Article(id=1199335055475700519, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1199335049175859209, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.0972.2023.1020, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1689696000000, receivedDateStr=2023-07-19, revisedDate=null, revisedDateStr=null, acceptedDate=1693756800000, acceptedDateStr=2023-09-04, onlineDate=1763873359792, onlineDateStr=2025-11-23, pubDate=1711555200000, pubDateStr=2024-03-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763873359792, onlineIssueDateStr=2025-11-23, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763873359792, creator=13701087609, updateTime=1763873359792, updator=13701087609, issue=Issue{id=1199335049175859209, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='3', pageStart='245', pageEnd='366', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763873358291, creator=13701087609, updateTime=1763874044185, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1199337926086721596, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1199335049175859209, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1199337926086721597, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1199335049175859209, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=355, endPage=359, ext={EN=ArticleExt(id=1199335056935318353, articleId=1199335055475700519, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress on the clinical classification correlation between liver cirrhosis and liver failure, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

The essence of cirrhosis is the over-repairing reaction of liver tissue damage in the process of chronic liver disease. During repair, the liver parenchyma is gradually replaced by fibrosis tissue, resulting in changes in liver tissue morphology, followed by portal hypertension and other related manifestations. Liver failure are serious disorder of liver functions (synthesis, metabolism, transformation, regeneration, etc.) caused by various factors, often mainly manifested as jaundice, coagulation disfunction, hepatic encephalopathy, ascites, etc. The naming and typing of the two are different, and they can exist independently of each other or intersect with each other. In recent years, with the in-depth exploration of cirrhosis and liver failure, many new definitions and classification methods have been put forward in the research. However, due to the confusion of classification methods, there is still a lack of summary, so this article briefly reviews the current progress of clinical classification of liver cirrhosis and liver failure and their differences and intersections.

, correspAuthors=Shan-Hong Tang, authorNote=null, correspAuthorsNote=
E-mail:
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肝硬化本质是慢性肝病过程中肝组织损伤的过度修复反应,修复时肝实质逐渐被纤维化组织取代,导致肝脏组织形态学发生改变,继而出现门静脉高压症等相关表现。肝衰竭是由各种因素引起的肝脏多种功能(合成、代谢、生物转化、再生等)发生严重障碍,常以黄疸、凝血功能障碍、肝性脑病、腹水等为主要表现。二者的命名及分型的关注点有差别,相互之间可独立存在,也可彼此交集。近年来随着对肝硬化及肝衰竭的深入探索,提出了许多新的定义及分类方法,但分类方法混杂,缺乏有效归纳总结。本文就目前肝硬化与肝衰竭临床分类的进展,以及二者的差异与交集进行综述。

, correspAuthors=汤善宏, authorNote=null, correspAuthorsNote=
汤善宏,E-mail:
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徐华谦,硕士研究生,主要从事肝病相关的临床研究

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ACLF. 慢加急性肝衰竭;SDC. 稳定性失代偿;UDC. 不稳定性失代偿;Pre-ACLF. 慢加急性肝衰竭前期;AD. 急性失代偿;NAD. 非急性失代偿

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ACLF. 慢加急性肝衰竭

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肝硬化与肝衰竭临床分类的相关性研究进展
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徐华谦 1, 2 , 李春燕 1, 2 , 汤善宏 1, 2, *
解放军医学杂志 | 综述 2024,49(3): 355-359
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解放军医学杂志 | 综述 2024, 49(3): 355-359
肝硬化与肝衰竭临床分类的相关性研究进展
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徐华谦1, 2, 李春燕1, 2, 汤善宏1, 2, *
作者信息
  • 1解放军西部战区总医院消化内科,四川成都 610083
  • 2成都中医药大学医学与生命科学学院,四川成都 610072
  • 徐华谦,硕士研究生,主要从事肝病相关的临床研究

通讯作者:

汤善宏,E-mail:
Research progress on the clinical classification correlation between liver cirrhosis and liver failure
Hua-Qian Xu1, 2, Chun-Yan Li1, 2, Shan-Hong Tang1, 2, *
Affiliations
  • 1Department of Gastroenterology, the General Hospital of Western Theater Command, Chengdu, Sichuan 610083, China
  • 2School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, China
出版时间: 2024-03-28 doi: 10.11855/j.issn.0577-7402.0972.2023.1020
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肝硬化本质是慢性肝病过程中肝组织损伤的过度修复反应,修复时肝实质逐渐被纤维化组织取代,导致肝脏组织形态学发生改变,继而出现门静脉高压症等相关表现。肝衰竭是由各种因素引起的肝脏多种功能(合成、代谢、生物转化、再生等)发生严重障碍,常以黄疸、凝血功能障碍、肝性脑病、腹水等为主要表现。二者的命名及分型的关注点有差别,相互之间可独立存在,也可彼此交集。近年来随着对肝硬化及肝衰竭的深入探索,提出了许多新的定义及分类方法,但分类方法混杂,缺乏有效归纳总结。本文就目前肝硬化与肝衰竭临床分类的进展,以及二者的差异与交集进行综述。

肝硬化  /  肝衰竭  /  失代偿  /  分类

The essence of cirrhosis is the over-repairing reaction of liver tissue damage in the process of chronic liver disease. During repair, the liver parenchyma is gradually replaced by fibrosis tissue, resulting in changes in liver tissue morphology, followed by portal hypertension and other related manifestations. Liver failure are serious disorder of liver functions (synthesis, metabolism, transformation, regeneration, etc.) caused by various factors, often mainly manifested as jaundice, coagulation disfunction, hepatic encephalopathy, ascites, etc. The naming and typing of the two are different, and they can exist independently of each other or intersect with each other. In recent years, with the in-depth exploration of cirrhosis and liver failure, many new definitions and classification methods have been put forward in the research. However, due to the confusion of classification methods, there is still a lack of summary, so this article briefly reviews the current progress of clinical classification of liver cirrhosis and liver failure and their differences and intersections.

cirrhosis  /  liver failure  /  decompensated  /  classification
徐华谦, 李春燕, 汤善宏. 肝硬化与肝衰竭临床分类的相关性研究进展. 解放军医学杂志, 2024 , 49 (3) : 355 -359 . DOI: 10.11855/j.issn.0577-7402.0972.2023.1020
Hua-Qian Xu, Chun-Yan Li, Shan-Hong Tang. Research progress on the clinical classification correlation between liver cirrhosis and liver failure[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (3) : 355 -359 . DOI: 10.11855/j.issn.0577-7402.0972.2023.1020
在慢性病因(如乙型病毒性肝炎、酒精性肝病、代谢相关性肝病等)的持续刺激损伤下,肝细胞可分泌多种细胞因子激活肝星状细胞,激活的肝星状细胞通过增生及分泌细胞外基质,参与肝纤维化的形成及肝脏结构的重建[1-2]。在不同的肝病病因、环境因素及宿主因素作用下,肝纤维化以不同的速率进展,直至发展到晚期肝硬化[3-5]。肠道菌群失调、免疫功能障碍、系统炎症等加速了代偿期肝硬化向终末期肝病的进展[6-7]。而肝衰竭作为肝脏的一种功能性改变,可发生于肝硬化病程的任一阶段,二者可相互交织,也可独立存在[8]。近年来,根据肝硬化疾病发展的急缓及严重程度等,一些新的分类方法被提出。本文就目前关于肝硬化与肝衰竭相关性的研究进展综述如下。
在不同病因(乙型肝炎病毒感染、酒精、代谢障碍、自身免疫等)的作用下,肝细胞不断被破坏,胶原不断沉积,肝脏体积逐渐缩小,形状扭曲,形成以宽纤维化带分隔的多发肝细胞结节,扰乱肝内血液循环,引起门静脉高压[9]。在肝硬化形成早期,机体对肝脏结构改变带来的不利影响尚能代偿,可无特异性症状及体征,这种肝硬化的无症状期可持续数月至数年[3]。但如未及时控制原发病因或诱因,则会加速疾病进程,出现腹水、食管静脉曲张破裂出血及肝性脑病等失代偿事件,甚至发生肝衰竭及肝细胞癌。一项大型前瞻性研究分析了1672例代偿性肝硬化患者的情况,其5年累积细菌感染发生率为13%,细菌感染通过加重全身性炎症反应及门静脉高压强度,加速失代偿事件的发生[10]。肝硬化患者中每年有1%~4%会发展为肝细胞癌,其中乙型及丙型肝炎病毒感染占60%~85%,乙型肝炎病毒可使肝细胞癌的发生风险增加5~100倍,丙型肝炎病毒感染可使其风险增加15~20倍[11]。有效控制病因如抗病毒治疗可以逆转慢性乙型肝炎所致肝纤维化及早期肝硬化,并能改善其远期临床结局[12]
部分代偿期肝硬化患者虽然从未发生失代偿事件,但在急性诱因如感染、乙肝病毒再激活等急性打击下,肝功能急剧恶化,并出现肝性脑病、腹水、电解质紊乱、感染、肝肾综合征、肝肺综合征等并发症,甚至发生肝脏和(或)肝外器官衰竭,即慢加急性肝衰竭(acute-on-chronic liver failure,ACLF)。随着对ACLF研究的深入,欧洲肝病协会[13]、亚太肝病学会[14]、中国肝衰竭指南[15]、重型乙型病毒性肝炎研究小组[16]等多个研究协会均制定了特异性的ACLF定义标准。2014年,世界胃肠病学组织发布共识,根据ACLF患者基础肝病特点将ACLF分为3型,即在慢性非肝硬化肝病基础上发生的ACLF为A型,在代偿期肝硬化基础上发生的ACLF为B型,在既往发生失代偿的肝硬化基础上发生的ACLF为C型[17]。这一分类方法进一步明确了代偿期肝硬化基础上发生肝衰竭患者的归属即B型ACLF。由于多数患者发生肝衰竭时无法准确评估其肝脏有无肝硬化及肝硬化程度,因此临床工作中难以鉴别B型与C型ACLF。笔者认为可以基于其病理生理将ACLF分为:在慢性非肝硬化及肝硬化基础上的急性肝脏和(或)肝外器官衰竭,即A型及B/C型两类,这种分类方法更简单易行,也更适于临床实际运用。一项针对代偿期肝硬化患者的队列研究发现,终末期肝病评估模式(model for end-stage liver disease,MELD)评分小于18分的代偿期肝硬化患者在28 d内发展为ACLF的可能性较低(低于1%),其全身炎症水平及28 d病死率均较发生了ACLF的患者更低[18]。同时Thanapirom等[19]对1621例ACLF患者研究发现,合并肝硬化的ACLF患者的平均生存期较非肝硬化患者更长,推测其原因可能是非肝硬化患者伴有更严重的全身性炎症。此外,肝衰竭后肝脏遭受严重打击,导致大量肝细胞坏死,组织塌陷。本课题组前期研究发现肝再生与患者预后密切相关[20-22],但随着时间推移,肝纤维化、肝硬化是否发生改变及其影响因素尚需进一步探讨。
失代偿期肝硬化常称为临床症状期,患者伴随着肝功能持续下降及门脉高压的持续升高。近期PREDICT及CANONIC研究将2周内首次发生或复发的腹水、肝性脑病、胃肠道出血、细菌感染或任意二者同时发生定义为急性失代偿(acute decompensation,AD),将AD的第一次发作作为代偿性肝硬化转变到失代偿性肝硬化的标志,失代偿性肝硬化以AD反复发作为主要特点[23-24]。细菌感染虽然并非既定的失代偿事件之一[3],但由于细菌感染会加速失代偿病程,并且细菌感染患病率高[25],Mezzano等[23]也将其纳入了AD的定义中。PREDICT研究通过观察AD患者3个月及12个月的死亡风险,并根据患者90 d再入院及是否发展为ACLF进一步将AD划分为稳定性失代偿(stable decompensated cirrhosis,SDC)、不稳定性失代偿(unstable decompensated cirrhosis,UDC)及慢加急性肝衰竭前期(Pre-ACLF)共3种临床类型。有研究发现,3种不同类型的临床病程死亡风险依次递增,其中Pre-ACLF发展为ACLF患者的3个月及1年病死率分别为53.7%及67.4%[26-27]。这一分类的提出进一步揭示了AD是独立于代偿性肝硬化、ACLF外的疾病病程。除此之外,D'Amico等[28]对既往已发生失代偿的患者根据肝硬化失代偿起病急缓提出了新的分类方法,将肝硬化失代偿分为缓慢进展的非急性失代偿(NAD)及2周内首次发生或复发起病的急性失代偿(AD)两种类型,其中AD的患者也可进一步发展至ACLF、肝移植或死亡。虽然该分类方法简单易行,但失代偿肝硬化疾病进展复杂多变,仅根据起病急缓分类尚缺乏足够的临床验证。
虽然失代偿期肝硬化作为肝硬化病程的分水岭常预示不良预后,但近年研究发现,经过对病因的有效治疗后,部分失代偿肝硬化患者的肝功能会好转并趋于稳定,并在较长时间内(至少1年)不再出现失代偿事件,呈现“再代偿”的疾病状态[29]。一项多中心前瞻性研究发现,乙肝失代偿肝硬化患者使用恩替卡韦治疗120周后,60.4%的患者腹水、肝性脑病及复发性静脉曲张出血在1年内得到缓解,总胆红素、凝血酶原国际标准化比值及白蛋白指标稳定改善,进一步证实了Baveno Ⅶ的“再代偿”理论[30]。“再代偿”概念的提出,再一次强调了失代偿肝硬化患者病因治疗的重要性及必要性,但关于如何准确界定“再代偿”及其发生的具体机制仍需更深入地探讨。
当肝硬化进展到终末期阶段,将会出现以反复腹水和(或)肝性脑病等为主要表现的慢性肝脏失代偿,又称为慢性肝衰竭(chronic liver failure,CLF)[15]。CLF在肝病基础、病理学改变、起病过程方面都不同于ACLF,CLF是在失代偿期肝硬化基础上出现的,以总胆红素持续缓慢升高、凝血功能持续缓慢恶化、蛋白合成逐渐减少等肝功能进行性减退为主要表现,而ACLF是慢性肝病基础上的急性起病[31]。因CLF常继发于失代偿肝硬化基础上,其肝脏储备、合成、转化、再生等功能均受损,经内科及人工肝治疗可延缓部分患者的病情进展,但总体疗效差。本课题组前期对乙型肝炎相关ACLF患者研究发现,部分非肝癌患者的甲胎蛋白(AFP)水平明显升高,并且比低AFP水平的患者有较好的生存预后[20-22]。AFP作为胚胎时期肝及卵黄囊产生的糖蛋白[32],虽是熟知的肿瘤标志物,但在排除肿瘤的情况下,高AFP水平可能是急性大面积肝细胞坏死后肝细胞迅速再生的反映,也间接证明了部分ACLF患者比CLF有更好的再生修复功能,有病程逆转的可能。
部分失代偿肝硬化患者在多种诱因的作用下发生急性的肝或肝外器官衰竭,基于世界胃肠病学组织发布的共识,可将其归类于ACLF-C型[8]。司诺等[33]通过比较不同分型及病因的ACLF发现,ACLF-C型患者的谷丙转氨酶、白蛋白、总胆红素及血小板水平明显低于ACLF-A、ACLF-B型组,且ACLF-C型的病死率明显高于ACLF-A、ACLF-B型。Tang等[34]对AD患者研究发现,约有6.8%的AD患者在28 d内发展为ACLF,同时患者入院时器官功能障碍的数量及是否合并细菌感染与ACLF的发生独立相关。Juanola等[35]在一项对444例失代偿肝硬化患者的前瞻性研究中发现,患者尿液中的肝脂肪酸结合蛋白(uL-FABP)水平可以反映失代偿肝硬化患者的肝肾功能及全身炎症情况,并且uL-FABP增高与ACLF发生密切相关。同时Arroyo等[36]提出急性失代偿性肝硬化中未发生ACLF及发生了ACLF患者的发展轨迹不同,后者因过度激活的系统性炎症导致病情恶化,预后不良。Engelmann等[37]也发现由损伤相关分子模式(DAMPs)及病原体相关分子模式(PAMPs)引起的系统性炎症、微循环功能障碍、代谢紊乱等在失代偿向ACLF的转变过程中起重要的“桥梁”作用。因此在失代偿肝硬化病程中,预防诱因的发生并及时消除“桥梁”作用的影响,将有利于抑制失代偿向ACLF的转变,从而改善患者预后。
肝硬化病程复杂多变,尤其是失代偿肝硬化与肝衰竭之间存在共通之处,但也存在差异(图12),正确认识二者之间的交集及区别,对患者的临床诊治至关重要。笔者认为,由于东西方的流行病学差异,ACLF定义难以达成共识,而针对不同地区患者制定特异性的诊断标准更利于患者疾病的转归。现有的分类方法繁多,临床应用难以抉择,如何确定一个临床适用且合理有效的分类方法值得进一步探索。
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doi: 10.11855/j.issn.0577-7402.0972.2023.1020
  • 接收时间:2023-07-19
  • 首发时间:2025-11-23
  • 出版时间:2024-03-28
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  • 收稿日期:2023-07-19
  • 录用日期:2023-09-04
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    1解放军西部战区总医院消化内科,四川成都 610083
    2成都中医药大学医学与生命科学学院,四川成都 610072

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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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