Sickle cell disease (SCD) is a group of inherited blood disorders involving hemoglobin, the oxygen-carrying protein in red blood cells. Affected people produce hemoglobin S (HbS), which can form rigid fibers when oxygen levels fall. This makes cells less flexible and sometimes sickle-shaped, promoting premature cell destruction and obstruction of blood flow. The resulting disease can cause chronic anemia, recurrent pain, and damage to multiple organs. Sickle cell anemia, usually referring to HbSS disease, is one form of SCD rather than an exact synonym for the whole group. (nhlbi.nih.gov)
Genetic basis and inheritance
SCD results from variants in the HBB gene, which encodes the beta-globin component of hemoglobin. The HbS-producing mutation changes one amino acid in beta-globin: valine replaces glutamic acid at position six in the mature chain. This substitution changes how hemoglobin molecules interact, allowing them to assemble into long fibers under low-oxygen conditions. (medlineplus.gov)
The disease follows an autosomal recessive inheritance pattern. An affected person inherits a disease-associated HBB allele from each parent, with at least one encoding HbS. Major forms include HbSS, in which both alleles encode HbS; HbSC, involving HbS and hemoglobin C; and sickle beta-thalassemia, involving HbS and reduced or absent beta-globin production. HbSS and sickle beta-zero thalassemia generally cause more severe disease, although clinical severity varies within each genotype. (medlineplus.gov)
Sickle cell trait occurs when a person inherits one HbS allele and one normal beta-globin allele. Most carriers do not have SCD symptoms, although uncommon complications can occur. When both parents have this trait, each pregnancy has a 25% probability of HbSS disease, a 50% probability of trait, and a 25% probability of neither. These probabilities apply independently to each pregnancy. (nhlbi.nih.gov)
Disease mechanisms and clinical features
Two central processes are vascular obstruction and hemolysis, the premature breakdown of red blood cells. Rigid cells can slow or block circulation, reducing oxygen delivery to tissues and producing painful vaso-occlusive episodes. Their shortened survival also means that replacement through blood cell production may not keep pace with destruction, producing anemia. (nhlbi.nih.gov)
Clinical manifestations commonly begin in infancy or early childhood. They include fatigue, jaundice, painful swelling of the hands and feet, delayed growth, and episodes of severe pain. The frequency and severity of episodes differ considerably between individuals. Pain can also become chronic, rather than occurring only during discrete crises. (medlineplus.gov)
Major complications include stroke, kidney impairment, retinal damage, gallstones, and acute chest syndrome, a potentially life-threatening lung complication involving chest pain, fever, and breathing difficulty. Splenic damage increases susceptibility to serious infections. Sudden trapping of blood in the spleen can cause severe anemia, while parvovirus B19 infection can temporarily suppress red blood cell production in the bone marrow. Pregnancy carries increased risks of maternal complications, pregnancy loss, and premature birth. (nhlbi.nih.gov)
Diagnosis and screening
Diagnosis depends on identifying abnormal hemoglobin and, when necessary, the underlying genetic variants. Newborn screening uses a small blood sample to detect hemoglobin patterns before symptoms develop. Common laboratory methods include high-performance liquid chromatography, capillary electrophoresis, and isoelectric focusing. An abnormal screening result requires confirmatory testing to distinguish disease from carrier status and determine the subtype. (nhlbi.nih.gov)
Genetic testing can clarify ambiguous blood-test results and identify combinations such as sickle beta-thalassemia. Prenatal diagnosis is possible using fetal genetic material obtained through placental or amniotic-fluid sampling. Such testing can establish whether a fetus has SCD but cannot reliably predict the eventual severity of symptoms. (nhlbi.nih.gov)
Treatment
Care combines infection prevention, management of pain and organ complications, and disease-modifying treatment. Vaccination and preventive penicillin are established components of childhood care. Hydroxyurea increases fetal hemoglobin, which inhibits sickling, and can reduce painful crises and other complications. Blood transfusion supplies functional red blood cells and is used for selected acute complications and stroke prevention. Repeated transfusions can cause iron overload and immune reactions against donor cells. (nhlbi.nih.gov)
Hematopoietic stem cell transplantation from a donor can cure SCD in selected patients, but involves risks including graft-versus-host disease, infection, infertility, and graft failure. It does not necessarily reverse established organ damage. (nhlbi.nih.gov)
On December 8, 2023, the US Food and Drug Administration approved Casgevy and Lyfgenia, the first cell-based gene therapies for SCD. Casgevy uses CRISPR-based genome editing to increase fetal hemoglobin; Lyfgenia introduces genetic instructions for an anti-sickling hemoglobin. Both modify the patient's own blood-forming stem cells outside the body and require conditioning chemotherapy before reinfusion. Treatment entails substantial risks and long-term monitoring; Lyfgenia carries a boxed warning for hematologic malignancy. (fda.gov)
Distribution and population burden
The World Health Organization reports an estimated 7.74 million people living with SCD worldwide in 2021, with approximately 515,000 affected births that year. Sub-Saharan Africa accounted for nearly 80% of global cases. The condition also occurs among populations with Mediterranean, Middle Eastern, Indian, and other ancestries. Its geographic distribution overlaps historically malaria-endemic regions, where the HbS carrier state provides protection against severe malaria. (who.int)
Outcomes vary with access to newborn screening, preventive care, medicines, transfusion services, and specialist treatment. Transplantation and gene therapy additionally require specialized facilities and substantial resources. Successful treatment of blood-forming cells does not remove the inherited variant from reproductive cells, so a treated person can still transmit an HbS allele to children. (who.int)