Advertisement

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

  • Lorenz Balcar
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Bernhard Scheiner
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Markus Urheu
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Patrick Weinberger
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Rafael Paternostro
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Benedikt Simbrunner
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Lukas Hartl
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Mathias Jachs
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • David Bauer
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Georg Semmler
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Claudia Willheim
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Matthias Pinter
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Peter Ferenci
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Michael Trauner
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Thomas Reiberger
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Albert Friedrich Stättermayer
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
  • Mattias Mandorfer
    Correspondence
    Corresponding author. Address: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Tel.: +43 1 40400 47440, fax: +43 1 40400 47350.
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
    Search for articles by this author
Open AccessPublished:August 19, 2022DOI:https://doi.org/10.1016/j.jhepr.2022.100562

      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

      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
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to JHEP Reports
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Sharp H.L.
        • Bridges R.A.
        • Krivit W.
        • Freier E.F.
        Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder.
        J Lab Clin Med. 1969; 73: 934-939
        • Eriksson S.
        • Carlson J.
        • Velez R.
        Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency.
        N Engl J Med. 1986; 314: 736-739
        • Lomas D.A.
        • Hurst J.R.
        • Gooptu B.
        Update on alpha-1 antitrypsin deficiency: new therapies.
        J Hepatol. 2016; 65: 413-424
        • Zoller H.
        • Wagner S.
        • Tilg H.
        Is heterozygosity for the alpha-1 antitrypsin risk allele Pi∗MZ a disease modifier or genetic risk factor?.
        Gastroenterology. 2020; 159: 433-434
        • Fromme M.
        • Schneider C.V.
        • Trautwein C.
        • Brunetti-Pierri N.
        • Strnad P.
        Alpha-1 antitrypsin deficiency: a re-surfacing adult liver disorder.
        J Hepatol. 2021;
        • Pons M.
        • Núñez A.
        • Esquinas C.
        • Torres-Durán M.
        • Rodríguez-Hermosa J.L.
        • Calle M.
        • et al.
        Utility of transient elastography for the screening of liver disease in patients with alpha1-antitrypsin deficiency.
        J Clin Med. 2021; 10
        • Schneider C.V.
        • Hamesch K.
        • Gross A.
        • Mandorfer M.
        • Moeller L.S.
        • Pereira V.
        • et al.
        Liver phenotypes of European adults heterozygous or homozygous for Pi∗Z variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and noncarriers.
        Gastroenterology. 2020; 159: 534-548.e11
        • Fromme M.
        • Schneider C.V.
        • Pereira V.
        • Hamesch K.
        • Pons M.
        • Reichert M.C.
        • et al.
        Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.
        Gut. 2022; 71: 415-423
        • Luukkonen P.K.
        • Salomaa V.
        • Åberg F.
        The Pi∗MZ allele in alpha-1 antitrypsin increases liver-related outcomes in a population-based study.
        Gastroenterology. 2021; 160: 1874-1875
        • Semmler G.
        • Balcar L.
        • Oberkofler H.
        • Zandanell S.
        • Strasser M.
        • Niederseer D.
        • et al.
        PNPLA3 and SERPINA1 variants are associated with severity of fatty liver disease at first referral to a tertiary center.
        J Pers Med. 2021; 11
        • Schaefer B.
        • Mandorfer M.
        • Viveiros A.
        • Finkenstedt A.
        • Ferenci P.
        • Schneeberger S.
        • et al.
        Heterozygosity for the alpha-1-antitrypsin Z allele in cirrhosis is associated with more advanced disease.
        Liver Transpl. 2018; 24: 744-751
        • Reiberger T.
        • Schwabl P.
        • Trauner M.
        • Peck-Radosavljevic M.
        • Mandorfer M.
        Measurement of the hepatic venous pressure gradient and transjugular liver biopsy.
        JoVE. 2020; : e58819
        • Ferlitsch A.
        • Bota S.
        • Paternostro R.
        • Reiberger T.
        • Mandorfer M.
        • Heinisch B.
        • et al.
        Evaluation of a new balloon occlusion catheter specifically designed for measurement of hepatic venous pressure gradient.
        Liver Int: official J Int Assoc Study Liver. 2015; 35: 2115-2120
        • Flanagin A.
        • Frey T.
        • Christiansen S.L.
        Updated guidance on the reporting of race and ethnicity in medical and science journals.
        Jama. 2021; 326: 621-627
        • de Franchis R.
        • Bosch J.
        • Garcia-Tsao G.
        • Reiberger T.
        • Ripoll C.
        Baveno VII - renewing consensus in portal hypertension.
        J Hepatol. 2022; 76: 959-974
        • Fine J.P.
        • Gray R.J.
        A proportional hazards model for the subdistribution of a competing risk.
        J Am Stat Assoc. 1999; 94: 496-509
        • Mandorfer M.
        • Scheiner B.
        • Stättermayer A.F.
        • Schwabl P.
        • Paternostro R.
        • Bauer D.
        • et al.
        Impact of patatin-like phospholipase domain containing 3 rs738409 G/G genotype on hepatic decompensation and mortality in patients with portal hypertension.
        Aliment Pharmacol Ther. 2018; 48: 451-459
        • Strnad P.
        • McElvaney N.G.
        • Lomas D.A.
        Alpha(1)-Antitrypsin deficiency.
        N Engl J Med. 2020; 382: 1443-1455
        • Strnad P.
        • Buch S.
        • Hamesch K.
        • Fischer J.
        • Rosendahl J.
        • Schmelz R.
        • et al.
        Heterozygous carriage of the alpha1-antitrypsin Pi∗Z variant increases the risk to develop liver cirrhosis.
        Gut. 2019; 68: 1099-1107
        • Clark V.C.
        • Marek G.
        • Liu C.
        • Collinsworth A.
        • Shuster J.
        • Kurtz T.
        • et al.
        Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort.
        J Hepatol. 2018; 69: 1357-1364
        • Chen V.L.
        • Burkholder D.A.
        • Moran I.J.
        • DiBattista J.V.
        • Miller M.J.
        • Chen Y.
        • et al.
        Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi∗MZ genotype.
        JHEP Rep. 2022; 4: 100483
        • Mandorfer M.
        • Simbrunner B.
        Prevention of first decompensation in advanced chronic liver disease.
        Clin Liver Dis. 2021; 25: 291-310
        • Strnad P.
        • Mandorfer M.
        • Choudhury G.
        • Griffiths W.
        • Trautwein C.
        • Loomba R.
        • et al.
        LP10: Aro-Aat reduces Z-AAT protein in PiZZ patients and leads to improvements in clinically relevant liver biomarkers.
        Hepatology. 2021; 74
        • Strnad P.
        • Mandorfer M.
        • Choudhury G.
        • Griffiths W.
        • Trautwein C.
        • Loomba R.
        • et al.
        Fazirsiran for liver disease associated with alpha(1)-antitrypsin deficiency.
        N Engl J Med. 2022;
        • Tang Y.
        • Blomenkamp K.S.
        • Fickert P.
        • Trauner M.
        • Teckman J.H.
        NorUDCA promotes degradation of α1-antitrypsin mutant Z protein by inducing autophagy through AMPK/ULK1 pathway.
        PLoS One. 2018; 13: e0200897
        • Scheiner B.
        • Stättermayer A.F.
        • Schwabl P.
        • Bucsics T.
        • Paternostro R.
        • Bauer D.
        • et al.
        Impact of HSD17B13 rs72613567 genotype on hepatic decompensation and mortality in patients with portal hypertension.
        Liver Int. 2020; 40: 393-404