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.

1st Department of Medicine Paracelsus Medical University Salzburg Salzburg Austria

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 Paris France

AP HP service d'hépatologie Hôpital Beaujon AP HP Clichy France DMU Digest Clichy France

Department of Gastroenterology and Hepatology KU Leuven University Hospitals Health Care Provider of the European Reference Network on Rare Liver Disorders Leuven Belgium

Department of Gastroenterology and Hepatology Leiden University Medical Center Leiden The Netherlands

Department of Gastroenterology and Hepatology Maastricht University Medical Centre Maastricht The Netherlands

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

Department of Gastroenterology and Hepatology University Hospital Zürich University of Zürich Zürich Switzerland

Department of Gastroenterology Hepatology Infectious Diseases and Endocrinology Hannover Medical School Hannover Germany

Department of Genetics and Clinical Immunology National Institute of Tuberculosis and Lung Diseases Warsaw Poland

Department of Hepatogastroenterology Institute for Clinical and Experimental Medicine Health Care Provider of the European Reference Network on Rare Liver Disorders Prague Czech Republic

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 Berlin Germany

Department of Hepatology Cambridge University Hospitals NHS Foundation Trust Cambridge United Kingdom

Department of Internal Medicine 1 Medical University Innsbruck Innsbruck Austria

Department of Internal Medicine 4 Jena University Hospital Friedrich Schiller University Jena Germany

Department of Medicine B Gastroenterology Hepatology Endocrinology Infectious Diseases Universitätsklinikum Muenster Muenster Germany

Department of Pulmonology Leiden University Medical Center Leiden The Netherlands

Department of Pulmonology Leiden University Medical Center Leiden The Netherlands; Department of Gastroenterology and Hepatology Leiden University Medical Center Leiden The Netherlands

Division of Gastroenterology and Hepatology Department of Internal Medicine 3 Medical University of Vienna Health Care Provider of the European Reference Network on Rare Liver Disorders Vienna Austria

Division of Gastroenterology Hepatology and Nutrition University of Florida Gainesville Florida

Division of Hepatology Department of Medicine Leipzig University Medical Center Leipzig Germany

Institute of Applied Health Research University of Birmingham Birmingham United Kingdom

Institute of Liver Studies King's College Hospital NHS Foundation Trust London United Kingdom

Irish Centre for Genetic Lung Disease Royal College of Surgeons in Ireland Beaumont Hospital Dublin Ireland

Liver Unit Hospital Clínic Barcelona Instituto de Investigaciones Biomédicas August Pi i Sunyer University of Barcelona Barcelona Spain

Liver Unit Hospital Universitari Vall d'Hebron Vall d'Hebron Institute of Research Instituto de Salud Carlos 3 Madrid Spain

Medical Clinic 3 Gastroenterology Metabolic Diseases and Intensive Care University Hospital RWTH Aachen Health Care Provider of the European Reference Network on Rare Liver Disorders Aachen Germany

Medical Clinic 3 Gastroenterology Metabolic Diseases and Intensive Care University Hospital RWTH Aachen Health Care Provider of the European Reference Network on Rare Liver Disorders Dortmund Germany

Pneumology Department Hospital Universitari Vall d'Hebron Vall d'Hebron Institut de Recerca Barcelona Spain

Storr Liver Centre The Westmead Institute for Medical Research Westmead Hospital and University of Sydney Sydney New South Wales Australia

University Clinic for Visceral Surgery and Medicine University Hospital Inselspital and University of Bern Bern Switzerland

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