SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. References

Atherosclerosis begins in childhood, and these early lesions are related to cardiovascular risk factors, including non–high-density lipoprotein cholesterol (HDL-C). Genetic disorders of lipid metabolism, principally familial hypercholesterolemia, have a high frequency in the population (about 1:300–1:500), and cause cardiovascular morbidity beginning in the third decade of life. The current obesity epidemic in children has worsened cardiovascular risk status. Cardiovascular risk factors present in youth often track into adulthood and are more predictive of future subclinical atherosclerosis than risk factors measured in young adulthood. Further, modification of risk factors beginning in childhood and young adulthood can lead to restoration to normal or improvement in measures of subclinical atherosclerosis measures both in those with genetic dyslipidemias and those with dyslipidemia secondary to obesity. Prior recommended selective lipid screening strategies based on family history or presence of other cardiovascular risk factors have failed to capture many with genetic dyslipidemia. Medium-term clinical trials of statin therapy for inherited dyslipidemias are safe and effective in lowering low-density lipoprotein cholesterol (LDL-C). Cholesterol screening in childhood is necessary to prevent cardiovascular morbidity in those with genetic dyslipidemias and to increase awareness of the need for behavioral intervention in those with multiple cardiovascular risk factors, often a result of the obesity epidemic.

Peter O. Kwiterovich, MD has received a research grants from Pfizer and is on the advisory board at Merck.

The authors have no other funding, financial relationships, or conflicts of interest to disclose.

The lipid and nonlipid risk factors for cardiovascular (CVD) disease in adults are expressed in childhood.1 Prospective pathologic studies2,3 starting in youth have clearly demonstrated that the extent of the atherosclerotic lesions over the next several decades is related to baseline CVD risk factors, and in a dose-dependent fashion. CVD risk factors, including increased LDL, decreased HDL, and obesity track from childhood to young adulthood.1 A decided link has been unequivocally demonstrated between childhood CVD risk factors by 9 years of age and more extensive lesions of carotid intima-medial thickness (IMT) or presence of coronary calcium in young adults from 4 large diverse populations.4

Atherosclerosis is not an intrinsic part of human biology. There are a number of examples of populations that have manifested longevity as a companion to a life free of excessive calories and undesirable fat, increased LDL levels, obesity, physical inactivity, cigarette smoking, diabetes, and hypertension. Thus, by starting prevention of CVD and its risk factors early in life, the goal is to develop populations where CVD is not a major health problem. We believe that it is imperative for our children to take the road less travelled if we are truly going to begin to prevent CVD.

However, some have expressed concern that both observational and clinical trial data are lacking that demonstrate a longitudinal relationship between the risk of developing CVD events in adults and either the presence of CVD risk factors in youth or subclinical atherosclerosis in young adults. One approach is to do nothing concerning CVD risk factor detection and treatment until adulthood, where the data are strong and internally consistent that treatment of risk factors prevents both primary and secondary CVD events. Although the incidence of CVD events has decreased in adults in Western countries, CVD is becoming the major health problem in the developing world. CVD remains the major cause of mortality in many countries, who are considering whether earlier detection and treatment of CVD risk factors may provide a more reasoned and effective approach to prevention of CVD.

Extensively studied genetic models of dyslipidemia also provide an unequivocal link between elevated LDL-C in childhood and CVD events in adulthood.5 Heterozygous familial hypercholesterolemia (FH) is the most common (1/300–1/500) Mendelian trait in humans causing premature CVD. The fundamental defect resides in a mutation in the LDL receptor that causes the incomplete removal of LDL from the blood. The parent with FH usually develops CVD in their 30s, 40s, and 50s unless treated. By 1 year of age the average total and LDL-C levels of an FH child are 300 and 240 mg/dL, respectively. These values remain consistently elevated until adolescence, when they temporarily fall but return to extreme levels when growth is completed.

How might one detect such children at markedly increased risk of premature coronary artery disease? The first expert pediatric panel from the National Cholesterol Education Program (NCEP)6 in 1992 recommended selective lipid screening of children with a family history of premature CVD or known hypercholesterolemia in a parent. However, selective screening misses 30% to 60% of FH children who are at the highest risk of developing premature CVD, whereas universal lipid screening detects 90% of FH children 1 to 9 years of age with a false-positive rate of <1%.7

Does such screening for children with FH lead to effective treatment? It appears so. Because FH children only respond to a stringent diet low in total fat, saturated fat, and cholesterol with an average 10% drop in LDL-C levels, the effect of statins to lower LDL-C significantly was examined in a number of randomized, placebo-controlled, clinical trials of 10- to 17-year-old FH children and found to be safe and efficacious.8 Further, Wiegman and coworkers9 randomized FH children, age 8 to 17 years, to either 20 or 40 mg of pravastatin/day (n = 104) or to placebo (n = 107) for 2 years to determine whether use of a statin changed the increased carotid IMT thickening in the treatment vs the control groups. Those in the placebo group had significantly greater progression or no change in carotid IMT, whereas those in the statin group had regression. This was the first evidence that treatment of FH children with a statin over a relatively short period produces a decrease in their early, subclinical lesions of atherosclerosis. There is, therefore, an apparently safe and effective early intervention in FH children, including the postulated potential to prevent premature CVD in adulthood. In the United Kingdom, treatment of young FH adults, age 20 to 39 years, with statins led to a substantial reduction in coronary mortality.10 Estimates of the cost effectiveness of identifying and treating patients with FH are highly favorable in health care systems that can implement cascade screening based on index case identification of middle-age adults and genetic testing; for example, in the United Kingdom the cost is about $7000/quality-adjusted life year.11 Although the additional costs of universal screening are not known, the benefits of earlier CVD prevention in high-risk individuals would be considerable as will cost savings, as statin costs are reduced as medication goes off patent.

Ritchie et al12 also assessed universal lipid screening vs selective screening in a general population of 20266 fasting 5th grade students in West Virginia. A total of 14470 (71.4%) children met NCEP guidelines for lipid screening on the basis of positive family history. Of those, 1204 (8.3%) had elevated LDL-C ≥130 mg/dL), and 170 (1.2%) of these 14470 children warranted possible pharmacologic treatment (LDL-C ≥160 mg/dL). Of the 5798 (28.6%) who did not have a positive family history, 548 (9.5%) had elevated LDL-C, and 98 (1.7%) had LDL-C >160 mg/dL, indicating consideration of pharmacologic treatment. Universal lipid screening identifies children with either a modest or more marked elevations in LDL-C, who are undetected by selective screening, missing the opportunity for hygienic treatment and pharmacologic therapy in those who have more extreme LDL-C elevations.

Obesity is a major health problem in our children. Close to 20% of youth are obese and up to 40% are dyslipidemic. What might become of such children as adults? To address this question, Juonala and coworkers13 pooled data from 4 large studies of CVD risk factors, the Bogalusa Heart Study, the Muscatine Study, the Childhood Determinants of Adult Health Study, and the Cardiovascular Risk in Young Finns Study. Analyses were adjusted for age, sex, height, length of follow-up, and cohort. Adiposity groups were defined as: group I (n = 4742), normal body mass index (BMI) in childhood and nonobese as adults; group II (n = 274), obese in childhood but nonobese as adults; group III (n = 500), overweight or obese in both childhood and adulthood; and group IV (n = 812), normal BMI in childhood but obese as adults. For each of the outcomes examined, namely type 2 diabetes, hypertension, high LDL-C, low HDL-C, elevated triglycerides, and high-risk carotid IMT, there was no significant difference between group I and II, indicating that if an obese child became a nonobese adult, they would not have increased CVD risk outcomes. In distinct contrast, both groups III and IV had highly significant relative risk for these outcomes, indicating that if a nonobese child becomes obese they will be in a high-risk category as an adult. In addition to the detection of FH children, universal lipid screening can detect those children with a modest elevation of LDL-C or non–HDL-C in the upper 25th percentile, who have been shown to develop significantly greater carotid IMT as adults than those children with a LDL-C below the top quartile.4

Finally, there has been concern about the adverse effects of labeling a child as having a cholesterol problem or being obese. There are few data in this regard and no clinical trial of which we are aware. Both authors participated in The Dietary Intervention Study of Children, in which thousands of children age 8 to 10 years were screened in schools to detect a higher LDL-C (average 90%). After being randomized into either a behaviorally based Intervention group or a usual care group, 3 years later both groups had extensive psychological testing. There were no adverse effects for children in the intervention group in terms of academic functioning, psychological symptoms, or family functioning.14 There was no evidence for adverse effects of being labeled as having high LDL-C or for obtaining dietary advice.

Whether the goal of universal lipid screening is to detect FH children,7 those youth with a LDL-C in the upper quintile,4 or both, the ages 9 to 11 years appear to be a good choice for screening. The recent pediatric expert panel15 in 2011 recommended such universal lipid screening starting with a nonfasting child and measuring total cholesterol (TC), HDL-C, and calculating non–HDL-C (TC − HDL-C).

All of the questions have not been answered, and the costs have not been completely estimated. The real questions are: Can we afford to let this epidemic of dyslipidemia and obesity continue to grow unabated? Will our children have a lower life expectancy than ours?

References

  1. Top of page
  2. Abstract
  3. References
  • 1
    McGill HC Jr, McMahan CA, Gidding SS. Preventing heart disease in the 21st century: implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study. Circulation. 2008;117:12161227.
  • 2
    Berenson GS, Srinivasan SR, Bao W, et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med. 1998;338:16501656.
  • 3
    McMahan CA, Gidding SS, Malcom GT, et al. Pathobiological Determinants of Atherosclerosis in Youth risk scores are associated with early and advanced atherosclerosis. Pediatrics. 2006;118:14471455.
  • 4
    Juonala M, Magnussen CG, Venn A, et al. Influence of age on associations between childhood risk factors and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium. Circulation. 2010;122:25142520.
  • 5
    Kwiterovich PO Jr. Clinical implications of the molecular basis of familial hypercholesterolemia and other inherited dyslipidemias. Circulation. 2011;123:11531155.
  • 6
    Wald DS, Bestwick JP, Wald NJ. Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis. BMJ. 2007;335:599.
  • 7
    National Cholesterol Education Program: report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992;89(3 pt 2):525584.
  • 8
    Avis HJ, Vissers MN, Stein EA, et al. A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007;27:18031810.
  • 9
    Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA. 2004;292: 331337.
  • 10
    Neil A, Cooper J, Betteridge J, et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolemia: a prospective registry study. Eur Heart J. 2008;29:20252033.
  • 11
    Wonderling D, Umans-Eckenhausen MA, Marks D, et al. Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands. D Semin Vasc Med. 2004;4:97104.
  • 12
    Ritchie SK, Murphy EC, Ice C, et al. Universal versus targeted blood cholesterol screening among youth: The CARDIAC Project. Pediatrics. 2010;126:260265.
  • 13
    Juonala M. Magnussen CG, Berenson GS, et al. Childhood adiposity, adult adiposity and cardiovascular risk factors. N Engl J Med. 2011;365:18761885.
  • 14
    Lavigne JV, Brown KM, Gidding S, et al. A cholesterol-lowering diet does not produce adverse psychological effects in children: three-year results from the dietary intervention study in children. Health Psychol. 1999;18:604613.
  • 15
    Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011;128(suppl 5):S213S256.