Table 5.

A proposal for the diagnosis of potential hepatotoxicity in NASH trials

Suspected hepatotoxicity (stopping rules) during clinical trials Increase in serum AST and/or ALT > 3 times the baseline value OR > 500 IU/L (on one reading unless the sample is hemolysed) New onset jaundice (total bilirubin ≥ 3 mg/dl) that is not explained by Gilbert’s or hemolysis, irrespective of other liver biochemistries Increase in serum AST and/or ALT < 3 times the baseline value but associated with symptoms (fatigue, nausea, vomiting)

Signals of hepatotoxic potential from clinical trials An excess of aminotransferase elevations to > 3×baseline values when compared to the control group Marked elevations of aminotransferases to 5×, 10×, or 20× baseline values in the test drug group and not seen (or less frequent) in the control group One or more Hy’s law cases (serum bilirubin >2×ULN in a setting of pure hepatocellular injury with no other explanation) in the test drug group, accompanied by an overall increased incidence of aminotransferase elevations > 3×baseline in the test drug group compared to placebo.