sickle cell disease

sickle cell disease
Name	Sickle cell disease
Synonyms	Sickle cell anaemia, HbS disease
Caption	Red blood cells showing characteristic sickle shape
Field	Hematology, Medical genetics
Symptoms	Anaemia, episodes of pain, swelling, infections
Complications	Stroke, Acute chest syndrome, Priapism, Leg ulcer
Onset	5–6 months of age
Duration	Lifelong
Types	HbSS, HbSC, HbS beta thalassemia
Causes	Genetic
Risks	Family history
Diagnosis	Blood test, Genetic testing
Differential	Iron-deficiency anaemia, Other haemoglobinopathies
Prevention	Genetic counseling
Treatment	Hydroxyurea, Blood transfusion, Pain management
Medication	Hydroxycarbamide, Penicillin
Prognosis	Variable; life expectancy reduced
Frequency	~100,000 in the United States
Deaths	~113,000 annually worldwide

sickle cell disease is a group of inherited red blood cell disorders. The condition results from a mutation in the HBB gene, which provides instructions for making part of haemoglobin, the oxygen-carrying protein in red blood cells. This leads to the production of abnormal haemoglobin S, which can distort red blood cells into a rigid, sickle shape, causing blockages in blood vessels and leading to a range of serious health complications. The disease is most prevalent in populations with ancestry from regions where malaria is or was common, such as sub-Saharan Africa, India, the Mediterranean, and parts of the Middle East.

Signs and symptoms

Clinical manifestations are highly variable but often include chronic haemolytic anaemia and recurrent episodes of vaso-occlusive crisis, which cause severe pain in areas like the bones, chest, and abdomen. Common complications involve multiple organ systems, including the spleen (leading to functional asplenia and increased risk of infection from pathogens like Streptococcus pneumoniae), the brain (increasing risk of ischaemic stroke), the lungs (causing acute chest syndrome), and the eyes (resulting in proliferative retinopathy). Other frequent issues are jaundice due to rapid red cell breakdown, gallstones, priapism, and leg ulcers, particularly around the ankles.

Genetics and pathophysiology

The disorder is autosomal recessive and caused by a specific point mutation in the beta-globin chain of haemoglobin, substituting glutamic acid for valine at position six. This mutation leads to the production of haemoglobin S (HbS). Under conditions of low oxygen tension, dehydration, or acidosis, HbS molecules polymerize, causing red cells to lose flexibility and assume the characteristic sickle shape. These sickled cells are prone to haemolysis and can obstruct the microvasculature, leading to tissue ischaemia and infarction. The heterozygous state, known as sickle cell trait, typically does not cause disease but confers some protection against falciparum malaria.

Diagnosis

Diagnosis is typically made through newborn screening programs in many countries, including the United States and the United Kingdom. Laboratory confirmation involves haemoglobin electrophoresis or high-performance liquid chromatography to identify the presence of HbS and other variant haemoglobins. Additional tests like a peripheral blood smear may show sickled cells, and genetic testing can identify mutations in the HBB gene. Prenatal diagnosis is available through procedures like chorionic villus sampling or amniocentesis, often guided by genetic counseling for at-risk families.

Management

Management is multidisciplinary and focuses on preventing complications and treating symptoms. The drug hydroxyurea is a cornerstone of therapy, as it increases production of foetal haemoglobin, which inhibits sickling. Prophylaxis with daily penicillin is recommended in children to prevent overwhelming infection. Acute painful crises are managed with aggressive analgesia, often including opioids like morphine, alongside hydration and oxygen. Regular blood transfusions are used to prevent stroke and treat severe anaemia, while allogeneic stem cell transplantation remains the only curative option, though with significant risks. Recent advances include therapies like crizanlizumab and voxelotor.

Epidemiology

The disease has a significant global distribution, with the highest burden in tropical regions. It is estimated to affect millions worldwide, with over 300,000 births annually, primarily in Africa. In the United States, it affects approximately 100,000 individuals, predominantly of African American descent. Other populations with notable prevalence include those from Saudi Arabia, India, Greece, Italy, and Turkey. The persistence of the sickle cell gene is attributed to the survival advantage against malaria conferred by the carrier state, a classic example of balanced polymorphism as described by J.B.S. Haldane.

History

The first modern description of the disease is attributed to James B. Herrick in Chicago, who in 1910 documented the unusual sickle-shaped red cells in a dental student from Grenada. The term "sickle cell anaemia" was later coined by Verne Mason in 1922. The genetic basis was elucidated by Linus Pauling and colleagues in 1949, who used electrophoresis to demonstrate it was a "molecular disease," a landmark discovery in molecular medicine. Further work by Vernon Ingram in 1956 identified the specific amino acid substitution. Major advances in management came in the latter 20th century, including the introduction of hydroxyurea and the establishment of comprehensive sickle cell centers funded by the National Institutes of Health.

Category:Genetic disorders Category:Hematology Category:African-American history