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Gastroenterology. 2019 May 20. pii: S0016-5085(19)40894-9. doi: 10.1053/j.gastro.2019.05.013. [Epub ahead of print]

Liver Fibrosis and Metabolic Alterations in Adults with Alpha1 Antitrypsin Deficiency Caused by the Pi*ZZ Mutation.

Author information

1
Coordinating center for alpha1-antitrypsin deficiency-related liver disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha1-Liver"; Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
2
Division of Gastroenterology und Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria.
3
Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal.
4
Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.
5
Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Clinic for Gastroenterology und Hepatology, Vall d'Hebron Hospital, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid.
6
Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
7
Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
8
Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
9
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.
10
Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
11
Department of Internal Medicine I, Paracelsus Medical University, Salzburg, Austria.
12
Department of Medicine I, Charité - Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
13
Gastroenterology Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.
14
Gastroenterology Department, Centro Hospitalar de São João, Faculty of Medicine of Porto University, Porto, Portugal.
15
Gastroenterology Department, Centro Hospitalar do Porto, Porto, Portugal.
16
Gastroenterology Department, Hospital de Braga, Braga, Portugal.
17
Gastroenterology Department, Hospital Universitário de Coimbra, Coimbra, Portugal.
18
Medical Care Centre, Dr Stein and Colleagues, Moenchengladbach, Germany.
19
Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital RWTH Aachen, Aachen, Germany; JARA-BRAIN, Jülich-Aachen Research Alliance, Germany.
20
Clinic for Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
21
Clinic for Pulmonology, University Hospital Frankfurt, Frankfurt, Germany.
22
Department of Pneumology, Cologne Merheim Hospital, Kliniken der Stadt Köln gGmbH, Witten/Herdecke University, Faculty of Health/School of Medicine, Cologne, Germany.
23
Department of Respiratory Medicine, Cambridge NIHR BRC, University of Cambridge, Cambridge, UK.
24
Department of Medicine V, Saarland University Medical Center, Saarland University, Homburg, Germany.
25
Clinic for Pneumology, Marburg University Hospital, Marburg, Germany; Institute for Pulmonary Rehabilitation Research, Schoen Clinic Berchtesgadener Land, Member of the DZL, Germany.
26
Department of Pneumology, Vall d'Hebron University Hospital, CIBER de Enfermedades Respiratorias CIBERES), Barcelona, Spain.
27
Clinic for Pneumology, German Center for Lung Research (DZL), Medical University Hannover, Hannover, Germany.
28
Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.
29
Coordinating center for alpha1-antitrypsin deficiency-related liver disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) registry group "Alpha1-Liver"; Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany. Electronic address: pstrnad@ukaachen.de.

Abstract

BACKGROUND:

Alpha1 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 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 features in adults with this form of AATD.

METHODS:

We collected data from 554 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 previously known 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 APRI 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 9-20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age >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, 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 patients 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.

KEYWORDS:

ALT; AST; TE; rare liver disease

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