Hepatotoxicity Research Articles

Interpretable multitemporal liver function indicator model for prediction and risk factor analysis of drug induced liver injury

The occurrence of liver injury during cancer treatment is extremely harmful. The risk factors for drug.induced liver injury (DILI) in the pancreatic cancer population have not been investigated. This study aims to develop and validate an interpretable decision tree (DT) model for the early prediction of DILI in pancreatic cancer patients using multitemporal clinical data and screening for related risk factors. A retrospective collection of data was conducted on 307 patients, the training set (n = 215) was used to develop the model, and the test set (n = 92) was used to evaluate the model. The classification and regression trees algorithm was employed to establish the DT model. The Shapley Additive explanations (SHAP) method was used to facilitate clinical interpretation. Model performance was assessed using AUC and the Hosmer‒Lemeshow test. The DT model exhibited superior diagnostic efficacy, the AUC values were 0.995 and 0.994 in the training and test sets, respectively. Four risk factors associated with DILI occurrence were identified: delta.albumin, delta.ALT, and post (AST: ALT), and post.GGT. The multiperiod liver function indicator.based interpretable DT model predicted DILI occurrence in the pancreatic cancer population and contributes to personalized clinical management of pancreatic cancer patients.

AIBP protects drug-induced liver injury by inhibiting MAPK-mediated NR4A1 expression

Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. AIBP is a binding protein of apolipoprotein AI involved in lipid metabolism and maintenance of oxidative respiration in mitochondria, but its role in DILI is unclear. By constructing AIBP knockout mice, overexpressing and knocking down AIBP in cell lines, we established animal and cell models of DILI. Using western blotting and real-time qPCR assay, we explored the influence of AIBP in activation of mitogen-activated protein kinases (MAPK) signal pathways and possible targets. AIBP was downregulated during hepatocyte injury. AIBP deficient mice develop severe liver injury and more sensitive to drug-induced cell death. Overexpression of AIBP protects cells under APAP treatment. Furthermore, AIBP inhibits the activation of MAPK pathways, through which AIBP regulates NR4A1. These results suggest that AIBP is expected to become a valuable biomarker and therapeutic target in liver injury.

Role of liver biopsy in the management of idiosyncratic DILI.

Drug-induced liver injury (DILI) presents unique challenges in clinical practice. While some types of DILI are mild and resolve quickly after removing the drug, other situations are more complex, with competing aetiologies or underlying liver disease. Guidelines from professional societies agree that the liver biopsy retains a role in understanding and managing DILI in certain situations. Liver biopsy allows characterization of the histological pattern of injury as well as assessment of severity. Inflammatory infiltrates, bile duct injury or loss and vascular injury are all revealed by liver biopsy. Communication between the hepatopathologist and clinical team with clinicopathological correlation of the findings is necessary for the best determination of causality and differentiation from other diseases of exclusion, like autoimmune hepatitis and graft-versus-host disease. This review highlights important aspects of the role of liver biopsy in DILI evaluation.

Histologic Features of Liver Injury Associated With SARS-CoV-2 Messenger RNA Vaccines.

Many drugs can induce liver injury; however, vaccine-induced liver injury is a rare phenomenon. SARS-CoV-2 messenger RNA (mRNA) vaccines are now widely administered, and clinical evidence of liver injury has been reported. To characterize the histologic features of SARS-CoV-2 mRNA vaccine-associated liver injury. Thirteen liver biopsies from 12 patients with elevated liver enzymes clinically favored to be secondary to SARS-CoV-2 mRNA vaccine were identified between 2021 and 2022. Demographics, clinical information, and histologic features of liver biopsies were reviewed. All patients (median age, 58 years; M:F = 4:8) received at least 1 dose of SARS-CoV-2 mRNA vaccines (7 Pfizer and 5 Moderna). Four patients had a history of liver disease. Nine patients developed symptoms between 1 day and 2 months after receiving the vaccine dose. Viral serologies were negative. Drug-induced liver injury was thought to be less likely clinically in the 3 patients who had started new medications. Autoimmune antibodies were detected in 9 patients. Moderate to severe active hepatitis was the dominant histologic pattern of injury (9 of 13 biopsies; 69%). Resolving hepatitis, cholestatic hepatitic injury, and bile duct injury were identified in 1 biopsy each. All patients recovered spontaneously or with steroid therapy except one patient who developed autoimmune hepatitis. Moderate to severe active hepatitis is commonly observed in SARS-CoV-2 mRNA vaccine-associated liver injury, and female patients may be more susceptible to injury. Liver injury resolves spontaneously or with steroid treatment. In rare cases, these vaccines may trigger an underlying immune condition.

Drug-induced liver injury related to gene therapy: A new challenge to be managed.

Gene therapy is being successfully developed for the treatment of several genetic disorders. Various methods of gene transfer have been developed to enable the production of the deficient enzyme or protein. One of the most important is adeno-associated virus vectors, which have been shown to be viable for use in invivo gene therapy. Several gene therapies have already been approved. They are also promising for acquired diseases. Important examples include gene therapy for haemophilia A and B, X-linked myotubular myopathy, spinal muscular atrophy and several liver diseases such as Criggler-Najjar disease, alpha-1 antitrypsin deficiency and Fabry disease. However, the introduction of a foreign compound into hepatocytes leads to hepatic reactions with heterogeneous phenotypic expression and a wide spectrum of severity, ranging from mild transaminase elevation to acute liver failure. Several mechanisms appear to be involved in liver injury, including an immune response, but also direct toxicity depending on the method of gene transfer. As a result, the incidence, expression and severity of liver injury vary from indication to indication and from patient to patient. Patients treated for haemophilia A are more prone to transaminase elevation than those treated for haemophilia B. Corticosteroids are successfully used to correct liver reactions but also to prevent degradation of the transferred gene and loss of therapeutic activity. The aim of this review is to describe the risk of liver injury according to the indication for gene therapy and the short- and long-term management currently proposed to prevent or correct liver reactions in clinical practice.

Inhibitory effects of flavonoids on organic cation transporter 1: Implications for food/herb-drug interactions and hepatoprotective effects

Organic cation transporter 1 (OCT1, gene symbol: SLC22A1) is mainly responsible for the hepatic uptake of various cationic drugs, closely associated with drug-induced liver injury (DILI). Screening and identifying potent OCT1 inhibitors with little toxicity in natural products is of great value in alleviating OCT1-mediated liver injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions (FDIs). Our objective was to investigate potential inhibitors of OCT1 from 96 flavonoids, evaluate the hepatoprotective effects on retrorsine-induced liver injury, and clarify the structure-activity relationships of flavonoids with OCT1. Thirteen flavonoids exhibited significant inhibition (>50%) on OCT1 in OCT1-HEK293 cells. Among them, the five strongest flavonoid inhibitors (IC50 < 10 μM), including α-naphthoflavone, apigenin, 6-hydroxyflavone, luteolin, and isosilybin markedly decreased oxaliplatin-induced cytotoxicity. In retrorsine-induced liver injury models, they also reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to different levels, the best of which was 6-hydroxyflavone. The pharmacophore model clarified that hydrogen bond acceptors at the 4,8,5’ position might play a vital role in the inhibitory effect of flavonoids on OCT1. Taken together, our findings would pave the way to predicting the potential risks of flavonoid-related FDIs in humans and optimizing flavonoid structure to alleviate OCT1-mediated liver injury.

Unraveling Logical Fallacies in the debate over Homeopathic Formulations and Severe Liver Injury"

This article explores the logical fallacies intertwined within the discourse surrounding the safety of homeopathic remedies, particularly in light of severe drug-induced liver injury (DILI). It delves into the complexities of the debate, highlighting common fallacies such as ad hominem, straw man, and slippery slope, which often obscure rational discourse. By analyzing arguments and proposing rational solutions, the article aims to promote informed decision-making and critical thinking in homeopathic practice. It emphasizes the importance of recognizing and addressing fallacies to foster transparent discussions and ensure patient safety. Proposed solutions include standardized causality assessment, enhanced pharmacovigilance, quality assurance measures, education, awareness, collaboration, and research. Through these measures, stakeholders can contribute to a nuanced understanding of homeopathy's safety profile and empower individuals to make well-informed healthcare choices grounded in evidence-based medicine. Ultimately, the goal is to uphold patient safety and well-being by navigating the discourse with integrity and a commitment to evidence-based practice.

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.

Incidence and risk factors of antituberculosis drug-induced liver injury in India: A systematic review and meta-analysis.

Antituberculosis drug-induced liver injury (ATDILI) is a significant problem of tuberculosis treatment. This systematic review and meta‑analysis aimed at evaluating the incidence and risk factors of ATDILI in adult patients with tuberculosis in India. Five electronic databases were searched comprehensively for studies on Indian adult patients with tuberculosis investigating the incidence and/or risk factors of ATDILI. The relevant data was pooled in a random or fixed-effect model to calculate the pooled incidence with a 95% confidence interval (CI), standardized mean difference (MD) or odds ratio (OR). Following the screening of 3221 records, 43 studies with 12,041 tuberculosis patients were finally included. Based on the random effect model, the pooled incidence of ATDILI was 12.6% (95% CI, 9.9-15.3%, p < 0.001, I2 = 95.1%). The pooled incidence was higher in patients with daily treatment regimen compared to the thrice weekly regimen (16.5% vs. 3.5%). The concurrent hepatitis B or C infection, alcohol consumption and underlying chronic liver disease were associated with high incidence of ATDILI. The pooled incidence of acute liver failure (ALF) among ATDILI patients was 6.78% (95% CI 3.9-9.5%). Female gender (OR 1.24), older age (MD 0.26), lean body mass index (OR 3.8), hypoalbuminemia (OR 3.09), N-acetyltransferase slow acetylator genotypes (OR 2.3) and glutathione S-transferases M null mutation (OR 1.6) were found to be associated with an increased risk of ATDILI. The pooled mortality rate of ATDILI patients was 1.72% (95% CI 0.4-3.0%) overall and 71.8% (95% CI 49.3-94.2%) in case of ALF. Overall, 12.6% patients of tuberculosis in India developed ATDILI when combination of first-line antituberculosis drugs was used. An average of 7% of ATDILI patients progressed to ALF which had a high mortality rate. Older age, female, poor nutritional status and some genetic polymorphisms were identified as significant risk factors.

Etiological Tracing Test and Drug Efficacy Test in a Case of Clinical Canine Toxic Liver Disease

This experiment is divided into three parts. A typical case report of canine toxic liver disease was recorded at the Huazhong Agricultural University Animal Hospital. The etiology tracing test focused on the daily life risk factors that induced the disease. The pathological model of toxic liver disease in mice was successfully established by the administration of household formaldehyde, floor cleaner and chlorine-containing disinfectant tablets. The drug efficacy test was carried out by the administration of self-made traditional Chinese medicine to the model mice, and to observe the therapeutic effect of traditional Chinese medicine prescription on the mice pathological model. It can be concluded that the daily life risk factors should be paid enough attention to in the dog's toxic liver disease. In comparison, within households that own dogs, the toxicity of chlorine-containing disinfectant is low in the normal dilution range, and its liver damage to mice is very light during the test. However, caution should be exercised when using floor cleaners and formaldehyde. Self-made traditional Chinese medicine has a good effect on this type of liver disease, but it should also pay attention to the dose, concentration and usage cycle.

Novel reduced heteropolyacid nanoparticles for effective treatment of drug-induced liver injury by manipulating reactive oxygen and nitrogen species and inflammatory signals

With the rapid advancements in biomedicine, the use of clinical drugs has surged sharply. However, potential hepatotoxicity limits drug exploitation and widespread usage, posing serious threats to patient health. Hepatotoxic drugs disrupt liver enzyme levels and cause refractory pathological damage, creating a challenge in the application of diverse first-line drugs. The activation and deterioration of reactive oxygen and nitrogen species (RONS) and inflammatory signals are key pathological mechanisms of drug-induced liver injury (DILI). Herein, a novel reduced heteropolyacid nanoparticle (RNP) has been developed, possessing high RONS-scavenging ability, strong anti-inflammatory activity, and excellent biosafety. These features enable it to swiftly restore the redox and immune balance of the liver. Intravenous administration of RNP effectively scavenged RONS storm, reversing liver oxidative stress and restoring normal mitochondrial membrane potential and function. Furthermore, by inhibiting c-Jun-N-terminal kinase phosphorylation, RNP facilitated the restoration of nuclear factor erythroid 2-related factor 2-mediated endogenous antioxidant signaling, ultimately rescuing the liver function and tissue morphology in acetaminophen-induced DILI mice. Crucially, the high biocompatible RNP exhibited superior efficacy in the DILI mouse model compared to the clinical antioxidant N-acetylcysteine. This targeted therapeutic approach, tailored to address the onset and progression of DILI, offers valuable new insights into controlling the condition and restoring liver structure and function.

Uncovering the scientific landscape: A bibliometric and visualized analysis of artificial intelligence in traditional Chinese medicine

The emergence of artificial intelligence (AI) technology has presented new challenges and opportunities for Traditional Chinese Medicine (TCM), aiming to provide objective assessments and improve clinical effectiveness. However, there is a lack of comprehensive analyses on the research trajectory, key directions, current trends, and future perspectives in this field. This research aims to comprehensively update the progress of AI in TCM over the past 24 years, based on data from the Web of Science database covering January 1, 2000, to March 1, 2024. Using advanced analytical tools, we conducted detailed bibliometric and visual analyses. The results highlight China's predominant influence, contributing 54.35 % of the total publications and playing a key role in shaping research in this field. Significant productivity was observed at institutions such as the China Academy of Chinese Medical Sciences, Beijing University of Chinese Medicine, and Shanghai University of Traditional Chinese Medicine, with Wang Yu being the most prolific contributor. The journal Molecules contributed the most publications in this field. This study identified hepatocellular carcinoma, chemical and drug-induced liver injury, Papillon-Lefèvre disease, Parkinson's disease, and anorexia as the most significant disorders researched. This comprehensive bibliometric assessment benefits both seasoned researchers and newcomers, offering quick access to essential information and fostering the generation of innovative ideas in this field.

P01-54 New fluorescent probes for quick assessment of drug induced liver injury effects on bile canaliculi dynamism and albumin expression

P01-54 New fluorescent probes for quick assessment of drug induced liver injury effects on bile canaliculi dynamism and albumin expression

Genetic variants associated with immune-mediated liver injury from checkpoint inhibitors.

The clinical features, liver histology, and genetic variants in 57 patients with moderate to severe immune-mediated liver injury from checkpoint inhibitors (ILICI) are presented. Between 2010 and 2022, 57 high-causality ILICI cases were enrolled in the Drug-Induced Liver Injury Network. HLA and selected candidate gene variants were tested for association with ILICI risk compared to the general population and other DILI controls. The 57 high-causality cases were attributed to pembrolizumab (16), ipilimumab (15), ipilimumab and nivolumab (13), and other immune checkpoint inhibitors (13) and occurred at a median of 72 days after the first infusion. Median age was 57.8 years, 66% male, and 89% were non-Hispanic Whites. At DILI onset, 53% had hepatocellular, 35% mixed, and 15% cholestatic, with younger patients more likely to have hepatocellular injury. The incidence of ANA, smooth muscle antibody, and elevated IgG levels was low (17%, 23%, and 0%), but corticosteroids were given to 86%. Microgranulomas and hepatic steatosis were seen in 54% and 46% of the 26 liver biopsies, respectively. The HLA alleles associated with autoimmune hepatitis were not over-represented, but 2 host immune response genes (EDIL3 and SAMA5A) and 3 other genes (GABRP, SMAD3, and SLCO1B1) were associated with ILICI (OR: 2.08-2.4, p<0.01). ILICI typically arises within 12 weeks of initiating immunotherapy and is self-limited in most cases. Genetic variants involved in host T-cell regulation and drug disposition were identified, implicating these pathways in the pathogenesis of ILICI. If validated, these findings could lead to improved diagnostic instruments and possible treatments for ILICI.

P02-18 Using individual-centric model to detect immune-mediated idiosyncratic drug-induced liver injury at preclinical stage

P02-18 Using individual-centric model to detect immune-mediated idiosyncratic drug-induced liver injury at preclinical stage

P02-33 Bridging the gap: human and preclinical animal microphysiological systems for assessing drug-induced liver injury during drug discovery

P02-33 Bridging the gap: human and preclinical animal microphysiological systems for assessing drug-induced liver injury during drug discovery

A case of refractory cholestatic drug-induced liver injury caused by amoxicillin/clavulanate effectively treated with phenobarbital

A case of refractory cholestatic drug-induced liver injury caused by amoxicillin/clavulanate effectively treated with phenobarbital

P06-23 Integration of metabolomics and transcriptomics for improved mechanism-based hazard characterization of drug-induced liver injury

P06-23 Integration of metabolomics and transcriptomics for improved mechanism-based hazard characterization of drug-induced liver injury

P02-12 Development of a hepatic spheroid co-culture model for prediction of cholestatic drug-induced liver injury

P02-12 Development of a hepatic spheroid co-culture model for prediction of cholestatic drug-induced liver injury

P12-09 Dissecting the idiosyncratic drug-induced liver injury (iDILI)-initiating mechanism using the individual-centric model: the role of the innate immune response

P12-09 Dissecting the idiosyncratic drug-induced liver injury (iDILI)-initiating mechanism using the individual-centric model: the role of the innate immune response