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

Area of Science:

• Genetics and Molecular Biology
• Pediatric Hepatology
• Biochemistry

Background:

• Alpha-1-antitrypsin deficiency (AATD) with the PiZZ (Glu342Lys) mutation causes intrahepatic AAT polymerization, a risk factor for pediatric liver disease.
• Most PiZZ children remain disease-free, indicating that the mutation alone is insufficient to cause liver disease.
• Understanding the molecular mechanisms underlying variable disease progression in PiZZ children is crucial for effective management.

Purpose of the Study:

• To investigate the presence of Z-AAT polymers and the expression of fibrosis-related genes in liver tissues of PiZZ children with diverse clinical outcomes.
• To identify molecular differences associated with varying degrees of liver injury in pediatric AATD.
• To explore the relationship between Z-AAT accumulation, gene expression patterns, and clinical course in PiZZ children.

Main Methods:

• Retrospective analysis of liver biopsies from PiZZ children diagnosed between 1979-2010.
• Histological re-evaluation and immunohistochemistry to detect Z-AAT polymers.
• NanoString-based transcriptome profiling of 760 fibrosis-related and 8 bile acid-related genes.

Main Results:

• Z-AAT polymers were abundant in hepatocytes across all clinical outcome groups (neonatal cholestasis with favorable outcome, neonatal cholestasis with cirrhosis/transplantation, no neonatal cholestasis with favorable outcome).
• Children with neonatal cholestasis and cirrhosis/transplantation (NCC group) exhibited significantly higher expression of liver fibrosis/cirrhosis-associated genes.
• The NCC group also showed lower expression of genes involved in lipid, aldehyde/ketone, and bile acid metabolism compared to other groups.

Conclusions:

• Z-AAT polymer accumulation alone does not fully explain the clinical variability observed in PiZZ children with AATD.
• Alterations in specific gene expression pathways, particularly those related to lipid, fatty acid, and steroid metabolism, correlate with the severity of liver injury in pediatric AATD.
• These metabolic pathway changes may serve as important biomarkers for predicting liver disease progression in PiZZ children.