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.
- Kamp, J. C.
- Kappe, N. N.
- Moro, C. F.
- Fuge, J.
- Kuehnel, M. P.
- Wrenger, S.
- Welte, T.
- Hoek, B. V.
- Jonigk, D. D.
- Khedoe, Ppsj
- Strnad, P.
- Björnstedt, M.
- Stolk, J.
- Janciauskiene, S.
- Nemeth, A.
Keywords
- PiZZ deficiency
- Z-AAT polymers
- cholestasis
- cirrhosis
- lipid metabolism
- liver
- mRNA expression
- nCounter Fibrosis Panel
- transcriptome profiling
