sickle cell anemia

sickle cell anemia
Name	Sickle Cell Anemia
Synonyms	Sickle cell disease, HbSS disease
Field	Hematology, Medical genetics
Symptoms	Anemia, Vaso-occlusive crisis, Infection
Complications	Stroke, Acute chest syndrome, Priapism, Avascular necrosis
Onset	Childhood
Duration	Lifelong
Causes	Inherited Mutation
Risks	Malaria endemic ancestry
Diagnosis	Blood test, Hemoglobin electrophoresis
Differential	Iron-deficiency anemia, Thalassemia
Prevention	Genetic counseling
Treatment	Hydroxyurea, Blood transfusion, Penicillin
Prognosis	Variable
Frequency	~100,000 in the United States

sickle cell anemia. It is an inherited blood disorder caused by a specific mutation in the hemoglobin gene, leading to the production of abnormal hemoglobin S. This results in rigid, sickle-shaped red blood cells that can obstruct blood vessels and cause severe pain, organ damage, and chronic anemia. The condition is most prevalent among individuals with ancestry from regions where malaria is or was historically endemic, such as sub-Saharan Africa, India, and the Mediterranean.

Signs and symptoms

Clinical manifestations are highly variable but often include chronic fatigue and jaundice due to ongoing hemolysis. The hallmark is the vaso-occlusive crisis, characterized by severe pain in bones, the chest, and the abdomen. Serious complications can involve multiple organ systems, including the brain, leading to stroke; the lungs, causing acute chest syndrome; and the spleen, resulting in functional asplenia and increased susceptibility to infections from pathogens like *Streptococcus pneumoniae* and *Haemophilus influenzae*. Other complications include priapism, avascular necrosis of the femur, and retinopathy.

Genetics and pathophysiology

The disorder is inherited in an autosomal recessive pattern, requiring a child to inherit two abnormal alleles, one from each parent. The underlying molecular defect is a point mutation in the HBB gene on chromosome 11, which leads to the substitution of valine for glutamic acid at the sixth position of the beta-globin chain, producing hemoglobin S. Under conditions of hypoxia, acidosis, or dehydration, hemoglobin S polymerizes, causing the red cell to deform into a sickle shape. These sickled cells are less flexible, increasing blood viscosity, causing hemolytic anemia, and triggering endothelial injury and ischemia.

Diagnosis

Diagnosis is typically made through newborn screening programs in many countries, including the United States and the United Kingdom. Initial tests include a complete blood count to detect anemia and a peripheral blood smear to look for sickled cells. Confirmatory testing involves hemoglobin electrophoresis or high-performance liquid chromatography to identify the presence of hemoglobin S and differentiate it from other hemoglobinopathies like hemoglobin C disease or beta-thalassemia. Prenatal diagnosis via chorionic villus sampling or amniocentesis is available for at-risk families.

Management and treatment

Management focuses on preventing complications and treating crises. Prophylaxis includes daily penicillin in children to prevent infection and routine vaccinations, including the pneumococcal and *Haemophilus influenzae* type b vaccines. The disease-modifying agent hydroxyurea is used to increase production of fetal hemoglobin, reducing the frequency of crises and the need for transfusions. Acute pain crises are managed with aggressive analgesia, hydration, and oxygen. For severe complications like stroke, chronic red cell transfusion programs or the hematopoietic stem cell transplantation may be considered, with the latter being potentially curative.

Epidemiology

Sickle cell anemia has a high global disease burden, with the greatest prevalence in the malaria-endemic regions of Africa, particularly within the sub-Saharan Sahel belt. It also occurs with significant frequency in parts of India, the Middle East, and the Mediterranean, including Greece and Italy. Due to historical population movements, it is now a major public health concern in the Americas, especially among people of African and Hispanic descent in the United States and the Caribbean. The World Health Organization recognizes it as a significant global health issue.

History

The first modern clinical description is attributed to James B. Herrick in Chicago in 1910, who noted "peculiar elongated and sickle-shaped" cells in a dental student from Grenada. The inherited nature of the disease was elucidated by E. Vernon Hahn and Elizabeth B. Gillespie in the 1920s. A major breakthrough came in 1949 when Linus Pauling and his colleagues at the California Institute of Technology used electrophoresis to demonstrate it was a "molecular disease" caused by abnormal hemoglobin, a discovery foundational to molecular medicine. The precise genetic mutation was identified by Vernon Ingram at the University of Cambridge in 1956 using protein sequencing.

Category:Hematology Category:Genetic disorders Category:Autosomal recessive disorders