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

作者：Malin Fromme, Audrey Payancé, Mattias Mandorfer, Katrine Holtz Thorhauge, Mònica Pons, Marc Miravitlles, Jan Stolk, Bart van Hoek, Guido Stirnimann, Soňa Fraňková, Jan Šperl, Andreas E. Kremer, Barbara Burbaum, Christina Schrader, Amine Kadioglu, Michelle Walkenhaus, Carolin V. Schneider, Fabienne Klebingat, Lorenz Balcar, Naomi Kappe, Benedikt Schaefer, Joanna Chorostowska-Wynimko, Elmar Aigner, Sophie Gensluckner, Philipp Striedl, Pauline Roger, John Ryan, Suzanne Roche, Marius Vögelin, Aftab Ala, Heike Bantel, Jef Verbeek, Zoe Mariñó, Michael Praktiknjo, Tom J.G. Gevers, Philipp A. Reuken, Thomas Berg, Jacob George, Münevver Demir, Tony Bruns, Christian Trautwein, Heinz Zoller, Michael Trauner, Joan Genescà, William J. Griffiths, Virginia Clark, Aleksander Krag, Alice Turner, Noel G. McElvaney, Pavel Strnad · 发表于：Gastroenterology · 年份：2024 · DOI：10.1053/j.gastro.2024.10.010 · 被引用次数：17 · 研究领域：Protease and Inhibitor Mechanisms、Blood Coagulation and Thrombosis Mechanisms、Protein Kinase Regulation and GTPase Signaling

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 ...