Table 3.

Controversies in Assigning Causality for DILI That Require Expert Interpretation

• Attributing tolerance/adaptation to the drug in question

• Diagnosing acute DILI in the setting of chronic liver disease

• Diagnosing DILI that might occur after a drug has been discontinued

• Determining when to initiate a workup for alternative causes, and how extensive the evaluation should be based on the injury pattern and height and ratio of the LAEs

• Interpreting histologic findings

• Determining the amount of alcohol that constitutes a risk factor

• Factoring in the influence of concomitant meds, drug–drug interactions and polypharmacy

• Differentiating DILI from an acute exacerbation of viral hepatitis, such as HAV, HBV, HCV, HEV, CMV, EBV

• Determining the influence of hepatobiliary malignancy, gallstones, CBD strictures, etc on LAEs

• Interpreting fluctuations in aminotransferase levels and ALT:AST ratios

• Taking the absolute height of ALT and AST into consideration and how to best interpret increases above elevated baseline values

• Interpreting atypical or negative rechallenge responses

• Interpreting atypical dechallenge responses that may not conform to RUCAM choices

• Interpreting the dechallenge response after suspected drug‐induced autoimmune hepatitis

• Interpreting the exact role played by pregnancy in awarding points in RUCAM

• Assessing herbal and dietary supplement‐ suspected DILI

Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBD, common bile duct; CMV, cytomegalovirus; EBV, Epstein Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus, HEV, hepatitis E virus; LAEs, liver‐associated enzymes.