Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

European Alpha-1 Liver Study Group

doi:10.1136/gutjnl-2020-323729

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

European Alpha-1 Liver Study Group

Applied Health Research

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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.

Original language	English
Journal	Gut
Early online date	25 Feb 2021
DOIs	https://doi.org/10.1136/gutjnl-2020-323729
Publication status	E-pub ahead of print - 25 Feb 2021

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FrommeM2021Hepatobiliary
This article has been accepted for publication in Gut, 2021 following peer review, and the Version of Record can be accessed online at: http://dx.doi.org/10.1136/gutjnl-2020-323729 © Authors (or their employer(s)) 2021. Reuse of this manuscript version (excluding any databases, tables, diagrams, photographs and other images or illustrative material included where a another copyright owner is identified) is permitted strictly pursuant to the terms of the Creative Commons Attribution-Non Commercial 4.0 International (CC-BY-NC 4.0) http://creativecommons.org
Accepted author manuscript, 1.3 MBLicence: Creative Commons: Attribution-NonCommercial (CC BY-NC)

Cite this

@article{df650050774f4d22a8603b25ba314ce0,

title = "Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency",

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 {\textquoteleft}Pi*Z{\textquoteright} variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous {\textquoteleft}Pi*Z{\textquoteright} carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common {\textquoteleft}Pi*S{\textquoteright} 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.",

author = "{European Alpha-1 Liver Study Group} and Malin Fromme and Schneider, {Carolin V.} and Vitor Pereira and Karim Hamesch and Monica Pons and Reichert, {Matthias C.} and Federica Benini and Paul Ellis and Katrine Thorhauge and Mattias Mandorfer and Barbara Burbaum and Vivien Woditsch and Joanna Chorostowska-Wynimko and Jef Verbeek and Frederik Nevens and Joan Genesca and Marc Miravitlles and Alexa Nu{\~n}ez and Benedikt Schaefer and Heinz Zoller and Sabina Janciauskiene and N{\'e}lia Abreu and Lu{\'i}s Jasmins and Rui Gaspar and Catarina Gomes and Schneider, {Kai Markus} and Michael Trauner and Aleksander Krag and Bibek Gooptu and Douglas Thorburn and Aileen Marshall and Hurst, {John R.} and Lomas, {David A.} and Frank Lammert and Gaisa, {Nadine T.} and Virginia Clark and Griffiths, {William J} and Christian Trautwein and Alice Turner and McElvaney, {Noel G} and Pavel Strnad",

year = "2021",

month = feb,

day = "25",

doi = "10.1136/gutjnl-2020-323729",

language = "English",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

}

TY - JOUR

T1 - Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

AU - European Alpha-1 Liver Study Group

AU - Fromme, Malin

AU - Schneider, Carolin V.

AU - Pereira, Vitor

AU - Hamesch, Karim

AU - Pons, Monica

AU - Reichert, Matthias C.

AU - Benini, Federica

AU - Ellis, Paul

AU - Thorhauge, Katrine

AU - Mandorfer, Mattias

AU - Burbaum, Barbara

AU - Woditsch, Vivien

AU - Chorostowska-Wynimko, Joanna

AU - Verbeek, Jef

AU - Nevens, Frederik

AU - Genesca, Joan

AU - Miravitlles, Marc

AU - Nuñez, Alexa

AU - Schaefer, Benedikt

AU - Zoller, Heinz

AU - Janciauskiene, Sabina

AU - Abreu, Nélia

AU - Jasmins, Luís

AU - Gaspar, Rui

AU - Gomes, Catarina

AU - Schneider, Kai Markus

AU - Trauner, Michael

AU - Krag, Aleksander

AU - Gooptu, Bibek

AU - Thorburn, Douglas

AU - Marshall, Aileen

AU - Hurst, John R.

AU - Lomas, David A.

AU - Lammert, Frank

AU - Gaisa, Nadine T.

AU - Clark, Virginia

AU - Griffiths, William J

AU - Trautwein, Christian

AU - Turner, Alice

AU - McElvaney, Noel G

AU - Strnad, Pavel

PY - 2021/2/25

Y1 - 2021/2/25

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85101702193&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2020-323729

DO - 10.1136/gutjnl-2020-323729

M3 - Article

SN - 0017-5749

JO - Gut

JF - Gut

ER -

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

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