P90 α-1 antitrypsin (a1AT) polymers cause extreme hepatocyte ageing

Introductiona1AT, synthesised predominantly in the liver, is the archetypal inhibitor of the serpin protein family. a1AT deficiency is a common inherited disorder; Glu342Lys substitution causes abnormal folding of mutant protein, which may polymerise and aggregate in the endoplasmic reticulum. a1AT aggregates are the histological hallmark of a1AT-related liver disease but it is unclear how aggregates induce liver injury.AimTo determine whether hepatocytes containing polymerised-a1AT (pa1AT) had accelerated ageing manifest as shortened telomeres.MethodLiver biopsy sections were studied from 60 patients with a1AT- related liver disease with a broad spectrum of fibrosis, recruited from the Cambridge metabolic liver clinic (30 were homozygous and 30 heterozygous). Comparison was made with sections from 20 age and sex matched time zero biopsies obtained at liver transplant. Mean hepatocyte telomere length, a reflection of age, was measured by quantitative fluorescent in situ hybridisation (QFISH) with a PNA Cy5 probe. Nuclei were identified with DAPI, hepatocytes with antibody against hepar-1 and pa1AT with specific mouse monoclonal antibody (2C1). Images were obtained and analysed using the Olympus ScanR software system (Abstract P90 figure 1). Statistical analysis used Graph Pad Prism.Abstract P90 Figure 1QFISH image which highlights the a1AT polymers (shown as bright white speckles), surrounding some of the affected hepatocytes.ResultsHepatocyte nuclei were larger in patients with both homozygous and heterozygous a1AT deficiency (p=0.002) and had shorter telomeres (p