Regular Consumption of Green Tea as an Element of Diet Therapy in Drug-Induced Liver Injury (DILI).

The liver is a highly metabolically active organ, and one of the causes of its dysfunction is the damage caused by drugs and their metabolites as well as dietary supplements and herbal preparations. A common feature of such damage is drugs, which allows it to be defined as drug-induced liver injury (DILI). In this review, we analysed available research findings in the global literature regarding the effects of green tea and/or its phenolic compounds on liver function in the context of protective action during prolonged exposure to xenobiotics. We focused on the direct detoxifying action of epigallocatechin gallate (EGCG) in the liver, the impact of EGCG on gut microbiota, and the influence of microbiota on liver health. We used 127 scientific research publications published between 2014 and 2024. Improving the effectiveness of DILI detection is essential to enhance the safety of patients at risk of liver damage and to develop methods for assessing the potential hepatotoxicity of a drug during the research phase. Often, drugs cannot be eliminated, but appropriate nutrition can strengthen the body and liver, which may mitigate adverse changes resulting from DILI. Polyphenols are promising owing to their strong antioxidant and anti-inflammatory properties as well as their prebiotic effects. Notably, EGCG is found in green tea. The results of the studies presented by various authors are very promising, although not without uncertainties. Therefore, future research should focus on elucidating the therapeutic and preventive mechanisms of polyphenols in the context of liver health through the functioning of gut microbiota affecting overall health, with particular emphasis on epigenetic pathways.

Intestinal deguelin drives resistance to acetaminophen-induced hepatotoxicity in female mice.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI), with gender-specific differences in susceptibility. However, the mechanism underlying this phenomenon remains unclear. Our study reveals that the gender-specific differences in susceptibility to APAP-induced hepatotoxicity are due to differences in the gut microbiota. Through microbial multi-omics and cultivation, we observed increased gut microbiota-derived deguelin content in both women and female mice. Administration of deguelin was capable of alleviating hepatotoxicity in APAP-treated male mice, and this protective effect was associated with the inhibition of hepatocyte oxidative stress. Mechanistically, deguelin reduced the expression of thyrotropin receptor (TSHR) in hepatocytes with APAP treatment through direct interaction. Pharmacologic suppression of TSHR expression using ML224 significantly increased hepatic glutathione (GSH) in APAP-treated male mice. These findings suggest that gut microbiota-derived deguelin plays a crucial role in reducing APAP-induced hepatotoxicity in female mice, offering new insights into therapeutic strategies for DILI.

Triptolide-induced acute liver injury and its mechanism with estradiol in regulating macrophage-mediated inflammation and hepatocyte function.

Triptolide (TP), a diterpene from Tripterygium wilfordii, exhibits potent anti-inflammatory, immunomodulatory, and antitumor properties but is limited by severe hepatotoxicity. This study investigates sex differences in TP-induced liver injury and the protective role of estradiol (E2) in modulating macrophage-mediated inflammation and hepatocyte function. An acute liver injury model was established in male and female Balb/c mice using intraperitoneal TP injection. Liver function tests, histological analyses, and immunohistochemical staining were performed. THP-1 macrophage and various liver cell lines were used to study the effects of TP and E2 in vitro. Virtual screening, molecular docking, luciferase assays, and qPCR were employed to identify potential targets and elucidate underlying mechanisms. TP caused more severe liver injury in female mice, evidenced by increased liver indices, aspartate aminotransferase (AST) levels, and extensive hepatocyte damage. TP promoted M1 macrophage polarization, enhancing inflammation, particularly in female mice. E2 mitigated TP-induced inflammatory responses by downregulating pro-inflammatory cytokines and macrophage activation markers. Molecular docking and functional assays identified Nuclear receptor subfamily 1 group I member 2 (NR1I2) as a key target mediating the protective effects of E2. The study highlights significant sex differences in TP-induced hepatotoxicity, with females being more susceptible. E2 exerts protective effects against TP-induced liver injury by modulating immune responses, presenting a potential therapeutic approach to mitigate drug-induced liver injury (DILI). Further research on NR1I2 could lead to targeted therapies for reducing drug-induced liver damage.

Acute Liver Failure Induced by Provitalize: A Menopause Supplement Concocted From Herbs & Probiotics.

Drug-induced liver injury is one of the most common causes of acute liver failure in the Western world. Despite discontinuation of the offending agent, it can still tax a grim prognosis. We describe a case of a menopausal woman taking a herbal supplement called "Provitalize" to relieve hot flashes and bloating. This is the first case report of liver injury from this supplement. She initially presented with mild jaundice and elevated transaminases. Unfortunately, she rapidly progressed to encephalopathy, experienced multiorgan failure, and then died.

Association of DNA methylation, polymorphism and mRNA level of ALAS1 with antituberculosis drug-induced liver injury.

Aim: To investigate the association of DNA methylation, genetic polymorphisms and mRNA level of aminolevulinate synthase 1 (ALAS1) with antituberculosis drug-induced liver injury (AT-DILI) risk.Methods: Based on a 1:1 matched case-control study with 182 cases and 182 controls, one CpG island and three single nucleotide polymorphisms (SNPs) were detected. ALAS1 mRNA level was detected in 34 samples.Results: Patients with methylation status were at high risk of AT-DILI (odds ratio: 1.567, 95% CI: 1.015-2.421, p = 0.043) and SNP rs352169 was associated with AT-DILI risk (GA vs. GG, odds ratio: 1.770, 95% CI: 1.101-2.847, p = 0.019). ALAS1 mRNA level in the cases was significantly lower than that in the controls (0.75 ± 0.34 vs. 1.00 ± 0.42, p = 0.021).Conclusion: The methylation status and SNP rs352169 of ALAS1 were associated with AT-DILI risk.

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Certolizumab-Induced Liver Injury in Ankylosing Spondylitis: A Case Report and Causality Assessment.

Certolizumab-induced liver injury is exceptionally rare, with only a few cases reported in the literature. We present the case of a 34-year-old man with axial ankylosing spondylitis (AS) who developed a drug-induced liver injury following treatment with certolizumab. Despite the initial ineffectiveness of non-steroidal anti-inflammatory drugs and an inadequate response to infliximab, the patient achieved remission of AS symptoms with certolizumab. However, he subsequently developed elevated liver enzymes indicative of hepatocellular injury. Investigations excluded viral hepatitis and autoimmune liver diseases, pointing to certolizumab as the likely cause. The updated Roussel Uclaf Causality Assessment Method confirmed a probable causal relationship between certolizumab and hepatotoxicity. Discontinuation of certolizumab led to normalization of liver enzymes without recurrence of liver injury. This case highlights the need for vigilant monitoring for hepatotoxicity in patients receiving tumor necrosis factor inhibitors.

Difficulty in differentiating liver injury from an immune checkpoint inhibitor from chemotherapy.

This study investigated the potential of immune checkpoint inhibitors (ICIs) combined with chemotherapy as a promising treatment approach for malignancies. This report focuses on a patient with drug-induced liver injury (DILI) following the administration of chemotherapy and ICIs. A 63-year-old patient with non-small cell lung adenocarcinoma (NSCLC) initially underwent γ-knife treatment and subsequently received a combination of chemotherapy comprising bevacizumab and camrelizumab. Due to liver abnormalities, both chemotherapy and ICIs were stopped on day 21. The patient's liver function improved within a month after methylprednisolone treatment. Subsequently, the patient received carboplatin, pemetrexed, and bevacizumab without complications. This finding supported the notion that DILI was likely triggered by the ICI. This case series details a complex instance of DILI resulting from the use of ICIs and pemetrexed/carboplatin. The alignment of the pathological findings and clinical presentation strongly suggested ICI-induced DILI, which was further supported by the definitive response to steroid treatment. This information is important for clinicians, as it emphasizes the importance of closely monitoring liver function and being aware of potential adverse effects associated with ICIs. Such insights contribute to more effective patient care.

Clinical guidance for cannabidiol-associated hepatotoxicity: A narrative review.

There is increasing evidence that cannabidiol (CBD) use is associated with clinically significant liver enzyme (LE) elevations and drug-induced liver injury (DILI). The proportion of LE elevations and DILI events reported in the literature meet the Council for International Organizations of Medical Sciences' (CIOMS) classification of a common adverse drug reaction. However, these potential adverse events are unknown to many clinicians and may be overlooked. The increasing use of CBD for both medical and non-medical use necessitates clear direction in the diagnosis and management of CBD-associated hepatotoxicity. To our knowledge, no such clinical guidance currently exists. For people presenting with elevated LEs, CBD use should be screened for and be considered in the differential diagnosis. This narrative review will provide clinicians with guidance in the prevention, detection, and management of CBD-related hepatotoxicity.

Meeting report of the 5th European Biotransformation Workshop.

Challenges, strategies and new technologies in the field of biotransformation were presented and discussed at the 5th European Biotransformation Workshop, which was held on March 14, 2024 on the Novartis Campus in Basel, Switzerland.In this meeting report we summarise the presentations and discussions from this workshop.The topics covered are listed below:Advances in understanding drug induced liver injury (DILI) risks of carboxylic acids and targeted covalent inhibitors.Biotransformation of oligonucleotide-based therapeutics including automated software tools for metabolite identification.Recent advances in metabolite synthesisQualification and validation of a new compact Low Energy Accelerator Mass Spectrometry (LEA) system for metabolite profiling.

Rituximab-Associated Liver Toxicity Without Known Viral Reactivation.

Rituximab is a targeted immunotherapeutic agent that has demonstrated efficacy in treating CD20+ B-cell neoplasms as well as other lymphoproliferative and autoimmune disorders. A major adverse effect of rituximab is hepatocellular injury attributed to hepatitis B viral reactivation, necessitating viral titers before treatment. In this case report, we illustrate the rare presentation of a patient with marginal zone B-cell lymphoma who experienced symptomatic liver injury with a peak 15-fold aminotransferase elevation following his first dose of rituximab, without evidence of viral reactivation.

Hinokiflavone exerts dual regulation on apoptosis and pyroptosis via the SIX4/Stat3/Akt pathway to alleviate APAP-induced liver injury.

Hinokiflavone (HF), classified as a flavonoid, is a main bioactive compound in Platycladus orientalis and Selaginella. HF exhibits activities including anti-HIV, anti-inflammatory, antiviral, antioxidant and anti-tumor effects. The study aimed to explore the function and the mechanisms of HF on acetaminophen (APAP)-induced acute liver injury. Results indicated that HF treatment mitigated the impact of APAP on viability and restored levels of MDA, GSH and SOD on HepG2 cells. The accumulation of reactive oxygen species (ROS) mitochondrial membrane potential (MMP) in HepG2 cells stimulated by APAP were also blocked by HF. HF reduced the levels of pro-apoptotic and pro-pyroptotic proteins. Flow cytometry analysis and fluorescence staining results were consistent with western blot analysis. Following HF treatment in the APAP-induced cell model, there was observed an augmentation in the phosphorylation of Stat3 and an increase in the expression of SIX4. However, not only silenced the SIX4 protein in HepG2 cells by siRNA, but also adding the Stat3 inhibitor (Stattic), attenuated the anti-apoptotic and anti-pyroptotic effects of HF significantly. Furthermore, HF alleviated liver damage in C57BL/6 mice model. Overall, our study demonstrated that HF mitigates apoptosis and pyroptosis induced by APAP in drug-induced liver injury (DILI) through the SIX4/Akt/Stat3 pathway in vivo and in vitro. HF may have promising potential for for the treatment of DILI.

Sertraline induced acute hepatocellular liver injury in patient with major depressive disorder: a case report.

This case report describes a patient with major depressive disorder (MDD) who developed acute hepatocellular liver injury after being treated with sertraline, a selective serotonin reuptake inhibitor (SSRI). The diagnosis of MDD was made two years prior, and the patient had previously responded partially to escitalopram and cognitive-behavioral therapy (CBT). Upon switching to sertraline 50 mg daily, the patient presented with severe symptoms indicative of acute liver injury, including elevated liver enzymes, jaundice, and gastrointestinal distress. Following the discontinuation of sertraline, the patient's liver function tests gradually normalized over a 90-day period, confirming the diagnosis of sertraline-induced hepatotoxicity. This case underscores the importance of continuous monitoring for potential liver injury in patients treated with sertraline. The findings contribute to the existing body of evidence on the hepatotoxic risks associated with SSRIs and highlight the need for personalized treatment strategies to mitigate adverse effects and enhance patient safety. Further research is needed to explore the long-term safety and efficacy of sertraline, particularly in vulnerable populations.

Drug-induced liver injury associated with atypical generation antipsychotics from the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Recent studies have shown that liver enzyme abnormalities were not only seen with typical antipsychotics (APs) but also with atypical antipsychotics (AAPs). During the last 20 years, the hepatotoxicity of various antipsychotics received much attention. However, systematic evaluations of hepatotoxicity associated with APs are limited. METHODS: All drug related hepatic disorders cases were retrieved from the FDA Adverse Event Reporting System (FAERS) database using standardized MedDRA queries (SMQ) from the first quarter of 2017 to the first quarter of 2022. Patient characteristics and prognosis were assessed. In this study, a case/non-case approach was used to calculate reporting odds ratio (RORs) and 95% confidence intervals (CIs). We calculated the drug-induced liver injury (DILI) RORs for each AAPs. RESULTS: A total of 408 DILI cases were attributed to AAPs during the study period. 18.6% of these were designated as serious adverse event (SAE), which include death (19.74%), hospitalization (68.42%), disability (2.63%), and life-threatening (9.21%) outcomes. The RORs values in descending order were: quetiapine (ROR = 0.782), clozapine (ROR = 0.665), aripiprazole (ROR = 0.507), amisulpride (ROR = 0.308), paliperidone (ROR = 0.212), risperidone (ROR = 0.198), ziprasidone (0.131). CONCLUSION: The result found in our study was that all AAPs didn't have a significant correlation with increased hepatotoxicity. Future analysis of the FAERS database in conjunction with other data sources will be essential for continuous monitoring of DILI.

Glecaprevir-Pibrentasvir and Ethinyl Estradiol-Induced Liver Injury in a Patient Without Cirrhosis.

Most drug liver injury cases are the result of an unexpected interaction with medications. We present a 33-year-old woman, four months postpartum, on ethinyl estradiol/norgestrel, who presented in the ED with nausea, vomiting, abdominal pain, and severe pruritus six weeks after starting glecaprevir-pibrentasvir (GP) treatment. The patient was suspected to have a drug-induced liver injury (DILI), and GP was discontinued. Other potential causes of liver injury were ruled out via labs, imaging, and liver biopsy. The patient's liver function significantly improved after discontinuing GP. Few cases of DILI secondary to GP have been reported. However, to the best of our knowledge, DILI from the interaction of ethinyl estradiol and GP does not exist in published literature. In our case, DILI was likely due to the effect of GP and ethinyl estradiol on the liver's cytochrome 450 (CYP 450) system. The aim of this report is to raise awareness and improve pharmacovigilance, especially in patients receiving medications that are metabolized by the liver's CYP 450 system. Early detection of DILI secondary to drug-interaction and discontinuation of the culprit medication is the mainstay of treatment. However, there is a lack of evidence-based management strategies for premature discontinuation of GP in the setting of DILI while treating chronic hepatitis C virus (HCV) infection. Further investigations are warranted.

Turmeric-induced Liver Injury.

The use of herbal and dietary supplements has gained an increasing foothold in the United States. While often touted as safer alternatives to more traditional "western" therapeutics, the pharmacology and pharmacokinetics of these substances, their interactions with other medications, their purity, and individual pharmacogenomics, remain unknown. Turmeric is a popular supplement that has been demonstrated to be safe, and even hepatoprotective. Recently, however, there have been several reports of turmeric-induced liver injury. We report a case of drug-induced liver injury due to turmeric that was complicated by acute liver failure and hepatorenal syndrome.

Hepatic injury and hepatic failure adverse events in 3,4-methylenedioxymethamphetamine users reported to the FDA Adverse Event Reporting System.

3,4-Methylenedioxymethamphetamine (MDMA) is being investigated in controlled clinical trials for use as an adjunct medication treatment for post-traumatic stress disorder. MDMA is metabolized by N-demethylation, primarily by CYP2D6, to its main inactive metabolite, 4-hydroxy-3-methoxymethamphetamine. It is also metabolized to a lesser extent by CYP1A2, CYP2B6, and CYP3A4 to its active metabolite, 3,4-methylenedioxyamphetamine. Considering the extensive hepatic metabolism and excretion, MDMA use in psychiatry raises concerns over drug-induced liver injury (DILI), a rare but dangerous event. Majority of the drugs withdrawn from the market for liver injury caused death or transplantation at frequencies under 0.01%. Unfortunately, markers for liver injury were not measured in most published clinical trials. At the same time, no visible DILI-related symptoms and adverse events were observed. Idiosyncratic DILI cases are rarely registered during clinical trials due to their rare nature. In this study, we surveyed a larger, over 1,500, and a more diverse set of reports from the FDA Adverse Event Reporting System and found 23 cases of hepatic injury and hepatic failure, in which MDMA was reported to be taken in addition to one or more substances. Interestingly, 22 out of 23 cases had one or more listed drugs with a known DILI concern based on the FDA's DILIrank dataset. Furthermore, only one report had MDMA listed as the primary suspect. Considering the nearly 20 million doses of MDMA used annually, this single report is insufficient for establishing a significant association with DILI.

CDK4/6 inhibitor-induced liver injury: Clinical phenotypes and role of corticosteroid treatment.

Background & Aims: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the cornerstone of systemic therapy for patients with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer. In the various therapeutic studies with CDK4/6 inhibitors, elevations in liver tests were more frequent than in the control groups. The mechanism of CDK4/6 inhibitor-induced liver toxicity is not well understood; moreover, natural history and appropriate management are poorly described. Methods: We conducted a retrospective study, collecting cases of CDK4/6 hepatitis from the REFHEPS (Réseau Francophone pour l'étude de l'HEpatotoxicité des Produits de Santé) database. Results: In this study, we report on 22 cases of hepatitis induced by CDK4/6 inhibitors (ribociclib, n = 19 and abemaciclib, n = 3). According to the CTCAE classification, all hepatitis cases were grade 3 or 4. Twelve (54.6%) patients had a liver biopsy showing acute centrilobular hepatitis with foci of necrosis and lymphocytic infiltrate. Nine (40.9%) patients were treated with corticosteroids for resolution of hepatitis. In three cases, another CDK4/6 inhibitor could be resumed after resolution of the hepatitis without recurrence. Conclusions: CDK4/6 inhibitor-induced hepatitis is poorly described in the literature but there are several arguments pointing out that these drugs should be included in the DI-ALH (drug-induced autoimmune-like hepatitis) category. Impact and implications: This study highlights the clinical significance and hepatotoxic risks of CDK4/6 inhibitors, like ribociclib and abemaciclib, in HR+/HER2-metastatic breast cancer treatment. It underscores the necessity for enhanced hepatic monitoring and tailored management strategies, including corticosteroid intervention for unresolved hepatitis post-withdrawal. These findings are crucial for oncologists, hepatologists, and patients, guiding therapeutic decisions and indicating careful liver function monitoring during therapy. The utility of corticosteroids in managing drug-induced hepatitis and the feasibility of resuming CDK4/6 inhibitor therapy post-recovery are notable practical outcomes. Nonetheless, the study's retrospective nature and limited case numbers introduce constraints, underscoring the need for further research to refine our understanding of CDK4/6 inhibitor-associated hepatotoxicity.

The role of exosomal lncRNAs in acetaminophen-induced induced liver injury in SD rats.

Background: Drug-induced liver injury (DILI) is a leading cause of drug development failures during clinical trials and post-market introduction. Current biomarkers, such as ALT and AST, lack the necessary specificity and sensitivity needed for accurate detection. Exosomes, which protect LncRNAs from RNase degradation, could provide reliable and easily accessible options for biomarkers. Materials and methods: RNA-sequencing was used to identify differentially expressed LncRNAs (DE-LncRNAs), followed by isolation of LncRNAs from plasma exosomes in this study. Exosome characterization was conducted by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB). Bioinformatics analysis included functional enrichment and co-expression network analysis. Five rat models were established, and quantitative real-time PCR was used to verify the specificity and sensitivity of two candidate exosomal LncRNAs. Results: The APAP-induced hepatocellular injury model was successfully established for RNA-sequencing, leading to the identification of several differentially expressed exosomal LncRNAs. Eight upregulated exosomal DE-LncRNAs were selected for validation. Among them, NONRATT018001.2 (p < 0.05) and MSTRG.73954.4 (p < 0.05) exhibited a more than 2-fold increase in expression levels. In hepatocellular injury and intrahepatic cholestasis models, both NONRATT018001.2 and MSTRG.73954.4 showed earlier increases compared to serum biomarkers ALT and AST. However, no histological changes were observed until the final time point. In the fatty liver model, NONRATT018001.2 and MSTRG.73954.4 increased earlier than ALT and AST at 21 days. By the 7th day, minor steatosis was evident in liver tissue, while the expression levels of the two candidate exosomal LncRNAs exceeded 2 and 4 times, respectively. In the hepatic fibrosis model, NONRATT018001.2 and MSTRG.73954.4 showed increases at every time point. By the 49th day, hepatocellular necrosis and fibrosis were observed in the liver tissue, with NONRATT018001.2 showing an increase of more than 8 times. The specificity of the identified exosomal DE-LncRNAs was verified using a myocardial injury model and they showed no significant differences between the case and control groups. Conclusion: NONRATT018001.2 and MSTRG.73954.4 hold potential as biomarkers for distinguishing different types of organ injury induced by drugs, particularly enabling early prediction of liver injury. Further experiments, such as siRNA interference or gene knockout, are warranted to explore the underlying mechanisms of these LncRNAs.

Liver-on-chips for drug discovery and development.

Recent FDA modernization act 2.0 has led to increasing industrial R&D investment in advanced in vitro 3D models such as organoids, spheroids, organ-on-chips, 3D bioprinting, and in silico approaches. Liver-related advanced in vitro models remain the prime area of interest, as liver plays a central role in drug clearance of compounds. Growing evidence indicates the importance of recapitulating the overall liver microenvironment to enhance hepatocyte maturity and culture longevity using liver-on-chips (LoC) in vitro. Hence, pharmaceutical industries have started exploring LoC assays in the two of the most challenging areas: accurate in vitro-in vivo extrapolation (IVIVE) of hepatic drug clearance and drug-induced liver injury. We examine the joint efforts of commercial chip manufacturers and pharmaceutical companies to present an up-to-date overview of the adoption of LoC technology in the drug discovery. Further, several roadblocks are identified to the rapid adoption of LoC assays in the current drug development framework. Finally, we discuss some of the underexplored application areas of LoC models, where conventional 2D hepatic models are deemed unsuitable. These include clearance prediction of metabolically stable compounds, immune-mediated drug-induced liver injury (DILI) predictions, bioavailability prediction with gut-liver systems, hepatic clearance prediction of drugs given during pregnancy, and dose adjustment studies in disease conditions. We conclude the review by discussing the importance of PBPK modeling with LoC, digital twins, and AI/ML integration with LoC.