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Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis

  • Author Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.
    Mauro Bernardi
    Correspondence
    Corresponding author. Address: Semeiotica Medica, Policlinico S. Orsola-Malpighi, Via Albertoni 15, 40138 Bologna, Italy. Tel.: +39 051391549; fax: +39 0516362930.
    Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.
    Affiliations
    Department of Medical and Surgical Sciences – Alma Mater Studiorum, University of Bologna, Italy

    Semeiotica Medica, Policlinico S. Orsola-Malpighi, Bologna, Italy
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  • Author Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.
    Richard Moreau
    Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.
    Affiliations
    Inserm, U1149, Centre de Recherche sur l’Inflammation (CRI), Paris, France

    UMR_S1149, Université Paris Diderot, Faculté de Médecine, Paris, France

    Département Hospitalo-Universitaire (DHU) UNITY, Service d’Hépatologie, Hôpital Beaujon, AP-HP, Clichy, France
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  • Author Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.
    Paolo Angeli
    Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.
    Affiliations
    Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine-DIMED, University of Padova, Padova, Italy
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  • Author Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.
    Bernd Schnabl
    Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.
    Affiliations
    Department of Medicine, University of California San Diego, La Jolla, CA, United States

    Department of Medicine, VA San Diego Healthcare System, San Diego, CA, United States
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  • Author Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.
    Vicente Arroyo
    Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.
    Affiliations
    Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain

    Institut d’Investigacions Biomediques Agust Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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  • Author Footnotes
    † EASL-CLIF Consortium, Barcelona, Spain.

      Summary

      The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has given rise to hundreds of pathophysiological studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multiorgan dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance.

      Abbreviations:

      PAVH (peripheral arterial vasodilation hypothesis), HRS (hepatorenal syndrome), PRA (plasma renin activity), SNS (sympathetic nervous system), ACLF (acute-on-chronic liver failure), PAMPs (pathogen-associated molecular patterns), PRRs (pattern recognition receptors), TLR(s) (toll-like receptors), DAMPs (danger-associated molecular patterns), ECM (extracellular matrix), C-RP (plasma C-reactive protein), ROS (reactive oxygen species), TNF (tumor necrosis factor), IL (interleukin), HE (hepatic encephalopathy), BT (bacterial translocation), MLNs (mesenteric lymph nodes), NO (nitric oxide), CO (carbon monoxide), VEGFs (vascular endothelial growth factors), KATP (adenosine triphosphate-sensitive potassium channels), GMP (guanosine 5′ monophosphate), NOS (nitric oxide synthase), HSP (heat shock protein), BH4 (tetrahydrobiopterin), RTKs (receptor tyrosine kinases), LPS (lipopolysaccharide), GTP (guanosine 5′ triphosphate), AKI (acute kidney injury), HPS (hepatopulmonary syndrome), IPVD (intrapulmonary vasodilatation), CX3CL1 (fractaline chemokine), RAI (relative adrenal insufficiency), PICD (paracentesis-induced circulatory dysfunction), SBP (spontaneous bacterial peritonitis), SIH (systemic inflammation hypothesis)

      Keywords

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