. Since taking a blood sample from a fetus has greater risks, the latter test is usually used. Neonatal screening sometimes referred to as
newborn screening Newborn screening (NBS) is a public health program of screening in infants shortly after birth for conditions that are treatable, but not clinically evident in the newborn period. The goal is to identify infants at risk for these conditions ea ...
, provides not only a method of early detection for individuals with sickle cell disease but also allows for the identification of the groups of people who carry the sickle cell trait. Genetic counselors can help individuals of colour and their families tackle the racial and ethnic disparities that exist in healthcare. In 2010, there was significant consideration and debate in the US surrounding comprehensive screening of athletes for SCD. The American Society of Hematology concluded in a statement in 2012 that they do not support testing or disclosure of sickle cell trait status as a prerequisite for participation in athletic activities due to lack of scientific evidence, inconsistency with good medical practice, and inconsistency with public health ethics. They recommended universal interventions to reduce exertion-related injuries and deaths effective for all athletes irrespective of their sickle cell status.


Management

Treatment involves a number of measures. While it has been historically recommended that people with sickle cell disease avoid exercise, regular exercise may benefit people. Dehydration should be avoided. A diet high in calcium is recommended but the effectiveness of
vitamin D Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group ar ...
supplementation remains uncertain. L-glutamine use was supported by the FDA starting at the age of five, as it decreases complications.


Folic acid and penicillin

From birth to five years of age,
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
daily, due to the immature immune system that makes them more prone to early childhood illnesses, is recommended. Dietary supplementation of
folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing a ...
had been previously recommended by the WHO. A 2016
Cochrane Cochrane may refer to: Places Australia *Cochrane railway station, Sydney, a railway station on the closed Ropes Creek railway line Canada * Cochrane, Alberta * Cochrane Lake, Alberta * Cochrane District, Ontario ** Cochrane, Ontario, a town wit ...
review of its use found "the effect of supplementation on anaemia and any symptoms of anaemia remains unclear" due to a lack of medical evidence.


Malaria prevention

The protective effect of sickle cell trait does not apply to people with sickle cell disease; in fact, they are more vulnerable to malaria, since the most common cause of painful crises in malarial countries is infection with malaria. People with sickle cell disease living in malarial countries should receive lifelong medication for prevention.


Vaso-occlusive crisis

Most people with sickle cell disease have intensely painful episodes called vaso-occlusive crises. However, the frequency, severity, and duration of these crises vary tremendously. Painful crises are treated symptomatically with
pain medications An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It i ...
; pain management requires opioid drug administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manages on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids. Extra fluids, administered either orally or intravenously, are a routine part of treatment of vaso-occlusive crises but the evidence about the most effective route, amount and type of fluid replacement remains uncertain. Crizanlizumab, a monoclonal antibody target towards p-selectin was approved in 2019 in the United States to reduce the frequency of vaso-occlusive crisis in those 16 years and older.


Stroke prevention

Transcranial Doppler ultrasound (TCD) can detect children with sickle cell that have a high risk for stroke. The ultrasound test detects blood vessels partially obstructed by sickle cells by measuring the rate of blood into the brain, as blood flow velocity is inversely related to arterial diameter, and consequently, high blood-flow velocity is correlated with narrowing of the arteries. In 2002 the National Institute of Health (NIH) issued a statement recommending that children with sickle cell get the Transcranial Doppler ultrasound screen annually, and in 2014 a panel of experts convened by the NIH issued guidelines reiterating the same recommendation. One review of medical records, by hematologist Dr. Julie Kanter at the University of Alabama at Birmingham, showed that on average only 48.4 percent of children with sickle cell get the recommended ultrasound test. A 1994 NIH study showed that children at risk for strokes who received blood transfusions had an annual stroke rate of less than 1 percent, whereas those children who did not receive blood transfusions had a 10 percent stroke rate per year. (Also see 1998 study in the ''New England Journal of Medicine''.) In addition to ultrasounds and blood transfusions, the inexpensive
generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active c ...
hydroxyurea can reduce the risk of irreversible organ and brain damage. Guidelines from NIH published in 2014 state that all children and adolescents should take hydroxyurea, as should adults with serious complications or three or more pain crises in a year.


Acute chest syndrome

Management is similar to vaso-occlusive crisis, with the addition of antibiotics (usually a quinolone or macrolide, since cell wall-deficient atypical"bacteria are thought to contribute to the syndrome), oxygen supplementation for hypoxia, and close observation. In the absence of high quality evidence regarding the effectiveness of antibiotics for acute chest syndrome in people with sickle cell disease, there is no standard antibiotic treatment as of 2019. It is recommended that people with suspected acute chest syndrome should be admitted to the hospital with worsening A-a gradient an indication for ICU admission. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple
blood transfusion Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
or
exchange transfusion An exchange transfusion is a blood transfusion in which the patient's blood or components of it are exchanged with (replaced by) other blood or blood products. The patient's blood is removed and replaced by donated blood or blood components. This ...
is indicated. The latter involves the exchange of a significant portion of the person's red cell mass for normal red cells, which decreases the level of haemoglobin S in the patient's blood. However, there is currently uncertain evidence about the possible benefits or harms of blood transfusion for acute chest syndrome in people with sickle cell disease.


Hydroxyurea

Hydroxyurea, also known as hydroxycarbamide, probably reduces the frequency of painful episodes and the risk of life-threatening illness or death but there is currently insufficient evidence regarding the risk of adverse effects. Hydroxyurea and phlebotomy combined may be more effective than transfusion and chelation combined in terms of pain, life-threatening illness and risk of death. It was the first approved drug for the treatment of sickle cell anaemia, and was shown to decrease the number and severity of attacks in 1995 and shown to possibly increase survival time in a study in 2003. 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 (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
agent, and some concern exists that long-term use may be harmful, but this risk is either absent or very small and the benefits likely outweigh the risks. Voxelotor was approved in the United States in 2019 to increase hemoglobin in people with SS disease.


Blood transfusion

Blood transfusion Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
s are often used in the management of sickle cell disease in acute cases and to prevent complications by decreasing the number of red blood cells (RBCs) that can sickle by adding normal red blood cells. In children, preventive RBC transfusion therapy has been shown to reduce the risk of first stroke or silent stroke when
transcranial Doppler Transcranial Doppler (TCD) and transcranial color Doppler (TCCD) are types of Doppler ultrasonography that measure the velocity of blood flow through the brain's blood vessels by measuring the echoes of ultrasound waves moving transcranially ...
ultrasonography shows abnormal cerebral blood flow. In those who have sustained a prior stroke event, it also reduces the risk of recurrent stroke and additional silent strokes.


Bone marrow transplant

Bone marrow transplants have proven effective in children; they are the only known cure for SCD. However, bone marrow transplants are difficult to obtain because of the specific HLA typing necessary. Ideally, a close relative (allogeneic) would donate the bone marrow necessary for transplantation. Some gene therapies are under development that would alter the patient's own bone marrow stem cells ''ex vivo,'' which can then be transplanted back into the patient after chemotherapy eliminates the original unmodified cells.


Avascular necrosis

When treating avascular necrosis of the bone in people with sickle cell disease, the aim of treatment is to reduce or stop the pain and maintain joint mobility. Current treatment options include resting the joint,
physical therapy Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, pat ...
, pain-relief medicine, joint-replacement surgery, or
bone grafting Bone grafting is a surgical procedure that replaces missing bone in order to repair bone fractures that are extremely complex, pose a significant health risk to the patient, or fail to heal properly. Some small or acute fractures can be cured wit ...
. High quality, randomized, controlled trials are needed to assess the most effective treatment option and determine if a combination of physical therapy and surgery is more effective than physical therapy alone.


Psychological therapies

Psychological therapies such as patient education,
cognitive therapy Cognitive therapy (CT) is a type of psychotherapy developed by American psychiatrist Aaron T. Beck. CT is one therapeutic approach within the larger group of cognitive behavioral therapies (CBT) and was first expounded by Beck in the 1960s. Co ...
,
behavioural therapy Behaviour therapy or behavioural psychotherapy is a broad term referring to clinical psychotherapy that uses techniques derived from behaviourism and/or cognitive psychology. It looks at specific, learned behaviours and how the environment, or ot ...
, and psychodynamic psychotherapy, that aim to complement current medical treatments, require further research to determine their effectiveness.


Prognosis

About 90% of people survive to age 20, and close to 50% survive beyond age 50. In 2001, according to one study performed in Jamaica, the estimated mean survival for people was 53 years for men and 58 years for women with homozygous SCD. The specific life expectancy in much of the developing world is unknown. In 1975 about 7.3% of people with SCD died before their 23rd birthday; while in 1989 2.6% of people with SCD died by the age of 20.


Epidemiology

The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India, and the Middle East. Migration of substantial populations from these high-prevalence areas to low-prevalence countries in Europe has dramatically increased in recent decades and in some European countries, sickle cell disease has now overtaken more familiar genetic conditions such as
haemophilia Haemophilia, or hemophilia (), is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruisin ...
and cystic fibrosis. In 2015, it resulted in about 114,800 deaths. Sickle cell disease occurs more commonly among people whose ancestors lived in
tropical The tropics are the regions of Earth surrounding the Equator. They are defined in latitude by the Tropic of Cancer in the Northern Hemisphere at N and the Tropic of Capricorn in the Southern Hemisphere at S. The tropics are also referred to ...
and
subtropical The subtropical zones or subtropics are geographical and climate zones to the north and south of the tropics. Geographically part of the temperate zones of both hemispheres, they cover the middle latitudes from to approximately 35° north a ...
sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single sickle cell
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chrom ...
(trait) confers a
heterozygote advantage A heterozygote advantage describes the case in which the heterozygous genotype has a higher relative fitness than either the homozygous dominant or homozygous recessive genotype. Loci exhibiting heterozygote advantage are a small minority of ...
; humans with one of the two alleles of sickle cell disease show less severe symptoms when infected with malaria. This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.


Africa

Three-quarters of sickle cell cases occur in Africa. A recent WHO report estimated that around 2% of newborns in
Nigeria Nigeria ( ), , ig, Naìjíríyà, yo, Nàìjíríà, pcm, Naijá , ff, Naajeeriya, kcg, Naijeriya officially the Federal Republic of Nigeria, is a country in West Africa. It is situated between the Sahel to the north and the Gulf o ...
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. Studies in Africa show a significant decrease in infant mortality rate, ages 2–16 months, because of the sickle cell trait. This happened in areas of predominant malarial cases.
Uganda }), is a landlocked country in East Africa. The country is bordered to the east by Kenya, to the north by South Sudan, to the west by the Democratic Republic of the Congo, to the south-west by Rwanda, and to the south by Tanzania. The ...
has the fifth-highest sickle cell disease burden in Africa. One study indicates that 20 000 babies per year are born with sickle cell disease with the sickle cell trait at 13·3% and with disease 0·7%.


United States

The number of people with the disease in the
United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...
is about 100,000 (one in 3,300), mostly affecting Americans of sub-Saharan African descent. In the United States, about one out of 365 African-American children and one in every 16,300 Hispanic-American children have sickle cell anaemia. The life expectancy for men with SCD is approximately 42 years of age while women live approximately six years longer. An additional 2 million are carriers of the sickle cell trait. Most infants with SCD born in the United States are identified by routine neonatal screening. As of 2016 all 50 states include screening for sickle cell disease as part of their newborn screen. The newborn's blood is sampled through a heel-prick and is sent to a lab for testing. The baby must have been eating for a minimum of 24 hours before the heel-prick test can be done. Some states also require a second blood test to be done when the baby is two weeks old to ensure the results. Sickle cell anemia is the most common genetic disorder among African Americans. Approximately 8% are carriers and 1 in 375 are born with the disease. Patient advocates for sickle cell disease have complained that it gets less government and private research funding than similar rare diseases such as cystic fibrosis, with researcher Elliott Vichinsky saying this shows racial discrimination or the role of wealth in health care advocacy.


France

As a result of population growth in African-Caribbean regions of
overseas France Overseas France (french: France d'outre-mer) consists of 13 France, French-administered territories outside Europe, mostly the remains of the French colonial empire that chose to remain a part of the French state under various statuses after ...
and immigration from
North North is one of the four compass points or cardinal directions. It is the opposite of south and is perpendicular to east and west. ''North'' is a noun, adjective, or adverb indicating direction or geography. Etymology The word ''north ...
and sub-Saharan Africa to mainland France, sickle cell disease has become a major health problem in France. SCD has become the most common genetic disease in the country, with an overall birth prevalence of one in 2,415 in
metropolitan France Metropolitan France (french: France métropolitaine or ''la Métropole''), also known as European France (french: Territoire européen de la France) is the area of France which is geographically in Europe. This collective name for the European ...
, ahead of
phenylketonuria Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may als ...
(one in 10,862), congenital
hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as ...
(one in 3,132), congenital adrenal hyperplasia (one in 19,008) and cystic fibrosis (one in 5,014) for the same reference period. Since 2000, neonatal screening of SCD has been performed at the national level for all newborns defined as being "at-risk" for SCD based on ethnic origin (defined as those born to parents originating from sub-Saharan Africa, North Africa, the Mediterranean area (South Italy,
Greece Greece,, or , romanized: ', officially the Hellenic Republic, is a country in Southeast Europe. It is situated on the southern tip of the Balkans, and is located at the crossroads of Europe, Asia, and Africa. Greece shares land borders wi ...
, and
Turkey Turkey ( tr, Türkiye ), officially the Republic of Türkiye ( tr, Türkiye Cumhuriyeti, links=no ), is a transcontinental country located mainly on the Anatolian Peninsula in Western Asia, with a small portion on the Balkan Peninsula ...
), the Arabic peninsula, the French overseas islands, and the Indian subcontinent).


United Kingdom

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


West Asia

In
Saudi Arabia Saudi Arabia, officially the Kingdom of Saudi Arabia (KSA), is a country in Western Asia. It covers the bulk of the Arabian Peninsula, and has a land area of about , making it the fifth-largest country in Asia, the second-largest in the Ara ...
, about 4.2% of the population carry the sickle cell trait and 0.26% have sickle cell disease. The highest prevalence is in the Eastern province, where approximately 17% of the population carry the gene and 1.2% have sickle cell disease. In 2005, Saudi Arabia introduced a mandatory premarital test including HB electrophoresis, which aimed to decrease the incidence of SCD and thalassemia. In
Bahrain Bahrain ( ; ; ar, البحرين, al-Bahrayn, locally ), officially the Kingdom of Bahrain, ' is an island country in Western Asia. It is situated on the Persian Gulf, and comprises a small archipelago made up of 50 natural islands and a ...
, a study published in 1998 that covered about 56,000 people in hospitals in Bahrain found that 2% of newborns have sickle cell disease, 18% of the surveyed people have the sickle cell trait, and 24% were carriers of the gene mutation causing the disease. The country began screening of all pregnant women in 1992 and newborns started being tested if the mother was a carrier. In 2004, a law was passed requiring couples planning to marry to undergo free premarital counseling. These programs were accompanied by public education campaigns.


India and Nepal

Sickle cell disease is common in some ethnic groups of central India, where the prevalence has ranged from 9.4 to 22.2% in endemic areas of
Madhya Pradesh Madhya Pradesh (, ; meaning 'central province') is a state in central India. Its capital is Bhopal, and the largest city is Indore, with Jabalpur, Ujjain, Gwalior, Sagar, and Rewa being the other major cities. Madhya Pradesh is the second ...
,
Rajasthan Rajasthan (; lit. 'Land of Kings') is a state in northern India. It covers or 10.4 per cent of India's total geographical area. It is the largest Indian state by area and the seventh largest by population. It is on India's northwestern ...
, and
Chhattisgarh Chhattisgarh (, ) is a landlocked state in Central India. It is the ninth largest state by area, and with a population of roughly 30 million, the seventeenth most populous. It borders seven states – Uttar Pradesh to the north, Madhya Prad ...
. It is also endemic among Tharu people of Nepal and India; however, they have a sevenfold lower rate of malaria despite living in a malaria infested zone.


Caribbean Islands

In
Jamaica Jamaica (; ) is an island country situated in the Caribbean Sea. Spanning in area, it is the third-largest island of the Greater Antilles and the Caribbean (after Cuba and Hispaniola). Jamaica lies about south of Cuba, and west of Hispa ...
, 10% of the population carry the sickle cell gene, making it the most prevalent genetic disorder in the country.


History

The first modern report of sickle cell disease may have been in 1846, where the autopsy of an executed runaway slave was discussed; the key finding was the absence of the spleen. Reportedly, African slaves in the United States exhibited resistance to malaria, but were prone to leg ulcers. The abnormal characteristics of the red blood cells, which later lent their name to the condition, was first described by Ernest E. Irons (1877–1959), intern to Chicago cardiologist and professor of medicine
James B. Herrick James Bryan Herrick (11 August 1861 in Oak Park, Illinois – 7 March 1954 in Chicago, Illinois) was an American physician and professor of medicine who practiced and taught in Chicago. He is credited with the description of sickle-cell dis ...
(1861–1954), in 1910. Irons saw "peculiar elongated and sickle-shaped" cells in the blood of a man named Walter Clement Noel, a 20-year-old first-year dental student from Grenada. Noel had been admitted to the Chicago Presbyterian Hospital in December 1904 with anaemia. Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" but completed his studies and returned to the capital of Grenada (St. George's) to practice dentistry. He died of
pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
in 1916 and is buried in the Catholic cemetery at
Sauteurs Sauteurs (pronounced Sau-tez) is a fishing town in the Saint Patrick Parish, Grenada and is the fourth-largest city on the island of Grenada, with a population of about 1,300. It is located in the far north of Grenada. Sauteurs is overlooking ove ...
in the north of Grenada. Shortly after the report by Herrick, another case appeared in the ''Virginia Medical Semi-Monthly'' with the same title, "Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia." This article is based on a patient admitted to the
University of Virginia The University of Virginia (UVA) is a public research university in Charlottesville, Virginia. Founded in 1819 by Thomas Jefferson, the university is ranked among the top academic institutions in the United States, with highly selective ad ...
Hospital on 15 November 1910. In the later description by Verne Mason in 1922, the name "sickle cell anemia" is first used. Childhood problems related to sickle cells disease were not reported until the 1930s, despite the fact that this cannot have been uncommon in African-American populations. Memphis physician Lemuel Diggs, a prolific researcher into sickle cell disease, first introduced the distinction between sickle cell disease and trait in 1933, although until 1949, the genetic characteristics had not been elucidated by
James V. Neel James Van Gundia Neel (March 22, 1915 – February 1, 2000) was an American geneticist who played a key role in the development of human genetics as a field of research in the United States. He made important contributions to the emergence of gen ...
and E.A. Beet. 1949 was the year when Linus Pauling described the unusual chemical behaviour of haemoglobin S, and attributed this to an abnormality in the molecule itself. The molecular change in HbS was described in 1956 by Vernon Ingram. The late 1940s and early 1950s saw further understanding in the link between malaria and sickle cell disease. In 1954, the introduction of haemoglobin electrophoresis allowed the discovery of particular subtypes, such as HbSC disease. Large-scale natural history studies and further intervention studies were introduced in the 1970s and 1980s, leading to widespread use of prophylaxis against pneumococcal infections amongst other interventions. Bill Cosby's Emmy-winning 1972 TV movie, '' To All My Friends on Shore'', depicted the story of the parents of a child with sickle cell disease. The 1990s had the development of hydroxycarbamide, and reports of cure through bone marrow transplantation appeared in 2007. Some old texts refer to it as drepanocytosis.


Society and culture


United States

Effective 15 September 2017, the U.S.
Social Security Administration The United States Social Security Administration (SSA) is an independent agency of the U.S. federal government that administers Social Security, a social insurance program consisting of retirement, disability and survivor benefits. To qualify f ...
issued a Policy Interpretation Ruling providing background information on sickle cell disease and a description of how
Social Security Welfare, or commonly social welfare, is a type of government support intended to ensure that members of a society can meet basic human needs such as food and shelter. Social security may either be synonymous with welfare, or refer specifical ...
evaluates the disease during its adjudication process for disability claims. In the U.S., there are stigmas surrounding SCD that discourage people with SCD from receiving necessary care. These stigmas mainly affect people of African American and Latin American ancestries, according to the National Heart, Lung, and Blood Institute. People with SCD experience the impact of stigmas of the disease on multiple aspects of life including social and psychological well-being. Studies have shown that those with SCD frequently feel as though they must keep their diagnosis a secret to avoid discrimination in the workplace and also among peers in relationships. In the 1960s, the US government supported initiatives for workplace
screening Screening may refer to: * Screening cultures, a type a medical test that is done to find an infection * Screening (economics), a strategy of combating adverse selection (includes sorting resumes to select employees) * Screening (environmental), ...
for genetic diseases in an attempt to be protective towards people with SCD. By having this screening, it was intended that employees would not be placed in environments that could potentially be harmful and trigger SCD.


Uganda

Uganda has the 5th highest sickle cell disease (SCD) burden in the world. In
Uganda }), is a landlocked country in East Africa. The country is bordered to the east by Kenya, to the north by South Sudan, to the west by the Democratic Republic of the Congo, to the south-west by Rwanda, and to the south by Tanzania. The ...
, social stigma exists for those with sickle cell disease because of the lack of general knowledge of the disease. The general gap in knowledge surrounding sickle cell disease is noted among adolescents and young adults due to the culturally sanctioned secrecy about the disease. While most people have heard generally about the disease, a large portion of the population is relatively misinformed about how SCD is diagnosed or inherited. Those who are informed about the disease learned about it from family or friends and not from
health professional A health professional, healthcare professional, or healthcare worker (sometimes abbreviated HCW) is a provider of health care treatment and advice based on formal training and experience. The field includes those who work as a nurse, physician (suc ...
s. Failure to provide the public with information about sickle cell disease results in a population with a poor understanding of the causes of the disease, symptoms, and prevention techniques. The differences, physically and socially, that arise in those with sickle cell disease, such as jaundice, stunted physical growth, and delayed sexual maturity, can also lead them to become targets of bullying, rejection, and stigma.


Rate of sickle cell disease in Uganda

The data compiled on sickle cell disease in Uganda has not been updated since the early 1970s. The deficiency of data is due to a lack of government research funds, even though Ugandans die daily from SCD. Data shows that the trait frequency of sickle cell disease is 20% of the population in Uganda. This means that 66 million people are at risk of having a child who has sickle cell disease. It is also estimated that about 25,000 Ugandans are born each year with SCD and 80% of those people don't live past five years old. SCD also contributes 25% to the child mortality rate in Uganda. The Bamba people of Uganda, located in the southwest of the country, carry 45% of the gene which is the highest trait frequency recorded in the world. The Sickle Cell Clinic in Mulago is only one sickle cell disease clinic in the country and on average sees 200 patients a day.


Misconceptions about sickle cell disease

The stigma around the disease is particularly bad in regions of the country that are not as affected. For example, Eastern Ugandans tend to be more knowledgeable of the disease than Western Ugandans, who are more likely to believe that sickle cell disease resulted as a punishment from God or
witchcraft Witchcraft traditionally means the use of magic or supernatural powers to harm others. A practitioner is a witch. In medieval and early modern Europe, where the term originated, accused witches were usually women who were believed to have ...
. Other misconceptions about SCD include the belief that it is caused by environmental factors but, in reality, SCD is a genetic disease. There have been efforts throughout Uganda to address the social misconceptions about the disease. In 2013, the Uganda Sickle Cell Rescue Foundation was established to spread awareness of sickle cell disease and combat the social stigma attached to the disease. In addition to this organization's efforts, there is a need for the inclusion of sickle cell disease education in preexisting community health education programs in order to reduce the stigmatization of sickle cell disease in Uganda.


Social isolation of people with sickle cell disease

The deeply rooted stigma of SCD from society causes families to often hide their family members' sick status for fear of being labeled, cursed, or left out of social events. Sometimes in Uganda, when it is confirmed that a family member has sickle cell disease, intimate relationships with all members of the family are avoided. The stigmatization and social isolation people with sickle cell disease tend to experience is often the consequence of popular misconceptions that people with SCD should not socialize with those free from the disease. This mentality robs people with SCD of the right to freely participate in community activities like everyone else SCD-related stigma and social isolation in schools, especially, can make a life for young people living with sickle cell disease extremely difficult. For school-aged children living with SCD, the stigma they face can lead to peer rejection. Peer rejection involves the exclusion from social groups or gatherings. It often leads the excluded individual to experience emotional distress and may result in their academic underperformance, avoidance of school, and occupational failure later in life. This social isolation is also likely to negatively impact people with SCD's
self-esteem Self-esteem is confidence in one's own worth or abilities. Self-esteem encompasses beliefs about oneself (for example, "I am loved", "I am worthy") as well as emotional states, such as triumph, despair, pride, and shame. Smith and Mackie (2007) d ...
and overall quality of life. Mothers of children with sickle cell disease tend to receive disproportionate amounts of stigma from their peers and family members. These women will often be blamed for their child's
diagnosis Diagnosis is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in many different disciplines, with variations in the use of logic, analytics, and experience, to determine "cause and effect". In systems engin ...
of SCD, especially if SCD is not present in earlier generations, due to the suspicion that the child's poor health may have been caused by the mother's failure to implement preventative health measures or promote a healthy environment for her child to thrive. The reliance on theories related to environmental factors to place blame on the mother reflects many Ugandan's poor knowledge of how the disease is acquired as it is determined by genetics, not environment. Mothers of children with sickle cell disease are also often left with very limited resources to safeguard their futures against the stigma of having SCD. This lack of access to resources results from their subordinating roles within familial structures as well as the class disparities that hinder many mothers' ability to satisfy additional childcare costs and responsibilities. Women living with SCD who become pregnant often face extreme discrimination and discouragement in Uganda. These women are frequently branded by their peers as irresponsible for having a baby while living with sickle cell disease or even engaging in sex while living with SCD. The criticism and judgement these women receive, not only from healthcare professionals but also from their families, often leaves them feeling alone, depressed, anxious, ashamed, and with very little social support. Most pregnant women with SCD also go on to be single mothers as it is common for them to be left by their male partners who claim they were unaware of their partner's SCD status. Not only does the abandonment experienced by these women cause emotional distress for them, but this low level of parental support can be linked to depressive symptoms and overall lower quality of life for the child once they are born.


United Kingdom

In 2021 many patients were found to be afraid to visit hospitals so purchasing pain relief to treat themselves outside the NHS, such was the level of ignorance among staff. They were often waiting a long time for pain relief, and sometimes suspected of “drugs-seeking” behaviour. Delays to treatment, failure to inform the hospital haematology team and poor pain management had caused deaths. Specialist haematology staff prefer to work in bigger, teaching hospitals, leading to shortages of expertise elsewhere. In 2021 the NHS initiated its first new treatment in 20 years for Sickle Cell. This involved the use of Crizanlizumab, a drug given via transfusion drips, which reduces the number of visits to A and E by sufferers. The treatment can be accessed, via consultants, at any of ten new hubs set up around the country. In the same year, however, an All-Party Parliamentary Group produced a report on Sickle Cell and Thalassaemia entitled 'No-one is listening'. Partly in response to this, on 19 June 2022, World Sickle Cell Day, the NHS launched a campaign called " Can you tell it's sickle cell?". The campaign had twin aims. One was to increase awareness of the key signs and symptoms of the blood disorder so that people are as alert to signs of a sickle cell crisis as they are to an imminent heart attack or stroke. The second aim was to set up a new training programme to help paramedics, Accident and Emergency staff, carers and the general public to care effectively for sufferers in crisis.


Research


Umbilical cord blood transplant

While umbilical cord blood transplant can potentially cure the condition, a suitable donor is available in only 10% of people. About 7% of people also die as a result of the procedure and graft versus host disease may occur.


Gene therapy

Diseases such as sickle cell disease for which a person's normal
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...
or cell function may be restored in cells that have the disease by a normal copy of the gene that is mutated, may be a good candidate for gene therapy treatment. The risks and benefits related to gene therapy for sickle cell disease are not known. In 2001, sickle cell disease reportedly had been successfully treated in mice using
gene therapy Gene therapy is a Medicine, medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying ...
. The researchers used a viral vector to make the mice—which have essentially the same defect that causes human sickle cell disease—express production of fetal haemoglobin (HbF), which an individual normally ceases to produce shortly after birth. In humans, using hydroxyurea to stimulate the production of HbF has been known to temporarily alleviate sickle cell disease symptoms. The researchers demonstrated that this gene therapy method is a more permanent way to increase therapeutic HbF production. Phase 1 clinical trials of gene therapy for sickle cell disease in humans were started in 2014. The clinical trials will assess the safety of lentiviral vector-modified bone marrow for adults with severe sickle cell disease. As of 2020, however, no randomized controlled trials have been reported. A case report for the first person treated was published in March 2017, with a few more people being treated since then. Gene editing platforms like CRISPR/Cas9 have been used to correct the disease-causing mutation in hematopoietic stem cells taken from a person with the condition. In July 2019 the gene-editing tool CRISPR was used to edit bone marrow cells from a person with SCD to "turning on" the gene for fetal haemoglobin. A number of researchers have considered the ethical implications of SCD being one of the first potential applications of CRISPR technology, given the historical abuses and neglect of the African American community by the medical field. In 2017 twelve clinical trials were focusing on gene therapy to treat sickle cell anemia. Of those 12 trials, four of them replaced the mutated HBB gene with a healthy one. Three trials used Mozobil, a medication used to treat types of cancer, to determine whether the increase of stem cells can be used for gene therapy. One trial focused on analyzing bone marrow samples from patients with sickle cell anemia. Another trial experimented with using umbilical cord blood from babies both with and without sickle cell anemia to develop gene therapy.


Hematopoietic stem cell transplantation

There is no strong medical evidence to determine the risks and potential benefits related to treating people with sickle cell disease with hematopoietic stem cell transplantations.


Notes


References


Further reading

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External links

* {{DEFAULTSORT:Sickle-Cell Disease Autosomal recessive disorders Chronic pain syndromes Disorders of globin and globulin proteins Health in Africa Hematopathology Hereditary hemolytic anemias Wikipedia medicine articles ready to translate Wikipedia infectious disease articles ready to translate