Jürgen Borlak1, Florian van Bömmel2, Thomas Berg2. 1. Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany. 2. Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.
Abstract
BACKGROUND & AIMS: The analgesic flupirtine has been linked to cases of severe idiosyncratic drug-induced liver injury (sFILI). We therefore examined whether N-acetylcysteine (NAC) and glucocorticoid therapy is effective in the management of sFILI. METHODS: In a retrospective cohort study efficacy of NAC-infusion and oral prednisolone treatments on liver-function-tests (LFTs) and clinical outcome of 21 sFILI cases was evaluated by comparing it to an external cohort of 30 sFILI cases not receiving the antidote. LFTs were also assayed in human hepatocyte cultures treated with flupirtine for 96 hours. Additionally, modulation of glutathione stores in cultures of human hepatocytes treated with 80 drugs was investigated. RESULTS: Upon admission, patients presented Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin elevations of up to 90-, 35- and 30-fold of upper limits of normal (ULN) respectively. The average INR was 2.2, and 50% of patients had a high Model for end-stage liver disease (MELD) score of ≥25 and included 5 cases of 28-32. The combined NAC/prednisolone treatment was well tolerated and led to significant ALT, AST and INR improvements within 2 weeks. However, the hyperbilirubinaemia resolved slowly. Two patients with late start of NAC/prednisolone treatment developed hepatic encephalopathy and required liver transplantation; the remaining patients recovered without long-term sequela. Based on serum biochemistries sFILI cases resolved more rapidly (P < .01) when compared to untreated sFILI patients and included a case with fatal outcome. Additionally, in vitro studies revealed glutathione depletion as a common culprit for drugs with liver liabilities. CONCLUSIONS: Based on these initial findings a prospective randomized clinical trial (RCT) is needed to confirm safety and efficacy of NAC/prednisolone treatment in sFILI.
BACKGROUND & AIMS: The analgesic flupirtine has been linked to cases of severe idiosyncratic drug-induced liver injury (sFILI). We therefore examined whether N-acetylcysteine (NAC) and glucocorticoid therapy is effective in the management of sFILI. METHODS: In a retrospective cohort study efficacy of NAC-infusion and oral prednisolone treatments on liver-function-tests (LFTs) and clinical outcome of 21 sFILI cases was evaluated by comparing it to an external cohort of 30 sFILI cases not receiving the antidote. LFTs were also assayed in human hepatocyte cultures treated with flupirtine for 96 hours. Additionally, modulation of glutathione stores in cultures of human hepatocytes treated with 80 drugs was investigated. RESULTS: Upon admission, patients presented Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin elevations of up to 90-, 35- and 30-fold of upper limits of normal (ULN) respectively. The average INR was 2.2, and 50% of patients had a high Model for end-stage liver disease (MELD) score of ≥25 and included 5 cases of 28-32. The combined NAC/prednisolone treatment was well tolerated and led to significant ALT, AST and INR improvements within 2 weeks. However, the hyperbilirubinaemia resolved slowly. Two patients with late start of NAC/prednisolone treatment developed hepatic encephalopathy and required liver transplantation; the remaining patients recovered without long-term sequela. Based on serum biochemistries sFILI cases resolved more rapidly (P < .01) when compared to untreated sFILI patients and included a case with fatal outcome. Additionally, in vitro studies revealed glutathione depletion as a common culprit for drugs with liver liabilities. CONCLUSIONS: Based on these initial findings a prospective randomized clinical trial (RCT) is needed to confirm safety and efficacy of NAC/prednisolone treatment in sFILI.
Authors: Marcial Sebode; Martin Reike-Kunze; Sören Weidemann; Roman Zenouzi; Johannes Hartl; Moritz Peiseler; Timur Liwinski; Lisa Schulz; Christina Weiler-Normann; Martina Sterneck; Ansgar W Lohse; Christoph Schramm Journal: Br J Clin Pharmacol Date: 2020-03-03 Impact factor: 4.335