纯合型家族性高胆固醇血症诊疗进展
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摘要
家族性高胆固醇血症(familial hypercholesterolemia,FH)是严重遗传代谢性疾病,临床上分为纯合和杂合两种类型,纯合型FH (homozygous FH,HoFH)发病率为1/(16万～100万),被认为是罕见病。HoFH主要特点为极高水平的低密度脂蛋白胆固醇、多部位黄色瘤及早发动脉粥样硬化性心血管疾病,如不及时诊断、早期治疗,青少年期即可发生心肌梗死甚至死亡。近年来,国际上也越来越重视FH的早期诊断和治疗,发布了多项FH指南与共识,我国亦结合国情制定了适合中国人的筛查诊断标准,为更好治疗FH提供了基础。本文就HoFH现有的诊断标准、鉴别诊断筛查和治疗方法进行综述,旨在提高医生对该病的认识。
Familial hypercholesterolemia( FH) is a serious hereditary metabolic disease. It is clinically divided into homozygous and heterozygous. The incidence of homozygous FH( Ho FH) is 1/( 160 000-1 000 000)and considered as a rare disease. Ho FH is characterized by very high levels of low density lipoprotein cholesterol,multi-sited yellow tumors,and atherosclerosis cardiovascular disease. Without prompt diagnosis and early treatment,myocardial infarction and even death can occur in adolescence. In recent years,the international community has paid more and more attention to the early diagnosis and treatment of FH,and issued a number of guidelines and consensus on FH. China has also developed a screening and diagnostic standard suitable for Chinese people in combination with national conditions,which provides bases for better treatment of FH. This article reviewed Ho FH's existing diagnostic criteria,differential diagnostic screening,and treatment methods,to improve physicians' understanding of the disease.
Familial hypercholesterolemia( FH) is a serious hereditary metabolic disease. It is clinically divided into homozygous and heterozygous. The incidence of homozygous FH( Ho FH) is 1/( 160 000-1 000 000)and considered as a rare disease. Ho FH is characterized by very high levels of low density lipoprotein cholesterol,multi-sited yellow tumors,and atherosclerosis cardiovascular disease. Without prompt diagnosis and early treatment,myocardial infarction and even death can occur in adolescence. In recent years,the international community has paid more and more attention to the early diagnosis and treatment of FH,and issued a number of guidelines and consensus on FH. China has also developed a screening and diagnostic standard suitable for Chinese people in combination with national conditions,which provides bases for better treatment of FH. This article reviewed Ho FH's existing diagnostic criteria,differential diagnostic screening,and treatment methods,to improve physicians' understanding of the disease.
引文
[1]Mabuchi H,Koizumi J,Shimizu M,et al.Development of coronary heart disease in familial hypercholesterolemia[J].Circulation,1989,79:225-232.
[2]Jetty V,Glueck CJ,Lee K,et al.Eligibility for alirocumab or evolocumab treatment in 1090 hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol≥70 mg/d L despite maximal-tolerated LDL-Cholesterol-lowering therapy[J].Vasc Health Risk Manag,2017,13:247-253.
[3]Civeira F.Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia[J].Atherosclerosis,2004,173:55-68.
[4]Mortality in treated heterozygous familial hypercholesterolaemia:implications for clinical management.Scientific Steering Committee on behalf of the Simon Broome Register Group[J].Atherosclerosis,1999,142:105-112.
[5]Stephenson SH,Larrinaga-Shum S,Hopkins PN.Benefits of the MEDPED treatment support program for patients with familial hypercholesterolemia[J].J Clin Lipidol,2009,3:94-100.
[6]Shi Z,Yuan B,Zhao D,et al.Familial hypercholesterolemia in China:prevalence and evidence of underdetection and undertreatment in a community population[J].Int J Cardiol,2014,174:834-836.
[7]中华医学会心血管病学分会动脉粥样硬化及冠心病学组,中华心血管病杂志编辑委员会.家族性高胆固醇血症筛查与诊治中国专家共识[J].中华心血管病杂志,2018,46:99-103.
[8]Gidding SS,Champagne MA,de Ferranti SD,et al.The Agenda for Familial Hypercholesterolemia:A Scientific Statement From the American Heart Association[J].Circulation,2015,132:2167-2192.
[9]Cuchel M,Bruckert E,Ginsberg HN,et al.Homozygous familial hypercholesterolaemia:new insights and guidance for clinicians to improve detection and clinical management.Aposition paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society[J].Eur Heart J,2014,35:2146-2157.
[10]France M,Rees A,Datta D,et al.HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom[J].Atherosclerosis,2016,255:128-139.
[11]Harada-Shiba M,Arai H,Oikawa S,et al.Guidelines for the management of familial hypercholesterolemia[J].J Atheroscler Thromb,2012,19:1043-1060.
[12]陈在嘉,徐义枢,孔华宇.临床冠心病学[M].北京:人民军医出版社,1998:77.
[13]Mabuchi H,Nohara A,Noguchi T,et al.Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan[J].Atherosclerosis,2011,214:404-407.
[14]Nordestgaard BG,Chapman MJ,Humphries SE,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[J].Eur Heart J,2013,34:3478-3490a.
[15]Zhou M,Zhao D.Familial Hypercholesterolemia in Asian Populations[J].J Atheroscler Thromb,2016,23:539-549.
[16]Brown MS,Goldstein JL.A receptor-mediated pathway for cholesterol homeostasis[J].Science,1986,232:34-47.
[17]Fouchier SW,Kastelein JJ,Defesche JC.Update of the molecular basis of familial hypercholesterolemia in The Netherlands[J].Hum Mutat,2005,26:550-556.
[18]Soutar AK.Intracellular transport of the low-density lipoprotein receptor[J].Biochem Soc Trans,1996,24:547-552.
[19]Benito-Vicente A,Uribe KB,Jebari S,et al.Validation of LDLr Activity as a Tool to Improve Genetic Diagnosis of Familial Hypercholesterolemia:A Retrospective on Functional Characterization of LDLr Variants[J].Int J Mol Sci,2018,19:E1676.
[20]Stein EA,Dann EJ,Wiegman A,et al.Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations[J].J Am Coll Cardiol,2017,70:1162-1170.
[21]Sjouke B,Kusters DM,Kindt I,et al.Homozygous autosomal dominant hypercholesterolaemia in the Netherlands:prevalence,genotype-phenotype relationship,and clinical outcome[J].Eur Heart J,2015,36:560-565.
[22]Harada-Shiba M,Ohta T,Ohtake A,et al.Guidance for Pediatric Familial Hypercholesterolemia 2017[J].J Atheroscler Thromb,2018,25:1-15.
[23]Snchez-Herndez RM,Prieto-Matos P,Civeira F,et al.Autosomal recessive hypercholesterolemia in Spain[J].Atherosclerosis,2018,269:1-5.
[24]Kidambi S,Patel SB.Sitosterolaemia:pathophysiology,clinical presentation and laboratory diagnosis[J].J Clin Pathol,2008,61:588-594.
[25]Hansel B,CarriéA,Brun-Druc N,et al.Premature atherosclerosis is not systematic in phytosterolemic patients:severe hypercholesterolemia as a confounding factor in five subjects[J].Atherosclerosis,2014,234:162-168.
[26]Nguyen L,Salen G,Shefer S,et al.Unexpected failure of bile acid malabsorption to stimulate cholesterol synthesis in sitosterolemia with xanthomatosis Comparison with lovastatin[J].Arteriosclerosis,1990,10:289-297.
[27]Makary MS,Kisanuki YY,Amin NN,et al.Teaching NeuroImages:Cerebrotendinous xanthomatosis:A rare treatable adult-onset lipid storage disease[J].Neurology,2018,90:e637-e638.
[28]Jiang L,Sun LY,Pan XD,et al.Characterization of the unique Chinese W483X mutation in the low-density lipoprotein-receptor gene in young patients with homozygous familial hypercholesterolemia[J].J Clin Lipidol,2016,10:538-546,e5.
[29]中国成人血脂异常防治指南修订联合委员会.中国成人血脂异常防治指南(2016年修订版)[J].中国循环杂志,2016,31:833-853.
[30]Raal FJ,Honarpour N,Blom DJ,et al.Inhibition of PCSK9with evolocumab in homozygous familial hypercholesterolaemia(TESLA Part B):a randomised,double-blind,placebo-controlled trial[J].Lancet,2015,385:341-350.
[31]Ray KK,Landmesser U,Leiter LA,et al.Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol[J].N Engl J Med,2017,376:1430-1440.
[32]Leiter LA,Teoh H,Kallend D,et al.Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status:The ORI-ON-1 Randomized Clinical Trial[J].Diabetes Care,2019,42:173-176.
[33]Musunuru K,Pirruccello JP,Do R,et al.Exome sequencing,ANGPTL3 mutations,and familial combined hypolipidemia[J].N Engl J Med,2010,363:2220-2227.
[34]Dewey FE,Gusarova V,Dunbar RL,et al.Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease[J].N Engl J Med,2017,377:211-221.
[35]Gaudet D,Gipe DA,Pordy R,et al.ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia[J].N Engl JMed,2017,377:296-297.
[36]Bennett CF,Swayze EE.RNA targeting therapeutics:molecular mechanisms of antisense oligonucleotides as a therapeutic platform[J].Annu Rev Pharmacol Toxicol,2010,50:259-293.
[37]Parham JS,Goldberg AC.Mipomersen and its use in familial hypercholesterolemia[J].Expert Opin Pharmacother,2019,20:127-131.
[38]温文慧,匡泽民,王绿娅.关注动脉粥样硬化性心血管病的残余风险:高脂蛋白(a)血症[J].中华心血管病杂志,2018,46:92-95.
[39]Norata GD,Ballantyne CM,Catapano AL.New therapeutic principles in dyslipidaemia:focus on LDL and Lp(a)lowering drugs[J].Eur Heart J,2013,34:1783-1789.
[40]Vogt A.Lipoprotein(a)-apheresis in the light of new drug developments[J].Atheroscler Suppl,2017,30:38-43.
[2]Jetty V,Glueck CJ,Lee K,et al.Eligibility for alirocumab or evolocumab treatment in 1090 hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol≥70 mg/d L despite maximal-tolerated LDL-Cholesterol-lowering therapy[J].Vasc Health Risk Manag,2017,13:247-253.
[3]Civeira F.Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia[J].Atherosclerosis,2004,173:55-68.
[4]Mortality in treated heterozygous familial hypercholesterolaemia:implications for clinical management.Scientific Steering Committee on behalf of the Simon Broome Register Group[J].Atherosclerosis,1999,142:105-112.
[5]Stephenson SH,Larrinaga-Shum S,Hopkins PN.Benefits of the MEDPED treatment support program for patients with familial hypercholesterolemia[J].J Clin Lipidol,2009,3:94-100.
[6]Shi Z,Yuan B,Zhao D,et al.Familial hypercholesterolemia in China:prevalence and evidence of underdetection and undertreatment in a community population[J].Int J Cardiol,2014,174:834-836.
[7]中华医学会心血管病学分会动脉粥样硬化及冠心病学组,中华心血管病杂志编辑委员会.家族性高胆固醇血症筛查与诊治中国专家共识[J].中华心血管病杂志,2018,46:99-103.
[8]Gidding SS,Champagne MA,de Ferranti SD,et al.The Agenda for Familial Hypercholesterolemia:A Scientific Statement From the American Heart Association[J].Circulation,2015,132:2167-2192.
[9]Cuchel M,Bruckert E,Ginsberg HN,et al.Homozygous familial hypercholesterolaemia:new insights and guidance for clinicians to improve detection and clinical management.Aposition paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society[J].Eur Heart J,2014,35:2146-2157.
[10]France M,Rees A,Datta D,et al.HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom[J].Atherosclerosis,2016,255:128-139.
[11]Harada-Shiba M,Arai H,Oikawa S,et al.Guidelines for the management of familial hypercholesterolemia[J].J Atheroscler Thromb,2012,19:1043-1060.
[12]陈在嘉,徐义枢,孔华宇.临床冠心病学[M].北京:人民军医出版社,1998:77.
[13]Mabuchi H,Nohara A,Noguchi T,et al.Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan[J].Atherosclerosis,2011,214:404-407.
[14]Nordestgaard BG,Chapman MJ,Humphries SE,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[J].Eur Heart J,2013,34:3478-3490a.
[15]Zhou M,Zhao D.Familial Hypercholesterolemia in Asian Populations[J].J Atheroscler Thromb,2016,23:539-549.
[16]Brown MS,Goldstein JL.A receptor-mediated pathway for cholesterol homeostasis[J].Science,1986,232:34-47.
[17]Fouchier SW,Kastelein JJ,Defesche JC.Update of the molecular basis of familial hypercholesterolemia in The Netherlands[J].Hum Mutat,2005,26:550-556.
[18]Soutar AK.Intracellular transport of the low-density lipoprotein receptor[J].Biochem Soc Trans,1996,24:547-552.
[19]Benito-Vicente A,Uribe KB,Jebari S,et al.Validation of LDLr Activity as a Tool to Improve Genetic Diagnosis of Familial Hypercholesterolemia:A Retrospective on Functional Characterization of LDLr Variants[J].Int J Mol Sci,2018,19:E1676.
[20]Stein EA,Dann EJ,Wiegman A,et al.Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations[J].J Am Coll Cardiol,2017,70:1162-1170.
[21]Sjouke B,Kusters DM,Kindt I,et al.Homozygous autosomal dominant hypercholesterolaemia in the Netherlands:prevalence,genotype-phenotype relationship,and clinical outcome[J].Eur Heart J,2015,36:560-565.
[22]Harada-Shiba M,Ohta T,Ohtake A,et al.Guidance for Pediatric Familial Hypercholesterolemia 2017[J].J Atheroscler Thromb,2018,25:1-15.
[23]Snchez-Herndez RM,Prieto-Matos P,Civeira F,et al.Autosomal recessive hypercholesterolemia in Spain[J].Atherosclerosis,2018,269:1-5.
[24]Kidambi S,Patel SB.Sitosterolaemia:pathophysiology,clinical presentation and laboratory diagnosis[J].J Clin Pathol,2008,61:588-594.
[25]Hansel B,CarriéA,Brun-Druc N,et al.Premature atherosclerosis is not systematic in phytosterolemic patients:severe hypercholesterolemia as a confounding factor in five subjects[J].Atherosclerosis,2014,234:162-168.
[26]Nguyen L,Salen G,Shefer S,et al.Unexpected failure of bile acid malabsorption to stimulate cholesterol synthesis in sitosterolemia with xanthomatosis Comparison with lovastatin[J].Arteriosclerosis,1990,10:289-297.
[27]Makary MS,Kisanuki YY,Amin NN,et al.Teaching NeuroImages:Cerebrotendinous xanthomatosis:A rare treatable adult-onset lipid storage disease[J].Neurology,2018,90:e637-e638.
[28]Jiang L,Sun LY,Pan XD,et al.Characterization of the unique Chinese W483X mutation in the low-density lipoprotein-receptor gene in young patients with homozygous familial hypercholesterolemia[J].J Clin Lipidol,2016,10:538-546,e5.
[29]中国成人血脂异常防治指南修订联合委员会.中国成人血脂异常防治指南(2016年修订版)[J].中国循环杂志,2016,31:833-853.
[30]Raal FJ,Honarpour N,Blom DJ,et al.Inhibition of PCSK9with evolocumab in homozygous familial hypercholesterolaemia(TESLA Part B):a randomised,double-blind,placebo-controlled trial[J].Lancet,2015,385:341-350.
[31]Ray KK,Landmesser U,Leiter LA,et al.Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol[J].N Engl J Med,2017,376:1430-1440.
[32]Leiter LA,Teoh H,Kallend D,et al.Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status:The ORI-ON-1 Randomized Clinical Trial[J].Diabetes Care,2019,42:173-176.
[33]Musunuru K,Pirruccello JP,Do R,et al.Exome sequencing,ANGPTL3 mutations,and familial combined hypolipidemia[J].N Engl J Med,2010,363:2220-2227.
[34]Dewey FE,Gusarova V,Dunbar RL,et al.Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease[J].N Engl J Med,2017,377:211-221.
[35]Gaudet D,Gipe DA,Pordy R,et al.ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia[J].N Engl JMed,2017,377:296-297.
[36]Bennett CF,Swayze EE.RNA targeting therapeutics:molecular mechanisms of antisense oligonucleotides as a therapeutic platform[J].Annu Rev Pharmacol Toxicol,2010,50:259-293.
[37]Parham JS,Goldberg AC.Mipomersen and its use in familial hypercholesterolemia[J].Expert Opin Pharmacother,2019,20:127-131.
[38]温文慧,匡泽民,王绿娅.关注动脉粥样硬化性心血管病的残余风险:高脂蛋白(a)血症[J].中华心血管病杂志,2018,46:92-95.
[39]Norata GD,Ballantyne CM,Catapano AL.New therapeutic principles in dyslipidaemia:focus on LDL and Lp(a)lowering drugs[J].Eur Heart J,2013,34:1783-1789.
[40]Vogt A.Lipoprotein(a)-apheresis in the light of new drug developments[J].Atheroscler Suppl,2017,30:38-43.