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Endothelial dysfunction markers predict short-term mortality in patients with severe alcoholic hepatitis

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Abstract

Objectives

Alcoholic hepatitis (AH) is a severe condition characterized by a marked inflammatory response and high short-term mortality. Endothelial dysfunction (ED) is an early event in vascular and inflammatory disorders. The aim of this study is to evaluate ED in AH patients.

Methods

Prognostic value of ED biomarkers was evaluated in patients with severe AH (n = 67), compensated alcoholic cirrhosis (n = 15), heavy drinkers without liver disease (n = 15) and controls (n = 9), and in a validation cohort of 50 patients with AH. Gene expression of ED markers was analyzed in liver tissue.

Results

Plasma levels of ED markers such as vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin and von Willebrand factor (vWF) increased along alcohol-related liver disease (ALD) progression. Intergroup analysis showed a significant increase of these markers in AH patients. In addition, VCAM-1 showed a positive correlation with Maddrey, MELD and ABIC scores and inflammation parameters (i.e. C-reactive protein and LPS levels). Importantly, levels of VCAM-1 were higher in patients with increased mortality and were independently associated with short-term survival (90-day) when adjusted by ABIC score. These results were confirmed in an independent cohort of AH patients. In addition, severe AH patients showed altered hepatic expression of ED markers.

Conclusions

In this study we show that advanced ALD and particularly severe AH is associated with an increase of ED biomarkers, which correlate with patient outcomes. These results suggest that ED may be a pathogenic event in AH and highlight endothelial factors as potential biomarkers in AH.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary material. Further questions can be addressed to the corresponding authors.

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Acknowledgements

Authors would like to thank Adrià Juanola for his help with interpretation of the data and statistical analysis and Cristina Millán for her technical support.

Funding

Supported by Fondo de Investigación Sanitaria Carlos III, co-financed by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, “Una manera de hacer Europa” (FIS PI20/00765, FIS PI17/00673, FIS PI12/01265 to P.S.-B., J.C.) and Miguel Servet (CPII16/00041). Funded by the NIH National Institute on Alcohol Abuse and Alcoholism grant 1U01AA026972-01 to P.S.-B. and 1U01AA021908 to R.B. and by the European Foundation for Alcohol Research (ERAB) Grant EA1653 to P.S.-B. D.R.-T. received a grant from the Ministerio de Educación, Cultura y Deporte, FPU program.

Author information

Author notes

  1. Delia Blaya and Teresa Rubio-Tomás contributed equally to this work.

Authors and Affiliations

  1. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/ Rosselló, 149-153, 08036, Barcelona, Spain

    Delia Blaya, Teresa Rubio-Tomás, Daniel Rodrigo-Torres, JuanJosé Lozano, Mar Coll, José Altamirano, Silvia Affò, Oriol Morales-Ibanez, Elisa Pose, Joan Caballería & Pau Sancho-Bru

  2. School of Medicine, University of Crete, 70013, Heraklion, Crete, Greece

    Teresa Rubio-Tomás

  3. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain

    JuanJosé Lozano, Mar Coll, Jordi Gratacós-Ginès, Elisa Pose & Pau Sancho-Bru

  4. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Center for Liver Diseases, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA

    Josepmaria Argemi & Ramon Bataller

  5. Liver Unit, Clínica Universidad de Navarra, Hepatology Program, Centro de Investigación Medica Aplicada, IdisNA, Universidad de Navarra, Pamplona, Spain

    Josepmaria Argemi

  6. Liver Unit, Hospital Clínic, Barcelona, Spain

    Elisa Pose & Joan Caballería

  7. Service d’Hépatologie, DHU Unity, Pôle des Maladies de l’Appareil Digestif, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Paris, France

    Marion Tanguy, Tazime Issoufaly & Pierre-Emmanuel Rautou

  8. Centre de Référence des Maladies Vasculaires du Foie, French Network for Rare Liver Diseases, European Reference Network Rare-Liver, Centre de Recherche sur l’inflammation, Inserm, Université de Paris, Paris, France

    Marion Tanguy, Tazime Issoufaly & Pierre-Emmanuel Rautou

  9. Universitat de Barcelona, Barcelona, Spain

    Pau Sancho-Bru

Authors
  1. Delia Blaya
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  2. Teresa Rubio-Tomás
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  3. Daniel Rodrigo-Torres
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  4. JuanJosé Lozano
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Contributions

DB and TR-T performed the analysis, interpreted the data and wrote the manuscript, DR-T and SA participated in the experiments and critically reviewed the manuscript, JJL performed bioinformatic analysis, OM-I participated in the experiments, MC critically reviewed the manuscript, JG-G, EP and JA collected patients’ data and critically reviewed the manuscript, MT, TI, PE-R and RB collected patients’ data, JA and JC designed the study, and PS-B designed the study and supervised the manuscript.

Corresponding author

Correspondence to Pau Sancho-Bru.

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Conflict of interest

All authors declare no conflicts of interest.

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Informed consent was obtained from all individual participants included in the study.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Hospital Clinic of Barcelona and Beaujon Hospital) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Animal research

This article does not contain any studies with animals performed by any of the authors.

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Blaya, D., Rubio-Tomás, T., Rodrigo-Torres, D. et al. Endothelial dysfunction markers predict short-term mortality in patients with severe alcoholic hepatitis. Hepatol Int 15, 1006–1017 (2021). https://doi.org/10.1007/s12072-021-10165-y

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  • DOI: https://doi.org/10.1007/s12072-021-10165-y

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