EBM Tools for Practice: Myths and Misunderstandings - The Rationale and Evidence for the Screeing and Treatment of Pediatric Dyslipidemia

Landmark autopsy studies have demonstrated that atherosclerosis begins in youth and is associated with numerous cardiovascular disease (CVD) risk factors, including dyslipidemia.(1,2) Having fewer cardiometabolic risk factors and maintaining them at low levels throughout childhood is associated with reduced atherosclerotic burden in adulthood. (3,4) Therefore, the early identification, evaluation and treatment of pediatric dyslipidemia likely will reduce or delay the development of CVD in adulthood, especially for children with moderate to severe lipid abnormalities related to inherited lipid disorders, such as familial hypercholesterolemia (FH).(5) Children with FH who were treated with statin therapy early on had reduced sub-clinical atherosclerosis progression and burden. (6-10) Despite this evidence, numerous misconceptions remain about pediatric lipid screening and management. In this section of LipidSpin, we address three common myths.

Myth 1: There are no pediatric guidelines for the screening and management of dyslipidemia. In 2011, an expert panel formed by the National Heart, Lung and Blood Institute (NHLBI) produced a revised set of guidelines addressing cardiovascular health and risk reduction in youth. (11) Included in these guidelines is a new recommendation for universal lipid screening for all children between ages 9 and 11 years and again between 17 and 21 years. A primary motivation for recommending universal screening was to improve and promote the detection of FH, which in its heterozygous form is prevalent in about 1:250 people,(12,13) making it the most common inherited lipid disorder. When left untreated, heterozygous FH (HeFH) significantly increases the risk for premature CVD.(14-17)

Myth 2: Family history is sufficient to alert clinicians of the need to perform cholesterol screening. Screening for FH based on family history, as recommended in previous guidelines (Figure 1),(18) has proven to be largely ineffective for detecting new cases of FH in youth, with up to 50% of cases missed, despite being inherited in an autosomal dominant trait.(19) Family histories often are incomplete; for instance, parents may lack recognition of their own diagnosis of FH and young children with elevated cholesterol levels may not routinely see a primary care physician or have a lipid profile. The limitations of selective screening proved the need for universal lipid screening in childhood to optimize early detection and treatment of those with FH through point of care or laboratory measurement of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C).(20,21) While genetic testing has been advocated(22) and appears to be a cost-effective strategy in countries with centrally organized healthcare systems,(23-26) the clinical utility of genetic testing in children to identify FH requires further study. As the cost declines, the value of genetic testing in FH likely will increase.

“FH is a common inherited genetic disorder with a prevalence greater than most diseases included in state newborn screening panels.”

Myth 3: Screening for lipid disorders and treatment with lipid-lowering medications is likely to result in psychosocial and physical harm. The psychological implications of lipid screening and FH diagnosis in youth have been questioned, though no studies to date have demonstrated psychological harms. (22,27-29) In fact, children generally have been shown to cope well.(30,31) Although concerns regarding the long-term safety of statin use in youth have been raised, particularly with respect to the risk of type 2 diabetes mellitus, data from 10-year follow-up studies has shown no risk. (32,33) In a population of youth treated with statins, creatine kinase (CK) levels did not differ compared to those not treated

1. Lipid profile: total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).
2. Family history: includes parents, siblings, grandparents, and aunts/uncles
3. Includes diabetes, hypertension, obesity, and/or cigarette smoking.
4. Moderate risk: Kawasaki disease with regressed aneurysms, chronic inflammatory disease, HIV infection, nephrotic syndrome. High risk: diabetes mellitus, chronic kidney disease or post-renal transplant, post-heart transplant, Kawasaki disease with current aneurysms.

Non-HDL-C: non-high-density lipoprotein cholesterol; CVD: cardiovascular disease

Table 1. Current lipid screening recommendations. Adapted from: “Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report.” Pediatrics. 2011;128 Suppl 5:S213-256.

Figure 1. Trends in pediatric lipid screening recommendations over time.

with statins, and the initiation of statin therapy did not result in an increase in CK levels.(34) In a rosuvastatin trial involving 197 children, intermittent myalgias were reported in 11 (6%) and no participants discontinued treatment.(35)

Future Directions

Key evidence gaps remain regarding the identification and treatment of lipid disorders in youth. Strategies are urgently needed to optimize the detection of FH, because most cases are missed (5,22), in part because of low screening rates of children by health care providers.(37,38) More precise risk stratification likely will better inform and individualize treatment thresholds. As reviewed in this article, the role of genetic testing for FH in youth and the treatment goals, specifically the degree of LDL-C lowering providers should aim to achieve when initiating a statin, require further study.

Conclusion

FH is a common inherited genetic disorder with a prevalence greater than most diseases included in state newborn screening panels. Identification of FH in youth allows for screening of their parents, potentially leading to a multiplier effect and improved detection and prevention of CVD in the population at risk. Evidence to date suggests that statin treatment in youth with FH effectively lowers LDL-C and slows the progression of atherosclerosis(7-10), resulting in a reduced incidence of CVD compared with previous generations that did not implement treatment until adulthood.(6) Clinicians and researchers should focus their attention on improving the screening and detection of FH in children and their families. This upstream approach will improve awareness of lipid disorders in youth with the hope of reducing future CVD burden.

Disclosure statement: Dr. Khoury has no financial disclosures to report. Dr. McNeal has no financial disclosures to report. Dr. Wilson received honoraria from Osler Institute, Alexion Pharmaceuticals,Merck Sharpe & Dohme, and Novo Nordisk Inc.