Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Pavel Strnad^#^{1

2}, Stephan Buch^#³, Karim Hamesch^#^{1

2}, Janett Fischer⁴, Jonas Rosendahl^{4

5}, Renate Schmelz³, Stefan Brueckner³, Mario Brosch³, Carolin V Heimes¹, Vivien Woditsch¹, David Scholten¹, Hans Dieter Nischalke⁶, Sabina Janciauskiene⁷, Mattias Mandorfer⁸, Michael Trauner⁸, Michael J Way^{9

10}, Andrew McQuillin¹⁰, Matthias C Reichert¹¹, Marcin Krawczyk^{11

12}, Markus Casper¹¹, Frank Lammert¹¹, Felix Braun¹³, Witigo von Schönfels¹³, Sebastian Hinz¹³, Greta Burmeister¹³, Claus Hellerbrand¹⁴, Andreas Teufel¹⁵, Alexandra Feldman¹⁶, Joern M Schattenberg¹⁷, Heike Bantel¹⁸, Anita Pathil¹⁹, Muenevver Demir²⁰, Johannes Kluwe²¹, Tobias Boettler²², Monika Ridinger²³, Norbert Wodarz²⁴, Michael Soyka²⁵, Marcella Rietschel²⁶, Falk Kiefer²⁶, Thomas Weber²⁷, Silke Marhenke¹⁸, Arndt Vogel¹⁸, Holger Hinrichsen²⁸, Ali Canbay^{29

30}, Martin Schlattjan³⁰, Katharina Sosnowsky³¹, Christoph Sarrazin³¹, Johann von Felden²¹, Andreas Geier³², Pierre Deltenre^{33

34}, Bence Sipos³⁵, Clemens Schafmayer¹³, Michael Nothnagel³⁶, Elmar Aigner¹⁶, Christian Datz³⁷, Felix Stickel³⁸, Marsha Yvonne Morgan⁹, Jochen Hampe^#³, Thomas Berg^#⁴, Christian Trautwein^#^{1

2}

Affiliations

¹ Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
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 Medical Department 1, University Hospital Dresden, Dresden, Germany.
⁴ Section of Hepatology, Department of Internal Medicine, University Hospital Leipzig, Leipzig, Germany.
⁵ Department of Internal Medicine I, University Hospital Halle, Martin Luther University, Halle, Germany.
⁶ Department of Internal Medicine I, University of Bonn, Bonn, Germany.
⁷ Clinic for Pneumology, German Center for Lung Research (DZL), Medical University Hannover, Hannover, Germany.
⁸ Clinic for Gastroenterology und Hepatology, Medical University Vienna, Vienna, Austria.
⁹ Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK.
¹⁰ Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
¹¹ Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
¹² Laboratory of Metabolic Liver Diseases, Department of General, Transplantation and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
¹³ Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
¹⁴ Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
¹⁵ Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
¹⁶ Department of Internal Medicine I, University Hospital Salzburg, Salzburg, Austria.
¹⁷ Department of Medicine I, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany.
¹⁸ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
¹⁹ Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany.
²⁰ Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany.
²¹ I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²² Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
²³ Department of Psychology, University of Konstanz, Konstanz, Germany.
²⁴ Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
²⁵ Psychiatric Hospital, Ludwig Maximilians University, Munich, Germany.
²⁶ Faculty of Medicine Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
²⁷ Department for Clinical Research, University Hospital Bern, Bern, Switzerland.
²⁸ Department of Gastroenterology, University Hospital Kiel, Kiel, Germany.
²⁹ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.
³⁰ Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany.
³¹ Department of Internal Medicine 1, J.W. Goethe University Hospital Frankfurt, Frankfurt, Germany.
³² Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany.
³³ Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
³⁴ Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
³⁵ Institute of Pathology, University of Tuebingen, Tuebingen, Germany.
³⁶ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
³⁷ Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria.
³⁸ Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.

^# Contributed equally.

PMID: 30068662
DOI: 10.1136/gutjnl-2018-316228

Multicenter Study

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Pavel Strnad et al. Gut. 2019 Jun.

. 2019 Jun;68(6):1099-1107.

doi: 10.1136/gutjnl-2018-316228. Epub 2018 Aug 1.

Authors

Affiliations

¹ Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
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 Medical Department 1, University Hospital Dresden, Dresden, Germany.
⁴ Section of Hepatology, Department of Internal Medicine, University Hospital Leipzig, Leipzig, Germany.
⁵ Department of Internal Medicine I, University Hospital Halle, Martin Luther University, Halle, Germany.
⁶ Department of Internal Medicine I, University of Bonn, Bonn, Germany.
⁷ Clinic for Pneumology, German Center for Lung Research (DZL), Medical University Hannover, Hannover, Germany.
⁸ Clinic for Gastroenterology und Hepatology, Medical University Vienna, Vienna, Austria.
⁹ Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK.
¹⁰ Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
¹¹ Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
¹² Laboratory of Metabolic Liver Diseases, Department of General, Transplantation and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
¹³ Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
¹⁴ Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
¹⁵ Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
¹⁶ Department of Internal Medicine I, University Hospital Salzburg, Salzburg, Austria.
¹⁷ Department of Medicine I, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany.
¹⁸ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
¹⁹ Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany.
²⁰ Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany.
²¹ I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²² Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
²³ Department of Psychology, University of Konstanz, Konstanz, Germany.
²⁴ Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
²⁵ Psychiatric Hospital, Ludwig Maximilians University, Munich, Germany.
²⁶ Faculty of Medicine Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
²⁷ Department for Clinical Research, University Hospital Bern, Bern, Switzerland.
²⁸ Department of Gastroenterology, University Hospital Kiel, Kiel, Germany.
²⁹ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.
³⁰ Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany.
³¹ Department of Internal Medicine 1, J.W. Goethe University Hospital Frankfurt, Frankfurt, Germany.
³² Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany.
³³ Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
³⁴ Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
³⁵ Institute of Pathology, University of Tuebingen, Tuebingen, Germany.
³⁶ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
³⁷ Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria.
³⁸ Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.

^# Contributed equally.

PMID: 30068662
DOI: 10.1136/gutjnl-2018-316228

Abstract

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.

Keywords: NASH; SERPINA1; alcoholic liver disease; alpha1-antitrypsin deficiency; fibrosis.

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Conflict of interest statement

Competing interests: None declared.

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Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Affiliations

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Research Materials

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