Alpha-1 antitrypsin Pi*Z allele is an independent risk factor for liver transplantation and death in patients with advanced chronic liver disease

Background & Aims: Alpha-1 antitrypsin (AAT) deficiency causes/predisposes individuals to advanced chronic liver disease (ACLD). However, the role of the SERPINA1 Pi*Z allele in patients who have already progressed to ACLD is unclear. Thus, we aimed to evaluate the impact of the Pi*Z allele on the risk of liver transplantation/liver-related death in patients with ACLD, while adjusting for the severity of liver disease at inclusion. Methods: A total of 1,118 patients with ACLD who underwent hepatic venous pressure gradient (HVPG) measurement and genotyping for the Pi*Z/Pi*S allele at the Vienna Hepatic Hemodynamic Lab were included in this retrospective analysis. The outcome of interest was liver transplantation/liver-related death, while non-liver-related death and removal/suppression of the primary etiological factor were considered as competing risks. Results: Viral hepatitis was the most common etiology (4 4%), followed by alcohol-related (31%) and non-alcoholic fatty liver disease (11%). Forty-two (4%) and forty-six (4%) patients harboured the Pi*Z and Pi*S variants, respectively. Pi*Z carriers had more severe portal hypertension (HVPG: 19 +/- 6 vs.15 +/- 7 mmHg; p < 0.001) and hepatic dysfunction (Child-Turcotte-Pugh: 7.1 +/- 1.9 vs. 6.5 +/- 1.9 points; p = 0.050) at inclusion, compared to non-carriers. Contrarily, the Pi*S allele was unrelated to liver disease severity. In competing risk regression analysis, harbouring the Pi*Z allele was significantly associated with an increased probability of liver transplantation/liver-related death, even after adjusting for liver disease severity at inclusion. The detrimental impact of the common Pi*MZ genotype (adjusted subdistribution hazard ratio: z1.56 vs. Pi*MM) was confirmed in a fully adjusted subgroup analysis. In contrast, Pi*S carriers had no increased risk of events. Conclusion: Genotyping for the Pi*Z allele identifies patients with ACLD at increased risk of adverse liver-related outcomes, thereby improving prognostication. Therapies targeting the accumulation of abnormal AAT should be evaluated as disease -modifying treatments in Pi*Z allele carriers with ACLD. Lay summary: Alpha-1 antitrypsin deficiency is a genetic disease that affects the lung and the liver. Carrying two dysfunctional copies of the gene causes advanced liver disease. Harbouring one dysfunctional copy increases disease severity in patients with other liver illness. However, the significance of this genetic defect in patients who already suffer from advanced liver disease is unclear. Our study found that harbouring at least one dysfunctional copy of the alpha-1 antitrypsin gene increases the risk of requiring a liver transplantation or dying from a liver disease. This indicates the need for medical therapies aimed at treating the hepatic consequences of this genetic defect. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).