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

Jan C. Kamp; Naomi N. Kappe; Carlos Fernández Moro; Jan Fuge; Mark P. Kuehnel; Sabine Wrenger; Tobias Welte; Bart van Hoek; Danny D. Jonigk; Padmini P. S. J. Khedoe; Pavel Strnad; Mikael Björnstedt; Jan Stolk; Sabina Janciauskiene; Antal Nemeth

doi:10.3390/ijms24032485

International Journal of Molecular Sciences (Jan 2023)

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

Jan C. Kamp,
Naomi N. Kappe,
Carlos Fernández Moro,
Jan Fuge,
Mark P. Kuehnel,
Sabine Wrenger,
Tobias Welte,
Bart van Hoek,
Danny D. Jonigk,
Padmini P. S. J. Khedoe,
Pavel Strnad,
Mikael Björnstedt,
Jan Stolk,
Sabina Janciauskiene,
Antal Nemeth

Affiliations

Jan C. Kamp: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany
Naomi N. Kappe: Department of Pulmonology, Leiden University Medical Center, Member of European Reference Network Lung, Section Alpha-1-Antitrypsin Deficiency, 2333 ZA Leiden, The Netherlands
Carlos Fernández Moro: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Jan Fuge: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany
Mark P. Kuehnel: Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center of Lung Research (DZL), 30625 Hannover, Germany
Sabine Wrenger: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany
Tobias Welte: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany
Bart van Hoek: Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Danny D. Jonigk: Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center of Lung Research (DZL), 30625 Hannover, Germany
Padmini P. S. J. Khedoe: Department of Pulmonology, Leiden University Medical Center, Member of European Reference Network Lung, Section Alpha-1-Antitrypsin Deficiency, 2333 ZA Leiden, The Netherlands
Pavel Strnad: 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
Mikael Björnstedt: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Jan Stolk: Department of Pulmonology, Leiden University Medical Center, Member of European Reference Network Lung, Section Alpha-1-Antitrypsin Deficiency, 2333 ZA Leiden, The Netherlands
Sabina Janciauskiene: Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany
Antal Nemeth: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden

DOI: https://doi.org/10.3390/ijms24032485
Journal volume & issue: Vol. 24, no. 3
p. 2485

Abstract

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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.

Published in International Journal of Molecular Sciences

ISSN: 1661-6596 (Print); 1422-0067 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General); Science: Chemistry
Website: http://www.mdpi.com/journal/ijms

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