Idiosyncratic Drug-induced Liver Injury Research Articles

Hepatotoxicity of Antibiotics and Antifungals and Their Safe Use in Hepatic Impairment.

Idiosyncratic drug-induced liver injury (DILI) is a rare and unpredictable form of hepatotoxicity. While its clinical course is usually benign, cases leading to liver transplantation or death can occur. Based on modern prospective registries, antimicrobials including antibiotics and antifungals are frequently implicated as common causes. Amoxicillin-clavulanate ranks as the most common cause for DILI in the Western World. Although the absolute risk of hepatotoxicity of these agents is low, as their usage is quite high, it is not uncommon for practitioners to encounter liver injury following the initiation of antibiotic or antifungal therapy. In this review article, mechanisms of hepatoxicity are presented. The adverse hepatic effects of well-established antibiotic and antifungal agents are described, including their frequency, severity, and pattern of injury and their HLA risks. We also review the drug labeling and prescription guidance from regulatory bodies, with a focus on individuals with hepatic impairment.

The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury.

Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI.

Rechallenge in idiosyncratic drug-induced liver injury: An analysis of cases in two large prospective registries according to existing definitions

IntroductionData on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. MethodsCases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. ResultsOf 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. ConclusionsEpisodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

Compatibility with Fructus Ligustri Lucidi Effectively Mitigates Idiosyncratic Liver Injury of Epimedii Folium by Modulating NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome Activation

Abstract Background: Idiosyncratic drug-induced liver injury (IDILI) is a serious side effect of drugs, Epimedii Folium (EF) is unequivocally implicated in idiosyncratic liver injury onset, potentially due to its ability to perturb the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Fructus Ligustri Lucidi (FLL), a frequently used medicinal combination with EF, has not yet been investigated for its ability to ameliorate EF-associated hepatotoxicity. Aims and Objectives: Study on the mechanism of compatibility of FLL to alleviate liver injury caused by EF. Materials and Methods: Western blot was used to determine the expression of related proteins, ELISA was used to detect the secretion of related inflammatory factors IL-1β, IL-18, IL-6 and TNF-α, liver injury indexes were detected and liver pathological tissue staining was used to evaluate the liver injury. Results: Our results demonstrated that EF exerted a particular augmenting effect on the stimulation of the NLRP3 inflammasome mediated by nigericin or ATP, whereas FLL suppressed the NLRP3 inflammasome stimulation. Furthermore, an equal EF to FLL ratio significantly reduced the stimulatory effects of EF. Moreover, EF has the potential to induce hepatic injury and augment pro-inflammatory cytokine synthesis in rats subjected to LPS. However, when combined with FLL, the detrimental effects of EF were mitigated. Conclusion: FLL possesses the capacity to attenuate EF-associated hepatotoxicity by suppressing EF-triggered NLRP3 inflammasome activation. Thus, FLL holds promise for improving the clinical safety profile of EF, shedding light on the potential of compatibility and detoxification theories in traditional Chinese medicine.

Human Leucocyte Antigen Genetics in Idiosyncratic Drug-Induced Liver Injury with Evidence Based on the Roussel Uclaf Causality Assessment Method.

The human leucocyte antigen (HLA) allele variability was studied in cohorts of patients with idiosyncratic drug-induced liver injury (iDILI). Some reports showed an association between HLA genetics and iDILI, proposing HLA alleles as a potential risk factor for the liver injury. However, the strength of such assumptions heavily depends on the quality of the iDILI diagnosis, calling for a thorough analysis. Using the PubMed database and Google Science, a total of 25 reports of case series or single cases were retrieved using the terms HLA genes and iDILI. It turned out that in 10/25 reports (40%), HLA genetics were determined in iDILI cases, for which no causality assessment method (CAM) was used or a non-validated tool was applied, meaning the findings were based on subjective opinion, providing disputable results and hence not scoring individual key elements. By contrast, in most iDILI reports (60%), the Roussel Uclaf Causality Assessment Method (RUCAM) was applied, which is the diagnostic algorithm preferred worldwide to assess causality in iDILI cases and represents a quantitative, objective tool that has been well validated by both internal and external DILI experts. The RUCAM provided evidence-based results concerning liver injury by 1 drug class (antituberculotics + antiretrovirals) and 19 different drugs, comprising 900 iDILI cases. Among the top-ranking drugs were amoxicillin-clavulanate (290 cases, HLA A*02:01 or HLA A*30:02), followed by flucloxacillin (255 cases, HLA B*57:01), trimethoprim-sulfamethoxazole (86 cases, HLA B*14:01 or HLA B*14:02), methimazole (40 cases, HLA C*03:02), carbamazepine (29 cases, HLA A*31:01), and nitrofurantoin (26 cases, HLA A*33:01). In conclusion, the HLA genetics in 900 idiosyncratic drug-induced liver injury cases with evidence based on the RUCAM are available for studying the mechanistic steps leading to the injury, including metabolic factors through cytochrome P450 isoforms and processes that activate the innate immune system to the adaptive immune system.

Exploiting the predictive power of educated spheroids to detect immune-mediated idiosyncratic drug-induced liver injury: the case of troglitazone.

Idiosyncratic drug-induced liver injury (iDILI) is a major concern in drug development because its occurrence is unpredictable. Presently, iDILI prediction is a challenge, and cell toxicity is observed only at concentrations that are much higher than the therapeutic doses in preclinical models. Applying a proprietary cell educating technology, we developed a person-dependent spheroid system that contains autologous educated immune cells that can detect iDILI risk at therapeutic concentrations. Integrating this system into a high-throughput screening platform will help pharmaceutical companies accurately detect the iDILI risk of new molecules de-risking drug development.

Drug-induced liver injury (DILI) ascribed to non-steroidal anti-inflammatory drugs (NSAIDs) in the USA-Update with genetic correlations.

To describe patients with NSAID-DILI, including genetic factors associated with idiosyncratic DILI. In DILIN, subjects with presumed DILI are enrolled and followed for at least 6 months. Causality is adjudicated by a Delphic approach. HLA sequencing of multiethnic NSAID-DILI patients and HLA allele imputation of matching population controls were performed following overall, class and drug-based association analysis. Significant results were tested in a non-Hispanic White (NHW) case-control replication cohort. Between September 2004 and March 2022, causality was adjudicated in 2498, and 55 (41 [75%] women) were assessed as likely due to NSAIDs. Median age at onset was 55 y (range 22-83 y). Diclofenac was the causative drug in 29, celecoxib in 7, ibuprofen in 5, etodolac and meloxicam each in 4. Except for meloxicam and oxaprozin (n = 2), the liver injury was hepatocellular with median R 15-25. HLA-DRB1*04:03 and HLA-B*35:03 were significantly more frequent in NSAID-DILI patients than in non-NSAID DILI controls. Interestingly, 85% of the HLA-DRB1*04:03 carriers developed DILI due to the use of acetic acid derivative NSAIDs, supporting the hypothesis that HLA-DRB1*04:03 could be a drug and/or class risk factor. HLA-B*35:03 but not HLA-DRB1*04:03 association was confirmed in the independent NHW replication cohort, which was largely driven by diclofenac. Despite prevalent use, NSAID-DILI is infrequent in the United States. Diclofenac is the most commonly implicated, and adherence to warnings of risk and close observation are recommended. The increased frequency of HLA-B*35:03 and DRB1*04:03, driven by diclofenac, suggests the importance of immune-mediated responses.

Integrated analysis of metabolomic and gut microbiota reveals idiosyncratic drug-induced liver injury resulting from the combined administration of bavachin and icariside II

Background: Xianlinggubao (XLGB), a widely used Chinese patent medicine for osteoporosis, has garnered significant attention due to its potential to cause liver injury. The constituents Psoraleae Fructus (PF) and Epimedii Folium (EF) present in XLGB have been implicated in causing idiosyncratic drug-induced liver injury (IDILI). However, the specific components and mechanisms underlying liver injury related to these tonics remain elusive. This study aimed to establish that the combination of bavachin, the primary active compound in PF, and icariside II, the main active compound in EF, induces IDILI in a TNF-α-mediated mouse model. Methods: To assess the impact of bavachin and icariside II on the liver in the presence of TNF-α immune stress, an animal model was developed. LC-MS/MS metabolomics technology was employed to identify biomarkers associated with TNF-α-induced IDILI and the combination of bavachin and icariside II. Additionally, 16S rRNA high-throughput sequencing technology was utilized to explore changes in the species composition and relative abundance of gut microbiota at the genus level. Spearman correlation analysis was conducted to unveil the relationship between gut microbiota and in vivo metabolites. Results: The study observed that the combined administration of bavachin and icariside II induced hepatic injury in the TNF-α-mediated susceptibility mouse model of IDILI. Under TNF-α stimulation, there was an elevation in methylcarbamyl PAF, LPE (22:5/0:0), and PC (O-1:0/O-16:0) levels in mouse livers following bavachin and icariside II administration, while Gly-Tyr, Leu-Gly, and Trp-Ser levels decreased. These differentially expressed metabolites associated with liver injury were predominantly enriched in metabolic pathways such as sphingolipid metabolism, sphingolipid signaling pathway, and necroptosis. Noteworthy, the gut of mice with liver injury induced by the bavachin and icariside II combination exhibited a significant increase in Bacteroides and Desulfovibrionaceae abundance. Correlation analysis revealed a positive association between Bacteroidaceae and Desulfovibrionaceae with methylcarbamoyl PAF and indole-3-acetate, while a negative correlation was observed with Gly-Tyr, Leu-Gly, and Trp-Ser. Conclusions: These findings demonstrated that the combination of bavachin and icariside II increased the risk of IDILI in vivo, providing a promising scientific basis for understanding the component basis of IDILI resulting from the compatibility of EF and PF. http://links.lww.com/AHM/A97

Pseudo-targeted metabolomics study of immune stress-mediated idiosyncratic liver injury induced by synergistic effects of bavachin and epimedin B

Chinese patent medicine preparations containing Epimedii Folium and Psoraleae Fructus have been associated with the occurrence of idiosyncratic drug-induced liver injury(IDILI). However, the specific toxic biomarkers and mechanisms underlying these effects remain unclear. This study aimed to comprehensively assess the impact of bavachin and epimedin B, two principal consti-tuents found in Psoraleae Fructus and Epimedii Folium, on an IDILI model induced by tumor necrosis factor-α(TNF-α) treatment, both in vitro and in vivo. To evaluate the extent of liver injury, various parameters were assessed. Lactate dehydrogenase(LDH) release in the cell culture supernatant, as well as the levels of alanine aminotransferase(ALT) and aspartate transaminase(AST) in mouse plasma were measured. Additionally, histological analysis employing hematoxylin-eosin staining was performed to observe liver tissue changes indicative of the severity of liver injury. Furthermore, a pseudo-targeted metabolomics approach was employed, followed by multivariate analysis, to identify differential metabolites. These identified metabolites were subsequently subjected to Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. The results showed that at the cellular level, after 2 hours of TNF-α stimulation, bavachin significantly increased the release of LDH in HepG2 cells compared to the normal group and the group treated alone; after the combination of bavachin and epimedin B, the release of LDH further significantly increased on the original basis. Similarly, although the individual or combination treatments of bavachin and epimedin B did not induce liver injury in normal mice, the combination of both drugs induced marked liver injury in TNF-α treated mice, leading to a significant elevation in plasma AST and ALT levels and substantial infiltration of inflammatory immune cells in the liver tissue. Pseudo-targeted metabolomics analysis identified seven common differential metabolites. Among these, D-glucosamine-6-phosphate, N1-methyl-2-pyridone-5-carboxamide, 17beta-nitro-5a-androstane, irisolidone-7-O-glucuronide, and N-(1-deoxy-1-fructosyl) valine emerged as potential biomarkers, with an area under the curve(AUC) exceeding 0.9. Furthermore, our results suggest that the metabolism of nicotinic acid and nicotinamide, as well as the linoleic acid metabolic pathway, may play pivotal roles in bavachin and epimedin B-induced IDILI. In conclusion, within an immune-stressed environment mediated by TNF-α, bavachin and epimedin B appear to induce IDILI through disruptions in metabolic processes.

Efficacy and safety of bicyclol for treating patients with antituberculosis drug-induced liver injury.

BACKGROUND: Bicyclol was used for treating idiosyncratic acute drug-induced liver injury (DILI) in a phase II trial. This study was aimed at evaluating the efficacy and safety of bicyclol 25 and 50 mg thrice a day (TID) for treating acute DILI caused by anti-TB drugs in the light of the trial results.METHODS: We analysed clinical data of patients with TB drug-induced DILI in the trial database. The primary endpoint was reduction in serum alanine aminotransferase (ALT) levels after 4 weeks of treatment compared to baseline.RESULTS: Overall, 148 patients were included, with respectively 48, 52 and 48 patients included in the control (456 mg polyene phosphatidylcholine TID), high-dose (50 mg bicyclol TID) and low-dose (25 mg bicyclol TID) groups. ALT levels decreased by respectively â-"149.0 (IQR â-"299.3 to â-"98.3 (), â-"225.5 (IQR â-"309.3 to â-"181.8 ) and â-"242.5 (IQR â-"364.8 to â-"153.8) U/L in the control, high-dose and low-dose groups (P < 0.001). The ALT normalisation rates at weeks 1, 2, 4, 6 and 8 were higher in the high- and low-dose groups, while adverse events and serious adverse events were similar across groups.CONCLUSIONS: Bicyclol (25 and 50 mg TID) is effective and safe in treating anti-TB DILI, and bicyclol 50 mg TID showed higher efficacy.

Prior drug allergies are associated with worse outcome in patients with idiosyncratic drug-induced liver injury: A machine learning approach for risk stratification

The impact of prior drug allergies (PDA) on the clinical features and outcomes of patients who develop idiosyncratic drug-induced liver injury (DILI) is largely unknown. We aimed to assess the clinical presentation and outcomes of DILI patients based on the presence or absence of PDA and explore the association between culprit drugs responsible for DILI and allergy. We analysed a well-vetted cohort of DILI cases enrolled from the Spanish DILI Registry. Bootstrap-enhanced least absolute shrinkage operator procedure was used in variable selection, and a multivariable logistic model was fitted to predict poor outcomes in DILI. Of 912 cases with a first episode of DILI, 61 (6.7%) had documented PDA. Patients with PDA were older (p = 0.009), had higher aspartate aminotransferase (AST) levels (p = 0.047), lower platelet count (p = 0.011) and higher liver-related mortality than those without a history of drug allergies (11% vs. 1.6%, p < 0.001). Penicillin was the most common drug associated with PDA in DILI patients (32%). A model including PDA, nR-based type of liver injury, female sex, AST, total bilirubin, and platelet count showed an excellent performance in predicting poor outcome in patients from the Spanish DILI Registry (area under the ROC curve [AUC] 0.887; 95% confidence interval [CI] 0.794 – 0.981) and the LATINDILI Network (AUC 0.932; 95% CI 0.884 – 0.981). Patients with suspected DILI should be screened for PDA as they would require a close monitoring for early detection of worsening clinical course.

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

Human liver organoid models for assessment of drug toxicity at the preclinical stage.

The hepatotoxicity of drugs is one of the leading causes of drug withdrawal from the pharmaceutical market and high drug attrition rates. Currently, the commonly used hepatocyte models include conventional hepatic cell lines and animal models, which cannot mimic human drug-induced liver injury (DILI) due to poorly defined dose-response relationships and/or lack of human-specific mechanisms of toxicity. In comparison to 2D culture systems from different cell sources such as primary human hepatocytes and hepatomas,, 3D organoids derived from an inducible pluripotent stem cell (iPSC) or adult stem cells are promising accurate models to mimic organ behavior with a higher level of complexity and functionality owing to their ability to self-renewal. Meanwhile, the heterogeneous cell composition of the organoids enables metabolic and functional zonation of hepatic lobule important in drug detoxification and has the ability to mimic idiosyncratic DILI as well. Organoids having higher drug-metabolizing enzyme capacities can culture long-term and be combined with microfluidic-based technologies such as organ-on-chips for a more precise representation of human susceptibility to drug response in a high-throughput manner. However, there are numerous limitations to be considered about this technology, such as enough maturation, differences between protocols and high cost. Herein, we first reviewed the current preclinical DILI assessment tools and looked at the organoid technology with respect to in vitro detoxification capacities. Then we discussed the clinically applicable DILI assessment markers and the importance of liver zonation in the next generation organoid-based DILI models.

Idiosyncratic DILI: Immunology in Cases with Evidence Based on RUCAM

Idiosyncratic DILI: Immunology in Cases with Evidence Based on RUCAM

Bavachin combined with epimedin B induce idiosyncratic liver injury under immunological stress conditions

Reports on Chinese patent medicines preparations containing Epimedii Folium (EF) and Psoraleae Fructus (PF) resulting in idiosyncratic drug-induced liver injury (IDILI) have received widespread attention. Previous studies have shown that bavachin and epimedin B—two active ingredients derived from both EF and PF—are potential components associated with IDILI, but the underlying mechanism remains unclear. We evaluated bavachin and epimedin B-induced IDILI under TNF-α-mediated immunological stress conditions and generated liver lipid metabolism profiles using lipidomics and multivariate statistical analysis. We next applied transcriptomics to identify the differential gene expression on the transcription level. Our results showed that co-exposure to bavachin, epimedin B under immunological stress conditions resulted in obvious liver injury. The differential metabolites screened in our study were closely related to the immune homeostasis of the liver. Sixteen differentially expressed genes were found, Zc3h6 and R3hdml were upregulated, while Sumo2, Cd74, Banp, Oas3, Oas2, Gbp8, Slfn8, Gbp2b, Serpina3g, Zbtb40, H2-Ab1, Osgin1, Tgtp1 and Hspa1b were all downregulated. These differentially expressed genes were associated with biological processes concerning metabolic process and immune system process. Further integrative analysis indicated that bavachin combined with epimedin B affected genes that were not only related to immune system processes, but also to lipid metabolism. Ultimately, this led to an imbalance in the immune microenvironment in the liver and may have contributed to the observed liver injury.

Metabolomic Analysis of Pediatric Patients with Idiosyncratic Drug-Induced Liver Injury According to the Updated RUCAM.

Hepatotoxicity, a common adverse drug effect, has been extensively studied in adult patients. However, it is equally important to investigate this condition in pediatric patients to develop personalized treatment strategies for children. This study aimed to identify plasma biomarkers that characterize hepatotoxicity in pediatric patients through an observational case-control study. Metabolomic analysis was conducted on 55 pediatric patients with xenobiotic liver toxicity and 88 healthy controls. The results revealed clear differences between the two groups. Several metabolites, including hydroxydecanoylcarnitine, octanoylcarnitine, lysophosphatidylcholine, glycocholic acid, and taurocholic acid, were identified as potential biomarkers (area under the curve: 0.817; 95% confidence interval: 0.696-0.913). Pathway analysis indicated involvement of primary bile acid biosynthesis and the metabolism of taurine and hypotaurine (p < 0.05). The findings from untargeted metabolomic analysis demonstrated an increase in bile acids in children with hepatotoxicity. The accumulation of cytotoxic bile acids should be further investigated to elucidate the role of these metabolites in drug-induced liver injury.

Investigation of synergistic induction of idiosyncratic drug-induced liver injury by Bavachin and Icariin under immunological stress conditions using pseudotargeted metabonomics

Investigation of synergistic induction of idiosyncratic drug-induced liver injury by Bavachin and Icariin under immunological stress conditions using pseudotargeted metabonomics

Idiosyncratic DILI and RUCAM under One Hat: The Global View

Drugs are prescribed worldwide to treat diseases but with the risk of idiosyncratic drug-induced liver injury (iDILI). The most important difficulty is how best to establish causality. Based on strong evidence and principles of artificial intelligence (AI) to solve complex processes through quantitative algorithms using scored elements, progress was achieved with the Roussel Uclaf Causality Assessment Method (RUCAM) in its original and updated versions, often viewed now as the gold standard. As a highly appreciated diagnostic algorithm, the RUCAM is in global use with around 100,000 iDILI cases published worldwide using RUCAM to assess causality, largely outperforming any other specific causality assessment tool in terms of case numbers. Consequently, the RUCAM helps to establish a list of top-ranking drugs worldwide implicated in iDILI and to describe clinical and mechanistic features of iDILI caused by various drugs. In addition, the RUCAM was recently applied in iDILI cases of patients treated for coronavirus disease 2019 (COVID-19) infections or cancer patients treated with immune checkpoint inhibitors (ICIs), as well as in the search for new treatment options with conventional drugs in iDILI. Analyses of RUCAM-based iDILI cases are helpful to support pathogenetic steps like immune reactions, genetic predisposition as evidenced by human leucocyte antigens (HLA) genotypes for selected drugs, and the role of the gut microbiome. To achieve consistency in data collection, analysis, and specific clinical and pathogenetic presentation, researchers, regulatory agencies, and pharmaceutical firms should place iDILI and the updated RUCAM as the causality tool under one and the same hat in review articles and clinical guidelines for the diagnosis and treatment of iDILI.

An original donor-dependent spheroid system for the prediction of idiosyncratic drug-induced liver injury risk

One major drawback of preclinical models to test drug-induced liver injury (DILI) is their inability to predict the interindividual difference of DILI effect in a population. Consequently, a high number of molecules that passed preclinical phases, fail clinical trials, and many FDA-approved drugs were removed from the market due to idiosyncratic DILI. We use a proprietary-depleted human serum-based cell educating technology to generate donor-dependent spheroids with distinct morphology and functionality. We demonstrate that educated spheroids could capture the large variations in susceptibility to drug-induced liver injury between donors. We show that the model could predict clinical apparent DILI risk with a high specificity and sensitivity. We provide evidence that the model could address non-genetic factor-associated DILI risk and severity such as age or sex. Our study supports the benefit of using donor-dependent educated spheroids for hepatotoxicity evaluation in preclinical phase or in an exploratory study clinical trial phase 2 to provide a robust safety profile to a drug.

Patients with naproxen-induced liver injury display T-cell memory responses toward an oxidative (S)-O-desmethyl naproxen metabolite but not the acyl glucuronide.

Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (IBU) and naproxen (NAP) is associated with idiosyncratic drug-induced liver injury (DILI). Carboxylate bioactivation into reactive metabolites (e.g., acyl glucuronides, AG) and resulting T-cell activation is hypothesized as causal for this adverse event. However, conclusive evidence supporting this is lacking. In this work, we identify CD4+ and CD8+ T-cell hepatic infiltration in a biopsy from an IBU DILI patient. Lymphocyte transformation test and IFN-γ ELIspot, conducted on peripheral blood mononuclear cells (PBMCs) of patients with NAP-DILI, were used to explore drug-specific T-cell activation. T-cell clones (TCC) were generated and tested for drug specificity, phenotype/function, and pathways of T-cell activation. Cells were exposed to NAP, its oxidative metabolite 6-O-desmethyl NAP (DM-NAP), its AG or synthesized NAP-AG human-serum albumin adducts (NAP-AG adduct). CD4+ and CD8+ T-cells from patients expressing a range of different Vβ receptors were stimulated to proliferate and secrete IFN-γ and IL-22 when exposed to DM-NAP, but not NAP, NAP-AG or the NAP-AG adduct. Activation of the CD4+ TCC was HLA-DQ-restricted and dependent on antigen presenting cells (APC); most TCC were activated with DM-NAP-pulsed APC, while fixation of APC blocked the T-cell response. Cross-reactivity was not observed with structurally-related drugs. Our results confirm hepatic T-cell infiltrations in NSAID-induced DILI, and show a T-cell memory response toward DM-NAP indicating an immune-mediated basis for the adverse event. Whilst bioactivation at the carboxylate group is widely hypothesized to be pathogenic for NSAID associated DILI, we found no evidence of this with NAP.