Hofer Benedikt Silvester, Simbrunner Benedikt, Königshofer Philipp, Brusilovskaya Ksenia, Petrenko Oleksandr, Taru Vlad, Sorz-Nechay Thomas, Zinober Kerstin, Regnat Katharina, Semmler Georg, Lackner Carolin, Trauner Michael, Mandorfer Mattias, Schwabl Philipp, Reiberger Thomas
Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Vienna Hepatic Haemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
United European Gastroenterol J. 2025 Apr;13(3):317-329. doi: 10.1002/ueg2.12643. Epub 2024 Dec 21.
Portal hypertension (PH) resulting from static and dynamic intrahepatic changes drives liver-related complications even after removing the underlying aetiological factor.
We investigated the impact of inflammation on the dynamic component of PH during disease regression in animal models of toxin-induced cirrhosis and patients with alcohol-related cirrhosis.
In mice, cirrhosis was induced via toxin application for 12 weeks followed by toxin-withdrawal allowing for one or 2 weeks of regression. Furthermore, 128 patients with alcohol-related cirrhosis and alcohol abstinence undergoing same-day hepatic venous pressure gradient (HVPG) and liver stiffness measurement (LSM) were included. The influence of inflammation on the dynamic PH component was assessed using linear models. Specifically, we explored proinflammatory changes in mice/patients in whom the measured portal pressure (PP)/HVPG was significantly higher than the PP/HVPG expected from the static PH component (histological collagen proportionate area [CPA; %] in mice, LSM in patients).
In mice, toxin discontinuation induced a significant decrease in PP, CPA, histological hepatic inflammation and hepatic expression of proinflammatory genes (Tnfa, Il6, Cxcl1, Mcp1; all p < 0.05 for one/2 week regression vs. peak disease). Similarly, prolonged abstinence in alcohol-related cirrhosis was linked to lower HVPG/LSM and longer abstinence was correlated to lower C-reactive protein (CRP), IL-6, immunoglobulin A (IgA) and IgG levels (all p < 0.05). Nevertheless, the persistence of a low-grade proinflammatory state during regression was linked to a higher PP/HVPG than expected from static PH components. In regressive mice, higher hepatic proinflammatory gene expression (Tnfa, Il6, Il1b; all p < 0.05) was linked to higher-than-expected PP. Similarly, higher CRP, IL-6, IgA and IgG and lower complement factor C3c (all p < 0.05) were associated with higher-than-expected HVPG in abstinent patients with alcohol-related cirrhosis.
Although removing the underlying aetiological factor resulted in significant improvements, a persistent hepatic proinflammatory environment remained a key driver of the dynamic PH component in regressive liver disease.
NCT03267615.
由肝脏内静态和动态变化引起的门静脉高压（PH）即使在去除潜在病因后仍会引发肝脏相关并发症。
我们在毒素诱导的肝硬化动物模型和酒精性肝硬化患者中，研究了炎症在疾病消退过程中对PH动态成分的影响。
在小鼠中，通过应用毒素12周诱导肝硬化，随后撤掉毒素，使肝脏有1或2周的消退期。此外，纳入了128例酒精性肝硬化且已戒酒的患者，他们在同一天接受了肝静脉压力梯度（HVPG）和肝脏硬度测量（LSM）。使用线性模型评估炎症对PH动态成分的影响。具体而言，我们探究了小鼠/患者体内促炎变化，这些小鼠/患者的测量门静脉压力（PP）/HVPG显著高于根据静态PH成分（小鼠的组织学胶原比例面积[CPA；%]，患者的LSM）预期的PP/HVPG。
在小鼠中，撤掉毒素导致PP、CPA、组织学肝脏炎症以及促炎基因（Tnfa、Il6、Cxcl1、Mcp1）的肝脏表达显著降低（与疾病高峰期相比，1/2周消退期时所有p<0.05）。同样，酒精性肝硬化患者长期戒酒与较低的HVPG/LSM相关，且戒酒时间越长与较低的C反应蛋白（CRP）、IL-6、免疫球蛋白A（IgA）和IgG水平相关（所有p<0.05）。然而，在消退过程中持续存在的低度促炎状态与高于静态PH成分预期的PP/HVPG相关。在消退期小鼠中，较高的肝脏促炎基因表达（Tnfa、Il6、Il1b；所有p<0.05）与高于预期的PP相关。同样，在酒精性肝硬化戒酒患者中，较高的CRP、IL-6、IgA和IgG以及较低的补体因子C3c（所有p<0.05）与高于预期的HVPG相关。
尽管去除潜在病因后有显著改善，但持续存在的肝脏促炎环境仍是消退期肝病中PH动态成分的关键驱动因素。
NCT03267615。
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