抗结核药所致药物性肝损伤诊断与处理.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,抗结核药所致药物性肝损伤诊断与,处理,专家,建议,2013,定义,临床分型,临床表现,相关危险因素,发生机制,诊断,处理,发生率,目录,在结核病抗结核治疗过程中可能会出现各种不同程度的药物不良反应,，其中,以抗结核药所致药物性肝损伤（,drug-induced liver injury,，,DILI,）最为多见，危害性最大，也是我国,DILI,的常见类型,之一,部分患者因此不得不中止抗结核治疗,从而影响结核病的治,疗效果,临床医生应高度重视这个问题,轻,者 表现,为一过性转氨酶升高,重,者 可,致肝衰竭,甚至危及生命,概述,抗结核药所致,DILI,是指在使用抗结核药过程中，由于药物或其代谢产物引起的肝细胞毒性损伤或肝脏对药物及其代谢产物的变态反应所致病理过程。,临床表现,可以表现为无症状丙氨酸转氨酶（,ALT,）升高，也可呈急性肝炎表现，甚至发生暴发性肝细胞坏死，少数患者可表现为慢性肝炎,生,化学指标,ALT2,倍正常值上限（,ULN,）或结合胆红素,2,倍,ULN,；或天冬氨酸转氨酶（,AST,）、碱性磷酸酶（,ALP,）和总胆红素同时升高，且至少,1,项,2,倍,ULN,一、抗结核药所致,DILI,的,定义,各国报告的抗结核药所致,DILI,发生率不同，这种差别,可能与以下四个因素有关,研究的标准,地理位置,社会经济状况,种族,研究者对,DILI,的诊断标准、病毒性肝炎的,流行预防性,保肝治疗和研究对象不同等因素,有关,二、抗结核药所致,DILI,的,发生率,印度的抗结核药所致,DILI,发生率较高（,8%10%,）,西方国家,较低,美国,50%,为高度,提示,30,d,内下降,50%,为重要,提示,胆汁淤积,型,血清,ALP,或,总,TBIL,值,180,d,内下降,50%,为重要提示,七、抗结核药所致,DILI,的,诊断,排除其他因素,01,02,04,03,须,排除其他病因,或,疾病,所致的肝损伤,七、抗结核药所致,DILI,的,诊断,再次用药,01,02,04,03,有,再次用药后肝损伤复发,史,肝,酶活性水平升高,2,倍,ULN,符合,上述诊断标准中,第,1,、,2,、,3,项,或,前,3,项中有,2,项符合，加上,第,4,项,均,可确诊为抗结核药所致,DILI,七、抗结核药所致,DILI,的,诊断,确诊病例,疑似病例,七、抗结核药所致,DILI,的,诊断,用药,与肝损伤之间存在合理的时序,关系,但,同时存在可能导致肝损伤的其他病因或疾病状态,01,02,七、抗结核药所致,DILI,的,诊断,用药,与肝损伤之间存在合理的时序,关系,但,同时存在可能导致肝损伤的其他病因或疾病状态,01,02,建议采用,1993,年修订的国际共识意见,的,RUCAM,进行,量化评估,（,1,）药物治疗与发生肝损伤的时间：,次治疗,590 d,，后续治疗,115,d,（,+2,分,）,初次治疗,90 d,，后续治疗,15,d,（,+1,分,）,停药时间,15,d,（,+1,分,）,（,2,）撤药反应：,药后,8 d,内,ALT,从峰值下降,50,%,（,+3,分,）,停药后,30 d,内,ALT,从峰值下降,50,%,（,+2,分,）,停药,30 d,后,ALT,从峰值下降,50,%,（,0,分,）,停药,30 d,后,ALT,峰值下降,50,%,（,2,分,）,（,3,）危险因素：,饮酒或,妊娠 （,+1,分）,无饮酒或,妊娠 （,0,分,）,年龄,55,岁 （,+1,分,）,年龄,2,倍,ULN,（,+2,分,）,可疑阳性：再用药后,ALT,升高,2,倍,ULN,，同时合并使用其他,药物 （,+,1,分,）,阴性：再用药后,ALT,升高,8,分为极有可能，,68,分为很可能有关，,35,分为可能有关，,12,分为可能无关，,0,分为,无关,七、抗结核药所致,DILI,的,诊断,诊断依据,诊断标准,鉴别诊断,七、抗结核药所致,DILI,的,诊断,抗结核药,所致,DILI,需与,病毒性肝炎,巨细胞病毒感染,、,EB,病毒,感染,自身免疫,性肝炎、酒精性肝病和血吸虫性肝病等进行鉴别,七、抗结核药所致,DILI,的,诊断,01,及时调整抗结核方案,02,保证患者抗结核治疗的顺利完成,03,有助于提高抗结核治疗的,完成率和,治愈率,04,防止耐药结核病的发生,正确的处理,及时,纠正肝功能异常,逆转,肝功能,损伤,本共识仅介绍原则性问题的处理,，提供,5,点参考,八、抗结核药所致,DILI,的,处理,01,02,03,04,05,抗结核药所致,DILI,处理,原则,预防,治疗,肝功能,恢复中和恢复后,的,抗结核药,物应用,预后,八、抗结核药所致,DILI,的,处理,治疗,前应综合评估患者,的,结核病,病情、肝损伤程度,、,相关,危险因素及全身状况等,仅,ALT3,倍,ULN,，无明显,症状、无黄疸,可,在密切观察下保肝,治疗,并,酌情停用肝损伤发生频率高的抗结核药物,ALT,3,倍,ULN,，或总胆红素,2ULN,应,停用有关抗结核药物，保肝治疗，密切观察,ALT,5,倍,ULN,，或,ALT3,倍,ULN,伴有黄疸、恶心、呕吐,、,乏力,等症状，或总胆红素,3,倍,ULN,应,立即停用所有抗结核药物，积极保肝,治疗,严重,肝损伤患者应住院采取综合治疗,措施,有,肝功能衰竭表现时应积极采取抢救措施,。,N,o,.,1,N,o.2,N,o.3,N,o.4,八、抗结核药所致,DILI,的,处理,处理,原则,预防,治疗,肝功能,恢复中和恢复后,的,抗结核药,物应用,预后,01,02,03,04,05,抗结核药所致,DILI,八、抗结核药所致,DILI,的,处理,抗结核药所致,DILI,是影响抗结核治疗成败的重要因素之一，有效的预防可减少,DILI,的发生。,3,2,6,5,1,4,1,抗,结核治疗前应详细询问既往用药史，有无酗酒史和肝病史等，同时应进行较全面的检查，包括肝脏生化指标、肝炎病毒血清免疫标志物检查等，必要时进行肝脏、胆囊影像学检查等,八、抗结核药所致,DILI,的,处理,抗结核药所致,DILI,是影响抗结核治疗成败的重要因素之一，有效的预防可减少,DILI,的发生。,3,2,6,5,4,2,有高危因素的患者需谨慎选用抗结核药物，尽量少用或慎用肝损伤发生频率较高的抗结核药物,八、抗结核药所致,DILI,的,处理,抗结核药所致,DILI,是影响抗结核治疗成败的重要因素之一，有效的预防可减少,DILI,的发生。,3,6,5,4,八、抗结核药所致,DILI,的,处理,抗结核药所致,DILI,是影响抗结核治疗成败的重要因素之一，有效的预防可减少,DILI,的发生。,6,5,4,八、抗结核药所致,DILI,的,处理,抗结核药所致,DILI,是影响抗结核治疗成败的重要因素之一，有效的预防可减少,DILI,的发生。,6,5,八、抗结核药所致,DILI,的,处理,抗结核药所致,DILI,是影响抗结核治疗成败的重要因素之一，有效的预防可减少,DILI,的发生。,6,八、抗结核药所致,DILI,的,处理,处理,原则,预防,治疗,肝功能,恢复中和恢复后,的,抗结核药,物应用,预后,01,02,03,04,05,抗结核药所致,DILI,八、抗结核药所致,DILI,的,处理,01,02,03,04,05,06,07,08,保肝治疗,降酶治疗,一般处理,降低胆红素,改善,肝细胞能量代谢,促肝细胞生长和,肝功能替代疗法,糖皮质激素,中草药,双环醇,：,具有,抗炎、抗氧化、保护肝细胞膜及细胞器等作用，临床应用可改善肝脏生物化学,指标,双,环醇除抗炎保肝作用外，也具有明显的降酶作用,八、抗结核药所致,DILI,的,处理,处理,原则,预防,治疗,肝功能,恢复中和恢复后,的,抗结核药,物应用,预后,01,02,03,04,05,抗结核药所致,DILI,八、抗结核药所致,DILI,的,处理,肝功能,恢复中和恢复后如何应用抗结核药物，国内外均无统一的规定和标准,对于,这个问题本专家组认为，应根据患者的肝损伤程度、有无肝损伤相关危险因素和结核病严重程度等进行综合判断，并参考,ATS,建议、,英国胸科学会指南,提出以下几点,建议,八、抗结核药所致,DILI,的,处理,抗结核药所致药物性肝损伤诊断与处理的专家建议,1,2,对于仅表现为单纯,ALT,升高的肝损伤,患者,待,ALT,降至,3,倍,ULN,时，可加用链霉素或阿米卡星、异烟肼和乙胺丁醇，每周复查肝功能，若肝功能进一步恢复则加用利福平或利福喷丁，待肝功能恢复正常后，视其基础肝脏情况等考虑是否加用吡嗪酰胺,3,对于肝损伤合并过敏反应（同时有发热、皮疹等）的,患者,待机,体过敏反应全部消退后再逐个试用抗结核药物，试药原则：可先试用未曾用过的药物，此后按照药物致敏可能性由小到大逐步,试药,对于,ALT,升高伴有总胆红素升高或黄疸等症状的,患者,待,ALT,降至,3,倍,ULN,及总胆红素,2,倍,ULN,时，可加用链霉素或阿米卡星、乙胺丁醇和氟喹诺酮类药物，若肝功能进一步恢复则加用异烟肼，待肝功能恢复正常后，视其结核病严重程度及基础肝脏情况等考虑是否加用利福喷丁或吡嗪酰胺,肝功能,恢复中和恢复后,的,抗结核药,物应用,处理,原则,预防,治疗,01,02,03,04,05,抗结核药所致,DILI,预后,八、抗结核药所致,DILI,的,处理,01,03,02,02,大部分,抗结核药所致,DILI,患者经过正确、及时的治疗可以治愈，仅有少数患者发展成肝功能衰竭，严重者可致死亡，病死率报道不一,对,氨基水杨酸钠过敏反应者如不及时停药可发生重症肝炎，病死率可达,21%,。溶血进行性加重者的病死率更高,年龄,、性别、,ALT,升高水平、,HIV,或,HBV,感染并不影响抗结核药所致,DILI,的预后，而抗结核治疗时间、肝性脑病和腹水、血清胆红素水平、血清白蛋白水平、血肌酐水平、凝血酶原时间标准化比值及白细胞计数等均与,DILI,预后有关，伴有黄疸、肝性脑病和腹水的患者病死率较高,八、抗结核药所致,DILI,的,处理,1,唐神结，高文,.,临床结核病学,.,北京：人民卫生出版社，,2011,：,191-200.,2,肖东楼，马玙，朱莉贞,.,抗结核药品不良反应诊疗手册,.,北京：人民卫生出版社，,2010,：,14-62.,3,刘,旭东，王炳元,.,我国药物性肝损害,20032008,年文献调查分析,.,临床误诊误治，,2010,，,23,：,487-488,.,4,夏,愔愔，詹思延,.,国内抗结核药物不良反应发生率的综合分析,.,中华结核和呼吸杂志，,2007,，,30,：,419-423,.,5,谢莉，高微微，卜建玲，等,702,例抗结核药物所致不良反应分析中国防痨杂志，,2008,，,30,：,275-278,.,6,中华医学会消化病学分会肝胆疾病协作组,.,急性药物性肝损伤诊治建议（草案,.,中华消化杂志，,2007,，,27,：,765-767.,7,陈新谦，金有豫，汤光,.,新编药物学,.17,版,.,北京：人民卫生出版社，,2011,：,504-517.,8,陈悦，龚作炯,.,肝脏疾病诊疗进展,.,武汉：湖北科学技术出版社，,2008,：,234-235.,9,罗雁，陈营清，孙丽，等,.,抗结核药致药物性肝损伤的临床分析,.,中华传染病杂志，,2007,，,25,：,247-249.,主要参考文献,中文,4,Saukkonen,JJ,Cohn 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