Obesity in Pediatric Sickle Cell Disease: A New Phenomenon

SIGNIFICANCE Sickle Cell Disease (SCD) is the most common genetic disorder in the world and in the United States (U.S.), with about 1 in 13 African Americans born with sickle cell trait and approximately 100,000 individuals currently living with SCD. In this disease, irregular shaped red blood cells (RBC) termed sickle RBC, get trapped in the microcirculation thereby causing ischemic organ damage throughout the body. Due to the chronic hemolysis (breaking of RBCs), patients with SCD have traditionally had a high basal metabolic rate and increased energy consumption (measured by resting energy expenditure) resulting from rapid production of new RBCs. Therefore, patients with SCD tended to be underweight and did not experience weight-related comorbidities such as hypertension, dyslipidemia and hyperglycemia. In recent years, there has been significant improvement in the medical management for patients with SCD, which has resulted in improved morbidity and mortality and increased life span. With these advancements in medical management, recent research has begun to describe increased rates of overweight and obesity in both pediatric and adult patients with SCD. Our research team's pilot data in Mississippi shows that 24% of our pediatric patients with SCD are overweight or obese, defined as body mass indexes (BMI) ≥ 85th percentile. Overweight and obesity is a new medical phenomena in SCD.

The two leading causes of death in individuals with SCD are cardiovascular disease and stroke. In 1973, Lemuel Whitley Diggs estimated a median survival of 14.3 years for individuals with SCD, with 20 percent of deaths occurring in the first 2 years of life. However, as a result of improved medical management, patients with SCD are living longer. In 1994, life expectancy had increased to 42-48 years for the most severe SCD genotype HbSS, and 60-68 years for the less severe SCD genotype HbSC. Since patients with SCD are no living longer and overweight and obesity is a new phenomenon in SCD there is very little knowledge regarding its clinical impact on precipitant risk factors (i.e., hypertension, hyperlipidemia, and hyperglycemia) for cardiovascular disease, stroke, and overall morbidity.

The two published studies to date have been in adults with SCD and document that overweight and obese weight status is associated with metabolic syndrome, hypertension and dyslipidemia resulting in a higher risk for cardiovascular disease and stroke. Type 2 Diabetes (T2D) has historically not been clinically documented in patients with SCD. Yet, recent studies have shown that the prevalence of T2D in adult patients with SCD now approaches that of their healthy African American counterparts. The same study showed that the risk of stroke and overall morbidity for patients with both SCD and T2D was significantly higher compared to patients with just one disease. It is critically important to assess and characterize these potential increased risk factors for cardiovascular disease and stroke in pediatric patients with SCD.

Accurate Measurement of Outcomes in SCD In order to accurately assess weight-related risk factors for cardiovascular disease and stroke (i.e., hypertension, hyperlipidemia, and hyperglycemia) in pediatric patients with SCD, research is needed that appropriately adjusts for disease-related blood processes. Specifically, individuals with SCD have lower systemic blood pressures compared to individuals without SCD. In adults with SCD, clinical problems are observed with blood pressures at or greater than the 90th percentile. When utilizing the 90th percentile, rates of hypertension are similar in adults with SCD (40%) as their healthy counterparts. It is thus recommended that blood pressure values be assessed relative to the lower values expected for patients with SCD, and that a lower threshold of ≥ 90th percentile be used to define 'relative hypertension' in individuals with SCD. Unfortunately, there are no current published age, sex and height-matched norms for blood pressure in youth with SCD. To robustly characterize the association between weight status and elevated blood pressure, the current study will utilize published age, sex and height blood pressure norms for healthy youth without SCD but define relative hypertension (primary outcome) ≥ 90th percentile.

Overweight/obesity is associated with impaired glucose intolerance and is a strong predictor of development of T2DM, which increases the risk for cardiovascular disease and stroke. Specifically, early development of T2DM leads to significant microvascular and macrovascular complications in early adulthood. The greatest risks for impaired glucose tolerance in children is weight status (overweight and obesity) and family medical history of overweight and obesity. Screening for hyperglycemia and insulin resistance in high-risk youth is recommended, as children are often asymptomatic. Expert committees and the American Diabetes Association have endorsed the use of fasting plasma glucose or HbA1c for screening those who are overweight or obese (BMI > 85th percentile), staring at age 10 years of age. However, the use of HbA1c for glucose tolerance testing in SCD is not reliable due to the shortened life span of RBCs in SCD. Therefore, fasting glucose levels and serum fructosamine are recommended for patients with SCD. Fructosamine is a glycated protein and predicts glucose levels over a period of approximately 3-4 weeks and will be used as the primary measure of hyperglycemia (secondary outcome) in the current study.