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Childhood Obesity, Inflammation, and Apnea

What Is the Future for Our Children?

University of Pennsylvania School of Medicine Philadelphia, PA

In this issue of the Journal (pp. 282–286), Kaditis and colleagues describe normal levels of C-reactive protein (CRP) in Greek children with the obstructive sleep apnea syndrome (OSAS) (1). This is in contrast to a previous study by Tauman and coworkers of children living in Kentucky (2), as well as studies of adults with OSAS (3).

What can explain the discrepancy between these studies? Both pediatric studies had a similar sample size, and subjects had a similar spectrum of disease severity. The children in the Greek study were slightly younger, and perhaps had a shorter duration of disease, with less time for inflammation to occur. However, the major difference between the two populations was body size. In the Kentucky cohort, the relative body mass index (BMI) (100 x absolute BMI/BMI at 50th percentile for age) was 147% in the control/mild OSAS group, and 175% in the OSAS group, versus a relative BMI of approximately 110% for all groups in the Greek study. In both studies, as well as other studies in the literature (4), BMI correlated with CRP. This finding of subclinical inflammation in overweight children with OSAS suggests that the OSAS associated with obesity may be different from the OSAS associated with adenotonsillar hypertrophy. It has been speculated that OSAS unmasks or exacerbates—through recurrent hypoxia, increased sympathetic output, or other mechanisms—the chronic subclinical inflammation that characterizes obese adipose tissue.

Obesity has reached epidemic proportions globally, but especially in the United States, and is afflicting children and adults alike. Currently, 15% of American children are overweight (5). This increase in pediatric obesity is associated with the earlier emergence of insulin resistance and diabetes (6), hypertension, and dyslipidemia (6)—harbingers of cardiovascular disease. The appearance of these metabolic abnormalities in youth poses a potentially enormous public health crisis, given that increasing numbers of individuals may demonstrate complications of diabetes and cardiovascular disease earlier in life.

Cardiovascular disease is already recognized as an important public health issue in adults, and the role of obesity, including that found in childhood, in promoting atherosclerosis is the subject of much investigation. The metabolic abnormalities frequently found in obese individuals, such as hyperglycemia, hypertension, and atherogenic lipoproteins, promote vascular injury (7). Development of the atherosclerotic plaque ensues, with inflammation playing a central role in its initiation and propagation (7). The key role of inflammation in the pathogenesis of cardiovascular disease is highlighted by the finding that elevations in inflammatory markers such as CRP, tumor necrosis factor-, and interleukin-6 have been identified in individuals with obesity and in whom cardiovascular disease subsequently develops (8). Underscoring the role of obesity in inflammation, adipose tissue from obese individuals is characterized by inflammation and is capable of secreting humoral factors that regulate systemic acute phase reactants such as CRP, as well as inflammatory factors such as tumor necrosis factor- and interleukin-6 (9).

CRP is the product of hepatic stimulation, and, like other components of the inflammatory cascade, its elevation is not limited to the atherosclerotic process. Other factors associated with increased CRP levels include elevated BMI, hypertension, cigarette smoking, exogenous estrogen, chronic infections, and inflammatory processes (7). The finding of elevated CRP in both adults and children with increased BMI suggests that obesity is a chronic inflammatory state. However, whether CRP directly contributes to the atherosclerotic process or is merely a risk marker is not clear, because the extent of CRP elevation has not uniformly correlated with the extent of atherosclerosis (7).

Although not well studied, it can be assumed that the increased prevalence of obesity in the United States has also been accompanied by a rise in the incidence of OSAS. In adults, OSAS is associated with insulin resistance, hypertension, and increases in inflammatory markers. These metabolic abnormalities improve with treatment of OSAS, indicating that OSAS plays a direct role in their development (3, 10–12). The few studies performed in children suggest a similar relationship (13).

These studies raise the question of the relationship between the childhood and adult forms of OSAS. Classically, children with OSAS have been described as being underweight, with adenotonsillar hypertrophy. Although it has not been formally studied, those of us who treat children with OSAS have seen a dramatic change in the epidemiology of the disease. We now see waiting rooms filled with obese children and adolescents, rather than skinny, mouth-breathing children. It is unclear whether childhood OSAS related to adenotonsillar hypertrophy is the same disease process seen in obese children, whether the latter more closely resembles the adult disease, and what overlap is present. Be that as it may, numerous recent studies have demonstrated the presence of hypertension and increased inflammation in children with OSAS (13–16). It is frightening to think of the medical future awaiting this generation.

FOOTNOTES

Conflict of Interest Statement: A.K. does not have a financial relationship with a commercial entity that has an interest in the subject of the manuscript; C.L.M. does not have a financial relationship with a commercial entity that has an interest in the subject of the manuscript.

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