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

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 168; no. 2; pp. 367 - 381
• Main Authors: Fromme, Malin, Payancé, Audrey, Mandorfer, Mattias, Thorhauge, Katrine H., Pons, Monica, Miravitlles, Marc, Stolk, Jan, van Hoek, Bart, Stirnimann, Guido, Frankova, Sona, Sperl, Jan, Kremer, Andreas E., Burbaum, Barbara, Schrader, Christina, Kadioglu, Amine, Walkenhaus, Michelle, Schneider, Carolin V., Klebingat, Fabienne, Balcar, Lorenz, Kappe, Naomi N., Schaefer, Benedikt, Chorostowska-Wynimko, Joanna, Aigner, Elmar, Gensluckner, Sophie, Striedl, Philipp, Roger, Pauline, Ryan, John, Roche, Suzanne, Vögelin, Marius, Ala, Aftab, Bantel, Heike, Verbeek, Jef, Mariño, Zoe, Praktiknjo, Michael, Gevers, Tom J.G., Reuken, Philipp A., Berg, Thomas, George, Jacob, Demir, Münevver, Bruns, Tony, Trautwein, Christian, Zoller, Heinz, Trauner, Michael, Genesca, Joan, Griffiths, William J., Clark, Virginia, Krag, Aleksander, Turner, Alice M., McElvaney, Noel G., Strnad, Pavel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2025
• Subjects: Adult; Aged; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin Deficiency - complications; alpha 1-Antitrypsin Deficiency - diagnosis; alpha 1-Antitrypsin Deficiency - genetics; alpha 1-Antitrypsin Deficiency - mortality; Aspartate Aminotransferases - blood; Disease Progression; Elasticity Imaging Techniques; Female; Fibroscan; Genotype; Homozygote; Humans; Liver Cirrhosis - blood; Liver Cirrhosis - diagnosis; Liver Cirrhosis - etiology; Liver Cirrhosis - genetics; Liver Cirrhosis - mortality; Longitudinal Studies; Lung Emphysema; Male; Middle Aged; Mutation; SERPINA1; Severity of Illness Index; Lung Emphysema; SERPINA1; GLDH; ALT; Pi∗ZZ; LTOT; AUC; Pi∗Z; ULN; Fibroscan; Pi; SHR; BMI; AST; LSM; HCC; cACLD; ATD; CAP; AAT; GGT; VCTE; CAT; CSPH; APRI; NIT; FEV1; FIB-4
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2024.10.010

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. 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. 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. 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. [Display omitted] Noninvasive liver fibrosis surrogates are superior to lung parameter for prediction of organ-related outcomes. Liver disease progresses primarily in those with risk factors/signs of liver injury.