急性药物性肝损伤179例临床分析

目的探讨急性药物性肝损伤临床表现特点、分型、病因、治疗及分析预后，以指导临床诊断和治疗。方法采用急性药物性肝损伤诊断及分类国际共识标准，回顾性调查近5年来中山大学附属第一医院179例急性药物性肝损伤住院患者的临床资料。结果本研究中有48％的患者无明显临床症状体征，其余亦缺乏特异性；有肝细胞型137例（76．11％），胆汁淤积型24例（14．33％），混合型18例（10．56％）。符合重症肝损伤者6例；引起肝功能损伤的药物种类很多，本组最常见的为化疗药、抗结核药、中草药；85．55％患者预后较好，主要肝功能指标于30d内恢复至正常上限两倍以内。6例发展为重型肝损伤，预后较差。结论急性药物性肝损伤症状缺乏特异性，不能单纯根据症状确定诊断；本组患者急性药物性肝损伤的类型以肝细胞型为主；临床上可以引起急性药物性肝损伤的药物种类很多，但以化疗药、抗结核药、中草药发生率最高，临床应用此类药物时，应注意监测肝功能在本组患者中急性药物性肝损伤一般预后较好，但亦可发生严重肝损害，应及时采取措施处理。     

全国多中心急性药物性肝损伤住院病例调研分析

目的回顾性调查我国多中心急性药物性肝损伤住院患者的诊治情况，对急性药物性肝损伤病例进行关联性评价。方法收集全国13个地区16家大型医院2000年至2005年期间因急性药物性肝损伤住院病例及其肝损伤病史和住院诊治经过。采用急性药物性肝损伤国际共识意见的量化评分系统，评价药物与肝损伤的相关程度并列出可能导致急性药物性肝损伤的主要药物。结果全国16家医院报告的急性药物肝损伤5年间住院诊治数共1541例，住院病例有逐渐增加趋势。在可供进行关联性评价的1204例中，急性药物性肝损伤与药物之间的关联性程度及其比例依次为：极有可能（评分〉8分）占14．3％，很可能有关（6～8分）占39．6％，可能有关（3～5分）占40．9％，可能无关（1～2分）占3．8％，无关（≤0分）占1．3％。在药物与肝损伤相关的1142例中，男女比例接近，平均年龄（45．7±16．7）岁，重症药物性肝损伤76例（6．65％），死亡17例，病死率1．5％。导致急性肝损伤的药物种类繁多，其中以中成药或中草药（21．5％）和抗结核药物（21．2％）为多见。结论我国急性药物性肝损伤住院诊断病例数有逐年增加趋势，国际共识意见的量化评分系统有助于重新审定急性肝损伤与药物之间的关联程度，抗结核药物和中成药或中草药可能是我国急性药物性肝损伤的主要病因。     

111例抗结核药致肝损伤住院病例调研分析

目的评价我国急性药物性肝损伤诊断标准与国际标准RUCAM评分系统的一致性。方法采用国际共识会议诊断标准和我国急性药物性肝损伤诊断标准对111例抗结核药致肝损伤病例进行回顾性调查分析。结果111例抗结核药导致的肝损伤中,101例符合美国药物性肝损伤网络提出的资料完整性标准。按照国际共识意见进行临床分型：肝细胞型81例（80.2％）,胆汁淤积型16例（15.8％）,混合型4例（4.0％）。采用RUCAM量化评分系统评分结果是：非常可能2例（2.0％）,很可能63例（62.4％）,可能32例（31.7％）,不大可能4例（4.0％）,无关0例;采用我国急性药物性肝损伤诊断标准对人选病例进行评定：确诊38例（37.6％）,疑似57例（56.4％）,排除6例（5.9％）。结论抗结核药致肝损伤的临床特点符合急性药物性肝损伤的临床规律。我国急性药物性肝损伤临床诊断方法简便,町操作性强,与RUCAM评分有较强的相关性。     

中草药和相关保健食品引起药物性肝病的研究

目的 分析因服用中草药或含草药成分的保健食品引起肝损害的情况。方法收集1982年至2005年诊断为“药物性肝病”患者82例。诊断根据为病史、药物史、临床表现、肝功能及其他实验室检查。最后回顾诊断，按药物性肝损伤评分进行评估。结果24年中诊断的82例“药物性肝病”患者占同期因肝功能异常住院患者的2．2％。其中男性28例，女性54例，年龄16～81岁．平均（50．1±16．9）岁。服用的与肝损伤有关药物中，减肥保健品占30．5％、皮肤科用药占12．2％、抗风湿病用药占8．5％、心血管用药占8．5％、妇科疾病用药占7．3％、肝病药占6．1％、调节血脂药占6．1％、乳房小叶增生药占3．7％、甲状腺肿块用药占3．7％、其他用药占13．4％。用药疗程6d～6个月不等．潜伏期6d～3个月。临床表现中，肝细胞损伤型占36．59％、胆汁淤积型占39．02％，其他为混合型，尚有10％的患者同时伴有变态反应表现。所有患者在停药后一般病情恢复较快，预后良好。结论中药和草药是引起药物性肝病的重要原因，应提高临床医师对药物引起肝损伤的认知及在治疗过程中加强监测。     

186例药物性肝损伤组织病理学及临床特征分析

目的探讨药物性肝损伤的组织病理学特点及临床特征,为早期诊治提供帮助。方法回顾性分析186例经肝活组织穿刺病理学诊断的药物性肝损伤患者的用药史、病理特点、临床表现、生化、血清学标志以及治疗转归等。结果引起药物性肝损伤前3位的药物是中药91例（49％）、抗生素41例（22％）、解热镇痛药23例（12．4％）;临床分类：药物性肝功能衰竭8例（4．4％）、急性药物性肝损伤93例（50％）、慢性药物性肝损伤83例（44．6％）、药物性肝硬化2例（1．1％）;临床分型：肝细胞损伤型98例（52．7％）、胆汁淤积型35例（18．8％）、混合型55例（29．6％）。病理学特征主要表现为：肝细胞坏死、汇管区扩大、肝细胞脂肪变性、汇管区或窦周混合炎细胞浸润、嗜酸性粒细胞浸润、肝细胞胆汁淤积、肝细胞凋亡、可见吞噬色素的Kuffer细胞。治愈79例（42．5％）,好转102例（54．8％）,无效5例（2．7％）。无一例患者死亡或病情恶化。结论引起药物性肝损伤的首位药物为中药,临床表现无特异性,但组织病理学改变有一定特征。     

老年药物性肝损伤139例临床分析

目的回顾性分析解放军302医院2003年-2010年间老年药物性肝损伤的临床特点。方法将患者分为老年组（139例）和中青年组（105例）,比较二者之间的临床特征和生化学指标。结果导致药物性肝损伤的药物有14种,老年组药物性肝损伤前5位的药物分别是中药（31．7％）、抗生素（13．7％）、解热镇痛药（12．2％）、心血管药（11．5％）和抗结核药（6．5％）;而中青年组则是中药（43．8％）、解热镇痛药（18．1％）、抗生素（13_3％）、抗结核药（6．7％）和治疗甲状腺功能亢进药（4．8％）,两组之间存在统计学差异。老年组y-谷氨酰基转肽酶及治愈患者平均住院时间均较中青年组为高。老年组黄疸发生率为77．1％,肝衰竭发生率为2．9％;中青年组黄疸发生率82．0％,肝衰竭发生率为4．8％,二者之间无统计学差异。老年组肝损伤类型分别为胆汁淤积型（45．9％）、肝细胞型（28．6％）和混合型（25．5％）,中青老年组上述3种损伤类型分别为39．3％、34．8％和25．8％,两组间无统计学差异。结论导致药物性肝损伤的药物以中药占首位,老年与中青年患者药物性肝损伤均以胆汁淤积型为主,有少数患者可发展为肝衰竭,老年患者临床治愈时间长;建议对中药、抗生素、解热镇痛药等易导致肝损伤的药物慎重选用;预防措施之一是用药后要定期检测肝功能的峦化．     

药物性肝损伤394临床特点分析

目的：探讨药物性肝损伤的临床特点。方法回顾性分析2009年1月至2011年1月本院收治的394例药物性肝损伤患者的年龄、性别、肝损伤药物种类和名称、发病时间、肝功能、是否肝活组织检查、治疗情况及预后。结果药物性肝损伤病例呈逐年上升趋势。394例患者中男170例（43．15％）,女224例（56．85％）,男女发病比例为1∶1．3。高发年龄段为41～50岁（25.63％）及51～60岁（25．13％）。能引起药物性肝损伤的药物有很多种,居前3位的依次为：中药（45．43％）、多药联合应用（11.42％）及抗结核药（7．61％）。中药类别以治疗骨关节病中药（11％）和皮肤病中药（11％）为主,中药名称及成分多数不明。43例患者行病理检查确诊,占10．91％。较多见的病理改变为：中性粒细胞和嗜酸性粒细胞浸润（65．01％）,毛细胆管性淤胆（39.93％）等,对临床诊断无特异性,有一定提示意义。394例患者中,治愈102例,占25．89％;好转184例,占46．70％。发生肝衰竭最终死亡的患者7例,占1.78％。总体预后较好,预后影响因素包括：年龄、临床分型、起病时TBil峰值等。结论致药物性肝损伤的药物种类繁多,临床表现缺乏特异性,诊断无金标准,故易漏诊及误诊,多数预后较好,但少数病例可发生肝衰竭。     

102例药物性肝损伤临床流行病学分析

目的：探讨药物性肝损伤（DILI）临床流行病学特征。方法对2005年1月至2012年12月期间成都军区机关院消化内科门诊就诊患者中 DILI 进行临床流行病学调查,对诊断为 DILI 的102例患者进行临床流行病学分析。结果DILI 占该门诊病人总数及肝功能损伤者的比例分别为0．27％、7．1％,女性（0．35％、10．2％）高于男性（0．20％、5．0％）（P＜0．01,P＜0．001）。临床分型分别为肝细胞型肝损伤（59．8％）,胆汁淤积型肝损伤（14．7％）,混合型肝损伤（25．5％）。常见药物病因分别为中草药（28．4％）、抗生素（20．6％）、各种保健药（9．8％）等。发病年龄以≥45岁者居多（78．0％）,而用药到发病时间以2周至1个月者多见（52．9％）。常见临床表现分别为乏力55例（53．9％）、黄疸45例（44．1％）、食欲不振40例（39．2％）等。结论DILI 已成为较为常见的肝功能损害因素,临床上无特征性表现,药物病因涉及面较广,有必要提高对该病的预防及诊治能力。     

276例药物性肝损伤的病因和临床表现分析

目的探讨药物性肝损伤的病因及临床特点，以提高临床医师对该病的认识。方法对2000-2005年本院的药物性肝损伤病例276例进行回顾性研究，分析其所用药物，临床表现和转归等特点。结果引起肝损伤的药物种类繁多，中药占首位（26．1％），其次为抗肿瘤药物（17％）；引起的肝损伤以轻、中度为主，临床表现主要为乏力、纳差，尿黄，恶心和右上腹不适等；治疗后，88％治愈好转，而病死率为5．1％。结论致肝损伤的药物种类繁多，临床表现无特异性，但病死率较高，临床医师用药时应注意监测肝功能。     

药物性肝损伤98例临床分析

［摘要］　目的　通过分析药物性肝损伤（DILI）的临床特点，以提高对药物性肝损伤的认识及重视。方法　连续收集98例药物性肝损伤患者，根据服药史、临床表现、肝功能、血清肝炎病毒标志物、B超及停用已知或可疑药物后疾病的转归特点等指标进行分析。结果　药物性肝损伤无明显性别差异，年龄以40岁以上者多见，占75.51%。导致药物性肝损伤前三位药物依次为中草药（41.84%）、解热镇痛消炎药（14.29%）、抗生素（11.22%）。肝功能检测几乎都有转氨酶升高，以谷丙转氨酶（ALT）升高为主（92.86%），ALT≥500 U/L者占59.18%。胆红素升高占85.71%，以直接胆红素升高为主（64.29%）。发生药物性肝损伤的时间因药物种类不同而异，最快发生在用药后5 d，最慢发生在用药后10月余，多发生在3个月内。药物性肝损伤预后良好，无死亡病例，及时停药为治疗的关键。结论　药物性肝损伤的临床表现无特异性，以肝细胞损伤及胆汁淤积为主要表现，详细询问用药史至为重要，单纯药物性肝损伤预后良好。     

两种国际诊断标准对230例药物性肝损害诊断的分析比较

目的分析比较我国药物性肝损害常用的两种国际诊断标准诊断的准确性。方法采用回顾性调查方法，总结分析引起药物性肝损害常用药物的种类。用Danan的药物性肝损害相关评价标准与Mafia评分标准，对230例药物性肝损害患者进行重新诊断，比较这两种诊断方法的差异。结果230例患者中引起药物性肝损害的常用药物依次为：中药类、抗生素、解热镇痛类、抗结核药、心血管类、保健药、精神类药、皮肤病类、降糖药等。230例患者以Danan的药物性肝损害相关评价进行诊断，有149例（64．8％）为药物引起的肝损害，不能确定的有71例（30．9％），非药物引起的肝损害有10例（4．3％）；以Maria评分标准进行诊断，确定为药物性肝损害的无一例患者，可能性大的有55例（23．9％），不能确定、仅仅为可能的126例（54．8％），可能性小的有33例（14．3％），可除外药物性肝损害的有16例（7．0％）。结论Danan的药物性肝损害相关评价标准与临床诊断符合率比Maria评分标准高，但还需进行改进修正。     

Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions

BACKGROUND/AIM: Due to an absence of specific markers, the diagnosis of drug-induced hepatotoxicity is necessarily based on circumstantial evidence and is often inaccurate. We have evaluated the use of the clinical diagnostic scale (CDS) in the causality assessment of hepatotoxic adverse drug reaction (ADR) reports. METHODS: 135 hepatic adverse ADRs reported to the Committee on Safety of Medicines in North East England 1992-6 were evaluated. Initially, "International Consensus Criteria" were used to classify reactions as "drug-related", "drug-unrelated" and "indeterminate". Using the CDS, each ADR was then categorised as either definite drug hepatotoxicity (score >17), probable (14-17), possible (10-13), unlikely (6-9), or drug hepatotoxicity excluded (<6). RESULTS: 49 ADRs were considered drug-related, 65 unrelated and 21 indeterminate. Reports classified as drug-related by consensus criteria scored higher on the CDS, with a median score of 12, range: 8-15, than either the indeterminate (8; [3-12]) or drug-unrelated reports (5; [2-11]) (p<0.0001). A CDS score of >9, identified 88% of the cases classified as drug-related hepatotoxicity by consensus criteria and excluded 98% of those unrelated to the drugs. CONCLUSIONS: CDS scoring correlates well with the international consensus classification and may be a useful tool in the routine evaluation of suspected hepatotoxic drug reactions.     

Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden

OBJECTIVE: There are only a few data on the prevalence of drug-induced liver injury associated with fatal outcome. The aim of this study was to determine the nature and number of suspected adverse drug-induced liver disease associated with fatalities and/or liver transplantation since reporting of adverse drug reactions (ADRs) started in Sweden. MATERIAL AND METHODS: All reports of suspected hepatic ADRs with fatal outcome received by the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) from 1966 to 2002 were reviewed and causality assessed. RESULTS: The SADRAC received 151 reports of suspected ADRs with fatal outcome from liver injury; 48 cases were either unlikely or excluded. Of the remaining 103 cases, 13 (13%) were highly probable, 48 (47%) probable and 42 (41%) possible. The median age of the 103 patients was 64 years (47-77 interquartile range (IQR)) and 59 (57%) were males. The majority of cases were classified as hepatocellular (75%), with only 15% cholestatic and 10% mixed. Halothane, paracetamol, flucloxacillin, sulfamethoxazole/trimethoprim and diclofenac were the most common drugs associated with fatal outcome. Seventeen patients underwent liver transplantation, most commonly because of paracetamol and disulfiram toxicity. CONCLUSIONS: A wide range of suspected ADRs are associated with fatalities. Antibiotics and analgesics are associated with the greatest number of reports of deaths.     

急性药物性肝损伤的治疗及临床转归分析

目的探讨急性药物性肝损伤的治疗及预后情况,查找有用的信息及线索,以指导临床实践。方法采用国际共识标准,回顾性分析近5年来本院179例急性药物性肝损伤住院患者的临床资料,并按其不同临床类型分析其治疗方法及临床转归。结果本研究中有肝细胞型137例(76.11%),胆汁淤积型24例(14.33%),混合型18例(10.56%)。多数病例(173例)给予停药或换用其他药物,6例肝损伤较轻且不宜停药者未停药。所有病例均应用一种或多种护肝药;发展至重症肝损伤者给予补充血浆、白蛋白;有并发症(如肝性脑病)者给予相应治疗;有手术指征且经济条件允许、供肝条件允许者行同种异体肝移植术。其中好转154例(86.03%),肝细胞型、胆汁淤积型、混合型分别为121例、20例、13例。未愈25例(13.97%),3种类型分别为16例、4例、5例。在未愈患者中,有4例肝功能于3月内恢复正常;15例患者出院时肝功仍高,且未复查;6例(3.35%)发展为重症肝损伤,包括肝细胞型5例,混合型1例,预后差。3种类型的好转率分别为88.32%、83.33%、72.22%,其差别无统计学意义(P>0.05)。值得注意的是,同时伴有胆红素升高的肝细胞型药物性肝损伤(43例)有5例(11.63%)发展至重症肝损伤,与总体相比差别有统计学意义(P=0.04)。结论急性药物性肝损伤经及时停药及护肝治疗一般预后较好,但发展至重症肝损伤者预后差;急性药物性肝损伤等3种类型预后之间的差异无统计学意义,但可能与本研究病例数尚少有关;同时伴有胆红素升高的肝细胞型药物性肝损伤预后较差。     

特异质型药物性肝损伤病因评估及生物标志物的研究进展

特异质型药物性肝损伤是少数特异性体质人群发生的药物性肝损伤。对于疑似特异质型药物性肝损伤的诊断,目前主要依靠排他性诊断,临床中易被误诊或漏诊。近年来对于特异质型药物性肝损伤的病因评估及生物标志物的研究取得了一定的进展。本文主要针对目前特异质型药物性肝损伤的病因评估方法及具有应用前景的诊断生物标志物的研究进展进行总结,为今后特异质型药物性肝损伤诊断提供思路。     

Criteria of drug-induced liver disorders. Report of an international consensus meeting

International reporting of adverse drug reactions by pharmaceutical manufacturers to national drug regulatory authorities requires internationally accepted standard definitions of reactions and criteria for assessment of causality. The Council for International Organizations of Medical Sciences (CIOMS) undertook a pilot project to prepare such definitions and criteria, and proposed to use as its model a series of expert consensus meetings organized in France by the pharmaceutical company, Roussel Uclaf, with the participation of the official French network of pharmacovigilance. Under CIOMS auspices, an international meeting was organized to test the feasibility of adapting for international use the outcome of the French consensus meetings on drug-induced liver disorders. The meeting resulted in a series of proposed standard designations of drug-induced liver disorders and criteria of causality assessment.     

Modified diagnostic criteria of drug-induced liver injury proposed by the international consensus meeting

BACKGROUND/AIMS: The usefulness of the diagnostic criteria of the International Consensus Meeting (criteria A) has been previously reported. However, these criteria are not clinically adaptable in Japan where allergic reaction is one of the major etiologies of drug-induced liver injury and thus it was revised and reported in the Digestive Disease Week-Japan of 2002 as DDW-J criteria (criteria B). It remains controversial whether the revised criteria can exclude drugs not causing liver injury. METHODOLOGY: Two new diagnostic criteria (criteria C and D) were designed to supplement the DDW-J criteria. Usefulness and limitations of the four criteria were retrospectively examined using cases of drug-induced liver injury experienced in 8 hospitals. RESULTS: It was confirmed that the sensitivity of criteria B is excellent for diagnosis of drug-induced liver injury. However, diagnostic criteria B were found to be disadvantageous in relation to specificity, while diagnostic criteria D were disadvantageous in relation to sensitivity. Sensitivity of diagnostic criteria C was a little superior to that of diagnostic criteria A. CONCLUSIONS: On the basis, the significant sensitivity of criteria B was confirmed again, however, modification should be done for increasing specificity. Criteria C appear to be the best for their sensitivity and specificity.     

Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden

Objective. There are only a few data on the prevalence of drug-induced liver injury associated with fatal outcome. The aim of this study was to determine the nature and number of suspected adverse drug-induced liver disease associated with fatalities and/or liver transplantation since reporting of adverse drug reactions (ADRs) started in Sweden.Material and methods. All reports of suspected hepatic ADRs with fatal outcome received by the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) from 1966 to 2002 were reviewed and causality assessed.Results. The SADRAC received 151 reports of suspected ADRs with fatal outcome from liver injury; 48 cases were either unlikely or excluded. Of the remaining 103 cases, 13 (13%) were highly probable, 48 (47%) probable and 42 (41%) possible. The median age of the 103 patients was 64 years (47–77 interquartile range (IQR)) and 59 (57%) were males. The majority of cases were classified as hepatocellular (75%), with only 15% cholestatic and 10% mixed. Halothane, paracetamol, flucloxacillin, sulfamethoxazole/trimethoprim and diclofenac were the most common drugs associated with fatal outcome. Seventeen patients underwent liver transplantation, most commonly because of paracetamol and disulfiram toxicity.Conclusions. A wide range of suspected ADRs are associated with fatalities. Antibiotics and analgesics are associated with the greatest number of reports of deaths.     

Drug‐induced liver disease: an 8‐year study of patients from one gastroenterological department

OBJECTIVE: To analyze drug‐induced liver disease over an 8‐year period from January 2000 to December 2007 in one gastroenterological department. METHODS: International consensus of standard definitions and criteria for assessing causality of adverse drug reactions were applied to all patients with abnormal hepatic test results. RESULTS: Drugs were implicated in hepatic injury in 30 patients (15 men and 15 women) in whom there was a causal or highly probable relationship between drug use and liver disease. The drugs responsible for liver damage were Chinese medicinal herbs (n = 12), cyclosporin (n = 2), fosfomycin, gentamicin, flutamide, acipimox and nimesulide (n = 1 each). Of the 30 patients, 19 (63.3%) were classified as having hepatocellular or mixed hepatitis, eight (26.7%) as having cholestatic injury and the remaining three as having a severe hepatic drug reaction (prothrombin < 50%), including death. CONCLUSION: A thorough history of medication should be taken in all patients presenting with abnormal hepatic test results. Chinese medicinal herbs were the most frequent hepatotoxic factor in our patients, although the liver injury was not severe in most cases and was relieved after the prompt withdrawal of the suspected drug.