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Novel drug discovery strategies for the treatment of decompensated cirrhosis
Sven Lamatsch
, Richard Sittner
, Frank Tacke
& Cornelius Engelmann
ORCID Icon
Pages 273-282 | 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.
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发表于 2022-3-7 21:07