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Karim Hamesch, MD1,2 Pavel Strnad, MD1,2
Author Affiliations
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
- Coordinating Center for Alpha-1 Antitrypsin Deficiency-Related Liver Disease of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the European Association for the Study of the Liver (EASL) Registry Group “Alpha-1 Liver”
Address correspondence to:
Pavel Strnad, MD
European Reference Network on Hepatological Diseases
European Association for the Study of the Liver Registry Group
University Hospital Aachen
Aachen, Germany
Email: pstrnad@ukaachen.de
Phone: +49 241 80-35324
Abstract
Alpha-1 antitrypsin deficiency (AATD) is a systemic disorder affecting mainly the lung and the liver and is caused by mutations in SERPINA1, the AAT gene. A homozygous “Pi*Z” mutation (Pi*ZZ genotype) may cause liver fibrosis on its own independently of pulmonary AATD manifestation, while heterozygous Pi*Z carriage (Pi*MZ genotype) is considered a strong risk factor for development of liver cirrhosis in patients with concomitant liver disease such as alcoholic and non-alcoholic liver disease. In Pi*ZZ homozygotes, liver disease constitutes the second leading cause of death and is highly heterogeneous. About 35% of Pi*ZZ individuals display significant liver fibrosis on biopsy (i.e., fibrosis stage ≥ 2 on scale 0–4). Among non-invasive methods for liver fibrosis assessment, liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE) has been most widely evaluated. Based on these data, Pi*ZZ adults have 20x increased odds of developing advanced liver fibrosis (i.e., fibrosis stage ≥ 3) than adults without AAT mutation. Risk factors for accelerated fibrosis progression are male sex, age ≥ 50 years, alcohol misuse, obesity, diabetes mellitus, or metabolic syndrome. Unlike VCTE, other ultrasound- and magnetic resonance-based elastography methods have been assessed in small cohorts of Pi*ZZ individuals and remain to be comprehensively validated. Among blood-based fibrosis tests, AST-to-platelet ratio index (APRI) correlates moderately with histologic fibrosis stage and LSM. Given APRI’s wide availability, it can be used for risk stratification as an adjunct to LSM or when LSM is not at hand. Despite recent efforts, AATD-related liver disease, especially for genotypes other than Pi*ZZ, remains greatly understudied. AATD individuals should be offered liver biochemistry, liver ultrasound, and non-invasive fibrosis assessment at the time of diagnosis to detect potential complications and for proper risk stratification. If signs of AATD-related liver disease occur (i.e., pathologic fibrosis test or repeatedly elevated liver enzymes), patients should be referred to a health care center specialized in AATD-related liver disease and be screened for potentially treatable comorbidities. To exclude the latter, they may need a liver biopsy. Moreover, every health care provider of an AATD individual should be aware of the potential liver manifestation, counsel their patient on modifiable hepatic risk factors, and offer them regular liver check-ups.
Citation
Citation: Hamesch K, Strnad P. Non-invasive assessment and management of liver involvement in adults with alpha-1 antitrypsin deficiency. Chronic Obstr Pulm Dis. 2020; 7(3):In press. doi: http://dx.doi.org/10.15326/jcopdf.7.3.2019.0161
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Author Affiliations
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
Address correspondence to:
Elizabeth Sapey, MD
Email: E.sapey@bham.ac.uk
Phone: ++44 121 472 2000.
Abstract
Neutrophils have been implicated in the pathogenesis of alpha-1 antitrypsin deficiency (AATD) since the first descriptions of the disease. Neutrophil proteinases can cause all lung manifestations of AATD, from small airways destruction, to emphysema, to chronic bronchitis and airflow obstruction. Initially, it was proposed that neutrophil functions were normal in AATD, responding in an initially physiological manner to a high burden of pulmonary inflammation. More recent studies have shed new light on this, describing changes in neutrophil responses (a modulation of usual cellular functions) in the presence of inflammation or infection which might enhance tissue damage while impeding bacterial clearance, providing some evidence to support there being an AATD neutrophil phenotype.
Many facets of neutrophil function in AATD can be explained by the loss of alpha-1 antitrypsin (AAT) in diverse biological processes. If this were the only reason for altered neutrophil functions, one would predict similar disease presentation across affected people. However, this is not the case. Despite similar (low) levels of AAT, lung disease is extremely variable in AATD, with some patients suffering a significant burden of lung disease and some much less, irrespective of smoking habits and, in some cases, despite augmentation therapy. This review will explore how complex neutrophil responses are and how they are altered with age, inflammation and AATD. Further, it will discuss the need to understand more completely which aspects of AATD-associated disease are driven by neutrophils and how patients more susceptible to neutrophil dysfunction could be identified to potentially stratify treatment approaches.
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Brian D. Hobbs, MD, MMSc1 Michael H. Cho, MD, MPH1
Author Affiliations
- Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
Address correspondence to:
Brian D Hobbs, MD, MMSc
phone: 617-525-2140
email: brian.hobbs@channing.harvard.edu
Abstract
Individuals with alpha-1 antitrypsin deficiency (AATD) have marked heterogeneity in lung function, suspected to be related to a combination of both environmental (e.g., cigarette smoking) and genetic factors. Lung function is heritable in the general population and in persons with severe AATD. Several genetic modifiers of lung function in persons with AATD have been described; however, replication is lacking. A genome-wide association study (GWAS) of lung function in persons with AATD has yet to be performed and may inform whether genetic determinants of lung function are overlapping in persons with AATD and in the general population. As GWASs require large sample sizes for adequate power, genetic risk scores offer an alternate approach to assess the overlap of genetic determinants of lung function in the general population in persons with AATD. Where GWASs are limited to common genetic variant discovery, whole genome sequencing (for rare variant discovery) and integrative genomic studies (examining the influence of genetic variants on gene, protein, and metabolite levels) offer potential for an expanded discovery of genetic modifiers of lung function in AATD. In the following review we examine past descriptions of genetic modifiers of lung function in AATD and describe a path forward to further investigate and define the likely genetic modifiers of lung function in AATD.
Citation
Citation: Hobbs BD, Cho MH. Why is disease penetration so variable? Role of genetic modifiers of lung function in alpha-1 antitrypsin deficiency. Chronic Obstr Pulm Dis. 2020; 7(3):In press. doi: http://dx.doi.org/10.15326/jcopdf.7.3.2019.0159
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Oisín F. McElvaney, MB, MRCPI1 Mark P. Murphy, PhD1 Emer P. Reeves, PhD1 Noel G. McElvaney, MD, DSc1
Author Affiliations
- Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
Address correspondence to:
Emer P. Reeves, PhD
Irish Centre for Genetic Lung Disease
Royal College of Surgeons in Ireland
Education and Research Centre
Beaumont Hospital
Dublin 9, Ireland
Email: emerreeves@rcsi.ie
Phone: +35318093877
Abstract
For many years, the lung disease associated with alpha-1 antitrypsin (AAT) deficiency (AATD) was perceived as being secondary to an imbalance between this serine protease inhibitor and the target protease, neutrophil elastase (NE). More recently, a greater understanding of the pathways leading to lung inflammation has shed light on new potential attributes and presented AATD as an inflammatory condition in which proteases and neutrophils still play a major role, but in which pro-inflammatory cytokines, either induced by the actions of NE or by other pro-inflammatory processes normally modulated by AAT, are involved. In this review, we will look at the various cytokines centrally involved in AATD lung disease, and how a greater understanding of their contribution may help development of targeted therapies.
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Sabina Janciauskiene, PharmD, PhD1
Author Affiliations
- Department of Respiratory Medicine, Hannover Medical School, Member of German Centre for Lung Research (DZL), Hannover, Germany; Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
Abstract
Reactive oxygen and nitrogen species can be generated endogenously (by mitochondria, peroxisomes, and phagocytic cells) and exogenously (by pollutions, UV exposure, xenobiotic compounds, and cigarette smoke). The negative effects of free radicals are neutralized by antioxidant molecules synthesized in our body, like glutathione, uric acid, or ubiquinone, and those obtained from the diet, such as vitamins C, E, and A, and flavonoids. Different microelements like selenium and zinc have no antioxidant action themselves but are required for the activity of many antioxidant enzymes. Furthermore, circulating blood proteins are suggested to account for more than 50% of the combined antioxidant effects of urate, ascorbate, and vitamin E. Antioxidants together constitute a mutually supportive defense against reactive oxygen and nitrogen species to maintain the oxidant/antioxidant balance. This article outlines the oxidative and anti-oxidative molecules involved in the pathogenesis of chronic obstructive lung disease. The role of albumin and alpha-1 antitrypsin in antioxidant defense is also discussed.
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Marion Bouchecareilh, PhD1
Author Affiliations
- National Institute of Health and Medical Research (INSERM), National Center for Scientific Research (CNRS), University Bordeaux, Bordeaux Research In Translational Oncology, BaRITOn, Bordeaux, France
Abstract
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease caused by mutations in the SERPINA1 gene and is associated with a decreased level of circulating alpha-1 antitrypsin (AAT). Among all the known mutations in the SERPINA1 gene, homozygous for the Z allele is well-known to result in both lung and liver disease. Unlike the lung injury that occurs in adulthood with the environment (notably, tobacco) as a co-factor, the hepatic damage is more complicated. Despite a common underlying gene mutation, the liver disease associated with AATD presents a considerable variability in the age-of-onset and severity, ranging from transient neonatal cholestasis (in early childhood) to cirrhosis and liver cancer (in childhood and adulthood). Given that all the cofactors– genetics and/or environmental– have not been fully identified, it is still impossible to predict which individuals with AATD may develop severe liver disease. The discovery of these modifiers represents the major challenge for the detection, diagnosis, and development of new therapies to provide alternative options to liver transplantation. The aim of this current review is to provide an updated overview of our knowledge on why some AATD patients associated with liver damage progress poorly.
Citation
Citation: Bouchecareilh M. Alpha-1 antitrypsin deficiency-mediated liver toxicity: why do some patients do poorly? What do we know so far? Chronic Obstr Pulm Dis. 2020; 7(3):In press. doi: http://dx.doi.org/10.15326/jcopdf.7.3.2019.0148
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Robert A. Stockley, MD, DSc1
Author Affiliations
- Lung Investigation Unit, University Hospitals, Birmingham National Health Service Foundation Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom
Address correspondence to:
Professor Robert A. Stockley
Lung Investigation Unit
University Hospitals Birmingham NHS Foundation Trust
Queen Elizabeth Hospital Birmingham
Edgbaston, Birmingham,
United Kingdom
Email: rob.stockley@uhb.nhs.uk
Telephone: +44 121 3716808
Abstract
Alpha-1 antitrypsin deficiency (AATD) has traditionally been associated with the development of early onset panlobular emphysema thought to reflect the direct interstitial damage caused by neutrophil elastase. Since this enzyme is highly sensitive to irreversible inhibition by alpha-1 antitrypsin (AAT), the logic of intravenous augmentation therapy has remained unquestioned and efficacy is supported by both observational studies and formal clinical trials. However, evidence suggests that although AAT augmentation modulates the progression of emphysema, it only slows it down. This raises the issue of whether our long-held beliefs of the cause of the susceptibility to develop emphysema in deficient individuals are correct. There are several aspects of our understanding of the disease that might benefit from a radical departure from traditional thought. This review addresses these concepts and alternative pathways that may be central to progression of emphysema.
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