Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

Malin Fromme; Carolin V Schneider; Vitor Pereira; Karim Hamesch; Monica Pons; Matthias C Reichert; Federica Benini; Paul Ellis; Katrine H Thorhauge; Mattias Mandorfer; Barbara Burbaum; Vivien Woditsch; Joanna Chorostowska-Wynimko; Jef Verbeek; Frederik Nevens; Joan Genesca; Marc Miravitlles; Alexa Nuñez; Benedikt Schaefer; Heinz Zoller; Sabina Janciauskiene; Nélia Abreu; Luís Jasmins; Rui Gaspar; Rodrigo Liberal; Guilherme Macedo; Ravi Mahadeva; Catarina Gomes; Kai Markus Schneider; Michael Trauner; Aleksander Krag; Bibek Gooptu; Douglas Thorburn; Aileen Marshall; John R Hurst; David A Lomas; Frank Lammert; Nadine T Gaisa; Virginia Clark; William Griffiths; Christian Trautwein; Alice M Turner; Noel G McElvaney; Pavel Strnad

doi:10.1136/gutjnl-2020-323729

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

Gut. 2022 Feb;71(2):415-423. doi: 10.1136/gutjnl-2020-323729. Epub 2021 Feb 25.

Authors

Malin Fromme^#¹, Carolin V Schneider^#¹, Vitor Pereira², Karim Hamesch¹, Monica Pons^{3

4}, Matthias C Reichert⁵, Federica Benini⁶, Paul Ellis⁷, Katrine H Thorhauge⁸, Mattias Mandorfer⁹, Barbara Burbaum¹, Vivien Woditsch¹, Joanna Chorostowska-Wynimko¹⁰, Jef Verbeek¹¹, Frederik Nevens¹¹, Joan Genesca^{3

4}, Marc Miravitlles¹², Alexa Nuñez¹², Benedikt Schaefer¹³, Heinz Zoller¹³, Sabina Janciauskiene¹⁴, Nélia Abreu², Luís Jasmins², Rui Gaspar¹⁵, Rodrigo Liberal¹⁵, Guilherme Macedo¹⁵, Ravi Mahadeva¹⁶, Catarina Gomes¹⁷, Kai Markus Schneider¹, Michael Trauner⁹, Aleksander Krag⁸, Bibek Gooptu^{18

19}, Douglas Thorburn^{19

20}, Aileen Marshall^{19

20}, John R Hurst^{19

21}, David A Lomas^{19

21}, Frank Lammert^{5

22}, Nadine T Gaisa²³, Virginia Clark²⁴, William Griffiths²⁵, Christian Trautwein¹, Alice M Turner⁷, Noel G McElvaney²⁶, Pavel Strnad²⁷

Affiliations

¹ Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany.
² Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal.
³ Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Catalunya, Spain.
⁴ Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Comunidad de Madrid, Spain.
⁵ Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
⁶ Gastroenterology Unit, Department of Medicine, Spedali Civili and University, Brescia, Italy.
⁷ Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
⁸ Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.
⁹ Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Vienna, Austria.
¹⁰ Department of Genetics and Clinical Immunology, National Tuberculosis and Lung Diseases Institute, Warszawa, Poland.
¹¹ Department of Gastroenterology & Hepatology, KU Leuven University Hospitals Leuven, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Leuven, Flanders, Belgium.
¹² Pneumology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.
¹³ Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Tirol, Austria.
¹⁴ Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
¹⁵ Gastroenterology Department, Centro Hospitalar de São João, Faculty of Medicine of Porto University, Porto, Portugal.
¹⁶ Department of Respiratory Medicine, Cambridge University Hospitals, Cambridge, UK.
¹⁷ Gastroenterology Department, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila Nova de Gaia, Porto, Portugal.
¹⁸ NIHR Leicester BRC-Respiratory and Leicester Institute of Structural & Chemical Biology, University of Leicester, Leicester, Leicestershire, UK.
¹⁹ London Alpha-1 Antitrypsin Deficiency Service, Royal Free Hospital, London, UK.
²⁰ Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.
²¹ UCL Respiratory, Division of Medicine, University College London, London, UK.
²² Hannover Medical School (MHH), Hannover, Germany.
²³ Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
²⁴ Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida, USA.
²⁵ Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, Cambridgeshire, UK.
²⁶ Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
²⁷ Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany pstrnad@ukaachen.de.

^# Contributed equally.

PMID: 33632708
DOI: 10.1136/gutjnl-2020-323729

Abstract

Objective: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.

Design: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.

Results: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.

Conclusion: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Keywords: cancer; fibrosis; liver; liver cirrhosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Case-Control Studies
Cholelithiasis / epidemiology*
Cohort Studies
Female
Humans
Liver Cirrhosis / epidemiology*
Liver Neoplasms / epidemiology*
Male
Middle Aged
Phenotype
Prevalence
United Kingdom
alpha 1-Antitrypsin Deficiency / complications*

Abstract

Publication types

MeSH terms

Grants and funding