Outcome and prognostic markers in severe drug-induced liver disease

The combination of high aminotransferases (hepatocellular injury) and jaundice has been reported to lead to a mortality rate of 10 % to 50 % for different drugs, a phenomenon known as Hy's rule. However, Hy's rule has never been validated, and limited data exist on predictors for outcome in hepatocellular and other forms of drug-induced liver disease. All reports of suspected hepatic adverse drug reactions received by the Swedish Adverse Drug Reactions Advisory Committee (1970-2004) were reviewed. Cases with bilirubin levels 2 or more times the upper limit of normal (ULN) were analyzed. A total of 784 cases were retrieved-409 with hepatocellular injury, 206 with cholestatic injury, and 169 with mixed liver injury. The mortality/transplantation rate was 9.2 %, and bilirubin (median 18.7 X ULN [IQR 12.6-25]; range 4.5-42) was higher (P < .0001) in the deceased/transplant recipients compared with the surviving patients (median 5:5 X ULN [IQR 3.3-9.51; range 2.0-38). A total of 7.8 % with cholestatic and 2.4 % with a mixed pattern died. The mortality rate in hepatocellular injury for different drugs varied from 40 % (6 of 15) for halothane to 0 % (0 of 32) for erythromycin, in total 12.7 %. Using logistic regression analysis, age, aspartate aminotransferase (AST) and bilirubin were found to independently predict death or liver transplantation in the hepatocellular group, whereas among patients with cholestatic/mixed liver injury, bilirubin was the only independent predictor. In conclusion, hepatocellular jaundice has a high but variable mortality rate, depending on the drug involved. The AST and bilirubin levels are the most important predictors of death or liver transplantation.