Longitudinal evaluation of individuals with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype)

Malin Fromme, Audrey Payancé, Mattias Mandorfer, Katrine H Thorhauge, Monica Pons, Marc Miravitlles, Jan Stolk, Bart van Hoek, Guido Stirnimann, Sona Frankova, Jan Sperl, Andreas E Kremer, Barbara Burbaum, Christina Schrader, Amine Kadioglu, Michelle Walkenhaus, Carolin V Schneider, Fabienne Klebingat, Lorenz Balcar, Naomi N KappeBenedikt 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 Mariño, Michael Praktiknjo, Tom J G Gevers, Philipp A Reuken, Thomas Berg, Jacob George, Münevver Demir, Tony Bruns, Christian Trautwein, Heinz Zoller, Michael Trauner, Joan Genesca, William J Griffiths, Virginia Clark, Aleksander Krag, Alice M Turner, Noel G McElvaney, Pavel Strnad*, European AATD Research Collaboration

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND AND 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 one 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 that received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least six months. Cohort 2 consisted of 135 Pi*ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least two 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. 41 Pi*ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, i.e., LSM (24 vs. 5 kPa, p<.001) and AST-to-platelet ratio index (APRI, 1.1 vs. 0.3 units, p<.001). Liver-related endpoints within five years were most accurately predicted by LSM (area under the curve [AUC] 0.95) followed by APRI (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within five years (FEV1 AUC 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors.

CONCLUSIONS: Non-invasive 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.

Original languageEnglish
JournalGastroenterology
Early online date15 Oct 2024
DOIs
Publication statusE-pub ahead of print - 15 Oct 2024

Bibliographical note

Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.

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