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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)367-381
Number of pages15
JournalGastroenterology
Volume168
Issue number2
Early online date14 Oct 2024
DOIs
Publication statusPublished - Feb 2025

Keywords

  • Fibroscan
  • SERPINA1
  • lung emphysema

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