Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury

Gastroenterology. 2014 Jul;147(1):109-118.e5. doi: 10.1053/j.gastro.2014.03.050. Epub 2014 Apr 1.


Background & aims: Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI.

Methods: We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL).

Results: Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity.

Conclusions: When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.

Keywords: Idiosyncratic Hepatotoxicity; Prediction; Prognostic Risk Factor; Progression.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alanine Transaminase / metabolism
  • Algorithms*
  • Alkaline Phosphatase / metabolism
  • Aspartate Aminotransferases / metabolism
  • Bilirubin / metabolism
  • Biomarkers / metabolism
  • Chemical and Drug Induced Liver Injury / complications*
  • Chemical and Drug Induced Liver Injury / epidemiology*
  • Chemical and Drug Induced Liver Injury / metabolism
  • Child
  • Cohort Studies
  • Comorbidity
  • Female
  • Humans
  • Jaundice / complications*
  • Jaundice / epidemiology*
  • Jaundice / metabolism
  • Liver Failure, Acute / epidemiology*
  • Liver Failure, Acute / metabolism
  • Male
  • Middle Aged
  • Models, Statistical*
  • Predictive Value of Tests
  • Retrospective Studies
  • Risk Factors
  • Sensitivity and Specificity
  • Sex Factors
  • Young Adult


  • Biomarkers
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Alkaline Phosphatase
  • Bilirubin