Katharina Brandl1, Phillipp Hartmann2, Lily J Jih3, Donald P Pizzo4, Josepmaria Argemi5, Meritxell Ventura-Cots5, Sally Coulter6, Christopher Liddle6, Lei Ling7, Stephen J Rossi7, Alex M DePaoli7, Rohit Loomba8, Wajahat Z Mehal9, Derrick E Fouts10, Michael R Lucey11, Francisco Bosques-Padilla12, Philippe Mathurin13, Alexander Louvet13, Guadalupe Garcia-Tsao9, Elizabeth C Verna14, Juan G Abraldes15, Robert S Brown16, Victor Vargas17, Jose Altamirano18, Juan Caballería19, Debbie Shawcross20, Peter Stärkel21, Samuel B Ho22, Ramon Bataller5, Bernd Schnabl23. 1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA. 2. Department of Pediatrics, University of California San Diego, La Jolla, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA. 3. Department of Pathology, University of California San Diego, La Jolla, CA, USA; Department of Pathology, VA San Diego Healthcare System, San Diego, CA, USA. 4. Department of Pathology, University of California San Diego, La Jolla, CA, USA. 5. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh Liver Research Center, Pittsburgh, PA, USA. 6. Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Australia. 7. NGM Bio, South San Francisco, CA, USA. 8. Department of Medicine, University of California San Diego, La Jolla, CA, USA. 9. Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA, and Section of Digestive Diseases, VA-CT Healthcare System, West Haven, CT, USA. 10. J. Craig Venter Institute, Rockville, MD, USA. 11. Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, WI, USA. 12. Hospital Universitario, Departamento de Gastroenterología, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico. 13. Service des Maladies de L'appareil Digestif et Unité INSERM, Hôpital Huriez, Lille, France. 14. Division of Digestive and Liver Diseases, Department of Medicine, Columbia College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA. 15. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. 16. Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA. 17. Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain. 18. Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. 19. Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain; Liver Unit, Hospital Clinic, Barcelona, Spain. 20. Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, King's College Hospital, London, UK. 21. St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. 22. Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA. 23. Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA. Electronic address: beschnabl@ucsd.edu.
Abstract
BACKGROUND & AIMS: The degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. We aimed to identify the largely unknown mechanisms and biomarkers linked to cholestasis in alcoholic hepatitis. METHODS: Herein, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acid synthesis. RESULTS: We found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in patients with alcoholic hepatitis. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (model for end-stage liver disease score). FGF19 correlated best with conjugated cholic acid, and model for end-stage liver disease score best with taurine-conjugated chenodeoxycholic acid. Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma glutamyl transferase, and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte infiltration, in all patients with alcoholic hepatitis. CONCLUSION: Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans. LAY SUMMARY: Understanding the underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Herein, we describe a molecule that is increased in patients with alcoholic hepatitis. Modulating the molecular pathway of this molecule might lead to promising targets for the treatment of alcoholic hepatitis. Published by Elsevier B.V.
BACKGROUND & AIMS: The degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. We aimed to identify the largely unknown mechanisms and biomarkers linked to cholestasis in alcoholic hepatitis. METHODS: Herein, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acid synthesis. RESULTS: We found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in patients with alcoholic hepatitis. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (model for end-stage liver disease score). FGF19 correlated best with conjugated cholic acid, and model for end-stage liver disease score best with taurine-conjugated chenodeoxycholic acid. Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma glutamyl transferase, and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte infiltration, in all patients with alcoholic hepatitis. CONCLUSION: Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans. LAY SUMMARY: Understanding the underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Herein, we describe a molecule that is increased in patients with alcoholic hepatitis. Modulating the molecular pathway of this molecule might lead to promising targets for the treatment of alcoholic hepatitis. Published by Elsevier B.V.
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