A 10-year-old boy of Mediterranean descent with sickle cell disease (SCD) that was diagnosed during his first year of life presented to the operating room for laparoscopic cholecystectomy. At age 8 years, he was hospitalized for 3 days with vasoocclusive painful crisis. He currently takes no medication and had no previous surgeries.
Which patient populations are at risk for sickle cell trait and sickle cell disease?
Sickle cell trait results from asymptomatic heterozygous carriers of the abnormal hemoglobin S (HbS) gene. It occurs in 10%–30% of people in equatorial Africa as well as Mediterranean areas such as Sicily, southern Italy, northern Greece, Turkey, Saudi Arabia, southwest Asia, and central India. Malaria is endemic in these areas. It has been postulated that HbS may be protective against malaria. However, descendants of people from these areas are more likely to have sickle cell disease (SCD). About 8% of African Americans have sickle cell trait, whereas 0.3%–1.3% of African Americans have SCD.
What is the underlying genetic abnormality responsible for sickle cell disease, and how does this lead to sickling?
SCD is a heterogeneous, inherited disorder of the beta-hemoglobin chain. It is a multisystem disorder that may manifest during childhood or adulthood, with marked variability in onset and severity.
Normally, hemoglobin A (HbA), which makes up most normal adult hemoglobin (96%–98%), is composed of two alpha-globin and two beta-globin chains. However, HbS possesses one abnormal beta-globin chain because of a single valine substitution for glutamic acid at the sixth position of the beta-globin chain. The heterozygous carrier state HbAS (i.e., one abnormal and one normal beta-globin gene) is called sickle cell trait. This genetic makeup of sickle cell trait may confer protection to individuals exposed to the malaria-causing parasite Plasmodium falciparum.
The homozygous genotype HbSS (i.e., two abnormal beta-globin chains) results in SCD, with the potential for hemolysis and its resultant complications. The manifestations of SCD result from deoxygenation of HbS, which leads to hemoglobin instability and decreased molecular solubility. With prolonged deoxygenation, irreversible polymerization of intracellular insoluble HbSS strands (gelation) begin to form; this activates sickling, a process of cell membrane distortion and cell deformability, giving red blood cells the microscopic appearance referred to as sickle cells. The sickle shape of red blood cells makes for slower and difficult, or impossible, propagation through blood vessels. A multifactorial process of red blood cell clumping, hemolysis, reduced cell life span, sludging of vasculature, endothelial damage, vascular obstruction or occlusion, and an inflammatory response eventually leads to some of the clinical conditions discussed in Question 3. The baseline hemoglobin of patients with SCD is usually 5–9 g/dL owing to chronic hemolysis.
Describe the presentations of sickle cell disease.
Acute vasoocclusive (pain) crisis , the most common presentation, manifests as skeletal bone pain from occlusion by sickled cells of the vasculature resulting in inflammatory mediator release and subsequent increased intramedullary pressure and nociceptor stimulation. Pain can occur at an early age (6 months) in the hands and feet (i.e., hand-foot syndrome) and at later ages in the long bones (e.g., ribs, spine, hips.) More than three pain episodes per year indicate severe disease and risk of early death. Aggressive management of these patients includes analgesics (e.g., patient-controlled analgesia), hydration, warmth, rest, reassurance, antibiotics, and possibly steroids.
Acute chest syndrome (ACS) is a medical emergency in which the patient presents with chest pain, hypoxemia, and respiratory distress. ACS is the leading cause of death and hospitalization in patients with SCD. Treatment consists of oxygen, continuous positive airway pressure or mechanical ventilation, antibiotics, bronchodilators, hydration, and possibly steroids. Pulmonary infarcts and pulmonary fibrosis are potential complications.
Hemolytic crisis (or aplastic crisis), although rare, occurs when there is rapid red blood cell death and massive suppression of normal erythropoiesis. An infection is often implicated (e.g., parvovirus B19, Epstein-Barr virus). If treated appropriately, this crisis can be self-limited with bone marrow activity returning in 10 days.
Splenic sequestration crisis typically occurs during childhood and is the result of the spleen sequestering a massive amount of red blood cells. It may be a minor or major event. Transfusion and elective splenectomy may be necessary.
Because SCD is a multisystem disease ( Table 50-1 ), these patients can present with liver dysfunction, jaundice, cholelithiasis, stroke, cranial nerve neuropathies, sickle retinopathy, impaired growth, pregnancy complications, bone marrow infarcts, cardiomegaly, hematuria, renal infarcts, renal failure, or priapism. Autoinfarction of the spleen renders these patients functionally hyposplenic or asplenic and susceptible to infections with encapsulated bacterial organisms (e.g., Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae ). Patients with SCD are placed on prophylactic antibiotics.