Drug-induced liver injury secondary to biologic medications in inflammatory bowel disease: meta-analysis and systematic review

Introduction
Drug-induced hepatotoxicity and biologic drugs have historically been challenging in inflammatory bowel disease (IBD). We aimed to study the prevalence of hepatotoxicity in adult patients using biologic medications.

Material and methods
With the guidelines described by PRISMA-P, a detailed search strategy for each electronic database was developed based on the one used for PubMed, Medline, and Embase. We included prospective and retrospective randomized controlled trials (RCTs) that assessed the efficacy and hepatotoxicity of biologics in IBD patients. Hepatotoxicity was defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2× upper limit of normal or cholestasis. We used Review Manager 5 (RevMan5) to analyse the data. We calculated the odds ratio (OR) with a 95% confidence interval (CI). We assessed heterogeneity using the 2 test and the I2 statistic.

Results
We identified 862 records in total. After we had removed duplicates 564 records were left for review. Four studies did not report on how participants were randomized to treatment groups or how allocation concealment was achieved; we rated these studies at unclear risk of bias for these domains. There was no presence of any heterogeneity among studies (2 = 2.21, df = 6, p = 0.90, and I2 = 0%), when all seven studies were involved for analysis. Our meta-analysis was conducted on the fixed effects model, with 0.770, 95% CI (–0.630, 0.957), and p = 0.02. Hepatotoxicity was not related to any tumor necrosis factor  antagonist. Thiopurine-induced liver injury occurred more frequently within the first months of treatment, 50% of cases within the first 3 months. However, risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4% vs. 2.3%, p < 0.05).

Conclusions
This study summed up the broad information on occurrence of biologic-related hepatotoxicity in IBD patients in a clinical practice setting. When hepatotoxicity occurred, the treatment was withdrawn in 31% of patients, but an important percentage, 44%, were able to continue the full dose of thiopurine once the dose was temporarily adjusted. This group of patients had a dose-dependent hepatotoxicity rather than an immunologic hepatitis.