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Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease.

Authors
  • Schönauer, Ria1
  • Sierks, Dana2
  • Boerrigter, Melissa3
  • Jawaid, Tabinda4
  • Caroff, Lea5
  • Audrezet, Marie-Pierre6
  • Friedrich, Anja7
  • Shaw, Melissa8
  • Degenhardt, Jan9
  • Forberger, Mirjam10
  • de Fallois, Jonathan11
  • Bläker, Hendrik10
  • Bergmann, Carsten7
  • Gödiker, Juliana12
  • Schindler, Philipp13
  • Schlevogt, Bernhard14
  • Müller, Roman-U15
  • Berg, Thomas16
  • Patterson, Ilse17
  • Griffiths, William J18
  • And 12 more
  • 1 Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin), Berlin, Germany; Division of Nephrology, Department of Internal Medicine, University of Leipzig Medical Center, Leipzig, Germany. , (Germany)
  • 2 Division of Nephrology, Department of Internal Medicine, University of Leipzig Medical Center, Leipzig, Germany; Department of Pediatric Surgery, Universitätsklinikum Leipzig, Leipzig, Germany. , (Germany)
  • 3 Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands. , (Netherlands)
  • 4 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
  • 5 University of Brest, Institut National de la Santé et de la Recherche Médicale, UMR 1078, Génétique, Génomique Fonctionnelle et Biotechnologies, Brest, France; Centre Hospitalier Universitaire Brest, Service de Néphrologie, Centre de Référence Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Brest, France. , (France)
  • 6 Centre Hospitalier Universitaire Brest, Service de Génétique Moléculaire, Brest, France. , (France)
  • 7 Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany. , (Germany)
  • 8 Departments of Internal Medicine and Nephrology, Yale University School of Medicine, New Haven, Connecticut.
  • 9 Department 2 of Internal Medicine, University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany. , (Germany)
  • 10 Department of Pathology, University of Leipzig Medical Center, Leipzig, Germany. , (Germany)
  • 11 Division of Nephrology, Department of Internal Medicine, University of Leipzig Medical Center, Leipzig, Germany. , (Germany)
  • 12 Department of Internal Medicine B, University Hospital Münster, Münster, Germany. , (Germany)
  • 13 Clinic for Radiology, University Hospital Münster, Münster, Germany. , (Germany)
  • 14 Department of Internal Medicine B, University Hospital Münster, Münster, Germany; Department of Gastroenterology, Medical Center Osnabrück, Osnabrück, Germany. , (Germany)
  • 15 Department 2 of Internal Medicine, University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. , (Germany)
  • 16 Division of Hepatology, Department of Medicine II, University of Leipzig Medical Center, Leipzig, Germany. , (Germany)
  • 17 Department of Radiology, Cambridge University Hospitals, Cambridge, United Kingdom. , (United Kingdom)
  • 18 Department of Hepatology, Cambridge Liver Unit, Cambridge University Hospitals, Cambridge, United Kingdom. , (United Kingdom)
  • 19 Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Renal Services, Newcastle upon Tyne National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom; National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne, United Kingdom. , (United Kingdom)
  • 20 Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Center of Functional Genomics, Berlin, Germany. , (Germany)
  • 21 Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
  • 22 Department of Hepatology and Liver Transplantation Unit, University Hospitals Katholieke Universiteit Leuven, Leuven, Belgium. , (Belgium)
  • 23 Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: [email protected]. , (Netherlands)
  • 24 Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin), Berlin, Germany; Division of Nephrology, Department of Internal Medicine, University of Leipzig Medical Center, Leipzig, Germany. Electronic address: [email protected]. , (Germany)
Type
Published Article
Journal
Gastroenterology
Publication Date
May 01, 2024
Volume
166
Issue
5
Pages
902–914
Identifiers
DOI: 10.1053/j.gastro.2023.12.007
PMID: 38101549
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Autosomal dominant polycystic liver disease is a rare condition with a female preponderance, based mainly on pathogenic variants in 2 genes, PRKCSH and SEC63. Clinically, autosomal dominant polycystic liver disease is characterized by vast heterogeneity, ranging from asymptomatic to highly symptomatic hepatomegaly. To date, little is known about the prediction of disease progression at early stages, hindering clinical management, genetic counseling, and the design of randomized controlled trials. To improve disease prognostication, we built a consortium of European and US centers to recruit the largest cohort of patients with PRKCSH and SEC63 liver disease. We analyzed an international multicenter cohort of 265 patients with autosomal dominant polycystic liver disease harboring pathogenic variants in PRKCSH or SEC63 for genotype-phenotype correlations, including normalized age-adjusted total liver volumes and polycystic liver disease-related hospitalization (liver event) as primary clinical end points. Classifying individual total liver volumes into predefined progression groups yielded predictive risk discrimination for future liver events independent of sex and underlying genetic defects. In addition, disease severity, defined by age at first liver event, was considerably more pronounced in female patients and patients with PRKCSH variants than in those with SEC63 variants. A newly developed sex-gene score was effective in distinguishing mild, moderate, and severe disease, in addition to imaging-based prognostication. Both imaging and clinical genetic scoring have the potential to inform patients about the risk of developing symptomatic disease throughout their lives. The combination of female sex, germline PRKCSH alteration, and rapid total liver volume progression is associated with the greatest odds of polycystic liver disease-related hospitalization. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

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