• Pavel Strnad, Stephan Buch, Karim Hamesch, Janett Fischer, Jonas Rosendahl, Renate Schmelz, Stefan Brueckner, Mario Brosch, Carolin V Heimes, Vivien Woditsch, David Scholten, Hans Dieter Nischalke, Sabina Janciauskiene, Mattias Mandorfer, Michael Trauner, Michael J Way, Andrew McQuillin, Matthias C Reichert, Marcin Krawczyk, Markus Casper, Frank Lammert, Felix Braun, Witigo von Schönfels, Sebastian Hinz, Greta Burmeister, Claus Hellerbrand, Andreas Teufel, Alexandra Feldman, Joern M Schattenberg, Heike Bantel, Anita Pathil, Muenevver Demir, Johannes Kluwe, Tobias Boettler, Monika Ridinger, Norbert Wodarz, Michael Soyka, Marcella Rietschel, Falk Kiefer, Thomas Weber, Silke Marhenke, Arndt Vogel, Holger Hinrichsen, Ali Canbay, Martin Schlattjan, Katharina Sosnowsky, Christoph Sarrazin, Johann von Felden, Andreas Geier, Pierre Deltenre, Bence Sipos, Clemens Schafmayer, Michael Nothnagel, Elmar Aigner, Christian Datz, Felix Stickel, Marsha Yvonne Morgan, Jochen Hampe, Thomas Berg, and Christian Trautwein.
• Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
• Gut. 2019 Jun 1; 68 (6): 1099-1107.

ObjectiveHomozygous 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.DesignWe 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.ResultsThe 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)).ConclusionThe 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.© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

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