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Original research
Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans
  1. Christoph Grander1,
  2. Benedikt Schaefer1,
  3. Julian Schwärzler1,
  4. Felix Grabherr1,
  5. Dennis M de Graaf2,
  6. Barbara Enrich1,
  7. Georg Oberhuber3,
  8. Lisa Mayr1,
  9. Moris Sangineto1,
  10. Nikolai Jaschke1,
  11. Timon E Adolph1,
  12. Maria Effenberger1,
  13. Alexander R Moschen1,
  14. Charles A Dinarello2,
  15. Heinz Zoller1,
  16. Herbert Tilg1
  1. 1 Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
  2. 2 Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
  3. 3 INNPATH, Institute of Pathology, University Hospital of Innsbruck, Innsbruck, Austria
  1. Correspondence to Professor Herbert Tilg, Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck 6020, Austria; herbert.tilg{at}i-med.ac.at

Abstract

Objective Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD.

Design An unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models.

Results Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis.

Conclusion Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.

  • ALCOHOLIC LIVER DISEASE
  • LIVER CIRRHOSIS

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Footnotes

  • CG, BS and JS contributed equally.

  • Contributors CG, BS, JS and FG designed, performed and analysed both human studies and animal experiments together with DMD and BE. GO performed histological analysis. CAD provided the alpha-1 antitrypsin transgenic mice. TEA, LM, MS, NJ, ME, CAD and ARM provided expertise and edited the manuscript. CG, BS and JS prepared the manuscript. HZ and HT coordinated the project.

  • Funding This study is supported by the excellence initiative VASCage (Centre for Promoting Vascular Health in the Ageing Community), an R&D K-Centre (COMET program - Competence Centers for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol, Salzburg and Vienna.This research was funded by a private donation by the Fischer family.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval This single-centre retrospective study was approved by the ethics committee of the Medical University of Innsbruck (study number UN4218/AN3478)

  • Provenance and peer review Not commissioned; externally peer reviewed.

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