【作者】 陈卫星；

【导师】 马亦林； 厉有名；

【作者基本信息】 浙江大学 ， 内科学（传染病）， 2001， 博士

【摘要】 在欧美国家，酒精性肝病（alcoholic liver disease，ALD）在肝脏疾病发病中占相当高的比例，在一些酗酒严重的国家如美国、法国、德国、意大利、西班牙等，酒精性肝病的发病率较高，资料显示酒精性肝硬化发病占所有肝硬化的50％—75％；而在亚洲的日本，酒精性肝硬化占肝硬化总数的25％—30％。由于地域、饮食结构、饮酒习惯以及病毒性肝炎的流行情况不同，各地的不同阶段的酒精性肝病的构成也不尽相同，并且由于东方国家人群中存在患乙型肝炎或丙型肝炎的比例较西方高，其肝细胞癌发生率也较纯酒精性肝硬化高。不同阶段酒精性肝病的病理变化有相应发病机制，酒精性脂肪肝的发病主要与脂质代谢、脂肪酸氧化受阻、载脂蛋白缺乏等有关；酒精性肝炎的发病与单核细胞毒性作用、肝内谷胱甘肽缺少、氧自由基增加、细胞因子参与和炎症介质积聚相关；肝纤维化的发生与乙醛引起反复炎症、细胞因子主要是转化生长因子-β（TGF-β）、在血小板衍化生长因子（PDGF）、免疫反应参与导致肝星状细胞（HSC）激活而胶原酶受抑制，胶原合成增加而降解减少，最终由于反复炎症和纤维化导致酒精性肝硬化。目前的研究表明，酒量的大小与肝内乙醇脱氢酶（alcohol dehydrogenas，ADH），乙醛脱氢酶（aldehyde dehydrogenase，ALDH）的多态性的变化密切相关。长期大量饮酒是发生酒精性肝病的发病基础，酒精及其乙醛等代谢物直接或通过免疫机制损害肝细胞，使其发生脂肪变性、酒精性肝炎、酒精性肝纤维化，到终末期的 酒精性肝硬化。 近年来随着我国社会经济的发展，酒的生产和消耗不断增加，饮酒对身体健 康尤其是对肝脏的损害日益显现，我国自80年代以来，进行了多次全国性或区域 性的酒依赖的流行学调查，而未作肝功能检查、肝炎病毒标志的检验和B超的检 查，对酒精性肝病防治的实用价值欠佳。本流行病学研究课题选择浙江长广地区 作为调代区域，对一服悄况，饮测有大问撇，如饮酒从、饮测灿仪壮进行了问卷 调查，并作了肝功能检查。肝炎病毒标志的检验和B超的检查。对该人群的酒精 性肝炯的忠病率进行了统计，对年龄、性别、饮泅址、饮俩年附X泄mY性肝病的 危险因素进行了分析。并建立血标本库，提取了外周血单核细胞基因组DNA和 RNA，对此作了三个方面的进一步研究；（）用基因芯片技术和 PCR技术，对他 们的ADH、ALDH多种基因型多态性与酒精性肝病的关系进行相对危险度的分子 流行病学分析：（2）用＊＊R技术，对他们的白介素1受体拈抗剂基冈门LIRN） 数目可变的串联重复多态性进行了分析，探讨ILIRN内含子2多态性与不同类型 的酒粕性肝病的关系；（3〕川＊卜＊＊R羽10。IN叶技术，定挝分析酒梢性肝病患 者的TGF－61 iRNA表达，探讨其与酒精性肝病不同发展阶段或严重程度的相关 性，从而对酒精性肝病的分于流行病学和发病机理作了探讨。 材料与方法 流行病学调查对象 选抒长厂“地区为凋查点，分层仙样灿到符合洲查标准的 对象共43 10人，剔除各不合格对象，共获资料4084份，合格率为99刀5％。调查 饮酒～般情况：性别、年龄等；饮酒悄况：每次饮酒量、饮酒额度、常饮的酒类、 饮酒持续时间等。每一问题都必须回答“是”或“不是”。采用面对而的调查方式， 全部调查对象均要填写调查表，若每日饮酒檀大于或等于40克者并持续5年及以 上者，确定为嗜酒者，再做肝功能检查。肝炎病毒标志的检验和 B超的检查。调 忏时m1为1999年9月至11）】。制定训仟手）w，根孤凋查手册，i）ah前由主持单 位工作负责人召集各调查人员进行培训【，以便统一标准下，进行问卷、诊断和检 查，以保证质过。酒梢性门伤的诊断参收1998年版的“酒粉性肝V刚勺诊断依据及 2 治愈、好转标准”，井测定乙型肝炎表面抗原和丙型肝炎抗体，不典型者做肝穿刺 活检。 实验材料 浙江省酒精性肝病流行病学调查人群中随机抽样 165例嗜酒者， 其中酒依赖者43例，酒粘性脂肪肝3O例，酒梢性脂肪性肝炎61例，酒梢性肝炎 引例；全部为男性；年龄25－70岁，平均44．4484d10．7621岁。正常对照组65例， 年龄26－68岁，平均45．9077if0．8768岁（与研究对象比较显著无差异性，t＝0．9189， p＝0．1800）。每例抽取新鲜全血（EDTA抗凝）2ml，以 Ficojj分离液分离 PBMC， 提耿丛冈组DNAXll RNA。 RT－PCR和 Dot blot法 定量分析 ALD患者的 PBMC中的 TGF－DI mRNA 的表?更多还原

【Abstract】 Long term and excessive drinking is the base of alcoholic liver disease (ALD). Hepatic cell can be injuried by excessive drinking,.with the progression of ALD, alcoholic fatty liver, alcoholic hepatitis, alcoholic hepatic fibrosis and the telophase of ALD-alcoholic Hepatic cirrhosis occur in succession or simultaneously. In developed country, the morbidity of ALD is much higher than other liver disease. Especially in serious alcohol abused country, such as American, French, Germany, Italy and Spain, incidence rate of alcoholic liver disease occupies 50%-75% in all cirrhosis of liver. Meanwhile alcoholic cirrhosis occupies 25%-30% in Asiatic Japan. The distinct of geographical distribution, diet structure, habituation of drinking, epidemic of viral hepatitis, and race microsomal ethanol oxidizing system (MEOS), alcohol dehydrogenas, aldehyde dehydrogenase polymorphism variation, episode constituent of alcoholic liver disease are various. In two investigations of eastern and western countries, the proportion of pathologic type of ALD, fatty liver, alcoholic hepatitis, hepatic fibrosis, cirrhosis of liver, chronic hepatitis and unspecific variance, are 46%> 31% ,11%>8%,0%NO% (breach type in western countries sand in Japan, the proportionare 12%, 10%, 25%> 33%> 10%, 11%. Besides, as the proportion of the population with Hepatitis B or Hepatitis C are higher than western countries in Japan, the hepatocellular carcinoma morbidity is also higher than alcoholic hepatic cirrhosis. In present studying, pathologic change in different ALD stage has different pathogenesis. Alcoholic fatly liver is related to lipid metabolism, lipo-acid oxidation blocking, lacking of apolipoprotein, VLDL allo-excretion; alcoholic hepatitis is related to toxic effect of monocyt, insufficiency of glotathione-SH, oxygen-derived free radidicals gaining, cytokine and inflammation medium accumulating; hepatic fibrosis is related to inflammation by acetaldehyde, transforming growth factor-β(TGF-β, platelet derived growth factor (PDGF) and immunologic reaction result in activation of hepatic stellate cell and Inhibition of collagenase. With Synthesis of collagen and reduction of degradation, repeated inflammation and fibrosis result in alcoholic cirrhosis.With the developing of our social economy, production and consumption of liquor increase. Impairment to the health .especially to liver gradually shows. Several national and regional epidemiological survey has been carried out in our country since 80’s, but these survey focus on alcohol addiction and about psyche , nerves . We choose the Zhejiang Changguang coal mine as the survey region in this epidemiological survey. It involves in population with different occupation. Questionnaire includes drinking capacity for liquor, drinking frequency and morbidity of alcoholic liver disease. And some laboratory examination was carried out. In the topic, the population in this survey was in sampling action. Variable number of tandem repeat (VNTR) polymorphism of nterleukin-1 receptor antagonist gene (IL-1RN) and single nucleotide polymorphisms (SNPs) of the alcohol metaboliting related enzymes were analyzed. Also we want to ques the the relationship between the genes polymorphisms and alcoholic liver disease, In order to explorating the correlation with different stage or severe degree, Assayingthe peripheral blood mononuclear cells (PBMC), the expression of TGF- P i in patientwith ALD were quantitative analysised. Thus we study the molecular biology mechanisms relating with ALD advancedly. Epidetniological survey and experiment methodsEpiderniological material and methods Survey region was Changguang coal mine, objects Were various kinds occupation population working in Changguang coal mine region, for instance worker performancing under coal mine and institution rear service people. Stratified sampling 4310 people coincidenced with survey standard. Reject unqualification object, there are 4084 datas altogether. Qualification rate was 99.05%. General information of al更多还原