Skip to main content

Advertisement

Log in

Prevention of Atherosclerotic Cardiovascular Disease in Children with Familial Hypercholesterolemia

  • Cardiovascular Disease and Stroke (J.A. Underberg and J. Newman, Section Editors)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Familial hypercholesterolemia (FH), a common inherited disorder of LDL-C metabolism that predisposes to premature cardiovascular disease, is underdiagnosed. Despite recommendations for screening all children and initiation of lipid-lowering medication beginning at 8–10 years of age, adherence to guidelines is low. Most individuals with FH are inadequately treated, especially women and children. The purpose of this review is to discuss current literature and recommendations for the diagnosis and treatment of heterozygous FH (HeFH) in the pediatric population.

Recent Findings

Twenty-year outcome data demonstrate lower rates of atherosclerotic cardiovascular disease (ASCVD) related events and death in individuals with FH who were treated with statins from childhood, compared to those who initiated statins in adulthood. While diagnosis rates of FH are slowly improving, most clinicians do not adhere to recommendations for cholesterol screening in youth.

Summary

Identifying youth with FH offers the opportunity for early intervention to prevent ASCVD and identify affected relatives through reverse cascade screening.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as:• Of importance •• Of major importance

  1. Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard BG. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. Eur Heart J. 2016;37(17):1384–94.

    Article  CAS  PubMed  Google Scholar 

  2. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3 Suppl):S1-8.

    Article  PubMed  Google Scholar 

  4. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011;128 Suppl 5:S213–56.

  5. National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992;89(3):495–501.

  6. Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991;303(6807):893–6.

  7. Williams RR, Hunt SC, Schumacher MC, Hegele RA, Leppert MF, Ludwig EH, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993;72(2):171–6.

    Article  CAS  PubMed  Google Scholar 

  8. Gidding SS, Champagne MA, Ferranti SDd, Defesche J, Ito MK, Knowles JW, et al. The Agenda for Familial Hypercholesterolemia. Circulation. 2015;132(22):2167–92.

    Article  PubMed  Google Scholar 

  9. Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide Prevalence of Familial Hypercholesterolemia. Meta-Analyses of 11 Million Subjects. 2020;75(20):2553–66.

  10. Hu P, Dharmayat KI, Stevens CAT, Sharabiani MTA, Jones RS, Watts GF, et al. Prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease. Circulation. 2020;141(22):1742–59.

    Article  PubMed  Google Scholar 

  11. De Backer G, Besseling J, Chapman J, Hovingh GK, Kastelein JJ, Kotseva K, et al. Prevalence and management of familial hypercholesterolaemia in coronary patients: an analysis of EUROASPIRE IV, a study of the European Society of Cardiology. Atherosclerosis. 2015;241(1):169–75.

    Article  PubMed  CAS  Google Scholar 

  12. de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES)CLINICAL PERSPECTIVE. Circulation. 2016;133(11):1067–72.

    Article  PubMed  CAS  Google Scholar 

  13. Pang J, Martin AC, Mori TA, Beilin LJ, Watts GF. Prevalence of Familial Hypercholesterolemia in Adolescents: Potential Value of Universal Screening? J Pediatr. 2016;170:315–6.

    Article  PubMed  Google Scholar 

  14. •• de Ferranti SD, Steinberger J, Ameduri R, Baker A, Gooding H, Kelly AS, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association. Circulation. 2019;139(13):e603–34. This comprehensive scientific statement reviews diagnostic evaluation and treatment recommendations for children with medical conditions, including HeFH, known to significantly increase their lifetime ASCVD risk.

    Article  PubMed  Google Scholar 

  15. Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Borén J, Catapano AL, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J. 2011;32(11):1345–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Raal FJ, Pilcher GJ, Waisberg R, Buthelezi EP, Veller MG, Joffe BI. Low-density lipoprotein cholesterol bulk is the pivotal determinant of atherosclerosis in familial hypercholesterolemia. Am J Cardiol. 1999;83(9):1330–3.

    Article  CAS  PubMed  Google Scholar 

  17. Pérez de Isla L, Alonso R, Mata N, Fernández-Pérez C, Muñiz O, Díaz-Díaz JL, et al. Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry. Circulation. 2017.

  18. Hopkins PN, Stephenson S, Wu LL, Riley WA, Xin Y, Hunt SC. Evaluation of coronary risk factors in patients with heterozygous familial hypercholesterolemia. Am J Cardiol. 2001;87(5):547–53.

    Article  CAS  PubMed  Google Scholar 

  19. •• Luirink IK, Wiegman A, Kusters DM, Hof MH, Groothoff JW, de Groot E, et al. 20-year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med. 2019;381(16):1547–56. This landmark cohort study reports lower rates of ASCVD events in adults with HeFH treated with statins since childhood compared to their parents with HeFH who started treatment in adulthood. None of the adults treated since childhood reported significant side effects from long-term statin therapy.

    Article  CAS  PubMed  Google Scholar 

  20. Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69(6):692–711.

    Article  CAS  PubMed  Google Scholar 

  21. Wilson DP, Jacobson TA, Jones PH, Koschinsky ML, McNeal CJ, Nordestgaard BG, et al. Use of Lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol. 2019;13(3):374–92.

    Article  PubMed  Google Scholar 

  22. Ellis KL, Pang J, Chieng D, Bell DA, Burnett JR, Schultz CJ, et al. Elevated lipoprotein(a) and familial hypercholesterolemia in the coronary care unit: between Scylla and Charybdis. Clin Cardiol. 2018;41(3):378–84.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zawacki AW, Dodge A, Woo KM, Ralphe JC, Peterson AL. In pediatric familial hypercholesterolemia, lipoprotein(a) is more predictive than LDL-C for early onset of cardiovascular disease in family members. J Clin Lipidol. 2018;12(6):1445–51.

    Article  PubMed  Google Scholar 

  24. Wiegman A, Rodenburg J, de Jongh S, Defesche JC, Bakker HD, Kastelein JJP, et al. Family history and cardiovascular risk in familial hypercholesterolemia. Data in More Than 1000 Children. Circulation. 2003;107(11):1473–8.

    Article  PubMed  Google Scholar 

  25. de Jongh S, Lilien MR, Bakker HD, Hutten BA, Kastelein JJP, Stroes ESG. Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia. Atherosclerosis. 2002;163(1):193–7.

    Article  PubMed  Google Scholar 

  26. Leander K, Hallqvist J, Reuterwall C, Ahlbom A, de Faire Ulf. Family history of coronary heart disease, a strong risk factor for myocardial infarction interacting with other cardiovascular risk factors: results from the Stockholm Heart Epidemiology Program (SHEEP). Epidemiology. 2001;12(2):215–21.

    Article  CAS  PubMed  Google Scholar 

  27. Khera AV, Won H-H, Peloso GM, Lawson KS, Bartz TM, Deng X, et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol. 2016;67(22):2578–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Umans-Eckenhausen MA, Defesche JC, Sijbrands EJ, Scheerder RL, Kastelein JJ. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet. 2001;357(9251):165–8.

    Article  CAS  PubMed  Google Scholar 

  29. Huijgen R, Hutten BA, Kindt I, Vissers MN, Kastelein JJ. Discriminative ability of LDL-cholesterol to identify patients with familial hypercholesterolemia: a cross-sectional study in 26,406 individuals tested for genetic FH. Circ Cardiovasc Genet. 2012;5(3):354–9.

    Article  CAS  PubMed  Google Scholar 

  30. Starr B, Hadfield SG, Hutten BA, Lansberg PJ, Leren TP, Damgaard D, et al. Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing. Clin Chem Lab Med. 2008;46(6):791–803.

    Article  CAS  PubMed  Google Scholar 

  31. Wald DS, Bestwick JP, Wald NJ. Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis. BMJ. 2007;335(7620):599.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Bell DA, Pang J, Burrows S, Bates TR, van Bockxmeer FM, Hooper AJ, et al. Effectiveness of genetic cascade screening for familial hypercholesterolaemia using a centrally co-ordinated clinical service: an Australian experience. Atherosclerosis. 2015;239(1):93–100.

    Article  CAS  PubMed  Google Scholar 

  33. Jannes CE, Santos RD, de Souza Silva PR, Turolla L, Gagliardi AC, Marsiglia JD, et al. Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. Atherosclerosis. 2015;238(1):101–7.

    Article  CAS  PubMed  Google Scholar 

  34. Bhatnagar D, Morgan J, Siddiq S, Mackness MI, Miller JP, Durrington PN. Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia. BMJ. 2000;321(7275):1497–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Morris JK, Wald DS, Wald NJ. The evaluation of cascade testing for familial hypercholesterolemia. Am J Med Genet A. 2012;158a(1):78–84.

    Article  PubMed  Google Scholar 

  36. Daniels SR, Greer FR. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122(1):198–208.

    Article  PubMed  Google Scholar 

  37. Ritchie SK, Murphy EC, Ice C, Cottrell LA, Minor V, Elliott E, et al. Universal versus targeted blood cholesterol screening among youth: The CARDIAC project. Pediatrics. 2010;126(2):260–5.

    Article  PubMed  Google Scholar 

  38. Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, Garcia FA, et al. Screening for lipid disorders in children and adolescents: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;316(6):625–33.

    Article  PubMed  Google Scholar 

  39. Dixon DB, Kornblum AP, Steffen LM, Zhou X, Steinberger J. Implementation of lipid screening guidelines in children by primary pediatric providers. J Pediatr. 2014;164(3):572–6.

    Article  PubMed  Google Scholar 

  40. DeSantes K, Dodge A, Eickhoff J, Peterson AL. Improving universal pediatric lipid screening. J Pediatr. 2017;188:87–90.

    Article  PubMed  Google Scholar 

  41. Allen-Tice C, Steinberger J, Murdy K, Zierhut H. Pediatric cholesterol screening practices in 9- to 11-year-olds in a large midwestern primary care setting. J Clin Lipidol. 2020;14(2):224–30.

    Article  PubMed  Google Scholar 

  42. Valle CW, Binns HJ, Quadri-Sheriff M, Benuck I, Patel A. Physicians’ lack of adherence to national heart, lung, and blood institute guidelines for pediatric lipid screening. Clin Pediatr (Phila). 2015;54(12):1200–5.

    Article  Google Scholar 

  43. Zachariah JP, McNeal CJ, Copeland LA, Fang-Hollingsworth Y, Stock EM, Sun F, et al. Temporal trends in lipid screening and therapy among youth from 2002 to 2012. J Clin Lipidol. 2015;9(5 Suppl):S77-87.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Stempel H, Dodge A, Marriott E, Peterson AL. Referral patterns and cascade screening for familial hypercholesterolemia in a pediatric lipid clinic. J Pediatr. 2016;178:285–7.

    Article  PubMed  Google Scholar 

  45. Wu X, Pang J, Wang X, Peng J, Chen Y, Wang S, et al. Reverse cascade screening for familial hypercholesterolemia in high-risk Chinese families. Clin Cardiol. 2017;40(11):1169–73.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35(32):2146–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Peterson AL, DeLine J, Korcarz CE, Dodge AM, Stein JH. Phenotypic variability in atherosclerosis burden in an old-order amish family with homozygous sitosterolemia. JACC: Case Rep. 2020;2(4):646–50.

    Google Scholar 

  48. Liebeskind A PA, Wilson DP. Sitosterolemia in the pediatric population. In: Feingold KR, Anawalt B, Boyce A, et al, editors. Endotext [Internet] South Dartmouth (MA): MDTextcom, Inc;2000-. Updated 2020 Jan 16.

  49. Patel AM, Brautbar A, Desai NK, Wilson DP. Severe hypercholesterolemia and liver disease in a 3-year old. J Clin Lipidol. 2016;10(3):650–3.

    Article  PubMed  Google Scholar 

  50. Freedman DS, Byers T, Sell K, Kuester S, Newell E, Lee S. Tracking of serum cholesterol levels in a multiracial sample of preschool children. Pediatrics. 1992;90(1):80–6.

    CAS  PubMed  Google Scholar 

  51. Ashraf AP, Kohn B, Wilson DP. Improving long-term outcomes of youth with lipid abnormalities—expanding the role of pediatric endocrinologists. J Clin Endocrinol Metab. 2019;104(10):4421–6.

    Article  PubMed  Google Scholar 

  52. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 2019;73(24):e285–e350.

  53. Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, et al. Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72(6):662–80.

    Article  PubMed  Google Scholar 

  54. Musunuru K, Hershberger RE, Day SM, Klinedinst NJ, Landstrom AP, Parikh VN, et al. Genetic testing for inherited cardiovascular diseases: a scientific statement from the American Heart Association. Circ Genom Precis Med. 2020;13(4):e000067.

    Article  PubMed  Google Scholar 

  55. • Brown EE, Sturm AC, Cuchel M, Braun LT, Duell PB, Underberg JA, et al. Genetic testing in dyslipidemia: a scientific statement from the National Lipid Association. J Clin Lipidol. 2020;14(4):398–413. Informative discussion of pros and cons of genetic testing in individuals with dyslipidemia. This publication provides relevant guidelines for clinical practice.

    Article  PubMed  Google Scholar 

  56. Ethical and Policy Issues in Genetic Testing and Screening of Children. Pediatrics. 2013;131(3):620–2.

  57. Ribas SA, Paravidino VB, Brandão JM, Santana da Silva LC. The Cardiovascular Health Integrated Lifestyle Diet (CHILD) lowers LDL-cholesterol levels in Brazilian dyslipidemic pediatric patients. J Am Coll Nutr. 2021:1–8.

  58. Daniels SR, Couch SC. 25 - Lipid disorders in children and adolescents. In: Sperling MA, editor. Sperling Pediatric Endocrinology. 5th ed. Philadelphia: Elsevier; 2021. p. 1004–21.

    Chapter  Google Scholar 

  59. Williams LA WD. Nutritional management of pediatric dyslipidemia. In: Feingold KR, Anawalt B, Boyce A, et al., editors Endotext [Internet] South Dartmouth (MA): MDTextcom, Inc;2000-. 2020.

  60. Daniels SR, Couch SC. CHAPTER 23 - Lipid disorders in children and adolescents. In: Sperling MA, editor. Pediatric Endocrinology (Fourth Edition); 2014. p. 1015–34.e1.

  61. Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol. 2014;171(3):309–25.

    Article  PubMed  Google Scholar 

  62. Anagnostis P, Vaitsi K, Kleitsioti P, Mantsiou C, Pavlogiannis K, Athyros VG, et al. Efficacy and safety of statin use in children and adolescents with familial hypercholesterolaemia: a systematic review and meta-analysis of randomized-controlled trials. Endocrine. 2020;69(2):249–61.

    Article  CAS  PubMed  Google Scholar 

  63. deGoma EM, Ahmad ZS, O’Brien EC, Kindt I, Shrader P, Newman CB, et al. Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States. Circ Cardiovasc Genet. 2016;9(3):240–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amy L. Peterson.

Ethics declarations

Conflict of Interest

Amy L. Peterson is serving on the steering committee for the ORION-13 and ORION-16 trials (sponsored by Novartis Pharmaceuticals) (payments are made to her institution); she is on the Scientific Advisory Committee for Familial Hypercholesterolemia Foundation (unpaid); and she is an AHOY Committee member for the American Heart Association (unpaid) and the Health Quality and Research Committee for the National Lipid Association (unpaid), and on the Board of Directors for the American Board of Clinical Lipidology (unpaid). Catherine J. McNeal is on the Speaker’s Bureau for Novo Nordisk. Don P. Wilson reports no disclosures.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Cardiovascular Disease and Stroke

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peterson, A.L., McNeal, C.J. & Wilson, D.P. Prevention of Atherosclerotic Cardiovascular Disease in Children with Familial Hypercholesterolemia. Curr Atheroscler Rep 23, 64 (2021). https://doi.org/10.1007/s11883-021-00959-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11883-021-00959-8

Keywords

Navigation