Sickle cell disease
Sickle cell disease (SCD), also simply called sickle cell, is a group of hemoglobin-related blood disorders typically inherited.[2] The most common type is known as sickle cell anaemia.[2] It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells.[2] This leads to a rigid, sickle-like shape under certain circumstances.[2] Problems in sickle cell disease typically begin around 5 to 6 months of age.[1] A number of health problems may develop, such as attacks of pain (known as a sickle cell crisis), anemia, swelling in the hands and feet, bacterial infections, and stroke.[1] Long-term pain may develop as people get older.[2] The average life expectancy in the developed world is 40 to 60 years.[2] All the major organs are affected by sickle cell disease. The liver, heart, kidneys gallbladder, eyes, bones, and joints also can suffer damage from the abnormal functions of the sickle cells, and their inability to flow through the small blood vessels correctly.
Sickle cell disease
Sickle cell disorder; drepanocytosis (dated)
Attacks of pain, anemia, swelling in the hands and feet, bacterial infections, stroke[1]
Chronic pain, stroke, aseptic bone necrosis, gallstones, leg ulcers, priapism, pulmonary hypertension, vision problems, kidney problems[2]
5–6 months of age[1]
Genetic, Homozygous mutation in the hemoglobin S gene.[3]
Vaccination, antibiotics, high fluid intake, folic acid supplementation, pain medication, blood transfusions[5][6]
Life expectancy 40–60 years (developed world)[2]
4.4 million (2015)[7]
114,800 (2015)[8]
Sickle cell disease occurs when a person inherits two abnormal copies of the β-globin gene (HBB) that makes haemoglobin, one from each parent.[3] This gene occurs in chromosome 11.[9] Several subtypes exist, depending on the exact mutation in each haemoglobin gene.[2] An attack can be set off by temperature changes, stress, dehydration, and high altitude.[1] A person with a single abnormal copy does not usually have symptoms and is said to have sickle cell trait.[3] Such people are also referred to as carriers.[5] Diagnosis is by a blood test, and some countries test all babies at birth for the disease.[4] Diagnosis is also possible during pregnancy.[4]
The care of people with sickle cell disease may include infection prevention with vaccination and antibiotics, high fluid intake, folic acid supplementation, and pain medication.[5][6] Other measures may include blood transfusion and the medication hydroxycarbamide (hydroxyurea).[6] In 2023, new gene therapies were approved.[10][11] A small percentage of people can be cured by a transplant of bone marrow cells.[2]
As of 2015, about 4.4 million people have sickle cell disease, while an additional 43 million have sickle cell trait.[7][12] Sickle cell disease (SCD) affects millions of people worldwide, with a higher prevalence in sub-Saharan Africa, Spanish-speaking regions in the Western Hemisphere (South America, the Caribbean, and Central America), Saudi Arabia, India, and Mediterranean countries like Turkey, Greece, and Italy.[13] In 2015, it resulted in about 114,800 deaths.[8] The condition was first described in the medical literature by American physician James B. Herrick in 1910.[14][15] In 1949, its genetic transmission was determined by E. A. Beet and J. V. Neel.[15] In 1954, the protective effect against malaria of sickle cell trait was described.[15]
Diagnosis[edit]
In HbS, the complete blood count reveals haemoglobin levels in the range of 6–8 g/dl with a high reticulocyte count (as the bone marrow compensates for the destruction of sickled cells by producing more red blood cells). In other forms of sickle cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (target cells and Howell-Jolly bodies).[72]
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").[73] 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.[74]
Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds. Sickle cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography. Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.[75]
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.[76]
People who are known carriers of the disease or at risk of having a child with sickle cell anemia may undergo genetic counseling. 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.[77][78] During pregnancy, genetic testing can be done on either a blood sample from the fetus or a sample of amniotic fluid. During the first trimester of pregnancy, chorionic villus sampling (CVS) is also a technique used for SCD prenatal diagnosis.[79] 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, 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.[80] Genetic counselors can help individuals of colour and their families tackle the racial and ethnic disparities that exist in healthcare.[81]
In 2010, there was significant consideration and debate in the US surrounding comprehensive screening of athletes for SCD.[82][83][84][85] In 2012, the American Society of Hematology concluded 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.[86]
Prognosis[edit]
About 90% of people survive to age 20, and close to 50% survive beyond age 50.[116] 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.[117] The life expectancy in much of the developing world is unknown.[118] 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.[119]: 348
History[edit]
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.[153][154] Reportedly, African slaves in the United States exhibited resistance to malaria, but were prone to leg ulcers.[154] 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 (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.[14][155] Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" but completed his studies and returned to the capital of Grenada (St. George's) to practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada.[14][15] 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."[156] This article is based on a patient admitted to the University of Virginia Hospital on 15 November 1910.[157] In the later description by Verne Mason in 1922, the name "sickle cell anemia" is first used.[15][158] 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.[154]
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 and E.A. Beet.[15] 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.[15][159] The molecular change in HbS was described in 1956 by Vernon Ingram.[160] 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.[15]
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.[161] The 1990s had the development of hydroxycarbamide, and reports of cure through bone marrow transplantation appeared in 2007.[15]
Some old texts refer to it as drepanocytosis.[162]
Society and culture[edit]
United States[edit]
Sickle cell disease is frequently contested as a disability.[163] Effective 15 September 2017, the U.S. Social Security Administration issued a Policy Interpretation Ruling providing background information on sickle cell disease and a description of how Social Security evaluates the disease during its adjudication process for disability claims.[164][165]
In the US, 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.[166] 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.[167] In the 1960s, the US government supported initiatives for workplace screening 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.[168]
Uganda[edit]
Uganda has the 5th highest sickle cell disease (SCD) burden in the world.[169] In Uganda, 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.[169] 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 professionals. 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.[170] 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.[169]
Research[edit]
Umbilical cord blood transplant[edit]
While umbilical cord blood transplant can potentially cure the condition, a suitable donor is available in only 10% of people.[181] About 7% of people also die as a result of the procedure and graft versus host disease may occur.[181]
Gene therapy[edit]
Diseases such as sickle cell disease for which a person's normal phenotype 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.[182]
In 2001, sickle cell disease reportedly had been successfully treated in mice using gene therapy.[183][184] 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.[185]
Phase 1 clinical trials of gene therapy for sickle cell disease in humans were started in 2014. The clinical trials assessed the safety of lentiviral vector-modified bone marrow for adults with severe sickle cell disease.[186][187] A case report for the first person treated was published in March 2017, with a few more people being treated since then.[188][189]
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.[190] In July 2019 the gene-editing tool CRISPR was used to edit bone marrow cells from a person with SCD to boost fetal haemoglobin by inhibiting the BCL11A gene.[191][192] 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.[193]
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.[194]
In November 2023, a gene treatment using the CRISPR gene editing tool was approved by UK regulators for the treatment of sickle cell disease and also for the blood disorder transfusion-dependent beta thalassemia.[11][195]