Sickle cell disease (SCD) is a multisystem disorder and the most common genetic disease in the United States, affecting 1 in 500 African Americans. About 1 in 12 African Americans carry the autosomal recessive mutation, and approximately 300,000 infants are born with sickle cell anemia annually. The understanding of the phenotypic expression of the disease is still limited although environmental factors such as cold weather and air quality, infections, fetal hemoglobin level, and other genetic subtypes play a role in the manifestation of the disease. Clinical manifestations are variable and affect multiple systems and generally cause lower life expectancy.
Sickle cell is caused by a mutation in the hemoglobin beta chain in which glutamic acid is substituted with valine at position six on chromosome 11.
Sickle cell anemia is the most common monogenic disorder. Prevalence of the disease is high among the people of Sub-Saharan Africa, South Asia, Middle East, and the Mediterranean. It is estimated that in the United States, the population of sickle cell disease is approximately 100,000 and likely to increase. The most common genotype is homozygous hemoglobin SS (HbSS), and common heterozygous conditions are hemoglobin sickle beta zero thalassemia, hemoglobin sickle beta plus thalassemia (hemoglobin sickle beta plus thalassemia), and hemoglobin sickle cell disease (HbSC).
The genetic mutation described causes polymerization of the Hemoglobin molecule that alters the erythrocyte shape and its ability to deform. There is increased adhesion of erythrocytes followed by formation of heterocellular aggregates, which physically cause small vessel occlusion and resultant local hypoxia. This process triggers a vicious cycle of increased HbS formation, the release of inflammatory mediators and free radicals that contribute to reperfusion injury. Hemoglobin also binds to nitric oxide (NO), a potent vasodilator, and releases oxygen. Erythrocytes are more likely to sickle and become rigid in the presence of dehydration. This process is in large part caused by changes in cation homeostasis, specifically increased potassium and water efflux mediated by potassium-chloride cotransport and Gardos channels (calcium-dependent potassium channel). Other associated pathological events include increased neutrophil adhesiveness, nitric oxide binding, increased platelet activation, and hypercoagulability.
The histopathology in sickle cell disease is very variable. Findings compatible with necrosis and ischemia are seen in the affected organ system, with liver, bone marrow, lungs, spleen, kidneys, and lungs the commonly affected organs.
The history and physical exam of sickle cell patients range from being asymptomatic to a broad range of presentations. Patients are completely asymptomatic during the first 6 months of life due to the presence of fetal hemoglobin which gradually decreases, and HbS begins to predominate. The clinical presentation of SCD is variable depending on the type of complication and the body system affected. Few of the common presentations are described below.
Vaso-Occlusive Crisis (VOC)
This is the most common presentation of SCD. Microvascular occlusion (the cardinal pathophysiologic cause of acute pain) leads to ischemia and hypoxia, followed by tissue and vascular damage and inflammation, the release of inflammatory mediators, all of which activate nociceptors. Reperfusion intensifies the inflammation and resultant pain. Patients complain of severe debilitating pain in any part of the body but typically in the long bones, back, pelvis, chest and the abdomen. Symptoms may start as early as six months of age with pain and swelling in both hands and feet (dactylitis). In most instances, there are no reliable signs or tests to indicate the presence or absence of pain associated with VOC.
Acute Chest Syndrome (ACS)
ACS is defined as the appearance of a new pulmonary infiltrate on chest radiography accompanied by a fever and respiratory symptoms, including a cough, tachypnea, and chest pain. It is hypothesized that ACS is the result of hypoxia and an inflammatory mediator-induced increase in adhesion of the pulmonary microvasculature to sickled erythrocytes. This process is coupled with a reduction in nitric oxide (NO), which would normally counteract it. The most common symptoms in patients with ACS are fever, cough, chest pain, dyspnea, and lung exam may show reduced air entry, rales and sometimes wheeze. ACS can progress rapidly to hypoxemia and respiratory failure if not treated promptly. When possible to identify infectious organisms, chlamydia, Streptococcus pneumonia, and Mycoplasma predominate.
Patients with SCD are especially at risk for infections with encapsulated organisms because of their functional asplenia, as well as because of functionally immunocompromised state (increased bone marrow turnover and altered complement activation). Penicillin prophylaxis in children and widespread use of the pneumococcal vaccine has made tremendous strides in reducing the incidence of bacterial infections and sepsis.
Pulmonary Hypertension (PHTN)
PHTN has an incidence of 6% to 10% and a mortality of 2% to 5%. PHTN is believed to be caused in large part by changes in medial smooth muscle and endothelial cells. The key clinical finding is reduced exercise capacity (45% of patients are New York Heart Association class III or IV). Diagnostic findings include an increased N-terminal pro-brain natriuretic peptide (NT-proBNP), an increased tricuspid valve regurgitated jet velocity on echocardiography, and increased pulmonary pressures on right heart catheterization.
Cerebrovascular Accidents (CVA)/Stroke
CVA can occur in children as young as two years of age, with 11% of patients with SCD having a stroke by 20 years of age. However, silent cerebral infarcts (SCI) associated with the small-vessel disease are more common than overt strokes, with 34% of patients with SCD having evidence of SCI by age 14 years. Transcranial Doppler is an effective screening test started at age of two years in SCD patients to identify those at higher risk of CVA.
Pulmonary Embolism (PE)
The incidence of PE is higher in patients with SCD. There is a 50-fold to 100-fold increase in annual incidence in inpatients with SCD compared to those without SCD.
Renal complications are extremely common in SCD, with 30% of adults developing chronic renal failure. This is due to the low partial pressure of oxygen, low pH, and high osmolality in the renal medulla which contribute to erythrocyte dehydration and vaso-occlusion. Microalbuminuria and proteinuria are common diagnostic findings.
Proliferative retinopathy is the most common ophthalmologic complication of SCD (more common in HbSC, as high as 70%) and results from occlusion of the peripheral retinal vasculature.
Splenic sequestration is a potentially catastrophic complication of SCD and is characterized by an acute decrease in hemoglobin level, which can result in severe abdominal pain and circulatory collapse that is more common in the pediatric population, especially HbSS anemia. This due to splenic auto-infarction occurring around six years of age. However, this can be seen in adults with HbSC and other hemoglobinopathies.
Priapism associated with SCD is typical of the low-flow type associated with stasis, hypoxia, and ischemia.
Cholelithiasis and biliary sludge develop as a result of chronic hemolysis and increased bilirubin turnover.
The femoral and humeral heads are common sites of osteonecrosis, which occurs as a result of increased pressure from increased erythrocyte marrow or vascular occlusion. Surgical treatment is sometimes indicated.
Parvovirus B19-induced aplastic crisis caused by interruption of erythropoiesis can lead to severe anemia and cardiovascular decompensation. This self-limited infection typically lasts 7 to 10 days and can be life-threatening.
In the United States, most patients with sickle cell disease are diagnosed with newborn or prenatal screening. The diagnosis is based on hemoglobin electrophoresis that quantifies the types of hemoglobin and detects the various hemoglobinopathies. Among patients presenting with symptoms, the usual lab evaluation consists of complete blood count (CBC) with differential, reticulocyte count, complete metabolic panel, LDH level, bilirubin level and determination of blood type, and crossmatch for possible transfusion therapy. Appropriate cultures including that of blood should be obtained if the infectious process is suspected.
Have a low threshold to obtain chest x-rays to diagnose acute chest syndrome. Get a sonogram of the abdomen as needed. Transcranial sonograms are recommended as screening tests from age two years to prevent strokes. Other imaging studies such as bone scan, MRI, and MRA can be considered depending on clinical suspicion.
Sickle cell anemia management can be considered in two categories, health maintenance, and management of complications. The goal of health maintenance is to screen and identify risk factors and early signs of complications. There is evidence that pneumococcal vaccination, penicillin prophylaxis (early infancy until at least age five and education of the management of fever have considerably reduced mortality and morbidity from invasive infections. Routine screening with transcranial Doppler (TCD) of large intracranial blood vessels may predict the risk of stroke in children with sickle cell disease, but this may not be universally available. Further, the treatment (chronic transfusion therapy) is not feasible in many developing nations.
Management of sickle cell complications is tailored to the type of complication. VOC management consists of rapid pain assessment, early initiation of analgesic therapy and maintaining this analgesia (consider PCA pump) and hydration until there is symptom relief. For most patients with mild pain, acetaminophen or NSAIDs may suffice, but for moderate and severe pain, opiates with or without NSAIDs are indicated. More recently Ketamine in sub-dissociative doses has shown to reduce opiate use. Patients presenting with fever should be immediately assessed for life-threatening infections including the performance of complete blood count (CBC) with differential, reticulocyte count, blood culture, and urine culture if urinary tract infection (UTI) suspected, and broad-spectrum antibiotic therapy should be initiated. For most other complications like acute chest syndrome splenic sequestration and strokes, meticulous supportive care (oxygen, judicious fluid administration) and transfusion therapy are needed. Among patients who have frequent and severe complications, hydroxyurea has been shown to offer significant benefit. Hematopoietic stem cell transplantation (bone marrow transplantation) shows great promise as a cure for sickle cell disease. Antihistamines (diphenhydramine, hydroxyzine) may reduce itching caused by the opiates and may have some opioid-sparing effect. For acute chest syndrome, empirical antibiotics (cephalosporin and macrolide), adequate analgesics, oxygen supplementation, simple or exchange transfusion, beta-agonist inhalations and incentive spirometry may be needed.
The life expectancy in sickle cell disease is overall reduced (perhaps by 20 to 30 years) compared to normal adults, but advances in therapy are prolonging survival. Factors that predict poor prognosis include dactylitis in infancy, hemoglobin level less than 7 g/dL, and higher white cell count in the absence of infection.
Future gene therapy or genetic re-engineering may enable permanent cure through a reprogramming of human pluripotent cells to produce normal hemoglobin or high fetal hemoglobin.
Sickle cell disease has no cure and is associated with life-threatening complications. Thus, the disorder is best managed by a multidisciplinary team that includes a hematologist, surgeon, pulmonologist, orthopedic surgeon, internist, nurse practitioner and the pharmacist. The key is patient education. By maintaining good health, getting vaccinated and avoiding triggers, some patients can lead a decent quality of life. The outcomes for most patients are guarded and sickle cell crises often require readmissions to the hospital. Many of these patients have chronic non-healing wounds, and hence a wound care nurse must be consulted. Overall, patients with sickle cell disease have a much shorter life span compared to the healthy population.
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