Rationale and objectivesAlpha-1 antitrypsin deficiency (AATD) is a genetic condition that leads to an increased risk of emphysema and liver disease. Despite extensive investigation, there remain unanswered questions concerning the natural history, pathophysiology, genetics and the prognosis of the lung disease in association with AATD. The European Alpha-1 Clinical Research Collaboration (EARCO) is designed to bring together researchers from European countries and to create a standardised database for the follow-up of patients with AATD.Study design and populationThe EARCO Registry is a non-interventional, multicentre, pan-European, longitudinal observational cohort study enrolling patients with AATD. Data will be collected prospectively without interference/modification of patient's management by the study team. The major inclusion criterion is diagnosed severe AATD, defined by an AAT serum level <11 µM (50 mg·dL−1) and/or a proteinase inhibitor genotype ZZ, SZ or compound heterozygotes or homozygotes of other rare deficient variants. Assessments at baseline and during the yearly follow-up visits include lung function testing (spirometry, body plethysmography and diffusing capacity of the lung), exercise capacity, blood tests and questionnaires (symptoms, quality of life and physical activity). To ensure correct data collection, there will be designated investigator staff to document the data in the case report form. All data will be reviewed by the EARCO database manager.SummaryThe EARCO Registry aims to understand the natural history and prognosis of AATD better with the goal to create and validate prognostic tools to support medical decision-making.

Background: The natural history of adult liver disease due to a1-antitrypsin deficiency (A1AD) remains poorly understood. Objective: We investigated whether heterozygosity for the Z-allele predisposes for the development of clinically significant portal hypertension (CSPH). Moreover, we aimed to non-invasively assess the prevalence of liver fibrosis and hepatic steatosis in adults with A1AD treated by pulmonologists. Methods: SERPINA1 rs28929474 (Z-allele) was genotyped in 315 patients with CSPH (hepatic venous pressure gradient !10 mmHg; cases) and 248 liver donors (controls). In addition, 31 adults with A1AD (Pi*ZZ/Pi*SZ) and 11 first-degree relatives (Pi*MZ/Pi*MS) underwent liver stiffness and controlled attenuation parameter (CAP) measurement. Results: Heterozygosity for the Z-allele was observed in 6.7% of patients with CSPH and 2.8% of liver donors. Thus, harboring the Z-allele was associated with increased odds of CSPH (odds ratio: 2.47; 95% confidence interval: 1.03-5.9; P ¼ 0.042). Among Pi*ZZ/Pi*SZ patients, 23%/3% had liver stiffness values indicative of liver fibrosis ( !F2/ !F3). Interestingly, 65%/52% of Pi*ZZ/Pi*SZ patients had CAP values indicative of hepatic steatosis ( !S1/ !S2). Conclusions: Heterozygosity for the Z-allele predisposes for the development of CSPH, confirming its role as a genetic (co)factor in liver disease. Pi*ZZ/SZ patients rarely develop liver fibrosis !F3 during adulthood; however, liver fibrosis !F2 is common. Elevated CAP values hint at underlying hepatic steatosis, which might promote liver fibrosis progression.

Alpha1-antitrypsin deficiency is a rare condition with delayed diagnosis. Because of the benefit of an early diagnosis further effort should be put towards early detection.