Fibrosis-Related Gene Profiling in Liver Biopsies of PiZZ α1-Antitrypsin Children with Different Clinical Courses-Reference-Cited by-同舟云学术

Fibrosis-Related Gene Profiling in Liver Biopsies of PiZZ α1-Antitrypsin Children with Different Clinical Courses

Published:2023-01-27 Issue:3 Volume:24 Page:2485
ISSN:1422-0067
Container-title:International Journal of Molecular Sciences
language:en
Short-container-title:IJMS

Author:

Kamp Jan C.¹²^ORCID,Kappe Naomi N.³⁴,Moro Carlos Fernández⁵,Fuge Jan¹²^ORCID,Kuehnel Mark P.²⁶,Wrenger Sabine¹²^ORCID,Welte Tobias¹²,Hoek Bart van⁴^ORCID,Jonigk Danny D.²⁷^ORCID,Khedoe Padmini P. S. J.³^ORCID,Strnad Pavel⁸^ORCID,Björnstedt Mikael⁵^ORCID,Stolk Jan³,Janciauskiene Sabina¹²,Nemeth Antal⁵

Affiliation:

1. Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany

2. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center of Lung Research (DZL), 30625 Hannover, Germany

3. Department of Pulmonology, Leiden University Medical Center, Member of European Reference Network Lung, Section Alpha-1-Antitrypsin Deficiency, 2333 ZA Leiden, The Netherlands

4. Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

5. Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden

6. Institute of Pathology, Hannover Medical School, 30625 Hannover, Germany

7. Institute of Pathology, RWTH University of Aachen, 52074 Aachen, Germany

8. 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), 52074 Aachen, Germany

Abstract

PiZZ (Glu342Lys) α1-antitrypsin deficiency (AATD) is characterized by intrahepatic AAT polymerization and is a risk factor for liver disease development in children. The majority of PiZZ children are disease free, hence this mutation alone is not sufficient to cause the disease. We investigated Z-AAT polymers and the expression of fibrosis-related genes in liver tissues of PiZZ children with different clinical courses. Liver biopsies obtained during 1979–2010 at the Department of Paediatrics, Karolinska University Hospital, Sweden, were subjected to histological re-evaluation, immunohistochemistry and NanoString-based transcriptome profiling using a panel of 760 fibrosis plus 8 bile acid-related genes. Subjects were divided into three groups based on clinical outcomes: NCH (neonatal cholestasis, favourable outcome, n = 5), NCC (neonatal cholestasis, early cirrhosis and liver transplantation, n = 4), and NNCH (no neonatal cholestasis, favourable outcome, n = 5, six biopsies). Hepatocytes containing Z-AAT polymers were abundant in all groups whereas NCC showed higher expression of genes related to liver fibrosis/cirrhosis and lower expression of genes related to lipid, aldehyde/ketone, and bile acid metabolism. Z-AAT accumulation per se cannot explain the clinical outcomes of PiZZ children; however, changes in the expression of specific genes and pathways involved in lipid, fatty acid, and steroid metabolism appear to reflect the degree of liver injury.

Funder

Stichting Marcel Brus Fonds

DFG

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Link

https://www.mdpi.com/1422-0067/24/3/2485/pdf

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