Published online July 2, 2007
PEDIATRICS Vol. 120 No. 1 July 2007, pp. e189-e214 (doi:10.1542/peds.2006-1801)
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SPECIAL ARTICLE

Screening and Treatment for Lipid Disorders in Children and Adolescents: Systematic Evidence Review for the US Preventive Services Task Force

Elizabeth M. Haney, MDa,b, Laurie Hoyt Huffman, MSa, Christina Bougatsos, BSa, Michele Freeman, MPHa, Robert D. Steiner, MDc and Heidi D. Nelson, MD, MPHa,b,d

a Oregon Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology
b Department of Medicine
c Departments of Pediatrics and Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon
d Women and Children's Health Research Center, Providence Health System, Portland, Oregon


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. This was a systematic evidence review for the US Preventive Services Task Force, intended to synthesize the published evidence regarding the effectiveness of selecting, testing, and managing children and adolescents with dyslipidemia in the course of routine primary care.

METHODS. Literature searches were performed to identify published articles that addressed 10 key questions. The review focused on screening relevant to primary care of children without previously identified dyslipidemias, but included treatment trials of children with dyslipidemia because some drugs have only been tested in that population.

RESULTS. Normal values for lipids for children and adolescents are defined according to population levels (percentiles). Age, gender, and racial differences and temporal trends may alter these statistical cut points. Approximately 40% to 55% of children with elevated total cholesterol and low-density lipoprotein levels will continue to have elevated lipid levels on follow-up. Current screening recommendations based on family history will fail to detect substantial numbers (30%–60%) of children with elevated lipid levels. Drug treatment for dyslipidemia in children has been studied and shown to be effective only for suspected or proven familial monogenic dyslipidemias. Intensive dietary counseling and follow-up can result in improvements in lipid levels, but these results have not been sustained after the cessation of the intervention. The few trials of exercise are of fair-to-poor quality and show little or no improvements in lipid levels for children without monogenic dyslipidemias. Although reported adverse effects were not serious, studies were generally small and not of sufficient duration to determine long-term effects of either short or extended use.

CONCLUSIONS. Several key issues about screening and treatment of dyslipidemia in children and adolescents could not be addressed because of lack of studies, including effectiveness of screening on adult coronary heart disease or lipid outcomes, optimal ages and intervals for screening children, or effects of treatment of childhood lipid levels on adult coronary heart disease outcomes.

Key Words: dyslipidemia • children • adolescents • mass screening • cholesterol • interventions

Abbreviations: TC—total cholesterol • LDL-C—low-density lipoprotein cholesterol • HDL-C—high-density lipoprotein cholesterol • CHD—coronary heart disease • FH—familial hypercholesterolemia • FCH—familial combined hyperlipidemia • AHA—American Heart Association • USPSTF—US Preventive Services Task Force • RCT—randomized, controlled trial • LRC—Lipid Research Clinics • AAP—American Academy of Pediatrics • NCEP—National Cholesterol Education Program • IMT—intima-media thickness

Dyslipidemias are disorders of lipoprotein metabolism that result in abnormal excesses of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), or triglyceride or deficiency of high-density lipoprotein cholesterol (HDL-C).1,2 Dyslipidemia is an established risk factor for coronary heart disease (CHD), which is the leading cause of death for adults in the United States.3 Dyslipidemia rarely leads to adverse health outcomes in childhood, but its long-term effects may be considerable. Although no long-term studies of the direct relationship between lipid levels measured in children and CHD later in life have been conducted, this relationship can be inferred. Large epidemiologic studies indicate that children's lipid levels correlate with those of adult family members.4 Children of parents with CHD have a higher prevalence of dyslipidemia in childhood,5 and identification of dyslipidemia in children can identify families at increased risk for CHD.4 Studies of children and young adults who died accidentally have reported correlations between lipid levels and arterial fat deposition6,7 and noted early lesions of atherosclerosis (fatty streaks) in the abdominal aorta at 3 years of age, coronary arteries at 10 years of age, and further progression with age.8–12 Increasing prevalence of risk factors for CHD among children, including metabolic syndrome and obesity, as well as continued emphasis on primary prevention of CHD has raised interest in screening children for dyslipidemia.13–15

Dyslipidemia is defined by laboratory testing and statistically determined criteria. An elevated LDL-C level is the most common clinically significant marker of dyslipidemia in children. The majority of children with dyslipidemia will have idiopathic dyslipidemias (polygenic, risk factor–associated, or multifactorial), whereas a minority will have monogenic or secondary dyslipidemias. The more common genetic dyslipidemias include familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCH), familial defective apoprotein-B, and familial hypertriglyceridemia.

Most treatment recommendations advise a low-fat, low-cholesterol diet, such as the American Heart Association (AHA) Step I diet, for children with dyslipidemia beginning at the age of 2 years or older.14 Children younger than 2 years should not be prescribed a low-fat, low-cholesterol diet, because their rapid growth and development require adequate fat and cholesterol intake.16,17 Children and adolescents with FH or FCH are the only nonadults for whom trials of drug therapy are available and drugs are approved by the US Food and Drug Administration. Bile-acid–binding resins are the only medications approved for treatment of dyslipidemia for children younger than 8 years of age. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors (statins) are approved for use in older children with heterozygous FH.18,19 Other medications used in adults for treatment of hyperlipidemia, such as niacin, are either not recommended for children or have not been adequately evaluated for safety and efficacy in children. Additional interventions for children include dietary supplements (fiber, sterol or stanol margarines, and omega-3 fatty acids), exercise, weight loss for overweight children, and identification and treatment of diabetes mellitus or other causes of secondary dyslipidemia.

The relationship between childhood and adult dyslipidemia, increasing prevalence of related CHD risk factors in children (eg, obesity and diabetes),13–15 and continued emphasis on a primary prevention approach for CHD has raised interest in screening children for dyslipidemia. Identifying children with dyslipidemia could lead to interventions or treatments that could prevent or delay adult dyslipidemia and CHD. This rationale lends support to consideration of screening for dyslipidemia as part of well-child care and at other opportunities. Clinic-based screening, neonatal screening, community-based screening, and other prevention strategies have been proposed, but most recommendations support selective strategies to test children who have family members with dyslipidemia or premature CHD and those with unknown family histories.16,20

This evidence review focuses on the strengths and limitations of evidence for identifying and managing children and adolescents with dyslipidemia determined by screening in the course of routine primary care. Our objective was to determine the balance of potential benefits and adverse effects of screening for development of guidelines by the US Preventive Services Task Force (USPSTF). The target population includes children and adolescents 0 to 21 years old without previously known conditions associated with dyslipidemia. There is potential to identify children and adolescents with dyslipidemia in this population from among 3 groups: those with undiagnosed monogenic dyslipidemias such as FH; those with undiagnosed secondary causes of dyslipidemia (diabetes, nephrotic syndrome, hypothyroidism, others); and those with idiopathic dyslipidemia (polygenetic, risk factor–associated, or multifactorial) (Fig 1). Although children and adolescents with idiopathic dyslipidemia generally have less severe lipid-level abnormalities than children and adolescents with monogenic disorders, such abnormal levels could still potentially improve with intervention.


Figure 1
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  		FIGURE 1 Defining the screening population. Children and adolescents identified by screening include those with undiagnosed monogenic dyslipidemia, undiagnosed secondary dyslipidemia, and idiopathic (polygenic or risk factor–driven) dyslipidemia. Children and adolescents with previously known monogenic or secondary dyslipidemia would be specifically evaluated for these indications and are not included in the screening pool for the general population.

 

   METHODS
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 METHODS
RESULTS
 CONCLUSIONS
 REFERENCES
 
Evidence reviews for the USPSTF follow a specific methodology21 (Fig 2). Key questions examine a chain of evidence about the accuracy and feasibility of screening children and adolescents for dyslipidemia in primary care or community settings (key question 1), abnormal lipid values (key question 2a), appropriate tests (key question 2b), tracking of lipid levels through childhood to adulthood (key question 2c), accuracy of family history (key question 2d), role of risk factors in selecting children and adolescents for screening (key question 2e), effectiveness of interventions for children and adolescents identified with dyslipidemia (key questions 4–8 and 10), and adverse effects of screening and interventions (key questions 3 and 9).


Figure 2
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  		FIGURE 2 Analytic framework and key questions. The analytic framework represents an outline of the systematic evidence review and includes patient populations, risk assessment and testing, treatment, and outcomes. The key questions examine a chain of evidence about the accuracy, effectiveness, feasibility of screening asymptomatic children for dyslipidemia in primary care settings, adverse effects of screening, risk factors, effectiveness of interventions, and adverse effects of interventions. a Includes those without previously known conditions that cause dyslipidemia such as genetic dyslipidemia, diabetes, nephrotic syndrome, organ transplant, and others.

 
Studies that addressed key question 1 (Fig 2) include all components in the continuum of the screening process: the screening evaluation, diagnostic evaluation for those identified by the screening results, interventions for those diagnosed with dyslipidemia, and outcome measures that allow determination of the effectiveness of the overall screening process.

Studies of children with previously diagnosed conditions that are known to cause dyslipidemia were not included, because the scope of this review is screening children without known diagnoses. Specifically, studies of children with diabetes were not included, because these children would already be under surveillance for dyslipidemia as a result of their primary disease. This review includes treatment trials of children and adolescents who used dietary, exercise, and drug interventions. Trials of drug therapy in children with heterozygous FH or FCH are included, because drug-treatment trials have been conducted exclusively in this population.

Relevant studies were identified from multiple searches of Medline (1966 through September 2005).22 We obtained additional articles from recent systematic reviews, reference lists of related studies, reviews, editorials, and Web sites and from consulting experts. Retrieved abstracts were entered into an electronic database (EndNote; Thomson ResearchSoft, Carlsbad, CA).

Investigators reviewed all identified abstracts and determined eligibility by applying inclusion and exclusion criteria specific to each key question. Full-text articles of included abstracts were reviewed for relevance. Eligible studies were English language and applicable to US clinical practice and provided primary data relevant to the key questions. Studies of risk factors were included only if they provided multivariate adjusted analyses.

For treatment studies, full-text randomized, controlled trials (RCTs), noncontrolled clinical trials, and noncontrolled prospective studies that provided data on the treatment of children and adolescents with drug therapy, diet, exercise, or combinations of these interventions were reviewed initially. Subsequently, only RCTs and meta-analyses of RCTs that reported serum lipid outcomes were included. Crossover trials were included if they reported data before crossover. For key question 10, outcomes included either adult lipid levels or adult CHD. Information about adverse effects of treatment was obtained from RCTs and additional sources such as nonrandomized, controlled treatment trials and noncomparative studies of treatment.

Data were extracted from each study, entered directly into evidence tables, and summarized. Benefits and adverse effects of therapies were considered equally important, and both types of outcomes were abstracted. Trials of therapy for children and adolescents with dyslipidemia were categorized by population and intervention. Two reviewers independently rated the RCTs’ quality by using USPSTF criteria21 (Appendix).


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  		APPENDIX USPSTF Quality Rating Criteria

 

   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
CONCLUSIONS
 REFERENCES
 
Our literature search identified 2507 unique citations including 144 articles about screening and testing for dyslipidemia (key question 2); 43 about interventions and tracking of lipid values over time (key questions 4–8 and 10); 6 about the adverse effects of screening (key question 3); and 84 about adverse effects of treatment (key question 9).

Key Question 1: Is Screening for Dyslipidemia in Children/Adolescents Effective in Delaying the Onset and Reducing the Incidence of CHD-Related Events?
No studies evaluated the effect of screening children and adolescents on adult lipid-level or disease outcomes.

Key Question 2: What Is the Accuracy of Screening for Dyslipidemia in Identifying Children/Adolescents at Increased Risk of CHD-Related Events and Other Outcomes?
Key Question 2a: What Are Abnormal Lipid Values in Children/Adolescents?
Although several studies conducted in the United States during the 1970s obtained lipid levels from large samples of normal healthy children,23–25 current recommendations14,16,20,26 are based on distributions of lipid and lipoprotein levels obtained from the Lipid Research Clinics (LRC) Prevalence Study.27 This study included 1 Canadian and 9 US sites and enrolled subjects primarily on the basis of residency within census tracts, school enrollment, and employment in occupational and industrial groups. Fasting (≥12 hours) lipoprotein levels were obtained from 15626 children 0 to 19 years old between 1972 and 1976. The selected populations included a broad range of geographic, socioeconomic, occupational, gender, and ethnic groups but were not selected to be a representative sample of the North American population.

In the LRC sample, TC levels increased from birth and stabilized at approximately 2 years of age. At puberty, TC levels declined slightly for both boys and girls, and HDL-C levels declined for boys. For all children, the mean serum level for TC was ~160 mg/dL and for LDL-C was 100 mg/dL. The 95th percentile level was 200 mg/dL for TC and 130 mg/dL for LDL-C. Although the results for black children were similar, they were based on smaller numbers and provided only TC and triglyceride data.27

More recent data from the National Health and Nutrition Examination Survey III (1988–1994) were derived from 7499 children and adolescents aged 4 to 19 years. These data provided 95th-percentile levels of 216 mg/dL for serum TC and 152 mg/dL for LDL-C.28 Mean age-specific TC levels peaked at 171 mg/dL at 9 to 11 years and declined at older ages. Girls had significantly higher mean TC and LDL-C levels than boys (P[r] < .005). Non-Hispanic black children and adolescents had significantly higher mean TC, LDL-C, and HDL-C levels compared with non-Hispanic white and Mexican-American children and adolescents. In linear regression models of these data, age, gender, and race have significant effects on lipid levels, which raises questions about the utility of fixed screening cut points.29

Key Question 2b: What Are the Appropriate Tests? How Well Do Screening Tests (Nonfasting TC, Fasting TC, Fasting Lipoprotein Analysis) Identify Children and Adolescents With Dyslipidemia?
In the American Academy of Pediatrics (AAP) and National Cholesterol Education Program (NCEP) guidelines, TC is used as an initial laboratory measurement for children tested because of a family history of high cholesterol or vascular disease, and a lipoprotein profile is obtained if the patient has a TC over a certain defined target.16,20 In children, the LDL-C level is the basis for initiating treatment and determining goals of therapy.

How well TC levels detect elevated LDL-C levels has been examined with LRC data (ages 6–19, n = 1325)30 and data from the biracial Bogalusa cohort (ages 5–17, n = 2857).31 Elevated levels were defined as >95th percentile. With LRC data, an elevated fasting TC level identified children with elevated LDL-C and triglyceride levels with 69% sensitivity and 98% specificity.30

In the Bogalusa cohort, elevated TC levels detected elevated LDL-C levels with 44% (white females) to 50% (white males, black males and females) sensitivity and 90% specificity (black and white males and females).31

In adults, both TC and HDL-C levels are recommended for screening. Although this has not been recommended in guidelines for children and adolescents, it is common in practice (E. Neufeld, MD, PhD [Boston, MA], personal communication regarding screening tests for children, 2005). HDL-C may help distinguish false-negative from true-negative results when used with TC.30 In 260 black adolescents aged 12 to 20 years, fasting TC minus HDL-C above the 95th percentile was 88% to 96% sensitive and 98% specific for predicting an LDL-C level of ≥130 mg/dL.32 Using a lower threshold of fasting TC (≥75th percentile) to detect LDL-C levels ≥95th percentile in a sample of Hispanic children aged 4 to 5, sensitivities were 86% (using an LRC-defined 75th percentile) and 96% (using the sample-defined 75th percentile), and specificities were 93% (LRC defined) and 87% (sample defined).33 A TC level of >215 mg/dL is required, however, to accurately identify a child with elevated LDL-C levels with 95% confidence. No single TC value places a child in the borderline category (170–200 mg/dL) with 95% confidence.34 Direct measurement of LDL-C levels can be made by using nonfasting serum samples and may be as precise as calculated LDL-C levels, but this remains controversial.35,36

Key Question 2c: How Well Do Lipid Levels Track From Childhood to Adulthood?
Twenty-three prospective cohort studies contributed information on tracking lipid levels during childhood.37–59 These studies drew from 7 US cohorts and 8 non-US cohorts. Approximately 40% to 55% of children with elevated lipid levels, defined by percentile within a population distribution, will continue to have elevated lipid levels on follow-up (4–15 years later).22 None of these studies, however, evaluated the proportion of children and adolescents with lipid levels >95th percentile who remained in the top 5% at follow-up.

Key Question 2d: What Is the Accuracy of Family History in Determining Risk?
Several good-quality studies of diagnostic accuracy evaluated the sensitivity and specificity of family-history information in determining risk for dyslipidemia in children and adolescents (Table 1).32,33,60–73 Studies used different definitions of family history, such as any parental history of heart attack, other parental risk factors, and varying age definitions of early CHD, and selected different levels of LDL-C or TC as the lipid-detection threshold. For example, parental history of early CHD alone was 5% to 17% sensitive for TC >170 mg/dL or LDL-C >130 mg/dL,33,62 whereas parental or grandparental history of early CHD was 46% sensitive for LDL >95th percentile.64


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  		TABLE 1 Summary of Studies That Evaluated Sensitivity and Specificity of Family History

 
Regardless of the precise definition, using positive family-history information to trigger lipid testing misses substantial numbers of children with elevated lipid levels, ranging from 17% to 90% overall and 30% to 60% in most studies.32,63,64,67,69,71,74–76 The proportion of children and adolescents who qualify for screening on the basis of family history is generally between 25% and 55% depending on the sensitivity of the specific family-history question.*

Key Question 2e: What Are Other Important Risk Factors?
Forty-three cohort and cross-sectional studies of mixed quality with adjusted statistical analyses contributed information on additional risk factors for identifying children at increased risk for elevated lipid levels and/or CHD-related events.65,78–119 Thirty studies examined overweight or body fat composition measures as a risk factor for dyslipidemia.{dagger} These measures were the most consistently effective in predicting risk of dyslipidemia compared with other factors assessed.22 Childhood overweight, as measured by BMI, was the best independent predictor of adult dyslipidemia after LDL-C level, specifically when considering BMI increases from childhood to adulthood.120 Of 6 studies that evaluated overweight as a risk, 5 found that overweight was associated with abnormal lipid levels.84,85,93,109,114,116

Key Question 2f: What Are Effective Screening Strategies for Children/Adolescents (Including Frequency of Testing, Optimal Age for Testing)?
Thirty-two studies evaluated screening strategies among children in various settings.{ddagger} The only RCT compared 2 regimens for screening college students.130 All others were noncomparative prospective studies that described screening interventions and differed considerably in venue (school, pediatric clinic, hospital, or population-based cohort), methods (fasting or nonfasting samples, method for detecting positive family history), and outcomes. Most of them reported low parental compliance with follow-up testing75,135–138 even when follow-up was provided free of charge, as in prepaid health plans.

Studies demonstrated low compliance among primary care physicians in following current guidelines for screening.139 In an ancillary study of the Child Adolescent Trial for Cardiovascular Health (CATCH), parents were given recommendations to consult their child's physician if his or her TC level exceeded 200 mg/dL on ≥1 occasion.140 After physicians examined the children, only 59% were evaluated further for possible elevated cholesterol levels. Of these, half of the physicians repeated cholesterol tests, 42% asked about family history, 38% made recommendations for dietary management, and only 12% referred children to dietitians.140

Neonatal screening for dyslipidemia has been examined in multiple studies of cord blood testing,53,141–154 dried filter paper blood spots from cord blood,155 or heel sticks of 3- to 7-day-old infants.156–161 No studies screened a general population of infants and followed abnormal results with mutation analysis or LDL-C receptor activity assays, which makes it difficult to determine the value of such screening.

Key Question 3: What Are the Adverse Effects of Screening (Including False-Positive and False-Negative Results, Labeling, etc)?
Potential adverse effects of screening for dyslipidemia among children were examined in 1 RCT162 and 5 noncomparative studies.75,135–138 Although 1 small study showed increased parental reporting of behavior difficulties among children with dyslipidemia, these reports were not confirmed objectively.138 No studies reported increased anxiety or depression among screened children or their parents.136–138

Key Question 4: In Children/Adolescents, What Is the Effectiveness of Drug, Diet, Exercise, and Combination Therapy in Reducing the Incidence of Adult Dyslipidemia and Delaying the Onset and Reducing the Incidence of CHD-Related Events (Including Optimal Age for Initiation of Treatment)?
No studies evaluated the effect of a childhood intervention on the incidence of adult dyslipidemia or CHD-related events and outcomes.

Key Questions 5–8: What Is the Effectiveness of Drug, Diet, Exercise, and Combination Therapy for Treating Dyslipidemia in Children/Adolescents?
Forty RCTs that met the inclusion criteria addressed the effectiveness of interventions for treatment of dyslipidemia in children and adolescents.18,19,163–200 Statins, bile-acid–binding resins, and fibrates have been tested and reported only in children with FH and FCH. Applicability of results from these trials to children without these conditions may be limited. In addition, 18 studies used populations recruited from single lipid clinics.§ Major limitations of trials include <20 subjects in each study arm,|| high loss to follow-up,176,186,190 failure of blinding,173,190,191,195–197 lack of results presented for the period before crossover, lack of intention-to-treat analyses,# and lack of data reported for the placebo group.178

Studies in Children With Probable or Definite FH
Drug Treatment
Eleven trials evaluated drug therapies for treatment of children with probable or definite heterozygous FH (Table 2). ** Most of these studies included children who were already compliant with a recommended low-saturated-fat, low-cholesterol diet, and both treatment and control groups were maintained on the diet during the trials.


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  		TABLE 2 RCTs of Drug Treatment for Children With Monogenic Dyslipidemia

 
All the trials of statin drugs{dagger}{dagger} demonstrated improvement in TC and LDL-C levels among children and adolescents with FH. The decrease in TC compared with baseline ranged from 17% to 32% for subjects in the treatment groups versus changes of +3.6% to –2.3% for those in the placebo groups. The decreases in LDL-C level ranged from 19% to 41% for subjects in the treatment groups versus changes of +0.67% to –3% for those in the placebo groups. Changes in HDL-C and triglyceride levels were mixed.{ddagger}{ddagger}

Trials of cholestyramine186 and colestipol185 demonstrated decreased TC and LDL-C levels but no change in HDL-C or triglyceride levels. Trials that evaluated bezafibrate,192 vitamins C and E,181 docosahexaenoic acid,198,200 p-aminosalicylic acid,184 combined colestipol and pravastatin versus colestipol alone,165 and powder versus pill form of cholestyramine173 failed to report precrossover data.

Diet Treatment
Five trials that evaluated diet treatments in children with FH or FCH met inclusion criteria.166,167,177,179,199 Although trials of sterol margarines and psyllium were crossover trials without precrossover results presented, the wash-out periods between treatment phases were 4 to 6 weeks, suggesting that results may be valid.166,177,179 Reductions in TC and LDL-C levels were significant in these trials (reduction of 7.4%–11% and 10%–14%, respectively). There was no significant improvement in lipid levels with 8 weeks of treatment with garlic extract.199

Exercise Treatment
No studies evaluated exercise treatment for lowering lipid levels in children with FH.

Studies in Children With Elevated Lipid Levels but Not Meeting Criteria for FH
Drug Treatment
No studies evaluated drug interventions in children without monogenic dyslipidemia.

Diet Treatment
Dietary interventions in general populations of children and adolescents were addressed in 7 studies (Table 3). §§ A trial conducted by the Dietary Intervention Study in Children (DISC) Collaborative Research Group showed that intensive dietary counseling over 3 years was effective (8% improvement in LDL-C level compared with control)170 but not sustained at 5- and 7-year follow-ups once the intervention ceased.169 A study of the Parent-Child AutoTutorial (PCAT) program173 reported 8% improvement in LDL-C level compared with the at-risk control group (P < .05). One trial of psyllium did not present precrossover data.80


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  		TABLE 3 RCTs of Diet and/or Exercise for Children and Adolescents Without Monogenic Dyslipidemia

 
Exercise Treatment
Six studies182,196,197,188,191,194 evaluated exercise in normal-weight or obese children with elevated lipid levels (Table 3). Three studies were limited by differential or low completion rates, small numbers of participants, or other deficiencies (lack of blinding, lack of intention-to-treat analysis).188,191,194 Four trials that compared supervised, scheduled sessions of aerobic and fitness training to control groups showed minimal or no change in lipid levels compared with control groups.188,191,196,197 Two trials showed improvements in HDL-C for the exercise-intervention group compared with controls.182,194

Combination Diet and Exercise Treatment
Three trials174,176,163 evaluated combined regimens of diet and exercise (Table 3). Although all the interventions showed some improvement in lipid levels, a group that undertook exercise, diet, and behavior changes had a 23% increase in HDL-C levels compared with both the diet-plus-behavior-change group and the control group.174

Key Question 9: What Are the Adverse Effects of Drug, Diet, Exercise, and Combination Therapy in Children/Adolescents?
Drug Treatment
Information about adverse events was reported in 15 studies of statins,|||| 22 studies of bile-acid–binding resins,165,175,185,186,208–226 and 8 studies of various other drugs or drug combinations26,184,192,227–231 (Table 4). Studies used RCT, open-label–trial, and observational designs.


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  		TABLE 4 Adverse Effects Reported in Studies of Statins, Bile-Acid–Binding Resins, and Other Drugs and Combinations

 
Statins were associated with increased alanine aminotransaminase and/or aspartate aminotransferase levels in some,168,187,203,206 but not all,18,164,202,204 of these studies. Reports of elevated creatine kinase levels were similarly conflicting.¶¶

Bile-acid–binding resins were associated with gastrointestinal complaints (8%–26%), such as flatulence and constipation,## and unpalatability (up to 50%).211,215–218,221,223 One study of cholestyramine reported transient increases in lactate dehydrogenase and abnormalities in aspartate aminotransferase levels that persisted for 6 months,210 but others showed normal liver-function test results.223,225,226 Growth was reported to be normal in 9 studies.*** One study reported a child whose height for age dropped below –2 SD while on colestipol (1 SD = 2.4 cm),212 whereas growth was normal in all other children in the study. Sexual maturation was followed over 4.3 years of treatment and found to be normal.224

Two studies of niacin reported increased liver enzyme levels (6 of 21 children in 1 study) and multiple other symptoms such as flushing, abdominal pain, nausea, and headache.228,230 There are also case reports of hepatitis228 and hepatotoxicity230 with the use of niacin.

Low-Fat Diet
Nineteen studies of dietary fat restriction reported effects on growth, nutrient intake, laboratory safety parameters, or other adverse effects.169,170,189,232–247

Twelve studies reported normal height growth,{dagger}{dagger}{dagger} although weight loss occurred among 3 children in 2 of these studies.234,241 In 1 study, growth failure occurred in 8 (20%) of 40 children with dyslipidemia, 3 (7.5%) of whom had nutritional dwarfing and no progression of puberty.240 In this study, families were unsupervised in the implementation of low-fat, low-cholesterol diets for a period up to 4.5 years; those with nutritional dwarfing had longer periods of time between diagnosis and formal dietary assessment and counseling.240 Failure to thrive has been demonstrated in children under 2 years of age who eat fat-restricted diets248; these diets are not recommended for children in this age group.16

Dietary Supplements
Fourteen studies provided information about adverse effects of various dietary supplements.167,177,180,199,249–258 Two children (4% of the treatment group) reported abdominal discomfort using fiber tablets (containing 50% wheat bran and 50% pectin) administered at 100 to 150 mg/kg per day.180,252,255 There were no adverse effects with psyllium fiber in 2 other studies.180,252 Other adverse effects of dietary supplements were mild or transient.22

Exercise
A school-based program examined the effect of supervised exercise training on the lipid profiles of normal prepubertal children and reported 100% adherence and no adverse effects.259 In another study, treadmill tests elicited an exaggerated blood-pressure response in boys with dyslipidemia.260

Key Question 10: Does Improving Dyslipidemia in Childhood Reduce the Risk of Dyslipidemia in adulthood?
No studies were identified that directly evaluated whether treatment of idiopathic dyslipidemia in childhood reduces risk of dyslipidemia in adulthood.


   CONCLUSIONS
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 RESULTS
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REFERENCES
 
Although many studies have resolved the various aspects of dyslipidemia in children, few key questions about screening have been addressed (Table 5). Studies are not available that address the overarching key question about efficacy of screening children and adolescents for dyslipidemia in delaying the onset and reducing the incidence of CHD-related events (key question 1), effectiveness of treatments (drug, diet, exercise, and combination) on reducing incidence of adult dyslipidemia or delaying the onset and reducing the risk of CHD-related events (key question 4), or whether improving dyslipidemia in children and adolescents reduces the risk of adult dyslipidemia (key question 10).


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  		TABLE 5 Summary of Evidence

 
Studies that evaluated risk factors are also limited. Risk factors that might contribute to a risk-assessment tool have not been studied adequately. Family-history questions are not standardized and have limited diagnostic accuracy. Evidence for risk factors other than family history for predicting dyslipidemia in children is strongest for overweight, but the magnitude of the effect of overweight on lipid levels, and the potential impact of incorporating overweight into a screening strategy for dyslipidemia, has not been addressed. Multiple other risk factors such as diet, physical inactivity, and aerobic capacity/fitness have not been evaluated adequately to assess their contribution to dyslipidemia or usefulness as screening tools either alone or in combination.

Currently recommended screening strategies have low adherence by providers and limited compliance by parents and children. No trials compared strategies by location, venue, age, or provider. No studies addressed the frequency and optimal age for testing. Adverse effects of screening for dyslipidemia have not been studied adequately.

Drug treatments for dyslipidemia in children have been studied only in children with FH or FCH, the population for whom these drugs are Food and Drug Administration–approved and recommended by the NCEP. Statins are effective for reducing TC and LDL-C levels in children with FH; it is not clear how this efficacy translates to children with milder and/or nonmonogenic dyslipidemia, and it is not known how frequently these medications are used in children without FH in practice. There are no trials with long-term follow-up for adult lipid outcomes or CHD-related events. Adverse effects of treatment are reported in controlled and noncontrolled studies of drug, diet, exercise, and combination therapy in children and adolescents. Studies were generally not of sufficient duration to determine long-term effects of either short or extended use.

Directions for future research should include identification of the impact of risk factors other than family history, such as overweight and physical inactivity, on lipid levels to develop risk-assessment strategies. Such tools may provide a better indication of actual risk and could facilitate screening by narrowing the number of children who require serum lipid testing. New vascular markers such as apolipoprotein B and apolipoprotein A-I may prove to be useful for screening in children.261,262 There is a growing literature on noninvasive vascular outcomes such as carotid intima-media thickness (IMT), nitrate dilation, and brachial IMT. Carotid IMT is significantly higher in overweight children, and adult IMT measurements seem to correlate with lipid measurements taken in childhood.263–266 Additional evaluation of arterial IMT as a risk factor identifiable in children and its usefulness as a screening tool may be warranted.

Randomized, controlled clinical trials of screening strategies to determine which are more effective than current practice in terms of both parental compliance and provider adherence to guidelines are important. Screening strategies for ensuring adequate assessment of minorities and those with unknown family history deserve attention. Continued follow-up of currently established cohorts to assess the impact of screening for dyslipidemia in childhood on adult CHD outcomes is important.

More rigorous study designs, enrollment of larger population-based samples, and systematic reporting of adverse effects could improve studies of dyslipidemia treatments. Long-term follow-up of children treated with statins to determine the impact of sustained improvement of lipid levels in childhood on adult lipid levels, adult CHD outcomes, and long-term safety will help further assess the efficacy and safety of treatment options. The effect of exercise on lipid levels should be evaluated further, particularly in children with lipid levels >95th percentile. Standardized methods for collecting and reporting adverse effects in treatment trials would facilitate combining data across trials and lead to a more thorough understanding of the risks of treatment among children and adolescents.


   ACKNOWLEDGMENTS
 
This study was conducted by the Oregon Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (contract 290-02-0024, task order 2).

Agency staff, USPSTF members, and content experts reviewed interim reports. We thank Andrew Hamilton, MLS, MS, for conducting the literature searches; expert reviewers for commenting on draft versions of the systematic evidence synthesis22; and Agency for Healthcare Research and Quality Medical Officer Janelle Guirguis-Blake and members of the USPSTF who served as leads for this project, including Leon Gordis, MD, DrPH, Carol Loveland-Cherry, PhD, RN, FAAN, Albert Siu, MD, MSPH, and Barbara Yawn, MD, MSc, FAAFP.


   FOOTNOTES
 
Accepted Jan 25, 2007.

Address correspondence to Elizabeth M. Haney, MD, Oregon Health and Science University, Mail Code L-475, 3181 SW Sam Jackson Park Rd, Portland, OR 97239. E-mail: haneye{at}ohsu.edu

The authors have indicated they have no financial relationships relevant to this article to disclose

The authors are responsible for the content of this article and the decision to submit it for publication.

* Refs 32, 33, 60–64, 66, 69, 70, 72, and 77. Back

{dagger} Refs 78–81, 83–85, 88–94, 98, 100–103, 105–111, 113, 114, 116, and 118. Back

{ddagger} Refs 32, 33, 60, 62–65, 67, 69, 71, 75, 76, and 121–140. Back

§ Refs 18, 164–168, 175, 177, 178, 180, 181, 184, 185, 188, 190, 192, 195, and 201. Back

|| Refs 167, 174, 177, 180, 181, 184, 192, and 194. Back

Refs 165–167, 175, 177, 179–181, 184, 188, 189, 191, 194, 197, 198, and 200. Back

# Refs 163, 165, 176–179, 181, 183, 186, 188, 190–193, and 195–197. Back

** Refs 18, 19, 162, 166, 169, 170, 176, 181, and 183–185. Back

{dagger}{dagger} Refs 18, 19, 164, 168, 171, 172, 178, 183, and 187. Back

{ddagger}{ddagger} Refs 164, 168, 171, 172, 178, 183, and 187. Back

§§ Refs 169, 170, 173, 189, 190, 193, and 195. Back

|||| Refs 18, 19, 164, 168, 171, 172, 178, 183, 187, and 202–207. Back

¶¶ Refs 18, 164, 171, 172, 183, 187, 202–204, and 206. Back

## Refs 165, 175, 184–186, 210, 213, 215, 217, 222, 223, 228, and 229. Back

*** Refs 26, 185, 186, 192, 214, 219, 220, 224, and 226. Back

{dagger}{dagger}{dagger} Refs 169, 189, 233–235, 238, 239, 241, 242, and 244–246. Back


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