Suppression of bile acid synthesis as a tipping point in the disease course of primary sclerosing cholangitis
Peder Rustøen Braadland,
Kai Markus Schneider,
Annika Bergquist,
Antonio Molinaro,
Anita Lövgren-Sandblom,
Marcus Henricsson,
Tom Hemming Karlsen,
Mette Vesterhus,
Christian Trautwein,
Johannes Roksund Hov,
Hanns-Ulrich Marschall
Affiliations
Peder Rustøen Braadland
Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
Kai Markus Schneider
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany#; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Annika Bergquist
Unit of Gastroenterology and Rheumatology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden#
Antonio Molinaro
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden#; Department of Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital Gothenburg, Gothenburg, Sweden
Anita Lövgren-Sandblom
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
Marcus Henricsson
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden#
Tom Hemming Karlsen
Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
Mette Vesterhus
Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Department of Medicine, Haraldsplass Deaconess Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
Christian Trautwein
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany#
Johannes Roksund Hov
Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
Hanns-Ulrich Marschall
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden#; Department of Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital Gothenburg, Gothenburg, Sweden; Corresponding author. Address: Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy and University Hospital, S-413 45 Gothenburg, Sweden. Tel.: +46708774073; fax: +4631822152.
Background & Aims: Farnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy. Methods: Concentrations of individual bile acids and 7α-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort. Results: The bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06–1.43) and validation (adjusted HR = 1.23, 95% CI 1.03–1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis. Conclusions: Bile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation. Lay summary: We show, by measuring the level of the metabolite C4 in the blood from patients with primary sclerosing cholangitis (PSC), that low production of bile acids in the liver predicts a more rapid progression to severe disease. Many people with PSC appear to have fully suppressed bile acid production, and both established and new drugs that aim to reduce bile acid production may therefore be futile for them. We propose C4 as a test to find those likely to respond to these treatments.
