酒精性肝病的流行病学现状

酒精性肝病(alcoholic liver disease,ALD)是指由于酒精摄入过量而导致的肝脏损害等一系列病变,可分为轻型ALD、酒精性脂肪肝、酒精性肝炎、酒精性肝纤维化和酒精性肝硬化5种类型[1].随着人们生活方式的转变,酗酒者不断增多,导致ALD有迅速增加的趋势.目前对ALD的流行病学研究取得了一定进展.     

细胞凋亡在非酒精性脂肪性肝病中的作用

非酒精性脂肪性肝病(non-alcoholic fatty liver disease.NAFLD)是指除外酒精和其他明确的损肝因素所致的,以弥漫性肝细胞大泡性脂肪变为主要特征的临床病理综合征.随着生活水平的提高、生活习惯、饮食结构的改变,肥胖和糖尿病的发病率增加,NAFLD的发病率呈上升趋势,严重危害人民健康.而非酒精性脂肪性肝病的发病机制仍不十分清楚,最近研究表明细胞凋亡及其相关因素Fas系统、TNF家族、Bel-2蛋白家族、Caspases蛋白酶家族、NF-κB、细胞色素C及组织蛋白酶B等在NAFLD中表达异常增多,说明肝细胞凋亡在NAFLD的发生进展中扮演了至关重要角色.本文就这方面的研究进展作一综述.     

细胞凋亡与酒精性肝病

细胞凋亡与许多肝病的发生有关，酒精性肝病也不例外。在临床和实验性酒精性肝病中，细胞凋亡常被描述为“嗜酸性小体”。Ｋａｗａｈａｒａ等用Ｔｕｎｅｌ法研究ＬｅｗｉｓＹ抗原的表达，以评估人类酒精性肝病中的细胞凋亡现象。结果发现含Ｍａｌｌｏｒｙ小体的肝细胞呈ＬｅｗｉｓＹ抗原的阳性表达，提示含Ｍａｌｌｏｒｙ小体的肝细胞至少部分以细胞凋亡的方式被清除。在正常大鼠肝脏，肝细胞凋亡仅散在见于中央静脉周围两排的肝细胞，而长期以酒精饲养的大鼠，其肝脏肝细胞凋亡比例显著高于正常大鼠，并且肝细胞凋亡程度与肝损伤的轻重密切…     

库普弗细胞与酒精性肝病

酒精性肝病(Alcohol Liver Disease,ALD)是酒精滥用的主要医学并发症之一.2003年浙江省发布的一组调查报告表明,ALD人群发病率23.1%;其中酒精性肝硬化为4.0%,酒精性肝炎7.6%,酒精性脂肪肝5.1%;男性酒精性肝病患病率为32.6%,女性为3.0%[1].湖南省ALD的患病率为43.6%,其中酒精性肝硬化6.8%,酒精性脂肪肝9.7%,酒精性肝炎15.0%,轻症酒精性肝损伤12.1%;男性ALD患病率为60%,女性为5.2%[2],ALD已成为危害我国人民健康的严重疾患.ALD发病机制复杂,至今仍未完全阐明,主要考虑为:酒精及其代谢产物对肝脏的损伤,其机制涉及乙醇的代谢产物--乙醛的毒性,还原型辅酶Ⅰ/辅酶Ⅰ(NADPH/NAD)的比值增高所致的代谢紊乱,缺氧、自由基的损害,以及炎症介质损伤等多个方面.新近的研究进一步明确了ALD与氧化应激与脂质过氧化作用的关系.正常肝内存在具有保护性抗氧化反应物质,如谷胱甘肽(GSH)和维生素A、C、E等.长期饮酒者,肝细胞内GSH含量明显降低或耗竭,线粒体内GSH减少,加剧对线粒体结构和功能的损害.长期饮酒导致机体内促氧化物质明显增多和抗氧化物质的减少,促发氧化应激最终导致肝细胞死亡或凋亡[3].目前,许多学者认为肠源性内毒素血症及其对肝库普弗细胞(Kupffer cell,KC)的激活是一系列肝毒性作用的起始因素.     

酒精性肝病诊治

酒精性肝病（ALD）是由于长期大量饮酒所致的肝脏疾病。初期通常表现为脂肪肝,进而可发展成酒精性肝炎、酒精性肝纤维化和酒精性肝硬化。严重酗酒时可诱发广泛肝细胞坏死甚或肝功能衰蝎。     

内质网应激在酒精性肝病细胞凋亡中的作用

内质网应激是内质网生理功能发生紊乱的一种亚细胞器的病理状态,既是机体的一种自我保护机制,也是促进细胞凋亡的一条重要途径,在酒精性肝病中,可通过高同型半胱氨酸血症等的作用诱导内质网应激,并可导致肝细胞凋亡.本文就内质网应激在酒精性肝病细胞凋亡中的作用作一综述.     

细胞凋亡与脂肪性肝病研究进展

脂肪性肝病是指脂肪（主要是甘油三酯）在肝脏过度沉积的临床病理综合征。目前,我国脂肪性肝病的发病率仅次于病毒性肝炎,居第二位。临床上,脂肪性肝病主要包括酒精性肝病（alcoholic liver disease,ALD）和非酒精性脂肪性肝病（non-alcoholic fatty liver disease,NAFLD）。     

酒精性肝病诊疗指南2006年2月修订

酒精性肝病是由于长期大量饮酒所致的肝脏疾病。初期通常表现为脂肪肝，进而可发展成酒精性肝炎、酒精性肝纤维化和酒精性肝硬化；严重酗酒时可诱发广泛肝细胞坏死甚或肝功能衰竭；该病是我国常见的肝脏疾病之一，严重危害人民健康。为进一步规范酒精性肝病的诊断和治疗，中华医学会肝病学分会脂肪肝和酒精性肝病学组组织国内有关专家，在参考国内外最新研究成果的基础上，按照循证医学的原则，制订了本《指南》。其中推荐的意见所依据的证据等级共分为3个级别5个等次，见表1，文中以括号内斜体罗马数字表示。     

细胞凋亡与肥胖相关的非酒精性脂肪性肝病

近年来，肥胖相关的非酒精性脂肪性肝病的发病率呈上升趋势，并严重影响着人们的健康。其中细胞凋亡及其相关因素肿瘤坏死因子-α，Fas系统，核因子-κB及组织蛋白酶B在肥胖相关的非酒精性脂肪性肝病的发病机制中起了重要的作用。本文概括综述细胞凋亡与其相关因素在肥胖相关的非酒精性脂肪性肝病中的作用。     

瘦素、胰岛素在非酒精性脂肪肝发病中的作用

近年来,非酒精性脂肪性肝病（nonalcoholic fatty liver disease,NAFLD）发病率呈上升趋势,特别是非酒精性脂肪性肝炎（non—alcoholic steatohepatitis,NASH）已成为仅次于慢性病毒性肝炎和酒精性肝病（alcoholic liver disease,ALD）的重要肝硬化前期病变,并成为健康体检肝酶学异常的常见原因。虽然Day等提出的“二次打击”学说在NAFLD的发病机制上似可以解释其复杂的病理机制,     

Role of apoptosis in alcoholic liver injury

This article represents the proceedings of a symposium at the 2002 ISBRA/RSA meeting in San Francisco, USA. The organizer and chair was H. Ishii and co-chair was A.A. Nanji. The presentations were (1) Introduction: Apoptosis in alcoholic liver disease, by A. A. Nanji; (2) Mitochondria, oxidative stress and apoptosis in alcoholic liver disease, by M. Adachi; (3) Regulation of cell death by mitochondrial glutathione, by J.C. Fernández-Checa; (4) Toxicity of ethanol in HepG2 cells that express CYP2E1, by A.I. Cederbaum; (5) Is alcohol-enhanced liver apoptosis a pathogenic factor in alcoholic liver disease? by I.V. Deaciuc.     

炎症因子在酒精性肝病发生发展中的作用

酒精性肝病(ALD)是全球范围内引起肝损伤的最常见疾病。炎症反应是引起ALD肝损伤的重要原因。酒精入肠后可使肠源性内毒素经肝肠循环入血增多,进而激活肝脏Kupffer细胞中Toll样受体4引起炎症因子的释放。肿瘤坏死因子α等炎症因子引起肝损伤,而白细胞介素(IL)6、10等通过调节炎症反应起到保护肝脏的作用。其中IL-6通过激活信号转导和转录激活因子(STAT)3通路上调肝细胞中多种抗损伤基因的表达,IL-10通过激活Kupffer细胞中STAT3抑制肝脏炎症反应。促炎因子和抗炎因子的失衡和再平衡的过程就是ALD的发展和转归过程。从炎症反应角度系统的综述了炎症因子在ALD发生发展中的作用。     

Role of mitochondria in alcoholic liver disease

Alcohol abuse is the leading cause of liver related morbidity and mortality. Chronic or binge alcohol drinking causes hepatic steatosis which can develop to steatohepatitis, cirrhosis and ultimately hepatocellular carcinoma. The pathogenesis of alcoholic liver disease (ALD) is poorly characterized, however several recent studies point to a major role of mitochondria in this process. Mitochondria play a crucial role in cellular energy metabolism and in reactive species formation. Alcohol treatment causes mitochondrial DNA damage, lipid accumulation and oxidative stress. Studies in both animal models and in humans showed that alcohol administration causes changes in the mitochondrial morphology and function suggesting a role of these changes in the pathogenesis of ALD. We review recent findings on mechanisms by which alcohol negatively impacts mitochondrial biogenesis and function and we will discuss the specific intracellular pathways affected by alcohol consumption. Interestingly, recent findings indicate that a large number of mitochondrial proteins are acetylated and that mitochondrial proteins acetylation and sirtuins are modulated by alcohol. Understanding the mechanisms behind alcohol mediated impaired mitochondrial biogenesis and function may help identify potential therapeutic targets for treating ALD in humans.     

Cellular cytotoxicity against autologous hepatocytes in alcoholic liver disease

ABSTRACT— We tested lymphocyte cytotoxicity against autologous hepatocytes in patients with alcoholic liver disease (ALD). The following cytotoxicity values were found (mean ± SEM): alcohol-induced steatosis with or without fibrosis 16.5±2% (n = 29), alcoholic cirrhosis 28±4% (n = 13), controls with normal liver histology or minimal changes 6±2% (n = 11). The differences were statistically significant (both forms of ALD versus controls p<0.005). T-cell as well as non-T-cell-enriched lymphocyte fractions showed increased cytotoxicity in ALD. We did not observe a correlation between cellular cytotoxicity and the degree of biochemical or histological alterations within the groups tested. Thus, our study demonstrating enhanced cellular cytotoxicity against autologous hepatocytes in ALD further supports the hypothesis that cellular immune reactions are involved in the pathogenesis of ALD, especially of alcoholic cirrhosis.     

Lymphocyte cytotoxicity to autologous hepatocytes in alcoholic liver disease

ABSTRACT— Cytotoxicity of peripheral blood lymphocytes for autologous hepatocytes has been studied in 18 patients with different histological types of alcoholic liver disease. Cytotoxicity was significantly increased in five of ten patients with cirrhosis and/or alcoholic hepatitis but in only one of eight with fatty infiltration or minor histological changes. The cytotoxic effect of T- and non-T-effector cells was separately evaluated in 11 cases. Of six patients with alcoholic hepatitis, non-T lymphocyte cytotoxicity was increased in five and T-cell in only one. These preliminary results are consistent with the concept that autoimmune reactions may play a role in the development and progression of alcoholic hepatitis and cirrhosis, although it is likely that direct hepatotoxic effects of ethanol or its metabolites are also important in determining the pattern of liver injury and perhaps in initiating the immune reactions observed in this study.     

Pancreatitis associated with alcoholic liver disease

The prevalence with which alcoholic pancreatitis is associated with alcoholic liver disease is unclear. To investigate this association further, we have reviewed the autopsy findings of 1022 patients who died from alcoholic liver disease and compared these findings with those from 352 patients who died from cardiac or pulmonary disease. All patients who died from liver disease had a history of chronic alcoholism with clinical and biochemical evidence of severe liver damage. Death resulted from hepatic coma, gastrointestinal bleeding, or infection. Liver disease patients were classified into two groups: (1) those with cirrhosis (77%) and (2) those without cirrhosis but with acute and/or chronic sclerosing hyaline necrosis (23%). Anatomic and histopathologic changes characteristic of chronic pancreatitis were found in 203 patients in approximately the same frequency (20% and 18%, respectively) in both groups. Acute pancreatitis without chronic lesions was observed in 8% and 10% of both groups, respectively. In the control group of 352 autopsies (122 cardiac and 230 pulmonary patients), the overall prevalence of pancreatitis, at 2.6%, was significantly (P<0.001) lower than that observed in the alcoholic liver disease groups. A total of 22 cases (50%) dying from acute or chronic sclerosing hyaline necrosis had severe chronic calcifying pancreatitis compared to 29 patients (18%) (P<0.001) dying from cirrhosis. By contrast, dense fibrosis was significantly (P<0.001) more commonly observed in patients with cirrhosis. We conclude that pancreatitis occurs frequently in patients dying from alcoholic liver disease but is an uncommon finding in patients dying from other causes. Biliary tract pathology was more prevalent (P<0.05) in patients dying from cirrhosis without pancreatitis than those patients dying from liver disease with pancreatitis. In the control group of patients dying from pulmonary or cardiac disease, biliary pathology was far less frequently (P<0.01) observed.     

硝化应激在酒精性肝病中的作用

在酒精性肝病发病过程中存在诱导型一氧化氮合酶的表达增强,生成大量一氧化氮,在氧化应激的状态下与活性氧反应生成过氧化亚硝酸根离子,从而引发硝化应激,通过介导蛋白质、核酸等的硝化,影响细胞信号转导通路,最终影响细胞的代谢等功能及细胞凋亡,参与酒精性肝病的发病。本文旨在阐述硝化应激在酒精性肝病发病机制中可能发挥的作用。     

酒精性肝病的危险因素

酒精滥用与肝脏损伤、数种癌症、交通事故、婚姻破裂以及家庭和社会暴力等密切相关,长期过量饮酒者脂肪性肝病患病率高达75%,然而仅20%～25%的重度嗜酒者发生脂肪性肝炎,10%～20%发生肝硬化,提示酒精中毒与遗传和环境因素相互作用共同导致酒精性肝病(ALD)的发生和发展~([1-2]).除了饮酒量、持续时间和饮酒方式外,ALD的危险因素主要有乙醇代谢酶的基因多态性、女性、营养不良、肥胖症以及合并嗜肝病毒感染等.     

Role of transmethylation reactions in alcoholic liver disease

Alcoholic liver disease is a major health care problem worldwide. Findings from many laboratories, induding ours,have demonstrated that ethanol feeding impairs several of the many steps involved in methionine metabolism.Ethanol consumption predominantly results in a decrease in the hepatocyte level of S-adenosylmethionine and the increases in two toxic metabolites, homocysteine and S-adenosylhomocysteine. These changes, in turn,result in serious functional consequences which include decreases in essential methylation reactions via inhibition of various methyltransferases. Of particular interest to our laboratory is the inhibition of three important enzymes, phosphatidylethanolamine methyltransferase,isoprenylcysteine carboxyl methyltransferase and protein L-isoaspartate methyltransferase. Decreased activity of these enzymes results in increased fat deposition, increased apoptosis and increased accumulation of damaged proteinsall of which are hallmark features of alcoholic liver injury.Of all the therapeutic modalities available, betaine has been shown to be the safest, least expensive and most effective in attenuating ethanol-induced liver injury. Betaine, by virtue of aiding in the remethylation of homocysteine,removes both toxic metabolites (homocysteine and S-adenosylhomocysteine), restores S-adenosylmethionine level, and reverses steatosis, apoptosis and damaged proteins accumulation. In conclusion, betaine appears to be a promising therapeutic agent in relieving the methylation and other defects associated with alcoholic abuse.     

CD14与酒精性肝病

白细胞分化抗原14(clusterofdifferentiationantigen,CD14)为内毒素脂多糖(lipopolysac-charide,LPS)高亲和力受体,在机体免疫、防御系统引起的一系列反应中起着关键的作用.细胞膜CD14识别LPS并引起细胞酪氨酸磷酸化、核因子(nuclearfactor-κB,NF-κB)转位、触发细胞因子释放和氧自由基的产生.而可溶性CD14则与细胞膜CD14竞争结合LPS,并且介导不表达膜CD14的内皮细胞和平滑肌细胞对LPS的应答.近年来发现,CD14在酒精性肝病的发病机制中起着重要的作用.