Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis: Implications for Drug Hepatotoxicity Monitoring

Introduction Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. Objective We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. Methods We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. Results In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy’s law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34–299) and 56 U/L (47–85)] than for those with normal baseline values [median 26.5 U/L (range 18–33) and 29 U/L (25.5–30.5)] in both studies, respectively, with p