Gastroenterology

Gastroenterology

Volume 147, Issue 1, July 2014, Pages 109-118.e5
Gastroenterology

Original Research
Full Report: Clinical—Liver
Use of Hy's Law and a New Composite Algorithm to Predict Acute Liver Failure in Patients With Drug-Induced Liver Injury

https://doi.org/10.1053/j.gastro.2014.03.050Get rights and content

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.

Section snippets

Patients and Methods

The study cohort encompassed all patients with idiosyncratic drug-induced liver injury entered into the Spanish DILI Registry since its foundation in April 1994 until August 2012. This prospective database contains detailed demographic, clinical, laboratory, imaging, and histologic (when available) information both at presentation and at follow-up evaluation of the patients included. Each case included in the study was evaluated by a clinician and remitted to the coordinating center where it

Demographic and Clinical Presentation of DILI Patients Who Did or Did Not Develop ALF/OLT

A total of 771 patients, who had 805 DILI episodes between April 1994 and August 2012, were included in the analysis. Thirty-two of these DILI patients (4%) developed ALF resulting in death (19; 59%), OLT (12; 38%), or recovery (1; 3%). In addition, 10 patients died within 6 months of DILI recognition of non–liver-related causes. The overall mean age was 54 years (range, 11–89 y), and 394 (51%) were men. The main causative drug group was antibiotics (36%), followed by nervous system (13%),

Discussion

Prediction of severe outcome at DILI recognition remains a challenge in clinical practice. Prompt discontinuation of the offending drug is a crucial step in DILI management, but it is not enough by itself to prevent further damage and even a fulminant outcome in some cases. Assessment of DILI severity is based on derangement in coagulation parameters and the development of encephalopathy.13, 18 However, these are delayed features and at this time point liver parenchymal mass is lost extensively

Acknowledgments

The authors are grateful to D. Ramon Hidalgo of the Servicio Central de Informatica de la Universidad de Malaga for his invaluable help in the statistical analyses.

The authors thank the following Collaborators for their contributions.

On behalf of the Safer and Faster Evidence-based Translation Consortium, the members of the DILI work package are as follows: R. J. Andrade, M. I. Lucena, M. Robels-Díaz, C. Stephens, G. A. Kullak-Ublick, T. Poynard, S. Ormarsdottir, M. Merz, and I.

References (32)

  • E. Björnsson et al.

    Severe jaundice in Sweden in the new millennium: causes, investigations, treatment and prognosis

    Scand J Gastroenterol

    (2003)
  • G. Ostapowicz et al.

    Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States

    Ann Intern Med

    (2002)
  • G. Wei et al.

    Acute liver failure in Sweden: etiology and outcome

    J Intern Med

    (2007)
  • H.J. Zimmerman

    The spectrum of hepatotoxicity

    Perspect Biol Med

    (1968)
  • E. Björnsson et al.

    Outcome and prognostic markers in severe drug-induced liver disease

    Hepatology

    (2005)
  • Temple R. Hepatotoxicity through the years: impact on the FDA. 2001. Available:...
  • Cited by (242)

    View all citing articles on Scopus

    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by a research grant (Fondo de Investigación Sanitaria, PI12-00620), the Agencia Española del Medicamento, and the Innovative Medicines Initiative Safer and Faster Evidence-based Translation consortium (Framework Programme for Research and Technological Development (FP-7) grant agreement number 523 705, IMI-2008-T5). CIBERehd is funded by the Instituto de Salud Carlos III.

    The personal views expressed in this article may not be understood nor quoted as being made on behalf of or reflecting the position of the Innovative Medicines Initiative or its membership companies. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the manuscript for publication.

    View full text