Alpha-1 antitrypsin (AAT) augmentation and the liver phenotype of adults with AAT deficiency (genotype Pi*ZZ)

Malin  Fromme; Karim  Hamesch; Carolin V.  Schneider; Mattias  Mandorfer; Monica  Pons; Katrine  Thorhauge; Vitor  Pereira; Jan  Sperl; Sona  Frankova; Matthias C.  Reichert; Federica  Benini; Barbara  Burbaum; Moritz  Kleinjans; Samira  Amzou; Laura  Rademacher; Lisa  Bewersdorf; Jef  Verbeek; Frederik Nevens; Joan  Genesca; Marc Miravitlles; Alexa  Nuñez; Benedikt  Schaefer; Heinz  Zoller; Sabina Janciauskiene; Johan  Waern; António  Oliveira; Luís  Maia; Carolina  Simões; Ravi Mahadeva; Daniel D  Fraughen; Michael Trauner; Aleksander  Krag; Frank Lammert; Robert Bals; Nadine T.  Gaisa; Elmar  Aigner; William J Griffiths; Helmut  Denk; Alexander Teumer; Noel G McElvaney; Alice Turner; Christian Trautwein; Pavel  Strnad

doi:10.1016/j.cgh.2023.08.038

Alpha-1 antitrypsin (AAT) augmentation and the liver phenotype of adults with AAT deficiency (genotype Pi*ZZ)

Malin Fromme, Karim Hamesch, Carolin V. Schneider, Mattias Mandorfer, Monica Pons, Katrine Thorhauge, Vitor Pereira, Jan Sperl, Sona Frankova, Matthias C. Reichert, Federica Benini, Barbara Burbaum, Moritz Kleinjans, Samira Amzou, Laura Rademacher, Lisa Bewersdorf, Jef Verbeek, Frederik Nevens, Joan Genesca, Marc MiravitllesAlexa Nuñez, Benedikt Schaefer, Heinz Zoller, Sabina Janciauskiene, Johan Waern, António Oliveira, Luís Maia, Carolina Simões, Ravi Mahadeva, Daniel D Fraughen, Michael Trauner, Aleksander Krag, Frank Lammert, Robert Bals, Nadine T. Gaisa, Elmar Aigner, William J Griffiths, Helmut Denk, Alexander Teumer, Noel G McElvaney, Alice Turner, Christian Trautwein, Pavel Strnad^*

^*Corresponding author for this work

Applied Health Research

Research output: Contribution to journal › Article › peer-review

Abstract

Background and aims: Alpha-1 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 non-invasively via the serum test AST-to-platelet ratio index (APRI) as well as via transient elastography-based liver stiffness measurement (LSM). Histological parameters were compared in 15 Pi*ZZ adults with and 35 without augmentation.

Results: Compared to non-augmented subjects, augmented Pi*ZZ individuals displayed lower serum liver enzyme levels (AST 71 vs. 75 % ULN, P
Conclusion: 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.

Original language	English
Journal	Clinical Gastroenterology and Hepatology
Early online date	15 Sept 2023
DOIs	https://doi.org/10.1016/j.cgh.2023.08.038
Publication status	E-pub ahead of print - 15 Sept 2023

Keywords

Fibroscan
Pi*Z
liver fibrosis
SERPINA1
alpha-1 antitrypsin deficiency

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Fromme, M., Hamesch, K., Schneider, C. V., Mandorfer, M., Pons, M., Thorhauge, K., Pereira, V., Sperl, J., Frankova, S., Reichert, M. C., Benini, F., Burbaum, B., Kleinjans, M., Amzou, S., Rademacher, L., Bewersdorf, L., Verbeek, J., Nevens, F., Genesca, J., ... Strnad, P. (2023). Alpha-1 antitrypsin (AAT) augmentation and the liver phenotype of adults with AAT deficiency (genotype Pi*ZZ). Clinical Gastroenterology and Hepatology. Advance online publication. https://doi.org/10.1016/j.cgh.2023.08.038

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title = "Alpha-1 antitrypsin (AAT) augmentation and the liver phenotype of adults with AAT deficiency (genotype Pi*ZZ)",

abstract = "Background and aims: Alpha-1 antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the {\textquoteleft}Pi*Z{\textquoteright} 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 non-invasively via the serum test AST-to-platelet ratio index (APRI) as well as via transient elastography-based liver stiffness measurement (LSM). Histological parameters were compared in 15 Pi*ZZ adults with and 35 without augmentation.Results: Compared to non-augmented subjects, augmented Pi*ZZ individuals displayed lower serum liver enzyme levels (AST 71 vs. 75 % ULN, PConclusion: 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.",

keywords = "Fibroscan, Pi*Z, liver fibrosis, SERPINA1, alpha-1 antitrypsin deficiency",

author = "Malin Fromme and Karim Hamesch and Schneider, {Carolin V.} and Mattias Mandorfer and Monica Pons and Katrine Thorhauge and Vitor Pereira and Jan Sperl and Sona Frankova and Reichert, {Matthias C.} and Federica Benini and Barbara Burbaum and Moritz Kleinjans and Samira Amzou and Laura Rademacher and Lisa Bewersdorf and Jef Verbeek and Frederik Nevens and Joan Genesca and Marc Miravitlles and Alexa Nu{\~n}ez and Benedikt Schaefer and Heinz Zoller and Sabina Janciauskiene and Johan Waern and Ant{\'o}nio Oliveira and Lu{\'i}s Maia and Carolina Sim{\~o}es and Ravi Mahadeva and Fraughen, {Daniel D} and Michael Trauner and Aleksander Krag and Frank Lammert and Robert Bals and Gaisa, {Nadine T.} and Elmar Aigner and Griffiths, {William J} and Helmut Denk and Alexander Teumer and McElvaney, {Noel G} and Alice Turner and Christian Trautwein and Pavel Strnad",

year = "2023",

month = sep,

day = "15",

doi = "10.1016/j.cgh.2023.08.038",

language = "English",

journal = "Clinical Gastroenterology and Hepatology",

issn = "1542-3565",

publisher = "Elsevier",

}

Fromme, M, Hamesch, K, Schneider, CV, Mandorfer, M, Pons, M, Thorhauge, K, Pereira, V, Sperl, J, Frankova, S, Reichert, MC, Benini, F, Burbaum, B, Kleinjans, M, Amzou, S, Rademacher, L, Bewersdorf, L, Verbeek, J, Nevens, F, Genesca, J, Miravitlles, M, Nuñez, A, Schaefer, B, Zoller, H, Janciauskiene, S, Waern, J, Oliveira, A, Maia, L, Simões, C, Mahadeva, R, Fraughen, DD, Trauner, M, Krag, A, Lammert, F, Bals, R, Gaisa, NT, Aigner, E, Griffiths, WJ, Denk, H, Teumer, A, McElvaney, NG, Turner, A, Trautwein, C & Strnad, P 2023, 'Alpha-1 antitrypsin (AAT) augmentation and the liver phenotype of adults with AAT deficiency (genotype Pi*ZZ)', Clinical Gastroenterology and Hepatology. https://doi.org/10.1016/j.cgh.2023.08.038

TY - JOUR

T1 - Alpha-1 antitrypsin (AAT) augmentation and the liver phenotype of adults with AAT deficiency (genotype Pi*ZZ)

AU - Fromme, Malin

AU - Hamesch, Karim

AU - Schneider, Carolin V.

AU - Mandorfer, Mattias

AU - Pons, Monica

AU - Thorhauge, Katrine

AU - Pereira, Vitor

AU - Sperl, Jan

AU - Frankova, Sona

AU - Reichert, Matthias C.

AU - Benini, Federica

AU - Burbaum, Barbara

AU - Kleinjans, Moritz

AU - Amzou, Samira

AU - Rademacher, Laura

AU - Bewersdorf, Lisa

AU - Verbeek, Jef

AU - Nevens, Frederik

AU - Genesca, Joan

AU - Miravitlles, Marc

AU - Nuñez, Alexa

AU - Schaefer, Benedikt

AU - Zoller, Heinz

AU - Janciauskiene, Sabina

AU - Waern, Johan

AU - Oliveira, António

AU - Maia, Luís

AU - Simões, Carolina

AU - Mahadeva, Ravi

AU - Fraughen, Daniel D

AU - Trauner, Michael

AU - Krag, Aleksander

AU - Lammert, Frank

AU - Bals, Robert

AU - Gaisa, Nadine T.

AU - Aigner, Elmar

AU - Griffiths, William J

AU - Denk, Helmut

AU - Teumer, Alexander

AU - McElvaney, Noel G

AU - Turner, Alice

AU - Trautwein, Christian

AU - Strnad, Pavel

PY - 2023/9/15

Y1 - 2023/9/15

N2 - Background and aims: Alpha-1 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 non-invasively via the serum test AST-to-platelet ratio index (APRI) as well as via transient elastography-based liver stiffness measurement (LSM). Histological parameters were compared in 15 Pi*ZZ adults with and 35 without augmentation.Results: Compared to non-augmented subjects, augmented Pi*ZZ individuals displayed lower serum liver enzyme levels (AST 71 vs. 75 % ULN, PConclusion: 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.

AB - Background and aims: Alpha-1 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 non-invasively via the serum test AST-to-platelet ratio index (APRI) as well as via transient elastography-based liver stiffness measurement (LSM). Histological parameters were compared in 15 Pi*ZZ adults with and 35 without augmentation.Results: Compared to non-augmented subjects, augmented Pi*ZZ individuals displayed lower serum liver enzyme levels (AST 71 vs. 75 % ULN, PConclusion: 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.

KW - Fibroscan

KW - PiZ

KW - liver fibrosis

KW - SERPINA1

KW - alpha-1 antitrypsin deficiency

U2 - 10.1016/j.cgh.2023.08.038

DO - 10.1016/j.cgh.2023.08.038

M3 - Article

SN - 1542-3565

JO - Clinical Gastroenterology and Hepatology

JF - Clinical Gastroenterology and Hepatology

ER -

Alpha-1 antitrypsin (AAT) augmentation and the liver phenotype of adults with AAT deficiency (genotype Pi*ZZ)

Abstract

Keywords

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