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

• 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
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24032485

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.