关于建立中国家族性高胆固醇血症新简化诊断标准的探索性研究

目的:家族性高胆固醇血症(FH)现有的诊断标准复杂且不完全适用于中国人群,故本研究拟探索一种基于中国人群的新的家族性胆固醇血症简化诊断标准(Chinese Simplified Criteria for Familial Hypercholesterolemia,CSCFH)的可靠性。方法:连续纳入2011年11月至2018年5月就诊于阜外医院血脂中心的12 901例住院患者,并收集临床特征、实验室检查和基因检测等数据。FH的诊断基于Simon Broome(SB)标准、荷兰脂质诊所网络(DLCN)标准和CSCFH,并分析CSCFH相对于上述两个标准的敏感度、特异度和一致性。结果:12 901例受试者中,根据DLCN、SB和CSCFH标准,FH的患病率分别为1.73%(223/12 901),1.57%(202/12 901)和1.59%(205/12 901)。与DLCN和SB标准相比,CSCFH显示出高灵敏度(91.9%和100%)、高特异度(100%和99.9%)和良好的一致性(κ=0.957;κ=0.993)。当根据不同地区对受试者进行分层分析时,CSCFH得到了相似的结果。结论:CSCFH与现有标准相比具有高敏感度和特异度,临床上更易于使用,未来需要进一步开展更大规模的前瞻性研究来评估该标准的可行性和可靠性。     

家族性高胆固醇血症的临床特点及其与早发心肌梗死的关系

目的观察家族性高胆固醇血症(familial hypercholesterolemia,FH)的临床特点,并探讨其与早发心肌梗死(myocardial infarction,MI)的相关性。方法将潍坊阳光融合医院2000年1月至2018年12月收治的5 584例MI患者资料纳入此次回顾性分析,以男性55岁、女性60岁为早发标准,将患者分别纳入早发MI组、非早发MI组,参照荷兰临床脂质网络(Dutch lipid clinic network,DLCN)标准,计算两组患者FH患病率并比较FH患者、非FH患者的临床特点,运用Logistic多因素回归分析,总结FH对早发MI的影响。结果 5 584例患者中,2532例为早发MI,其余3 052例为非早发MI;共有252例患者确诊FH,其中早发MI组220例,非早发MI组32例,早发MI组FH患病率为8.67%,高于非早发MI组的1.05%,差异有统计学意义(P0.05)。FH组年龄、体质量指数(body mass index,BMI)低于非FH组,其总胆固醇(total cholesterol,TC)、低密度脂蛋白胆固醇(lowdensity lipoprotein cholesterol,LDL-C)、三酰甘油(triglyceride,TG)浓度高于非FH组;FH组男性比例、原发性高血压(高血压)患病率、糖尿病患病率低于非FH组,其冠状动脉粥样硬化性心脏病(冠心病)家族史比例高于非FH组,差异有统计学意义(P0.05)。Logistic多因素回归分析示,校正体质量指数、TC、高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)等传统危险因素后,FH是导致早发MI的独立危险因素,较非FH患者而言,FH患者早发MI风险上升20.122倍(P0.05)。结论 FH是导致早发冠心病与早发MI的独立危险因素,应重视FH的早期诊断与强化调脂治疗。     

早发心肌梗死患者基因检测对家族性高胆固醇血症的诊断价值评估

目的在早发心肌梗死患者中评估基因检测对家族性高胆固醇血症(FH)的诊断价值。方法该研究为单中心横断面研究。选取2015年5月1日至2017年3月31日在北京大学人民医院就诊的早发心肌梗死患者, 收集患者的一般临床资料, 进行FH相关基因低密度脂蛋白受体(LDLR)、前蛋白转化酶枯草溶菌素9(PCSK9)、载脂蛋白B(APOB)和低密度脂蛋白受体衔接因子蛋白1(LDLRAP1)的基因检测。临床诊断分别采用Simon Broome标准、DLCN标准和FH中国专家共识诊断FH患者。结果 225例早发心肌梗死患者中, 男性188例(83.6%), 首次心肌梗死的年龄为(46.6±7.2)岁。共有10例(4.4%)患者携带FH致病或可能致病的突变。较单独采用Simon Broome标准、DLCN标准和FH中国专家共识3种临床标准, 基因检测使FH的诊断率分别提高了53.3%, 33.3%和42.1%。结论基因检测有助于提高FH的诊断, 对早发心肌梗死患者及早启动FH的规范治疗具有重要的意义。     

家族性高胆固醇血症家系低密度脂蛋白受体基因突变分析

家族性高胆固醇血症(FH)是一种严重的常染色体单基因显性遗传性疾病,临床特点为血浆胆固醇大幅增高、特征性黄色瘤和早发冠心病,同时具有阳性家族史。低密度脂蛋白受体(LDLR)基因突变是引起FH最主要的原因。本研究对一临床诊断为纯合子FH先证者及其父母进行基因突变分析,以从分     

中国家族性高胆固醇血症诊疗现状

家族性高胆固醇血症(FH)是最常见的血脂代谢异常单基因遗传病,FH患者因从胎儿期血浆总胆固醇水平开始升高,故易发生早发冠心病。诊断主要依赖血浆低密度脂蛋白胆固醇水平、黄色瘤、早发冠心病、基因检测等。FH的早期发现与干预对预后尤为重要,我国FH诊断严重不足,且治疗后低密度脂蛋白胆固醇达标率低下。     

早发急性冠状动脉综合征患者家族性高胆固醇血症院内诊疗现状调查

目的探讨早发急性冠状动脉综合征(ACS)患者家族性高胆固醇血症(FH)的患病率及诊疗现状。方法回顾性收集2016年1月至2017年12月收治于第906医院的早发ACS患者275例,收集患者的人口学资料、既往病史、血脂水平、冠状动脉造影检查结果及药物治疗情况等,采用荷兰脂质监测指南标准进行评分并分为可能FH组(评分≥3分)和不可能FH组(评分<3分),分析ACS患者FH患病率及院内诊疗特点。结果早发ACS患者FH患病率为0.36%。与不可能FH组比较,可能FH组患者的年龄更小(t=-2.021,P<0.05),合并冠心病家族史及冠状动脉多支病变的比例更高(χ²=5.131、2.366,P<0.05),可能FH组患者具有更高的总胆固醇、低密度脂蛋白胆固醇及载脂蛋白B水平(t=1.042、2.043、8.458,P<0.05),出院时可能FH组仍以低强度他汀治疗为主(68.66%),中等强度他汀治疗比例及联合依折麦布治疗比例较不可能FH组更高(χ²=-3.381、-2.473,P<0.05)。结论早发ACS患者具有一定的FH患病率,但诊断率较低。可能FH组患者具有更高的总胆固醇、低密度脂蛋白胆固醇及载脂蛋白B水平,发作ACS时的年龄更小,合并冠状动脉多支病变更常见,且强化降脂治疗比例低。     

家族性高胆固醇血症患者新的致病基因——PCSK9基因突变分析

家族性高胆固醇血症(FH)是一种严重的常染色体单基因显性遗传性疾病,血浆胆固醇大幅增高、皮肤黄色瘤和早发冠心病为其典型临床特征。FH的主要病理基础是低密度脂蛋白受体(LDLR)基因突变。新近发现FH具有遗传异质性,多种基因的变异均可导致FH样临床表型。本研究对一临床诊断为F     

我国成人冠心病患者中家族性高胆固醇血症检出率及治疗现状

目的:分析我国成人冠心病患者中家族性高胆固醇血症(FH)检出率及临床特征。方法:选择2015年9月至2020年8月纳入"心血管病高危人群早期筛查与综合干预项目"中的冠心病(CAD)人群(定义为自报心肌梗死或冠状动脉血管重建病史),依据《家族性高胆固醇血症筛查与诊治中国专家共识》,筛查我国成年CAD患者的FH检出率,并描述CAD合并FH患者的临床特征以及降脂药物使用情况,分析不同亚组间FH检出率的差异。结果:研究共纳入我国35～75岁CAD患者26 732例,平均年龄为(61.9±8.2)岁,其中男性15 484例(57.9%),城市患者12 296例(46.0%)。在所有CAD患者中,识别109例FH患者,检出率为0.41%(1:244)。东部、中部及西部地区CAD患者的FH检出率分别为0.57%、0.26%以及0.35%。城市CAD患者的FH检出率高于农村CAD患者(0.52%vs. 0.31%,P0.01)。FH患者中早发冠心病比例显著高于非FH患者(72.5%vs. 52.4%,P0.001)。在CAD合并FH患者中,接受降脂药物治疗比例为67.0%,接受降脂治疗后无一例患者达到指南推荐LDL-C1.8 mmol/L水平。结论:我国2.6万成人CAD中,每244人中可筛查出1人患FH。东部地区FH检出率最高,城市FH检出率高于农村。FH患者中,早发冠心病比例显著高于非FH患者,接受降脂药物治疗比例和LDL-C达标率均较低。这提示需尽早识别和治疗FH患者,以降低未来心血管事件风险,改善患者的预后。     

依洛尤单抗注射液对高低密度脂蛋白胆固醇血症患者脂蛋白a和高敏C反应蛋白的影响研究

目的评估依洛尤单抗注射液在高低密度脂蛋白胆固醇血症患者用药前后血清脂蛋白a和高敏C反应蛋白的变化。方法收集2019年7月至2019年12月北京阜外医院心内科应用依洛尤单抗注射液的高低密度脂蛋白胆固醇血症(LDL-C)患者,分为家族性高胆固醇血症组(FH)和非家族性高胆固醇血症组(NFH),比较两组间基线人口学特征、传统心血管危险因素、口服降脂药应用、以及应用依洛尤单抗前后血清LDL-C、脂蛋白a[Lp(a)]、高敏C反应蛋白(hsCRP)水平的变化。结果 (1)总计49例使用依洛尤单抗注射液的高LDL-C患者,女性12例(24.5%),平均年龄(54.1±11.8)岁,其中FH组15例,NFH组34例。FH组更加年轻,NFH组心血管危险因素合并症发生情况则更高。基线LDL-C水平FH组显著高于NFH组,(3.86±1.65)mmol/L对(3.19±0.60)mmol/L,P=0.041。(2)依洛尤单抗注射液对LDL-C水平在FH组和NFH组较用药前分别降低54.9%和49.5%,均有显著改善。(3)FH组患者在用药前后,其Lp(a)和hsCRP水平未见显著变化;而在NFH组患者,Lp(a)和hsCRP水平在用药后较用药前均有显著下降,用药前后Lp(a)分别为(433±389)mg/L对(216±270)mg/L,P=0.049,hsCRP分别为(2.68±2.57)mg/L对(1.62±1.52)mg/L,P=0.037。结论依洛尤单抗注射液可显著降低高危患者LDL-C水平,其对Lp(a)和hsCRP的影响在NFH患者中具有更高的敏感性。     

中国家族性高胆固醇血症简化诊断标准:提高中国患者诊治水平的新尝试

正家族性高胆固醇血症(FH)是一种并非少见的显性遗传性疾病,临床上许多患者常因早发冠心病而得以诊断[1],既往因对此病的关注程度不够,全球范围内均存在对FH发病情况的严重低估,中国之状况则更为沮丧[2]。事实上,FH患者具有明显的临床特征,表现为显著升高的血浆低密度脂蛋白胆固醇(LDL-C),广泛的皮肤、肌腱黄色瘤及早发冠心病[1-4]。杂合型FH(HeFH)患者的LDL-C水平约为正常人的2～3倍,而     

Simplified Canadian Definition for Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal codominant lipoprotein disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease. Definitions for FH rely on complex algorithms that are on the basis of levels of total or LDL-C, clinical features, family history, and DNA analysis that are often difficult to obtain. We propose a novel simplified definition for FH. Definite FH includes: (1) elevated LDL-C (≥ 8.50 mmol/L); or (2) LDL-C ≥ 5.0 mmol/L (for age 40 years or older; ≥ 4.0 mmol/L if age younger than 18 years; and ≥ 4.5 mmol/L if age is between 18 and 39 years) when associated with at least 1 of: (1) tendon xanthomas; or (2) causal DNA mutation in the LDLR, APOB, or PCSK9 genes in the proband or first-degree relative. Probable FH is defined as subjects with an elevated LDL-C (≥ 5.0 mmol/L) and the presence of premature atherosclerotic cardiovascular disease in the patient or a first-degree relative or an elevated LDL-C in a first-degree relative. LDL-C cut points were determined from a large database comprising > 3.3 million subjects. To compare the proposed definition with currently used algorithms (ie, the Simon Broome Register and Dutch Lipid Clinic Network), we performed concordance analyses in 5987 individuals from Canada. The new FH definition showed very good agreement compared with the Simon Broome Register and Dutch Lipid Clinic Network criteria (κ = 0.969 and 0.966, respectively). In conclusion, the proposed FH definition has diagnostic performance comparable to existing criteria, but adapted to the Canadian population, and will facilitate the diagnosis of FH patients.     

Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by very high plasma concentrations of low density lipoprotein cholesterol (LDLc), tendon xanthomas and increased risk of premature coronary heart disease (CHD). FH is a public health problem throughout the world. There are 10,000,000 people with FH worldwide, mainly heterozygotes, and approximately 85% of males and 50% of females with FH will suffer a coronary event before 65 years old if appropriate preventive efforts are not implemented. Early identification of persons with FH and their relatives, and the early start of treatment are essential issues in the prevention of premature cardiovascular disease (CVD) and death in this population. However, guidelines for the general population formally exclude FH from their diagnostic and treatment recommendations. These guidelines have been elaborated by a group of international experts with the intention to answer the main questions about heterozygous FH (heFH) subjects that physicians worldwide face in the diagnosis and management of these patients.     

Clinical, diagnostic, and therapeutic aspects of familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism. FH is characterized by elevated levels of low-density lipoprotein cholesterol, the presence of tendon xanthomas, and premature cardiovascular disease. The underlying molecular defect of FH consists of mutations in the gene coding for the low-density-lipoprotein-receptor protein, detection of which provides the only unequivocal diagnosis. Although the cause of FH is monogenic, there is wide variation in the onset and severity of atherosclerotic disease in these patients. Additional atherogenic risk factors of environmental, metabolic, and genetic origin are presumed to influence the clinical phenotype in FH. Criteria used to identify individuals with FH include a combination of clinical characteristics, personal and family history of early coronary artery disease, and biochemical parameters. Since the introduction in 1989 of statins, which have been shown to be effective and to delay or prevent the onset of cardiovascular disease, drug treatment of FH has greatly improved. New lipid-lowering agents are presently being developed for clinical use. This review provides an update on the clinical, diagnostic, and therapeutic aspects of heterozygous familial hypercholesterolemia.     

Prevalence of familial hypercholesterolemia in premature coronary artery disease patients admitted to a tertiary care hospital in North India

AimsThe prevalence of premature coronary artery disease (CAD) in India is two to three times more than other ethnic groups. Untreated heterozygous familial hypercholesterolemia (FH) is one of the important causes for premature CAD. As the age advances, these patients without treatment have 100 times increased risk of cardiovascular (CV) mortality resulting from myocardial infarction (MI). Recent evidence suggests that one in 250 individuals may be affected by FH (nearly 40 million people globally). It is indicated that the true global prevalence of FH is underestimated. The true prevalence of FH in India remains unknown.MethodsA total of 635 patients with premature CAD were assessed for FH using the Dutch Lipid Clinical Network (DLCN) criteria. Based on scores, patients were diagnosed as definite, probable, possible, or no FH. Other CV risk factors known to cause CAD such as smoking, diabetes mellitus, and hypertension were also recorded.ResultsOf total 635 patients, 25 (4%) were diagnosed as definite, 70 (11%) as probable, 238 (37%) as possible, and 302 (48%) without FH, suggesting the prevalence of potential (definite + probable) FH of about 15% in the North Indian population. FH is more common in younger patients, and they have lesser incidence of common CV risk factors such as diabetes, hypertension, and smoking than the younger MI patients without FH (26.32% vs.42.59%; 17.89% vs.29.44%; 22.11% vs.40.74%).ConclusionFH prevalence is high among patients with premature CAD admitted to a cardiac unit. To detect patients with FH, routine screening with simple criteria such as family history of premature CAD combined with hypercholesterolemia, and a DLCN criteria score >5 may be effectively used.     

Familial Hypercholesterolemia,Familial Combined Hyperlipidemia,and Elevated Lipoprotein(a) in Patients With Premature Coronary Artery Disease

BackgroundFamilial hypercholesterolemia (FH), familial combined hyperlipidemia (FCHL), and elevated lipoprotein (a) (Lp[a]) increase risk of premature coronary artery disease (CAD). The objective of this study was to assess the prevalence of FH, FCHL, elevated Lp(a) and their impact on management in patients with premature CAD.MethodsWe prospectively recruited men ≤ 50 years and women ≤ 55 with obstructive CAD. FH was defined as Dutch Lipid Clinic Network scores ≥ 6. FCHL was defined as apolipoprotein B > 1.2 g/L, triglyceride and total cholesterol > 90th population percentile, and family history of premature cardiovascular disease. Lp(a) ≥ 50 mg/dL was considered to be elevated.ResultsAmong 263 participants, 9.1% met criteria for FH, 12.5% for FCHL, and 19.4% had elevated Lp(a). Among patients with FH, 37.5% had FH-causing DNA variants. Patients with FH, but not other dyslipidemias, were more likely than nondyslipidemic patients to have received lipid-lowering therapy before presenting with CAD (33.3% vs 12.3%, P = 0.04) and combined lipid-lowering therapy after the presentation (41.7% vs 7.7%, P < 0.001). One year after presentation, 58.3%, 54.5%, and 58.8% of patients with FH, FCHL, and elevated Lp(a) had low-density lipoprotein cholesterol (LDL-C) < 1.8 mmol/L, respectively, compared with 68.0 % in reference group. Patients with FCHL were more likely to have non–high-density lipoprotein (HDL) and apolipoprotein B above recommended lipid goals (70.0% and 87.9%, respectively).ConclusionsFH, FCHL, and elevated Lp(a) are common in patients with premature CAD and have differing impact on treatment and achievement of lipid targets. Assessment for these conditions in patients with premature CAD provides valuable information for individualized management.     

Tendon xanthomas as indicators of atherosclerotic burden on coronary arteries

The presence of tendon xanthomas is an almost certain indicator of familial hypercholesterolemia (FH). They also reflect coronary atherosclerotic burden and therefore must be treated aggressively. Tendon xanthomas also occur in two rare conditions, cerebrotendinous xanthomatosis and sitosterolemia, which are not easily confused with FH, can be easily differentiated with clinical history and biochemical tests.     

Prevalence and Treatment of Familial Hypercholesterolemia in France

BackgroundFamilial hypercholesterolemia (FH) is known to be underdiagnosed and undertreated. The prevalence of heterozygous FH is estimated to be 1 in 500. Nevertheless, a recent meta-analysis of screening in the general population seems to show that the prevalence of FH is more likely to be 1 in 250.MethodsAnalysis was based on the third French MONICA and MONALISA population surveys. Participants were randomly recruited in 1995 and 2005 from the general population of 3 regions of France. FH was diagnosed using a modified version of the Dutch Lipid Clinic Network (DLCN) without genetic testing.ResultsThe DLCN score was assessed in 7928 participants aged 35 to 74 years; 50% were men. The prevalence of definite or probable FH was 0.85% (95% CI, 0.63-1.06). Among patients with definite or probable FH, 12% had histories of premature cardiovascular disease (vs less than 1% among subjects without FH; P < 0.0001), 70% were treated (13% with high-intensity, 83% with moderate-intensity, and 4% with low-intensity statin therapy), 90% had cholesterol screening within the past 12 months, and 97% were aware of their hypercholesterolemia. None reached the recommended low-density lipoprotein cholesterol (LDL-C) target (< 2.5 or < 1.8 mmol/L for subjects in primary prevention vs in secondary prevention or with diabetes, respectively), with a mean distance to target of 3.0 mmol/L.ConclusionsIn a sample from the French general population aged 35 to 74 years, the prevalence of FH was close to 1 in 120, and the patients with FH were undertreated.     

Elevated lipoprotein(a) and familial hypercholesterolemia in the coronary care unit: Between Scylla and Charybdis

Background

Elevated lipoprotein(a) (Lp[a]) and familial hypercholesterolemia (FH) are inherited lipid disorders. Their frequencies, coexistence, and associations with premature coronary artery disease (CAD) in patients admitted to the coronary care unit (CCU) remain to be defined.

Hypothesis

Elevated Lp(a) and FH are commonly encountered among CCU patients and independently associated with increased premature CAD risk.

Methods

Plasma Lp(a) concentrations were measured in consecutive patients admitted to the CCU with an acute coronary syndrome (ACS) or prior history of CAD for 6.5 months. Elevated Lp(a) was defined as concentrations ≥0.5 g/L. Patients with LDL‐C ≥ 5 mmol/L exhibited phenotypic FH. Premature CAD was diagnosed in those age < 60 years, and the relationship between this and elevated Lp(a) and FH was determined by logistic regression.

Results

316 patients were screened; 163 (51.6%) had premature CAD. Overall, elevated Lp(a) and FH were identified in 27.0% and 11.6% of patients, respectively. Both disorders were detected in 4.4% of individuals. Elevated Lp(a) (32.0% vs 22.2%; P = 0.019) and FH phenotype (15.5% vs 8.0%; P = 0.052) were more common with premature vs nonpremature CAD. Elevated Lp(a) alone conferred a 1.9‐fold, FH alone a 3.2‐fold, and the combination a 5.3‐fold increased risk of premature CAD (P = 0.005).

Conclusions

Elevated Lp(a) and phenotypic FH were commonly encountered and more frequent with premature CAD. The combination of both disorders is especially associated with increased CAD risk. Patients admitted to the CCU with ACS or previously documented CAD should be routinely screened for elevated Lp(a) and FH.     

家族性高胆固醇血症的临床与基因治疗新进展

家族性高胆固醇血症（FH）是一种常染色体显性遗传病，临床表现为血浆总胆固醇和低密度脂蛋白胆固醇水平升高、皮肤或肌腱黄色瘤和早发冠心病。FH的治疗手段主要包括临床治疗和基因治疗，近年来新药的研发和基因研究的快速发展为FH的治疗提供了更多的手段，本文将对FH的临床和基因治疗的新进展进行综述。     

Long-term effect of low-density lipoprotein apheresis in patients with homozygous familial hypercholesterolemia

Patients that are homozygous for familial hypercholesterolemia (FH) exhibit severe hypercholesterolemia, cutaneous and tendon xanthomas and premature atherosclerosis beginning in childhood. They are resistant to drug therapy and low-density lipoprotein (LDL) apheresis is the practical treatment. Here we review the technique of LDL apheresis treatment, the long-term effects of LDL apheresis, the effect of apheresis on pregnancy, and the drugs that have proven beneficial in patients with homozygous FH. We also record our experiences of treating eight homozygous FH patients using the LDL apheresis treatment. Among the eight patients, one has been free from cardiovascular disease and two patients have each regressed once. In two patients, aortic valve stenosis developed and the other two patients died for acute myocardial infarction. Furthermore, two patients delivered healthy babies in spite of coronary artery disease. Thus, LDL apheresis therapy has the possibility of preventing the progression of atherosclerosis, but the prognosis assessed by long-term observation is still not satisfactory. A recent clinical trial showed some efficacy of the combination therapy of LDL apheresis and atorvastatin for reducing serum cholesterol levels in homozygous FH, suggesting that this combination therapy may be useful for prevention of atherosclerosis in patients homozygous for FH.