家族性高胆固醇血症(FH)致病基因的研究进展

 家族性高胆固醇血症(familial hypercholesterolemia,FH)的临床特征为血总胆固醇升高,尤其是低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-c)升高,沉积于组织,形成皮肤或肌腱黄色瘤,导致动脉粥样硬化甚至早发冠心病。FH的发病机制为LDL受体(LDL receptor,LDLR)或apoB基因突变引起LDL受体途径功能缺陷,主要为常染色体显性遗传疾患,具有基因剂量效应;部分患者为常染色体隐性遗传,机制为LDL受体衔接蛋白1(LDL receptor adaptor protein 1,LDLRAP1)失功能型突变,导致LDL内化活性降低。罕见的人类枯草溶菌素转化酶9 (proprotein convertase subtilisin/kexin type 9,PCSK9)发生功能型突变也可引起严重的FH表型。PCSK9通过降解LDLR蛋白间接下调LDL受体途径,其失功能突变可致血浆LDL水平下降。因此PCSK9是目前降脂药物的研究热点。     

One year experience in the treatment of familial hypercholesterolaemia with simvastatin.

Patients with heterozygous familial hypercholesterolaemia (FH) have a substantially increased risk of atherosclerosis due to very high plasma levels of cholesterol. Recent evidence has shown that coronary heart disease in these patients may regress with lipid-lowering therapy. In this study the efficacy and safety of simvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A, was investigated in 30 patients with FH over a period of one year. Substantial reductions in the plasma concentrations of total cholesterol (-28%), low-density lipoprotein (LDL) cholesterol (-32%), intermediate-density lipoprotein (IDL) cholesterol and apolipoprotein (apo) B (-33%) were achieved with 20 mg/day of simvastatin; there were no significant changes in triglycerides high-density lipoprotein cholesterol or apo A. In contrast to previous studies, 40 mg/day of simvastatin did not result in a further statistically significant fall in LDL cholesterol, IDL cholesterol or apo B in the group as a whole. The drug was well tolerated and no adverse clinical or laboratory events were recorded. In particular, no ophthalmological, hepatic or renal disorders were observed and there were no sleep disturbances. We conclude that simvastatin is an efficacious and safe drug to treat patients with heterozygous FH and that rarely will the dose need to be increased above 20 mg/day.     

Familial hypercholesterolemia due to ligand-defective apolipoprotein B100: first case report in a Mexican family

BACKGROUND: Familial defective apolipoprotein B100 (FDB) is one of the known causes of familial hypercholesterolemia (FH). Its frequency among subjects with FH varies among ethnic groups; information on FH is insufficient for populations from Latin America. We proposed to describe prevalence of FDB in a cohort of Mexican FH probands (n = 30). METHODS: We searched for the known FDB mutations using polymerase chain reaction assays. In this set of patients, mean lipid values were representative of FH (cholesterol 351 mg/dL, LDL cholesterol 274 mg/dL, HDL cholesterol 51 mg/dL, and triglycerides 132 mg/dL). RESULTS: One subject with Arg3500Gln mutation was found: a 44-year-old male with a history of coronary heart disease (CHD) among paternal relatives. His lipid profile was cholesterol 370 mg/dL, LDL-cholesterol 300 mg/dL, HDL-cholesterol 32 mg/dL, and triglycerides 189 mg/dL. Tendinous xanthomata were detected. Three of four siblings, one of three sons, and one of nine nieces and nephews carried the mutation. The mutation was confirmed by automated sequencing. Tendinous xanthomata were absent in affected subjects younger than age 20 years; additionally, the subjects had borderline cholesterol levels. CONCLUSIONS: Our data suggest that FDB explains the small number of FH cases in Mexico. Inclusion of molecular biology assays to the clinical laboratory makes it possible to diagnose affected individuals with borderline cholesterol levels or without tendinous xanthomata.     

China, Japan sign agreement to share marrow donation information

Background Familial hypercholesterolemia (FH) is a type of dominant autosomal disease that causes high levels of plasma low-density lipoprotein cholesterol (LDL-C). In the past years, molecular data related to FH were limited in China. Now, to gain more information about FH, we analyzed one proband with a severe FH phenotype as well as his relatives. Methods After the entire coding sequence and the intron-exon junctions of the low-density lipoprotein receptor (LDLR) gene were amplified using PCR, we sequenced the LDLR gene of a Chinese FH family. RT-PCR was used to detect changes in the mRNA.Results Two novel mutations were identified in the LDLR gene of this family. One, W165X, was a G>A substitution at the third nucleotide of codon 165. The other, IVS5–1G>A, was also a G>A substitution at the acceptor splice site of intron 5. The most striking discovery is that the proband was heterozygous for W165X but homozygous for IVS5–1G>A. The cDNA sequencing showed that the IVS5–1G>A mutation caused the insertion of 10 nucleotides, namely GCTCTCACAA, between exon 5 and exon 6. Conclusions The two nucleotide variations are thought to be the FH-causing mutations because the co-segregation of the mutant allele with the phenotype of FH has been shown in this Chinese family. These data show an increase in the mutational spectrum of FH in China and verify a scarce mutational form in the LDLR gene.     

A study on body mass index (BMI) and some biochemical parameters of the medicos with family history of diabetes mellitus, hypertension and coronary heart disease

Increasing prevalence of diabetes mellitus (DM), hypertension (HT), coronary heart disease (CHD) is alarming; risk factors are fairly stable, passing fairly well from childhood to adulthood; genetic factors play a role. This is important to know the status of some biochemical parameters viz, fasting plasma glucose level, fasting serum insulin (FI), serum triglyceride (STG), total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL) among the medicos with family history (FH) of DM, HT or CHD and the relationship of biochemical parameters with body mass index (BMI). Mean age of the sample (n=67) was 22 years with 76.12% males and 23.88% females; 44.78%, 29.85% and 19.40% had FH of DM, HT and CHD respectively; 8.96% had the FH of three diseases. High BMI was seen in 62.69% cases; it was significantly high among those with FH of DM (p<0.05) but not significant against HT (p>0.05) or CHD (p>0.05). All had normal fasting plasma glucose level. Positive association existed (a) between BMI with FI, LDL and HDL, FI with LDL and HDL, TG with TC, TC with LDL and HDL, LDL with HDL among those with FH of DM; (b) between BMI with FI, STG and HDL, FI with LDL and HDL, TC with LDL and HDL, LDL with HDL among those with FH of HT; (c) between BMI with FI, STG and HDL, FI with TC, LDL and HDL, TC with LDL and HDL, LDL with HDL among those with FH of CHD. Multiple correlation coefficients (R) also indicated moderate association.     

氟哌噻吨美利曲辛治疗功能性烧心临床观察

目的探讨氟哌噻吨美利曲辛（商品名黛力新）对功能性烧心（Functional Heartburn FH）的疗效。方法选取符合＂罗马Ⅲ标准＂确诊为FH的患者56例,随机分为治疗组28例,对照组28例。对照组选用奥美拉唑20mg Bid和安慰剂治疗。治疗组奥美拉唑20 mg,Bid和氟哌噻吨美利曲辛1片,Bid,4周为1个疗程,根据症状积分变化评定疗效。结果治疗组治疗4周后的显效率和总有效率分别为（35.7%和96.4%）,而对照组则为（28.6%和64.3%）。经统计学处理,两组的显效率比较差异无统计学意义（P〉0.05）,而总有效率比较差异有统计学意义（P〈0.05）。结论 FH患者存在精神情绪障碍,其中焦虑和抑郁情绪障碍特别突出。黛力新在改善FH患者精神情绪障碍的同时对改善其烧心症状,疗效确切。     

2代3人同患家族性高胆固醇血症及其低密度脂蛋白受体基因突变分析

目的　调查姐妹二人同患家族性高胆固醇血症的家系并进行系谱分析。方法　根据患者及其家系的血缘关系绘制家系图谱,分析临床症状和血脂检查资料。结果　先证者女性,17岁,血清胆固醇浓度为18.89 mmol/L,3岁时即有臀部黄色瘤, 17岁时首次发生前壁心肌梗死,其姐血清胆固醇浓度为15.23 mmol/L,全身多处黄脂瘤。初步诊断先证者为纯合子型,其姐为杂合型。检查患儿4代29人,根据血脂和临床表现确诊2例杂子型家族性高胆固醇血症患者,系谱分析该家系遗传方式符合常染色体显性遗传规律。结论　初步证实一个纯合子型家族性高胆固醇血症系谱。     

家族性高脂血症家系血浆载脂蛋白B与代谢综合征的相关性研究

目的　对不同类型家族性高脂血症及血脂正常对照家系代谢综合征 (MS)的患病率及其相关因素进行探讨。方法　共搜集了 70个家系,其中年龄大于 20岁的家系成员共 560人:分别为家族性混合型高脂血症(FCHL)家系 43个共 379人;家族性高甘油三酯血症 (FHTG)家系 3个共 30人;家族性高胆固醇血症(FH)家系 16个共 102人;血脂正常对照家系 8个共 49人。MS诊断标准参考美国国家胆固醇宣教计划(NCEP ATPⅢ),并结合中国人群资料,以体重指数替代腰围作为诊断标准之一。采用多元Logistic回归分析不同家系中MS的相关因素。结果　 60 7%的FCHL患者及71 4%的FHTG患者符合MS的诊断标准,这两种类型高脂血症家系MS的患病率最高。MS在不同家系成员(包括高脂血症受累者和未受累者 )中的患病率分别为:FCHL为 36 7%,FHTG为 33 3%,FH为 17 6%,血脂正常对照家系为 16 3%。FCHL与血脂正常对照家系MS患病率的危险度优势比(OR值)和 95%可信区间为 2 97 (1 29~7 07)。调整年龄、载脂蛋白A1及低密度脂蛋白胆固醇,多元Logistic回归分析显示血浆载脂蛋白B与MS相关,不同家系OR值如下:FCHL家系为 1 05(1 03~1 07);FHTG家系为 1 26 (1 03~1 55);FH家系为 1 07 (1 01~1 12);而血脂正常对照家系却未显示有意义的相关(P> 0 05)。血浆载脂蛋白A1与     

冠心病虚实证型与血液粘度和血脂变化之关系

将９５例冠心病（ＣＨＤ）患者分为标实和本虚两个证型，观察其血液粘度中的３ｂ高切、３ｂ低切和３Ｐ以及血脂中的ＨＤＬ－Ｃ和ＨＤＬ－Ｃ／ＴＣ。结果标实证各项指标均有明显变化，完全呈现高血粘状态和低ＨＤＬ－Ｃ状态；本虚证仅三项血液粘度明显升高、二项血脂与对照组相同，呈现高血粘状态而不呈现低ＨＤＬ－Ｃ状态；将标实证和本虚证两者比较，除女性患者３Ｐ和ＨＤＬ－Ｃ／ＴＣ无差别外，其余指标均有显著差异。提示ＣＨＤ标实证与本虚证与血液粘度和血脂变化关系密切。     

高密度脂蛋白与冠心病的关系研究进展

流行病学调查、实验研究和临床观察发现,血浆高密度脂蛋白胆固醇作为一个独立的预测因素与冠心病的发病率呈负相关,HDL促进循环中的胆固醇向肝脏转运即“逆向胆固醇转运”,HDL中的两种酶－二乙基对硝基苯磷酸酯酶和血小板激活因子酰水解酶能够降低氧化HDL的形成;通过戒烟、降低到理想体重、规律的需氧锻炼、药物治疗,能绝对或相对的升高HDL－c浓度,降低冠心病的发病率。     

Primary hypertriglyceridemia with borderline high cholesterol and elevated apolipoprotein B concentrations. Comparison of gemfibrozil vs lovastatin therapy

A common pattern of dyslipidemia is elevated levels of plasma triglyceride, borderline high total cholesterol, reduced high-density lipoprotein, and increased apolipoprotein B. This pattern of dyslipidemia frequently is associated with premature coronary heart disease. Nicotinic acid is the drug of first choice for this pattern. In this study, gemfibrozil and lovastatin were compared for their effects on the overall lipoprotein profile in 13 men with this type of dyslipidemia. Both drugs significantly reduced very-low-density lipoprotein and intermediate-density lipoprotein cholesterol levels, and both modestly raised high-density lipoprotein cholesterol levels. Gemfibrozil therapy, however, failed to reduce total cholesterol or total apolipoprotein B levels, whereas lovastatin therapy lowered levels of total cholesterol by 28%, low-density lipoprotein cholesterol by 33%, and total apolipoprotein B by 32%. Moreover, lovastatin therapy caused greater declines in lipoprotein cholesterol ratios than gemfibrozil therapy. Lovastatin thus seems to have certain advantages over gemfibrozil for treatment of elevated plasma triglyceride levels accompanied by borderline high total cholesterol and raised apolipoprotein B levels; therefore, lovastatin therapy should be considered as one approach for management of this condition.     

Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT)

The 356,222 men aged 35 to 57 years, who were free of a history of hospitalization for myocardial infarction, screened by the Multiple Risk Factor Intervention Trial (MRFIT) in its recruitment effort, constitute the largest cohort with standardized serum cholesterol measurements and long-term mortality follow-up. For each five-year age group, the relationship between serum cholesterol and coronary heart disease (CHD) death rate was continuous, graded, and strong. For the entire group aged 35 to 57 years at entry, the age-adjusted risks of CHD death in cholesterol quintiles 2 through 5 (182 to 202, 203 to 220, 221 to 244, and greater than or equal to 245 mg/dL [4.71 to 5.22, 5.25 to 5.69, 5.72 to 6.31, and greater than or equal to 6.34 mmol/L]) relative to the lowest quintile were 1.29, 1.73, 2.21, and 3.42. Of all CHD deaths, 46% were estimated to be excess deaths attributable to serum cholesterol levels 180 mg/dL or greater (greater than or equal to 4.65 mmol/L), with almost half the excess deaths in serum cholesterol quintiles 2 through 4. The pattern of a continuous, graded, strong relationship between serum cholesterol and six-year age-adjusted CHD death rate prevailed for nonhypertensive nonsmokers, nonhypertensive smokers, hypertensive nonsmokers, and hypertensive smokers. These data of high precision show that the relationship between serum cholesterol and CHD is not a threshold one, with increased risk confined to the two highest quintiles, but rather is a continuously graded one that powerfully affects risk for the great majority of middle-aged American men.     

家族性高胆固醇血症的诊断及治疗研究进展

家族性高胆固醇血症(FH)是脂蛋白代谢异常所导致的遗传性疾病，通常为常染色体显性遗传，由于长期暴露于高水平低密度脂蛋白下，FH患者发生冠状动脉疾病的风险显著升高。基因检测对FH的诊断至关重要，除此之外，低密度脂蛋白受体功能检测对FH的治疗也具有重要意义。本文将从FH的诊断筛查、治疗方案及低密度脂蛋白受体功能检测等方面进行综述。     

Plasma cholesterol concentration and death from coronary heart disease: 10 year results of the Whitehall study

Ten year mortality from coronary heart disease in 17,718 middle aged men was related to their initial plasma cholesterol concentrations. The relative risk of death from coronary heart disease declined with age, but the absolute excess risk did not. The risk gradient was continuous over the whole range of cholesterol concentrations, the lowest mortality being among men with concentrations below the lowest decile. It seems that, as with blood pressure, the average cholesterol concentration in the blood pressure, the average cholesterol concentration in the population is too high: lowest concentrations are prognostically the best. A quarter of all deaths from coronary heart disease related to cholesterol occurred among men with concentrations above the top decile, but 55% occurred among men with concentrations in the middle three fifths of the distribution; this figure of 55% could be reduced only by a policy aimed at lowering concentrations in the whole population.     

Population screening for plasma cholesterol: community-based results from Miami

Plasma cholesterol was measured in 7,338 participants of a cholesterol screening in Miami, Florida. They were typically health conscious as evidenced by the low prevalence of current cigarette smoking (16%). However, more than 30% of males and 49% of females over age 50 had cholesterol levels in excess of 240 mg/dl, placing them at moderate to high risk for coronary artery disease. Results revealed a dose response relationship between cigarette smoking and cholesterol in men of all age groups and in women of premenopausal age; whereas the average cholesterol was similar in exsmokers and never smokers. Risk analysis revealed a strong positive association between cholesterol and the period prevalence of myocardial infarction in men and women. Male and female patients with newly diagnosed hypercholesterolemia reduced their cholesterol an average of 13 and 10 mg/dl, respectively, under care of a physician. These results indicate that cholesterol screening coupled with physician follow-up and treatment can lower cholesterol and its attendant risk of cardiovascular disease.     

功能性烧心与功能性消化不良、肠易激综合征症状重叠研究

目的 研究功能性烧心（FH）患者重叠功能性消化不良(FD)、肠易激综合征（IBS）及其亚型症状的发生率。 方法 对110例以烧心为主要症状且上消化道内镜检查示食管黏膜无破损的患者行问卷调查、24 h食管多通道腔内阻流-pH(MII-pH)联合监测及质子泵抑制剂（PPI）治疗。根据罗马Ⅲ诊断标准对患者重叠FD、IBS症状的情况进行问卷调查,并根据汉密尔顿焦虑／抑郁量表(HAMA／HAMD)调查焦虑及抑郁症状的发生情况。根据24 h食管MII-pH监测结果及PPI治疗结果将患者分为非糜烂性反流病（NERD）组及FH组,比较两组重叠FD、IBS症状发生率及其与FD、IBS亚型重叠的情况。 结果 FH组女性患者多于NERD组（P<0.05）;FH患者焦虑抑郁症状发生率均高于NERD患者（分别为92% vs.75%,88% vs.65%）,差异有统计学意义（P<0.05）。52例（47.3%）患者重叠FD症状,31例（28.2%）重叠IBS症状,10例（9.09%）同时重叠FD症状及IBS症状。FH患者重叠FD症状及IBS症状的发生率显著高于NERD患者（分别为62% vs.35%,48% vs.11.7%）,差异有统计学意义（P<0.01）。重叠的FD症状以上腹疼痛综合征（EPS）症状略多于餐后不适综合征（PDS）症状、IBS症状以腹泻型（IBS-D）略多于便秘型（分别为29.1% vs. 18.2%、16.4% vs.11.8%）,但差异无统计学意义（P>0.05）。 结论 FH较NERD更多见于女性患者,焦虑抑郁症状发生率更高,且更易重叠FD、IBS症状,重叠的症状以EPS及IBS-D亚型更多见。     

Treatment of primary moderate hypercholesterolemia with lovastatin (mevinolin) and colestipol

The introduction of inhibitors of cholesterol biosynthesis offers a new approach to treatment of hypercholesterolemia. One such agent, lovastatin (formerly, mevinolin), causes significant reductions in plasma cholesterol levels. This action can be enhanced by bile acid sequestrants. In this study, lovastatin and colestipol hydrochloride together were administered to ten patients with primary moderate hypercholesterolemia. Compared with a control period, the combined-drug therapy caused a 36% reduction in plasma total cholesterol level, a 48% decrease in low-density lipoprotein (LDL) cholesterol level, and a 17% increase in high-density lipoprotein cholesterol level. The reduction in LDL cholesterol level was due to three factors: a 27% decrease in the production rate of LDL, a 20% increase in fractional catabolic rate of LDL, and a 15% depletion of cholesterol in LDL particles. This major reduction in LDL cholesterol level produced by combined-drug therapy may be valuable for prevention of coronary heart disease in high-risk patients with primary moderate hypercholesterolemia.     

Genetic causes of familial hypercholesterolaemia in a Malaysian population

A total of 86 unrelated Malaysian patients with familial hypercholesterolaemia (FH) were studied for mutations in their low-density lipoprotein receptor (LDL-R) gene. Amongst them, 23 had a LDL-R gene mutation, while none having an Apolipoprotein B-3500 (Apo B-3500) mutation. Patients with the LDL-R gene defect appeared to have a higher level of low-density lipoprotein cholesterol (LDL-C), an increased incidence of xanthomas and coronary heart disease (CHD), but no relationships were found between the type of LDL-R gene mutations and their lipid levels or clinical signs of CHD. In contrast to Western data, our findings seemed to indicate a predominance of mutations in the ligand binding domain and an absence of Apo B-3500 gene mutation. The latter finding may offer a genetic basis as to why Asian patients with familial hypercholesterolaemia have lower LDL-C levels and less premature CHD than their Western counterparts.