Современная стратегия диагностики и лечения семейной гетерозиготной гиперхолестеринемии у детей

Семейная гетерозиготная гиперхолестеринемия — наследуемое по аутосомно-доминантному типу заболевание, характеризующееся высоким уровнем в крови холестерина липопротеинов низкой плотности, что приводит к началу атеросклеротического поражения сосудов уже в детском возрасте и развитию инфаркта миокарда на втором—третьем десятилетии жизни. Семейная гиперхолестеринемия остается малоизвестным заболеванием в клинической практике педиатра. Это ведет к запоздалой диагностике и позднему началу терапии. Заболевание длительно протекает бессимптомно, в связи с чем его выявление составляет менее 1% случаев. Освещены генетические аспекты заболевания. Изложены критерии диагностики семейной гетерозиготной гиперхолестеринемии у детей, представлены различные варианты скрининга. Рассмотрены возможности ранней диагностики сосудистого поражения атеросклеротического генеза. Освещена стратегия ведения пациентов с семейной гетерозиготной гиперхолестеринемией, обсуждаются возможности немедикаментозной и медикаментозной терапии. Изложены показания к назначению, эффективность и безопасность применения статинов как основного класса препаратов для лечения заболевания.

1. Gidding S.S., Champagne M.A., de Ferranti S.D., Defesche J., Ito M.K. et al. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation 2015; 132(22): 2167-2192. DOI: 10.1161/CIR.0000000000000297

2. Nordestgaard B.J., Chapman M.J., Humphries S.E., Ginsberg H.N., Masana L. 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): 3478-3490. DOI: 10.1093/eurheartj/eht273

3. Wiegman A., Gidding S., Watts G., Chapman M., Ginsberg H., Cuchel M. et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing. Eur Heart J 2015; 36: 2425-2437. DOI: 10.1093/eurheartj/ehv157

4. Ramaswamia U., Humphriesb S. E., Priestley-Barnhamc L., Greend P., Walde D.S., Cappsf N. Current management of children and young people with heterozygous familial hypercholesterolaemia — HEART UK statement of care. Atherosclerosis 2019; 290: 1—8. DOI: 10.1016/j.atherosclero-sis.2019.09.005

5. Coakley J.C. Lipids in Children and Links to Adult Vascular Disease. Clin Biochem Rev 2018; 39(3): 65—76.

6. Ежов М.В., Бажан С.С., Ершова А.И., Мешков А.Н., Соколов А.А., Кухарчук В.В. и др. Клинические рекомендации по семейной гиперхолестеринемиии. Атеросклероз и дислипидемии 2019; 34(1): 5—43.

7. Daniels S.R., Gidding S.S., de Ferranti S.D. National Lipid Association Expert Panel on Familial Hypercholesterolemia. Pediatric aspects of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011; 5: S30—37. DOI: 10.1016/j.jacl. 2011.03.453

8. Daniels S.R. Pediatric guidelines for dyslipidemia. J Clin Lipidol 2015; 9: S5—S10. DOI: 10.1016/j.jacl.2015.03.105

9. Elkins C., Fruh S., Jones L., Bydalek К. Clinical Practice Recommendations for Pediatric Dyslipidemia J Pediatr Health Care 2019; 33: 494—504. DOI: 10.1016/j.pedhc.2019.02.009

10. Cuchel M., Bruckert E., Ginsberg H.N., RaalF.J., Santos R.D., Hegel R.A. et al. Homozygous familial hypercholesterolae-mia: 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—2157. DOI: 10.1093/eurheartj/ehu274

11. Collins R., Reith C., Emberson J., Armitage J., Baigent C., Blackwell L. et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388: 2532—2561. DOI: 10.1016/S0140-6736(16)31357-5

12. Ference B., GinsbergH., Graham I., Ray K., Packard C., Bruck-ert E. et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017; 38(32): 2459—2472. DOI: 10.1093/eurheartj/ehx144

13. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: Summary Report. Pediatrics 2011; 128(S5):213—256. DOI: 10.1542/peds.2009-2107C

14. Usifo E., Leigh S.E., Whittall R.A., Lench N., Taylor A., Yeats C. Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Ann Hum Genet 2012; 76: 387—401 DOI: 10.1111/j.1469-1809.2012.00724.x

15. Raal F.J., Santos R.D. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis 2012; 223: 262—268. DOI: 10.1016/j.atheroscle-rosis.2012.02.019

16. Lambert G., Sjouke B., Choque B., Kastelein J., Hovingh G.K. The PCSK9 decade. J Lipid Res 2012; 53: 2515—2524. DOI: 10.1194/jlr.R026658

17. Watts G.F., Gidding S., Wierzbicki A.S., Toth P.P., Alonso R., Brown W. et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation Int J Cardiol 2014; 171(3): 309—325. DOI: 10.1016/j.ijcard.2013.11.025

18. France M. Homozygous familial hypercholesterolaemia: update on management. Paediatr Int Child Health 2016; 36(4): 243—247/ DOI: 10.1080/20469047.2016.1246640

19. Kolansky D.M., Cuchel M., Clark B.J., Paridon S., McCrin-dle B.W., Wiegers S. et al. Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. Am J Cardiol 2008; 102: 1438—1444. DOI: 10.1016/j.amjcard.2008.07.035

20. Rajendran R., Srinivasa K.H., Rangan K., Hegde M., Ahmed N. Supra-valvular aortic stenosis in a patient with homozygous familial hypercholesterolaemia. Eur Heart J Cardiovasc Imaging 2013; 14: 1023. DOI: 10.1093/ehjci/jet072

21. Ference B., YooW., Ales I., Mahajan N.,Mirowska K.K., Me-wada A. et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012; 60(25): 2631—2639.

22. Risk of fatal coronary heart disease in familial hypercholes-terolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ 1991; 303(6807): 893— 896. DOI: 10.1136/bmj.303.6807.893

23. Kusters D.M, Wiegman A., Kastelein J.J, Hutten B.A. Carotid intima-media thickness in children with familial hypercholesterolemia. Circ Res 2014; 114: 307—310. DOI: 10.1161/CIR-CRESAHA.114.301430

24. Kusters D.M., Avis H.J., Wijburg F.A., Kastelein J.J., Wiegman A., Hutten B.A. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. JAMA 2014; 312: 1055—1057. DOI: 10.1001/jama.2014.8892

25. Youngblom E., Pariani M., Knowles J.W. Familial Hypercholesterolemia. 2014 [updated 2016]. In: Adam M.P., Arding-er H.H., Pagon R.A., Wallace S.E., Bean L.J.H., Stephens K., Amemiya A. (eds). GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993—2020. http://www.ncbi.nlm.nih.gov/books/NBK174884/

26. Sjouke B., Kusters D.M., Kindt I., Besseling J., Defesche J.C, Sijbrands E. et al. Homozygous autosomal dominant hy-percholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome Eur Heart J 2015; 36(9): 560-565. DOI: 10.1093/eurheartj/ehu058

27. Datta B.N., McDowell IF., Rees A. Integrating provision of specialist lipid services with cascade testing for familial hy-percholesterolaemia. Curr Opin Lipidol 2010; 21: 366-371. DOI: 10.1097/MOL.0b013e32833c14e2

28. Wald D.S., Bestwick J.P., Wald N.J. Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis. BMJ 2007; 335: 599. DOI: 10.1136/bmj.39300.616076.55

29. Kusters D.M., de Beaufort C., Widhalm K., Guardamagna O., Bratina N, Ose L., Wiegman A. Paediatric screening for hy-percholesterolaemia in Europe. Arch Dis Child 2012; 97: 272-276. DOI: 10.1136/archdischild-2011-300081

30. Ritchie S.K., Murphy E.C., Ice C., Cottrell L.A., Minor V., Elliott E., Neal W. Universal versus targeted blood cholesterol screening among youth: the cardiac project. Pediatrics 2010; 126: 260-265. DOI: 10.1542/peds.2009-2546

31. La Bresh K.A., Lazorick S, Ariza A.J., Furberg R.D., Whetstone L, Hobbs C. et al. Implementation of the NHLBI Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Rationale and Study Design for Young Hearts, Strong Starts, a Cluster-Randomized Trial Targeting Body Mass Index, Blood Pressure, and Tobacco. Contemp Clin Trials 2014; 37(1): 98-105. DOI: 10.1016/j.cct.2013.11.011

32. Park J.H. Sitosterolemia Presenting With Severe Hypercholesterolemia and Intertriginous Xanthomas in a Breastfed Infant: Case Report and Brief Review. Clin Endocrinol Metab 2014; 99(5): 1512-1518. DOI: 10.1210/jc.2013-3274

33. Reiner Z., Guardamagna C., Nair D, Soran H., Hovingh K, Bertolini S., Jones S. Acid Lipase Deficiency-An Under-Recognized Cause of Dyslipidaemia and Liver Dysfunction. Atherosclerosis. 2014; 235(1): 21-30. DOI: 10.1016/j.atheroscle-rosis.2014.04.003

34. Bernstein D.L., Halkova H., Bialer M.G., Desnick R.J. Cho-lesteryl Ester Storage Disease: Review of the Findings in 135 Reported Patients With an Underdiagnosed Disease. J Hepatol 2013; 58(6): 1230-1243. DOI: 10.1016/j.jhep.2013.02.014

35. Besseling J., Kindt I., Hof M., Kastelein J.J., Hutten B.A., Hovingh G.K. Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers. Atherosclerosis 2014; 233: 219— 223. DOI: 10.1016/j.atherosclerosis.2013.12.020

36. 2015 Dietary Guidelines Advisory Committee. Scientific Report of the 2015 Dietary Guidelines Advisory Committee. 2015. http://www.health.gov/dietaryguidelines/2015-scien-tific-report/.

37. Gylling H., Plat J., Turley S., GinsbergH.N., EllegardL., Jessup W. et al. Atherosclerosis Society Consensus Panel on Phytosterols. Plant sterols and plant stanols in the management of dyslipidaem and prevention of cardiovascular disease. Atherosclerosis 2014; 232: 346-360. DOI: 10.1016/j.atherosclerosis.2013.11.04

38. Davidson M.H., Dugan L.D., Burns J.H., Sugimoto D., Story K., Drennan K. A Psyllium-enriched cereal for the treatment of hypercholesterolemia in children: a controlled, double-blind, crossover study. Am J Clin Nutr 1996; 63: 96-102. DOI: 10.1093/ajcn/63.1.96

39. McCrindle B.W., Helden E., Conner W.T.Garlic extract therapy in children with hypercholesterolemia. Arch Pediatr Adolesc Med 1998; 152: 1089-1094. DOI: 10.1001/archpe-di.152.11.1089

40. Engler M.M., Engler M.B., Arterburn L.M., Bailey E., Chiu E.Y., Malloy M.J., Mietus-SnyderM.L. Docosahexaeno-ic acid supplementation alters plasma phospholipid fatty acid composition in hyperlipidemic children: results from the Endothelial Assessment of Risk from Lipids in Youth (EARLY) study. Nutr Res 2004; 24: 721-729.

41. Robinson J.G., Goldberg A.C., National Lipid Association Expert Panel on Familial Hypercholesterolemia. Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011; 5(3 Suppl.): S18-S29. DOI: 10.1016/j.jacl.2011.03.451

42. Sever P.S., ChangC.L, Gupta A.K., WhitehouseA., PoulterN.R. ASCOT Investigators. The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the U.K. Eur Heart J 2011; 32: 2525-2532. DOI: 10.1093/eurheartj/ehr333

43. Radaelli G., Sausen G, CiceriCesa C., Santo F., Porta V., Neye-loff J., Pellanda L. Statin Treatments And Dosages In Children With Familial Hypercholesterolemia: Meta-Analysis. Arq Bras Cardiol 2018; 111(6): 810-821. DOI: 10.5935/abc.20180180/

44. VuorioA. ,Kuoppala J., Kovanen P.T., HumphriesS.E., Tonstad S., Wiegman A. et al. Statins for children with familial hypercholesterolemia (Review). Cochrane Database Syst Rev 2017; 7: CD006401. DOI: 10.1002/14651858.CD006401.pub4

45. McCrindle B.W., Ose L., Marias D.A. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial. J Pediatr 2003; 143(1): 74-80. DOI: 10.1016/S0022-3476(03)00186-0

46. van der Graaf A., Nierman M., Firth J.C., Wolmarans K., Marais A.D., de Groot E. Efficacy and Safety of Fluvastatin in Children and Adolescents With Heterozygous Familial Hypercholesterolaemia l. Acta Paediatr 2006; 95(11): 14611466. DOI: 10.1080/08035250600702602

47. Lambert M., Lupien P.J., Gagne C., Levy E., Blaichman S., Langlois S. et al. Treatment of Familial Hypercholesterolemia in Children and Adolescents: Effect of Lovastatin. Canadian Lovastatin in Children Study Group. Pediatrics 1996; 97(5): 619-628.

48. Rodenburg J., Vissers M.N., Wiegman A., Miller E.R., Ridker P.M., Witztum J.L. et al. Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings: effect of pravastatin. J Am Coll Cardiol 2006; 47(9): 1803-1810. DOI: 10.1016/j.jacc.2005.12.047

49. Avis L.M., Hutten.BA, Gagne C., Langslet G. McCrindle B.W., Wiegman A. et al. Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. J Am Coll Cardiol 2010; 55(11): 1121-1126. DOI: 10.1016/j.jacc.2009.10.042

50. De Jongh S., Ose L., Szamosi T., Gagne C., Lambert M., Scott R., Perron P. Simvastatin in Children Study Group: Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin. Circulation 2002; 106: 2231-2237.

51. Reiner Z., Catapano A.L., De Backer G., Graham I., Taskin-en M.R., Wiklund O. et al. Guidelines for the management of dyslipidaemias: the Task Force for the management of dys-lipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32: 1769-1818. DOI: 10.1093/eurheartj/ehr158

52. Braamskamp M., Langslet G, McCrindle B.W., Cassiman D., Francis G.A., Gagne C. et al. Effect of rosuvastatin therapy on carotid intima media thickness in children with familial hypercholesterolemia; findings from the CHARON study. Circulation 2017; 136(4): 359-366. DOI: 10.1161/circulationa-ha.116.025158

53. Baigent C., Blackwell L. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376: 1670-1681. DOI: 10.1016/S0140-6736(10)61350-5

54. Braamskamp M.J., Kusters D.M., Wiegman A., Avis H.J., Wijburg F.A., Kastelein J.J. et al. Gonadal steroids, gonadotropins and DHEAS in young adults with familial hypercholesterolemia who had initiated statin therapy in childhood. Atherosclerosis 2015; 241(2): 427-432. DOI: 10.1016/j.ath-erosclerosis.2015.05.034

55. Kusters D.M., Avis H.J., Braamskamp M.J., Huijgen R., Wijburg F.A., Kastelein J.J. et al. Inheritance pattern of familial hypercholesterolemia and markers of cardiovascular risk. Lipid Res 2013; 54(9): 2543-2549. DOI: 10.1194/jlr.M034538

56. Harada-Shiba M., Arai H., Oicava S, Ohta T.J. Guidelines for the management of familial hypercholesterolemia Athero-scler Tromb 2012; 19: 1043-1060.

57. Van der Graaf A., Cuffie-Jackson C., Vissers M.N., Trip M.D., Gagne C., Shi G. et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J Am Coll Cardiol 2008; 52(17): 1421-1429. DOI: 10.1016/j.jacc.2008.09.002

58. Raal F.J., Stein E.A., Dufour R., Turner T., Civeira F., Burgess L. et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385(9965): 331-340. DOI: 10.1016/S0140-6736(14)61399-4.

59. Braamskamp M.J., Kusters D.M., Avis H.J., Smets E.M., Wijburg F.A., Kastelein J.J. et al. Long-term statin treatment in children with familial hypercholesterolemia: more insight into tolerability and adherence, Pediatr Drugs 2015; 17: 159— 166. DOI: 10.1007/s40272-014-0116-y