Christina Schrader, Malin Fromme, Paul Ellis, Audrey Payancé, Mattias Mandorfer, Jan Stolk, B. van Hoek, Katrine Holtz Thorhauge, Monica Pons, Marc Miravitlles, Guido Stirnimann, Sona Frankova, Jan Šperl, Andreas E. Kremer, Katharina Remih, E Weber, Lorenz Balcar, Annelot D. Sark, Benedikt Schaefer, Joanna Chorostowska-Wynimko, Elmar Aigner, Sophie Gensluckner, H Bantel, Jef Verbeek, Zoe Mariñó, Rohit Loomba, Heinz Zoller, Michael Trauner, J Genesca, Virginia Clark, Aleksander Krag, N G Mcelvaney, W.J.H. Griffiths, A. W. Turner, P Strnad
BACKGROUND AND AIMS: Severe (Pi*ZZ) and heterozygous (Pi*MZ) alpha-1 antitrypsin deficiency (AATD) confer increased liver- and lung-related mortality, but the phenotype is highly variable. We aimed to evaluate the impact of obesity and diabetes mellitus on individuals with/without AATD. APPROACH AND RESULTS: Cohort 1 prospectively recruited 1678 Pi*ZZ adults from an international initiative with a systematic liver assessment. In all, 983 participants had a longitudinal follow-up. The data were compared with 16,768 Pi*MZ and 415,208 non-AATD individuals from the United Kingdom Biobank (cohort 2). Findings were ascertained by multivariable adjustment and propensity score matching. At baseline, diabetes was present in 52 (3%), overweight (BMI 25.0-29.9 kg/m 2 ) in 540 (52%), and obesity (BMI≥30 kg/m 2 ) in 266 (32%) Pi*ZZ adults. Pi*ZZ individuals with diabetes showed higher transaminases, and surrogates of advanced liver fibrosis (APRI≥1.0, LSM≥15 kPa) were 4-6 times more common [adjusted odds ratio (aOR) 5.7/4.3, p <0.01]. Elevated transaminases were rare among lean Pi*ZZ subjects, but more common in overweight (aOR 1.5/2.0) and obese Pi*ZZ participants (aOR 2.1/2.9). APRI≥1.0 was more than 4 times elevated in obese versus lean Pi*ZZ individuals (aOR 4.1, p <0.001). During a median follow-up of 4.2 years, 54 Pi*ZZ participants experienced a hepatic and 64 a pulmonary endpoint. While Pi*ZZ participants with diabetes/obesity had an increased risk of hepatic endpoints (aHR 6.03/3.38, p <0.001) compared with non-diabetic/lean Pi*ZZ subjects, overweight was associated with a decreased risk of pulmonary endpoints (aHR 0.45, p =0.004). CONCLUSIONS: Our data demonstrate the interaction between genetic and metabolic risk factors in AATD and provide evidence for patient management.