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

Author(s):
Fromme, M.; Payancé, A.; Mandorfer, M.; Thorhauge, K.H.; Pons, M.; Miravitlles, M.; Stolk, J.; Hoek, B. van; Stirnimann, G.; Frankova, S.; Sperl, J.; Kremer, A.E.; Burbaum, B.; Schrader, C.; Kadioglu, A.; Walkenhaus, M.; Schneider, C.V.; Klebingat, F.; Balcar, L.; Kappe, N.N.; Schaefer, B.; Chorostowska-Wynimko, J.; Aigner, E.; Gensluckner, S.; Striedl, P.; Roger, P.; Ryan, J.; Roche, S.; Vögelin, M.; Ala, A.; Bantel, H.; Verbeek, J.; Marino, Z.; Praktiknjo, M.; Gevers, T.J.G.; Reuken, P.A.; Berg, T.; George, J.; Demir, M.; Bruns, T.; Trautwein, C.; Zoller, H.; Trauner, M.; Genesca, J.; Griffiths, W.J.; Clark, V.; Krag, A.; Turner, A.M.; Mcelvaney, N.G.; Strnad, P.
Published
2025
Publication type
Article / Letter to editor

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 fi brosis, 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 fi brosis 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 fi rst second area under the curve 0.76). Fibrosis progression in those with no/mild fi brosis at baseline was rare and primarily seen in those with preexisting risk factors. CONCLUSIONS: Noninvasive liver fi brosis surrogates accurately stratify liver-related risks in Pi*ZZ individuals. Our fi ndings have direct implications for routine care and future clinical trials of Pi*ZZ patients.

FibroscanLung EmphysemaSERPINA1
Date issued
2025-01-23
Language
English
Publisher
W B SAUNDERS CO-ELSEVIER INC
Is part of
Gastroenterology (2025), Vol. 168, no. 2, p. 367-381
hdl
1887/4297924
doi
10.1053/j.gastro.2024.10.010