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Gut. 2019 Jun;68(6):1099-1107. doi: 10.1136/gutjnl-2018-316228. Epub 2018 Aug 1.

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

Author information

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

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

PMID:
30068662
DOI:
10.1136/gutjnl-2018-316228
[Indexed for MEDLINE]

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