PMID- 33632708
OWN - NLM
STAT- MEDLINE
DCOM- 20220308
LR  - 20220308
IS  - 1468-3288 (Electronic)
IS  - 0017-5749 (Linking)
VI  - 71
IP  - 2
DP  - 2022 Feb
TI  - Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.
PG  - 415-423
LID - 10.1136/gutjnl-2020-323729 [doi]
AB  - 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.
CI  - (c) Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and 
      permissions. Published by BMJ.
FAU - Fromme, Malin
AU  - Fromme M
AUID- ORCID: 0000-0003-0382-5705
AD  - 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.
FAU - Schneider, Carolin V
AU  - Schneider CV
AD  - 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.
FAU - Pereira, Vitor
AU  - Pereira V
AD  - Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal.
FAU - Hamesch, Karim
AU  - Hamesch K
AUID- ORCID: 0000-0002-1702-2746
AD  - 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.
FAU - Pons, Monica
AU  - Pons M
AD  - Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute 
      (VHIR), Universitat Autonoma de Barcelona, Barcelona, Catalunya, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas 
      (CIBERehd), Instituto de Salud Carlos III, Madrid, Comunidad de Madrid, Spain.
FAU - Reichert, Matthias C
AU  - Reichert MC
AUID- ORCID: 0000-0002-8192-0575
AD  - Department of Medicine II, Saarland University Medical Center, Saarland 
      University, Homburg, Germany.
FAU - Benini, Federica
AU  - Benini F
AD  - Gastroenterology Unit, Department of Medicine, Spedali Civili and University, 
      Brescia, Italy.
FAU - Ellis, Paul
AU  - Ellis P
AD  - Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
FAU - H Thorhauge, Katrine
AU  - H Thorhauge K
AD  - Department of Gastroenterology and Hepatology, Odense University Hospital, 
      Odense, Denmark.
FAU - Mandorfer, Mattias
AU  - Mandorfer M
AUID- ORCID: 0000-0003-2330-0017
AD  - 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.
FAU - Burbaum, Barbara
AU  - Burbaum B
AD  - 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.
FAU - Woditsch, Vivien
AU  - Woditsch V
AD  - 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.
FAU - Chorostowska-Wynimko, Joanna
AU  - Chorostowska-Wynimko J
AD  - Department of Genetics and Clinical Immunology, National Tuberculosis and Lung 
      Diseases Institute, Warszawa, Poland.
FAU - Verbeek, Jef
AU  - Verbeek J
AD  - 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.
FAU - Nevens, Frederik
AU  - Nevens F
AD  - 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.
FAU - Genesca, Joan
AU  - Genesca J
AD  - Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute 
      (VHIR), Universitat Autonoma de Barcelona, Barcelona, Catalunya, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas 
      (CIBERehd), Instituto de Salud Carlos III, Madrid, Comunidad de Madrid, Spain.
FAU - Miravitlles, Marc
AU  - Miravitlles M
AD  - 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.
FAU - Nunez, Alexa
AU  - Nunez A
AD  - 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.
FAU - Schaefer, Benedikt
AU  - Schaefer B
AD  - Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, 
      Tirol, Austria.
FAU - Zoller, Heinz
AU  - Zoller H
AD  - Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, 
      Tirol, Austria.
FAU - Janciauskiene, Sabina
AU  - Janciauskiene S
AD  - Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
FAU - Abreu, Nelia
AU  - Abreu N
AD  - Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal.
FAU - Jasmins, Luis
AU  - Jasmins L
AD  - Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal.
FAU - Gaspar, Rui
AU  - Gaspar R
AUID- ORCID: 0000-0003-0332-3844
AD  - Gastroenterology Department, Centro Hospitalar de Sao Joao, Faculty of Medicine 
      of Porto University, Porto, Portugal.
FAU - Liberal, Rodrigo
AU  - Liberal R
AD  - Gastroenterology Department, Centro Hospitalar de Sao Joao, Faculty of Medicine 
      of Porto University, Porto, Portugal.
FAU - Macedo, Guilherme
AU  - Macedo G
AD  - Gastroenterology Department, Centro Hospitalar de Sao Joao, Faculty of Medicine 
      of Porto University, Porto, Portugal.
FAU - Mahadeva, Ravi
AU  - Mahadeva R
AD  - Department of Respiratory Medicine, Cambridge University Hospitals, Cambridge, 
      UK.
FAU - Gomes, Catarina
AU  - Gomes C
AD  - Gastroenterology Department, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, 
      Vila Nova de Gaia, Porto, Portugal.
FAU - Schneider, Kai Markus
AU  - Schneider KM
AD  - 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.
FAU - Trauner, Michael
AU  - Trauner M
AUID- ORCID: 0000-0002-1275-6425
AD  - 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.
FAU - Krag, Aleksander
AU  - Krag A
AUID- ORCID: 0000-0002-9598-4932
AD  - Department of Gastroenterology and Hepatology, Odense University Hospital, 
      Odense, Denmark.
FAU - Gooptu, Bibek
AU  - Gooptu B
AUID- ORCID: 0000-0002-5223-1121
AD  - NIHR Leicester BRC-Respiratory and Leicester Institute of Structural & Chemical 
      Biology, University of Leicester, Leicester, Leicestershire, UK.
AD  - London Alpha-1 Antitrypsin Deficiency Service, Royal Free Hospital, London, UK.
FAU - Thorburn, Douglas
AU  - Thorburn D
AD  - London Alpha-1 Antitrypsin Deficiency Service, Royal Free Hospital, London, UK.
AD  - Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, 
      Royal Free Hospital, London, UK.
FAU - Marshall, Aileen
AU  - Marshall A
AD  - London Alpha-1 Antitrypsin Deficiency Service, Royal Free Hospital, London, UK.
AD  - Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, 
      Royal Free Hospital, London, UK.
FAU - Hurst, John R
AU  - Hurst JR
AUID- ORCID: 0000-0002-7246-6040
AD  - London Alpha-1 Antitrypsin Deficiency Service, Royal Free Hospital, London, UK.
AD  - UCL Respiratory, Division of Medicine, University College London, London, UK.
FAU - Lomas, David A
AU  - Lomas DA
AUID- ORCID: 0000-0003-2339-6979
AD  - London Alpha-1 Antitrypsin Deficiency Service, Royal Free Hospital, London, UK.
AD  - UCL Respiratory, Division of Medicine, University College London, London, UK.
FAU - Lammert, Frank
AU  - Lammert F
AD  - Department of Medicine II, Saarland University Medical Center, Saarland 
      University, Homburg, Germany.
AD  - Hannover Medical School (MHH), Hannover, Germany.
FAU - Gaisa, Nadine T
AU  - Gaisa NT
AD  - Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Clark, Virginia
AU  - Clark V
AD  - Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, 
      Gainesville, Florida, USA.
FAU - Griffiths, William
AU  - Griffiths W
AD  - Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, 
      Cambridge, Cambridgeshire, UK.
FAU - Trautwein, Christian
AU  - Trautwein C
AD  - 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.
FAU - Turner, Alice M
AU  - Turner AM
AD  - Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
FAU - McElvaney, Noel G
AU  - McElvaney NG
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Beaumont Hospital, Dublin, Ireland.
FAU - Strnad, Pavel
AU  - Strnad P
AUID- ORCID: 0000-0002-7122-6379
AD  - 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.
LA  - eng
GR  - DH_/Department of Health/United Kingdom
GR  - MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210225
PL  - England
TA  - Gut
JT  - Gut
JID - 2985108R
SB  - IM
MH  - Adult
MH  - Aged
MH  - Case-Control Studies
MH  - Cholelithiasis/*epidemiology
MH  - Cohort Studies
MH  - Female
MH  - Humans
MH  - Liver Cirrhosis/*epidemiology
MH  - Liver Neoplasms/*epidemiology
MH  - Male
MH  - Middle Aged
MH  - Phenotype
MH  - Prevalence
MH  - United Kingdom
MH  - alpha 1-Antitrypsin Deficiency/*complications
OTO - NOTNLM
OT  - cancer
OT  - fibrosis
OT  - liver
OT  - liver cirrhosis
COIS- Competing interests: None declared.
EDAT- 2021/02/27 06:00
MHDA- 2022/03/09 06:00
CRDT- 2021/02/26 05:53
PHST- 2020/11/28 00:00 [received]
PHST- 2021/01/07 00:00 [revised]
PHST- 2021/01/25 00:00 [accepted]
PHST- 2021/02/27 06:00 [pubmed]
PHST- 2022/03/09 06:00 [medline]
PHST- 2021/02/26 05:53 [entrez]
AID - gutjnl-2020-323729 [pii]
AID - 10.1136/gutjnl-2020-323729 [doi]
PST - ppublish
SO  - Gut. 2022 Feb;71(2):415-423. doi: 10.1136/gutjnl-2020-323729. Epub 2021 Feb 25.