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Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ)
M. Fromme, K. Hamesch, CV. Schneider, M. Mandorfer, M. Pons, KH. Thorhauge, V. Pereira, J. Sperl, S. Frankova, MC. Reichert, F. Benini, B. Burbaum, M. Kleinjans, S. Amzou, L. Rademacher, L. Bewersdorf, J. Verbeek, F. Nevens, J. Genesca, M....
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- alpha 1-Antitrypsin Deficiency * complications drug therapy MeSH
- Adult MeSH
- Phenotype MeSH
- Genotype MeSH
- Liver Cirrhosis etiology MeSH
- Humans MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.
1st Department of Medicine Paracelsus Medical University Salzburg Austria
Centro Hospitalar Universitário do Porto Porto Portugal
Clinic for Pneumology Medical University Hannover Hannover Germany
Department of Gastroenterology and Hepatology Odense University Hospital Odense C Denmark
Department of Gastroenterology Centro Hospitalar do Funchal Madeira Portugal
Department of Internal Medicine 1 Medical University Innsbruck Innsbruck Austria
Department of Medicine 5 Saarland University Medical Center Saarland University Homburg Germany
Department of Psychiatry and Psychotherapy University Medicine Greifswald Greifswald Germany
Department of Respiratory Medicine Cambridge University Hospitals Cambridge United Kingdom
DZHK partner site Greifswald Greifswald Germany
Hannover Medical School Hannover Germany
Hospital Santa Maria Lisboa Portugal
Institute of Applied Health Research University of Birmingham Birmingham United Kingdom
Institute of Pathology Medical University of Graz Graz Austria
Institute of Pathology University Hospital RWTH Aachen Aachen Germany
References provided by Crossref.org
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- $a Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ) / $c M. Fromme, K. Hamesch, CV. Schneider, M. Mandorfer, M. Pons, KH. Thorhauge, V. Pereira, J. Sperl, S. Frankova, MC. Reichert, F. Benini, B. Burbaum, M. Kleinjans, S. Amzou, L. Rademacher, L. Bewersdorf, J. Verbeek, F. Nevens, J. Genesca, M. Miravitlles, A. Nuñez, B. Schaefer, H. Zoller, S. Janciauskiene, J. Waern, A. Oliveira, L. Maia, C. Simões, R. Mahadeva, DD. Fraughen, M. Trauner, A. Krag, F. Lammert, R. Bals, NT. Gaisa, E. Aigner, WJ. Griffiths, H. Denk, A. Teumer, NG. McElvaney, AM. Turner, C. Trautwein, P. Strnad
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- $a BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.
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