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Acute-on-chronic liver failure (ACLF) is an acute decompensated syndrome that occurs on the basis of chronic liver disease, with rapid disease progression and poor prognosis, thus being an important cause of death in patients with cirrhosis. Predisposing factors play an important role in the occurrence, progression and prognosis of ACLF, which are heterogeneous in different definitions and regions. With the development of medical and health services and changes in lifestyles, the composition of predisposing factors also changes. These factors cause damage to organ function in various ways, leading to different types of organ failure and prognosis. Early warning of the predisposing factors can prevent the occurrence of ACLF. Actively removing predisposing factors can improve the prognosis of ACLF. Reasonable management of precipitating factors is important for ACLF.

, correspAuthors=Yu Chen, authorNote=null, correspAuthorsNote=
E-mail:
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慢加急性肝衰竭(ACLF)是在慢性肝病基础上发生的一种急性失代偿综合征,病情进展迅速,预后不佳,是肝硬化患者死亡的重要原因。诱发因素在ACLF的发生、发展及预后中有重要作用,不同标准下的ACLF对诱因的定义有所差别,地区之间也存在一定异质性。随着医疗卫生事业的发展及生活方式的改变,ACLF诱因的构成也不断发生变化。诱发因素通过多种途径对器官功能造成损伤,导致的器官衰竭种类及预后也存在差异性,早期预警诱发因素可预防ACLF的发生,积极去除诱发因素可改善ACLF的预后,合理管理诱发因素对ACLF患者有积极意义。

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杨颜榕,硕士研究生,主要从事肝衰竭防治方面的研究

陈煜,主任医师,教授,博士研究生导师,中华医学会肝病学分会副秘书长、重肝及人工肝学组副组长,全国疑难及重症肝病协作组副组长,全国重型肝病及人工肝血液净化攻关协作组副组长,中国研究型医院学会肝病专业委员会重症肝病学组副组长,中国重症血液净化协作组副主任委员、人工肝学组组长;曾荣获北京市科技新星,北京市卫生局“十百千”卫生百名人才,北京市卫生系统高层次卫生技术人才,北京市优秀人才等称号。

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杨颜榕,硕士研究生,主要从事肝衰竭防治方面的研究

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陈煜,主任医师,教授,博士研究生导师,中华医学会肝病学分会副秘书长、重肝及人工肝学组副组长,全国疑难及重症肝病协作组副组长,全国重型肝病及人工肝血液净化攻关协作组副组长,中国研究型医院学会肝病专业委员会重症肝病学组副组长,中国重症血液净化协作组副主任委员、人工肝学组组长;曾荣获北京市科技新星,北京市卫生局“十百千”卫生百名人才,北京市卫生系统高层次卫生技术人才,北京市优秀人才等称号。

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陈煜,主任医师,教授,博士研究生导师,中华医学会肝病学分会副秘书长、重肝及人工肝学组副组长,全国疑难及重症肝病协作组副组长,全国重型肝病及人工肝血液净化攻关协作组副组长,中国研究型医院学会肝病专业委员会重症肝病学组副组长,中国重症血液净化协作组副主任委员、人工肝学组组长;曾荣获北京市科技新星,北京市卫生局“十百千”卫生百名人才,北京市卫生系统高层次卫生技术人才,北京市优秀人才等称号。

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Hepatology, 2015, 62(1): 232-242., articleTitle=Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults, refAbstract=null), Reference(id=1203061236033364327, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, doi=null, pmid=null, pmcid=null, year=2021, volume=74, issue=5, pageStart=1097, pageEnd=1108, url=null, language=null, rfNumber=[25], rfOrder=25, authorNames=Trebicka J, Fernandez J, Papp M, journalName=J Hepatol, refType=null, unstructuredReference=Trebicka J, Fernandez J, Papp M, et al. PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis[J]. J Hepatol, 2021, 74(5): 1097-1108., articleTitle=PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis, refAbstract=null)], funds=[Fund(id=1203061231428018353, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, awardId=DFL20221501, language=EN, fundingSource=Beijing Hospitals Authority’s Ascent Plan(DFL20221501), fundOrder=null, country=null), Fund(id=1203061231558041783, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, awardId=DFL20221501, language=CN, fundingSource=北京市医院管理中心“登峰”计划专项(DFL20221501), fundOrder=null, country=null), Fund(id=1203061231692259518, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, awardId=, language=EN, fundingSource=Construction Project of High-level Technology Talents in Public Health(Discipline leader-01-12)(), fundOrder=null, country=null), Fund(id=1203061231847448775, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, awardId=, language=CN, fundingSource=北京高层次公共卫生技术人才建设项目(学科带头人-01-12)(), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1203061226239664161, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, xref=null, ext=[AuthorCompanyExt(id=1203061226256441378, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, companyId=1203061226239664161, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Difficult and Complicated Liver Diseases and Artificial Liver Center/Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing You'an Hospital Affiliated to Capital Medical University, Beijing 100069, China), AuthorCompanyExt(id=1203061226273218595, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, companyId=1203061226239664161, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=首都医科大学附属北京佑安医院肝病中心四科/肝衰竭与人工肝治疗研究北京市重点实验室,北京 100069)])], figs=[ArticleFig(id=1203061230815649938, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, language=EN, label=Tab. 1, caption=

Definitions for ACLF in different standards

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指南定义基础肝病诱发因素器官衰竭
APASL[5]急性肝损伤引起的肝功能损伤,表现为黄疸及凝血功能障碍,发病4周内并发腹水或肝性脑病,与28 d高病死率有关慢性肝病、代偿期肝硬化HBV再激活、药物、自身免疫性肝病等引起肝功能损伤的因素肝内器官衰竭伴或不伴肝外器官衰竭
EASL-CLIF[6]以肝功能急性失代偿、器官衰竭及短期高病死率为特征代偿期及失代偿期肝硬化肝内诱因(HBV再激活、饮酒)肝外诱因(感染、消化道出血、手术)肝内器官衰竭和(或)肝外器官衰竭
WGO共识[2]急性肝功能失代偿导致肝衰竭及一个或多个肝外器官衰竭,伴28 d至3个月高病死率慢性肝病、代偿期肝硬化、失代偿期肝硬化未声明未声明
ACG[3]慢性肝病伴或不伴肝硬化患者的潜在可逆性疾病,可能导致多器官衰竭及3个月内死亡慢性肝病、代偿期肝硬化、失代偿期肝硬化肝内诱因(HBV再激活、饮酒)肝外诱因(感染、手术)肝内器官衰竭肝外器官衰竭
), ArticleFig(id=1203061230937284756, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, language=CN, label=表1, caption=

不同标准中的ACLF定义

, figureFileSmall=null, figureFileBig=null, tableContent=
指南定义基础肝病诱发因素器官衰竭
APASL[5]急性肝损伤引起的肝功能损伤,表现为黄疸及凝血功能障碍,发病4周内并发腹水或肝性脑病,与28 d高病死率有关慢性肝病、代偿期肝硬化HBV再激活、药物、自身免疫性肝病等引起肝功能损伤的因素肝内器官衰竭伴或不伴肝外器官衰竭
EASL-CLIF[6]以肝功能急性失代偿、器官衰竭及短期高病死率为特征代偿期及失代偿期肝硬化肝内诱因(HBV再激活、饮酒)肝外诱因(感染、消化道出血、手术)肝内器官衰竭和(或)肝外器官衰竭
WGO共识[2]急性肝功能失代偿导致肝衰竭及一个或多个肝外器官衰竭,伴28 d至3个月高病死率慢性肝病、代偿期肝硬化、失代偿期肝硬化未声明未声明
ACG[3]慢性肝病伴或不伴肝硬化患者的潜在可逆性疾病,可能导致多器官衰竭及3个月内死亡慢性肝病、代偿期肝硬化、失代偿期肝硬化肝内诱因(HBV再激活、饮酒)肝外诱因(感染、手术)肝内器官衰竭肝外器官衰竭
), ArticleFig(id=1203061231050530973, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, language=EN, label=Tab. 2, caption=

Mechanism of liver injury caused by different drugs

, figureFileSmall=null, figureFileBig=null, tableContent=
药物种类造成肝损伤的机制
补充及替代药物
 中草药促进肝活性物质的代谢[21]
 合成代谢类固醇药物对胆盐或其他药物转运体的直接毒性而造成肝损伤[20]
抗结核药物干扰肝脏脂代谢;影响胆汁运输
抗感染药物干扰肝脏脂代谢;可通过影响肠道菌群加重肝损伤[22]
抗癫痫药物急性线粒体功能损伤,肝细胞中聚集脂肪小滴(如丙戊酸钠)
抗病毒药物线粒体慢性损耗导致肝细胞大滴脂肪积聚[20]
), ArticleFig(id=1203061231180554405, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203061221906948102, language=CN, label=表2, caption=

不同药物因素造成肝损伤的机制

, figureFileSmall=null, figureFileBig=null, tableContent=
药物种类造成肝损伤的机制
补充及替代药物
 中草药促进肝活性物质的代谢[21]
 合成代谢类固醇药物对胆盐或其他药物转运体的直接毒性而造成肝损伤[20]
抗结核药物干扰肝脏脂代谢;影响胆汁运输
抗感染药物干扰肝脏脂代谢;可通过影响肠道菌群加重肝损伤[22]
抗癫痫药物急性线粒体功能损伤,肝细胞中聚集脂肪小滴(如丙戊酸钠)
抗病毒药物线粒体慢性损耗导致肝细胞大滴脂肪积聚[20]
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肝硬化慢加急性肝衰竭的发病诱因及管理
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杨颜榕 , 徐曼曼 , 陈煜 *
解放军医学杂志 | 肝硬化及其并发症的评估与管理专题 2023,48(1): 7-12
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解放军医学杂志 | 肝硬化及其并发症的评估与管理专题 2023, 48(1): 7-12
肝硬化慢加急性肝衰竭的发病诱因及管理
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杨颜榕, 徐曼曼, 陈煜*
作者信息
  • 首都医科大学附属北京佑安医院肝病中心四科/肝衰竭与人工肝治疗研究北京市重点实验室,北京 100069
  • 杨颜榕,硕士研究生,主要从事肝衰竭防治方面的研究

    陈煜,主任医师,教授,博士研究生导师,中华医学会肝病学分会副秘书长、重肝及人工肝学组副组长,全国疑难及重症肝病协作组副组长,全国重型肝病及人工肝血液净化攻关协作组副组长,中国研究型医院学会肝病专业委员会重症肝病学组副组长,中国重症血液净化协作组副主任委员、人工肝学组组长;曾荣获北京市科技新星,北京市卫生局“十百千”卫生百名人才,北京市卫生系统高层次卫生技术人才,北京市优秀人才等称号。

通讯作者:

陈煜,E-mail:
Predisposing factors and management of acute-on-chronic liver failure in cirrhosis
Yan-Rong Yang, Man-Man Xu, Yu Chen*
Affiliations
  • Difficult and Complicated Liver Diseases and Artificial Liver Center/Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing You'an Hospital Affiliated to Capital Medical University, Beijing 100069, China
出版时间: 2023-01-28 doi: 10.11855/j.issn.0577-7402.2023.01.0007
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慢加急性肝衰竭(ACLF)是在慢性肝病基础上发生的一种急性失代偿综合征,病情进展迅速,预后不佳,是肝硬化患者死亡的重要原因。诱发因素在ACLF的发生、发展及预后中有重要作用,不同标准下的ACLF对诱因的定义有所差别,地区之间也存在一定异质性。随着医疗卫生事业的发展及生活方式的改变,ACLF诱因的构成也不断发生变化。诱发因素通过多种途径对器官功能造成损伤,导致的器官衰竭种类及预后也存在差异性,早期预警诱发因素可预防ACLF的发生,积极去除诱发因素可改善ACLF的预后,合理管理诱发因素对ACLF患者有积极意义。

慢加急性肝衰竭  /  肝硬化  /  诱发因素  /  预后

Acute-on-chronic liver failure (ACLF) is an acute decompensated syndrome that occurs on the basis of chronic liver disease, with rapid disease progression and poor prognosis, thus being an important cause of death in patients with cirrhosis. Predisposing factors play an important role in the occurrence, progression and prognosis of ACLF, which are heterogeneous in different definitions and regions. With the development of medical and health services and changes in lifestyles, the composition of predisposing factors also changes. These factors cause damage to organ function in various ways, leading to different types of organ failure and prognosis. Early warning of the predisposing factors can prevent the occurrence of ACLF. Actively removing predisposing factors can improve the prognosis of ACLF. Reasonable management of precipitating factors is important for ACLF.

acute-on-chronic liver failure  /  cirrhosis  /  predisposing factors  /  prognosis
杨颜榕, 徐曼曼, 陈煜. 肝硬化慢加急性肝衰竭的发病诱因及管理. 解放军医学杂志, 2023 , 48 (1) : 7 -12 . DOI: 10.11855/j.issn.0577-7402.2023.01.0007
Yan-Rong Yang, Man-Man Xu, Yu Chen. Predisposing factors and management of acute-on-chronic liver failure in cirrhosis[J]. Medical Journal of Chinese People’s Liberation Army, 2023 , 48 (1) : 7 -12 . DOI: 10.11855/j.issn.0577-7402.2023.01.0007
慢加急性肝衰竭(acute-on-chronic liver failure,ACLF)是在慢性肝病基础上由多种诱发因素引起的综合征,往往造成器官衰竭及短期高病死率。ACLF病情凶险,进展迅速,约40%的患者在确诊后病情变化很快[1]。目前不同地区对ACLF的定义仍有差异,欧洲慢性肝衰竭联盟(European Association for the Study of the Liver-Chronic Liver Failure,EASL-CLIF)及亚太肝脏研究学会(Asian Pacific Association for the Study of the Liver,APASL)分别针对患有不同基础疾病的人群建立了ACLF标准,并对诱因及器官衰竭的种类进行了区分。乙肝病毒(hepatitis B virus,HBV)再激活、肝毒性药物、自身免疫性肝病等作为诱发因素在两种定义中均得到了认可,但APASL认为只有当感染诱发了肝功能损伤时才能作为诱发因素,否则不作为ACLF的诱因。世界胃肠病组织(World Gastroenterology Organization,WGO)在各大定义的基础上综合考虑,将ACLF分为3种类型:慢性肝病型(A型)、代偿期肝硬化型(B型)、失代偿期肝硬化型(C型)[2]。近期,美国胃肠病学会(American College of Gastroenterology,ACG)首次发布的ACLF临床指南也指出ACLF的基础肝病包括慢性肝病、代偿期肝硬化及失代偿期肝硬化,并提出了与WGO相似的ACLF定义,且该指南首次在定义中强调了ACLF具有潜在可逆性[3]。我国肝衰竭指南对ACLF的定义为发生在上述3种肝病基础上的急性加重,以肝脏衰竭为主要表现,可合并肝外器官衰竭(表1)[4]
肝硬化是一种由慢性肝病发展而来的病理阶段,以肝脏弥漫纤维化、假小叶形成、肝内外血管增殖为特征,根据其临床进程,可分为代偿期肝硬化及失代偿期肝硬化。由于社会发展、人口增长及老龄化程度的提高,全球肝硬化的发病率逐渐下降,但病死率仍然较高。在肝硬化患者中,ACLF的发病率约为35%,90 d病死率约为58%[7]。随着医疗水平的提高以及人们疾病管理意识的增强,由肝硬化发展至终末期死亡的人数逐渐减少,而由急性打击引起的肝功能急性恶化导致死亡的人数逐渐增多;对于失代偿期肝硬化患者,进展至ACLF会在很大程度上升高病死率。失代偿期肝硬化分为三个临床进程:(1)ACLF前期;(2)不稳定性失代偿期肝硬化;(3)稳定性失代偿期肝硬化。有研究通过比较3组人群的3个月及1年病死率,认为ACLF前期的病死率远高于其他两个临床进程[8]。由此可见,肝硬化ACLF已逐渐成为患者死亡的最大原因。诱发因素在ACLF的发生发展中有重要作用,不同诱因会导致不同类型或数量的器官衰竭,进而导致不同的临床结局。分析肝硬化ACLF的诱因及预后,对诱因进行早期识别及管理,对提高肝硬化患者的生活水平,改善生存质量,以及减轻社会负担十分必要。了解肝硬化患者ACLF诱因的分类及变迁,并针对不同诱因引起的ACLF预后差异进行管理,可为肝硬化ACLF患者的早期预警与长期管理提供参考。
不同ACLF定义中的诱因各异。欧洲肝脏研究协会(European Association for the Study of the Liver,EASL)将ACLF的诱因分为肝内诱因及肝外诱因,肝内诱因包括HBV再激活、饮酒等,肝外诱因包括感染等。HBV再激活在欧洲人群中很少见,但在亚洲人群中是不可忽视的诱发因素。APASL定义ACLF的核心是肝功能损伤,故其诱因只考虑能够诱发肝衰竭的因素,如HBV再激活、肝毒性药物、自身免疫性肝病等,对于细菌感染及消化道出血,APASL认为只有当该因素引发肝功能损伤时,才能称为诱因,否则不纳入诱因范畴。HBV再激活仍是亚洲国家ACLF最主要的诱因,药物及自身免疫性肝病诱发的ACLF也逐渐增多[5]。在WGO分类中,HBV再激活及细菌感染是最常见的诱因,其中A型以HBV再激活为主要诱因,而B型及C型ACLF更容易被细菌感染诱发[9]
不同地区ACLF的发病诱因也有所差异。在以EASL标准定义的ACLF(EASL-ACLF)患者中,欧洲地区最常见的诱因为细菌感染,我国以HBV再激活为最常见的肝内诱因,其次是甲肝或戊肝病毒的重叠感染,细菌感染是最常见的肝外诱因,东南亚地区以大量饮酒为EASL-ACLF最常见的肝内诱因,细菌感染是最常见的肝外诱因。在APASL定义的ACLF(APASL-ACLF)患者中,我国与东南亚国家均以HBV再激活为主要诱因[10-13]
随着社会的发展,ACLF的诱因构成也在不断变化。APASL指南指出,饮酒在ACLF诱因中的占比增加,有逐渐取代HBV再激活成为亚洲人群ACLF主要诱因的趋势,而自身免疫性肝病及药物诱发的ACLF所占比例也在逐年上升[5]。肝毒性药物通常包括补充及替代治疗的药物、抗结核药物及抗癫痫药物。欧洲药物性肝损伤指南中提到,常用药物(包括别嘌呤醇、胺碘酮、他汀类及磺胺类等)引起的特殊效应是肝损伤的主要原因,这些药物造成的肝损伤通常与其剂量无关[14]。在APASL研究中,补充及替代治疗药物位于ACLF药物诱因的第一位,其次是抗结核药物[15]。在ACG指南中,抗感染药物是最常见的诱发肝损伤的药物。在我国,中草药造成的肝脏损伤也是值得注意的问题。
不同标准定义的ACLF诱因存在差异,可能与其基础疾病不同有关。EASL定义以代偿期及失代偿期肝硬化人群为基础,APASL定义以慢性肝病及代偿期肝硬化人群为基础,肝硬化人群较非肝硬化人群更易由于肝外因素造成损伤,以细菌感染为主要肝外诱因。不同地区ACLF患者诱因的差异可能与基础肝病的病因有关,西方国家基础肝病的病因主要是酒精性肝炎及慢性丙型肝炎,而亚洲则主要是慢性乙型肝炎(chronic hepatitis B,CHB)。随着医疗水平的提高、生活方式的改变、保健品及其他药物的滥用,HBV再激活导致的ACLF比例有所下降,而饮酒、药物等诱发的ACLF比例逐渐上升。针对不同基础疾病、病因及诱因的ACLF患者,尽早开始个体化治疗是值得临床医师关注的问题。
ACLF可以发生在肝硬化的任何临床阶段,其发病机制尚不明确,诱发因素在ACLF发生发展中起着重要的作用。
CHB是导致亚洲人群肝硬化的主要原因,HBV再激活是CHB患者发生ACLF最常见的诱因,可以是自发性的HBV再激活,也可以是其他因素[包括停用抗病毒药物、HBV对抗病毒药物出现耐药性,以及应用免疫抑制疗法和(或)细胞毒性疗法]引起的HBV再激活。免疫失调对乙肝相关ACLF(HBV-ACLF)的发生有一定作用:CHB患者由于免疫功能受损,体内常持续存在HBV,病毒复制导致人体免疫功能失调,固有免疫系统活化,乙肝表面抗原及乙肝核心抗原相关T细胞数量增加,引起细胞因子风暴,出现全身炎症反应,进而导致肝损伤[16],坏死的肝细胞或细胞外基质释放内源性诱导剂,激活损伤相关分子模式(damage-associated molecular patterns,DAMPs)产生无菌性炎症,进一步造成器官损伤[17]
感染是ACLF常见的诱发因素。肝脏作为人体重要的免疫器官,易受到来自胃肠道、门静脉及体循环毒素的攻击,失代偿期肝硬化患者因门静脉高压、肝功能受损及免疫功能障碍,更易发生感染。细菌感染是最常见的感染因素,其中最常见的是革兰阴性菌感染。近年来,由于抗生素的使用,多重耐药菌的感染率也逐渐上升。研究表明,不同地区细菌感染的类型存在差异,如亚洲以自发性腹膜炎及肺部感染为主,欧美国家以尿路感染为主[18]。细菌主要通过病原体相关分子模式(pattern-associated molecular patterns,PAMPs)及直接毒素作用引起全身炎症反应,募集固有免疫细胞如巨噬细胞进入肝脏,进而造成肝脏损伤,同时,炎症反应增加了血管内皮因子的释放,诱发肝外器官的损伤。
饮酒也是ACLF的诱发因素之一。在非感染性因素中,酒精是慢性肝病患者肝功能急剧恶化的主要因素,尤其是在西方国家[5]。饮酒诱发ACLF的机制尚不明确,可能以直接毒性作用导致肝脏发生炎症反应或细胞死亡为主要机制。大量饮酒可使肠道通透性发生改变,导致从肠道进入门静脉内的毒素增加,固有免疫系统激活,通过细胞因子及氧化应激级联反应导致肝细胞发生炎症损伤、凋亡、坏死及纤维化。严重酒精性肝炎引起的肝衰竭也可能与肝细胞再生受到抑制有关[19]
近年来,药物诱发ACLF的比例逐渐上升。肝脏是药物转化与代谢的主要器官,不同药物通过不同的途径对肝脏造成损伤。目前对ACLF药物诱因的研究较少,尽管人们对于肝毒性药物的认识不断提高,低毒性的替代药物也逐渐增多,但发生药物性肝损伤的人数并没有明显减少。目前关于ACLF药物诱因的研究主要包括抗感染药物、抗结核药物、免疫抑制剂及补充替代治疗药物(表2)。例如,四环素可对肝细胞线粒体造成急性损伤,他莫西芬及各种用于治疗人类免疫缺陷病毒感染的双脱氧核苷类似物可对肝细胞线粒体造成慢性损伤及消耗[20]。肝硬化患者的肝脏储备功能下降,对药物的耐受性降低,也增加了药物性肝损伤的风险。当肝硬化患者受到药物毒性作用时,其肝脏功能受损加重,损伤的细胞及组织释放炎性因子,诱发全身炎症反应,从而导致肝衰竭。
目前,消化道出血作为ACLF诱因并不被普遍认可,可以作为一种并发症出现。EASL标准将消化道出血作为诱因,而APASL标准目前不认为消化道出血是ACLF的诱因,仅当急性静脉曲张出血导致患者肝脏缺血并出现黄疸,且肝功能指标符合肝衰竭的标准时,可认为出血是ACLF的诱因。出血引起ACLF的机制尚不明确,目前认为其可引起肝脏缺血性损伤,而后者通过DAMPs机制引起炎症风暴,导致器官衰竭。还有一种可能是消化道出血导致肠道细菌易位,引发后续的细菌感染。消化道出血导致肠道积血,蛋白质在肠道细菌的腐败作用下产生大量氨进入血液,氨的毒性作用会导致大脑代谢紊乱,出现脑功能障碍及脑水肿;肝硬化患者肠道微生物释放的毒素及其诱发机体产生的炎性因子对脑功能障碍也有协同作用。严重的消化道出血可导致低血容量性休克,也可能对ACLF的进程造成一定影响。
关于手术诱发ACLF的研究较少。在失代偿期肝硬化患者中,经颈静脉肝内门体分流术(transjugular intrahepatic portosystemic shunting,TIPS)、大手术、大容量穿刺术(large-volume paracentesis,LVP)可诱发8.6%的ACLF[6]。无论是肝内还是肝外手术,都会对组织造成一定损伤,引起局部无菌性炎症,可能诱发全身炎症反应,进而导致ACLF。手术诱发ACLF的机制也可能与术后并发症有关,如内镜逆行胰胆管造影(endoscopic retrograde cholangiopancreatography,ERCP)术后ACLF的发生可能与并发胆管炎有关[23],侵入性手术引起ACLF可能与术后并发细菌感染有关。TIPS是否为ACLF的危险因素目前尚有争议,其诱发机制可能与肝脏再灌注损伤导致的肝功能恶化有关。
不同诱发因素引起的ACLF器官衰竭种类存在差异,这种差异与基础肝病的异质性有关。酒精性肝炎与慢性丙型肝炎是西方国家肝硬化最常见的病因,感染是该病因基础上ACLF最常见的诱发因素,主要引起肾衰竭,其次是肝脏、凝血系统、脑、循环系统及呼吸系统衰竭。CHB仍是我国肝硬化人群的主要病因,Shi等[24]以EASL标准定义的ACLF人群为基础,对ACLF的发病诱因及患者器官衰竭种类进行分析,结果表明,肝外诱因诱发的ACLF相较于肝内诱因更易导致肝外器官衰竭,以肾衰竭为主。有研究以WGO标准对HBV-ACLF患者进行分类,发现A型以HBV再激活为主要诱因,通常引起肝衰竭及凝血系统衰竭,B型及C型以细菌感染为主要诱因,发生循环衰竭的比例明显高于A型,其中C型较B型更易出现肾衰竭[9]。也有研究指出,阿片类药物及苯二氮䓬类药物通常与严重的中毒性脑病相关[25]。在Xu等[13]的研究中,失代偿期肝硬化人群发生ACLF主要由肝外诱因造成,代偿期肝硬化人群主要由肝内诱因造成,失代偿期肝硬化患者比代偿期肝硬化患者发生ACLF时更易并发腹水、消化道出血及肾功能不全。肝硬化患者主要由肝外诱因诱发ACLF,肝内诱因更倾向于引起肝内衰竭(如肝衰竭及凝血系统衰竭),肝外诱因更倾向于诱发肝外器官衰竭,以肾衰竭最为常见。失代偿期肝硬化较代偿期肝硬化更易受到肝外诱因的影响,出现肾衰竭的可能性更大,考虑与低蛋白血症、腹水及门体分流有关。
不同诱因导致的ACLF在28 d及90 d病死率方面存在差异。肝内诱因及肝外诱因诱发的ACLF分别称为肝内ACLF及肝外ACLF,肝内及肝外ACLF的28 d病死率均较高,90 d病死率及1年病死率后者显著高于前者[24]。有研究显示,肝内ACLF患者28 d病死率较高,两组ACLF的90 d、6个月及1年病死率差异无统计学意义[11]。也有研究者认为,两组的28 d及90 d病死率差异均无统计学意义[10]。出现这样的差异与ACLF的基础病因不同有关。亚洲人群以HBV-ACLF居多,肝内ACLF的诱因以HBV再激活为主,经过积极的抗病毒治疗可以改善患者的中长期预后。同时,肝外ACLF患者的基础肝功能损伤重,肝储备功能差,不易改善,肝功能持续恶化,长期病死率高于肝内ACLF患者。欧洲ACLF人群多以酒精性肝硬化为基础,肝内ACLF以大量饮酒为主要诱因,对基础病因的治疗获益有限,故肝内、肝外ACLF病死率无明显差异。
有研究对失代偿期肝硬化患者进行评估分析发现,ACLF诱因的类型与其临床特征显著相关,但与临床进程及病死率无关,而诱因的数量与临床病程及90 d病死率显著相关[25]。该研究只考虑了4种诱发因素:细菌感染、酒精、消化道出血、药物,其中以细菌感染为主要诱因,单独由酒精、消化道出血及药物引起的ACLF患者较少,即大部分为肝外诱因及肝外合并肝内诱因诱发的ACLF,因此90 d病死率未见明显差异,随着诱因数量的增多,患者全身炎症反应更严重,预后更差,住院期间对器官支持的需求较高。
肝内、肝外诱因导致的ACLF临床表现存在差异,肝内诱因以肝内器官衰竭为主,肝外诱因以肝外器官衰竭为主。肝硬化人群出现肝外器官衰竭的可能性大于非肝硬化人群,失代偿期肝硬化患者出现肾衰竭的可能性大于代偿期肝硬化患者,这可能与肝硬化患者本身具有肝脏慢性炎症、肝脏储备功能下降以及失代偿期肝硬化造成的并发症有关。
诱因在ACLF的进程中具有关键作用,与多器官衰竭及临床预后密切相关。我国肝硬化患者的基础病因以HBV感染为主,HBV再激活仍是CHB肝硬化患者进展为ACLF的主要因素,故应加强对CHB患者的管理,对使用免疫抑制剂的CHB患者立即行抗病毒治疗,根据免疫治疗前HBV病毒载量选择不同耐药屏障的抗病毒药物。同时,还应向CHB患者宣传规律服用抗病毒药物的必要性,以减少停药引起的HBV再激活。细菌感染也是ACLF的重要诱因,肝硬化ACLF患者住院后应调查流行病学史及感染途径,结合患者的一般状况、白细胞计数、C反应蛋白及降钙素原等检查指标,尽早进行感染评估,对于疑似感染的患者,早期抗生素治疗是否获益应根据具体情况进行评估。近年来由于保健品的滥用,药物诱发的ACLF较前增多,应对有基础肝病的患者宣传正确的保健理念,谨慎使用肝毒性药物,并在用药前进行合理性评估。向肝硬化患者倡导健康的生活方式,尤其提倡以酒精性肝炎为基础肝病的患者戒酒,重型酒精性肝炎患者口服激素治疗可以在一定程度上改善预后。为预防消化道出血诱发ACLF,可使用非选择性β-受体阻滞剂,其在降低门脉压力、预防消化道出血方面有一定作用,但该类药物在自发性腹膜炎、难治性腹水患者中的应用还有待商榷,临床医师在使用非选择性β-受体阻滞剂前需充分评估患者的耐受性。肝硬化患者的肝储备功能下降,基础免疫力差,在进行手术前评估肝功能,在围手术期加强对患者的管理,可以预防ACLF的发生或延缓其发展。
ACLF进展快速,常伴有多器官衰竭,且预后不佳,增加了肝硬化患者的死亡风险。对有肝硬化基础的ACLF人群,内科综合治疗措施提高存活率的效果有限,肝移植仍是改善预后的最佳手段,但因费用昂贵,肝源紧缺,常常难以实现,因此加强对肝硬化患者的管理,早期识别并积极去除ACLF的诱因对减轻疾病负担、改善预后具有重要的意义。目前仍有部分ACLF患者没有明确的诱发因素,这是不能忽视的问题,无明确诱因的ACLF同样以全身炎症为主要特征,其发生的具体机制及个体化治疗方案的制定是未来的研究方向。
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2023年第48卷第1期
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doi: 10.11855/j.issn.0577-7402.2023.01.0007
  • 接收时间:2022-04-15
  • 首发时间:2025-12-03
  • 出版时间:2023-01-28
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  • 收稿日期:2022-04-15
  • 录用日期:2022-06-22
基金
Beijing Hospitals Authority’s Ascent Plan(DFL20221501)
北京市医院管理中心“登峰”计划专项(DFL20221501)
Construction Project of High-level Technology Talents in Public Health(Discipline leader-01-12)()
北京高层次公共卫生技术人才建设项目(学科带头人-01-12)()
作者信息
    首都医科大学附属北京佑安医院肝病中心四科/肝衰竭与人工肝治疗研究北京市重点实验室,北京 100069

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陈煜,E-mail:
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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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