重视药物性肝病的研究

肝脏为体内最大最主要的生化和药物代谢器官 ,也是药物损伤的主要靶器官。药物及经肠道吸收的其他化合物经门脉进入肝脏 ,药物吸收的亲和力、生物转化、运输及排泄过程决定了其生物利用度。正常药物生物转化的 1相代谢由细胞色素Ｐ4 5 0 (ＣＹＰ)进行 ,目的是将非极性药物通过氧化还原和水解反应生成极性基团。 2相反应为上述生成物与内因性高极性化物质结合 ,生成水溶性高的物质以利排泄。肝脏在药物的体内分布上也起着重要作用。肝脏的生物转化、细胞内转化和胆汁分泌是体内药物清除的重要过程。分子药理学最新研究表明 ,ＣＹＰ存在广泛的…     

重视药物性肝病

当前人类正暴露于6万种以上化学物质的威胁中,其中包括3万种以上药品和保健品,另3万余种食品添加剂和环境污染物质.这些外因性化学物质多在肝脏各种酶作用下转变为水溶性强的物质由肾脏排出,通常他们生物转化的1相代谢由肝细胞的细胞色素P450(CYP)进行,将非极性药物通过氧化还原和水解反应生成极性基团.2相反应为上述生成物与内因性高极性化物质结合,生成水溶性高的物质以利排泄.第3相反应系通过肝细胞毛细胆管膜的转运体将药物代谢产物排泄到胆汁.肝脏是人体最大最主要的生化反应脏器,因而也是药物损伤的主要靶器官.     

重视药物性肝病的研究

药物引起的肝脏损伤早已受国内外学者的重视 ,但在实际工作中 ,药物性肝病往往被忽略或误诊。据报道 ,在诊断为“肝炎”的病人中 ,约1 0 %～ 2 0 %为药物性肝病 ,在老年病人中此比例可更高。这是因为药物性肝病的临床表现多样化 ,可表现为急性或慢性的肝细胞损伤、胆汁淤积和血管病变等。另一方面是临床医师对药物性肝病的认识不足 ,当病人发现血清转氨酶(ＡＬＴ)、碱性磷酸酶 (ＡＬＰ)或γ 谷氨酰转肽酶(γ ＧＴ)增高时 ,如血清病毒标志阴性 ,往往被诊断为非甲～非戊型肝炎 ,或原因不明的病毒性肝炎 ,而忽视了曾有服药的病史。特别在慢性乙…     

应重视药物性肝病的研究--答巫协宁教授

随着社会进步、科学技术发展、工业化进程加速,以及新材料新药品的不断开发,人类健康面临化学物质的威胁越来越严重。肝脏是人体最大的生化代谢脏器,多数化学物质在肝脏得以解毒,但解毒过程中,出现活化中间代谢产物诱导肝毒性是不可预测性(或称特异质性)肝损伤最重要的原因,其机制主要与个体代谢酶类的遗传多态性密切相关。     

药物性肝病诊治的困惑和建议

药物性肝病（drug—induced liver diseases）是指在使用某种或几种药物后，由药物本身或其代谢产物引起的肝脏损害。在已上市应用的化学性或生物性药物中，有1100种以上具有潜在的肝毒性，很多药物的赋形剂、中草药以及保健药亦有导致肝损伤的可能。欲更有效地监测和预防日益增多的药物性肝损伤，需要在认识药物性肝病现行诊治原则的基础上。分析其中存在的主要问题。探讨有效可行的诊治策略。     

药物性肝病的防治

预防 当今,任何药物可对某一个体在某个阶段引起肝损伤。通常,引起肝损伤的药物分为两类:诱导肝毒素产生和引起特异反应的药物(如产生个体独特的药物变态反应或异常代谢反应)。     

老年人药物性肝病

由于老年人有其自身的特点,容易发生药物性肝病。如老年人肝脏本身的重量、血流量、肝药酶活性等均随增龄降低,影响了药物在肝脏的浓度、转化和代谢;又如肝外因素,老年人常有肾功能不全、心排出量减少、药物蛋白结合减少、老年人体内水分减少而脂肪相对增加,凡此都影响着药物的作用和不良反应的发生。再加老年人常身患多种慢性病,以致常联合多种药物治疗,且又长期服药。     

加强慢性药物性肝病的防治

药物性肝损伤是一个重要的临床问题。任何药物凡能引起胆汁形成和分泌障碍者均可引起胆汁淤积性肝损伤。据报道，一向被认为毒性反应小的中药，其中毒性病例也在不断增加，如土三七、昆布、山海棠等均可引起肝中毒，已引起临床工作者的重视。据统计，使用抗结核药物时15％～30％患者发生转氨酶升高，80％发生于用药1～7周；使用免疫抑制剂环孢素时肝毒性发生率为20％～40％。目前可造成肝脏损伤的药物达2000余种之多，其中以抗结核药、抗真菌药、降血脂药、抗肿瘤药对肝脏毒性较大。     

老年人药物性肝损伤的特点与防治

药物性肝损伤（drug-induced liver injury,DILI）,是指由于药物本身或其代谢产物毒性作用以及特殊体质对药物的超敏感性或耐受性降低引起的肝脏损伤.老年人由于器官功能衰退、肝脏对药物毒性的耐受性降低,同时常常因其合并多种疾病、服用的药物种类和数量多等原因,发生药物性肝损害的风险显著增高.     

30例老年药物性肝病的临床分析

目的对老年药物性肝病特点进行分析,提高对该病的认识。方法对2006年1月～2009年6月,复旦大学附属中山医院住院治疗的30例≥60岁的老年药物性肝病患者的病例资料进行回顾性分析,并与58例同期住院的60岁以下成年人药物性肝病临床特点进行比较。结果老年药物性肝病潜伏期为10d～1年。引起老年药物性肝病的药物主要包括：中药（43.3％）、非甾体类消炎药（10．0％）、HMG—CoA还原酶抑制剂（10．0％）。主要症状包括：纳差（60．0％）、黄疸（56．7％）、乏力（53．3％）。临床分型为：肝脏检查异常3．3％;肝损伤96．7％,其中包括肝细胞损伤型33．3％、胆汁淤积型40．0％、混合型23．3％。老年组潜伏期≤4周的比例低于60岁以下中青年组;老年组由抗微生物药物引起药物性肝病的比例低于60岁以下中青年组,老年组纳差的发生率高于60岁以下中青年组。结论临床医师应提高对老年人药物性肝病的认识,重视中草药所致的药物性肝病。     

85例老年药物性肝炎患者临床分析

目的分析老年人药物性肝炎的临床特点、药物种类及防治原则。方法对85例老年和87例非老年药物性肝炎患者进行回顾性临床对照分析。结果在老年药物性肝炎患者,由中（成）草药引起的42例（49.4%）,抗生素28例（32.9%）,抗结核药7例（8.2%）,其他8例（9.4%）;肝细胞型38例（44.5%）,胆汁淤积型34例（40.0%）,混合型13例（15.3%）,死亡4例（4.7%）;在非老年患者,抗结核药38例（43.7%）,抗生素26例（29.9%）,中（成）草药15例（17.2%）,其他7例（8.0%）;肝细胞型58例（66.7%）,胆汁淤积型18例（20.7%）,混合型11例（12.6%）,无一例死亡。结论中草药和抗生素是引起老年人药物性肝损害的常见药物。应用中草药和抗生素的老年人应定期检测肝功能。     

老年药物性肝损伤的研究进展

药物性肝损伤目前已成为临床用药及药物研发过程中一个越来越引起重视的问题。从老年药物性肝损伤的流行病学、易感因素、临床特点、导致药物性肝损伤的常见药物和预后等几方面介绍了老年药物性肝损伤的特点。指出要加强对老年群体的健康宣教,指导老年人合理用药,发生不良反应时,及时处理并调整治疗方案。     

Immune-mediated drug-induced liver disease

Drug-induced immune-mediated hepatic injury is an adverse immune response against the liver that results in a disease with hepatitic, cholestatic, or mixed clinical features. Drugs such as halothane, tienilic acid, dihydralazine, and anticonvulsants trigger a hepatitic reaction, and drugs such as chlorpromazine, erythromycins, amoxicillin-calvulanic acid, sulfonamides and sulindac trigger a cholestatic or mixed reaction. Unstable metabolites derived from the metabolism of the drug may bind to cellular proteins or macromolecules, leading to a direct toxic effect on hepatocytes. Protein adducts formed in the metabolism of the drug may be recognized by the immune system as neoantigens. Immunocyte activation may then generate autoantibodies and cell-mediated immune responses, which in turn damage the hepatocytes. Cytochromes 450 are the major oxidative catalysts in drug metabolism, and they can form a neoantigen by covalently binding with the drug metabolite that they produce. Autoantibodies that develop are selectively directed against the particular cytochrome isoenzyme that metabolized the parent drug. The hapten hypothesis proposes that the drug metabolite can act as a hapten and can modify the self of the individual by covalently binding to proteins. The danger hypothesis proposes that the immune system only responds to a foreign antigen if the antigen is associated with a danger signal, such as cell stress or cell death. Most clinically overt adverse hepatic events associated with drugs are unpredictable, and they have intermediate (1 to 8 weeks) or long latency (up to 12 months) periods characteristic of hypersensitivity reactions. Immune-mediated drug-induced liver disease nearly always disappears or becomes quiescent when the drug is removed. Methyldopa, minocycline, and nitrofurantoin can produce a chronic hepatitis resembling AIH if the drug is continued.     

Serious drug-induced liver disease secondary to ezetimibe

Ezetimibe is the first member of a new family of lipidlowering drugs that inhibits uptake of dietary and biliary cholesterol. It was approved by the FDA in 2002 for hypercholesterolemia alone or in combination with statins. Its use has been spreading over the last years. Ezetimibe was considered a safe drug. We report a case of a woman who developed a serious hepatocellular drug-induced liver disease after 4 mo therapy with 10 mg daily of ezetimibe. After withdrawal of the drug, the patient recovered slowly. Ezetimibe may produce serious toxic hepatitis and prompt withdrawal is mandatory in case of a significant abnormality in liver testing after beginning or during treatment with ezetimibe.     

老年药物性肝损伤的临床特点

目的探讨引起老年药物性肝损伤的药物种类、临床特点及防治原则。方法对2005年1月～2009年6月复旦大学附属华东医院160例发生药物性肝损害的老年住院病例临床资料进行回顾性分析。结果药物性肝损害患病率为3．17％（160／5047）;老年患者联合用药多,易出现肝损害,以心血管药物最多,构成比为25．6％（41／160）,其次是抗肿瘤药,构成比为21．9％（35／160）,再次是抗生素,构成比为18．1％（29／160）。主要临床症状为疲乏纳差、恶心呕吐,构成比为39．4％（63／160）,黄疸构成比为8．1％（13／160）,低热构成比为5．6％（9／160）,皮肤搔痒构成比为4．4％（7／160）,无症状者构成比为59．4％（95／160）。临床治愈率为71．3％。结论心血管药、抗肿瘤药和抗生素是引起老年药物性肝损害的常见药物。老年患者肝功能受损后大多无明显症状。老年人肝损伤与其肝药物代谢酶活性降低及长期联合用药有关。     

老年人急性药物性肝损伤临床特点分析

目的 探讨老年人急性药物性肝损伤的病因、分型和肝功能变化特点.方法 采用急性药物性肝损伤诊断标准及国际共识分型标准,回顾性分析近10年来我院167例因急性药物性肝损伤住院患者的临床资料.结果 急性药物性肝损伤患者167例,老年组和中青年组分别为53例(31.7%)和114例(68.3%);导致急性药物性肝损伤最常见的药物为中药类(47.9%),老年组心血管系统用药比例高于中青年组(P＜0.05),临床表现以乏力(50.3%)和黄疸(46.7%)者多见,无明显临床表现者仅25例(15.0%),老年组与中青年组临床表现差异无统计学意义;老年组肝细胞型、胆汁淤积型和混合型肝损伤分别为40例(75.5%)、5例(9.4%)和8例(15.1%),中青年组分别为91例(78.9%)、8例(7.4%)和15例(13.7%),两组比较差异无统计学意义(x2=0.80,P＞0.05).结论 老年患者药物性肝损伤以中草药类及心血管药物为主,临床表现缺乏特异性.

Abstract：

Objective To investigate the causes, clinical features, classifications and liver function change of drug-induced liver damage (DILD) in the elderly. Methods One hundred and sixty seven inpatients with acute drug-induced liver injury in our hospital in the past ten years (January 2000 to December 2009) were retrospectively investigated,and the diagnosis and classification methods of acute DILD were based on international consensus meeting (international criteria). Results Among 167 DILI cases, there were 53 cases (31.7%) in the older group and 114 cases (68.3%) in middle-youth age group. Fatigue and jaundice were the more common symptoms, accounting for 50.3% and 46.7%, respectively. In 167 cases, no obvious symptoms and signs were shown in 25 cases. There were no significance differences in clinical manifestation between two groups. Many drugs could induce liver injury. The most common drugs inducing DILD were Chinese traditional and herbal drugs, accounting for 47.9%. Drugs used in heart diseases and inducing liver injury were more common in the older group. In this study, 40 (75.5%), 5 (9.4%) and 8 (15.1%) cases were designated as hepatocellular, cholestetic and mixed DILD in the older group, and 91 (78.9%), 8 (7.4%) and 15 (13.7%) in middle-youth age group, respectively. There were no significance differences between two groups in classifications. Conclusions Many drugs could cause liver injury. The symptoms of acute DILD are nonspecific. Drugs used in heart diseases and inducing liver injury are more common in older patients.     

Management of drug-induced liver disease

The treatment and prevention of drug-induced liver injury starts with the recognition of hepatotoxicity at the earliest possible time so that the suspected drug can be discontinued expeditiously. Both liver enzyme monitoring and vigilance for signs of hypersensitivity involving the liver are useful strategies for many agents known to cause hepatocellular necrosis leading to liver failure. Specific antidotes to prevent or limit hepatic damage exist for only a few drugs, the most important being N-acetylcysteine for the treatment of acetaminophen hepatotoxicity. Corticosteroids are of unproven benefit in the setting of fulminant failure. Ursodiol may be helpful in instances of cholestatic injury. For other agents, supportive measures and the increasing use of liver-assist devices as well as emergency liver transplantation are available when drug injury evolves into irreversible liver failure. It is hoped that a better understanding of hepatotoxicity mechanisms will lead to the development of more specific and effective forms of therapy in the near future.     

Mechanisms of drug-induced liver disease

Drug-induced liver injury depends initially on development of hepatocyte stress and cell death, which can be induced directly by parent drugs or by toxic metabolites. Hepatocyte stress can lead to activation of built-in death programs for apoptosis or necrosis. Subsequently, the innate immune system's participation is recruited. The interplay between proinflammatory and anti-inflammatory components of innate immune system determines the outcome of drug-induced liver injury. Both environmental factors and genetic differences in cellular responses to stress and the innate immune response may account for different susceptibilities between individuals to drug-induced liver injury.     

药物性肝病的发病机制

药物所致肝损害取决于两方面的因素，一为药物本身对肝脏的损害，二为机体对药物的特异质反应。故前者常被称为可预测性损害，后者则多呈不可预测性。