This Monograph offers a comprehensive and up-to-date overview of AATD. It covers basic biology, genetics, laboratory diagnostics and the major organ manifestations; describes the clinical presentation of AATD in both adults and children; and features chapters on genetic counselling, patient views and future therapies. The content has been tailored to meet the needs of the physician, who takes care of lung and liver patients in daily practice, and the general practitioner, who is responsible for the medical guidance of these patients.
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- ERS Monograph
- Page 6AbstractDavid A. Lomas, UCL Respiratory, Division of Medicine, Rayne Building, University College London, London, WC1E 6JF, UK. E-mail d.lomas@ucl.ac.uk
The serpin family of serine protease inhibitors plays an important role in regulating enzymes involved in proteolytic cascades. Point mutations result in aberrant conformational transitions that underlie diseases as diverse as cirrhosis, emphysema, thrombosis, angio-oedema and dementia. In view of their common underlying molecular mechanism, we have grouped these together as a novel class of disease: the serpinopathies. We review here the pathobiology of the serpinopathies, with a focus on their clinical features. Specifically, we show how serpinopathies may result from point mutations that cause polymer formation, transition to the latent conformer, inactivation of the inhibitory mechanism as well as failure of secretion (null alleles). We illustrate how a combination of these mechanisms underlies the lung disease associated with AATD. Finally we show that the severity of the mutations in neuroserpin that underlie the dementia FENIB (familial encephalopathy with neuroserpin inclusion bodies) can be explained by the rate of polymer formation.
Cite as: Lomas DA, Irving JA, Gooptu B. Serpinopathies. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 6–26 [https://doi.org/10.1183/2312508X.10032318].
- Page 27AbstractBrian D. Hobbs, Harvard Medical School, Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Room 460, Boston, MA 02115, USA. E-mail: brian.hobbs@channing.harvard.edu
Following the discovery of AAT in 1962, a genetic basis for AATD and the associated lung disease risk was suspected. In the ensuing decades, studies have illustrated inheritance patterns, identified numerous deficiency and null variants, and described the contribution of these variants to lung and liver disease. The most common genetic variant contributing to AATD is the Z allele, with an estimated 250 000 individuals worldwide being homozygous for this deleterious allele (Pi*ZZ). AATD probably contributes to up to 1–2% of all cases of COPD; however, AATD remains undiagnosed in a large number of individuals in part due to the incomplete penetrance of disease. Heterozygotes for the Z allele are also likely to be at risk for lung disease and liver disease. The advent of large-scale genetic studies, including sequencing studies and biobanks, may help elucidate the impact of SERPINA1 variants and genetic modifiers of disease.
Cite as: Hobbs BD, Silverman EK, Cho MH. Genetics and epidemiology. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 27–38 [https://doi.org/10.1183/2312508X.10013119].
- Page 39AbstractIlaria Ferrarotti, Piazza Golgi 1 – 27100 Pavia, Italy. E-mail: i.ferrarotti@smatteo.pv.it
AATD is a genetic disorder that is frequently underdiagnosed (or misdiagnosed). Its diagnosis consists of biochemical serum analysis to evaluate protein deficiency and electrophoretic abnormalities, as well as genetic analysis to identify SERPINA1 gene variants responsible for the protein deficiency. The accurate and complete identification of the AATD geno/phenotype forms the basis of clinical decisions regarding potential treatment options for individual patients, including augmentation therapy. Each specialised laboratory has developed its own flow chart for local or national AATD detection programmes, which begins with sample collection (blood, plasma or dried blood spot).
Cite as: Ferrarotti I, Ottaviani S. Laboratory diagnosis. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 39–51 [https://doi.org/10.1183/2312508X.10032418].
- Page 52AbstractCesare Saltini, Division of Pulmonary and CC Medicine, Dept of Medicine, University of Florida College of Medicine, 1600SW Archer Road, Room M332, PO Box 100225, Gainesville, FL 32610, US. E-mail: cesare.saltini@medicine.ufl.edu
AAT emphysema is caused by “deficient” gene mutations, most frequently the Glu342 to Lys “Z” mutation, causing protein misfolding and defective protein secretion, with ensuing six- to eight-fold reduced serum and even lower pulmonary alveolar levels, or the rare null mutations leading to zero protein expression. Loss of antiprotease protection, chiefly against NE, leads to increased alveolar epithelial and elastic tissue degradation, and macrophage activation with excessive production of neutrophil chemotactic factors, triggering a vicious cycle of neutrophil inflammation in response to the elastase–anti-elastase imbalance. Additionally, lung epithelia and macrophages can express higher AAT levels in response to stressors of environmental and bacterial origin. In Z mutation homozygous subjects, this may generate exaggerated levels of misfolded/polymerised AAT, thereby inducing ER stress, release of proinflammatory cytokines and activation of macrophage proteases, i.e. a proteopathic type of inflammation that could impact disease progression.
Cite as: Saltini C, Krotova K. Mechanisms of lung disease. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 52–63 [https://doi.org/10.1183/2312508X.10032518].
- Page 64AbstractMarc Miravitlles, Pneumology Dept, University Hospital Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), P. Vall d'Hebron 119-129, 08035 Barcelona, Spain. E-mail: marcm@separ.es
AATD is a genetic disorder that predisposes individuals to liver disease and lung disease, particularly in smokers. Lung disease is caused by the severe reduction in anti-elastase protection caused by the deficiency. The typical presentation of lung disease is in the form of panacinar emphysema starting in the fourth or fifth decade of life; however, the clinical expression of lung disease is very variable and ranges from asymptomatic disease to different phenotypes of COPD, chronic nonfully reversible asthma and bronchiectasis. This heterogeneity makes it important to test all adults with chronic obstructive lung disease for the deficiency, as early diagnosis allows a change in habits (particularly quitting smoking), pharmacological and nonpharmacological treatment, and specific augmentation therapy with intravenous AAT in patients in whom it is indicated. As AATD is a rare disease, follow-up of these patients must be performed in specialised regional or national reference centres.
Cite as: Barrecheguren M, Bals R, Miravitlles M. Clinical approach to diagnosis and assessment. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 64–77 [https://doi.org/10.1183/2312508X.10032618].
- Page 78AbstractAlice M. Turner, Institute of Applied Health Research, University of Birmingham, Birmingham B15 2TT, UK. E-mail: a.m.turner@bham.ac.uk
Lung disease in AATD patients typically presents earlier than in those with usual COPD and is initially managed in the same way, namely smoking cessation and use of inhaled therapies. AAT augmentation therapy is the only specific treatment available to modify the progression of emphysema and involves intravenous administration of AAT from pooled human plasma. Randomised controlled trials have consistently demonstrated its efficacy in reducing the decline in computed tomography lung density. Once emphysema has developed, surgical intervention may be indicated. Lung volume reduction can be achieved via direct surgical removal of the hyperinflated area of lung or endobronchial deflation with one-way valves, and can be used a standalone therapy or as a bridge to lung transplant. The use of gene therapy is an exciting prospect in the treatment of AATD-related lung disease, with demonstration of its potential feasibility in multiple early-phase trials in humans.
Cite as: Ellis P, Dirksen A, Turner AM. Treatment of lung disease. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 78–92 [https://doi.org/10.1183/2312508X.10032718].
- Page 93AbstractNicola Brunetti-Pierri, Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078 – Pozzuoli, Italy. E-mail: brunetti@tigem.it
Deficiency of AAT is among the most frequent genetic disorders and causes both lung and liver diseases. Most affected individuals carry the Z allele of the SERPINA1 gene encoding AAT. The spectrum of liver disease ranges from asymptomatic state to chronic hepatitis, hepatic failure and increased risk of HCC. The great variability in disease expressivity suggests that genetic modifiers and/or environmental factors play an important role. However, these factors have not yet been identified and it is currently not possible to predict whether a patient will develop the liver disease and its severity. Mutant AAT is unable to efficiently traverse the secretory pathway and forms polymers which accumulate in the ER of hepatocytes resulting in liver injury. Several intracellular pathways are affected by proteotoxic AAT but mechanisms of disease remain to be fully elucidated. Understanding genetic and acquired events triggering the liver disease is important to develop effective strategies for prevention and treatment of the disease.
Cite as: Piccolo P, Attanasio S, Brunetti-Pierri N. Mechanisms of liver disease. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 93–104 [https://doi.org/10.1183/2312508X.10032818].
- Page 105AbstractJeffrey H. Teckman, 1465 S Grand Blvd, St Louis, MO 63104, USA. E-mail: Jeff.teckman@health.slu.edu
Clinical liver disease is highly variable in homozygous ZZ AATD, and not all patients with the same homozygous ZZ genotype develop liver disease. It is likely that genetic and environmental modifiers of the intracellular injury cascade and of the fibrotic response have a strong influence, although this has not been fully identified. The most common presentation in children is neonates with cholestatic hepatitis (the “neonatal hepatitis syndrome”). However, most ZZ children are well and are undiagnosed. Several new natural history studies have identified risk factors for severe disease, but there is still no conclusive approach to confidently predict the minority of children who will progress to liver failure. This is a disease that usually has excellent liver transplant outcomes. Consistent follow-up of all diagnosed children is needed. With improved understanding of liver injury mechanisms, new strategies for treatment are now being explored, including RNA interference technology, enhancers of proteolysis, molecules to modulate secretion and antifibrotic therapies.
Cite as: Teckman JH, Patel D. Clinical approach to paediatric liver disease. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 105–113 [https://doi.org/10.1183/2312508X.10032918].
- Page 114AbstractPavel 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
AATD-associated liver disease arises as a consequence of chronic proteotoxic liver injury caused by accumulation of misfolded AAT. The inclusions are visualised using periodic acid–Schiff–diastase staining and constitute the histological hallmark of the disease. Individuals with the characteristic homozygous Pi*Z mutation (Pi*ZZ), producing a protein that is highly prone to polymerisation, are at highest risk for disease development, while heterozygous Pi*Z carriage (Pi*MZ) constitutes a disease-accelerating factor, particularly in subjects with alcoholic/nonalcoholic fatty liver disease. AATD-associated liver disease is highly heterogeneous, and factors promoting the development of liver injury remain largely unknown. Liver transplantation represents the only curative treatment option in individuals with end-stage liver disease and exhibits excellent survival rates. AATD-associated liver disease poses an area of active investigations, and approaches inhibiting AAT production or accelerating its degradation have entered clinical trials. Ongoing large collaborative efforts hold great promise to improve the understanding of this hitherto-understudied disease.
Cite as: Strnad P, Schneider CV, Clark V. Clinical approach to liver disease in adults. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 114–126 [https://doi.org/10.1183/2312508X.10033018].
- Page 127AbstractNoel G. McElvaney, Dept of Medicine, Smurfit Building, Beaumont Hospital, Dublin 9, Ireland. E-mail: gmcelvaney@rcsi.ie
AATD is usually diagnosed following pulmonary or hepatic manifestations; however, rarer presentations may alert clinicians to its presence. Of these, panniculitis and anti-neutrophilic cytoplasmic autoantibody (ANCA)-positive vasculitis are the most commonly reported. Panniculitis is a histopathological finding from skin biopsies attributable to many causes. However, lobular fat necrosis with dense neutrophil infiltration on biopsy may represent AAT-related disease, a subtype associated with significant morbidity and frequent relapses. Treatment with doxycycline, dapsone and AAT replacement therapy have all shown reliable effect, with the latter particularly effective in refractory disease. A significant body of work has been performed examining the role of AATD variants in ANCA vasculitis. The association between antibodies against both myeloperoxidase and proteinase (PR)3 (both neutrophil derived) and AATD has been shown to be significant, with clear evidence of over-representation of the AATD variants in ANCA vasculitis cohorts. While in vitro mechanistic evidence exists demonstrating a role for AAT replacement in anti-PR3 positive disease, there is little evidence for its use in vivo. In addition to these two conditions, AATD has also been associated with other systemic illness but the associations are as yet not fully proven.
Cite as: Franciosi AN, Carroll TP, McElvaney NG. Rare manifestations. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 127–142 [https://doi.org/10.1183/2312508X.10033118].
- Page 143AbstractJoanna Chorostowska-Wynimko, Dept of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, 26 Płocka Street, 01-138 Warsaw, Poland. E-mail: j.chorostowska@igichp.edu.pl
AATD is a genetically determined condition that results from carrying biallelic pathogenic variants of the SERPINA1 gene. It is inherited in an autosomal recessive pattern with the co-dominant expression of alleles. Considering the large number of SERPINA1-deficient variants, the diversity of AATD clinical manifestations and the potential preventative role of lifestyle modification (e.g. smoking cessation), genetic counselling plays a fundamental role in the medical care of individuals affected with or at risk of AATD. Pre-testing consultation focuses on the advantages and disadvantages of genetic evaluation, and its major aim is to enable fully informed decisions by all tested individuals. At the post-testing counselling visit, the genetic laboratory report is discussed and the pattern of AATD inheritance is explained, together with the risks for both the proband and their next-of-kin. Recommendations are made, including the need for regular medical assessment or treatment.
Cite as: Chorostowska-Wynimko J, Jezela-Stanek A. Genetic counselling. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 143–149 [https://doi.org/10.1183/2312508X.10033218].
- Page 150AbstractJ. Stolk, Dept of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands. Email: j.stolk@lumc.nl
Rare disease patient registries are key to increasing knowledge about rare diseases by collecting data from basic and clinical research, epidemiological research and real-life observational studies. Lack of knowledge about the AATD-related disease course and phenotype heterogeneity are restricting the development of therapies for this rare disease. AATD registries can help by providing data to improve our understanding about the course of the lung and liver disease, and by collecting the information necessary for clinical trial design. In this chapter, we describe the available AATD registries and the type of information they incorporate. We also evaluate the Alpha-1 International Registry database in more detail to show the possibilities and limitations of combining multinational data into the AATD registers.
Cite as: Schouten IGM, Stolk J, Fuge J, Kasteleyn MJ, Janciauskiene S. Registries: roles, objectives and registry data study outcomes. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 150–158 [https://doi.org/10.1183/2312508X.10033318].
- Page 159AbstractSabina Janciauskiene, Dept of Pulmonology, German Center for Lung Research, Hannover Medical School, 30625 Hannover, Germany. E-mail: janciauskiene.Sabina@mh-hannover.de
Inherited AATD caused by mutations in the SERPINA1 gene is a significant risk factor for developing lung and liver disease and sometimes skin disorders such as panniculitis. Over the past decades, there has been a remarkable advancement in the understanding of the structural and biological properties of human AAT. New findings support the broad role of AAT in modulating acute inflammatory processes via protease inhibitory and noninhibitory mechanisms. A deeper understanding of the molecular mechanisms involved in AATD allows the employment of new strategies to prevent or delay the progression of this complex syndrome. In this chapter, we provide an overview of the current diagnostic and therapeutic approaches used in AATD. Advancements in the intravenous application of human plasma-derived AAT for the treatment of AATD-related emphysema and other diseases not related to AATD are also highlighted. In addition, emerging new therapies, including pharmacological manipulations and surgical procedures, as well as stem-cell and gene therapies, are reviewed.
Cite as: Janciauskiene S, Welte T. Future directions: diagnostic approaches and therapy with AAT. In: Strnad P, Brantly ML, Bals R, eds. α1-Antitrypsin Deficiency (ERS Monograph). Sheffield, European Respiratory Society, 2019; pp. 159–178 [https://doi.org/10.1183/2312508X.10033418].