. 2025 Mar 20;7(6):101398.

doi: 10.1016/j.jhepr.2025.101398. eCollection 2025 Jun.

Severe alpha-1 antitrypsin deficiency is associated with a higher risk of complications after first decompensation than other aetiologies of cirrhosis

Lorenz Balcar^{1

2}, Malin Fromme³, Naomi Kappe⁴, Benedikt Schaefer⁵, Soňa Fraňková⁶, Lukas van Melkebeke⁷, Jan Stolk⁴, Mathias Jachs^{1

2

8}, Georg Semmler^{1

2}, Benedikt S Hofer^{1

2}, Tammo L Tergast⁸, Hannah Rieland⁸, Anna Sophie Karl³, Jan Sperl⁶, Martin Wagner⁹, Mònica Pons¹⁰, Harald Hofer¹¹, Markus Peck-Radosavljevic¹², Michael Trauner¹, Thomas Reiberger^{1

2}, Benjamin Maasoumy⁸, Heinz Zoller⁵, Bart van Hoek⁴, Jef Verbeek⁷, Pavel Strnad^{3

13}, Mattias Mandorfer^{1

2}

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.
² Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
³ Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.
⁴ Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria.
⁶ Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Prague, Czech Republic.
⁷ Department of Gastroenterology and Hepatology, KU Leuven University Hospitals, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Leuven, Belgium.
⁸ Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
⁹ Department of Gastroenterology and Hepatology, Medical University Graz, Austria.
¹⁰ Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research, Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Barcelona, Spain.
¹¹ Department of Internal Medicine I, Klinikum Wels-Grieskirchen, Wels, Austria.
¹² Department of Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology Including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria.
¹³ Coordinating Center for Alpha-1 Antitrypsin Deficiency-related Liver Disease of the European Reference Network (ERN) 'Rare Liver' and the European Association for the Study of the Liver (EASL) Registry Group 'Alpha1- Liver' University Hospital Aachen, Aachen, Germany.

PMID: 40535554
PMCID: PMC12174978
DOI: 10.1016/j.jhepr.2025.101398

Severe alpha-1 antitrypsin deficiency is associated with a higher risk of complications after first decompensation than other aetiologies of cirrhosis

Lorenz Balcar et al. JHEP Rep. 2025.

. 2025 Mar 20;7(6):101398.

doi: 10.1016/j.jhepr.2025.101398. eCollection 2025 Jun.

Authors

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.
² Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
³ Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.
⁴ Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria.
⁶ Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Prague, Czech Republic.
⁷ Department of Gastroenterology and Hepatology, KU Leuven University Hospitals, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Leuven, Belgium.
⁸ Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
⁹ Department of Gastroenterology and Hepatology, Medical University Graz, Austria.
¹⁰ Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research, Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Barcelona, Spain.
¹¹ Department of Internal Medicine I, Klinikum Wels-Grieskirchen, Wels, Austria.
¹² Department of Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology Including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria.
¹³ Coordinating Center for Alpha-1 Antitrypsin Deficiency-related Liver Disease of the European Reference Network (ERN) 'Rare Liver' and the European Association for the Study of the Liver (EASL) Registry Group 'Alpha1- Liver' University Hospital Aachen, Aachen, Germany.

PMID: 40535554
PMCID: PMC12174978
DOI: 10.1016/j.jhepr.2025.101398

Abstract

Background & aims: Alpha-1 antitrypsin deficiency (AATD) causes/predisposes to advanced chronic liver disease. However, the role of the SERPINA1 Pi∗ZZ genotype in patients with decompensated cirrhosis is unclear. Thus, we evaluated the impact of the Pi∗ZZ genotype on the disease course after the first hepatic decompensation event.

Methods: We retrospectively included 59 adults with decompensated cirrhosis and severe AATD (Pi∗ZZ) from 12 European tertiary care centres. First decompensation was considered as baseline. To compare the course of AATD to other cirrhosis aetiologies, we applied propensity score matching for Child-Turcotte-Pugh (CTP) score as well as age/sex. Patients were followed until further decompensation, liver transplantation or liver-related death.

Results: Most patients were male (74.6%), with a mean age of 55 years. The most common type of first decompensation was ascites (n = 40; 67.8%), followed by variceal bleeding (n = 13; 22.0%) and overt hepatic encephalopathy (n = 6; 10.2%). Median CTP and MELD (model for end-stage liver disease) scores at first decompensation were 8 and 14, respectively. Median MELD scores were 16 and 20 points at listing and liver transplantation (median time on list: 2.9 [IQR 1.1-7.2] months), respectively. Patients with other aetiologies (subdistribution hazard ratio: steatotic liver disease: 0.62, 95% CI 0.44-0.88, p = 0.007; abstinent alcohol-associated liver disease: 0.50, 95% CI 0.35-0.71, p <0.001; hepatitis C virus-associated cirrhosis: 0.56, 95% CI 0.37-0.83, p = 0.004) had a significantly lower risk of further hepatic decompensation, liver transplantation, or liver-related death, compared to those with Pi∗ZZ. Exchanging further decompensation with acute-on-chronic liver failure yielded similar results.

Conclusion: Our study defines the course of decompensated cirrhosis in patients with severe AATD (Pi∗ZZ), who are particularly prone to complications of cirrhosis and exhibit a more progressive disease course than those with cirrhosis of other aetiologies.

Impact and implications: Alpha-1 antitrypsin deficiency is an inherited disease that affects the lung and the liver. Carrying two severely dysfunctional copies of the alpha-1 antitrypsin gene may cause advanced chronic liver disease/cirrhosis. Affected individuals with a first complication of cirrhosis are more prone to developing further liver-related events (including multiorgan dysfunction) and requiring liver transplantation (which cures the inherited liver disease) compared to patients who have similarly advanced liver disease. These findings should prompt the development of disease-modifying treatments and early listing for liver transplantation.

Keywords: AATD; acute-on-chronic liver failure; advanced chronic liver disease; ascites; hepatic encephalopathy; liver transplantation; portal hypertension; variceal bleeding.

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Conflict of interest statement

The authors have nothing to disclose regarding the work under consideration for publication. The following authors disclose conflicts of interests outside the submitted work: L.B. received speaker fees from Chiesi and Gilead. M.F. received consulting fees from Takeda and honoraria from CSL Behring, Grifols, and Takeda. N.K. has nothing to disclose. B.S. has nothing to disclose. S.F. received consulting fees from MSD and AOP Orphan; honoraria from AOP Orphan Gilead, and AbbVie; travel support from AbbVie and AOP Orphan; and advisory board fees from AOP Orphan. L.v.M. has nothing to disclose. J.St. has nothing to disclose. M.J. served as a speaker and/or consultant for Gilead. G.S. has nothing to disclose. B.S.H. has nothing to disclose. T.T. served as speaker for Dr. Falk Pharma. H.R. has nothing to disclose. A.S.K. has nothing to disclose. J.Sp. received consulting fees from AOP Orphan and MSD; honoraria from AOP Orphan, AbbVie and Gilead; travel support from AbbVie and AOP Orphan; and advisory board fees from AOP Orphan. M.W. has nothing to disclose. M.P. received speaker fees from CSL Behring and consulting fees from Takeda Pharamaceuticals. H.H. has nothing to disclose. M.P.-R. is advisor/consultant for AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he served as a speaker for Bayer, Eli Lilly, Eisai, Ipsen, and Roche. M.T. received speaker fees from BMS, Falk Foundation, Gilead, Intercept, Ipsen, Jannsen, Madrigal, MSD, and Roche; he advised for AbbVie, Agomab, Albireo, BiomX, Boehringer Ingelheim, Chemomab, Cymabay, Dr. Falk Pharma, Genfit, Gilead, GSK, Hightide, Intercept, Ipsen, Janssen, MSD, Novartis, Phenex, Pliant, Rectify, Regulus, Siemens, and Shire. He further received travel support from AbbVie, Dr. Falk Pharma, Gilead, Intercept, and Jannsen and research grants from Albireo, Alnylam, Cymabay, Dr. Falk Pharma, Genentech, Gilead, Intercept, MSD, Takeda, and UltraGenyx. He is also a co-inventor of patents on the medical use of norUDCA filed by the Medical Universities of Graz and Vienna. T.R. received grant support from AbbVie, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Myr, Philips Healthcare, Pliant, Siemens, and W. L. Gore & Associates; speaking/writing honoraria from AbbVie, Echosens, Gilead, GSK, Intercept/Advanz Pharma, MSD, Pfizer, Roche, Siemens, and W. L. Gore & Associates; consulting/advisory board fees from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Intercept/Advanz Pharma, MSD, Resolution Therapeutics, and Siemens; and travel support from AbbVie, Boehringer Ingelheim, Dr. Falk Pharma, Gilead, and Roche. B.M. served as a speaker and/or advisory board member for AbbVie, Fujirebio, Gilead, Luvos, MSD, Norgine, Roche, W. L. Gore & Associates and received research support from Altona, ewimed, Fujirebio, and Roche. H.Z. received grant support from Pharmacosmos and Vifor as well as honoraria for lecturing from Pharmacosmos, Pierre Fabre, Medice, and Falk Foundation as well as for consulting from Novo Nordisk. B.v.H. has nothing to disclose. J.V. received grant support from Gilead, speaker fees from Gilead and Orphalan, travel support from AbbVie, Astellas, Dr. Falk Pharma, Gilead, Ipsen, and Janssen, as well as consultancy fees from Astellas, AstraZeneca, Eisai, Ipsen, and Takeda. P.S. received grants from Arrowhead, CSL Behring, and Grifols; consulting fees from Arrowhead, BioMarin, BridgeBio, Dicerna, GSK, Intellia, Novo Nordisk, Ono, and Takeda; honoraria from Alnylam, CSL Behring, and Grifols; and material transfer support for Vertex and Dicerna. M.M. received grant support from Echosens, served as a speaker and/or consultant and/or advisory board member for AbbVie, AstraZeneca, Echosens, Eli Lilly, Falk Foundation, Gilead, Ipsen, Takeda, and W. L. Gore & Associates, and received travel support from AbbVie and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

**Fig. 1**
Study flowchart. MELD, model for end-stage liver disease.

**Fig. 2**
Cumulative incidence curves for further decompensation, liver transplantation, or liver-related death as events of interest with non-liver-related death as a competing risk. Cumulative incidence curves of the outcomes of interest are depicted in bold compared to those of the competing events. Comparison of different aetiology-specific courses of disease were calculated using a competing risk regression analysis and respective subdistribution hazard ratios (95% CIs) with AATD as the comparison group are displayed. A p value <0.05 was considered significant. AATD, alpha-1 antitrypsin deficiency; ALD, alcohol-associated liver disease; HCV hepatitis C virus; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic ALD; SHR, subdistribution hazard ratio; SLD, steatotic liver disease.

**Fig. 3**
Cumulative incidence curves for acute-on-chronic liver failure, liver transplantation, or liver-related death as events of interest with non-liver-related death as a competing risk. Cumulative incidence curves of the outcomes of interest are depicted in bold compared to those of the competing events. Comparison of different aetiology-specific courses of disease were calculated using a competing risk regression analysis and respective subdistribution hazard ratios (95% CI) with AATD as the comparison group are displayed. A p value <0.05 was considered significant. AATD, alpha-1 antitrypsin deficiency; ACLF, acute-on-chronic liver failure; ALD, alcohol-associated liver disease; HCV hepatitis C virus; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic ALD; SHR, subdistribution hazard ratio; SLD, steatotic liver disease.

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Cited by

Underdiagnosis of Alpha-1 Antitrypsin Deficiency in Cirrhotic Liver Transplant Candidates: Findings From a Multicenter Retrospective Study.
Evain M, Ruiz I, Antonini T, Lassailly G, Mazzola A, Debry PH, Elkrief L, Anty R, Sebagh M, Ichai P, Cherqui D, Samuel D, Kounis I, Coilly A; GREF 2 group. Evain M, et al. Aliment Pharmacol Ther. 2025 Jul;62(2):193-203. doi: 10.1111/apt.70183. Epub 2025 May 30. Aliment Pharmacol Ther. 2025. PMID: 40448303 Free PMC article.

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Severe alpha-1 antitrypsin deficiency is associated with a higher risk of complications after first decompensation than other aetiologies of cirrhosis

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Severe alpha-1 antitrypsin deficiency is associated with a higher risk of complications after first decompensation than other aetiologies of cirrhosis

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