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

Gut - Tập 68 Số 6 - Trang 1099-1107 - 2019
Pavel Strnad1,2, Stephan Buch3, Karim Hamesch1,2, Janett Fischer4, Jonas Rosendahl5,4, Renate Schmelz3, Stefan Brueckner3, Mario Brosch3, Carolin V. Schneider2, V Woditsch2, David Scholten2, Hans Dieter Nischalke6, Sabina Janciauskiene7, Mattias Mandorfer8, Michael Trauner8, M. J. Way9,10, Andrew McQuillin10, Matthias Reichert11, Marcin Krawczyk11,12, Markus Casper11, Frank Lammert11, Felix Braun13, Witigo von Schönfels13, Sebastian Hinz13, Greta Burmeister13, Claus Hellerbrand14, Andreas Teufel15, A. Feldman16, Jörn M. Schattenberg17, Heike Bantel18, Anita Pathil19, Münevver Demir20, Johannes Kluwe21, Tobias Boettler22, Monika Ridinger23, Norbert Wodarz24, Michael B. Soyka25, Marcella Rietschel26, Falk Kiefer26, Thomas Weber27, Silke Marhenke18, Arndt Vogel18, Holger Hinrichsen28, Ali Canbay29,30, Martin Schlattjan29, K Sosnowsky31, Christoph Sarrazin31, Johann von Felden21, Andreas Geier32, Pierre Deltenre33,34, Bence Sipos35, Frederik J. Hes13, Michael Nothnagel36, Elmar Aigner16, Christian Datz37, Felix Stickel38, Marsha Y. Morgan9, Jochen Hampe3, Thomas Berg39, Christian Trautwein1,2
1Coordinating 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
2Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
3Medical Department 1, University Hospital Dresden, Dresden, Germany
4Section of Hepatology, Department of Internal Medicine, University Hospital Leipzig, Leipzig, Germany
5Department of Internal Medicine I, University Hospital Halle, Martin Luther University, Halle, Germany
6Department of Internal Medicine I, University of Bonn, Bonn, Germany
7Clinic for Pneumology, German Center for Lung Research (DZL), Medical University Hannover, Hannover, Germany
8Clinic for Gastroenterology und Hepatology, Medical University Vienna, Vienna, Austria
9Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
10Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK
11Department of Medicine II, Saarland University Medical Center, Homburg, Germany
12Laboratory of Metabolic Liver Diseases, Department of General, Transplantation and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
13Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany
14Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
15Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
16Department of Internal Medicine I, University Hospital Salzburg, Salzburg, Austria
17Department of Medicine I, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany
18Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
19Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
20Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany
21I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
22Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
23Department of Psychology, University of Konstanz, Konstanz, Germany
24Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany
25Psychiatric Hospital, Ludwig Maximilians University, Munich, Germany
26Faculty of Medicine Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
27Department for Clinical Research, University Hospital Bern, Bern, Switzerland
28Department of Gastroenterology, University Hospital Kiel, Kiel, Germany
29Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany
30Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
31Department of Internal Medicine 1, J.W. Goethe University Hospital Frankfurt, Frankfurt, Germany
32Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany
33Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
34Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
35Institute of Pathology, University of Tuebingen, Tuebingen, Germany
36Cologne Center for Genomics, University of Cologne, Cologne, Germany;
37Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, Oberndorf, Austria
38Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
39Section of Hepatology, Department of Internal Medicine, University Hospital Leipzig, Leipzig 04103, Germany

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

10.1016/S0140-6736(16)31470-2

10.1016/S0140-6736(09)60746-7

10.1053/j.gastro.2012.04.001

Anstee, 2016, Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease, Gastroenterology, 150, 1728, 10.1053/j.gastro.2016.01.037

10.1053/j.gastro.2015.08.011

Stickel, 2017, The genetics of alcohol dependence and alcohol-related liver disease, J Hepatol, 66, 195, 10.1016/j.jhep.2016.08.011

Greene, 2016, α1-Antitrypsin deficiency, Nat Rev Dis Primers, 2, 16051, 10.1038/nrdp.2016.51

10.1056/NEJMcp0900449

Blanco, 2017, Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers worldwide: an update, Int J Chron Obstruct Pulmon Dis, 12, 561, 10.2147/COPD.S125389

Strnad, 2013, Broad spectrum of hepatocyte inclusions in humans, animals, and experimental models, Compr Physiol, 3, 1393, 10.1002/cphy.c120032

10.1056/NEJM198603203141202

10.1164/rccm.168.7.818

10.1002/hep.21329

Goltz, 2014, Α1-antitrypsin PiMZ heterozygosity has an independent aggravating effect on liver fibrosis in alcoholic liver disease, Virchows Arch, 465, 539, 10.1007/s00428-014-1633-3

10.1016/S0168-8278(00)80119-1

Propst, 1992, High prevalence of viral infection in adults with homozygous and heterozygous alpha 1-antitrypsin deficiency and chronic liver disease, Ann Intern Med, 117, 641, 10.7326/0003-4819-117-8-641

Al-Jameil N , Hassan AA , Buhairan A , et al . Genotyping diagnosis of alpha-1 antitrypsin deficiency in Saudi adults with liver cirrhosis. Medicine 2017;96:e6071.doi:10.1097/MD.0000000000006071

Schaefer, 2018, Heterozygosity for the alpha-1-antitrypsin Z allele in cirrhosis is associated with more advanced disease, Liver Transpl, 24, 744, 10.1002/lt.25057

Eriksson, 1975, Liver, lung and malignant disease in heterozygous (Pi MZ) alpha1-antitrypsin deficiency, Acta Med Scand, 198, 243, 10.1111/j.0954-6820.1975.tb19535.x

Hodges, 1981, Heterozygous MZ alpha 1-antitrypsin deficiency in adults with chronic active hepatitis and cryptogenic cirrhosis, N Engl J Med, 304, 557, 10.1056/NEJM198103053041001

Bell, 1990, Heterozygous MZ alpha-1-antitrypsin deficiency in adults with chronic liver disease, Scand J Gastroenterol, 25, 788, 10.3109/00365529008999216

Eigenbrodt, 1997, Heterozygous alpha 1-antitrypsin phenotypes in patients with end stage liver disease, Am J Gastroenterol, 92, 602

10.1016/S0168-8278(97)80278-4

10.1002/hep.510280421

10.1097/01.mpg.0000226387.56612.1e

Feldman, 2017, Clinical and Metabolic Characterization of Lean Caucasian Subjects With Non-alcoholic Fatty Liver, Am J Gastroenterol, 112, 102, 10.1038/ajg.2016.318

Stättermayer, 2017, Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome, J Trace Elem Med Biol, 39, 100, 10.1016/j.jtemb.2016.08.006

Teufel, 2016, Comparison of Gene Expression Patterns Between Mouse Models of Nonalcoholic Fatty Liver Disease and Liver Tissues From Patients, Gastroenterology, 151, 513, 10.1053/j.gastro.2016.05.051

10.1073/pnas.1412759111

Eslam, 2016, Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes, Hepatology, 64, 34, 10.1002/hep.28475

10.1038/ajg.2010.170

10.1111/j.1365-2796.2011.02377.x

10.1194/jlr.P067454

10.1038/ng.3417

10.1002/humu.20306

Cacciottolo, 2014, Pi*Z heterozygous alpha-1 antitrypsin states accelerate parenchymal but not biliary cirrhosis, Eur J Gastroenterol Hepatol, 26, 412, 10.1097/MEG.0000000000000061

10.1172/JCI4874

10.1002/hep.23622

Liu, 2014, TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease, Nat Commun, 5, 4309, 10.1038/ncomms5309

Mancina, 2016, The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent, Gastroenterology, 150, 1219, 10.1053/j.gastro.2016.01.032

10.1056/NEJMra010772

Weinstein, 1991, Ethanol induces a1-protease inhibitor mRNA in Hep 3B cells, J Surg Res, 51, 463, 10.1016/0022-4804(91)90165-I

10.1126/science.1190354

10.1016/j.jhep.2010.11.005

10.1038/nrendo.2016.124

Ueno, 2017, Autophagy in the liver: functions in health and disease, Nat Rev Gastroenterol Hepatol, 14, 170, 10.1038/nrgastro.2016.185

10.1016/j.cmet.2013.03.005

Ferrarotti I , Poplawska-Wisniewska B , Trevisan MT , et al . How Can We Improve the Detection of Alpha1-Antitrypsin Deficiency? PLoS One 2015;10:e0135316.doi:10.1371/journal.pone.0135316

10.1111/j.1478-3231.2009.02179.x

Thông tin
Thông tin xuất bản

Gut

Tập 68 Số 6

1099-1107

Thông tin tác giả