Longitudinal Evaluation of Individuals With Severe Alpha-1 Antitrypsin Deficiency (Pi∗ZZ Genotype)

Malin Fromme¹, Audrey Payancé², Mattias Mandorfer³, Katrine H Thorhauge⁴, Monica Pons⁵, Marc Miravitlles⁶, Jan Stolk⁷, Bart van Hoek⁸, Guido Stirnimann⁹, Sona Frankova¹⁰, Jan Sperl¹⁰, Andreas E Kremer¹¹, Barbara Burbaum¹, Christina Schrader¹, Amine Kadioglu¹, Michelle Walkenhaus¹, Carolin V Schneider¹, Fabienne Klebingat¹, Lorenz Balcar³, Naomi N Kappe¹², Benedikt Schaefer¹³, Joanna Chorostowska-Wynimko¹⁴, Elmar Aigner¹⁵, Sophie Gensluckner¹⁵, Philipp Striedl¹⁵, Pauline Roger¹⁶, John Ryan¹⁷, Suzanne Roche¹⁷, Marius Vögelin¹¹, Aftab Ala¹⁸, Heike Bantel¹⁹, Jef Verbeek²⁰, Zoe Mariño²¹, Michael Praktiknjo²², Tom J G Gevers²³, Philipp A Reuken²⁴, Thomas Berg²⁵, Jacob George²⁶, Münevver Demir²⁷, Tony Bruns¹, Christian Trautwein²⁸, Heinz Zoller¹³, Michael Trauner³, Joan Genesca⁵, William J Griffiths²⁹, Virginia Clark³⁰, Aleksander Krag⁴, Alice M Turner³¹, Noel G McElvaney¹⁷, Pavel Strnad³²

Affiliations

¹ 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.
² AP-HP, Service d'hépatologie, Hôpital Beaujon, AP-HP, Clichy, France, DMU Digest, Centre de référence des Maladies Vasculaires du foie, FILFOIE, Clichy, France, Université Paris Cité, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Paris, France.
³ Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.
⁴ Department of Gastroenterology and Hepatology, Odense University Hospital, Odense C, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C, Denmark.
⁵ Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
⁶ Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Health Care Provider of the European Reference Network on Rare Respiratory Diseases (ERN LUNG), Barcelona, Spain.
⁷ Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
⁸ Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
⁹ University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital and University of Bern, Bern, Switzerland.
¹⁰ 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.
¹¹ Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland.
¹² Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
¹³ Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
¹⁴ Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
¹⁵ First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria.
¹⁶ AP-HP, service d'hépatologie, Hôpital Beaujon, AP-HP, Clichy, France, DMU Digest, Clichy, France.
¹⁷ Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
¹⁸ Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom.
¹⁹ Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
²⁰ Department of Gastroenterology & Hepatology, KU Leuven University Hospitals, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Leuven, Belgium.
²¹ Liver Unit, Hospital Clínic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), University of Barcelona, Barcelona, Spain.
²² Department of Medicine B, Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, Universitätsklinikum Muenster, Muenster, Germany.
²³ Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands.
²⁴ Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
²⁵ Division of Hepatology, Department of Medicine, Leipzig University Medical Center, Leipzig, Germany.
²⁶ Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.
²⁷ Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité Universitätsmedizin Berlin, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Berlin, Germany.
²⁸ 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; Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany.
²⁹ Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
³⁰ Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida.
³¹ Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom.
³² 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. Electronic address: pstrnad@ukaachen.de.

PMID: 39414159
DOI: 10.1053/j.gastro.2024.10.010

Free article

Multicenter Study

Longitudinal Evaluation of Individuals With Severe Alpha-1 Antitrypsin Deficiency (Pi∗ZZ Genotype)

Malin Fromme et al. Gastroenterology. 2025 Feb.

Free article

. 2025 Feb;168(2):367-381.

doi: 10.1053/j.gastro.2024.10.010. Epub 2024 Oct 15.

Authors

Affiliations

¹ 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.
² AP-HP, Service d'hépatologie, Hôpital Beaujon, AP-HP, Clichy, France, DMU Digest, Centre de référence des Maladies Vasculaires du foie, FILFOIE, Clichy, France, Université Paris Cité, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Paris, France.
³ Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.
⁴ Department of Gastroenterology and Hepatology, Odense University Hospital, Odense C, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C, Denmark.
⁵ Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
⁶ Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Health Care Provider of the European Reference Network on Rare Respiratory Diseases (ERN LUNG), Barcelona, Spain.
⁷ Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
⁸ Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
⁹ University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital and University of Bern, Bern, Switzerland.
¹⁰ 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.
¹¹ Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland.
¹² Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
¹³ Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
¹⁴ Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
¹⁵ First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria.
¹⁶ AP-HP, service d'hépatologie, Hôpital Beaujon, AP-HP, Clichy, France, DMU Digest, Clichy, France.
¹⁷ Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
¹⁸ Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom.
¹⁹ Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
²⁰ Department of Gastroenterology & Hepatology, KU Leuven University Hospitals, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Leuven, Belgium.
²¹ Liver Unit, Hospital Clínic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), University of Barcelona, Barcelona, Spain.
²² Department of Medicine B, Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, Universitätsklinikum Muenster, Muenster, Germany.
²³ Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands.
²⁴ Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
²⁵ Division of Hepatology, Department of Medicine, Leipzig University Medical Center, Leipzig, Germany.
²⁶ Storr Liver Centre, The Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.
²⁷ Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité Universitätsmedizin Berlin, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Berlin, Germany.
²⁸ 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; Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany.
²⁹ Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
³⁰ Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida.
³¹ Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom.
³² 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. Electronic address: pstrnad@ukaachen.de.

PMID: 39414159
DOI: 10.1053/j.gastro.2024.10.010

Abstract

Background & aims: Homozygous Pi∗Z mutation in alpha-1 antitrypsin (Pi∗ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only 1 organ, we systematically evaluated an international, multicenter, longitudinal, Pi∗ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints.

Methods: Cohort 1 recruited 737 Pi∗ZZ individuals from 25 different centers without known liver comorbidities who received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least 6 months. Cohort 2 consisted of 135 Pi∗ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least 2 years later, both including LSM.

Results: During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. Forty-one Pi∗ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, that is, LSM (24 vs 5 kPa, P < .001) and aspartate aminotransferase-to-platelet ratio index (1.1 vs 0.3 units, P < .001). Liver-related endpoints within 5 years were most accurately predicted by LSM (area under the curve 0.95) followed by aspartate aminotransferase-to-platelet ratio index (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within 5 years (forced expiratory volume in the first second area under the curve 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors.

Conclusions: Noninvasive liver fibrosis surrogates accurately stratify liver-related risks in Pi∗ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi∗ZZ patients.

Keywords: Fibroscan; Lung Emphysema; SERPINA1.

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Longitudinal Evaluation of Individuals With Severe Alpha-1 Antitrypsin Deficiency (Pi∗ZZ Genotype)

Affiliations

Longitudinal Evaluation of Individuals With Severe Alpha-1 Antitrypsin Deficiency (Pi∗ZZ Genotype)

Authors

Affiliations

Abstract

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Full Text Sources

Medical

Research Materials

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