Drug-induced liver injury in inflammatory bowel disease: 1-year prospective observational study

Abstract

AIMTo analyze 1-year liver injury burden in inflammatory bowel disease (IBD) patients.METHODSDuring a 6-mo inclusion period, consecutive IBD cases having a control visit at IBD center were included. Basic demographics, IBD phenotype and IBD treatment were recorded on entry. Aminotransferase (AT) activities of ALT, AST, ALP and gamma-glutamyl transpeptidase (GGT) were measured at baseline, 3 mo prior to study entry and prospectively every 3 mo for 1 year. Liver injury patterns were predefined as: Grade 1 in ALT 1-3 × upper limit of normal (ULN), grade 2 in ALT > 3 × ULN, hepatocellular injury in ALT > 2 × ULN, cholestatic injury in simultaneous GGT and ALP elevation > ULN. Persisting injury was reported when AT elevations were found on > 1 measurement. Risk factors for the patterns of liver injury were identified among demographic parameters, disease phenotype and IBD treatment in univariate and multivariate analysis. Finally, implications for the change in IBD management were evaluated in cases with persisting hepatocellular or cholestatic injury.RESULTSTwo hundred and fifty-one patients were included having 917 ALT and 895 ALP and GGT measurements. Over one year, grade 1 injury was found in 66 (26.3%), grade 2 in 5 (2%) and hepatocellular injury in 16 patients (6.4%). Persisting hepatocellular injury was found in 4 cases. Cholestasis appeared in 11 cases (4.4%) and persisted throughout the entire study period in 1 case. In multivariate analysis, hepatocellular injury was associated with BMI (OR = 1.13, 1.02-1.26), liver steatosis (OR = 10.61, 2.22-50.7), IBD duration (1.07, 1.00-1.15) and solo infliximab (OR = 4.57, 1.33-15.7). Cholestatic liver injury was associated with prior intestinal resection (OR = 32.7, 3.18-335), higher CRP (OR = 1.04, 1.00-1.08) and solo azathioprine (OR = 10.27, 1.46-72.3). In one case with transient hepatocellular injury azathioprine dose was decreased. In 4 cases with persisting hepatocellular injury, fatty liver or alcohol were most likely causes and IBD treatment was pursued without change. In the case with persisting cholestatic injury, no signs of portal hypertension were identified and treatment with infliximab continued.CONCLUSIONLiver injury was frequent, mostly transient and rarely changed management. Infliximab or azathioprine were confirmed as its risk factors indicating the need for regular AT monitoring.

Biologic and Checkpoint Inhibitor‐Induced Liver Injury: A Systematic Literature Review

“…Additionally, even though ANA can be used to diagnose AIH, positive ANA status before the initiation of therapy did not seem to place the patient at greater risk of developing DILI . Out of the patients that developed an AIH‐like picture from TNF‐α inhibitors, at least half of the patients required steroids while the other half recovered after stopping treatment …”

“…Ghabril et al analyzed 34 cases of DILI related to TNF‐α inhibitors and found the most common presentation to be an autoimmune phenotype with improvement after drug withdrawal . In large retrospective studies, mild DILI (defined as ALT >2× ULN and/or ALP>2× ULN) was reported to have a 0.2%‐11% incidence, with the majority implicating infliximab . The absolute risk of DILI for patients that were started on infliximab was found in 1 of 120 users, 1 of 270 for adalimumab, and 1 of 430 for etancercept .…”

“…In large retrospective studies, mild DILI (defined as ALT >2× ULN and/or ALP>2× ULN) was reported to have a 0.2%‐11% incidence, with the majority implicating infliximab . The absolute risk of DILI for patients that were started on infliximab was found in 1 of 120 users, 1 of 270 for adalimumab, and 1 of 430 for etancercept . The median duration of TNF‐α inhibitors therapy was 3.3 months for those who developed DILI, mostly after four infusions of infliximab, and this time line was corroborated in a review of 26 cases of infliximab‐induced hepatocellular injury by Ghabril et al…”

Nonalcoholic Fatty Liver Disease and Inflammatory Bowel Disease: Complex Interactions, Evaluations, and Management Decisions

“…This is a major consideration given that the DILI Network has identified both thiopurine and biologic medications, specifically azathioprine and infliximab, as a Category A drug, indicating over 100 reported cases of liver toxicity [58]. A prospective cohort of treated IBD patients were followed with serial assessments of aminotransferase, bilirubin and alkaline phosphatase levels and most events were transients and did not require any significant change in IBD management [59]. A recent metaanalysis showed that immunomodulators and methotrexate did not result in an increase in NAFLD development; TNF alpha inhibitors had no association with rate of progression [59].…”

“…A prospective cohort of treated IBD patients were followed with serial assessments of aminotransferase, bilirubin and alkaline phosphatase levels and most events were transients and did not require any significant change in IBD management [59]. A recent metaanalysis showed that immunomodulators and methotrexate did not result in an increase in NAFLD development; TNF alpha inhibitors had no association with rate of progression [59]. We do not recommend adjusting medical therapy in the presence of NAFLD/NASH unless drug-induced liver injury (DILI) is suspected.…”