Elevation of liver enzyme under immunotherapy with checkpoint inhibitors

Aim to assess the incidence and management of liver enzyme elevation in these patients.

Methods Our retrospective study included tumor patients treated with ICIs between 01/2016-05/2019 in our hospital. Patients with significant elevation of liver enzymes(ALT/AST > 3xupper limit of normal(ULN) and/or bilirubin > 1.5xULN) were identified and analyzed for cause, management and clinical outcome.

Results We identified 208 tumor patients treated with ICIs(59.1 % Nivolumab;40.9 % Pembrolizumab) with a mean age of 66.1 ± 10.7years(69.8 % male).Most of the patients were treated for lung cancer(41.8 %),followed by melanoma(27,4 %),urologic cancers(11,1 %). Significant elevation of liver enzyme was diagnosed in 12 % of patients(Nivolumab-11.3 % vs. Pembrolizumab-13 %,p = 0.87):ALT/AST in 10.1 %,bilirubin-6.2 % and both in 4.8 % of patients. ALT/AST was elevated between 3-5xULN in 1.9 %, 5-10xULN in 1.9 % and  > 10xULN in 1.4 % of cases,while bilirubin was elevated between 1.5-3xULN in 4.3 %, 3-5xULN-0.9 %,between 5-10xULN-0.9 % and  > 10xULN in 0.4 %of patients. Abdominal ultrasounds or CT scans were performed in all the patients at the time of liver enzyme elevation. Steroid therapy was administered in 32 %of patients,28 % patients were presented to a hepatologist and liver biopsy was performed in none of the patients(2 patients rejected the performance of liver biopsy). The most probable cause of liver enzyme elevation were:ICIs induced liver injury-60 %, disease progression-32 %, combination of ICIs+progression of liver metastasis-4 % and choledocholithiasis-4 % of cases. ICIs were discontinued in 76 % of patients with elevated liver enzyme.ICIs were restarted after steroids in 8 %of patients(no further elevation of liver enzymes was observed). Liver enzyme dynamic after ICIs discontinuation by hepatotoxicity:normalization-53.3 %, declining but not achieving baseline values-33.3 %,stable-6.7 %.One patient(6.7 %) presented with an increase of 10xULN in ALT,AST and bilirubin with further increase even after discontinuation of ICIs-resulting in liver failure leading to death without response to the steroids.

Conclusion Significant elevation of liver enzymes under ICIs was observed in 12 % patients in our cohort, in 60 % of which ICIs hepatotoxicity was being suspected.

Publication History

Article published online:
26 May 2020