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Screening for Lipid Disorders in Children: US Preventive Services Task Force Recommendation Statement

Abbreviations: USPSTF—US Preventive Services Task Force • TC—total cholesterol • LDL-C—low-density lipoprotein cholesterol • HDL-C—high-density lipoprotein cholesterol • CHD—coronary heart disease • NCEP—National Cholesterol Education Program • RCT—randomized, controlled trial

	SUMMARY OF RECOMMENDATION

TOP SUMMARY OF RECOMMENDATION RATIONALE CLINICAL CONSIDERATIONS OTHER CONSIDERATIONS DISCUSSION RECOMMENDATIONS OF OTHERS APPENDIX 1: USPSTF... APPENDIX 2: USPSTF STRENGTH... USPSTF MEMBERS REFERENCES

 
The US Preventive Services Task Force (USPSTF) concludes that the evidence is insufficient to recommend for or against routine screening for lipid disorders in infants, children, adolescents, or young adults (up to age 20) (I recommendation).

	RATIONALE

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Importance
There is good evidence that children with lipid disorders (dyslipidemia) are at risk for becoming adults with lipid disorders.

Detection
For children with familial dyslipidemia, the group most likely to benefit from screening, use of family history in screening may be inaccurate because of variability of definitions and unreliability of information. Serum lipid levels are accurate screening tests for childhood dyslipidemia, although many children with multifactorial types of dyslipidemia would have normal lipid levels in adulthood. Fifty percent of children and adolescents with dyslipidemia will have dyslipidemia as adults.

Benefits of Detection and Early Treatment^*
Trials of statin drugs in children with monogenic dyslipidemia (defined below in "Clinical Considerations") indicate improved total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) measures. For children with multifactorial types of dyslipidemia, there is no evidence that diet or exercise interventions in childhood lead to improved lipid profiles or better health outcomes in adulthood.

Harms of Detection and Early Treatment
Potential harms of screening may include labeling of children whose dyslipidemia would not persist into adulthood or cause health problems, although evidence is lacking. Adverse effects from lipid-lowering medications and low-fat diets, including potential long-term harms, have been inadequately evaluated in children.

USPSTF Assessment
The USPSTF was unable to determine the balance between potential benefits and harms for routinely screening children and adolescents for dyslipidemia.

	CLINICAL CONSIDERATIONS

TOP SUMMARY OF RECOMMENDATION RATIONALE CLINICAL CONSIDERATIONS OTHER CONSIDERATIONS DISCUSSION RECOMMENDATIONS OF OTHERS APPENDIX 1: USPSTF... APPENDIX 2: USPSTF STRENGTH... USPSTF MEMBERS REFERENCES

 

• Dyslipidemias are abnormalities of lipoprotein metabolism and include elevations in TC, LDL-C, or triglyceride levels or deficiencies of HDL-C. These disorders can be acquired or familial; monogenic dyslipidemias are related to genetic conditions such as familial hypercholesterolemia in some individuals. Multifactorial dyslipidemias are caused by risk factors including environmental factors (obesity, diet) or currently unidentified genetic factors. This recommendation applies to all asymptomatic individuals from birth to age 20.
  
• Because abnormal lipid levels have been strongly associated with the risk of coronary heart disease (CHD) events in adulthood, and early identification and lipid-lowering intervention in certain populations of adults can prevent CHD events, much attention has been directed at screening individuals for dyslipidemia at young ages (eg, childhood). Among children and adolescents, 3 groups may be identified through screening: (1) children with undiagnosed monogenic dyslipidemias such as familial hypercholesterolemia; (2) those with undiagnosed secondary causes of dyslipidemia; and (3) those with multifactorial dyslipidemia (polygenetic or related to risk factors). However, the clinical health benefits shown in adults identified and treated for dyslipidemia have not been studied in children, which makes the role of screening children uncertain.
  
• Children and adolescents with diabetes may be at especially high risk for dyslipidemia and cardiovascular events. Screening children and adolescents with diabetes for dyslipidemia has been recommended by other groups as a part of appropriate care for these children.
  
• The use of family history as a screening tool for dyslipidemia has variable accuracy largely because definitions of a positive family history and lipid threshold values vary substantially. Screening using family history as defined by the National Cholesterol Education Program (NCEP) and the American Academy of Pediatrics has been shown to produce high rates of false-negative results.
  
• If clinicians choose to screen for dyslipidemia, the preferred screening tests are TC and HDL-C on nonfasting or fasting samples; calculating LDL-C requires fasting samples.
  

	OTHER CONSIDERATIONS

TOP SUMMARY OF RECOMMENDATION RATIONALE CLINICAL CONSIDERATIONS OTHER CONSIDERATIONS DISCUSSION RECOMMENDATIONS OF OTHERS APPENDIX 1: USPSTF... APPENDIX 2: USPSTF STRENGTH... USPSTF MEMBERS REFERENCES

 

• The effectiveness of treatment interventions (diet, exercise, lipid-lowering agents) in children with dyslipidemia (including multifactorial dyslipidemia) in improving health outcomes remains a critical research gap. Population-based screening studies or randomized, controlled trials (RCTs) following children and adolescents into adulthood after treatment interventions will be necessary to assess universal lipid screening in childhood or adolescence.
  
• Rising rates of childhood overweight may lead to a higher prevalence of dyslipidemia in childhood and adulthood. Continued tracking of dyslipidemia in all age groups will be important as the epidemiology of obesity evolves.
  

	DISCUSSION

TOP SUMMARY OF RECOMMENDATION RATIONALE CLINICAL CONSIDERATIONS OTHER CONSIDERATIONS DISCUSSION RECOMMENDATIONS OF OTHERS APPENDIX 1: USPSTF... APPENDIX 2: USPSTF STRENGTH... USPSTF MEMBERS REFERENCES

 
Epidemiology
Dyslipidemias are disorders of lipoprotein metabolism and include elevations in TC, LDL-C, or triglyceride levels or deficiencies of HDL-C. TC levels increase from birth, stabilize at 2 years of age, peak before puberty, and then decline slightly during adolescence. Normal values for lipids in children and adolescents are currently defined according to population distributions of lipid levels from the Lipid Research Clinics Prevalence Study conducted in the 1970s.¹ Dyslipidemia is commonly defined as TC > 200 mg/dL and LDL-C > 130 mg/dL; these values correspond to the 95th percentile observed in the Lipid Research Clinics study. More recent studies, including the National Health and Nutrition Examination Survey, indicate that age, sex, racial differences, and temporal trends shift these population-based cut points.²

Although dyslipidemia in adults is an established risk factor for CHD on the basis of good-quality evidence from long-term prospective studies, the CHD risk attributable to dyslipidemia during childhood is unknown. Indirect evidence from the Bogalusa Heart Study, a long-term epidemiologic study of risk factors for CHD from birth through 31 years of age, showed a correlation between lipid levels and arterial fat deposition seen at autopsy; however, such evidence does not directly link childhood lipid levels to health outcomes.³ Epidemiologic studies in children establish a strong statistical association between childhood overweight and dyslipidemia.² Other risk factors for dyslipidemia include an established family history for common familial dyslipidemias including familial hypercholesterolemia, familial combined hypercholesterolemia, familial defective apoprotein B, and familial hypertriglyceridemia. Secondary causes of dyslipidemia include diabetes, nephrotic syndrome, and hypothyroidism.²

The USPSTF did not find direct evidence that screening for dyslipidemia leads to improvements in CHD-related mortality or overall mortality; therefore, it reviewed the evidence on accuracy of screening tests including family history, efficacy of treatment, and harms of screening and treatment in children.

Accuracy of Screening Tests
TC and HDL-C levels can be measured on nonfasting venous or capillary blood samples, LDL-C measurement requires fasting samples, and direct LDL-C can be measured on nonfasting venous samples. At least 2 measurements are necessary to ensure that true values are within 10% of the mean of the measurements. Fair-quality evidence shows that a value of TC minus HDL-C above the 95th percentile is 88% to 96% sensitive and 98% specific for detecting LDL-C 130 mg/dL.^4–6 Although use of family history presents a potential method to target serum lipid screening to a group of children and adolescents with higher risk for dyslipidemia, its use is limited. Family history is time-consuming to elicit accurately, it has been variably defined in the literature, and its use as a screening tool has been shown to miss substantial numbers (30%–60%, in general) of children with elevated lipid levels. Family-history definitions vary substantially among studies, as do lipid-detection thresholds; those studies that show higher sensitivities (77%) have low specificities (55%).² Population-based estimates of the number of children who require serum lipid testing on the basis of positive family history may range from 25% to 55%, depending on definitions of family history and serum LDL cutoff values.

Accurate screening tests in children would be useful if childhood dyslipidemia correlated with adult CHD health outcomes or with adult dyslipidemia as an intermediate outcome and if treatment improved CHD outcomes. Serial correlations between lipid levels measured in individual children over time vary on the basis of the type of lipid level followed. On the basis of the evidence from 23 prospective cohort studies, correlations have been found to be higher for TC (r = 0.38–0.78) and LDL-C (r = 0.4–0.7) levels than for HDL-C (r = 0.0–0.8) and triglyceride (r = 0.1–0.58) levels, and good-quality evidence indicates that 40% to 55% of children with elevated TC and LDL levels will continue to have elevated lipid levels on follow-up into adolescence and early adulthood.² No studies examine tracking of lipid levels in those with risk factors for dyslipidemia (eg, childhood overweight).

Efficacy of Treatment
Treatment of childhood dyslipidemia has been shown to be effective in lowering lipid levels in select populations; however, no studies have addressed the effect of treatment on childhood or adult health outcomes (eg, CHD events). In those children with diagnosed monogenic dyslipidemia, a condition that has been associated with premature CHD events, no RCTs are likely be completed to provide health outcomes in untreated controls. In this population of children with familial monogenic dyslipidemias (familial hypercholesterolemia or familial combined hyperlipidemia), good-quality evidence based on a meta-analysis of 9 RCTs demonstrated the effectiveness of statins in reducing intermediate outcomes: TC and LDL (percent mean reduction [95% confidence limits] from meta-analysis of trials: 24.4% [19.5, 29.2] for TC and 30.8% [24.1, 37.5] for LDL in 8 studies).² Fair evidence based on 2 fair-quality trials shows that bile-acid–binding resins reduce lipid levels in children with monogenic dyslipidemia.^7,8 RCTs of diet supplements (psyllium, oat, garlic extract, and sterol margarine) and advice show marginal improvements in lipid levels in children with monogenic dyslipidemia.² There is fair-quality evidence that dietary counseling is associated with minimal improvements in lipid levels in children with monogenic and multifactorial dyslipidemias; however, these improvements may not be sustained after the counseling intervention ceases.^9–15 There are no studies of physical activity interventions in those with monogenic dyslipidemia and fair-quality evidence in those with multifactorial dyslipidemia based on a meta-analysis of 6 trials that showed that physical activity interventions were associated with minimal to no improvement in lipid levels in children with multifactorial dyslipidemia (percent mean reduction [95% confidence limits] from meta-analysis of trials: 0% [–5.6, 5.6] for TC and 3.1% [–7.7, 1.5] for LDL-C reduction in 4 studies).²

Harms of Screening and Treatment
There is poor-quality evidence on the adverse effects of screening. There are conflicting reports about behavioral difficulties in screened children and reports of parental noncompliance with recommendations for diet and follow-up. Studies have shown no increases in anxiety among screened children and adolescents.² Fair-quality evidence on the harms of treatment is based on 81 controlled and noncontrolled studies of treatment that reported a variety of adverse effects of drug, diet, exercise, and combination therapy in children and adolescents.² Lipid-lowering agents have been shown to cause elevations in creatine kinase and liver-function tests (statins), gastrointestinal adverse effects, and decreased absorption of vitamins and minerals (bile-acid resins). The adverse effects of long-term use of lipid-lowering agents (eg, for >20 years) have not been studied. There have been 3 reports of growth retardation and nutritional dwarfing in children on unmonitored diets; however, there are several reports of normal growth during monitored low-fat diet interventions.² Physical activity interventions have had no reported harms in children without monogenic dyslipidemia, but an exaggerated blood pressure response was seen in children with monogenic dyslipidemias who were undergoing physical activity intervention.

	RECOMMENDATIONS OF OTHERS

TOP SUMMARY OF RECOMMENDATION RATIONALE CLINICAL CONSIDERATIONS OTHER CONSIDERATIONS DISCUSSION RECOMMENDATIONS OF OTHERS APPENDIX 1: USPSTF... APPENDIX 2: USPSTF STRENGTH... USPSTF MEMBERS REFERENCES

 
No professional organization recommends universal screening for dyslipidemia in children or adolescents. The NCEP report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents recommends selective screening for children and adolescents with a family history of premature CHD or at least 1 parent with a high TC level (TC 240 mg/dL) in the context of regular health care. Optional cholesterol testing may be recommended in children and adolescents who are judged to be at higher risk independent of family history or parental hypercholesterolemia (eg, those who are overweight or have high-fat diets).

The American Academy of Pediatrics’ recommendations are based on this NCEP report and concur with its screening recommendations.¹⁶ The American College of Obstetricians and Gynecologists concurs with the NCEP recommendations for screening in adolescents.¹⁷ In 2003, the American Heart Association recommended performing targeted screening of fasting lipids in children >2 years of age with a family history of dyslipidemia or premature cardiovascular disease and in children for whom family history is unknown and other risk factors are present.¹⁸ In a 2007 update, the American Heart Association recommended, in addition, screening children who are overweight or obese.¹⁹

	APPENDIX 1: USPSTF RECOMMENDATIONS AND RATINGS

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The USPSTF grades its recommendations according to 1 of 5 classifications (A, B, C, D, and I) reflecting the strength of evidence and magnitude of net benefit (benefits minus harms).

1. The USPSTF strongly recommends that clinicians provide [the service] to eligible patients. The USPSTF found good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms.
   
2. The USPSTF recommends that clinicians provide [the service] to eligible patients. The USPSTF found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms.
   
3. The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation.
   
4. The USPSTF recommends against routinely providing [the service] to asymptomatic patients. The USPSTF found at least fair evidence that [the service] is ineffective or that harms outweigh benefits.
   
5. The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing [the service]. Evidence that [the service] is effective is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.
   

	APPENDIX 2: USPSTF STRENGTH OF OVERALL EVIDENCE

TOP SUMMARY OF RECOMMENDATION RATIONALE CLINICAL CONSIDERATIONS OTHER CONSIDERATIONS DISCUSSION RECOMMENDATIONS OF OTHERS APPENDIX 1: USPSTF... APPENDIX 2: USPSTF STRENGTH... USPSTF MEMBERS REFERENCES

 
The USPSTF grades the quality of the overall evidence for a service on a 3-point scale (good, fair, poor).

Good
Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes.

Fair
Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or indirect nature of the evidence on health outcomes.

Poor
Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.

	USPSTF MEMBERS

TOP SUMMARY OF RECOMMENDATION RATIONALE CLINICAL CONSIDERATIONS OTHER CONSIDERATIONS DISCUSSION RECOMMENDATIONS OF OTHERS APPENDIX 1: USPSTF... APPENDIX 2: USPSTF STRENGTH... USPSTF MEMBERS REFERENCES

 
The following were the members of the USPSTF at the time this recommendation was finalized (for a list of current USPSTF members, go to www.ahrq.gov/clinic/uspstfab.htm): Ned Calonge, MD, MPH, chair, USPSTF (chief medical officer and state epidemiologist, Colorado Department of Public Health and Environment, Denver, CO); Diana B. Petitti, MD, MPH, vice-chair, USPSTF (senior scientific advisor for health policy and medicine, regional administration, Kaiser Permanente Southern California, Pasadena, CA); Thomas G. DeWitt, MD (Carl Weihl professor of pediatrics and director of the Division of General and Community Pediatrics, Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, OH); Leon Gordis, MD, MPH, DrPH (professor, Epidemiology Department, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD); Kimberly D. Gregory, MD, MPH (director, Women's Health Services Research and Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA); Russell Harris, MD, MPH (professor of medicine, Sheps Center for Health Services Research, University of North Carolina School of Medicine, Chapel Hill, NC); Kenneth W. Kizer, MD, MPH (president and chief executive officer, National Quality Forum, Washington, DC); Michael L. LeFevre, MD, MSPH (professor, Department of Family and Community Medicine, University of Missouri School of Medicine, Columbia, MO); Carol Loveland-Cherry, PhD, RN (executive associate dean, Office of Academic Affairs, University of Michigan School of Nursing, Ann Arbor, MI); Lucy N. Marion, PhD, RN (dean and professor, School of Nursing, Medical College of Georgia, Augusta, GA); Virginia A. Moyer, MD, MPH (professor, Department of Pediatrics, University of Texas Health Science Center, Houston, TX); Judith K. Ockene, PhD (professor of medicine and chief of the Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, MA); George F. Sawaya, MD (associate professor, Department of Obstetrics, Gynecology, and Reproductive Sciences and Department of Epidemiology and Biostatistics, University of California, San Francisco, CA); Albert L. Siu, MD, MSPH (professor and chairman, Brookdale Department of Geriatrics and Adult Development, Mount Sinai Medical Center, New York, NY); Steven M. Teutsch, MD, MPH^* (executive director, Outcomes Research and Management, Merck & Company, Inc, West Point, PA); and Barbara P. Yawn, MD, MSc (director of research, Olmstead Research Center, Rochester, MN).

	FOOTNOTES

 
Accepted Jan 25, 2007.

Address correspondence to Ned Calonge, MD, MPH, Colorado Department of Public Health and Environment, 4300 Cherry Creek Dr S, Denver, CO 80246. E-mail: ned.calonge{at}state.co.us

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

^* Critical evidence gap.

Dr Teutsch was recused from the discussion and voting on this issue.

	REFERENCES

TOP SUMMARY OF RECOMMENDATION RATIONALE CLINICAL CONSIDERATIONS OTHER CONSIDERATIONS DISCUSSION RECOMMENDATIONS OF OTHERS APPENDIX 1: USPSTF... APPENDIX 2: USPSTF STRENGTH... USPSTF MEMBERS REFERENCES

 

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10. DISC Collaborative Research Group. Efficacy and safety of lowering dietary intake of fat and cholesterol in children with elevated low-density lipoprotein cholesterol: the Dietary Intervention Study in Children (DISC). The Writing Group for the DISC Collaborative Research Group. JAMA. 1995;273 :1429 –1435[Abstract]
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13. McCrindle BW, Helden E, Conner WT. Garlic extract therapy in children with hypercholesterolemia. Arch Pediatr Adolesc Med. 1998;152 :1089 –1094[Abstract/Free Full Text]
14. Amundsen AL, Ose L, Nenseter MS, Ntanios FY. Plant sterol ester-enriched spread lowers plasma total and LDL cholesterol in children with familial hypercholesterolemia. Am J Clin Nutr. 2002;76 :338 –344[Abstract/Free Full Text]
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19. McCrindle BW, Urbina EM, Dennison BA, et al. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation. 2007;115 :1948 –1967[Abstract/Free Full Text]

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