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Haney EM, Huffman LH, Bougatsos C, et al. Screening for Lipid Disorders in Children and Adolescents [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007 Jul. (Evidence Syntheses, No. 47.)

1Introduction

Dyslipidemias are disorders of lipoprotein metabolism, including elevations in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), or triglycerides (TG) or deficiencies of high-density lipoprotein cholesterol (HDL-C) (list of abbreviations in Appendix 1). 1, 2 These disorders can be acquired or familial and are related to genetic conditions such as familial hypercholesterolemia in some individuals. Children and adolescents with dyslipidemia may have dyslipidemia as adults. 3 The relationship between dyslipidemia and coronary heart disease (CHD) in adults is well-established. Young men (mean age 22) with TC above the 75th percentile followed for 30 years on average, had a relative risk of 2.01 (95% CI 1.59, 2.53) for incidence of CHD. 4

The prevalence of other CHD risk factors, such as overweight, diabetes, and metabolic syndrome, is increasing among children and adolescents. 5, 6 Using criteria of body mass index (BMI) > 95th percentile, 10% of 2–5 year-olds and 16% of children age 6 years and older are overweight, with higher prevalence in minority racial/ethnic groups. 7 Overweight is the primary factor contributing to development of metabolic syndrome in children and adolescents. 8 Metabolic syndrome can be defined by glucose level ≥110 mg/dL, systolic or diastolic blood pressure ≥90th percentile, TG ≥110 mg/dL, HDL-C ≤40 mg/dL, sex-specific waist circumference ≥90th percentile. (Please see Appendix 2 for units of measure conversion formulas.) Children and adolescents with metabolic syndrome are more likely to have evidence of inflammation measured by C-reactive protein (CRP) >3 mg/dL. 9 Metabolic risk factors are common. In a study of 758 U.S. high school students, 17% had three or more of the following metabolic risk factors: Waist circumference, high triglycerides, LDL-C, fibrinogen, HbgA1C, glucose, insulin and cortisol, and low HDL-C. 10

The relationship between childhood and adult dyslipidemia, increasing prevalence of related CHD risk factors in children, 5, 11, 12 as well as continued emphasis on primary prevention of CHD has raised interest in screening for dyslipidemia in children. Identification of children with dyslipidemia could lead to intervention services or treatment that might prevent or delay adult dyslipidemia and CHD. This rationale lends support to consideration of screening for dyslipidemia as part of routine well-child care and at other opportunities.

This evidence synthesis focuses on the strengths and limitations of evidence about identifying and managing children and adolescents found to have dyslipidemia by screening in the course of routine primary care. Its objective is to determine the balance of potential benefits and adverse effects of screening for the development of guidelines by the U.S. Preventive Services Task Force (USPSTF). The target population includes children and adolescents age 0–21 years without previously known conditions associated with dyslipidemia. Among this population, there is potential to identify children and adolescents with dyslipidemia from among three groups: Those with undiagnosed monogenic dyslipidemias such as familial hypercholesterolemia (FH), those with undiagnosed secondary causes of dyslipidemia, and those with idiopathic dyslipidemia (polygenetic, multi-factorial or risk factor associated) (Figure 1). This evidence synthesis emphasizes the patient's or parents' perspective in the choice of outcome measures and potential adverse effects, and focuses on tests and interventions that are easily interpreted in the context of primary care. It also considers the generalizability of efficacy studies performed in controlled settings and interprets the use of the tests and interventions in community-based populations.

Figure 1. Defining the Screening Population.

Figure

Figure 1. Defining the Screening Population.

Other systematic evidence reports that contribute information on this topic include Screening and Interventions for Childhood Overweight 7 and Screening for Dyslipidemia in Adults: Brief Update of 2001 USPSTF Review. 13

Burden of Condition/Epidemiology

Dyslipidemia rarely leads to frank illness in childhood and health effects are typically delayed many years. Lipid levels are low at birth, increasing to young-adult levels by age 2 or 3. 14, 15 Although no long-term studies of the direct relationship between blood cholesterol levels measured in children and CHD later in life have been conducted, the relationship between childhood cholesterol levels and CHD can be inferred from indirect evidence. The Muscatine Coronary Risk Factor Survey from 1971-73 measured lipid levels of 2,874 school aged children. 16 Children's cholesterol levels correlated with those of family members, and identification of hypercholesterolemia in children also identified families at risk for CHD. 16

The Bogalusa Heart Study is a long-term epidemiologic study of risk factors for CHD from birth through 31 years. 17 Seven surveys, including more than 3,500 children, have been conducted since 1973. 18 Children of parents with CHD had a higher prevalence of dyslipidemia in childhood. 19 Also, there was a correlation between pre-morbid lipid levels and arterial fat deposition by autopsy of children and young adults who died accidentally. 20 23 Early lesions of atherosclerosis (fatty streaks) began in the abdominal aorta at age three years, the coronary arteries at age 10 years, and progressed over time. 20 24 The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study of adolescent males who had died accidentally found atherosclerotic changes of a magnitude directly related to postmortem LDL-C. 25, 26

The prevalence of dyslipidemia is determined by the results of laboratory testing and statistically determined criteria. Elevated LDL-C is the most common manifestation of clinically significant dyslipidemia in children. If the cutoff for elevated LDL-C is set at the 95th percentile, then 5% of children in the reference population will have dyslipidemia. Within this group of children with LDL-C levels above the 95th percentile, a minority will have monogenic or secondary dyslipidemias, and the majority will have idiopathic (polygenic, multi-factorial or risk factor associated) dyslipidemias. The more common genetic dyslipidemias are described briefly below. Additional very rare dyslipidemias that can cause adverse effects on health during childhood include homozygous familial hypercholesterolemia, lipoprotein lipase deficiency, Tangier disease, Fish-Eye disease, sitosterolemia, familial hypoalphalipoproteinemia, and abetalipoproteinemia among others.

Familial hypercholesterolemia

Familial hypercholesterolemia (FH) results from a defect in the cell surface receptor that removes LDL-C particles from plasma. 27 The incidence is 1 in 500 in the U.S., Canada, and Europe. 28 and up to 1 in 100 in specific populations (e.g. Transvaal Afrikaners). 29, 30 On average, untreated men with FH have clinically evident CHD by age 40 and women by age 50. Most children with FH require drug treatment. The homozygous form of FH can result in TC levels > 500 mg/dL, LDL-C > 450 mg/dL, xanthomas by age 5, and vascular disease before age 20. 28, 31 Individuals with heterozygous FH display a broad range of lipid levels, with mean TC of 323±44 mg/dL and mean LDL-C of 262±45mg/dL. 32

Familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is the most common genetic lipid disorder overall, occurring in 1–2% of the general adult population, and accounts for at least 10% of persons with premature CHD. 32 This group tends to have high triglyceride levels, but LDL may be acceptable, borderline, or high (mean 149±48 mg/dL), 28 Elevations in LDL, when present, are not generally as extreme as those seen in FH.

Familial defective apoprotein B (apo B)

Familial defective Apo B is characterized by moderate to severe hypercholesterolemia. The mechanism for the effect is a single base substitution in the ApoB gene that diminishes the ability of LDL-C to bind to the LDL-C receptor. Heterozygous familial defective Apo B occurs in 1 in 1,000 Europeans, and approximately 1 in 20 of these have similar phenotypes to those with heterozygous FH. 28

Familial hypertriglyceridemia

Familial hypertriglyceridemia is autosomal dominant but usually not expressed until adulthood. Obesity can accelerate expression of the phenotype, with moderately elevated (100–200 mg/dL) triglyceride levels in youth and extremely elevated levels in adults. 28

In a study of diagnoses made systematically for 129 families referred to a single lipid clinic for dyslipidemia and family history of early CHD, 20 had FH, 65 had FCH, 11 had hyper-Apo B and 1 had familial hypertriglyceridemia 33 . Others were unexplained (32), presumed normal (17) or adopted (2).

In addition to detection of monogenic dyslipidemias, screening would also detect secondary causes of dyslipidemia such as diabetes, nephritic syndrome, hypothyroidism and others, and idiopathic dyslipidemia. Included in the idiopathic group are polygenic, environmental and behavioral causes such as overweight and smoking. While children and adolescents with idiopathic dyslipidemia generally have less severe lipid levels than children and adolescents with familial or rare genetic disorders, levels may be significantly abnormal and could potentially improve with intervention.

Healthcare Interventions

To reduce the burden of dyslipidemia in children, clinic-based screening, community-based screening, and other community-based prevention strategies have been proposed. Most recommendations support selective strategies that test children who have family members with dyslipidemia or premature CHD and those for whom family history is unknown. 34, 35 Alternatively, universal screening for all children has had some proponents, although this approach has not been recommended in recent guidelines.

For children over two years of age with dyslipidemia, most recommendations indicate that the initial intervention is a low-fat, low-cholesterol diet, such as the American Heart Association Step I diet (AHA) 11 (Table 1). Children younger than two years should not be prescribed a low fat diet because the first two years is a period of rapid growth and development that requires an adequate fat and cholesterol intake. 35 If the AHA Step I diet alone does not result in satisfactory improvement in the lipid profile, the AHA Step II diet may be prescribed. This is a more restrictive diet, lower still in fat and cholesterol content than the Step I diet, and should not be prescribed to children without close supervision by a physician and dietitian. If the Step II diet still does not lead to a satisfactory improvement, medications can be considered. In 2000, the AHA modified their dietary recommendations for children, 36 but these changes have not been reflected in American Academy of Pediatrics (AAP) or National Cholesterol Education Program (NCEP) guidelines.

Table 1. Descriptions of Diets in Studies.

Table 1

Descriptions of Diets in Studies.

Children and adolescents with FH are the only non-adults for whom trials of drug therapy are available and approved by the U.S. Food and Drug Administration (FDA). The only medications approved by the FDA for treatment of dyslipidemia for children younger than 8 years of age are bile acid-binding resins. However, adherence to a prescribed regimen of bile acid binding resins is difficult due to the character and taste of the compounds. In addition, the lipid lowering effects of bile acid-binding resins in children are limited and do not often result in lipid lowering to the degree desired. Recently, HMG Co-A reductase inhibitors (statins) were approved for use in children with heterozygous familial hypercholesterolemia (FH). Lovastatin, simvastatin, and atorvastatin are FDA approved for adolescent boys and girls at least one year post-menarche ages 10–17, and pravastatin for boys and girls ages 8–18. 37, 38 Other medications used in adults for treatment of hyperlipidemia are either not recommended for children (i.e., niacin) or have not been adequately evaluated for safety and efficacy in children.

Additional interventions often recommended in the management of dyslipidemia in children and adolescents include dietary counseling, exercise, weight loss for overweight children, identification and treatment of diabetes mellitus or other secondary cause, and control of high blood pressure. Dietary supplements such as fiber, omega 3 fatty acids, and sterol or stanol margarines are sometimes considered as interventions for children with dyslipidemia. 39 42

Prior Recommendations

In 2001, the USPSTF reviewed screening for dyslipidemia in children and adolescents but did not make a recommendation. 43 A 2001 Systematic Evidence Review for the USPSTF found that studies of drug therapy in children were too short (8 weeks to 1 year) and too small to draw definitive conclusions about harms or benefits. Determination of the efficacy, safety, and feasibility of low fat diets in children were also inconclusive. 44

The NCEP recommendations for adults (Adult Treatment Panel III [ATP III]) recommended that screening begin at age 20 and were updated as recently as 2004. 45 The ATP III and USPSTF guidelines for adults recommend initial testing and risk determination using TC and HDL-C. 13, 34 LDL-C is used as a criterion for initiation of drug therapy. 34

The NCEP Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents published guidelines in 1992 and have not been updated. 34 This report addressed children up to age 18, and is the basis for the most recent AAP and AHA guidelines. The NCEP report recommended selective screening for children and adolescents with a family history of premature CHD or at least one parent with high TC (TC ≥ 240 mg/dL) in the context of regular health care. It recommended that cardiologists make a routine practice of referring the offspring of their adult patients with premature CHD to a source of continuing health care for cholesterol testing and follow-up. Optional cholesterol testing may be appropriate in children and adolescents judged to be at higher risk independent of family history or parental hypercholesterolemia. For example, children and adolescents who are overweight and/or consume excessive amounts of saturated fatty acids, total fat, and/or cholesterol may warrant testing.

The NCEP screening protocol for children and adolescents varies according to the reason for testing (Figure 2). For those being tested because of parental hypercholesterolemia, NCEP guidelines suggest that a non-fasting total cholesterol be the initial test. Further testing with a lipoprotein profile is recommended depending on the level of total cholesterol. For those being tested for family history of premature CHD, a fasting lipoprotein analysis is recommended. 34

Figure 2. National Cholesterol Education Program Guidelines for Risk Assessment and Classification of Children.

Figure

Figure 2. National Cholesterol Education Program Guidelines for Risk Assessment and Classification of Children.

Interventions are determined by results of the fasting lipoprotein analysis (Figure 2). The NCEP panel recommended considering drug therapy in children aged 10 years and older if, after an adequate trial of diet therapy (6–12 months), LDL-C cholesterol remains >190 mg/dL, or LDL-C cholesterol remains >160 mg/dL and there is a family history of premature CHD or at least two or more other risk factors are present. Referral to a specialized lipid center may be appropriate in some cases, especially when high cholesterol is due to secondary causes or accompanied by multiple risk factors and a family history of premature CHD. 34

In preparing these recommendations, the NCEP decided not to recommend universal screening for the following reasons: 1) Although high cholesterol levels in childhood generally predict cholesterol elevations in adulthood, many children with high cholesterol levels will not have high enough levels as adults to qualify for individualized treatment; 2) Universal screening could lead to the labeling of many young people as patients with a “disease,” causing unjustified anxiety for them and their families; 3) For most children not from high-risk families, there is sufficient opportunity to begin cholesterol-lowering therapies when they reach adulthood; 4) There is insufficient evidence concerning the long-term safety and efficacy of drug therapy in childhood to reduce CHD morbidity and mortality in adulthood and universal screening could lead to overuse of cholesterol-lowering drugs in childhood and adolescence. 34, 46

The American Academy of Pediatrics Committee on Nutrition published additional guidelines in 1998, slightly modifying the NCEP Report. 35 The committee noted that although the precise fraction of risk for future CHD conveyed by elevated cholesterol levels in childhood is unknown, clear epidemiologic and experimental evidence indicates that the risk is significant. The guidelines stated that diet changes that lower total fat, saturated fat, and cholesterol intake in children > age 2 and adolescents can be applied safely and acceptably, resulting in improved plasma lipid profiles that, if carried into adult life, have the potential to reduce atherosclerotic vascular disease. The guideline also recommended reducing other risk factors. There was no change in the recommended initial screening tests.

The American Heart Association's (AHA) initial “Guide to the Primary Prevention of Cardiovascular Disease,” published in 1996 and updated in 2002, does not address prevention in children. 11 In 2003, the AHA published updated guidelines for children that generally follow those set forth by the NCEP Pediatric Panel in 1992. 11 The new AHA guidelines suggest that bile acid-binding resins or statins are usual first-line agents in the treatment of severe dyslipidemia, and that pharmacologic intervention for dyslipidemia should be accomplished in collaboration with a physician experienced in treatment of disorders of cholesterol in pediatric patients. This report also considered hypertriglyceridemia and low HDL-C, with the recommendation of a goal of a fasting triglyceride level <150 mg/dL, and HDL-C >35 mg/dL. No pharmacologic interventions were recommended in children with isolated elevation of fasting triglycerides unless ≥400 mg/dL, at which level there is an increased risk of pancreatitis. 11

Scope of Evidence Synthesis

The patient population, interventions, outcomes, and adverse effects of screening and treatment are summarized in an analytic framework (Figure 3). Corresponding key questions guided the literature review and evidence synthesis. The 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, tracking of lipid levels through childhood to adulthood, role of risk factors in selecting children and adolescents for screening, effectiveness of interventions for children and adolescents identified with dyslipidemia, and adverse effects of screening and interventions. This review includes treatment trials of children and adolescents using dietary, exercise, and drug interventions. Studies of children with previously diagnosed conditions known to cause dyslipidemia (e.g. secondary dyslipidemias and monogenic dyslipidemias) 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 ordinarily already be under surveillance for lipid disorders as a result of their primary disease. Trials of drug therapy in children with heterozygous FH or FCH are included because this population has been exclusively enrolled in treatment trials. Data on cholesterol levels and diagnostic criteria for heterozygous FH are included because identification of previously undiagnosed FH is also a goal of screening (Figure 1).

Figure 3. Analytic Framework and Key Questions.

Figure

Figure 3. Analytic Framework and Key Questions.

Cover of Screening for Lipid Disorders in Children and Adolescents
Screening for Lipid Disorders in Children and Adolescents [Internet].
Evidence Syntheses, No. 47.
Haney EM, Huffman LH, Bougatsos C, et al.

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