BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

1st Department of Medicine Paracelsus Medical University Salzburg Austria

Centro Hospitalar Universitário do Porto Porto Portugal

Clinic for Pneumology Medical University Hannover Hannover Germany

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 Odense University Hospital Odense C Denmark; Faculty of Health Sciences Department of Clinical Research University of Southern Denmark Odense C Denmark

Department of Gastroenterology Centro Hospitalar do Funchal Madeira Portugal

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 Cambridge University Hospitals NHS Foundation Trust Cambridge United Kingdom

Department of Internal Medicine 1 Medical University Innsbruck Innsbruck Austria

Department of Medicine 2 Saarland University Medical Center Saarland University Health Care Provider of the European Reference Network on Rare Liver Disorders Homburg Germany

Department of Medicine 2 Saarland University Medical Center Saarland University Health Care Provider of the European Reference Network on Rare Liver Disorders Homburg Germany; Hannover Medical School Hannover Germany

Department of Medicine 5 Saarland University Medical Center Saarland University Homburg Germany

Department of Psychiatry and Psychotherapy University Medicine Greifswald Greifswald Germany; DZHK partner site Greifswald Greifswald Germany

Department of Respiratory Medicine Cambridge University Hospitals Cambridge United Kingdom

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

Gastroenterology and Hepatology Unit Department of Medicine Sahlgrenska University Hospital Health Care Provider of the European Reference Network on Rare Liver Disorders Gothenburg Sweden

Gastroenterology Unit Department of Medicine Spedali Civili and University Health Care Provider of the European Reference Network on Rare Liver Disorders Brescia Italy

Hospital Santa Maria Lisboa Portugal

Institute of Applied Health Research University of Birmingham Birmingham United Kingdom

Institute of Pathology Medical University of Graz Graz Austria

Institute of Pathology University Hospital RWTH Aachen Aachen Germany

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

Liver Unit Hospital Universitari Vall d'Hebron Vall d'Hebron Institute of Research Vall d'Hebron Barcelona Hospital Campus Universitat Autonoma de Barcelona Health Care Provider of the European Reference Network on Rare Liver Disorders 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

Pneumology Department Hospital Universitari Vall d'Hebron Vall d'Hebron Institut de Recerca Vall d'Hebron Barcelona Hospital Campus CIBER de Enfermedades Respiratorias Barcelona Spain

Citace poskytuje Crossref.org

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