Amplification of genetic and metabolic factors in alpha-1 antitrypsin deficiency

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