Highlights
- •Pi∗Z allele is significantly associated with liver-related events in patients with ACLD.
- •This finding extends to patients harbouring the Pi∗MZ genotype.
- •Genotyping for the Pi∗Z allele might improve prognostication in patients with ACLD.
- •Therapies targeting accumulation of abnormal AAT should be assessed in Pi∗Z carriers with ACLD.
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 (44%), 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: ≈1.56
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.
Graphical abstract
Graphical Abstract
Keywords
Abbreviations:
AAT (Alpha-1 antitrypsin), AATD (Alpha-1 antitrypsin deficiency), ACLD (Advanced chronic liver disease), CTP (Child-turcotte-pugh score), ER (Endoplasmic reticulum), GWAS (Genome wide association studies), HCC (Hepatocellular carcinoma), (a[S])HR ((Adjusted [subdistribution]) hazard ratio), HVPG (Hepatic venous pressure gradient), NAFLD (Non-alcoholic fatty liver disease), SERPINA1 (Serpin family a member 1), UNOS MELD (2016) (United network for organ sharing model for end-stage liver disease)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: August 19, 2022
Accepted:
August 9,
2022
Received in revised form:
July 21,
2022
Received:
April 5,
2022
Footnotes
Author names in bold designate shared co-first authorship
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