Jacques Young1,2,3, Jérôme Bertherat4, Marie Christine Vantyghem5, Olivier Chabre6,7,8, Salima Senoussi9, Rita Chadarevian9,10, Frédéric Castinetti11. 1. Univ Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin Bicetre, France jacques.young@aphp.fr. 2. Service d'Endocrinologie et des Maladies de la ReproductionAssistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicetre, France. 3. INSERM U1185Le Kremlin-Bicetre, France. 4. Department of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, Paris, France. 5. Service d'Endocrinologie et Maladies MétaboliquesHôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, INSERM U1190, EGID, Lille, France. 6. Service d'Endocrinologie-Diabétologie-NutritionCHU Grenoble-Alpes, Grenoble, France. 7. Faculté de Médecine Université Grenoble-AlpesGrenoble, France. 8. INSERM U 1036iRTSV-BCI, CEA-Grenoble, Grenoble, France. 9. HRA FranceParis, France. 10. Service d'endocrinologie-métabolismeAssistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France. 11. Department of EndocrinologyAix Marseille Universite, CNRS UMR7286, Assistance Publique-Hopitaux de Marseille, La Conception Hospital, Marseille, France.
Abstract
OBJECTIVE: Ketoconazole (KTZ) is one of few available treatments for Cushing's syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ. DESIGN: An observational prospective French cohort study (Compassionate Use Programme (CUP)). METHODS: Enrolled patients were stratified into a KTZ-naive cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, γ-glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT > 3 × ULN (upper limit of normal), total bilirubin > 2 × ULN or both ALP > 2 × ULN and ALT > ULN were considered to have liver injury. RESULTS: Overall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. Four patients in the KTZ-naïve cohort (8.5%) and two in the KTZ-switch cohort (3.3%) developed liver injury, considered related to KTZ in three cases (all KTZ-naïve in the first month of treatment). Five patients had mild liver function abnormalities at baseline and two had proven liver metastases. Two patients recovered on discontinuation of KTZ and the remaining patient died of unrelated causes. CONCLUSIONS: These findings highlight the need for close monitoring of liver enzymes especially during the first six months of treatment. Liver enzyme abnormalities usually occurred within four weeks were asymptomatic and could be reversed on timely discontinuation of KTZ.
OBJECTIVE:Ketoconazole (KTZ) is one of few available treatments for Cushing's syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ. DESIGN: An observational prospective French cohort study (Compassionate Use Programme (CUP)). METHODS: Enrolled patients were stratified into a KTZ-naive cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, γ-glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT > 3 × ULN (upper limit of normal), total bilirubin > 2 × ULN or both ALP > 2 × ULN and ALT > ULN were considered to have liver injury. RESULTS: Overall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. Four patients in the KTZ-naïve cohort (8.5%) and two in the KTZ-switch cohort (3.3%) developed liver injury, considered related to KTZ in three cases (all KTZ-naïve in the first month of treatment). Five patients had mild liver function abnormalities at baseline and two had proven liver metastases. Two patients recovered on discontinuation of KTZ and the remaining patient died of unrelated causes. CONCLUSIONS: These findings highlight the need for close monitoring of liver enzymes especially during the first six months of treatment. Liver enzyme abnormalities usually occurred within four weeks were asymptomatic and could be reversed on timely discontinuation of KTZ.
Authors: Maria Fleseriu; Richard Auchus; Irina Bancos; Anat Ben-Shlomo; Jerome Bertherat; Nienke R Biermasz; Cesar L Boguszewski; Marcello D Bronstein; Michael Buchfelder; John D Carmichael; Felipe F Casanueva; Frederic Castinetti; Philippe Chanson; James Findling; Mônica Gadelha; Eliza B Geer; Andrea Giustina; Ashley Grossman; Mark Gurnell; Ken Ho; Adriana G Ioachimescu; Ursula B Kaiser; Niki Karavitaki; Laurence Katznelson; Daniel F Kelly; André Lacroix; Ann McCormack; Shlomo Melmed; Mark Molitch; Pietro Mortini; John Newell-Price; Lynnette Nieman; Alberto M Pereira; Stephan Petersenn; Rosario Pivonello; Hershel Raff; Martin Reincke; Roberto Salvatori; Carla Scaroni; Ilan Shimon; Constantine A Stratakis; Brooke Swearingen; Antoine Tabarin; Yutaka Takahashi; Marily Theodoropoulou; Stylianos Tsagarakis; Elena Valassi; Elena V Varlamov; Greisa Vila; John Wass; Susan M Webb; Maria C Zatelli; Beverly M K Biller Journal: Lancet Diabetes Endocrinol Date: 2021-10-20 Impact factor: 32.069
Authors: Eva L Alba; Emily A Japp; Gustavo Fernandez-Ranvier; Ketan Badani; Eric Wilck; Munir Ghesani; Andrea Wolf; Edward M Wolin; Virginia Corbett; David Steinmetz; Maria Skamagas; Alice C Levine Journal: J Endocr Soc Date: 2022-05-06