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1. Longitudinal Evaluation of Individuals With Severe Alpha-1 Antitrypsin Deficiency (Pi∗ZZ Genotype)

Author

Fromme, Malin, Payancé, Audrey, Mandorfer, Mattias, Thorhauge, Katrine H., Pons, Monica, Miravitlles, Marc, Stolk, Jan, van Hoek, Bart, Stirnimann, Guido, Frankova, Sona, Sperl, Jan, Kremer, Andreas E., Burbaum, Barbara, Schrader, Christina, Kadioglu, Amine, Walkenhaus, Michelle, Schneider, Carolin V., Klebingat, Fabienne, Balcar, Lorenz, Kappe, Naomi N., Schaefer, Benedikt, Chorostowska-Wynimko, Joanna, Aigner, Elmar, Gensluckner, Sophie, Striedl, Philipp, Roger, Pauline, Ryan, John, Roche, Suzanne, Vögelin, Marius, Ala, Aftab, Bantel, Heike, Verbeek, Jef, Mariño, Zoe, Praktiknjo, Michael, Gevers, Tom J.G., Reuken, Philipp A., Berg, Thomas, George, Jacob, Demir, Münevver, Bruns, Tony, Trautwein, Christian, Zoller, Heinz, Trauner, Michael, Genesca, Joan, Griffiths, William J., Clark, Virginia, Krag, Aleksander, Turner, Alice M., McElvaney, Noel G., and Strnad, Pavel

Published
2025
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2. Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ)

Author

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

Published
2024
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4. Contributors

Author

Agarwal, Kosh, primary, Armandi, Angelo, additional, Berná, Genoveva, additional, Boon-Bee Goh, George, additional, Bugianesi, Elisabetta, additional, Chan, Esther W., additional, Chan, Jacky C.H., additional, Cheung, Ka Wang, additional, Choi, Won-Mook, additional, Choi, Jonggi, additional, Cornejo, Andrea, additional, Crowley, Claire, additional, Dan, Yock Young, additional, Degré, Delphine, additional, Deltenre, Pierre, additional, Falade-Nwulia, Oluwaseun, additional, Fan, Jian-Gao, additional, Feng, Yi Bin, additional, Ferenci, Peter, additional, Fernández Gómez, Miguel, additional, Fromme, Malin, additional, Grønbæk, Lisbet, additional, Grønbæk, Henning, additional, Harisinghani, Mukesh, additional, Indolfi, Giuseppe, additional, Inoue, Takako, additional, Jang, Jeong Won, additional, Kew, Guan Sen, additional, Kim-Jun Teh, Kevin, additional, Kim, Min, additional, Kjær, Mikkel Breinholt, additional, Kornerup, Linda Skibsted, additional, Lara Romero, Carmen, additional, Lee, Sung Won, additional, Lee, Soon Kyu, additional, Lim, Young-Suk, additional, Liu, Chieh, additional, Liu, Chun-Jen, additional, Lok, James, additional, López Bermudo, Lucía, additional, Mak, Lung-Yi, additional, Méndez-Sánchez, Nahum, additional, Moreno, Christophe, additional, Muthiah, Mark, additional, Nam, Heechul, additional, Nartey, Yvonne A., additional, Nepal, Pankaj, additional, Nguyen, Mindie H., additional, Nicastro, Emanuele, additional, Ogawa, Eiichi, additional, Pawlotsky, Jean-Michel, additional, Pelusi, Serena, additional, Pik-Eu Chang, Jason, additional, Plauth, Mathias, additional, Romero-Gómez, Manuel, additional, Ronzoni, Luisa, additional, Seto, Mimi Tin-Yan, additional, Shi, Yi-Wen, additional, Shih, Yi-Fen, additional, Sridhar, Siddharth, additional, Stockdale, Alexander J., additional, Strnad, Pavel, additional, Tanaka, Yasuhito, additional, Teschke MD, Rolf, additional, Tucker, Joseph D., additional, Valenti, Luca, additional, Veloz, Maria Fernanda Guerra, additional, Yuen, Man-Fung, additional, Zhang, Cheng, additional, Zhao, Jiaxi, additional, and Zhou, Kali, additional

Published
2023
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6. Alpha‐1 Antitrypsin Inclusions Sequester GRP78 in a Bile Acid–Inducible Manner.

Author

Spivak, Igor, Guldiken, Nurdan, Usachov, Valentyn, Schaap, Frank, Damink, Steven W.M. Olde, Bouchecareilh, Marion, Lehmann, Alexandra, Fu, Lei, Mo, Fa‐Rong, Ensari, Gökce Kobazi, Hufnagel, Franziska, Fromme, Malin, Preisinger, Christian, and Strnad, Pavel

Subjects
BILE acids, CHOLIC acid, GENETIC disorders, LIVER diseases, LIVER cells
Abstract

Background and Aims: The homozygous PiZ mutation (PIZZ genotype) constitutes the predominant cause of severe alpha‐1 antitrypsin (AAT) deficiency and leads to liver disease via hepatocellular AAT aggregation. We systematically analysed the composition of AAT aggregates and studied the impact of bile acids. Methods: AAT inclusions were isolated from livers of PiZ overexpressing mice and PIZZ humans via fluorescence‐activated and immunomagnetic sorting (FACS/MACS), while insoluble proteins were obtained via Triton‐X extraction. Inclusion composition was evaluated through mass‐spectrometry (MS), immunoblotting and immunostaining. Hepatocytes with versus without AAT aggregates were obtained via microdissection. Serum bile acids were assessed in 57 PIZZ subjects and 19 controls. Mice were administered 2% cholic acid (CA)–supplemented chow for 7 days. Results: MS identified the key endoplasmic reticulum chaperone 78 kDa glucose‐regulated protein (GRP78) in FACS/MACS pulldowns. GRP78 was also enriched in insoluble fractions from PiZ mice versus wild types and detected in insoluble fractions/MACS isolates from PIZZ liver explants. In cultured cells/primary hepatocytes, PiZ overexpression was associated with increased GRP78 mRNA/protein levels. In human livers, hepatocytes with AAT aggregates had higher GRP78 levels than hepatocytes without. PIZZ subjects displayed higher serum bile acid levels than controls and the highest levels were seen in individuals with liver injury/fibrosis. In PiZ mice, CA‐mediated bile acid challenge resulted in increased liver injury and translocation of GRP78 into the aggregates. Conclusions: Our results demonstrate that GRP78 is sequestered within AAT inclusions. Bile acid accumulation, as seen in PIZZ subjects with liver disease, may promote GRP78 segregation and thereby augment liver damage. Trial Registration: NCT02929940 [ABSTRACT FROM AUTHOR]

Published
2025
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9. WED-135-YI Impact of metabolic alterations on liver phenotype of patients with homozygous alpha-1 antitrypsin deficiency (Pi*ZZ)

Author

Schrader, Christina, primary, Fromme, Malin, additional, Payancé, Audrey, additional, Mandorfer, Mattias, additional, Thorhauge, Katrine, additional, Pons, Monica, additional, Miravitlles, Marc, additional, Stolk, Jan, additional, van Hoek, Bart, additional, Stirnimann, Guido, additional, Fraňková, Soňa, additional, Sperl, Jan, additional, Kremer, Andreas E., additional, Balcar, Lorenz, additional, Schaefer, Benedikt, additional, Chorostowska-Wynimko, Joanna, additional, Trautwein, Christian, additional, Zoller, Heinz, additional, Trauner, Michael, additional, Genesca, Joan, additional, Griffiths, William J.H., additional, Clark, Virginia C., additional, Krag, Aleksander, additional, McElvaney, Noel G., additional, Turner, Alice, additional, and Strnad, Pavel, additional

Published
2024
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10. TOP-141 Longitudinal assessment of individuals with homozygous alpha-1 antitrypsin deficiency (Pi*ZZ genotype) provides evidence for clinical patient management

Author

Fromme, Malin, primary, Payancé, Audrey, additional, Mandorfer, Mattias, additional, Thorhauge, Katrine, additional, Pons, Monica, additional, Miravitlles, Marc, additional, Stolk, Jan, additional, van Hoek, Bart, additional, Stirnimann, Guido, additional, Fraňková, Soňa, additional, Sperl, Jan, additional, Kremer, Andreas E., additional, Schrader, Christina, additional, Balcar, Lorenz, additional, Schaefer, Benedikt, additional, Chorostowska-Wynimko, Joanna, additional, Ryan, John, additional, Trautwein, Christian, additional, Zoller, Heinz, additional, Trauner, Michael, additional, Genesca, Joan, additional, Griffiths, William J.H., additional, Clark, Virginia C., additional, Krag, Aleksander, additional, Turner, Alice, additional, McElvaney, Noel G., additional, and Strnad, Pavel, additional

Published
2024
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11. OS-041-YI A spatiotemporal map of the hepatocyte proteome in alpha-1 antitrypsin deficiency by single-cell and visual proteomics

Author

Rosenberger, Florian, primary, Thorhauge, Katrine, additional, Mädler, Sophia, additional, Fromme, Malin, additional, Weiss, Caroline, additional, Oeller, Marc, additional, Steigerwald, Sophia, additional, Thielert, Marvin, additional, Nordmann, Thierry, additional, Detlefsen, Sönke, additional, Boor, Peter, additional, Fabián, Ondřej, additional, Fraňková, Soňa, additional, Krag, Aleksander, additional, Strnad, Pavel, additional, and Mann, Matthias, additional

Published
2024
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12. Alcohol consumption and liver phenotype of individuals with alpha‐1 antitrypsin deficiency.

Author

Fromme, Malin, Schneider, Carolin V., Guldiken, Nurdan, Amzou, Samira, Luo, Yizhao, Pons, Monica, Genesca, Joan, Miravitlles, Marc, Thorhauge, Katrine H., Mandorfer, Mattias, Waern, Johan, Schneider, Kai Markus, Sperl, Jan, Frankova, Sona, Bartel, Marc, Zimmer, Holger, Zorn, Markus, Krag, Aleksander, Turner, Alice, and Trautwein, Christian

Subjects
*HEPATIC fibrosis, *ALCOHOL drinking, *HEPATOTOXICOLOGY, *CIRRHOSIS of the liver, *CONSORTIA, *ALPHA 1-antitrypsin deficiency
Abstract

Background and Aims: Alpha‐1 antitrypsin deficiency is an inherited disorder caused by alpha‐1 antitrypsin (AAT) mutations. We analysed the association between alcohol intake and liver‐related parameters in individuals with the heterozygous/homozygous Pi*Z AAT variant (Pi*MZ/Pi*ZZ genotype) found in the United Kingdom Biobank and the European Alpha1 liver consortium. Methods: Reported alcohol consumption was evaluated in two cohorts: (i) the community‐based United Kingdom Biobank (17 145 Pi*MZ, 141 Pi*ZZ subjects, and 425 002 non‐carriers [Pi*MM]); and (ii) the European Alpha1 liver consortium (561 Pi*ZZ individuals). Cohort (ii) included measurements of carbohydrate‐deficient transferrin (CDT). Results: In both cohorts, no/low alcohol intake was reported by >80% of individuals, while harmful consumption was rare (~1%). Among Pi*MM and Pi*MZ individuals from cohort (i), moderate alcohol consumption resulted in a <30% increased rate of elevated transaminases and ~50% increase in elevated gamma‐glutamyl transferase values, while harmful alcohol intake led to an at least twofold increase in the abnormal levels. In Pi*ZZ individuals from both cohorts, moderate alcohol consumption had no marked impact on serum transaminase levels. Among Pi*ZZ subjects from cohort (ii) who reported no/low alcohol consumption, those with increased CDT levels more often had signs of advanced liver disease. Conclusions: Pi*MZ/Pi*ZZ genotype does not seem to markedly aggravate the hepatic toxicity of moderate alcohol consumption. CDT values might be helpful to detect alcohol consumption in those with advanced fibrosis. More data are needed to evaluate the impact of harmful alcohol consumption. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers

Author

Schneider, Carolin V., Hamesch, Karim, Gross, Annika, Mandorfer, Mattias, Moeller, Linda S., Pereira, Vitor, Pons, Monica, Kuca, Pawel, Reichert, Matthias C., Benini, Federica, Burbaum, Barbara, Voss, Jessica, Gutberlet, Marla, Woditsch, Vivien, Lindhauer, Cecilia, Fromme, Malin, Kümpers, Julia, Bewersdorf, Lisa, Schaefer, Benedikt, Eslam, Mohammed, Bals, Robert, Janciauskiene, Sabina, Carvão, Joana, Neureiter, Daniel, Zhou, Biaohuan, Wöran, Katharina, Bantel, Heike, Geier, Andreas, Dirrichs, Timm, Stickel, Felix, Teumer, Alexander, Verbeek, Jef, Nevens, Frederik, Govaere, Olivier, Krawczyk, Marcin, Roskams, Tania, Haybaeck, Johannes, Lurje, Georg, Chorostowska-Wynimko, Joanna, Genesca, Joan, Reiberger, Thomas, Lammert, Frank, Krag, Aleksander, George, Jacob, Anstee, Quentin M., Trauner, Michael, Datz, Christian, Gaisa, Nadine T., Denk, Helmut, Trautwein, Christian, Aigner, Elmar, and Strnad, Pavel

Published
2020
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14. Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation

Author

Hamesch, Karim, Mandorfer, Mattias, Pereira, Vítor M., Moeller, Linda S., Pons, Monica, Dolman, Grace E., Reichert, Matthias C., Schneider, Carolin V., Woditsch, Vivien, Voss, Jessica, Lindhauer, Cecilia, Fromme, Malin, Spivak, Igor, Guldiken, Nurdan, Zhou, Biaohuan, Arslanow, Anita, Schaefer, Benedikt, Zoller, Heinz, Aigner, Elmar, Reiberger, Thomas, Wetzel, Martin, Siegmund, Britta, Simões, Carolina, Gaspar, Rui, Maia, Luís, Costa, Dalila, Bento-Miranda, Mário, van Helden, Josef, Yagmur, Eray, Bzdok, Danilo, Stolk, Jan, Gleiber, Wolfgang, Knipel, Verena, Windisch, Wolfram, Mahadeva, Ravi, Bals, Robert, Koczulla, Rembert, Barrecheguren, Miriam, Miravitlles, Marc, Janciauskiene, Sabina, Stickel, Felix, Lammert, Frank, Liberal, Rodrigo, Genesca, Joan, Griffiths, William J., Trauner, Michael, Krag, Aleksander, Trautwein, Christian, and Strnad, Pavel

Published
2019
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15. Association of circulating Z‐polymer with adverse clinical outcomes and liver fibrosis in adults with alpha‐1 antitrypsin deficiency

Author

Fromme, Malin, Rademacher, Laura, Amzou, Samira, Cook, Christi D., Zacharias, Isabel, Zhang, Lanju, Ripollone, John E., and Strnad, Pavel

Abstract

Circulating polymerized mutant Z‐alpha‐1 antitrypsin (Z‐polymer) constitutes a characteristic feature in alpha‐1 antitrypsin deficiency (AATD), but there is limited knowledge about its association with adverse clinical outcomes and liver fibrosis. We explored this association using data from a large cohort of adults with AATD. A total of 836 (431 PiZZ, 405 PiMZ) adults with AATD and 312 controls (PiMM) from the European Alpha‐1 Liver Cohort (2015–2020) were included. Time‐to‐event analyses were conducted for adults with the PiZZ genotype followed for adverse clinical outcomes (earliest occurrence of liver‐related hospitalization, liver transplant or all‐cause mortality). Cox proportional hazard models were used to describe the association between binary circulating Z‐polymer levels and adverse clinical outcomes. Correlations between baseline circulating Z‐polymer levels and baseline liver fibrosis (liver stiffness measurement [LSM] determined by transient elastography [FibroScan®]) were evaluated. The analyses were stratified by augmentation therapy status. Of 324 adults with the PiZZ genotype and longitudinal follow‐up data, 28 reported adverse clinical outcomes. Higher baseline circulating Z‐polymer levels were associated with an increased risk of adverse clinical outcomes in both crude (hazard ratio [95% confidence interval, CI], 2.88 [1.21, 6.87]) and age‐adjusted (1.96 [0.78, 4.94]) analyses. In adults with the PiZZ genotype, circulating Z‐polymer levels were weakly positively correlated with baseline LSM (Spearman's rho [95% CI]: 0.21 [0.11, 0.31]). Similar results were observed after stratification by augmentation therapy status. In adults with the PiZZ genotype, higher circulating Z‐polymer levels were associated with a shorter time to adverse clinical outcome, and positively correlated with baseline LSM. Circulating Z‐polymer levels may be a prognostic biomarker of clinically relevant disease in AATD.

Published
2024
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16. Generation of two Alpha-I antitrypsin deficiency patient-derived induced pluripotent stem cell lines ISRM-AATD-iPSC-1 (HHUUKDi011-A) and ISRM-AATD-iPSC-2 (HHUUKDi012-A)

Author

Ncube, Audrey, primary, Bewersdorf, Lisa, additional, Spitzhorn, Lucas-Sebastian, additional, Loerch, Christiane, additional, Bohndorf, Martina, additional, Graffmann, Nina, additional, May, Lea, additional, Amzou, Samira, additional, Fromme, Malin, additional, Wruck, Wasco, additional, Strnad, Pavel, additional, and Adjaye, James, additional

Published
2023
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17. Alpha-1 antitrypsin (AAT) augmentation and the liver phenotype of adults with AAT deficiency (genotype Pi*ZZ)

Author

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

Published
2023
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21. Impact of alcohol consumption on the liver phenotype in alpha-1 antitrypsin deficiency

Author

Fromme, Malin, primary, Schneider, Carolin V., additional, Gueldiken, Nurdan, additional, Amzou, Samira, additional, Luo, Yizhao, additional, Pons, Monica, additional, Genesca, Joan, additional, Miravitlles, Marc, additional, Thorhauge, Katrine, additional, Waern, Johan, additional, Sperl, Jan, additional, Frankova, Sona, additional, Bartel, Marc, additional, Zimmer, Holger, additional, Zorn, Markus, additional, Krag, Aleksander, additional, Turner, Alice, additional, Trautwein, Christian, additional, and Strnad, Pavel, additional

Published
2023
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25. Regarding: Alpha‐1 antitrypsin deficiency associated with increased risks of skin cancer, leukemia, and hepatic cancer: A nationwide cohort study.

Author

Fromme, Malin, Remih, Katharina, Schneider, Carolin Victoria, and Strnad, Pavel

Subjects
*LYMPHOCYTIC leukemia, *SKIN cancer, *MELANOMA, *TRYPSIN inhibitors, *DISEASE risk factors
Abstract

The article discusses a study on the association between Alpha-1 antitrypsin deficiency (AATD) and increased risks of skin cancer, leukemia, and hepatic cancer. The study analyzed data from the UK Biobank, focusing on individuals with different AATD genotypes. Results showed an increased risk of leukemia and skin cancer in individuals with specific AATD genotypes, providing insights into the association between AATD and various cancers. The study highlights the importance of considering genotype-specific risks and the underdiagnosis of AATD in real life. [Extracted from the article]

Published
2024
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26. Prediction of liver-related endpoints by non-invasive fibrosis tests – longitudinal follow-up in adults with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype)

Author

Fromme, Malin, additional, Amzou, Samira, additional, Burbaum, Barbara, additional, Striedl, Philipp, additional, Mandorfer, Mattias, additional, Pons, Monica, additional, Genesca, Joan, additional, Miravitlles, Marc, additional, Thorhauge, Katrine, additional, Schäfer, Benedikt, additional, Zoller, Heinz, additional, Krag, Aleksander, additional, Aigner, Elmar, additional, Trautwein, Christian, additional, and Strnad, Pavel, additional

Published
2023
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27. Association of Alpha-1 Antitrypsin Pi*Z Allele Frequency and Progressive Liver Fibrosis in Two Chronic Hepatitis C Cohorts

Author

Mücke, Victoria Therese, primary, Fischer, Janett, additional, Mücke, Marcus Maximilian, additional, Teumer, Alexander, additional, Koch, Alexander, additional, Vermehren, Johannes, additional, Fromme, Malin, additional, Zeuzem, Stefan, additional, Trautwein, Christian, additional, Sarrazin, Christoph, additional, Berg, Thomas, additional, Zhou, Biaohuan, additional, and Hamesch, Karim, additional

Published
2022
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30. Alpha-1 antitrypsin (AAT) augmentation therapy and liver phenotype in individuals with homozygous Pi*Z AAT mutation (Pi*ZZ genotype)

Author

Fromme, Malin, primary, Hamesch, Karim, additional, Schneider, Carolin Victoria, additional, Mandorfer, Mattias, additional, Thorhauge, Katrine, additional, Pereira, Vítor, additional, Pons, Monica, additional, Reichert, Matthias, additional, Amzou, Samira, additional, Bals, Robert, additional, Koczulla, Andreas Rembert, additional, Miravitlles, Marc, additional, Janciauskiene, Sabina, additional, Genesca, Joan, additional, Benini, Federica, additional, Chorostowska-Wynimko, Joanna, additional, Griffiths, Bill, additional, Aigner, Elmar, additional, Teumer, Alexander, additional, Trauner, Michael, additional, Krag, Aleksander, additional, Trautwein, Christian, additional, and Strnad, Pavel, additional

Published
2022
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35. Association of Alpha-1 Antitrypsin Pi*Z Allele Frequency and Progressive Liver Fibrosis in Two Chronic Hepatitis C Cohorts.

Author

Mücke, Victoria Therese, Fischer, Janett, Mücke, Marcus Maximilian, Teumer, Alexander, Koch, Alexander, Vermehren, Johannes, Fromme, Malin, Zeuzem, Stefan, Trautwein, Christian, Sarrazin, Christoph, Berg, Thomas, Zhou, Biaohuan, and Hamesch, Karim

Subjects
HEPATIC fibrosis, CHRONIC hepatitis C, GENE frequency, TRYPSIN inhibitors, ALPHA 1-antitrypsin deficiency, DISEASE risk factors
Abstract

(1) Background: The inherited alpha-1 antitrypsin (A1AT) deficiency variant 'Pi*Z' emerged as a genetic modifier of chronic liver disease. Controversial data exist on the relevance of heterozygous Pi*Z carriage ('Pi*MZ' genotype) as an additional risk factor in patients with chronic viral hepatitis C to develop progressive liver fibrosis. (2) Methods: Two prospectively recruited cohorts totaling 572 patients with therapy-naïve chronic viral hepatitis C (HCV) were analyzed. The Frankfurt cohort included 337 patients and a second cohort from Leipzig included 235 patients. The stage of liver fibrosis was assessed by liver biopsy, AST-to-platelet ratio index (APRI) score and Fibrosis-4 (FIB-4) score (Frankfurt) as well as liver stiffness measurement (LSM) via transient elastography (Leipzig). All patients were genotyped for the Pi*Z variant (rs28929474) of the SERPINA1 gene. (3) Results: In the Frankfurt cohort, 16/337 (4.7%) patients carried the heterozygous Pi*Z allele while 10/235 (4.3%) in the Leipzig cohort were Pi*Z carriers. In both cohorts, there was no higher proportion of Pi*Z heterozygosity in patients with cirrhosis compared to patients without cirrhosis or patients with cirrhosis vs. no liver fibrosis. Accordingly, Pi*Z frequency was not different in histological or serological stages of liver fibrosis (F0–F4) and showed no clear association with LSM. (4) Conclusions: Evaluation in two representative HCV cohorts does not indicate Pi*Z heterozygosity as a clinically relevant disease modifier in chronic HCV infection. However, validation in even larger cohorts with longitudinal follow-up is warranted. [ABSTRACT FROM AUTHOR]

Published
2023
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38. Polymerization of misfolded Z alpha-1 antitrypsin protein lowers CX3CR1 expression in human PBMCs

Author

Tumpara, Srinu, primary, Ballmaier, Matthias, additional, Wrenger, Sabine, additional, König, Mandy, additional, Lehmann, Matthias, additional, Lichtinghagen, Ralf, additional, Martinez-Delgado, Beatriz, additional, Korenbaum, Elena, additional, DeLuca, David, additional, Jedicke, Nils, additional, Welte, Tobias, additional, Fromme, Malin, additional, Strnad, Pavel, additional, Stolk, Jan, additional, and Janciauskiene, Sabina, additional

Published
2021
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39. Author response: Polymerization of misfolded Z alpha-1 antitrypsin protein lowers CX3CR1 expression in human PBMCs

Author

Tumpara, Srinu, primary, Ballmaier, Matthias, additional, Wrenger, Sabine, additional, König, Mandy, additional, Lehmann, Matthias, additional, Lichtinghagen, Ralf, additional, Martinez-Delgado, Beatriz, additional, Korenbaum, Elena, additional, DeLuca, David, additional, Jedicke, Nils, additional, Welte, Tobias, additional, Fromme, Malin, additional, Strnad, Pavel, additional, Stolk, Jan, additional, and Janciauskiene, Sabina, additional

Published
2021
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40. Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

Author

Fromme, Malin, primary, Schneider, Carolin V, additional, Pereira, Vitor, additional, Hamesch, Karim, additional, Pons, Monica, additional, Reichert, Matthias C, additional, Benini, Federica, additional, Ellis, Paul, additional, H Thorhauge, Katrine, additional, Mandorfer, Mattias, additional, Burbaum, Barbara, additional, Woditsch, Vivien, additional, Chorostowska-Wynimko, Joanna, additional, Verbeek, Jef, additional, Nevens, Frederik, additional, Genesca, Joan, additional, Miravitlles, Marc, additional, Nuñez, Alexa, additional, Schaefer, Benedikt, additional, Zoller, Heinz, additional, Janciauskiene, Sabina, additional, Abreu, Nélia, additional, Jasmins, Luís, additional, Gaspar, Rui, additional, Liberal, Rodrigo, additional, Macedo, Guilherme, additional, Mahadeva, Ravi, additional, Gomes, Catarina, additional, Schneider, Kai Markus, additional, Trauner, Michael, additional, Krag, Aleksander, additional, Gooptu, Bibek, additional, Thorburn, Douglas, additional, Marshall, Aileen, additional, Hurst, John R, additional, Lomas, David A, additional, Lammert, Frank, additional, Gaisa, Nadine T, additional, Clark, Virginia, additional, Griffiths, William, additional, Trautwein, Christian, additional, Turner, Alice M, additional, McElvaney, Noel G, additional, and Strnad, Pavel, additional

Published
2021
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47. Polymerization of misfolded protein lowers CX3CR1 expression in human PBMCs

Author

Tumpara, Srinu, primary, Ballmaier, Matthias, additional, Wrenger, Sabine, additional, König, Mandy, additional, Lehmann, Matthias, additional, Lichtinghagen, Ralf, additional, Martinez-Delgado, Beatriz, additional, DeLuca, David, additional, Jedicke, Nils, additional, Welte, Tobias, additional, Fromme, Malin, additional, Strnad, Pavel, additional, Stolk, Jan, additional, and Janciauskiene, Sabina, additional

Published
2020
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48. Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

Author

Fromme, Malin, Schneider, Carolin V., Pereira, Vitor, Hamesch, Karim, Pons, Monica, Reichert, Matthias C., Benini, Federica, Ellis, Paul, Thorhauge, Katrine H., Mandorfer, Mattias, Burbaum, Barbara, Woditsch, Vivien, Chorostowska-Wynimko, Joanna, Verbeek, Jef, Nevens, Frederik, Genesca, Joan, Miravitlles, Marc, Nuñez, Alexa, Schaefer, Benedikt, and Zoller, Heinz

Subjects
FATTY liver, TYPE 2 diabetes, TRYPSIN inhibitors, MEDICAL personnel
Published
2022
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49. Heterozygous alpha1-antitrypsin deficiency (Pi*MZ) is associated with increased liver stiffness and elevated liver enzymes in a multi-center European cohort

Author

Heimes, Carolin Victoria, Hamesch, Karim, Moeller, Linda S., Mandorfer, Mattias, Reichert, Matthias, Anita, Arslanow, Fromme, Malin, Woditsch, Vivien, Lindhauer, Cecilia, Voss, Jessica, Spivak, Igor, Bals, Robert, Janciauskiene, Sabina, Pereira, Vitor, Carvao, Joana, Griffiths, William J. H., Lammert, Frank, Krag, Aleksander, Trauner, Michael, Trautwein, Christian, and Strnad, Pavel

Published
2019
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