Drug-induced liver injury: Towards early prediction and risk stratification

Table 1 Similarities and differences between drug-induced torsade de pointes and drug-induced liver injury

	DITdP	DILI
Endpoint/biomarker	Surrogate, but well defined biomarker of risk (QT prolongation with specific thresholds)	Surrogate, but well defined biomarker of risk (transaminase elevation with specific thresholds)
Key mechanism	Largely described (dose-dependent hERG K+ channel inhibition)	Only partially understood (different hypotheses)
Dose-response relationship	Dose dependent (with only a few exceptions)	Idiosyncratic, although dose-dependence exists
Regulatory impact	Pre-clinical and clinical guidelines (pre-marketing)	Clinical guideline (pre-marketing)
Clinical impact	Significant (a leading cause of drug withdrawal worldwide)	Significant (a leading cause of drug withdrawal worldwide)
Predictivity of pre-clinical assays	Reasonably good (new models under investigation)	Sub-optimal (especially for in vivo models)
Predictivity of clinical studies	Good (thorough QT study), albeit imperfect	Good (Hy’s law), albeit imperfect
Role of genetics	Important (long QT syndrome)	Partially defined (only for some drugs)
Awareness (clinicians, regulators, drug developers, researchers)	Significant at all levels	Significant at some levels (drug developers, researchers)
Risk assessment tools (clinical)	Drug- and patient-related risk factors are well recognized (https://www.crediblemeds.org/); CDSSs are under implementation	Drug- and patient-related risk factors are only partially recognized (https://livertox.nlm.nih.gov/)
Causality assessment tools (clinical)	Not present, but the majority of TdP cases are drug induced (the so-called designated medical event); phenotype standardized	Specific, but challenging (several differential diagnoses)
Therapy	Magnesium sulphate, electrical cardioversion or isoproterenol (isoprenaline) or transvenous pacing (refractory TdP cases); removal or correction of precipitants, including drugs	No specific treatment other than drug discontinuation; liver transplantation may be required in acute liver failure cases

For details on DITdP[50-53]. CDSSs: Clinical decision support systems; DILI: Drug-induced liver injury; DITdP: Drug-induced torsade de pointes.