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Lozano P, Henrikson NB, Morrison CC, et al. Lipid Screening in Childhood for Detection of Multifactorial Dyslipidemia: A Systematic Evidence Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Aug. (Evidence Syntheses, No. 140.)

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Lipid Screening in Childhood for Detection of Multifactorial Dyslipidemia: A Systematic Evidence Review for the U.S. Preventive Services Task Force [Internet].

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1Introduction

Scope and Purpose

The Agency for Healthcare Research and Quality (AHRQ) commissioned a systematic evidence review to support the U.S. Preventive Services Task Force (USPSTF) in updating its 2007 recommendation on screening for lipid disorders in children.

Pediatric dyslipidemias are a heterogeneous set of conditions that include several monogenic disorders as well as dyslipidemias caused by a variety of factors, both genetic and environmental. On the basis of public input on the draft research plan, the USPSTF decided to conduct two separate systematic reviews: one on screening for familial hypercholesterolemia (FH) and a second on screening for elevated concentrations of atherogenic lipoproteins, which we refer to as multifactorial dyslipidemia.

The two reviews were conducted by the same Evidence-based Practice Center using a search strategy that produced one body of potential evidence encompassing both FH and multifactorial dyslipidemias. The evidence was assessed sequentially for each review's set of Key Questions (KQs). These two concurrent systematic reviews will allow the USPSTF to simultaneously consider both bodies of evidence when evaluating the preventive health benefits of screening children and adolescents for dyslipidemias involving elevated concentrations of low-density lipoprotein cholesterol (LDL-C) or total cholesterol (TC).

This review focuses on dyslipidemias involving elevated LDL-C or TC that are not FH, referred to in this report as multifactorial dyslipidemia. It reviews the evidence for benefits and harms of screening and treatment of multifactorial dyslipidemia in children and youth ages 0 to 20 years.

Cholesterol and Dyslipidemia in Childhood and Adolescence

Cholesterol concentrations in healthy children vary with age. The distribution of TC and LDL-C concentrations, for example, are bimodal in childhood. They start very low at birth, increase slowly in the first 2 years of life, peak prior to puberty, and decrease by 10 to 20 percent or more during adolescence before rising again during late adolescence and young adulthood.1 Concentrations of TC and LDL-C are generally higher in girls than in boys. The peak in girls precedes that in boys by about 1 year, reflecting maturational differences.

Lipid disorders are defined according to population norms. The Lipid Research Clinics prevalence studies2 used population distributions to determine age- and sex-specific cut points for TC and LDL-C concentrations.3, 4 The National Heart, Lung, and Blood Institute (NHLBI) and American Academy of Pediatrics have adopted the National Cholesterol Education Program's (NCEP's) recommendation for fixed cutoff values to define dyslipidemia in children (TC≥200 mg/dL and LDL-C ≥130 mg/dL).2 These cut points are commonly used in published studies and widely accepted in clinical practice. We will use these in the current review, although, as noted below, fixed thresholds that ignore cholesterol variations by age and sex may be problematic.

Box 1The National Cholesterol Education Program's Recommended Cut Points to Define Dyslipidemia in Children

CategoryTotal cholesterol (mg/dL)LDL cholesterol (mg/dL)
Acceptable<170<110
Borderline170 to 199110 to 129
High≥200≥130

Abbreviation: LDL=low-density lipoprotein.

Condition Definition

For purposes of this report, LDL-C concentrations of 130 mg/dL or greater or TC concentrations greater than 200 mg/dL not due to FH are referred to as “multifactorial dyslipidemia” and are the focus of the current review. Elevations in TC and LDL-C concentrations in children and adolescents are of concern because of the role of these lipids in cardiovascular disease in adults and in atherogenesis even at young ages. Non–high-density lipoprotein cholesterol (non–HDL-C, which is the difference between TC concentration and the HDL-C concentration) has emerged as the best marker of atherogenic risk in adults; however, few screening studies have relied on non–HDL-C in pediatric populations.

Extremely high LDL-C and TC concentrations are seen in FH, which is the subject of the companion systematic evidence review commissioned by the USPSTF. In the accompanying systematic review, FH is defined using any one of several established diagnostic criteria, all of which include a combination of elevated lipid concentrations, physical findings, family history, or genetic tests.

Children and adolescents with a variety of renal, infectious, hepatic, inflammatory and storage disorders, type 1 and 2 diabetes, and several other syndromes are also at risk for experiencing elevated LDL-C or TC concentrations. These secondary dyslipidemias are beyond the scope of this review.

Multifactorial dyslipidemia in children and adolescents may be associated with environmental factors, such as a high-fat diet, with or without inherited susceptibility. Elevated LDL-C and TC concentrations appear to be associated with measures of adiposity, such as body mass index (BMI)5-7, 8 and waist circumference.5, 6 Overweight and obesity, now present in nearly a third of U.S. children ages 2 to 19 years,9 are associated with poor nutrition and physical inactivity, each of which may be independently associated with childhood dyslipidemia. However, the strongest association of BMI is with triglyceride concentrations, which are not part of the definition of multifactorial dyslipidemia. Some evidence indicates that higher rates of physical activity are associated with lower LDL-C concentrations,10 and sedentary activity may be correlated with TC concentrations.11

A family history of dyslipidemia or premature cardiovascular disease is a risk factor for childhood dyslipidemia. Even apart from a monogenic condition with high penetrance, such as FH, there are a number of genetic variations with incomplete penetrance that contribute to multifactorial dyslipidemia.12 In the United States, dyslipidemia is experienced disproportionately by adults with Hispanic ethnicity13 and those of Asian ancestry.14

The prevalence of elevated TC in children ages 8 to 17 years is 7.8 percent, according to National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2012.8 The most recent national prevalence estimate (NHANES 2007 to 2010) of elevated LDL-C concentrations in adolescents is 7.4 percent.15 However, these NHANES data rely on a single lipid test. Within-person variability of lipid concentrations is considerable, such that repeat testing is required to reliably categorize children according to the NCEP ranges of acceptable, borderline, or high.16 Therefore, these figures overestimate the true prevalence of these dyslipidemias in the population.

Multifactorial dyslipidemia is a risk factor, not a disease. The definition of multifactorial dyslipidemia is based on pediatric norms, not on actual risks associated with specific TC or LDL-C concentrations. It is unclear to what extent elevated lipid concentrations at ages younger than 18 to 20 years confer future disease risk.

Natural History and Disease Burden

Dyslipidemia, Atherosclerosis, and Adult Coronary Heart Disease

Cholesterol is a lipid that is a vital component of cell membranes and plays a role in synthesis of steroid hormones, vitamin D, and bile acids. Humans absorb dietary cholesterol and also synthesize it de novo. Diet and genetics both affect blood cholesterol concentrations, as do other environmental factors. Cholesterol synthesis and absorption vary greatly in the general population. Plasma cholesterol concentrations are the sum of intestinal absorption and hepatic synthesis minus net biliary excretion and cell use. Three classes of lipoproteins transport cholesterol in the serum: LDL, HDL, and very-low-density lipoprotein (VLDL). TC is comprised of 60 to 70 percent LDL-C, 20 to 30 percent HDL-C, and 10 to 15 percent VLDL-C.

The burden of hypercholesterolemia is related to its link to atherosclerosis and coronary heart disease (CHD). LDL-C is the primary atherogenic lipoprotein and is the primary target of cholesterol-lowering therapy in adults. Some forms of VLDL-C are precursors to LDL-C and also promote atherosclerosis. HDL-C concentrations are inversely related to the risk for CHD. When elevated, LDL-C accumulates in blood vessels, contributing to plaque formation, which occurs in stages, starting with fatty streaks and progressing to fibrous plaques. Non–HDL-C provides an estimate of atherogenic particles including LDL-C, VLDL-C, lipoprotein a, and intermediate-density lipoprotein.17 In adults, elevations in TC, LDL-C, and non–HDL-C are risk factors for atherosclerotic cardiovascular disease, specifically CHD,17 which may lead to sudden coronary death and myocardial infarction (MI). The association of triglyceride levels with CHD is unclear and for this reason, our definition of multifactorial dyslipidemia excludes triglycerides. Other risk factors for CHD in adults are age, male sex, hypertension, smoking, diabetes, obesity, physical inactivity, an atherogenic diet, and family history of early CHD.

The prevalence of CHD increases with age and is higher in men than in women of the same age.18 In 2010, the overall age-adjusted prevalence of CHD was 6.0 percent in the United States. Age-specific prevalence was 1.2 percent in 18- to 44-year-olds, 7.1 percent in 45- to 64-year- olds, and 19.8 percent in age 65 years and older.18 CHD is the leading cause of death in the United States.19, 20

Identifying and treating dyslipidemia in adults older than age 40 years is common clinical practice in the United States. The USPSTF recommends screening adults for dyslipidemia, with specific recommendations depending on age, sex, and risk factors.21 This recommendation is currently being updated.

Association Between Dyslipidemia in Childhood and Adolescence and Atherosclerosis

Multifactorial dyslipidemia in childhood and adolescence is a risk factor for future atherosclerosis. Several longitudinal studies have found associations between childhood lipid concentrations and measures of atherosclerosis. Studies of 204 individuals in the Bogalusa cohort who died between age 2 and 39 years showed a positive association between antemortem LDL-C and TC concentrations and atherosclerosis at autopsy, as assessed by the presence of fatty streaks and fibrous plaques in the aorta and coronary arteries.22, 23 Data from the Muscatine study showed that LDL-C concentrations at ages 8 to 18 years predicted carotid intima-media thickness (CIMT) at ages 33 to 42 years.24 A followup of the Bogalusa cohort found that LDL-C concentrations at ages 5 to 17 years predicted CIMT at ages 16 to 19 years.25 In the Young Finns study, LDL26, 27 and ApoB/ApoA-128 concentrations in adolescence (ages 12 to18 years) were associated with CIMT in adulthood.

The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, a large cross-sectional autopsy study of 15- to 34-year-olds who died of external causes, found the extent of fatty streaks to be positively associated with postmortem LDL-C plus VLDL-C concentrations and negatively associated with HDL-C concentrations.29 In that same study, high non–HDL-C and low HDL-C concentrations were associated with more extensive fatty streaks and raised lesions in the abdominal aorta and right coronary artery.30 In contrast, a cross-sectional U.S. study of 599 children and adolescents found that CIMT was not correlated with LDL-C concentrations when controlling for obesity.31

In the Coronary Artery Risk Development in Young Adults study (CARDIA, not to be confused with the more recent CARDIAC [Coronary Artery Risk Detection in Appalachian Communities] study), lipid concentrations at baseline (in the mid-1980s) and at age 20 years were positively associated with CIMT and coronary calcium Hounsfield units at age 20 years.32, 33 Exposure to nonoptimal lipid concentrations in young adulthood is associated with atherosclerotic changes later in life. One prospective cohort study of 2,824 persons age 18 to 30 years with nonoptimal concentrations of LDL-C (defined as >100 mg/dL) at baseline found that cumulative exposure to higher LDL-C or lower HDL-C concentrations was associated with markers of atherosclerosis two decades later.33

Tracking of Dyslipidemia Over Childhood and Adolescence

Another important aspect of the natural history of multifactorial dyslipidemia in youth is the incomplete tracking of lipid concentrations between childhood, adolescence, and adulthood. Many studies have documented correlation of lipid measurements across the pediatric and young adult age span.34 Tracking to adulthood is highest for 12- to 18-year-olds.35 However, dyslipidemia identified in childhood or adolescence imperfectly predicts adult lipid concentrations.34 For example, the Muscatine study measured TC concentrations yearly for 6 years in a longitudinal cohort of almost 9,000 children and adolescents in Iowa. Although TC measurements were well correlated across the years, children in the highest quintile of the TC distribution had only about a 30 percent probability of being in the highest TC quintile 6 years later.36 Magnussen and colleagues studied three large longitudinal study populations using two different sets of cut points: the fixed NCEP cut point and age- and sex-specific cut points derived from NHANES data. They estimated a positive predictive value (PPV) of only 32.9 percent (NCEP) and 37.3 percent (NHANES) for LDL-C elevations in adolescence in predicting elevated LDL-C 15 to 20 years later,37 indicating that adolescent measurement inaccurately identifies adults with dyslipidemia.

In summary, there is evidence that elevated LDL-C and TC concentrations in childhood, and especially adolescence, are associated with markers of atherosclerosis in young adults. However, the association between multifactorial dyslipidemia in childhood and clinical CHD is unknown, and it is difficult to predict which dyslipidemic youth will continue to have elevated cholesterol concentrations in young adulthood.

Screening for Multifactorial Dyslipidemia

Rationale for Screening

In the absence of routine screening, elevated TC and LDL-C concentrations are unlikely to be detected in most children and adolescents. The rationale for screening children and adolescents for dyslipidemia is to identify affected children, interrupt the atherosclerotic process, reduce cholesterol burden over the long term, and prevent or delay cardiovascular events in adulthood through dietary modification or lipid-lowering therapy.

Screening strategies proposed for multifactorial dyslipidemia have included both selective and universal screening. Selective screening may be based on a family history of dyslipidemia or premature cardiovascular disease or on other risk factors, such as overweight or obesity. Family history–based screening has been recommended by several expert guidelines.3, 38 The most recent NHLBI expert recommendations advocate universal screening (at ages 9 to 11 years and again at ages 17 to 21 years) as well as selective screening at other ages.39

Laboratory Studies

TC may be measured with fasting or nonfasting serum testing. Concentrations of LDL-C may be calculated with the Friedewald formula:40 LDL-C = TC – (triglycerides/5) – HDL-C. Because the calculation depends on triglyceride concentration, an accurate calculated LDL-C concentration requires a fasting blood draw. Direct LDL-C measurement does not require fasting.34 There is evidence, however, that fasting and nonfasting LDL-C concentrations do not differ substantially.41 Recent screening recommendations for childhood dyslipidemia have included guidelines for using either LDL-C or non–HDL-C.39

Evolution of Clinical Practice Guidelines in the United States

This evidence review comes after more than two decades of efforts to arrive at an effective approach to screening for and treating dyslipidemia. Most of these efforts have targeted both multifactorial dyslipidemia as well as FH. In some cases, they have also addressed hypertriglyceridemia. Below is a chronological summary of the major U.S. expert opinion guidelines and evidence-based recommendations for identifying and treating dyslipidemia in childhood and adolescence, with a focus on elevated TC and LDL-C concentrations.

NCEP, 1992

In 1992, NCEP, a program of the NHLBI, convened an expert panel of representatives from the American Academy of Pediatrics, the American Academy of Family Practice, the American College of Cardiology, the American Dietetic Association, and other professional organizations. The panel recommended against universal screening, citing several reasons: many children with elevated lipid concentrations in childhood are not dyslipidemic as adults; the health benefit and safety of lipid-lowering treatments was unknown; and universal screening could lead to overuse of these drugs in children.2 The panel recommended selective screening based on a family history of premature CHD, first with TC concentrations and second, if TC concentrations were elevated, obtaining a fasting lipid panel (repeated if abnormal).

NCEP used cut points derived from the Lipid Research Clinics data but opted to use a single set of thresholds across the pediatric age range. A fasting lipid panel was recommended for children with a TC concentration greater than 200 mg/dL on initial screening or with an average TC concentration greater than 170 mg/dL on repeat testing. Children and adolescents with LDL-C concentrations greater than 130 mg/dL were counseled to begin a low-fat, low-cholesterol diet (NCEP Step II diet) (Table 1), with the goal of reducing LDL-C concentrations to below 130 mg/dL. For children age 10 years and older who had attempted the Step II diet for 6 to 12 months and who continued to have high LDL-C concentrations, the panel recommended considering treatment with bile-sequestering agents. The LDL-C cut points defining dyslipidemia were 190 mg/dL or, in the presence of risk factors, greater than 160 mg/dL. NCEP cautioned against the use of HMG CoA reductase inhibitors (statins) and other agents that had not been well studied in children at that time.

Table 1. Comparison of Recommended Diets for Treatment of Dyslipidemia in Children and Adolescents.

Table 1

Comparison of Recommended Diets for Treatment of Dyslipidemia in Children and Adolescents.

USPSTF, 2007

In the years following the 1992 NCEP recommendation, numerous studies documented the low sensitivity of screening based on family history.34 Some experts began to advocate for universal screening.42 In 2007, the USPSTF found insufficient evidence to recommend for or against either routine selective or universal screening of infants, children, adolescents, or young adults up to age 20 years, and cited a lack of evidence on the long-term efficacy and harms of treatment for dyslipidemia in this age group.34, 43

American Academy of Pediatrics, 2008

In 2008, the American Academy of Pediatrics Committee on Nutrition updated an earlier recommendation and continued to advocate for selective screening of children ages 2 to 10 years who had a family history of dyslipidemia or premature CHD or unknown family history with other cardiovascular disease risk factors (such as overweight, hypertension, tobacco use, or diabetes).44 This statement proposed age- and sex-specific cut points to define dyslipidemia that were derived from the Lipid Research Clinics prevalence study.4 Nutritional and physical activity counseling were recommended for most children. The Committee recommended that treatment with bile-sequestering agents, statins, cholesterol absorption inhibitors, or fibrates be considered for those age 8 years and older who had 1) LDL-C concentrations greater than 190 mg/dL, 2) LDL-C concentrations greater than160 mg/dL with family history of CHD and cardiac risk factors, or 3) LDL-C concentrations greater than 130 mg/dL and diabetes.

NHLBI, 2011

In 2011, the most recent guideline on this topic was issued by the NHLBI expert panel on cardiovascular health and risk reduction in children and adolescents.39 The panel issued recommendations for screening and treating dyslipidemia, including elevated LDL-C and TC concentrations. (The panel's recommendations on hypertriglyceridemia are not discussed here.) Despite noting the age and sex variations in LDL-C and TC concentrations, the panel recommended continued use of the 1992 fixed NCEP cut points. The panel recommended universal screening with a fasting lipid panel at ages 9 to 11 years (coinciding with the prepubertal peak in LDL-C and TC concentrations) and at ages 17 to 21 years. The recommendations also included selective screening based on family history and risk factors at ages 2 to 8 years and at ages 12 to 16 years (Table 2). The recommendations call for a two-step screening, in which children with an initial fasting LDL-C concentration greater than 130 mg/dL undergo a second fasting LDL-C measurement; the two measurements are averaged, and children with values greater than 130 mg/dL are treated for dyslipidemia. For all children and adolescents in this category, the panel recommended the CHILD-2 diet, increasing physical activity, reducing screen time, and consideration of the use of plant stanols and sterols and psyllium.

Table 2. Recommendations for Lipid Assessment From NHLBI Expert Panel Report.

Table 2

Recommendations for Lipid Assessment From NHLBI Expert Panel Report.

In addition, the panel recommended treating different groups of children and adolescents with statins, depending on age, LDL-C concentration, family history, and other risk factors. For example, children age 10 years and older with an LDL-C concentration of 190 mg/dL or greater, regardless of family history or risk factors, would be considered for statin treatment. Statins were also to be considered in 8- or 9-year-olds with LDL-C concentrations persistently greater than 190 mg/dL who were unresponsive to the CHILD-2 diet in the presence of family history or risk factors. Children older than age 10 years with an LDL-C concentration greater than 160 mg/dL or greater than 130 mg/dL with a family history or various combinations of risk factors (e.g., hypertension, obesity, tobacco use, and low HDL-C concentration) would also be candidates for statin treatment. The panel recommended reassessing LDL-C measurements after 6 to 12 months of dietary or medication treatment.

Current Clinical Practice in the United States

Rates of dyslipidemia screening in children and adolescents have been historically low. The frequency of lipid testing at well child visits, as documented in the National Ambulatory Medical Care Survey, was 2.5 percent in 1995 and 3.2 percent in 2010.45 Claims data from health plans indicate that pharmacologic treatment of 8- to 20-year-olds with lipid-lowering agents is rare.46

Limitations of Fixed Threshold Values for Dyslipidemia

All recent U.S. clinical guidelines for dyslipidemia screening in youth have relied on fixed thresholds proposed by NCEP in 1992. However, normal cholesterol concentrations vary with age and sex throughout childhood. Thus, these cut points (TC ≥200 mg/dL and LDL-C ≥130 mg/dL) may both overidentify and underidentify dyslipidemia in children and adolescents compared with those identified by age- and sex-specific cut points.

Two research groups have explored the impact of fixed cut points on prevalence estimates. Each group applied lambda mu sigma growth curve methods to NHANES data1, 41 and to cross-sectional data from the Bogalusa Heart Study, the Muscatine Study, the Fels Longitudinal Study, and the Princeton Lipid Research Clinics Study.1 These procedures generated smoothed age- and sex-specific curves for lipid concentrations for children from preschool through older adolescence.1, 41 The curves peak in TC, LDL-C, and HDL-C concentrations at ages 8 to 12 years for boys and 7 to 11 years for girls. These curves show that the fixed NCEP cut points label many children as abnormal who fall within the 95th percentile in the middle childhood years. At many ages, the 90th percentile of the curve for TC exceeds the fixed cut point of 200 mg/dL. The 95th percentile for LDL-C exceeds the 130-mg/dL threshold at almost all ages; in fact, the 90th percentile for LDL-C exceeds the 130-mg/dL threshold at many ages.1 NCEP and NHANES cut points perform comparably across the adolescent age range.37

Previous USPSTF Recommendation

In 2007, the USPSTF found insufficient evidence to recommend for or against routine screening for lipid disorders in infants, children, or adolescents up to age 20 years (I statement).34 The 2007 recommendation referred to screening for all forms of dyslipidemia in childhood and adolescence and did not include recommendations specific to screening for multifactorial dyslipidemia. The 2007 evidence review found these evidence gaps relevant to screening children and adolescents for multifactorial dyslipidemia:

  • Data on risk factors that could inform risk-based, selective screening approaches, including overweight and physical inactivity.
  • Data from randomized, controlled trials (RCTs) on alternative screening strategies and long-term followup data sufficient to assess the impact of childhood screening and treatment of dyslipidemia on cardiovascular events in adulthood.
  • Long-term data on the efficacy and safety of statin treatment and nondrug interventions, such as exercise and dietary interventions.

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