Karim Hamesch1, Mattias Mandorfer2, Vítor M Pereira3, Linda S Moeller4, Monica Pons5, Grace E Dolman6, Matthias C Reichert7, Carolin V Schneider8, Vivien Woditsch8, Jessica Voss8, Cecilia Lindhauer8, Malin Fromme8, Igor Spivak8, Nurdan Guldiken8, Biaohuan Zhou8, Anita Arslanow9, Benedikt Schaefer10, Heinz Zoller10, Elmar Aigner11, Thomas Reiberger2, Martin Wetzel12, Britta Siegmund12, Carolina Simões13, Rui Gaspar14, Luís Maia15, Dalila Costa16, Mário Bento-Miranda17, Josef van Helden18, Eray Yagmur18, Danilo Bzdok19, Jan Stolk20, Wolfgang Gleiber21, Verena Knipel22, Wolfram Windisch22, Ravi Mahadeva23, Robert Bals24, Rembert Koczulla25, Miriam Barrecheguren26, Marc Miravitlles26, Sabina Janciauskiene27, Felix Stickel28, Frank Lammert7, Rodrigo Liberal14, Joan Genesca5, William J Griffiths6, Michael Trauner2, Aleksander Krag4, Christian Trautwein1, Pavel Strnad29. 1. Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network "Rare Liver" and the European Association for the Study of the Liver Registry Group "Alpha1-Liver," University Hospital Aachen, Aachen, Germany; Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany. 2. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria. 3. Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal. 4. Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark. 5. Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain. 6. Department of Hepatology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK. 7. Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany. 8. Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany. 9. Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. 10. Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria. 11. Department of Internal Medicine I, Paracelsus Medical University, Salzburg, Austria. 12. Department of Medicine I, Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany. 13. Gastroenterology Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal. 14. Gastroenterology Department, Centro Hospitalar de São João, Faculty of Medicine of Porto University, Porto, Portugal. 15. Gastroenterology Department, Centro Hospitalar do Porto, Porto, Portugal. 16. Gastroenterology Department, Hospital de Braga, Braga, Portugal. 17. Gastroenterology Department, Hospital Universitário de Coimbra, Coimbra, Portugal. 18. Medical Care Centre, Dr Stein and Colleagues, Moenchengladbach, Germany. 19. Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany; Jülich Aachen Research Alliance-Brain, Aachen, Germany. 20. Clinic for Pulmonology, Leiden University Medical Center, Leiden, The Netherlands. 21. Clinic for Pulmonology, University Hospital Frankfurt, Frankfurt, Germany. 22. Department of Pneumology, Cologne Merheim Hospital, Kliniken der Stadt Köln gGmbH, Witten/Herdecke University, Faculty of Health/School of Medicine, Cologne, Germany. 23. Department of Respiratory Medicine, Cambridge National Institute for Health Research, Biomedical Research Centre, University of Cambridge, Cambridge, UK. 24. Department of Medicine V, Saarland University Medical Center, Saarland University, Homburg, Germany. 25. Clinic for Pneumology, Marburg University Hospital, Marburg, Germany; Institute for Pulmonary Rehabilitation Research, Schoen Clinic Berchtesgadener Land, Member of the Deutsches Zentrum für Lungenforschung, Schönau am Königssee, Germany. 26. Department of Pneumology, Vall d'Hebron University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Barcelona, Spain. 27. Clinic for Pneumology, German Center for Lung Research, Medical University Hannover, Hannover, Germany. 28. Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland. 29. Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network "Rare Liver" and the European Association for the Study of the Liver Registry Group "Alpha1-Liver," University Hospital Aachen, Aachen, Germany; Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany. Electronic address: pstrnad@ukaachen.de.
Abstract
BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.
BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.
Authors: Marianna Mela; Wendy Smeeton; Susan E Davies; Elena Miranda; Cinzia Scarpini; Nick Coleman; Graeme J M Alexander Journal: Chronic Obstr Pulm Dis Date: 2020-07
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Authors: Jack Dummer; Claudia C Dobler; Mark Holmes; Daniel Chambers; Ian A Yang; Lianne Parkin; Sheree Smith; Peter Wark; Anouk Dev; Sandra Hodge; Eli Dabscheck; Julian Gooi; Sameh Samuel; Steven Knowles; Anne E Holland Journal: Respirology Date: 2020-02-06 Impact factor: 6.424
Authors: Georg Semmler; Lorenz Balcar; Hannes Oberkofler; Stephan Zandanell; Michael Strasser; David Niederseer; Alexandra Feldman; Felix Stickel; Pavel Strnad; Christian Datz; Bernhard Paulweber; Elmar Aigner Journal: J Pers Med Date: 2021-03-01