Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop

Abstract

Idiosyncratic drug-induced liver injury (DILI) is an important but relatively infrequent cause of potentially severe acute and chronic liver injury. The aim of this clinical research workshop was to review and attempt to standardize the current nomenclature and terminology used in DILI research. Because DILI is a diagnosis of exclusion, selected elements of the medical history, laboratory tests, and previous reports were proposed to improve causality assessment. Definitions and diagnostic criteria regarding the onset of DILI, evolution of liver injury, risk factors, and mandatory testing versus optional testing for competing causes were reviewed. In addition, the role of intentional and inadvertent rechallenge, liver histology, and host genetic polymorphisms in establishing the diagnosis and prognosis of DILI were reviewed. Consensus was established regarding the need to develop a web-of-knowledge database that provides concise, reliable, and updated information on cases of liver injury due to drugs and herbal and dietary supplements. In addition, the need to develop drug-specific computerized causality assessment methods that are derived from prospectively phenotyped cases was a high priority. Proposed scales for grading DILI severity and assessing the likelihood of an agent causing DILI and written criteria for improving the reliability, accuracy, and reproducibility of expert opinion were reviewed. Finally, the unique challenges of assessing causality in children, patients with underlying liver disease, and subjects taking herbal and dietary supplements were discussed.

Conclusion: Workshop participants concluded that multicenter referral networks enrolling patients with suspected DILI according to standardized methodologies are needed. These networks should also collect biological samples that may provide crucial insights into the mechanism(s) of DILI with the ultimate aim of preventing future cases of DILI.

Fig. 1

Comparison of the R ratio at onset and at the time of peak bilirubin elevation in 192 subjects enrolled in the prospective DILIN study. Only patients with at least two determinations of ALT, Alk P, and bilirubin in whom DILI was attributed to a single agent and given a causality score of at least “probable” were included. Although there was a close correlation between the two scores (r = 0.80, P < 0.0001), there was a general shift to lower R values between onset and peak bilirubin. The dotted lines indicate levels of the R ratio used to separate cholestatic (≤2), mixed (2–5), and hepatocellular injury (≥5).