Lipid Issues in Children and Adolescents: Challenges and Possible Solutions

Is duration of exposure to higher levels of LDL-C the key?

As noted in the article in this issue “Lipoprotein-X Accumulation: A Mimic of Familial Hypercholesterolemia,”¹ lipid disorders occur in about 20% of children between 12 and 19 years of age.² The case in the article is rare, but it highlights the need to think of secondary causes of lipid disorders and the association of lipid disorders with liver disease and/or abnormal liver enzyme levels.

Causes of lipid abnormalities. There are a variety of secondary causes for abnormal lipid levels. The following medical conditions may produce increased low-density lipoprotein cholesterol (LDL-C): obstructive liver disease, nephrotic syndrome, use of high-dose diuretics, and hypothyroidism. Elevated triglyceride levels and reduced high-density lipoprotein cholesterol (HDL-C) levels are associated with renal disease; use of ß-blockers, protease inhibitors, glucocorticoids, and antipsychotics; pre-diabetes; diabetes; and metabolic syndrome.

The most common conditions associated with lipid abnormalities in adolescents are insulin resistance and metabolic syndrome. Metabolic syndrome in adolescence predicts metabolic syndrome in adulthood.³

Challenges with lipid screening in youths. Abnormal levels of liver enzymes (alanine aminotransferase, aspartate aminotransferase) secondary to fatty liver are commonly associated with lipid abnormalities, especially in association with metabolic syndrome. Patients with metabolic syndrome usually have insulin resistance and are pre-diabetic or diabetic. Treatment must address both the hyperglycemia and the lipid abnormalities. Lifestyle changes are the foundation of treatment, but some adolescents require medication in addition to lifestyle changes.

When to treat youths with abnormal lipid levels. The challenge is, of course, which youths should be given medication and which medications to choose. Fortunately, we now know that statins are not contraindicated when liver enzyme levels are increased. In February 2012, the FDA announced that routine periodic monitoring of liver enzymes in patients receiving statins is not effective and concluded that liver disease caused by statins is very rare.⁴ Serum bilirubin is the preferred laboratory test for screening and diagnosis when liver disease is suspected.

Which youths should be screened. Screening for lipid abnormalities in children and adolescents is controversial. An expert panel convened by the National Heart, Lung, and Blood Institute (NHLBI) in late 2011 recommended universal screening of all children 9 to 11 years of age with a nonfasting lipid panel, plus targeted screening with 2 fasting lipid profiles of children ages 2 to 8 years and 12 to 16 years.⁵ The recommendations were endorsed by the American Academy of Pediatrics. Previous recommendations suggested screening only high-risk children. This recommendation was followed by a significant negative reaction that appeared in several publications.

Critics argue that the recommendations were made without consideration of benefit, harm, and cost. The critics also argue that the evidence is not as strong as implied—the recommendations are based heavily on expert opinion—and that many panel members had conflicts of interest with industry.^6-8

In response, the authors of the NHLBI report argue that atherosclerosis is a lifelong process that begins in childhood and that not all high-risk children can be identified without lipid screening. They cite studies of traumatic death in young adults who have a 30 mg/dL increase in non-HDL-C, which is the equivalent of 2 years of vascular aging,⁹ and studies showing that associated markers (such as carotid intima media thickness) of cardiovascular disease (CVD) risk in adults are predicted by dyslipidemia in childhood and adolescence.¹⁰

Many unanswered questions. All clinicians would agree that the atherosclerotic process begins in childhood and a high LDL-C level is associated with an increased level of atherosclerosis. We also agree that identifying and treating children with heterozygous familial hypercholesterolemia appears to delay the atherosclerotic process. But is universal screening justified? And even more important, is lifelong treatment with lifestyle changes and, at times, medication justified? On the other hand, should we consider duration of LDL-C exposure or absolute level of LDL-C as the target we should address?

Possible solutions. The key seems to be the cumulative exposure to increased LDL-C. Does exposure to high LDL-C levels for prolonged periods lead to increased mortality and morbidity in later life? Theoretically, it makes sense. Horton and colleagues¹¹ provide insights into the causal role of LDL-C in CVD. They propose that modest lifelong reductions in LDL-C will confer reductions in CVD risk even in the presence of other risk factors, such as diabetes and hypertension. A graphic description of this is provided in the Figure.

This same concept is illustrated in the belief that prolonged exposure to lower LDL-C beginning early in life is associated with a greater reduction in the risk of CVD than lowering LDL-C beginning later in life.¹² This belief is based on a Mendelian analysis, which demonstrated that lower LDL-C was associated with a 55% reduction in the CVD risk for each 1 mmol/L (38.7 mg/dL) lower LDL-C early in life—or a 3-fold greater reduction in the risk of CVD compared to treatment with a statin later in life.

Practical reasons for universal screening. de Ferranti¹³ favors universal screening and suggests the formation of registries for children receiving long-term treatment. These registries could provide the databases that facilitate advanced studies, such as genetic testing, cost-effective analysis, screening methods, and response to therapy.

I feel that lifetime exposure to increased LDL-C levels is the culprit, and universal screening for all children in and around adolescence is the only way to identify those at risk. I would include a full lipid profile and a fasting blood sugar test. Lipid abnormalities often are found in association with dysglycemia. If these test results are abnormal, I would order a follow-up to include a 2-hour postprandial blood sugar test and liver enzyme tests. I suggest the addition of a glucose and liver enzyme evaluation because of the association of insulin resistance and fatty liver disease with lipid abnormalities.

Laboratory results seem to motivate patients and clinicians, and that should lead to more motivation for parents and patients to change their behavior.

Many patients, parents, and clinicians will not adhere to the NHLBI recommendations. However, for those who do believe in the guidelines, the results will provide the basis for analysis. Many of these analyses/studies will be done in the primary care setting because the use of registries in clinical practice is now more practical, and practice-based research is now a reality.

Final thoughts. So where does all this leave us? It is doubtful that a 50-year randomized study will be done to completely answer the question about screening, and if it were, clinicians still have to make decisions based on currently available data and opinions. However, it is of no use to screen without an equally aggressive approach to help our patients and their families achieve lifestyle changes.