About this Research Topic
Drug induced liver injury (DILI) is a rare but complex disease requiring clinical attention by all physicians caring for patients. This Research Topic focuses on clinical and mechanistic considerations of idiosyncratic DILI (iDILI) commonly caused by drugs at mostly recommended daily doses, as opposed to intrinsic DILI due to drugs such as acetaminophen (paracetamol) when taken in intentional or inadvertent overdoses. Idiosyncratic DILI presents as a multifaceted disease, which may mimic all non-drug causes of acute and chronic liver disease. Several key aspects of drug induced hepatotoxicity remain under study:
(1) As iDILI is rare, in contrast to other liver diseases such as alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), its diagnosis requires a high index of suspicion;
(2) Causality assessment methods (CAMs) are available, including the most commonly used RUCAM (Roussel Uclaf Causality Assessment Method) and rarely applied global introspection methods;
(3) Several global DILI registries are operational to better define the epidemiology of various drugs, including herbal and dietary supplements;
(4) iDILI cases evaluated by a robust CAM are best suited to characterize their clinical features and to help establish valid diagnostic biomarkers;
(5) The exact mechanistic causes of iDILI are difficult to describe due to the lack of appropriate animal models, which are available for intrinsic DILI;
(6) DILI affects not only hepatocytes but also non-parenchymal cells such as Kupffer cells, stellate cells, and sinusoidal endothelial cells with their signaling mediators (interleukins, interferons, and growth factors), which initiate and possibly perpetuate liver injury;
(7) The hepatic microsomal cytochrome P450 (CYP) system metabolizes most drugs to non-toxic products, but occasionally to toxic metabolites and/or reactive oxygen species (ROS), a process called microsomal (oxidative) stress;
(8) Other mechanistic aspects include the formation of haptens on membrane cells and the activation of the innate and adaptive immune systems which can lead to drug-induced autoimmune liver injury;
(9) drugs may modulate the intestinal microbiome, stimulating the production of endotoxins and providing new insights into the gut-liver axis;
(10) Under discussion are circadian rhythms of CYP and DILI, as well as SIRTUIN1 (SIRT1) influencing injury;
(11) Risk factors such as HLA polymorphisms, co-medications, daily drug dose, drug metabolism characteristics, lipophilicity, pre-existing liver disease, and obesity (often with NAFLD) are actively being studied;
(12) The early recognition of DILI in clinical trials remains challenging, and various biomarkers (including exosomes in the blood containing CYPs) are under study for clinical use, although most are as yet poorly validated and do not allow a clear differentiation of DILI from other liver diseases;
(13) New data on treating DILI remain limited; while NAC (N-acetyl cysteine) is highly effective in patients with acetaminophen toxicity, its role in iDILI remains limited.
Clearly, more study is needed to help us understand these and other aspects of detecting and managing DILI in the clinic as well as in drug development, and is the focus of this Research Topic. We hope to receive many manuscripts with balanced views that are refreshing and stimulating, aimed at these controversial topics and ask that all articles have a focus on the recent developments in this field with actual references limited to the last 5 years and historical-type appraisals excluded.
(1) As iDILI is rare, in contrast to other liver diseases such as alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), its diagnosis requires a high index of suspicion;
(2) Causality assessment methods (CAMs) are available, including the most commonly used RUCAM (Roussel Uclaf Causality Assessment Method) and rarely applied global introspection methods;
(3) Several global DILI registries are operational to better define the epidemiology of various drugs, including herbal and dietary supplements;
(4) iDILI cases evaluated by a robust CAM are best suited to characterize their clinical features and to help establish valid diagnostic biomarkers;
(5) The exact mechanistic causes of iDILI are difficult to describe due to the lack of appropriate animal models, which are available for intrinsic DILI;
(6) DILI affects not only hepatocytes but also non-parenchymal cells such as Kupffer cells, stellate cells, and sinusoidal endothelial cells with their signaling mediators (interleukins, interferons, and growth factors), which initiate and possibly perpetuate liver injury;
(7) The hepatic microsomal cytochrome P450 (CYP) system metabolizes most drugs to non-toxic products, but occasionally to toxic metabolites and/or reactive oxygen species (ROS), a process called microsomal (oxidative) stress;
(8) Other mechanistic aspects include the formation of haptens on membrane cells and the activation of the innate and adaptive immune systems which can lead to drug-induced autoimmune liver injury;
(9) drugs may modulate the intestinal microbiome, stimulating the production of endotoxins and providing new insights into the gut-liver axis;
(10) Under discussion are circadian rhythms of CYP and DILI, as well as SIRTUIN1 (SIRT1) influencing injury;
(11) Risk factors such as HLA polymorphisms, co-medications, daily drug dose, drug metabolism characteristics, lipophilicity, pre-existing liver disease, and obesity (often with NAFLD) are actively being studied;
(12) The early recognition of DILI in clinical trials remains challenging, and various biomarkers (including exosomes in the blood containing CYPs) are under study for clinical use, although most are as yet poorly validated and do not allow a clear differentiation of DILI from other liver diseases;
(13) New data on treating DILI remain limited; while NAC (N-acetyl cysteine) is highly effective in patients with acetaminophen toxicity, its role in iDILI remains limited.
Clearly, more study is needed to help us understand these and other aspects of detecting and managing DILI in the clinic as well as in drug development, and is the focus of this Research Topic. We hope to receive many manuscripts with balanced views that are refreshing and stimulating, aimed at these controversial topics and ask that all articles have a focus on the recent developments in this field with actual references limited to the last 5 years and historical-type appraisals excluded.
Keywords: Drug induced liver injury, drug hepatotoxicity, Diagnostic biomarkers, Causality assessment methods, Roussel Uclaf Causality Assessment Method
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