PMID- 31121167
OWN - NLM
STAT- MEDLINE
DCOM- 20190924
LR  - 20190925
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Linking)
VI  - 157
IP  - 3
DP  - 2019 Sep
TI  - Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin 
      Deficiency Caused by the Pi*ZZ Mutation.
PG  - 705-719.e18
LID - S0016-5085(19)40894-9 [pii]
LID - 10.1053/j.gastro.2019.05.013 [doi]
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 gamma-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.
CI  - Copyright (c) 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Hamesch, Karim
AU  - Hamesch K
AD  - 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-Westfalische Technische Hochschule 
      Aachen, Aachen, Germany.
FAU - Mandorfer, Mattias
AU  - Mandorfer M
AD  - Division of Gastroenterology and Hepatology, Department of Internal Medicine III, 
      Medical University Vienna, Vienna, Austria.
FAU - Pereira, Vitor M
AU  - Pereira VM
AD  - Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal.
FAU - Moeller, Linda S
AU  - Moeller LS
AD  - Department of Gastroenterology and Hepatology, Odense University Hospital, 
      Odense, Denmark.
FAU - Pons, Monica
AU  - Pons M
AD  - Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research 
      Institute, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de 
      Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Instituto 
      de Salud Carlos III, Madrid, Spain.
FAU - Dolman, Grace E
AU  - Dolman GE
AD  - Department of Hepatology, Cambridge University Hospitals National Health Service 
      Foundation Trust, Cambridge, UK.
FAU - Reichert, Matthias C
AU  - Reichert MC
AD  - Department of Medicine II, Saarland University Medical Center, Saarland 
      University, Homburg, Germany.
FAU - Schneider, Carolin V
AU  - Schneider CV
AD  - Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, 
      University Hospital Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, 
      Germany.
FAU - Woditsch, Vivien
AU  - Woditsch V
AD  - Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, 
      University Hospital Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, 
      Germany.
FAU - Voss, Jessica
AU  - Voss J
AD  - Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, 
      University Hospital Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, 
      Germany.
FAU - Lindhauer, Cecilia
AU  - Lindhauer C
AD  - Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, 
      University Hospital Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, 
      Germany.
FAU - Fromme, Malin
AU  - Fromme M
AD  - Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, 
      University Hospital Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, 
      Germany.
FAU - Spivak, Igor
AU  - Spivak I
AD  - Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, 
      University Hospital Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, 
      Germany.
FAU - Guldiken, Nurdan
AU  - Guldiken N
AD  - Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, 
      University Hospital Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, 
      Germany.
FAU - Zhou, Biaohuan
AU  - Zhou B
AD  - Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, 
      University Hospital Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, 
      Germany.
FAU - Arslanow, Anita
AU  - Arslanow A
AD  - 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.
FAU - Schaefer, Benedikt
AU  - Schaefer B
AD  - Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, 
      Austria.
FAU - Zoller, Heinz
AU  - Zoller H
AD  - Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, 
      Austria.
FAU - Aigner, Elmar
AU  - Aigner E
AD  - Department of Internal Medicine I, Paracelsus Medical University, Salzburg, 
      Austria.
FAU - Reiberger, Thomas
AU  - Reiberger T
AD  - Division of Gastroenterology and Hepatology, Department of Internal Medicine III, 
      Medical University Vienna, Vienna, Austria.
FAU - Wetzel, Martin
AU  - Wetzel M
AD  - Department of Medicine I, Charite-Universitaetsmedizin Berlin, Campus Benjamin 
      Franklin, Berlin, Germany.
FAU - Siegmund, Britta
AU  - Siegmund B
AD  - Department of Medicine I, Charite-Universitaetsmedizin Berlin, Campus Benjamin 
      Franklin, Berlin, Germany.
FAU - Simoes, Carolina
AU  - Simoes C
AD  - Gastroenterology Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.
FAU - Gaspar, Rui
AU  - Gaspar R
AD  - Gastroenterology Department, Centro Hospitalar de Sao Joao, Faculty of Medicine 
      of Porto University, Porto, Portugal.
FAU - Maia, Luis
AU  - Maia L
AD  - Gastroenterology Department, Centro Hospitalar do Porto, Porto, Portugal.
FAU - Costa, Dalila
AU  - Costa D
AD  - Gastroenterology Department, Hospital de Braga, Braga, Portugal.
FAU - Bento-Miranda, Mario
AU  - Bento-Miranda M
AD  - Gastroenterology Department, Hospital Universitario de Coimbra, Coimbra, 
      Portugal.
FAU - van Helden, Josef
AU  - van Helden J
AD  - Medical Care Centre, Dr Stein and Colleagues, Moenchengladbach, Germany.
FAU - Yagmur, Eray
AU  - Yagmur E
AD  - Medical Care Centre, Dr Stein and Colleagues, Moenchengladbach, Germany.
FAU - Bzdok, Danilo
AU  - Bzdok D
AD  - Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital 
      Rheinisch-Westfalische Technische Hochschule Aachen, Aachen, Germany; Julich 
      Aachen Research Alliance-Brain, Aachen, Germany.
FAU - Stolk, Jan
AU  - Stolk J
AD  - Clinic for Pulmonology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Gleiber, Wolfgang
AU  - Gleiber W
AD  - Clinic for Pulmonology, University Hospital Frankfurt, Frankfurt, Germany.
FAU - Knipel, Verena
AU  - Knipel V
AD  - Department of Pneumology, Cologne Merheim Hospital, Kliniken der Stadt Koln 
      gGmbH, Witten/Herdecke University, Faculty of Health/School of Medicine, Cologne, 
      Germany.
FAU - Windisch, Wolfram
AU  - Windisch W
AD  - Department of Pneumology, Cologne Merheim Hospital, Kliniken der Stadt Koln 
      gGmbH, Witten/Herdecke University, Faculty of Health/School of Medicine, Cologne, 
      Germany.
FAU - Mahadeva, Ravi
AU  - Mahadeva R
AD  - Department of Respiratory Medicine, Cambridge National Institute for Health 
      Research, Biomedical Research Centre, University of Cambridge, Cambridge, UK.
FAU - Bals, Robert
AU  - Bals R
AD  - Department of Medicine V, Saarland University Medical Center, Saarland 
      University, Homburg, Germany.
FAU - Koczulla, Rembert
AU  - Koczulla R
AD  - Clinic for Pneumology, Marburg University Hospital, Marburg, Germany; Institute 
      for Pulmonary Rehabilitation Research, Schoen Clinic Berchtesgadener Land, Member 
      of the Deutsches Zentrum fur Lungenforschung, Schonau am Konigssee, Germany.
FAU - Barrecheguren, Miriam
AU  - Barrecheguren M
AD  - Department of Pneumology, Vall d'Hebron University Hospital, Centro de 
      Investigacion Biomedica en Red de Enfermedades Respiratorias, Barcelona, Spain.
FAU - Miravitlles, Marc
AU  - Miravitlles M
AD  - Department of Pneumology, Vall d'Hebron University Hospital, Centro de 
      Investigacion Biomedica en Red de Enfermedades Respiratorias, Barcelona, Spain.
FAU - Janciauskiene, Sabina
AU  - Janciauskiene S
AD  - Clinic for Pneumology, German Center for Lung Research, Medical University 
      Hannover, Hannover, Germany.
FAU - Stickel, Felix
AU  - Stickel F
AD  - Department of Gastroenterology and Hepatology, University Hospital of Zurich, 
      Zurich, Switzerland.
FAU - Lammert, Frank
AU  - Lammert F
AD  - Department of Medicine II, Saarland University Medical Center, Saarland 
      University, Homburg, Germany.
FAU - Liberal, Rodrigo
AU  - Liberal R
AD  - Gastroenterology Department, Centro Hospitalar de Sao Joao, Faculty of Medicine 
      of Porto University, Porto, Portugal.
FAU - Genesca, Joan
AU  - Genesca J
AD  - Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research 
      Institute, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de 
      Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Instituto 
      de Salud Carlos III, Madrid, Spain.
FAU - Griffiths, William J
AU  - Griffiths WJ
AD  - Department of Hepatology, Cambridge University Hospitals National Health Service 
      Foundation Trust, Cambridge, UK.
FAU - Trauner, Michael
AU  - Trauner M
AD  - Division of Gastroenterology and Hepatology, Department of Internal Medicine III, 
      Medical University Vienna, Vienna, Austria.
FAU - Krag, Aleksander
AU  - Krag A
AD  - Department of Gastroenterology and Hepatology, Odense University Hospital, 
      Odense, Denmark.
FAU - Trautwein, Christian
AU  - Trautwein C
AD  - 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-Westfalische Technische Hochschule 
      Aachen, Aachen, Germany.
FAU - Strnad, Pavel
AU  - Strnad P
AD  - 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-Westfalische Technische Hochschule 
      Aachen, Aachen, Germany. Electronic address: pstrnad@ukaachen.de.
CN  - European Alpha1-Liver Study Group
LA  - eng
SI  - ClinicalTrials.gov/NCT02929940
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20190520
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (SERPINA1 protein, human)
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
CIN - Transl Gastroenterol Hepatol. 2019 Dec 12;4:82. PMID: 32039287
MH  - Adult
MH  - Age Factors
MH  - Aged
MH  - Animals
MH  - Case-Control Studies
MH  - Elasticity Imaging Techniques
MH  - Europe
MH  - Fatty Liver/blood/diagnosis/*etiology
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - Homozygote
MH  - Humans
MH  - *Lipid Metabolism
MH  - Liver/diagnostic imaging/*metabolism/pathology
MH  - Liver Cirrhosis/blood/diagnosis/*etiology
MH  - Liver Function Tests
MH  - Male
MH  - Mice, Transgenic
MH  - Middle Aged
MH  - *Mutation
MH  - Phenotype
MH  - Risk Factors
MH  - Sex Factors
MH  - alpha 1-Antitrypsin/*genetics
MH  - alpha 1-Antitrypsin Deficiency/*complications/diagnosis/enzymology/genetics
OTO - NOTNLM
OT  - ALT
OT  - AST
OT  - Rare Liver Disease
OT  - TE
EDAT- 2019/05/24 06:00
MHDA- 2019/09/26 06:00
CRDT- 2019/05/24 06:00
PHST- 2018/05/19 00:00 [received]
PHST- 2019/05/07 00:00 [revised]
PHST- 2019/05/09 00:00 [accepted]
PHST- 2019/05/24 06:00 [pubmed]
PHST- 2019/09/26 06:00 [medline]
PHST- 2019/05/24 06:00 [entrez]
AID - S0016-5085(19)40894-9 [pii]
AID - 10.1053/j.gastro.2019.05.013 [doi]
PST - ppublish
SO  - Gastroenterology. 2019 Sep;157(3):705-719.e18. doi: 10.1053/j.gastro.2019.05.013. 
      Epub 2019 May 20.