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 1Coordinating 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. 2Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany. 3Dept of Medicine, University of Florida, College of Medicine, Gainesville, FL, USA. 4Pulmonology, Hospital of the University of the Saarland, Homburg, Germany https://doi.org/10.1183/2312508X.10026219 ix
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