ERS | monograph Introduction Pavel Strnad 1,2 , Mark Brantly3 and Robert Bals 4 @ERSpublications AATD is an inherited condition that primarily affects the lung and liver. This ERS Monograph provides a comprehensive guide to AATD, ranging from basic biology, diagnostics and clinical presentation to reports from affected patients. http://bit.ly/2OeVD6H AAT is the most abundant serum antiprotease [1]. It is produced predominantly by liver hepatocytes that release it into the bloodstream and subsequently into other body compartments, where it exerts its function. The AAT gene has a number of mutations and as a consequence, one in 10 Caucasians carries an AAT variant giving rise to AATD [2]. To date, 120 AAT variants have been described and among them, Pi*Z is the most clinically relevant. Consequently, a homozygous carriage of the Pi*Z variant (Pi*ZZ genotype) is the characteristic cause of severe AATD. As Pi*Z mutation leads to the retention of AAT in hepatocytes, it is characterised by strongly diminished serum AAT levels [3, 4]. While severe AATD is a rare condition (with a frequency of 1:3000 in Caucasians), some AATD genotypes are more common, have modest reduction serum AAT levels and/or even AAT levels within a normal range [2, 3]. The resulting imbalance of antiprotease activity predisposes AATD individuals to proteolytic tissue damage and thereby to premature emphysema and COPD [5, 6]. In contrast, the accumulation of misfolded/polymerised AAT may lead to neonatal hepatitis and/or development of chronic liver disease, liver cirrhosis and HCC in adults [4, 7, 8]. While lung and the liver disease constitute the major causes of mortality in AATD, AAT is also a potent immunomodulatory protein and because of that, AATD subjects are predisposed to immune disorders such as panniculitis and granulomatous vasculitis [9]. More than 50 years after its initial description and despite the fact that it is fairly common, AATD remains a highly challenging condition. Although severe AATD can be easily recognised due to a five-fold reduction in serum AAT levels, only 10–15% of individuals are detected and it often takes many years and several physicians before the correct diagnosis is established [10]. To make things more difficult, many patients report symptoms that overlap with common respiratory diseases, such as asthma and bronchitis [6]. While the Copyright ©ERS 2019. Print ISBN: 978-1-84984-108-5. Online ISBN: 978-1-84984-109-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098. Correspondence: Pavel Strnad, Coordinating Center for Alpha1-antitrypsin Deficiency-related Liver Disease of the European Reference Network (ERN) “Rare Liver” and the European Association for the Study of the Liver (EASL) Registry Group “Alpha1-Liver”, University Hospital Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail: pstrnad@ukaachen.de 1 Coordinating Center for Alpha1-antitrypsin Deficiency-related Liver Disease of the European Reference Network (ERN) “Rare Liver” and the European Association for the Study of the Liver (EASL) Registry Group “Alpha1-Liver”, University Hospital RWTH Aachen, Aachen, Germany. 2 Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany. 3 Dept of Medicine, University of Florida, College of Medicine, Gainesville, FL, USA. 4 Pulmonology, Hospital of the University of the Saarland, Homburg, Germany https://doi.org/10.1183/2312508X.10026219 ix