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Perspectives |
1 The Johns Hopkins Medical Institutions, Department of Pediatrics, Baltimore MD.
aAddress correspondence to the author at: The Johns Hopkins Medical Institutions, Department of Pediatrics, 550 North Broadway, Suite 310, Baltimore MD 21205. E-mail pkwitero{at}jhmi.edu
Antecedent plasma concentrations of lipids and lipoproteins are associated with both early pathologic lesions of atherosclerosis and arterial changes in vivo, such as carotid intima media thickness (IMT)1 and endothelial dysfunction (1)(2). Healthy normolipidemic Finnish children, treated with a low–saturated fat, low-cholesterol diet from the age of 7 months to 11 years, had less carotid IMT than controls. In Dutch children and adolescents with heterozygous familial hypercholesterolemia (FH), treatment for 2 years with a similar diet and an inhibitor of hydroxymethylglutaryl CoA reductase led to decreased carotid IMT compared to IMT in FH children treated with diet and placebo. Impaired endothelial dysfunction in FH children, as judged by flow-mediated dilation, improved significantly in those treated with simvastatin vs those on placebo, to a level similar to that in healthy non-FH controls.
These findings have raised considerable interest in identifying children and adolescents with dyslipidemia and to initiate treatment with diet and, when necessary, with drugs. Screening of children for dyslipidemia has traditionally been focused on those with a positive family history of premature cardiovascular disease (CVD) and those whose parents have CVD or dyslipidemia (primarily hypercholesterolemia). Unfortunately, screening by family history of CVD or hypercholesterolemia fails to detect 17% to 90% of those with significant dyslipidemia (1). Although 50% of offspring of parents with premature CVD will have dyslipidemia, such parents are usually in their 40s, delaying the detection of dyslipidemia in their children. Conversely, considerable data indicate that lipid and lipoprotein concentrations track from childhood into adulthood, especially total cholesterol (TC), LDL-C, non–HDL-C (the estimated cholesterol concentration of all the apolipoprotein B–containing lipoproteins, i.e., TC minus HDL-C) (1). Given all of the above results, the alternative approach of universal screening is receiving greater attention.
Screening requires the use of cut points to identify individuals with dyslipidemia. Cut points in adults are primarily based on their association with CVD in middle age. Such CVD-based data are not available in children and adolescents, and cut points are primarily based on percentile values, derived from defined populations, and set at thresholds that increase the likelihood of detecting those dyslipidemic youth who will become dyslipidemic adults.
The selection of cut points is often empirically derived and arbitrarily chosen. There is no perfect paradigm. For example, as one increases the cut points for TC or LDL-C, sensitivity (the ability to detect those who are affected) decreases, but the specificity (the ability to detect those who are not affected) and the predictive value of a positive test (ability of a test results to identify an affected person) increases. Decreasing the cut point (e.g., from the 95th percentile to the 75th) increases sensitivity but decreases specificity and the predictive power of a positive test.
The National Cholesterol Education Program (NCEP) Expert Panel on Blood Cholesterol Levels in Children (3) recommended a single set of cut points to define pediatric dyslipidemia, primarily but not exclusively focused on LDL-C. The use of multiple cut points specific for these variables may be indicated because lipid and lipoprotein concentrations may vary with age, sex, ethnicity, and during periods of rapid growth and development, such as adolescence.
The report by Magnussen and colleagues (4) examines the use of multiple cut points in part by comparing the usefulness of lipid and lipoprotein concentration measurements in adolescence, classified according to the NCEP Pediatric Panel (3) and the National Health and Nutrition Education Survey (NHANES) cut points (5), to predict abnormal concentrations in adulthood. Adolescent and adult concentrations of TC, LDL-C, HDL-C, and triglycerides were measured in 365 Australian, 1185 Finnish, and 273 US individuals who participated in 3 population-based prospective cohort studies. According to diagnostic performance statistics, the NCEP cut points, compared with NHANES, were more strongly predictive of adult high TC, LDL-C, and triglycerides than NHANES, but less predictive of HDL-C.
The pooled data indicated that the risk of developing an abnormal condition in adulthood was significantly higher in those adolescents with borderline- and high-risk concentrations compared with those with normal concentrations for all lipoprotein variables. Moreover, a graded increase in the risk of developing abnormal concentrations in adulthood was observed when moving from the normal, to borderline-risk, to high-risk groups.
Interaction terms were significant between cohort and HDL-C cut points for both NCEP and NHANES, suggesting that the relationship between risk status in adolescents and the development of abnormal HDL-C concentrations as adults differed between cohorts. In cohort-stratified analyses, the relative risks for HDL-C in Bogalusa were substantially lower than estimates from the other 2 populations. This finding may reflect differences in the methods used to measure HDL-C or the greater proportion of blacks in the Bogalusa population. In this regard, NHANES did not develop race-specific growth curves and thresholds (5).
The NHANES investigators linked each curve (threshold) in adolescence to the adult NCEP Adult Treatment Panel III lipoprotein thresholds, using Lambda-Mu-Sigma growth curve regression models. It should be pointed out that the NCEP Adult Panel cut points are not age, sex, or race specific. This approach assumed that the Adult NCEP cut points were appropriate for all adults, males and females, age 20 years and older. In fact, an LDL-C of 4.14 mmol/L (160 mg/dL) represents about the 75th percentile in middle-aged white men, but approximately the following percentiles in younger white men: ages 20–24 years, 98th percentile; ages 25–29, 95th percentile; ages 30–34, 90th percentile; ages 35–39, 80th percentile. Thus, using such a cut point in young adulthood to define high LDL-C will miss those young adults with an LDL-C >75th percentile, many of whom are destined to become middle-aged adults with a high LDL-C >4.14 mmol/L (160 mg/dL). This problem becomes less important if an "affected" adult is defined as one who will require some intervention, usually diet or sometimes drug, whose NCEP adult LDL-C is in the "borderline-high" range of 3.36 mmol/L (130 mg/dL) to 4.11 mmol/L (159 mg/dL).
A comparison of the NCEP and NHANES cut points for LDL-C in adolescents is summarized in Table 1
. Because they were linked to adult NCEP thresholds, the NHANES cut points were higher than those from NCEP. One would predict that the sensitivity would be significantly higher using NCEP cut points but that the specificity and predictive power of a positive test would be lower, and this situation was in fact observed in the study by Magnussen et al. (4).
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Using the findings from the Finnish population, Magnussen et al. (4) also evaluated different screening strategies to identify adolescents more likely to develop dyslipidemia as adults. The best-performing high-risk cut points from the initial analyses were used in conjunction with universal screening and selective screening using: (a) positive family history of CVD, (b) overweight or obesity, and (c) positive family history of either CVD or obesity. For TC and LDL-C, the addition of family history or obesity to the cut points from screening only marginally improved the results of universal screening. Universal screening alone identified a much larger number of affected adults than selective screening. Universal screening identified 75% of participants with high LDL-C at follow-up in adulthood, but at the expense of a high false-positive rate (66%). HDL-C and TG from universal screening of adolescents was a poor predictor of low HDL-C and high TG in adulthood. The addition of obesity improved the yield of low HDL-C and high TG at follow-up from 10.8% to 29.0% and from 12.5% to 29.2%, respectively. This result highlights the important relationship of obesity in adolescence with low HDL-C and high TG later in life, and most likely reflects the proclivity of such youth to show effects of the metabolic syndrome, including insulin resistance. Although the LDL-C concentration may not be increased in such patients, they often have an increased number of small, dense LDL particles, an important part of the dyslipidemic triad in obese adolescents with multiple CVD risk factors.
What might be the most useful approach to identify young people more likely to develop clinically significant dyslipidemia later in life? Adolescence is not the only time amenable to screening. The age of 10 years precedes the changes in lipids and lipoproteins that occur during adolescence. A set of cut points might be adjusted for adolescence, but it is not clear that using cut points adjusted for each year and for sex improves the result of screening. In fact, the report by Magnussen et al. (4) suggests otherwise. Therefore pediatricians, family practitioners, and other healthcare providers may not have to scrutinize screening results in such detail. The implications of multiple cut points for the clinical chemist may be problematic as well.
Thus, a clear need exists to address CVD risk factors in children and to update the NCEP Pediatric Panel’s recommendations. Guidelines based on a systematic evidence review for the screening, diagnosis, and management of dyslipidemia, as well as obesity, hypertension and other risk factors in pediatric patients, are currently being developed by the National Heart, Lung and Blood Institute Pediatric Cardiovascular Risk Reduction Initiative.
Acknowledgments
Grant/Funding Support: None declared.
Financial Disclosures: None declared.
Footnotes
1 Nonstandard abbreviations: IMT, intima media thickness; FH, familial hypercholesterolemia; CVD, cardiovascular disease; TC, total cholesterol; NCEP, National Cholesterol Education Program; NHANES, National Health and Nutrition Education Survey. 
References
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