修回日期: 2024-02-01
接受日期: 2024-04-15
在线出版日期: 2024-05-28
作为慢性肝病研究的新兴概念, 近年来, 肝硬化逆转和再代偿得到了越来越多的证据支持. 增加对肝硬化逆转和再代偿的认识, 有助于进一步划分肝硬化的自然病程, 为肝硬化机制的基础研究和临床管理提供指导. 然而, 对两者的定义、潜在机制和影响因素的研究尚处于早期阶段. 本文强调了肝硬化组织学和功能上的可逆性, 概述了肝硬化逆转和再代偿的可能机制和诊断标准, 总结了现有的相关研究证据, 并提出了该领域亟待解决的挑战.
核心提要: 肝硬化逆转和再代偿可能是肝硬化患者预后改善的标志事件, 但相关概念和机制仍有待更深入的研究.
引文著录: 杜韬, 于冰, 罗薇. 肝硬化逆转和再代偿: 既有证据和未来展望. 世界华人消化杂志 2024; 32(5): 320-326
Revised: February 1, 2024
Accepted: April 15, 2024
Published online: May 28, 2024
As novel concepts in the field of hepatology, liver cirrhosis reversal and recompensation have gained more supporting evidence in recent years. Increasing awareness of these topics may help researchers classify the natural history of liver cirrhosis and provide guidance for fundamental research and clinical management. However, the research investigating the definition, mechanisms, and influencing factors of cirrhosis reversal and recompensation is still in the early stages. Here, we emphasize the reversibility of cirrhosis histologically and functionally. And we also discuss the potential mechanisms and diagnostic criteria for cirrhosis reversal and recompensation, summarize existing relevant study evidence, and present the urgent challenges in this field.
- Citation: Du T, Yu B, Luo W. Liver cirrhosis reversal and recompensation: Existing evidence and future prospects. Shijie Huaren Xiaohua Zazhi 2024; 32(5): 320-326
- URL: https://www.wjgnet.com/1009-3079/full/v32/i5/320.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v32.i5.320
肝硬化是慢性肝病进展至终末阶段的病理生理阶段, 当肝硬化进展至失代偿期时, 患者发生进一步失代偿和死亡的风险将显著增加. 因此, 肝硬化失代偿期被认为是慢性肝病患者不良预后的重要标志阶段. 据世界卫生组织报道[1], 每年约有100万人死于肝硬化, 为世界公共卫生带来了沉重的负担.
既往研究认为, 肝硬化进展是单向、不可逆的过程, 因此, 针对肝硬化的研究多着眼于延缓病情进展和预防并发症. 然而, 近年来的研究表明, 病因治疗和其他支持治疗措施可能能改善肝硬化组织病理学特征, 甚至实现肝硬化逆转和再代偿[2,3]. 然而, 目前国内外就肝硬化逆转和再代偿制定的定义尚不统一, 相关研究也存在定义异质性、研究样本较少等缺陷. 了解肝硬化逆转和再代偿有助于明确肝硬化自然病史的阶段划分, 从而指导肝硬化的研究和临床管理. 本文首先总结并比较了肝硬化逆转和再代偿现有的诊断标准, 同时对其背后的潜在机制进行了概述, 并通过总结相关研究证据, 确定了肝硬化逆转和再代偿事件的存在, 最后, 提出了先有研究的不足和挑战, 为未来慢性肝病的研究提供了参考.
1.1.1 肝硬化逆转的潜在机制: 肝硬化的病理特征主要表现为肝脏弥漫性纤维化、再生结节形成等. 在酒精、脂毒性等多种应激长期打击下, 肝脏内炎症反应持续激活, 库普弗细胞、肝窦内皮细胞等肝脏免疫微环境内细胞加强趋化因子、细胞因子和黏附因子表达, 引起肌成纤维细胞激活, 肌成纤维细胞增殖、移行至炎症浸润部位, 合成分泌大量细胞外基质(extracellular matrix, ECM), 减少ECM降解, ECM合成和降解的失衡造成进行性肝纤维化、肝血窦毛细血管化, 最终进展为肝硬化[4-7].
晚期肝纤维曾被认为不可逆转, 但近年的抗病毒治疗相关的临床实验表明: 晚期肝纤维化、甚至肝硬化在某些情况下可以出现逆转. 2015年, 通过回顾肝硬化形成和进展的病理特征, Bedossa等[8]提出了肝硬化逆转组织学上的潜在机制: (1)ECM降解; (2)肝细胞再生; (3)肝血管和小叶结构重建. 然而, 不同类型肝硬化参与进行性纤维化的分子机制存在差异, 可能意味着肝硬化逆转的分子机制同样存在差异[9,10].
1.1.2 肝硬化逆转的评估标准: 目前, 肝硬化逆转的评价标准仍主要依赖于肝脏病理活检, 由于失代偿期肝硬化患者往往伴随有凝血功能障碍等侵入性操作禁忌症, 因此, 绝大部分肝硬化逆转标准的研究是基于代偿期肝硬化患者开展.
肝硬化的重要病理特征之一是ECM的异常沉积, ECM的主要组分是交联的Ⅰ型和Ⅲ型胶原蛋白, 过度产生的ECM形成纤维瘢痕, 取代正常肝脏组织, 导致肝纤维化和肝硬化[11]. 肝硬化的传统半定量评分标准包括Knodell评分、Ishak评分体系和Metavir评分体系, 其中, Ishak评分作为肝纤维化和肝硬化逆转标准, 被广泛应用于抗病毒药物治疗肝硬化相关研究中[12-14]. 中国肝硬化诊治指南也将Ishak评分纤维化分期降低≥1期纳入肝硬化逆转的标准之一[15]. 然而, 传统的半定量评分标准在临床应用中会受到设备、病理医生经验等因素影响, 不能实现对肝硬化逆转客观、精确的诊断. 由于针对病理组织的胶原蛋白含量测定技术较为成熟, 肝硬化逆转的部分全定量评估标准聚焦于肝脏组织的胶原蛋白水平变化. 胶原蛋白面积比例作为肝硬化的全定量评分标准之一, 能够预测肝硬化患者的门静脉压力梯度, 且比Ishak评分效果能更好地反映肝硬化门脉压力梯度的组织学特征[16]. Gole等[17]在此研究基础上, 进一步提出了根据胶原面积比例和胶原纤维厚度预测肝硬化可逆性的分层模型. 此外, 首都医科大学还通过回顾慢性病毒性肝炎患者的活检标本, 提出了将肝硬化区分为进展型、中间型和退行型的P-I-R评分[18].
肝细胞再生和肝血管、小叶结构重建的组织病理学评估方法尚不完善. 肝脏再生主要涉及既有的肝细胞增殖和肝祖细胞增殖、分化, 后者是严重肝损伤情况下的主要肝细胞再生机制[19]. 目前, 针对肝细胞再生程度的估测原理是对肝祖细胞的生物标志物进行多重免疫组化染色, 然而, 相关生物标志物并非只表达于肝祖细胞中, 对肝硬化逆转评估效能造成未知影响[20]. 肝血管和小叶结构重建的评估同样依赖传统的肝硬化半定量评分, 值得注意的是, 北京友谊医院通过回顾、比较治疗前后肝小叶结构是否有恢复趋势患者的病理组织, 提出了肝小叶结构恢复指数以协助评估肝硬化逆转[21].
目前, 肝硬化再代偿的定义仍然存在争议, 国内外研究主要采用Baveno Ⅶ共识和中华医学会《肝硬化诊治指南(2019版)》中提出的两种诊断标准. 中华医学会在《肝硬化诊治指南(2019版)》中提出, 可将有效控制和预防病因和并发症后, 1年及以上未再发腹水、消化道出血、肝性脑病等肝硬化失代偿事件视为肝硬化再代偿阶段[15]. Baveno Ⅶ共识指出: 再代偿意味着在去除肝硬化原发病因后, 至少可观察到肝硬化在组织学和肝功能上的部分逆转, 临床上诊断肝硬化再代偿的需满足以下条件: (1)去除/抑制/治愈肝硬化的原发病因; (2)不使用利尿剂的情况下无再发腹水, 不使用乳果糖或利福昔明的情况下无再发肝性脑病, 无再发消化道出血至少12个月; (3)白蛋白、国际标准比值比和胆红素等肝功能指标改善[22].
已有的肝硬化再代偿的诊断标准主要是基于乙型肝炎病毒(hepatitis B virus, HBV)、丙型肝炎病毒(hepatitis C virus, HCV)感染引起的肝硬化和酒精性肝硬化患者制定的. 然而, 非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)相关肝硬化和自身免疫性肝硬化的原发病因较为复杂, 暂无明确的标准评定原发病因水平, 目前的标准并不能满足特殊类型肝硬化划分失代偿期和再代偿期的需求. 其次, 现有的指南和研究并未明确再代偿期肝功能指标改善须达到标准, 可能会造成研究和临床诊断的混乱.
评价肝硬化和纤维化逆转的金标准是肝脏活检术. 然而, 作为侵入性操作, 肝脏活检术多用于不明原因肝硬化诊断, 而非作为病情监测的指标; 其次, 现有针对肝脏组织学改善的研究, 其样本多收集自肝纤维化患者和动物模型. 因此, 尽管我们已从动物模型和部分临床实验中观察到肝硬化逆转的证据, 但针对肝硬化逆转的研究尚处于较为匮乏的状态. 我们对根据肝硬化的病因进行分类检索, 总结了部分可观察到肝硬化逆转事件的临床研究(表1).
| 肝硬化类型 | 研究年份 | 研究设计 | 研究药物 | 评分系统 | 研究对象数量 | 参考文献 |
| HBV肝硬化 | 2010 | 非随机对照研究 | ETV | Ishak评分 | 57 | [23] |
| 2011 | 非随机对照研究 | ETV | Ishak评分 | 10 | [24] | |
| 2013 | 随机对照研究 | TDF | Ishak评分 | 348 | [3] | |
| 2015 | 非随机对照研究 | (1)ETV; (2)LAM | Ishak评分 | 42 | [25] | |
| 2017 | 非随机对照研究 | ETV | Ishak评分 | 71 | [12] | |
| 2018 | 非随机对照研究 | 抗病毒药物治疗 | Ishak评分 | 556 | [26] | |
| 2019 | 非随机对照研究 | ETV | Ishak评分和P-I-R评分 | 212 | [27] | |
| 2022 | 随机对照研究 | (1)ETV; (2)ETV+鳖甲软肝片 | Ishak评分 | 500 | [13] | |
| 2022 | 非随机对照研究 | ETV | Metavir评分和P-I-R评分 | 73 | [28] | |
| 2023 | 随机对照研究 | (1)ETV; (2)ETV+安络化纤丸 | Ishak评分 | 780 | [29] | |
| 2023 | 随机对照研究 | (1)ETV; (2)ETV+软肝颗粒 | Ishak评分 | 240 | [14] | |
| HCV肝硬化 | 2006 | 非随机对照研究 | 干扰素γ-1b | Ishak评分 | 20 | [30] |
| 2007 | 随机对照研究 | 干扰素γ-1b | Ishak评分 | 488 | [31] | |
| 2021 | 非随机对照研究 | DAA | Ishak评分和P-I-R评分 | 38 | [32] | |
| 酒精性肝硬化 | 2012 | 随机对照研究 | (1)熊去氧胆酸; (2)熊去氧胆酸+坎地沙坦 | METAVIR 纤维化评分和Laennec 纤维化评分 | 85 | [33] |
| NAFLD相关肝硬化 | 2020 | 随机对照研究 | Selonsertib | NASH CRN纤维化评分 | 802 | [34] |
| 2022 | 随机对照研究 | (1)Selonsertib; (2)辛妥珠单抗 | Ishak评分和NASH CRN纤维化评分 | 1135 | [35] | |
| 2024 | 随机对照研究 | Pegbelfermin | NASH CRN纤维化评分 | 155 | [36] | |
| 自身免疫性肝硬化 | 2017 | 非随机对照研究 | 糖皮质激素 | Ishak评分 | 101 | [37] |
2.2.1 HBV相关肝硬化: HBV失代偿期肝硬化的主要治疗目标是延缓疾病进展和提高生存率, 在临床中需要抗病毒治疗和支持治疗同时进行, 以避免进一步失代偿和死亡等不良事件的发生. 在慢性乙肝肝病患者中, HBV复制是肝脏炎症、坏死和临床病情进展的关键驱动因素, 而Baveno Ⅶ共识同样强调了病因治疗在肝硬化再代偿实现中的重要性, 因此, 针对失代偿期肝硬化患者的抗病毒治疗尤为重要[22,38]. 目前, 核苷/核苷酸类似物作为广泛应用于失代偿肝硬化患者的治疗一线药物, 被证明可改善患者的症状和预后[39-41].
Wang等[42]开展的一项多中心前瞻性研究证明了失代偿期肝硬化患者在接受抗病毒治疗后, 患者失代偿期肝硬化相关临床表现和肝脏功能得以改善, 符合Baveno Ⅶ标准的肝硬化再代偿标准. He等[43]将腹水和消化道出血作为首发失代偿事件, 最终383名纳入研究的对象中有53%(n = 203)的患者在一年及以上无服用利尿药等支持治疗药物的情况下, 无再发腹水和消化道出血, 进一步证明了HBV相关肝硬化再代偿的概念. 同时, 还有其他研究也提供了肝硬化再代偿的进一步证据[44-46]. 值得注意的是, 有研究指出, 接受抗病毒药物的时间有可能会影响肝硬化再代偿的成功与否[47].
2.2.2 HCV相关肝硬化: HCV感染依然是全球范围内肝硬化失代偿和相关死亡的主要原因之一[48]. 目前, HCV相关慢性肝病的主要治疗手段仍然是DAA治疗, DAA通过抑制HCV复制必需的非结构性蛋白达到治疗效果, 并对失代偿期肝硬化患者保持肝功能的相对稳定、再代偿和改善预后等方面具有积极影响[49-51].
英国的一项真实世界研究表明DAA治疗在HCV肝硬化再代偿中起到一定作用, 且较低的血清肌酐基线水平与再代偿相关[52]. Gentile等[53]对HCV肝硬化患者的观察性研究进一步证明了HCV肝硬化再代偿和DAA治疗的作用, 89例接受DAAs治疗的Child-Pugh B级在接受治疗12周后, 有61.8%的患者Child-Pugh等级改善为A级, 还有33.7%的患者仍处于Child-Pugh B级, 4.5%的患者则出现病情进展(P<0.001), 患者的肝酶水平在接受治疗后得到了改善.
2.2.3 酒精性相关肝硬化: 酒精滥用是西方国家肝硬化的主要诱因之一. 既往研究发现在严格戒酒的酒精性肝炎患者可得到组织学上的改善, 并可观察到类似症状消退的现象[54]. 近年来的研究表明戒酒能够显著改善酒精性肝硬化患者肝功能, 并与良好预后和生存期有关. 244例戒酒的失代偿性酒精性相关性肝硬化患者在1年及以上的随访期间中, 18.1%患者(n = 37)实现了肝硬化再代偿, 且肝硬化再代偿的患者死亡风险较失代偿期患者显著下降[55]. 酒精性肝硬化再代偿患者在经过观察后, 可退出肝移植的等待队列, 并达到较好的长期预后[56,57].
2.2.4 其他病因引起的肝硬化: 在Baveno Ⅶ共识和中国指南中, 消除原发病因是肝硬化逆转的必备条件. 然而, 对于其他病因引起的肝硬化, 尤其是NAFLD相关肝硬化而言, 其病因具有高度复杂性, 无法仅用"一元论"解释疾病进展机制和治疗; 第二, 在接受治疗和观察的NAFLD相关肝硬化和自身免疫性肝硬化患者中, 目前仍缺乏精确的检测手段评价治疗前后病因的水平变化[58]. 目前的标准并不能满足对特殊类型肝硬化自然病程再划分的需求, 有必要对肝硬化再代偿的定义进行重新讨论, 并结合不同类型肝硬化的病理生理机制、临床表现等具体条件, 制定更精准的相关共识和指南, 为临床研究和管理提供指导.
肝硬化逆转研究主要关注的结局是肝脏组织学改善程度, 此外, 纳入的研究对象多为单一种族、地区的人群. 因此, 有必要在未来对人口特征学和常见临床参数与肝硬化逆转和进展的关系展开研究.
Kim等[59]通过对311例患者的临床数据进行回顾, 确定了胆红素、甲胎蛋白、丙氨酸氨基转移酶、国际标准比值比和严重并发症6个与HBV肝硬化再代偿相关的独立预测因子, 并构建了BC2AID评分, 与Child-Pugh评分[曲线下面积(area under the curve, AUC) = 0.691]、MELD评分(AUC = 0.638)、MELD-Na评分(AUC = 0.624)评分相比, BC2AID对再代偿的预测效能更高(AUC = 0.813, P<0.05). 还有研究显示白蛋白、血钠和甲胎蛋白等指标的水平能够预测以腹水为首发失代偿事件的HBV肝硬化再代偿的发生[46]. 在其他病因引起的肝硬化中, 白蛋白水平、门静脉压力梯度被发现与酒精性肝硬化再代偿相关[54,55].
然而, 正如我们在前文所阐述的, 现有研究中的肝硬化逆转和再代偿定义具有异质性, 因此, 需要谨慎地看待相关研究的结果.
近年来, 肝硬化逆转和再代偿的概念得到了一定数量研究证据的支持, 然而, 对两者定义的争论仍在继续[60]. 由于不同类型肝硬化的病因、病理生理机制等方面存在差异, 构建一个能统一所有类型肝硬化逆转和再代偿诊断标准的设想似乎有待商榷. 我们认为, 根据肝硬化类型, 分别制定特指性的标准或许能更好地应用于慢性肝病患者的分层管理.
肝硬化逆转诊断的明确依赖于肝脏组织活检术, 然而, 侵入性操作可能会提高肝硬化患者感染、出血和病情进展的风险, 因此, 有必要寻找兼备可靠性、准确性的新型无创检测手段以协助诊断肝硬化逆转. 此外, 受研究数量偏少、事件定义异质性等因素影响, 与肝硬化逆转和再代偿相干的生物标志物和预测模型研究领域尚处于探索阶段. 挖掘相关标志物不仅有利于预测逆转和再代偿事件的发生, 还能规范已有肝硬化再代偿定义中"肝功能稳定改善"的标准.
肝硬化逆转和再代偿的分子机制、再定义和诊疗策略仍有待阐明, 未来亟需更多大样本、多中心研究对领域内尚待解决的问题进行探索, 以实现基础和临床研究的双向反馈.
肝硬化逆转和再代偿事件往往在病因治疗和支持治疗后出现. 肝硬化逆转相关机制与肝纤维化消退机制类似, 即(1)ECM降解; (2)肝细胞再生; 和(3)肝血管和小叶结构重建, 肝硬化逆转可能为肝硬化再代偿奠定了组织学和功能学的基础. 肝硬化逆转和再代偿的发生能显著改善患者的生活质量, 对该领域的进一步研究能够为研究和临床诊疗提供新方向.
综上, 肝硬化逆转和再代偿概念的提出, 体现了对肝硬化自然病程理解的进步. 然而, 由于肝硬化逆转和再代偿的相关研究多为观察性研究, 或尚处于试验阶段, 其具体机制和驱动因素尚缺乏强有力的证据支持, 未来仍需要分子机制和大样本前瞻性临床研究, 以多层面进行探索和验证.
学科分类: 胃肠病学和肝病学
手稿来源地: 广西壮族自治区
同行评议报告学术质量分类
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C级 (良好): C, C
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科学编辑:张砚梁 制作编辑:张砚梁
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