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Interaction of inflammation and portal hypertension in cirrhosis progression

Nature Reviews Gastroenterology & Hepatology (2025)Cite this article

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Abstract

Decompensated cirrhosis describes an advanced clinical stage with clinical complications, such as ascites, variceal bleeding or hepatic encephalopathy, associated with considerable mortality. Portal hypertension is the main risk factor for developing decompensation in patients with compensated cirrhosis, whereas systemic inflammation is the key driving force for organ failure, that is, for acute-on-chronic liver failure in later stages of cirrhosis. As portal hypertension and systemic inflammation coexist in patients with cirrhosis, an improved understanding of their interaction and dynamic role in distinct stages of cirrhosis is an important step forward towards the development of urgently needed therapeutic interventions. Based on emerging evidence from clinical and translational studies, a novel concept of different predominant pathomechanisms of decompensated cirrhosis is presented, which includes portal hypertension-predominant, systemic inflammmation-predominant and mixed portal hypertension–systemic inflammation phenotypes. A comprehensive set of biomarkers and surrogates of portal hypertension and systemic inflammation might assist clinicians in identifying a predominance of one over the other cirrhosis phenotype. As survival rates of patients with decompensated cirrhosis have remained detrimental without liver transplantation over the past decades, future studies should build on this knowledge to develop effective portal hypertension and systemic inflammation-directed therapies for this underserved population.

Key points

  • Cirrhosis decompensation is defined by the development of ascites, variceal bleeding, hepatic encephalopathy, or jaundice and is linked to a considerable increase in the risk for mortality.

  • In compensated cirrhosis, the magnitude of portal hypertension is the key determinant of the risk for developing decompensation.

  • Inflammation, and particularly the severity of systemic inflammation, is particularly pronounced in advanced stages of cirrhosis, that is, in patients with further decompensated cirrhosis or acute-on-chronic liver failure.

  • We propose a concept of ‘pathophysiological’ phenotypes of decompensated cirrhosis by predominance of portal hypertension, systemic inflammation, or even mixed systemic inflammation and portal hypertension.

  • The evidence for the interaction of portal hypertension and systemic inflammation in the key pathomechanism driving cirrhosis decompensation and end-organ dysfunction or failure is presented.

  • A summary of promising therapeutic approaches targeting portal hypertension and systemic inflammation for which translational or clinical studies have been or are being conducted is presented.

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Fig. 1: Clinico-pathophysiological correlates in patients with different cirrhosis phenotypes.
Fig. 2: Organ-level consequences of PH and inflammation in cirrhosis.
Fig. 3: Model for the role of SI and PH in accentuating cirrhosis progression and acute-on-chronic liver failure development, including therapeutic approaches targeting the presented pathomechanisms.

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Acknowledgements

The authors acknowledge Lidia Garcia-Campmany for her valuable contribution in designing Fig. 3 of the manuscript.

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Authors and Affiliations

  1. Gastroenterology Department, Braga Hospital, Braga, Portugal

    Dalila Costa

  2. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal

    Dalila Costa

  3. Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria

    Dalila Costa & Thomas Reiberger

  4. Department of Internal Medicine B, University of Münster, Münster, Germany

    Jonel Trebicka

  5. European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain

    Jonel Trebicka, Richard Moreau & Rajiv Jalan

  6. Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany

    Cristina Ripoll

  7. INSERM, Université Paris Cité, Centre de Recherche sur l’Inflammation, Paris, France

    Richard Moreau

  8. Hôpital Beaujon, Service d’hépatologie, Clichy, France

    Richard Moreau

  9. Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom

    Rajiv Jalan

  10. Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria

    Thomas Reiberger

Authors
  1. Dalila Costa
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  2. Jonel Trebicka
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  3. Cristina Ripoll
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  4. Richard Moreau
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  5. Rajiv Jalan
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  6. Thomas Reiberger
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Thomas Reiberger.

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Competing interests

J.T. has received speaking and/or consulting fees from Versantis, Gore, Boehringer-Ingelheim, Falk, Grifols, Genfit and CSL Behring. C.R. has received speaker fees from GORE, Falk Foundation and Bristol-Myers Squibb, and has acted as a consultant for Boerhinger-Ingelheim. C.R. receives funding from the DFG (Deutsche Forschung Gemeinschaft) project number 431667134 and the European Union Horizon 2020 research and innovation programme under grant agreement 101136299 ARTEMIS. R.J. is the founder of Yaqrit Discovery Limited, which owns Amalive Limited and Enterosorb Limited; is a co-founder of Cyberliver Limited and Hepyx Limited; has received payment for sponsored talks and grant reviews from Grifols; and has received consulting fees from Boehringer Ingelheim. T.R. has received grant support from Abbvie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens and W. L. Gore & Associates; speaking/writing honoraria from Abbvie, Echosens, Gilead, GSK, Intercept/Advanz Pharma, Pfizer, Roche, MSD, Siemens and W. L. Gore & Associates; consulting/advisory board fees from Abbvie, Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics and Siemens; and travel support from Abbvie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead and Roche. D.C. and R.M. declare no competing interests.

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Peer review information

Nature Reviews Gastroenterology & Hepatology thanks Chien-Hao Huang and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Dedication

We dedicate this article, which provides an integrated view on the pathogenesis of cirrhosis complications, to the memory of Professor Jaume Bosch — a great teacher, mentor, colleague and dear friend to all of us, whose pioneering efforts in developing new concepts and therapies in the field of portal hypertension are immeasurable. Jaume was more than a brilliant clinician–scientist; he was a source of inspiration, wisdom, generosity and warmth for everyone privileged to work with him. His passion for advancing knowledge in the field of cirrhosis was matched only by his zest for life and love for his friends and family. Many of us owe our careers — and our love for hepatology — to his guidance and example. This article stands as a small tribute to a remarkable man whose legacy will continue to shape and inspire us.

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Related links

CANONIC: https://efclif.com/projects/canonic-chronic-liver-failure-acute-on-chronic-liver-failure/

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Costa, D., Trebicka, J., Ripoll, C. et al. Interaction of inflammation and portal hypertension in cirrhosis progression. Nat Rev Gastroenterol Hepatol (2025). https://doi.org/10.1038/s41575-025-01107-2

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