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Clinical and mechanistic considerations in idiosyncratic drug-induced liver injury (iDILI) remain challenging topics when they are derived from mere case narratives or iDILI cases without valid diagnosis. To overcome these issues, attempts should be made on pathogenetic aspects based on published clinical iDILI cases firmly diagnosed by the original RUCAM (Roussel Uclaf Causality Assessment Method) or the RUCAM version updated in 2016. Analysis of RUCAM-based iDILI cases allowed for evaluating immune and genetic data obtained from the serum and the liver of affected patients. For instance, strong evidence for immune reactions in the liver of patients with RUCAM-based iDILI was provided by the detection of serum anti-CYP 2E1 due to drugs like volatile anesthetics sevoflurane and desflurane, partially associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates that form protein adducts and may generate reactive oxygen species (ROS). This is accompanied by production of anti-TFA antibodies detected in the serum of these patients. Other RUCAM-based studies on serum ANA (anti-nuclear antibodies) and SMA (anti-smooth muscle antibodies) associated with AIDILI (autoimmune DILI) syn DIAIH (drug-induced autoimmune hepatitis) provide additional evidence of immunological reactions with monocytes as one of several promoting immune cells. In addition, in the blood plasma of patients, mediators like the cytokines IL-22, IL-22 binding protein (IL-22BP), IL-6, IL-10, IL 12p70, IL-17A, IL-23, IP-10, or chemokines such as CD206 and sCD163 were found in DILI due to anti-tuberculosis drugs as ascertained by the prospective updated RUCAM, which scored a high causality. RUCAM-based analysis also provided compelling evidence of genetic factors such as HLA (human leucocyte antigen) alleles contributing to initiate iDILI by a few drugs. In conclusion, analysis of published RUCAM-based iDILI cases provided firm evidence of immune and genetic processes involved in iDILI caused by specific drugs.

One of the most difficult challenges in clinical hepatology is the diagnosis of a drug-induced liver injury (DILI). The timing of the events, exclusion of alternative causes, and taking into account the clinical context should be systematically assessed and scored in a transparent manner. RUCAM (Roussel Uclaf Causality Assessment Method) is a well-established diagnostic algorithm and scale to assess causality in patients with suspected DILI. First published in 1993 and updated in 2016, RUCAM is now the worldwide most commonly used causality assessment method (CAM) for DILI. The following manuscript highlights the recent implementation of RUCAM around the world, by reviewing the literature for publications that utilized RUCAM, and provides a review of \"best practices\" for the use of RUCAM in cases of suspected DILI. The worldwide appreciation of RUCAM is substantiated by the current analysis of 46,266 DILI cases, all tested for causality using RUCAM. These cases derived from 31 reports published from 2014 to early 2019. Their first authors came from 10 countries, with China on top, followed by the US, and Germany on the third rank. Importantly, all RUCAM-based DILI reports were published in high profile journals. Many other reports were published earlier from 1993 up to 2013 in support of RUCAM. Although most of the studies were of high quality, the current case analysis revealed shortcomings in few studies, not at the level of RUCAM itself but rather associated with the work of the users. To ensure in future DILI cases a better performance by the users, a list of essential elements is proposed. As an example, all suspected DILI cases should be evaluated 1) by the updated RUCAM to facilitate result comparisons, 2) according to a prospective study protocol to ensure complete data sets, 3) after exclusion of cases with herb induced liver injury (HILI) from a DILI cohort to prevent confounding variables, and 4) according to inclusion of DILI cases with RUCAM-based causality gradings of highly probable or probable, in order to increase the specificity of the results. In conclusion, RUCAM benefits from its high appreciation and performs well provided the users adhere to published recommendations to prevent confounding variability.

Background Drug-induced liver injury (DILI) is a significant adverse drug reaction, manifesting through a range of clinical presentations from mild liver enzyme to acute liver failure. Main text This review provides a comprehensive overview of DILI, emphasizing the differences between intrinsic and idiosyncratic DILI. The underlying molecular mechanisms, like mitochondrial dysfunction, oxidative stress, and immune-mediated responses, are discussed in detail. The epidemiology of DILI is explored through various retrospective and prospective studies, highlighting the role of specific medications and individual susceptibility factors. The review also addresses the challenges in diagnosing DILI and the impact on drug development and clinical practice. Conclusion DILI poses a significant clinical threat due to its potential for causing acute liver failure and associated mortality. To improve patient outcomes, further research is crucial to identify effective therapeutic interventions.

The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The ‘MIP-DILI’ project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI.

Introduction: Apart from cessation of the implicated agent leading to drug-induced liver injury (DILI), there is no standard therapy for DILI. Corticosteroids have been used in DILI, although their efficacy is unclear. Published data showed either beneficial effects or no improvement associated with steroid therapy. The aim of the current study was to perform a systematic review of the role of corticosteroids in the treatment of DILI. Methods: A search was performed in PubMed, searching for the terms: “corticosteroids” and “drug-induced liver injury”. Observation studies were included, but case reports excluded. Results: A total of 24 papers were retrieved. Most of these were observational studies on the effects of corticosteroids in moderate/severe DILI (n = 8), reports on the corticosteroid treatment in patients with drug-induced autoimmune hepatitis (DI-AIH) (n = 5), and effects of corticosteroids in drug-induced fulminant acute liver failure (ALF, n = 2). Furthermore, treatment of corticosteroids in patients with liver injury due to check point inhibitors (CPIs) was addressed in nine studies. In moderate/severe DILI, six out of eight studies suggested steroid treatment to be beneficial, whereas two studies showed negative results. All five observational studies on the effects of corticosteroids in DI-AIH showed good therapeutic response with rapid and long lasting effects after discontinuation of corticosteroids and without evidence of relapse. Steroid therapy was not associated with improved overall survival in patients with drug-induced fulminant ALF. CPIs-induced liver injury was found to improve spontaneously in 33–50% without corticosteroids, and the rate of patients who were treated responded to steroids in 33–100% (mean 72%). Conclusions: The majority of studies analyzing the effects of corticosteroids in moderate/severe DILI have demonstrated beneficial effects. However, this was not the case in drug-induced fulminant ALF. Patients with DI-AIH had an excellent response to corticosteroids. The majority of those with CPIs-induced liver injury responded to corticosteroids; however, patients without treatment usually recovered spontaneously. The observational design and comparison with historical controls in these studies makes it very difficult to draw conclusions on the efficacy of corticosteroids in DILI. Therefore, there is a strong need for a randomized controlled trial to properly assess the role of corticosteroids in DILI.

The diagnosis of drug-induced liver injury (DILI) is a challenging problem, often confounded by incomplete clinical information and the difficulty of eliciting exposure to herbal products, over-the-counter agents and toxins. The task is further rendered difficult on biopsy, as drugs can mimic all the patterns found in primary liver disease. Acute hepatitis, with or without cholestasis, is the most common histological pattern of DILI, and drugs such as acetaminophen are the leading causes of acute liver failure. Most cases of DILI resolve on discontinuation of the drug, but recovery can take months or rarely the disease can progress despite drug withdrawal. Drugs such as methotrexate can lead to chronic hepatitis and cirrhosis, while others such as minocycline, nitrofurantoin and methyldopa are implicated in autoimmune hepatitis. Prolonged cholestasis and ductopenia resembling primary chronic biliary disease can occur. Drug-induced steatohepatitis is also an uncommon pattern, but is well described with drugs such as amiodarone and irinotecan. In the presence of risk factors such as obesity and diabetes, some drugs such as tamoxifen, oestrogens and nifedipine can precipitate or exacerbate steatohepatitis. Other observed patterns include granulomatous hepatitis, vascular injury (eg, sinusoidal obstruction syndrome), Ito cell lipidosis and neoplasms (eg, adenomas).

Drug-induced liver injury remains a concern during drug treatment and development. There is an urgent need for improved mechanistic understanding and prediction of DILI liabilities using in vitro approaches. We have established and characterized a panel of liver cell models containing mechanism-based fluorescent protein toxicity pathway reporters to quantitatively assess the dynamics of cellular stress response pathway activation at the single cell level using automated live cell imaging. We have systematically evaluated the application of four key adaptive stress pathway reporters for the prediction of DILI liability: SRXN1-GFP (oxidative stress), CHOP-GFP (ER stress/UPR response), p21 (p53-mediated DNA damage-related response) and ICAM1 (NF-κB-mediated inflammatory signaling). 118 FDA-labeled drugs in five human exposure relevant concentrations were evaluated for reporter activation using live cell confocal imaging. Quantitative data analysis revealed activation of single or multiple reporters by most drugs in a concentration and time dependent manner. Hierarchical clustering of time course dynamics and refined single cell analysis allowed the allusion of key events in DILI liability. Concentration response modeling was performed to calculate benchmark concentrations (BMCs). Extracted temporal dynamic parameters and BMCs were used to assess the predictive power of sub-lethal adaptive stress pathway activation. Although cellular adaptive responses were activated by non-DILI and severe-DILI compounds alike, dynamic behavior and lower BMCs of pathway activation were sufficiently distinct between these compound classes. The high-level detailed temporal- and concentration-dependent evaluation of the dynamics of adaptive stress pathway activation adds to the overall understanding and prediction of drug-induced liver liabilities.

Drug-induced liver injury (DILI) remains the most common cause of acute liver failure (ALF) in the western world. Excluding paracetamol overdose, nearly all DILI encountered in the clinical setting is idiosyncratic in nature because affected individuals represent only a small proportion of those treated with such drugs. In many cases, the mechanism for idiosyncrasy is immune-mediation and is often identified by genetic risk determined by human leukocyte antigen variants. In the absence of diagnostic tests and/or biomarkers, the diagnosis of DILI requires a high index of suspicion after diligently excluding other causes of abnormal liver tests. Antibiotics are the class of drugs most frequently associated with idiosyncratic DILI, although recent studies indicate that herbal and dietary supplements are an increasingly recognised cause. It is imperative that upon development of DILI the culprit drug be discontinued, especially in the presence of elevated transaminases (aspartate aminotransferase/alanine aminotransferase ratio ≥5 times the upper limit of normal) and/or jaundice. Risk factors for the development ALF include hepatocellular DILI and female gender, the treatment being supportive with some benefit of N-acetylcysteine in the early stages. In view of the poor transplant-free survival in idiosyncratic DILI, early consideration for liver transplant is mandatory.

Drug-induced liver injury (DILI) remains a challenge in clinical practice and is still a diagnosis of exclusion. Although it has a low incidence amongst the general population, DILI accounts for most cases of acute liver failure with a fatality rate of up to 50%. While multiple mechanisms of DILI have been postulated, there is no clear causal relationship between drugs, risk factors and mechanisms of DILI. Current best practice relies on a combination of high clinical suspicion, thorough clinical history of risk factors and timeline, and extensive hepatological investigations as supported by the international Roussel Uclaf Causality Assessment Method criteria, the latter considered a key diagnostic algorithm for DILI. This review focuses on DILI classification, risk factors, clinical evaluation, future biomarkers and management, with the aim of facilitating physicians to correctly identify DILI early in presentation.