Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation

European Alpha1-Liver Study Group

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftGastroenterology
Vol/bind157
Udgave nummer3
Sider (fra-til)705-719.e18
ISSN0016-5085
DOI
StatusUdgivet - 1. sep. 2019

Fingeraftryk

alpha 1-Antitrypsin Deficiency
Liver Cirrhosis
Mutation
Liver
Liver Diseases
Fatty Liver
Lipids
Lung
Serum
VLDL Cholesterol
Preexisting Condition Coverage
Autosomal Recessive alpha-1-Antitrypsin Deficiency
Alanine Transaminase
Platelet Count
Lung Diseases
Comorbidity
Counseling
Down-Regulation
Health
Enzymes

Citer dette

@article{cdd616ad94eb4c309bc94d0f191095ae,
title = "Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation",
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.",
keywords = "ALT, AST, Rare Liver Disease, TE",
author = "Karim Hamesch and Mattias Mandorfer and Pereira, {V{\'i}tor M.} and Moeller, {Linda S.} and Monica Pons and Dolman, {Grace E.} and Reichert, {Matthias C.} and Schneider, {Carolin V.} and Vivien Woditsch and Jessica Voss and Cecilia Lindhauer and Malin Fromme and Igor Spivak and Nurdan Guldiken and Biaohuan Zhou and Anita Arslanow and Benedikt Schaefer and Heinz Zoller and Elmar Aigner and Thomas Reiberger and Martin Wetzel and Britta Siegmund and Carolina Sim{\~o}es and Rui Gaspar and Lu{\'i}s Maia and Dalila Costa and M{\'a}rio Bento-Miranda and {van Helden}, Josef and Eray Yagmur and Danilo Bzdok and Jan Stolk and Wolfgang Gleiber and Verena Knipel and Wolfram Windisch and Ravi Mahadeva and Robert Bals and Rembert Koczulla and Miriam Barrecheguren and Marc Miravitlles and Sabina Janciauskiene and Felix Stickel and Frank Lammert and Rodrigo Liberal and Joan Genesca and Griffiths, {William J.} and Michael Trauner and Aleksander Krag and Christian Trautwein and Pavel Strnad and {European Alpha1-Liver Study Group}",
year = "2019",
month = "9",
day = "1",
doi = "10.1053/j.gastro.2019.05.013",
language = "English",
volume = "157",
pages = "705--719.e18",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "Heinemann",
number = "3",

}

Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation. / European Alpha1-Liver Study Group.

I: Gastroenterology, Bind 157, Nr. 3, 01.09.2019, s. 705-719.e18.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation

AU - Hamesch, Karim

AU - Mandorfer, Mattias

AU - Pereira, Vítor M.

AU - Moeller, Linda S.

AU - Pons, Monica

AU - Dolman, Grace E.

AU - Reichert, Matthias C.

AU - Schneider, Carolin V.

AU - Woditsch, Vivien

AU - Voss, Jessica

AU - Lindhauer, Cecilia

AU - Fromme, Malin

AU - Spivak, Igor

AU - Guldiken, Nurdan

AU - Zhou, Biaohuan

AU - Arslanow, Anita

AU - Schaefer, Benedikt

AU - Zoller, Heinz

AU - Aigner, Elmar

AU - Reiberger, Thomas

AU - Wetzel, Martin

AU - Siegmund, Britta

AU - Simões, Carolina

AU - Gaspar, Rui

AU - Maia, Luís

AU - Costa, Dalila

AU - Bento-Miranda, Mário

AU - van Helden, Josef

AU - Yagmur, Eray

AU - Bzdok, Danilo

AU - Stolk, Jan

AU - Gleiber, Wolfgang

AU - Knipel, Verena

AU - Windisch, Wolfram

AU - Mahadeva, Ravi

AU - Bals, Robert

AU - Koczulla, Rembert

AU - Barrecheguren, Miriam

AU - Miravitlles, Marc

AU - Janciauskiene, Sabina

AU - Stickel, Felix

AU - Lammert, Frank

AU - Liberal, Rodrigo

AU - Genesca, Joan

AU - Griffiths, William J.

AU - Trauner, Michael

AU - Krag, Aleksander

AU - Trautwein, Christian

AU - Strnad, Pavel

AU - European Alpha1-Liver Study Group

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

KW - ALT

KW - AST

KW - Rare Liver Disease

KW - TE

U2 - 10.1053/j.gastro.2019.05.013

DO - 10.1053/j.gastro.2019.05.013

M3 - Journal article

VL - 157

SP - 705-719.e18

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 3

ER -