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Sickle Cell Trait
Introduction
Sickle cell trait is a genetic condition that results when an individual inherits a gene for normal hemoglobin (A) and a gene for sickle hemoglobin (S) that results in the genotype (AS). Conversely, sickle cell disease occurs when an individual inherits 2 abnormal sickle genes (SS). There are different types of sickle cell disease, including hemoglobin SS (HbSS), hemoglobin SC (Hb SC), and hemoglobin S beta-thalassemia. These hemoglobin types cause a vaso-occlusive crisis; however, HbSS is the most common and severe type. HbSC results when an individual inherits HbS from 1 parent and HbC from the other. Hb C is caused by a switch from glutamic acid to lysine. HbS beta-thalassemia is a rare mutation that occurs when an individual inherits beta-thalassemia hemoglobin from 1 parent and HbS from the other. However, a vaso-occlusive crisis does not occur just because sickling hemoglobin is present; vaso-occlusion occurs due to multiple events, including deformed red blood cells, increased red blood cell fragility, and increased cation permeability and stickiness.[1]
Sickle cell disease, a significant public health issue, was first described by James B Herrick in 1910, and almost 4 decades later, Linus Pauling and his colleagues concluded that a genetic disorder caused sickle cell disease. Sickle cell disease results in lifelong debilitation and early mortality due to chronic anemia and organ damage, leading to poor quality of life. Sickle cell trait, on the other hand, is relatively benign because patients do not have vaso-occlusive crises as individuals with sickle cell disease do; they have a better quality of life, and mortality is the same as the rest of the general population. Due to the sickle cell trait's nature, it generally has no severe clinical implications. However, there have been reports of adverse conditions due to the patient's trait status. Patients with sickle cell trait can have the same presentation as sickle cell anemia if exposed to conditions that favor sickling, including severe hypoxia, dehydration, increased sympathetic outflow, hypothermia, hyperthermia, high 2,3-DPG levels, or released inflammatory cells. Pain characteristic of SCT is typically described as cramping, weakness, and a dull ache that occurs within minutes of activity due to reduced blood to the muscles, unlike heat stroke. An athlete with SCT with these symptoms should be treated as a sickling exacerbation until this diagnosis can be excluded. Other symptoms of sickling include upper left quadrant abdominal or chest pain, chest tightness, and shortness of breath.[1]
Sickle cell trait is generally diagnosed through screening tests followed by confirmatory testing or genetic analysis. Since the Sickle Cell Anemia Act was established in 1972, there has been increased screening for sickle cell trait and disease.[2] Furthermore, each state in the US now offers universal newborn screening before discharge from the hospital. Hemoglobin electrophoresis is used to confirm the diagnosis after a positive screening test. Treatment is only indicated to reverse conditions causing sickling (eg, dehydration or hypoxia) or comorbid medical conditions associated with the SCT. Clinicians need to recognize the complications associated with sickle cell trait so that prompt management can be started once patients present with symptoms (eg, hematuria or papillary necrosis).[1][3]
Etiology
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Etiology
Sickle cell trait is caused by abnormal hemoglobin called sickle hemoglobin or Hb S, secondary to a point mutation in the beta-globin chain. This point mutation replaces A with T at codon 6 of the beta hemoglobin chain, causing the switch from glutamic acid to valine amino acid. The valine-type hemoglobin causes red cells to sickle when exposed to a low oxygen threshold. Patients with sickle cell trait inherit HbS from 1 parent and HbA from the other, making them heterozygous.
Epidemiology
Sickle cell trait (SCT) is more prevalent in people who are of African descent and also whose ancestors come from tropical and sub-tropical regions where malaria is endemic. The prevalence rate of sickle cell trait in the US is 9% among African Americans and 0.2% among Caucasians.[4] Worldwide, 300 million people are estimated to have sickle cell trait, and one-third of this population lives in sub-Saharan Africa.[5]The prevalence of sickle cell trait is higher in areas where malaria is endemic. One study reported the prevalence of SCT as high as 25% in some parts of Africa and 60% in Saudi Arabia.[4] Because of the high migration of people from areas of high prevalence, like Africa and the Middle East, the prevalence of both SCT and disease will likely increase in the western part of the world [6].
Pathophysiology
SCT does not often cause vaso-occlusive crisis, unlike sickle cell disease. However, patients with sickle cell trait could have the same presentation as sickle cell anemia if exposed to conditions that favor sickling, including severe hypoxia, dehydration, increased sympathetic outflow, hypothermia, hyperthermia, high 2,3-DPG levels, or released inflammatory cells. Decreased oxygen levels may cause red blood cells to transform from a normal disc shape to a sickle shape. As a result, the sickled cells begin to adhere to vascular walls, eventually blocking blood vessels in the muscles, kidneys, and other organs, which causes tissue death. Apart from the sickling of the cells, other cells interact to cause more adhesion of the red blood cells, including inflammatory cells and platelets. This could occur in multiple organs in the body, including the chest, heart, lungs, abdomen, kidneys, and extremities. Due to repeated attacks, organ damage may happen due to constant ischemia.[1]
Histopathology
In those with SCT, red blood cells, at rest, appear in the normal disk shape when viewed under the microscope. However, when these cells are under oxidative stress, the red blood cells appear as drepanocytes, also known as sickle cells. There may also be increased reticulocyte counts if severe sicking occurs.
History and Physical
Clinicians should obtain a relevant history and clinical symptoms, as family history may be positive for HbSS. While sickle cell disease patients have broad clinical manifestations (eg, generalized pain and fatigue) due to vaso-occlusive crisis, hemolysis, and infectious exacerbations, sickle cell trait patients do not have crises. They are, for the most part, asymptomatic. Typically, patients with sickle cell trait remain asymptomatic with HbS levels less than 35%.[7] Therefore, their presentation is similar to patients with normal hemoglobin genotypes. When patients with sickle cell trait are symptomatic, they may present with hematuria and exertional rhabdomyolysis.[8] Hot climates, dehydration, or high-elevation locations can exacerbate this presentation.[9] However, because symptoms of sickling can be similar to other conditions (eg, heat stroke or cardiac arrhythmia), clinicians should perform a thorough clinical assessment, including the history of the present illness and physical examination, to help obtain the correct diagnosis.[1]
Pain characteristic of SCT is typically described as cramping, weakness, and a dull ache that occurs within minutes of activity due to reduced blood to the muscles, unlike heat stroke. An athlete with SCT with these symptoms should be treated as a sickling exacerbation until this diagnosis can be excluded. Other symptoms of sickling include upper left quadrant abdominal or chest pain, chest tightness, and shortness of breath. However, loss of consciousness or confusion is not typical.[1]
The larger muscles (eg, calves, quads, hamstrings, or glutes) typically are normal during physical exams compared to the cramping caused by heat exertion. Though patients with SCT sickling are alert, a positive finding of large muscle weakness may be identified on physical exam. Findings of dehydration, which is frequently reported in patients with sickle cell trait and sudden death, are also common. Findings are consistent with conditions more prevalent in patients with SCT (eg, pulmonary embolism, deep venous thrombosis, or chronic kidney disease) and may be found on exam also.[10][1]
Evaluation
Unlike other developing and some developed world countries, pregnant women in the US are offered genetic testing to identify fetuses with sickle cell disease. Also, newborn screening is required in all 50 states for the sickle cell trait before a baby is discharged from the hospital. The sickling test can be used as a primary screening procedure to evaluate this disease. A drop of blood is placed on a slide and then prepared to be inspected under the microscope.[5] If sickling is observed, hemoglobin electrophoresis is used to confirm the diagnosis. The hemoglobin electrophoresis gives a percentage of each hemoglobin type present in a sample. In sickle cell trait, patients have a mixture of normal hemoglobin A and hemoglobin S. The testing of transfusable blood products for sickle cell trait is no longer performed by some services that no longer view its presence with trepidation.[11]
Because SCT increases the incidence of comorbid conditions developing (eg, chronic kidney disease), clinicians should also perform assessments to diagnose these associated conditions in patients with SCT to allow for appropriate management. In patients with SCT and signs of kidney disease, annual renal function testing (eg, creatinine, urinalysis, and blood pressure) is recommended. Due to an increased prevalence of renal medullary cell carcinoma in patients with SCT, renal and urinary tract ultrasound imaging and computed tomography (CT) with contrast should be performed if these patients have hematuria.[12]
Treatment / Management
Management Approach
Asymptomatic patients with SCT do not require any treatment. Treatment is only indicated to reverse conditions causing sickling (eg, dehydration or hypoxia) or comorbid medical conditions associated with the SCT. Clinicians need to recognize the complications associated with sickle cell trait, including papillary necrosis, microvascular disease, and deep vein thrombosis, so prompt management can be started once patients present with symptoms (eg, hematuria or flank pain).
Preventative management is also recommended in patients with SCT. Acclimation programs are recommended for athletic individuals with SCT who engage in activities at moderate altitudes or high-altitude mountaineering. Precautions should also be taken to avoid dehydration, hypoxia, and hyperthermia. In children with SCT, yearly clinical assessment is recommended, including iron, folic acid, and vitamin D testing.[12](B3)
Pregnant Women With Sickle Cell Trait
Guidelines for pregnant women with SCT should be followed. Urine cultures every trimester to assess for asymptomatic cystitis is essential as this population is at increased risk for pyelonephritis. Additionally, early and aggressive treatment of pregnant women with SCT suspected to have pyelonephritis is recommended. Due to the prevalence of anemia, folic acid, and iron supplementation is recommended throughout pregnancy and breastfeeding. Some experts recommend hemoglobinopathy testing for women attempting to become pregnant and pregnant women with anemia, microcytosis, a positive family history for hemoglobinopathy, or from regions endemic for sickle cell disease and thalassemia.[12](B3)
Differential Diagnosis
Differential diagnoses of sickle cell trait include different types of sickle cell disease, beta-thalassemia major, and beta-thalassemia minor.
Prognosis
Although sickle cell trait has been associated with many complications like papillary necrosis, asymptomatic bacteriuria, splenic infarction, and exercise-induced death, the prognosis of patients with sickle cell trait is promising. One study reported that despite the associated complications of the sickle cell trait, the average life expectancy of people with the sickle cell trait is the same as that of the general population.[13] Sickle cell disease carries an increased risk of in-hospital mortality in general, whereas sickle trait does not.[14]
Complications
Although sickle cell trait is seen as benign, patients with these traits have a propensity for medical and clinical complications, including hematuria due to renal papillary necrosis, splenic infarction, renal medullary carcinoma, chronic kidney disease, sudden death due to exertion, and asymptomatic bacteriuria in females.[5]
Papillary Necrosis
Papillary necrosis is one of the complications that has been reported in several case studies. According to a study by Li EJ and Carroll VG, hematologic parameters allow sickle cell trait patients to develop this complication. Sickle cell trait patients with an average HbS level of 34% or higher are more likely to get papillary necrosis than those with a HbS of 20%.[15] Necrosis is caused by sickling hemoglobin in small capillaries or vasa recta of the kidney, which could cause microthrombi formation and then infarction. Patients with papillary necrosis usually present with gross hematuria and abdominal pain. The management is conservative, including IV fluids, bed rest, and pain management. The prognosis is generally good because a single papillary is primarily affected, and enough viable tissue is present.
Splenic Infarction
The pathogenesis causing splenic infarction is similar to other complications. Like other complications, splenic infarction occurs when the patient is exposed to a low oxygen environment in high altitudes, dehydration, increased acidity, and viscosity.[16] Unlike the other complications, splenic infarction also occurs even when the patient rests at low altitudes. Research has shown that the risk of splenic complications, especially infarction, increases with increasing altitude of the subject [7]. Elevated bilirubin, or LDH, denotes significant splenic complications. However, splenectomy was necessary in less than 20% of cases in one study. Several case reports of a young sickle cell trait patient presenting with multiple infarctions in the spleen have been reported.
Renal Medullary Carcinoma
Renal medullary carcinoma is also another complication associated with sickle cell trait. Usually, this carcinoma is an aggressive tumor at the time of presentation with possible metastasis on diagnosis. According to a case report, a 9-year-old boy presented with diffuse abdominal pain and was found to have renal medullary carcinoma with metastasis to the cervical, mediastinal, and retroperitoneal lymph nodes.[17]
Chronic Kidney Disease
Sickle cell trait has also been associated with increased chronic kidney disease in African American males. Studies have shown that SCT was associated with a decline in GFR and the development of albuminuria compared to those without the trait.[18] According to Niket and his colleagues, GFR decreased at 0.254 mL/min/1.73 m per year (95% CI, 0.089 to 0.418) in sickle cell trait individuals compared to noncarriers.[18] The reason for this is chronic reversible sickling induced by hypoxia in the renal medullae, leading to constant ischemia and microinfarction of the renal tubules. Ischemia of the renal medulla and tubules causes the release of vasoactive elements. These elements contribute to hyperfiltration, leading to sclerosis and proteinuria.
Sudden Death
Sudden death due to exertion has been associated with athletes, police, and military recruits. In one study, there was a 37 times higher risk of exertional death in Division I football players with sickle cell trait in their database study.[19] As a result of this complication found in athletes, a mandatory policy of the NCAA sickle cell screening program was proposed. Another study estimated that over 2000 athletes can be identified with this screening program. These identified individuals can be prevented from having a sudden death if proper intervention is made.[20]
Exertional Rhabdomyolysis
Studies have also shown that sickle cell is associated with exertional rhabdomyolysis. Rhabdomyolysis is the breakdown of skeletal muscle cells during physical exertion, causing myoglobinuria. There is a 54% higher rate of rhabdomyolysis during physical exertion in the presence of sickle cell trait.[8] The sudden death of a college athlete with SCT during intense football training led to the screening policy implemented by the NCAA.[2]
COVID-19
Sickle cell trait is felt to influence COVID outcomes as there is a 1.77-fold increase in COVID mortality with the heterogenous state.[21][22]
Deterrence and Patient Education
About 9% of the African American population has sickle cell trait.[4] Unfortunately, only 16% of individuals of childbearing age with sickle cell trait know their status.[23] Most of these individuals were identified as having the trait during newborn screening. However, after that, they are unlikely to be screened for the trait, which reduces their chances of knowing their status. Also, lack of knowledge and language barriers could deter individuals from not knowing their status. A study by Creary S and colleagues found that before educating caregivers about sickle cell trait, only 38.1% had knowledge of sickle cell at baseline. However, after educating caregivers about the sickle cell trait, 90.3% achieved better knowledge.[23] Sickle cell disease and trait can appear to be a nebulous topic for the patient and the family. Clinicians must provide education and genetic counseling to both.[24][25]
Enhancing Healthcare Team Outcomes
An estimated 3 million African Americans have the sickle cell trait in the US and 300 million worldwide.[4] More attention needs to be paid to individuals with sickle cell trait, and efforts should be made to reduce the percentage of this trait because it does not seem to be completely benign. Individuals with sickle cell trait have been shown to develop sickling of the hemoglobin, leading to organ damage when exposed to hypoxia, high altitude, dehydration, and excessive exercise. They can also transfer sickle cell traits and diseases to their offspring; therefore, efforts should be made to reduce this cycle.
Genetic counseling has been proven to reduce the percentage of traits and diseases. Genetic counseling should be offered to adolescents at risk of transferring sickle cell disease to offspring. This will educate them about their status and enable them to make knowledgeable choices when choosing a life partner. In the endemic region of the world, efforts should be made to offer genetic counseling to individuals. In a study by Memish DA and colleagues, they found that premarital screening in Saudi Arabia markedly reduced the number of individuals with sickle cell trait marrying another sickle cell trait individual.[26] This is why it is essential to implement sickle cell screening, not just for newborns but also for adolescents, because they are the ones that will produce the next generation of offspring.
Individuals who know their sickle cell trait status have a reduced risk of transferring the trait or disease to the next generation. Physicians and other health care professionals should educate the high-risk groups and encourage screening at least once during adolescence if the individual does not know their sickle cell trait status. By doing this, healthcare professionals would help reduce the percentage of sickle cell traits and diseases.
References
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Level 2 (mid-level) evidence