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Cholesterol is a lipid present in the cell membrane and subcellular organelles of tissues throughout the body. Because of its amphipathic nature, cholesterol plays a key role in maintaining membrane fluidity, thereby influencing transmembrane signaling and other fundamental cellular functions. Cholesterol in the brain, which accounts for about 25% of total body stores, promotes myelin formation, synaptogenesis, and neuronal plasticity.2 In addition, cholesterol serves as the building block for all steroid hormones, including cortisol, aldosterone, estrogen, and testosterone. The critical importance of cholesterol to health is demonstrated by Smith–Lemli–Opitz syndrome, a disorder resulting from decreased cholesterol biosynthesis that causes devastating multiorgan failure.
Before this year's policy statement, the AAP recommended only one class of lipid-lowering drugs, bile acid–binding resins such as cholestyramine and colestipol that bind cholesterol in the gut and have no clinically significant systemic side effects. Statins work through a novel mechanism, the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme involved in the synthesis of cholesterol (see diagram). Statins also inhibit production of mevalonate and other cholesterol intermediates in the isoprenoid pathway. These compounds, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, participate in the post-translational modification of small guanosine triphosphate–binding proteins involved in cell proliferation and other functions, providing a molecular explanation for the pleiotropic effects of statins that are observed both in vitro and in vivo.3 Though the primary site of action for statins is the liver, some agents in this class inhibit cholesterol synthesis in other tissues, including the brain.
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The subtext for this controversy is, of course, the epidemic of childhood obesity in the United States and, increasingly, around the world. Indeed, the word "obese" or "obesity" appears more than 20 times in the AAP's 2008 report, as compared with just twice in its previous report. During the past 25 years, the prevalence of pediatric obesity has tripled; in some minority-group populations, the majority of adolescents are overweight or obese. Recent research suggests that increasing body weight in childhood, even within the range considered normal, is strongly associated with the risk of cardiovascular disease in adulthood.4 Case reports have identified renal failure requiring dialysis, limb amputation, and death before 30 years of age among persons who developed type 2 diabetes during adolescence. Because of such effects, some experts have predicted that life expectancy will decrease in the United States for the first time in more than a century unless something is done about childhood obesity. Given the urgency of this situation, the expert committee formulating the new AAP guidelines faced the unenviable task of balancing the unknown risks associated with pharmacologic therapy in children against the prospect that myocardial infarction would become a common condition of young adulthood. In this scenario, the pediatrics community has no good choices.
The recommendation to use statins in childhood seems to have hit a collective nerve, perhaps awakening us to the fuller implications of the obesity epidemic. It's one thing to treat the rare child who has an inherited defect in cholesterol metabolism and quite another to extend treatment to children who are at risk for cardiovascular disease because of modifiable lifestyle factors.
At present, we do not know how many children or adolescents will meet the criteria for statin treatment because of the effects of obesity, poor diet, or physical inactivity. High levels of low-density lipoprotein cholesterol represent just one of many risk factors resulting from an unhealthful lifestyle, and among lipid abnormalities, low levels of high-density lipoprotein cholesterol and high triglyceride levels appear to be more strongly associated with excess body weight. Regardless of how many additional children may receive statin treatment under these new guidelines, the broader, more important question is whether we intend to treat pediatric obesity with an ever-increasing array of powerful adult drugs — beta-blockers and diuretics for hypertension, aspirin for coagulopathy, insulin sensitizers for the metabolic syndrome, and of course insulin for diabetes. Once this door has been opened, the pharmaceutical industry will happily walk through it. Instead of fewer advertisements for junk food, are we destined to see new commercials promoting the use of cholesterol-lowering medications in children?
The intense media coverage of the new statin policy may have shined a light on the profound cultural disconnect between our willingness to treat disease with drugs and our reluctance to institute preventive public health measures. These measures would include regulating food marketing to children, improving the quality of nutrition at school, promoting physical activity at school and elsewhere, and providing greater funding for obesity prevention and treatment programs.5 If the AAP recommendations have helped bring this disconnect to light, then their greatest effect may be not on the children who will receive pharmacologic treatment for hypercholesterolemia but rather on the adults who are responsible for the world in which our children live.
Dr. de Ferranti reports receiving research grants from GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported.
Source Information
Dr. de Ferranti is director of the Preventive Cardiology Clinic at Children's Hospital Boston and an assistant professor of pediatrics at Harvard Medical School, in Boston. Dr. Ludwig is director of the Optimal Weight for Life Program at Children's Hospital Boston and an associate professor of pediatrics at Harvard Medical School.
References
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