治疗失代偿期肝硬化的新药发现策略

StephenW

治疗失代偿期肝硬化的新药发现策略
斯文·拉玛奇
, 理查德·西特纳
, 弗兰克·塔克
& 科尼利厄斯·恩格尔曼
ORCID 图标
2021 年 10 月 6 日收稿，2021 年 12 月 16 日接受，在线发布：2021 年 12 月 31 日

    下载引文 https://doi.org/10.1080/17460441.2022.2020755 CrossMark 标志 CrossMark

抽象的
介绍

肝硬化的疾病进展导致失代偿和急性加慢性肝衰竭 (ACLF)，其特征是器官衰竭和高死亡率。门脉高压和心血管功能障碍会引发肝硬化相关并发症的发生，而组织损伤和细胞代谢功能障碍会导致器官衰竭。系统炎症是调节从代偿到失代偿以及进展到 ACLF 的首要机制。治疗突发事件和强化器官支持是唯一既定的治疗策略。肝移植是唯一的治愈性疗法，但禁忌症和器官短缺限制了其仅适用于少数终末期肝病患者。因此，发现和开发改变病程和改善患者预后的新型干预措施至关重要。
覆盖区域

本综述强调并讨论了终末期肝病领域的治疗创新。
专家意见

尽管进行了数十年的研究，但仍然没有既定的治疗方法来改善终末期肝病患者的破坏性预后。临床异质性和复杂的发病机制对药物发现提出了很高的要求。针对患者个体病理机制模式的组合疗法可能是改变病程的最有效方法。

关键词：急性慢性肝衰竭ACLF多器官衰竭疾病调节剂全身炎症
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文章亮点

    失代偿性肝硬化和 ACLF 的特点是预后不良，尚无既定的疾病改善疗法。

    Farnesoid-X 受体激动剂的肠道屏障稳定性可以防止肠道细菌易位，但需要肝硬化的概念验证数据。

    粪便微生物群移植的建立是为了纠正肠道微生物组成，并为测试其在患有终末期肝病的人类中的疗效提供依据。

    用于白蛋白交换和内毒素去除的体外装置在 2 期人体干预试验中显示出有希望的安全性和有效性数据。

    G-CSF 被认为通过调节免疫功能障碍来提高存活率。然而，第一次多中心试验未能证实较小的单中心试验的结果。

    Toll 样受体 4 的信号抑制可以防止器官损伤和免疫刺激。第一个人体 2 期试验的疗效数据将阐明这种干预措施的潜在益处。

    此框总结了文章中包含的要点。

StephenW

Novel drug discovery strategies for the treatment of decompensated cirrhosis
Sven Lamatsch
, Richard Sittner
, Frank Tacke
& Cornelius Engelmann
ORCID Icon
Received 06 Oct 2021, Accepted 16 Dec 2021, Published online: 31 Dec 2021

    Download citation https://doi.org/10.1080/17460441.2022.2020755 CrossMark Logo CrossMark

ABSTRACT
Introduction

Disease progression in cirrhosis leads to decompensation and acute-on-chronic liver failure (ACLF), which is characterized by organ failure and high mortality. Portal hypertension and cardiovascular dysfunction trigger the development of cirrhosis-related complications whilst tissue injury and cellular metabolic dysfunction lead to organ failure. System inflammation is the overarching mechanism mediating both the transition from compensation to decompensation as well as progression to ACLF. Treatment of precipitating events and intensive organ support is the only established therapeutic strategies. Liver transplantationrepresents the only curative therapy but contraindications and organ scarcity limit its availability to only a minority of patients with end-stage liver disease. Therefore, the discovery and development of novel interventions modifying the disease course and improving patients’ outcome are of utmost importance.
Areas covered

This review highlights and discusses therapeutic novelties in the field of end-stage liver disease.
Expert opinion

Despite decades of research, there are still no established therapies to improve the devastating prognosis of patients with end-stage liver disease. The clinical heterogeneity and complex pathogenesis will put high demands on drug discovery. Combinatorial therapies tailored to the patients’ individual pattern of pathomechanisms may be the most efficient way to modify disease course.

KEYWORDS: Acute-on-chronic liver failureACLFmulti-organ failuredisease modifying agentssystemic inflammation
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Article highlights

    Decompensated liver cirrhosis and ACLF are characterised by poor prognosis and no established disease modifying therapies are yet available.

    Gut barrier stabilisation by Farnesoid-X Receptor agonists may prevent intestinal bacterial translocation but requires proof-of concept data in cirrhosis.

    Fecal microbiota transplantation is established to correct intestinal microbial composition and provides the rational to test its efficacy in humans with end-stage liver disease.

    Extra-corporal devises for albumin exchange and endotoxin removal have shown promising safety and efficacy data in a phase 2 human interventional trial.

    G-CSF was believed to improve survival by modulation of immune dysfunction. However, the first multicentre trial failed to confirm the results from smaller single-center trials.

    Signalling inhibition of toll-like receptor 4 may prevent organ injury and immune stimulation. Efficacy data from the first human phase 2 trial will clarify the potential benefit of that type of intervention.

    This box summarizes key points contained in the article.