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Original article
Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis
  1. Pavel Strnad1,2,
  2. Stephan Buch3,
  3. Karim Hamesch1,2,
  4. Janett Fischer4,
  5. Jonas Rosendahl4,5,
  6. Renate Schmelz3,
  7. Stefan Brueckner3,
  8. Mario Brosch3,
  9. Carolin V Heimes1,
  10. Vivien Woditsch1,
  11. David Scholten1,
  12. Hans Dieter Nischalke6,
  13. Sabina Janciauskiene7,
  14. Mattias Mandorfer8,
  15. Michael Trauner8,
  16. Michael J Way9,10,
  17. Andrew McQuillin10,
  18. Matthias C Reichert11,
  19. Marcin Krawczyk11,12,
  20. Markus Casper11,
  21. Frank Lammert11,
  22. Felix Braun13,
  23. Witigo von Schönfels13,
  24. Sebastian Hinz13,
  25. Greta Burmeister13,
  26. Claus Hellerbrand14,
  27. Andreas Teufel15,
  28. Alexandra Feldman16,
  29. Joern M Schattenberg17,
  30. Heike Bantel18,
  31. Anita Pathil19,
  32. Muenevver Demir20,
  33. Johannes Kluwe21,
  34. Tobias Boettler22,
  35. Monika Ridinger23,
  36. Norbert Wodarz24,
  37. Michael Soyka25,
  38. Marcella Rietschel26,
  39. Falk Kiefer26,
  40. Thomas Weber27,
  41. Silke Marhenke18,
  42. Arndt Vogel18,
  43. Holger Hinrichsen28,
  44. Ali Canbay29,30,
  45. Martin Schlattjan30,
  46. Katharina Sosnowsky31,
  47. Christoph Sarrazin31,
  48. Johann von Felden21,
  49. Andreas Geier32,
  50. Pierre Deltenre33,34,
  51. Bence Sipos35,
  52. Clemens Schafmayer13,
  53. Michael Nothnagel36,
  54. Elmar Aigner16,
  55. Christian Datz37,
  56. Felix Stickel38,
  57. Marsha Yvonne Morgan9,
  58. Jochen Hampe3,
  59. Thomas Berg4,
  60. Christian Trautwein1,2
  1. 1 Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
  2. 2 Coordinating Center for Alpha1-antitrypsin Deficiency-related Liver Disease of the European Reference Network (ERN) ’Rare Liver', European Association for the Study of the Liver (EASL) Registry Group ’Alpha1-Liver', Aachen, Germany
  3. 3 Medical Department 1, University Hospital Dresden, Dresden, Germany
  4. 4 Section of Hepatology, Department of Internal Medicine, University Hospital Leipzig, Leipzig, Germany
  5. 5 Department of Internal Medicine I, University Hospital Halle, Martin Luther University, Halle, Germany
  6. 6 Department of Internal Medicine I, University of Bonn, Bonn, Germany
  7. 7 Clinic for Pneumology, German Center for Lung Research (DZL), Medical University Hannover, Hannover, Germany
  8. 8 Clinic for Gastroenterology und Hepatology, Medical University Vienna, Vienna, Austria
  9. 9 Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
  10. 10 Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK
  11. 11 Department of Medicine II, Saarland University Medical Center, Homburg, Germany
  12. 12 Laboratory of Metabolic Liver Diseases, Department of General, Transplantation and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
  13. 13 Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany
  14. 14 Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
  15. 15 Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
  16. 16 Department of Internal Medicine I, University Hospital Salzburg, Salzburg, Austria
  17. 17 Department of Medicine I, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany
  18. 18 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
  19. 19 Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
  20. 20 Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany
  21. 21 I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  22. 22 Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
  23. 23 Department of Psychology, University of Konstanz, Konstanz, Germany
  24. 24 Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany
  25. 25 Psychiatric Hospital, Ludwig Maximilians University, Munich, Germany
  26. 26 Faculty of Medicine Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
  27. 27 Department for Clinical Research, University Hospital Bern, Bern, Switzerland
  28. 28 Department of Gastroenterology, University Hospital Kiel, Kiel, Germany
  29. 29 Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
  30. 30 Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany
  31. 31 Department of Internal Medicine 1, J.W. Goethe University Hospital Frankfurt, Frankfurt, Germany
  32. 32 Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany
  33. 33 Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
  34. 34 Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
  35. 35 Institute of Pathology, University of Tuebingen, Tuebingen, Germany
  36. 36 Cologne Center for Genomics, University of Cologne, Cologne, Germany
  37. 37 Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria
  38. 38 Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
  1. Correspondence to Dr Thomas Berg, Section of Hepatology, Department of Internal Medicine, University Hospital Leipzig, Leipzig 04103, Germany; thomas.berg{at}


Objective Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.

Design We analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.

Results The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).

Conclusion The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.

  • alpha1-antitrypsin deficiency
  • alcoholic liver disease
  • NASH
  • fibrosis

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  • PS, SB and KH contributed equally.

  • JH, TB and CT contributed equally.

  • Contributors Study concept and design: PS, KH, FS, MYM, JH, ThB and CT. Acquisition of data: PS, SB, KH, JR, JF, RS, SB, MB, CVH, VW, DS, HDN, MM, MT, MJW, AM, MCR, MK, FL, FB, WvS, CH, AT, AF, JMS, HB, AP, MD, JK, ToB, MCR, NW, MS, MR, FK, TW, SM, AV, HH, AC, MS, KS, ChS, JVF, SH, GB, AG, PD, BS, ClS, EA, CD, FS, MYM, JH and ThB. Analysis and interpretation of data: PS, SB, KH, MK, SJ, MM, BS, MN, EA, MYM, JH and CT. Drafting of the manuscript: PS, KH, SJ, MYM, JH, ThB and CT. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: PS, SB, KH and MN. Figures and tables: PS, SB, KH, MYM and CT. Obtained funding: PS, KH, HDN, FL, MM, MT, CS, FS, MYM, JH and CT. Study supervision: PS, SB, KH, EA, FS, MYM, JH, ThB and CT. All authors had full access to all of the data and approved the final version of this manuscript. All authors can take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding This work was supported by the EASL registry grant on alpha1-antitrypsin-related liver disease (to PS and CT), the Interdisciplinary Center for Clinical Research (IZKF) within the faculty of Medicine at the RWTH Aachen University (to PS), the Else Kröner Excellence Fellowship (to PS), the Deutsche Forschungsgemeinschaft (DFG) consortium SFB/TRR57 ‘Liver fibrosis’ (to PS and CT), the German Liver Foundation (to KH), the German Gastroenterological Association (to KH), the German Ministry of Education and Research through the Virtual Liver Network (to JH), the Swiss National Funds (grant 310030_138747 to FS), the Deutsche Krebshilfe (to HDN), the Liver Systems Medicine (BMBF LiSyM 031L0051 to FL and CT), the Joseph-Skoda Award of the Austrian Society of Internal Medicine (to MM), the European Union 7th framework programme (/FP7/2007-2013, project ‘FLIP’ to MT). The British-Irish research effort was funded by a PhD studentship award jointly funded by University College London and an anonymous donor (to MYM). The non-alcoholic fatty liver disease cohort was supported by the German Ministry of Education and Research through the Virtual Liver and Liver Systems Medicine (LiSyM) Projects and through institutional funds from the Medical Faculty of the University of Kiel (to CS).

  • Disclaimer We attest that we did not use any copyright-protected material in our manuscript. No writing assistance was provided.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval The study protocol was approved by the responsible local ethics committee of participating multiple centres in Germany, Switzerland, Austria and Great Britain.

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

  • Data sharing statement Patient level data, technical appendix and statistical code are available from the corresponding author and can be shared upon request. An informed consent for data sharing was not obtained from study participants, but the presented data are anonymised and the risk of identification is low.

  • Correction notice This article has been corrected since it published Online First. Figure 5B has been corrected.