Alpha-1-antitrypsin Deficiency Biology, Diagnosis, Clinical Significance, and Emerging Therapies Noor Kalsheker University of Nottingham, Nottingham, United Kingdom Robert Stockley Birmingham University, Birmingham, United Kingdom Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2017 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. 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Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-803942-7 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals Publisher: Mica Haley Acquisition Editor: Stacy Masucci Editorial Project Manager: Samuel Young Production Project Manager: Sue Jakeman Designer: Vicky Pearson Esser Typeset by Thomson Digital List of Contributors Samuel Alam, PhD, University of Cambridge, Cambridge, United Kingdom Bibek Gooptu, BSc (Hons.), MBBChir, PhD, AFHEA, MRCP, Institute of Structural & Molecular Biology, University College London; London Alpha-1 Antitrypsin Deficiency Service, The Royal Free Hospital; Kings College London, Guy’s Hospital, London; Leicester Institute for Structural & Chemical Biology and NIHR Leicester BRC Respiratory, Leicester, United Kingdom Marian Hill, PhD, Nottingham University Hospitals National Health Service Trust, Nottingham, United Kingdom James A. Irving, PhD, University College London, Respiratory; Institute of Structural and Molecular Biology, University College London, London, United Kingdom Alistair Jagger, BSc, University College London, Respiratory; Institute of Structural and Molecular Biology, University College London, London, United Kingdom Sabina Janciauskiene, PharmD, PhD, PhD, Hannover Medical School, Hannover, Germany Noor Kalsheker, MD, MSc, FRCPath, University of Nottingham, Nottingham, United Kingdom David A. Lomas, PhD, ScD, FHEA, FRCP, FMedSci, University College London School of Life and Medical Sciences, University College London, London, United Kingdom Ravi Mahadeva, MD, University of Cambridge, Cambridge, United Kingdom David Parr, MD, University Hospitals Coventry and Warwickshire NHS Trust, Coventry; Warwick University, Warwick, Warwickshire, United Kingdom S. Tamir Rashid, MBBS, PhD, Centre for Stem Cells & Regenerative Medicine and Institute for Liver Sciences, Kings College London, Guy’s Hospital, London, United Kingdom Robert A. Sandhaus, MD, PhD, FCCP, National Jewish Health, Denver, CO; AlphaNet, Alpha-1 Foundation, Coral Gables, FL, United States Robert Stockley, MD, DSc, Birmingham University, Birmingham, United Kingdom Jan Stolk, MD, PhD, Leiden University Medical Center, Leiden, The Netherlands James K. Stoller, MD, MS, Education Institute Cleveland Clinic, Cleveland, OH, United States xi xii List of Contributors Charlie Strange, MD, Medical University of South Carolina, Charleston, SC, United States Tomas Sveger, MD, PhD, University Hospital, Malmo, Sweden Jeffrey H. Teckman, MD, Saint Louis University School of Medicine, Saint Louis, MO, United States Alice Turner, MBChB (Hons), MRCP, PhD, University of Birmingham, Birmingham, United Kingdom Preface The last edition of a textbook entitled “Alpha-1-antitrypsin deficiency” (AATD) was published in 1996, 33 years after the original discovery of the condition in 1963. We have made enormous progress since then, and this has been the stimu- lus for writing this book. Much of the earlier and more recent work is described in this book. The advent of powerful biomedical research methods and a collec- tive will to establish patient registries has enabled us to make progress in a num- ber of key areas and should ensure further progress in the years ahead. The idea behind the book was to collate and update the information in the field of AATD and to provide a resource to the AAT community, both researchers and patients. The editors of this book have contributed to the field of AAT research over several decades and this provided the stimulus to the conception of this text- book. Many other investigators, not all of whom are included in the author- ship of this book, have made important contributions to the field. The editors acknowledge the important cumulative effort of all involved that has resulted in the progress made in the field. This book is divided into 15 chapters beginning with a historical perspec- tive, through to the basic biology of alpha-1-antitrypsin (AAT), the regulation of the gene, the structural biology of the AAT protein, animal models of lung and liver disease, rare variants causing AATD through to the epidemiology, natural history, and clinical presentation of AATD. Patient registries has been estab- lished and replacement therapy has been trialled for the lung disease. The three- dimensional structure of the AAT protein molecule has been determined and facilitated our understanding of the elegant mechanism for proteinase inhibi- tion. The propensity for some of the more common molecular variants causing deficiency, particularly the Z variant to polymerize and consequently accumu- late in hepatocytes leading to liver disease in a proportion of proteinase inhibitor (Pi) homozygous Z individuals. This has also facilitated the search for synthetic polymer blockers which could be exploited therapeutically to alleviate the liver cell damage that occurs. An increasing array of biological functions in addition to the classical role as a proteinase inhibitor have been described, highlighting the broad-spectrum role of this molecule in the inflammatory state and in regu- lating aspects of the immune system. We have learnt about how the gene is regulated and the complex interactions that controls expression of the gene. The use of high throughput screening meth- ods has allowed us to characterize an increasing number of rare variants causing deficiency, providing mechanistic insights into the basis of the deficiency, and xiii xiv Preface in identifying other genetic variants of unknown significance, with some potentially modulating AAT expression. Importantly, our understanding of the natural progression of the disease, has improved as a result of establishing Registries in Europe and North America in addition to the long-term follow-up of patients from the Swedish Registry. The use of computerized tomography (CT) to better quantify the extent of lung damage that occurs in the emphysema related to AATD will allow for a more objective assessment of responses to AAT replacement therapy which has been trialled in several centers. We are now at the cusp of correction of genetic defects through gene editing, both in the germ line and somatically and it is only a matter of time before human trials of some of these technologies will be tested. Clinical trials and long-term studies of AATD patients should help in the evaluation of replacement therapy in these patients who desperately need ways to delay the onset of progressive disease. There are many hurdles to cross but the future holds much promise in this area. The AATD patients deserve our urgent attention in making future develop- ments work their way into clinical practice. Noor Kalsheker Robert Stockley Acknowledgments The editors would like to thank the staff of Elsevier for their help and patience in bringing this book to fruition. In particular, the enormous help of Sam Young who was always there to provide help and advice. NK would like to thank Caroline Kalsheker for the support and encouragement she has given him toward editing this book. Finally, I would like to thank my fellow editor, Rob Stockley, without whom this task would have been truly daunting. xv Chapter 1 Historical Perspective Robert A. Sandhaus, MD, PhD, FCCP INTRODUCTION In 1698, Sir John Floyer published “A Treatise of the Asthma” [1] in which the anatomy of the chest of a “broken-winded mare” was described. The thorax was said to appear “puffed-up or swelled” and much larger than that found in the nor- mal horse, although the animal appeared otherwise emaciated. When the chest cavity was entered, the lungs did not collapse as they would in a healthy animal and air blown into the lungs did not appear to come out again and “remained … in the over-distended bladders.” This, concluded Floyer, was the cause of the dys- pnea noted in animals suffering from this condition: “external air can’t pass freely thro’ the trachea and its branches in inspiration or expiration; and this difficulty occasions the labor and nisus of the respiratory muscles.” Although Bonet correlated dyspnea and orthopnea with autopsy findings of distended lungs in 1679 [2] and Ruysch used the title Vesiculas Pulmonales Obtouctas for an article in 1691 illustrating distended air vesicles in the lung [3], Floyer’s correlation of signs, symptoms, and pathology is considered the first conclusive report of emphysematous anatomy. Margagni reported two cases which would likely be called bullous emphysema today, in 1761 [4]. The pace of examination of obstructive lung disease picked up in the 19th century. In 1808, Badham reported findings similar to Floyer but in human au- topsies of people dying with severe dyspnea [5]. Ten years later, Bailie described additional autopsy results of a large number of individuals who died with chron- ic pulmonary symptoms [5]. He found the same hyperexpanded lungs but noted, in addition, the presence of distended air-filled vesicles on the lung surface and a preponderance of enlarged air spaces enclosed by thin membranes of pulmo- nary tissue. He suggested that this picture might be due to trapping of inspired air with rupture of contiguous septa. The earliest accurate clinical observations and anatomic correlations of pul- monary emphysema in humans have been attributed to Rene Laennec. In 1819, Laennec described a “dilatation of the air-cells to which the bronchus leads.” [6] Many of the pathological descriptions in the past did not have in-life find- ings on physical examination. Laennec felt this was due to the subtlety of the Alpha-1-antitrypsin Deficiency Copyright © 2017 Elsevier Inc. All rights reserved. 1 2 Alpha-1-antitrypsin Deficiency clinical signs and that his invention of the stethoscope would allow more to be diagnosed during life. After extensive evaluation of the clinical and pathological course of many individuals with obstructive lung disease, Laennec went so far as to propose a pathogenetic mechanism for emphysema which points toward modern disease concepts. He reasoned that since the airways were often partial- ly obstructed by “mucus or by the tumefactions of the lining membrane of the bronchi,” and “since the muscles of inspiration are strong and numerous, where- as expiration is effected by the elasticity of the parts and feeble contractions of the intercostal muscles,” inspired air is likely to be trapped, in ever increasing volume, distal to the site of impaired flow. In addition, he suggested that air, in- spired at room temperature, would be heated to that of the body in the “air-cells” and thus further expand the volume of entrapped gas. This entrapment, he rea- soned, leads to dilation of the “air-cells and must become a fixed and permanent condition.” In 1830s, William Stokes adopted Laennec’s stethoscope to evaluate a large number of patients with airway obstruction [7]. He noted the association of long-standing obstructive lung disease with enlargement of the right side of the heart. On the treatment of these patients, Stokes is clear, “It seems scarcely possible that any effort of medical skill can restore the lung to its original condi- tion, and all that we can hope for is to palliate the symptoms.” Later in that same decade, George Budd reviewed the emphysema literature of the previous 20 years [8]. His conclusions included a description of the in- creased antero-posterior diameter of the chest, the loss of rib obliquity, and the use of accessory muscles for inspiration. He went on to suggest that in the early stages of emphysema, small portions of the lung might be affected by this loss of elasticity and these small areas would not empty as completely as the rest of the lung during expiration, thus “the air also which these portions contain will be very imperfectly renewed: in fact, they will contribute little to the act of breathing, which will be performed almost entirely by the rest of the lungs.” Budd also thought that the loss of alveolar capillary blood supply accounted for the dilation of the right heart and peripheral edema seen in advanced cases of emphysema. Budd felt that it was important to distinguish between emphysema and bronchitis. He pointed out that emphysema “often develops itself without the occurrence of pulmonary catarrh.” Of special note, Budd cites a Mr. Jackson who examined a series of 28 pa- tients with emphysema and found that 18 were the offspring of parents with the disease. Budd’s conclusion? Emphysema is very frequently a hereditary disease. THE DISCOVERY OF ALPHA-1-ANTITRYPSIN DEFICIENCY (AATD) The diagnosis of pulmonary emphysema was difficult in the mid-20th century. Chest radiography gave suggestions of radiolucency in parallel with “pruning” of the vascular tree on plane films of the thorax. The flattened diaphragms and increased antero-posterior diameter suggested lung destruction but could be Historical Perspective Chapter | 1 3 simple air-trapping. Pulmonary function testing beyond spirometry was some- what brutal, asking short-of-breath individuals to swallow balloons on the end of stiff tubing so that lung compliance could be calculated. Many young physi- cians were taught that while chronic bronchitis could be diagnosed based on symptoms, emphysema was a disease diagnosed most accurately at autopsy, or by lung biopsy during life. There was certainly a growing appreciation of the role played by cigarette smoking in emphysema and the spectrum of fixed airflow obstruction included in the umbrella term, chronic obstructive pulmonary disease or COPD. But there were always those patients who seemed to develop COPD in spite of mini- mal cigarette smoke exposure. More than that, some had appreciated a family predilection to the development of COPD, often with symptom onset relatively early in adult life. It is on this background that alpha-1-antitrypsin deficiency (AATD) was first described by Laurell and Eriksson in 1963. In the mid-20th century, Malmö, Sweden was home to a number of scientists interested in identifying and quan- tifying plasma proteins. Carl-Bertil Laurell noted the absence of the α band in 1 the serum protein electrophoresis (SPEP) of several patients (Fig. 1.1) [9]. He assigned a young clinician, Sten Eriksson, to investigate the potential clinical implications of this finding. Dr. Eriksson found that the missing band appeared in several families and that these families had an unexpectedly high incidence of precocious emphysema. Previous work had described that the α band on 1 SPEP was composed predominantly of a protein that had been found to inhibit FIGURE 1.1 One of the first paper electrophoresis figures prepared by Sten Eriksson demonstrating the lack of α1 band in serum protein electrophoresis for normal and AATD individuals. (Gift from Dr. Eriksson to the author).