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

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-AA...

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Published in:International journal of molecular sciences 2023-01, Vol.24 (3), p.2485
Main Authors: Kamp, Jan C, Kappe, Naomi N, Moro, Carlos Fernández, Fuge, Jan, Kuehnel, Mark P, Wrenger, Sabine, Welte, Tobias, Hoek, Bart van, Jonigk, Danny D, Khedoe, Padmini P S J, Strnad, Pavel, Björnstedt, Mikael, Stolk, Jan, Janciauskiene, Sabina, Nemeth, Antal
Format: Article
Language:English
Subjects:
Age
Aldehydes
alpha 1-Antitrypsin Deficiency - pathology
Bile
Biopsy
Child
Children
Cholestasis
Cholestasis - metabolism
Cirrhosis
Clinical outcomes
Cluster analysis
Disease Progression
Fatty acids
Fibrosis
Gallbladder diseases
Gene expression
Genes
Genotype & phenotype
Hepatitis
Hepatocytes
Humans
Immunohistochemistry
Infant, Newborn
Ketones
Lipids
Liver
Liver - metabolism
Liver Cirrhosis - genetics
Liver Cirrhosis - pathology
Liver diseases
Metabolism
Mutation
Neonates
Polymers
Proteins
Risk factors
Transcriptomes
Transplantation
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container_end_page
container_issue 3
container_start_page 2485
container_title International journal of molecular sciences
container_volume 24
creator Kamp, Jan C
Kappe, Naomi N
Moro, Carlos Fernández
Fuge, Jan
Kuehnel, Mark P
Wrenger, Sabine
Welte, Tobias
Hoek, Bart van
Jonigk, Danny D
Khedoe, Padmini P S J
Strnad, Pavel
Björnstedt, Mikael
Stolk, Jan
Janciauskiene, Sabina
Nemeth, Antal
description 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, = 5), NCC (neonatal cholestasis, early cirrhosis and liver transplantation, = 4), and NNCH (no neonatal cholestasis, favourable outcome, = 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.
doi_str_mv 10.3390/ijms24032485
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source Publicly Available Content Database; PubMed Central
subjects Age
Aldehydes
alpha 1-Antitrypsin Deficiency - pathology
Bile
Biopsy
Child
Children
Cholestasis
Cholestasis - metabolism
Cirrhosis
Clinical outcomes
Cluster analysis
Disease Progression
Fatty acids
Fibrosis
Gallbladder diseases
Gene expression
Genes
Genotype & phenotype
Hepatitis
Hepatocytes
Humans
Immunohistochemistry
Infant, Newborn
Ketones
Lipids
Liver
Liver - metabolism
Liver Cirrhosis - genetics
Liver Cirrhosis - pathology
Liver diseases
Metabolism
Mutation
Neonates
Polymers
Proteins
Risk factors
Transcriptomes
Transplantation
title Fibrosis-Related Gene Profiling in Liver Biopsies of PiZZ α1-Antitrypsin Children with Different Clinical Courses
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