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Updated: Jun 4, 2025
Invasive Hemodynamic Characterization of the Portal-hypertensive Syndrome in Cirrhotic Rats
Published on: August 1, 2018
Inflammation remains a dynamic component of portal hypertension in regressive alcohol-related cirrhosis
Benedikt Silvester Hofer1,2,3, Benedikt Simbrunner1,2,3,4, Philipp Königshofer1,3
1Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Background:
Portal hypertension (PH) resulting from static and dynamic intrahepatic changes drives liver-related complications even after removing the underlying aetiological factor.
Objective:
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.
Methods:
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).
Results:
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.
Conclusions:
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.
Clinical Trial Number:
NCT03267615.
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