Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Vaso-occlusive events result in tissue ischemia leading to acute and chronic pain as well as organ damage that can affect any organ in the body, including the bones, lungs, liver, kidneys, brain, eyes, and joints. Dactylitis (pain and/or swelling of the hands or feet) in infants and young children is often the earliest manifestation of sickle cell disease. In children the spleen can become engorged with blood cells in a “splenic sequestration crisis.” The spleen is also particularly subject to infarction and the majority of individuals with SCD are functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation. Individuals with the highest rates of hemolysis are predisposed to pulmonary artery hypertension, priapism, and leg ulcers but are relatively protected from vaso-occlusive pain.
The term “sickle cell disease” encompasses a group of symptomatic disorders associated with mutations in HBB and defined by the presence of hemoglobin S (Hb S). Normal human hemoglobin is a heterotetramer composed of two α-hemoglobin chains and two β-hemoglobin chains. Hemoglobin S results from a point mutation in HBB, changing the sixth amino acid in the β-hemoglobin chain from glutamic acid to valine (Glu6Val). Sickle cell anemia (homozygous Hb SS) accounts for 60%-70% of sickle cell disease in the US. Other forms of sickle cell disease result from coinheritance of Hb S with other abnormal β-globin chain variants, the most common forms being sickle-hemoglobin C disease (Hb SC) and two types of sickle β-thalassemia (Hb Sβ+-thalassemia and Hb Sβ°-thalassemia); rarer forms result from coinheritance of other Hb variants such as D-Punjab and O-Arab. The diagnosis of sickle cell disease is established by demonstrating the presence of significant quantities of Hb S by isoelectric focusing (IEF), cellulose acetate electrophoresis, high-performance liquid chromatography (HPLC), or (less commonly) DNA analysis. Targeted mutation analysis is used to identify the common mutations of HBB associated with hemoglobin S, hemoglobin C, and additional rarer mutations. HBB sequence analysis may be used to detect mutations associated with β-thalassemia hemoglobin variants. Gel electrophoresis or HPLC can differentiate these disorders from heterozygous carriers of the Hb S mutation (Hb AS). In the US, mandatory newborn screening establishes the diagnosis of sickle cell disease in neonates with the goal of assuring referral to specialty care prior to the onset of symptoms.
Treatment of manifestations: The mainstay of therapy for pain episodes is supportive: hydration (e.g., intravenous fluids), anti-inflammatory agents, and pain medication (e.g., nonsteroidal anti-inflammatory drugs and narcotic analgesia). Pain episodes are additionally managed with a multi-model approach (e.g., warmth, massage, distraction, acupuncture, biofeedback, self-hypnosis). Aggressive pulmonary toilet and prompt evaluation and treatment of underlying infections are essential. Life-threatening or severe complications (e.g., acute chest syndrome and stroke) are often treated with transfusion to reduce the percentage of Hb S while increasing oxygen carrying capacity. Other treatments may include joint replacement, hemodialysis, kidney transplantation, splenectomy for splenic sequestration crisis, and/or cholecystectomy for cholelithiasis. Acute treatment of stroke includes red blood cell exchange transfusion and aggressive management of increased intracranial pressure and seizures. Severe priapism may require aspiration and irrigation. Management of pulmonary hypertension can include routine treatments and specific therapies such as phosphodiesterase inhibitors or nitric oxide. Prevention of primary manifestations: The mainstay is good hydration and avoidance of climate extremes, extreme fatigue, and activities leading to inflammation. Hydroxyurea can decrease the frequency and severity of vaso-occlusive processes, reduce transfusion needs, and increase life span. Chronic red blood cell transfusion is indicated in children with either a history of or risk factors for stroke and other specific complications, such as pulmonary hypertension and chronic renal failure. Prevention of secondary complications: Aggressive education on the management of fevers; prophylactic antibiotics, including penicillin in children; up-to-date immunizations; and iron chelation therapy for those with iron overload. Surveillance: Yearly: CBC and reticulocyte count, assessment of iron status, liver and renal function tests, and urinalysis. Yearly starting at age two to three years for all individuals with Hb SS and Hb Sβ°-thalassemia: transcranial Doppler studies of arterial blood flow velocity. Yearly starting at age seven years: chest x-ray, pulmonary function tests, abdominal ultrasound examination, eye examination, and vision screening. Agents/circumstances to avoid: Dehydration, extremes of temperature, physical exhaustion, and extremely high altitude. Evaluation of relatives at risk: Early diagnosis of at-risk family members allows education and intervention before symptoms or end-organ damage are present.
Sickle cell disease is inherited in an autosomal recessive manner. If one parent is a carrier of the HBB Hb S mutation and the other is a carrier of an HBB mutation (e.g., Hb S, Hb C, β-thalassemia), each child has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection for common forms of sickle cell disease is most commonly accomplished by HPLC. Prenatal diagnosis for pregnancies at increased risk for sickle cell disease is possible by molecular genetic testing if the HBB mutations have been identified in the parents.