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ABSTRACT Aims Methods Results Conclusions Drug‐induced liver injury (DILI) is a major global health concern resulting from adverse reactions to medications, supplements or herbal medicines. The relevance of DILI has grown with an aging population, the rising prevalence of chronic diseases and the increased use of biologics, including checkpoint inhibitors. This article aims to summarise current knowledge on DILI epidemiology and risk factors.This review critically appraises available evidence on DILI frequency, outcomes and risk determinants, focusing on drug properties and non‐genetic host factors that may influence susceptibility.DILI incidence varies across populations, with hospitalised patients experiencing notably higher rates than outpatients or the general population. Increased medication use, particularly among older adults and women, may partly explain age‐ and sex‐based disparities in DILI incidence and reporting. Physiological changes associated with aging likely increase susceptibility to DILI in older adults, though further exposure‐based studies are needed for definitive conclusions. Current evidence does not strongly support that women are inherently more susceptible to DILI than men; rather, susceptibility appears to depend on specific drugs. However, once DILI occurs, older age and female sex are associated with greater severity and poorer outcomes. Other less‐studied host‐related risk factors are also discussed based on available evidence.This article summarises existing data on DILI frequency, outcomes, drug properties affecting hepatotoxicity and non‐genetic host risk factors while identifying critical knowledge gaps. Addressing these gaps through future research could enhance understanding and support preventive measures. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) refers to drug-mediated damage to the structure and function of the liver, ranging from mild elevation of liver enzymes to severe hepatic insufficiency, and in some cases, progressing to liver failure. The mechanisms and clinical symptoms of DILI are diverse due to the varying combination of drugs, making clinical treatment and prevention complex. DILI has significant public health implications and is the primary reason for post-marketing drug withdrawals. The search for reliable preclinical models and validated biomarkers to predict and investigate DILI can contribute to a more comprehensive understanding of adverse effects and drug safety. In this review, we examine the progress of research on DILI, enumerate in vitro models with potential benefits, and highlight cellular molecular perturbations that may serve as biomarkers. Additionally, we discuss omics approaches frequently used to gather comprehensive datasets on molecular events in response to drug exposure. Finally, three commonly used gene modulation techniques are described, highlighting their application in identifying causal relationships in DILI. Altogether, this review provides a thorough overview of ongoing work and approaches in the field of DILI. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions Although turmeric is commonly ingested and well tolerated, there is increasing evidence that over‐the‐counter turmeric supplements can cause drug‐induced liver injury. We sought to thoroughly characterise clinicopathological features of patients for whom liver injury was attributed clinically to turmeric supplements.We identified 11 patients via retrospective pathology archive review: 10 females (91%) and one male, with a median age of 58 years (range = 37–66 years). Six patients (55%) were asymptomatic with abnormal liver function tests, while five patients (45%) presented with malaise and/or jaundice. Ten patients (91%) showed predominant transaminase abnormalities, while one exhibited predominant alkaline phosphatase elevation. Histologically, biopsies showed acute hepatitis (eight cases, 73%, including five pan‐lobular and three zone 3‐predominant inflammation), scattered lobular aggregates of histiocytes (two; 18%) and a chronic hepatitis pattern of injury (one; 9%). Mild bile duct injury was present in five biopsies (45%). All patients stopped ingesting turmeric supplements after presenting with liver injury, and four patients additionally received steroid therapy; liver function tests normalised in all patients. Roussel Uclaf causality assessment method (RUCAM) analysis estimated the likelihood of turmeric supplement‐associated liver injury to be probable (eight cases) and possible (three).Histological features in the ‘possible’ cases were consistent with drug‐induced injury, highlighting the added benefit of histological analysis relative to RUCAM analysis isolation. This study underscores the need to obtain a full history of over‐the‐counter medications and supplements when investigating aetiologies for liver injury, including supplements purportedly containing innocuous compounds such as turmeric. [ABSTRACT FROM AUTHOR]

Summary: Background: Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug‐induced liver injury (DILI) due to AZ. Methods: The clinical characteristics of individuals with definite, highly likely, or probable AZ‐DILI enrolled in the US Drug‐Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ‐DILI cases was compared to population controls, other DILI cases, and other antibiotic‐associated DILI cases. Results: Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ‐DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA‐DQA1*03:01 was significantly more common in AZ‐DILI versus population controls and amoxicillin‐clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively). Conclusion: Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA‐DQA1*03:01 was significantly more common in AZ cases compared to controls. [ABSTRACT FROM AUTHOR]

Objective: Drug-induced liver injury (DILI) is one of the most challenging forms of liver disorder. We aimed to use ultrasound dual elastography, by combining strain and shear wave imaging, to noninvasively assess liver inflammation and injury severity of DILI. Methods: 291 DILI patients were included in the prospective multicenter study and divided into training and validation cohorts. All patients received liver biopsy and dual elastography examination. Liver inflammation grading (G0-4) and fibrosis staging (F0-4) were considered as the gold standard of liver injury and G+F ≥ 5 was defined as severe liver injury. Indexes of dual elastography and serological indicators (DESI) were selected and analyzed with multivariable logistic regression to build DESI models for evaluating liver inflammation, and the C score model was built with the same method for diagnosing severe liver injury. Results: Areas under the receiver operating characteristic curve (AUCs) of the DESI model to assess liver inflammation ≥ G2 were 0.887 and 0.868 in training and validation cohorts, respectively. AUCs of the DESI model in diagnosing ≥ G3 were 0.893 and 0.896 in the two cohorts, respectively. The C score accurately assessed severe liver injury with AUCs of 0.909 and 0.885 in two cohorts. Of the 87 patients with mild clinical severity, 10 (11.49%) had severe pathological injury, which could be identified by C score. Conclusion: Dual elastography demonstrated high performance in diagnosing liver inflammation and identifying severe pathological liver injury of DILI, making up for the deficiency of serological indicators alone for evaluating DILI severity. [ABSTRACT FROM AUTHOR]

Understanding the endogenous mechanism of adaptive response to drug‐induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin‐induced liver injury (TILI) of mice. Exosomal miR‐106b‐5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Outstandingly, miR‐106b‐5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects, indicating that miR‐106b‐5p protects mice from liver injury. Injured hepatocytes released miR‐106b‐5p‐enriched exosomes taken up by surrounding hepatocytes. Vim (encodes vimentin) was identified as an important target of miR‐106b‐5p by dual luciferase reporter and siRNA assays. Furthermore, single‐cell RNA‐sequencing analysis of toosendanin‐injured mouse liver revealed a cluster of Vim+ hepatocytes; nonetheless declined following miR‐106b‐5p cotreatment. More importantly, Vim knockout protected mice from acetaminophen poisoning and TILI. In the clinic, serum miR‐106b‐5p expression levels correlated with the severity of DILI. Indeed, liver biopsies of clinical cases exposed to different DILI causing drugs revealed marked vimentin expression among harmed hepatocytes, confirming clinical relevance. Together, we report mechanisms of arDILI whereby miR‐106b‐5p safeguards restorative tissue repair by targeting vimentin. [ABSTRACT FROM AUTHOR]

Objective: Challenging differential diagnosis Background: Common causes of severely elevated transaminases, especially alanine transaminase, due to liver diseases include drug-induced liver injury and acute viral hepatitis, especially hepatitis E, which can present similarly in clinical practice. Broad differential diagnostic workup in patients with elevated transaminases is required to not overlook the possibility of hepatitis E infection. Case Report: We report on a 65-year-old asymptomatic man who was referred to the Emergency Department from the rehabilitation center due to markedly elevated liver transaminases. Physical examination revealed no jaundice or abdominal pain. Laboratory findings included severely elevated aspartate transaminase, alanine transaminase, and bilirubin levels. He was previously treated with imipenem/cilastatin and clindamycin for a surgical site infection of his jaw after the removal of a squamous cell carcinoma 2 weeks earlier. An ultrasound of the liver was unremarkable. Drug-induced liver injury was suspected, and all potentially hepatotoxic drugs, including antibiotics, were stopped. Due to the rapid and marked increase in liver transaminases, further tests were performed, including testing for hepatitis E. Serum anti-hepatitis E virus immunoglobulin M, immunoglobulin G antibodies, and hepatitis E virus-ribonucleic acid-polymerase chain reaction turned positive, and the diagnosis of hepatitis E was confirmed. Supportive care was applied. Liver transaminases decreased spontaneously. Conclusions: The diagnostic workup in patients with markedly elevated liver transaminases and suspected drug-induced liver injury should include the screening for hepatitis E. Making the correct diagnosis is crucial given the differing treatment approaches, the implications on further therapy, and the risk of contagion of hepatitis E. [ABSTRACT FROM AUTHOR]

Herbal and dietary supplements (HDS) are being used worldwide at an increasing rate. Mirroring this trend, HDS‐induced liver injury, also known as HDS‐induced liver injury (HILI), has increased significantly over the past three decades in the Drug‐Induced Liver Injury Network (DILIN), now accounting for 20% of cases of drug‐induced liver injury (DILI). There are significant challenges in the identification and prevention of HILI due to varying presentations, ability to make clear diagnosis, identification of the responsible ingredient, lack of treatment, and lack of regulatory oversight of HDS products to confirm their ingredients and ensure safety. The major implicated agents include anabolic steroids, green tea extract, garcinia cambogia, kratom, ashwagandha, turmeric and multi‐ingredient nutritional supplements. Fortunately, with the formation of major DILI consortiums across the world, the last decade has seen advances in the identification of at‐risk genetic phenotypes, the use of chemical analysis on multi‐ingredient nutritional supplements, and the publication of data/injury patterns of potentially risky HDS. [ABSTRACT FROM AUTHOR]

Objective: To analyze the clinical and laboratory characteristics and to identify predictors of moderate to severe anti-tuberculosis drug-induced liver injury (ATB-DILI) in patients with tuberculosis. Methods: This prospective study enrolled Tuberculosis (TB) patients treated with first-line anti-tuberculosis drugs at the Affiliated Hospital of Zunyi Medical University between May 2022 and June 2023. The occurrence of ATB-DILI was monitored, and demographic and clinical data were gathered. We analyzed risk factors for the development of moderate to severe ATB-DILI. Results: ATB-DILI was detected in 120 (10.7%) of the patients, with moderate to severe ATB-DILI occurring in 23 (2.0%) of the 1,124 patients treated with antituberculosis treatment. Multivariate cox regression analysis identified malnutrition (HR = 4.564, 95% CI: 1.029-20.251, p = 0.046) and hemoglobin levels <120 g/L (HR = 2.825, 95% CI: 1.268-11.540, p = 0.017) as independent risk factors for moderate to severe ATB-DILI. Conclusion: The incidence of moderate to severe ATB-DILI was found to be 2.0%. Malnutrition and hemoglobin levels below 120 g/L emerged as significant independent risk factors for the occurrence of moderate to severe ATB-DILI in this patient population. [ABSTRACT FROM AUTHOR]

With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (ICI‐induced liver injury) as an immune‐related adverse event has become a major concern in clinical practice. Because severe cases of liver injury require administration of corticosteroids, a comprehensive evaluation is crucial, including clinical course, blood and imaging tests, and if necessary, pathological examination through liver biopsy. As with liver injury induced by other drugs, classification of injury type by R‐value is useful in deciding treatment strategies for ICI‐induced liver injury. Histologically, the most representative feature is an acute hepatitis‐like hepatocellular injury, characterized by diffuse lobular inflammation accompanied by CD8‐positive T lymphocytes. Another condition that can cause liver injury during ICI treatment is cholangitis accompanied by non‐obstructive bile duct dilatation and bile duct wall thickening. Many cases of ICI‐induced cholangitis are classified as non‐hepatocellular injury type, and they have been reported to respond poorly to corticosteroids. It is essential that gastroenterologists/hepatologists and doctors in various departments work in cooperation to develop a system that achieves early diagnosis and appropriate treatment of ICI‐induced liver injury. [ABSTRACT FROM AUTHOR]

The process of developing new drugs is widely acknowledged as being time‐intensive and requiring substantial financial investment. Despite ongoing efforts to reduce time and expenses in drug development, ensuring medication safety remains an urgent problem. One of the major problems involved in drug development is hepatotoxicity, specifically known as drug‐induced liver injury (DILI). The popularity of new drugs often poses a significant barrier during development and frequently leads to their recall after launch. In silico methods have many advantages compared with traditional in vivo and in vitro assays. To establish a more precise and reliable prediction model, it is necessary to utilize an extensive and high‐quality database consisting of information on drug molecule properties and structural patterns. In addition, we should also carefully select appropriate molecular descriptors that can be used to accurately depict compound characteristics. The aim of this study was to conduct a comprehensive investigation into the prediction of DILI. First, we conducted a comparative analysis of the physicochemical properties of extensively well‐prepared DILI‐positive and DILI‐negative compounds. Then, we used classic substructure dissection methods to identify structural pattern differences between these two different types of chemical molecules. These findings indicate that it is not feasible to establish property or substructure‐based rules for distinguishing between DILI‐positive and DILI‐negative compounds. Finally, we developed quantitative classification models for predicting DILI using the naïve Bayes classifier (NBC) and recursive partitioning (RP) machine learning techniques. The optimal DILI prediction model was obtained using NBC, which combines 21 physicochemical properties, the VolSurf descriptors and the LCFP_10 fingerprint set. This model achieved a global accuracy (GA) of 0.855 and an area under the curve (AUC) of 0.704 for the training set, while the corresponding values were 0.619 and 0.674 for the test set, respectively. Moreover, indicative substructural fragments favorable or unfavorable for DILI were identified from the best naïve Bayesian classification model. These findings may help prioritize lead compounds in the early stage of drug development pipelines. [ABSTRACT FROM AUTHOR]

Background: Acetaminophen (APAP) overdose is a significant contributor to drug-induced liver injury worldwide. G-protein–coupled receptor 116 (GPR116) is an important homeostatic maintenance molecule in the body, but little is known about its role in APAP-induced liver injury (AILI). Methods: GPR116 expression was determined in both human and mouse AILI models. Hepatic function and damage response were analyzed in hepatocyte-specific GPR116 deletion (GPR116△HC) mice undergoing APAP challenge. RNA-sequencing, immunofluorescence confocal, and co-immunoprecipitation (CO-IP) were employed to elucidate the impact and underlying mechanisms of GPR116 in AILI. Results: Intrahepatic GPR116 was upregulated in human and mice with AILI. GPR116△HC mice were vulnerable to AILI compared to wild-type mice. Overexpression of GPR116 effectively mitigated AILI in wild-type mice and counteracted the heightened susceptibility of GPR116△HC mice to APAP. Mechanistically, GPR116 inhibits the binding immunoglobulin protein (BiP), a critical regulator of ER function, through its interaction with β-arrestin1, thereby mitigating ER stress during the early stage of AILI. Additionally, the activation of GPR116 by ligand FNDC4 has been shown to confer a protective effect against early hepatotoxicity caused by APAP in murine model. Conclusions: Upregulation of GPR116 on hepatocytes inhibits ER stress by binding to β-arrestin1, protecting mice from APAP-induced hepatotoxicity. GPR116 may serve as a promising therapeutic target for AILI. [ABSTRACT FROM AUTHOR]

In this experimental study we aimed to investigate the biochemical and histopathological effects of concomitantly administered taxifolin on tramadol-induced liver damage in rats. The rats were divided into three groups; control group (CG), tramadol alone (TRG), and taxifolin + tramadol given (TTRG) groups. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), total antioxidant status (TAS), nuclear factor-kappa beta (NF-kB), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels were measured in liver tissues. Liver tissues were also examined histopathologically. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were determined in blood samples. In tissue analyses, determinants of oxidative stress and inflammation, all were significantly higher in the TRG group compared with the control and TTRG groups. In the TTRG group, all oxidative stress and inflammation markers were significantly lower than in the TRG group. In addition, there was not any significant difference between the control and TTRG groups regarding the TOS and TAS status. Serum liver enzymes were also significantly higher in the TRG group than in the other two groups. In histopathological examinations, the control group had a normal histological appearance. Degenerative-necrotic hepatocytes and hemorrhage, which were seen at a severe level in the TRG group, were found to be moderate in the treated TTRG group. In addition, mononuclear cell infiltrations were found to be severe in the TRG group and mild in the treated TTRG group. Finally it was concluded that Taxifolin alleviated the toxic effects of tramadol on the liver including the histopathological and biochemical changes as well as the oxidative damage. [ABSTRACT FROM AUTHOR]

Antituberculosis drug‐induced liver injury (ATLI) is a major adverse effect during antituberculosis treatment. Early detection or prediction is essential to prevent ATLI in antituberculosis treatment patients. The purpose of this work is to explore the relationship between alanine aminotransferase (ALT) trajectories within 15 days of initial treatment and the risk of ATLI. Based on a historical cohort of patients hospitalized for antituberculosis treatment and group‐based trajectory modeling analysis, ALT trajectories within 15 days of initial treatment were determined. Conditional logistic regression model was used to estimate the association between different ALT trajectories and the risk of ATLI, and the corresponding odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated with covariates. Based on the ALT levels within 15 days of initial treatment, a total of 853 patients were divided into four ALT trajectories. The incidence of ATLI significantly increased with the increase of ALT trajectories (2.33%, 4.38%, 5.90%, and 2.44%, respectively). Compared with trajectory 1, the adjusted OR for ATLI in trajectory 2, trajectory 3, and trajectory 4 were 2.448 (95% CI: 0.302–19.856, P = 0.402), 5.373 (95% CI: 0.636–45.411, P = 0.123), 11.010 (95% CI: 0.720–168.330, P = 0.085), respectively, and there was an increasing trend of ATLI risk (Ptrend = 0.015). Different ALT trajectories within 15 days of initial treatment were associated with different risk of ATLI, and it is necessary to pay attention to the ALT trajectory within 15 days of initial treatment to predict the occurrence of ATLI. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains the second leading cause of death from a single infectious agent and long-term medication could lead to antituberculosis drug-induced liver injury (ATB-DILI). We established a prospective longitudinal cohort of ATB-DILI with multiple timepoint blood sampling and used untargeted metabolomics to analyze the metabolic profiles of 107 plasma samples from healthy controls and newly diagnosed TB patients who either developed ATB-DILI within 2 months of anti-TB treatment (ATB-DILI subjects) or completed their treatment without any adverse drug reaction (ATB-Ctrl subjects). The untargeted metabolome revealed that 77 metabolites (of 895 total) were significantly changed with ATB-DILI progression. Among them, levels of multiple fatty acids and bile acids significantly increased over time in ATB-DILI subjects. Meanwhile, metabolites of the same class were highly correlated with each other and pathway analysis indicated both fatty acids metabolism and bile acids metabolism were up-regulated with ATB-DILI progression. The targeted metabolome further validated that 5 fatty acids had prediction capability at the early stage of the disease and 6 bile acids had a better diagnostic performance when ATB-DILI occurred. These findings provide evidence indicating that fatty acids metabolism and bile acids metabolism play a vital role during ATB-DILI progression. Our report adds a dynamic perspective better to understand the pathological process of ATB-DILI in clinical settings. [ABSTRACT FROM AUTHOR]

Humans are continuously exposed to various heavy metals including copper, iron, cadmium, and arsenic, which were specifically selected for the current analysis because they are among the most frequently encountered environmental mankind and industrial pollutants potentially causing human health hazards and liver injury. So far, these issues were poorly assessed and remained a matter of debate, also due to inconsistent results. The aim of the actual report is to thoroughly analyze the positive as well as negative effects of these four heavy metals on human health. Copper and iron are correctly viewed as pollutant elements essential for maintaining human health because they are part of important enzymes and metabolic pathways. Healthy individuals are prepared through various genetically based mechanisms to maintain cellular copper and iron homeostasis, thereby circumventing or reducing hazardous liver and organ injury due to excessive amounts of these metals continuously entering the human body. In a few humans with gene aberration, however, liver and organ injury may develop because excessively accumulated copper can lead to Wilson disease and substantial iron deposition to hemochromatosis. At the molecular level, toxicities of some heavy metals are traced back to the Haber Weiss and Fenton reactions involving reactive oxygen species formed in the course of oxidative stress. On the other hand, cellular homeostasis for cadmium and arsenic cannot be provided, causing their life-long excessive deposition in the liver and other organs. Consequently, cadmium and arsenic represent health hazards leading to higher disability-adjusted life years and increased mortality rates due to cancer and non-cancer diseases. For unknown reasons, however, liver injury in humans exposed to cadmium and arsenic is rarely observed. In sum, copper and iron are good for the human health of most individuals except for those with Wilson disease or hemochromatosis at risk of liver injury through radical formation, while cadmium and arsenic lack any beneficial effects but rather are potentially hazardous to human health with a focus on increased disability potential and risk for cancer. Primary efforts should focus on reducing the industrial emission of hazardous heavy metals. [ABSTRACT FROM AUTHOR]

The early stages of brain injury can induce acute liver injury, which can be recovered in the short term. Continued medication treatment during hospitalization for brain injury alleviates the prognosis and contributes to a high incidence of drug-induced liver injury (DILI). We hypothesize that there is an interaction between changes in the hepatic environment after brain injury and liver injury produced by intensive drug administration, leading to an upregulation of the organism's sensitivity to DILI. In this study, mice models of TBI were established by controlled cortical impact (CCI) and models of DILI were constructed by acetaminophen (APAP). All mice were divided into four groups: Sham, TBI, APAP, and TBI+APAP, and related liver injury indicators in liver and serum were detected by Western blot, Quantitative real-time PCR (qRT-PCR), and immunohistochemical staining. The results suggested that liver injury induced in the early stages of brain injury recovered in 3 days, but this state could still significantly aggravate DILI, represented by higher liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), oxidative stress (increase in malondialdehyde [MDA] concentration and deregulation of glutathione [GSH] and superoxide dismutase [SOD] activities), inflammatory response (activation of the HMGB1/TLR4/NF-κB signaling pathway, and increased messenger RNA [mRNA] and protein levels of pro-inflammatory cytokines including tumor necrosis factor alpha [TNF-α], interleukin [IL]-6, and IL-1β), and apoptosis (TUNEL assay, upregulation of Bax protein and deregulation of Bcl-2 protein). In summary, our results suggested that TBI is a potential susceptibility factor for DILI and exacerbates DILI. [ABSTRACT FROM AUTHOR]

Background: Acute liver injury occurs most frequently due to trauma, but it can also occur because of sepsis or drug-induced injury. This review aims to analyze artificial intelligence (AI)'s ability to detect and quantify liver injured areas in adults and pediatric patients. Methods: A literature analysis was performed on the PubMed Dataset. We selected original articles published from 2018 to 2023 and cohorts with ≥10 adults or pediatric patients. Results: Six studies counting 564 patients were collected, including 170 (30%) children and 394 adults. Four (66%) articles reported AI application after liver trauma, one (17%) after sepsis, and one (17%) due to chemotherapy. In five (83%) studies, Computed Tomography was performed, while in one (17%), FAST-UltraSound was performed. The studies reported a high diagnostic performance; in particular, three studies reported a specificity rate > 80%. Conclusions: Radiomics models seem reliable and applicable to clinical practice in patients affected by acute liver injury. Further studies are required to achieve larger validation cohorts. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is a common clinical pharmacogenic disease. In the United States and Europe, DILI is the most common cause of acute liver failure. Drugs can cause hepatic damage either directly through inherent hepatotoxic properties or indirectly by inducing oxidative stress, immune responses, and inflammatory processes. These pathways can culminate in hepatocyte necrosis. The role of the gut microecology in human health and diseases is well recognized. Recent studies have revealed that the imbalance in the gut microecology is closely related to the occurrence and development of DILI. The gut microecology plays an important role in liver injury caused by different drugs. Recent research has revealed significant changes in the composition, relative abundance, and distribution of gut microbiota in both patients and animal models with DILI. Imbalance in the gut microecology causes intestinal barrier destruction and microorganism translocation; the alteration in microbial metabolites may initiate or aggravate DILI, and regulation and control of intestinal microbiota can effectively mitigate drug-induced liver injury. In this paper, we provide an overview on the present knowledge of the mechanisms by which DILI occurs, the common drugs that cause DILI, the gut microbiota and gut barrier composition, and the effects of the gut microbiota and gut barrier on DILI, emphasizing the contribution of the gut microecology to DILI. [ABSTRACT FROM AUTHOR]

Background and Aims: The use of corticosteroids in chronic drug‐induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48‐week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36‐week SSR can achieve efficacy similar to that of 48‐week SSR. Methods: A randomized open‐label trial was performed. Eligible patients were randomly assigned to the 36‐ or 48‐week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. Results: Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36‐week SSR group but 4.8% in the 48‐week SSR group, as determined by per‐protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p =.701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. Conclusions: Both the 36‐ and 48‐week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36‐week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146). [ABSTRACT FROM AUTHOR]

Drug-induced liver disease (DILI) represents one of the main problems in the therapeutic field. There are several non-modifiable risk factors, such as age and sex, and all drugs can cause hepatotoxicity of varying degrees, including those for the treatment of inflammatory bowel diseases (IBD). The aim of this review is to illustrate the adverse effects on the liver of the various drugs used in the treatment of IBD, highlighting which drugs are safest to use based on current knowledge. The mechanism by which drugs cause hepatotoxicity is not fully understood. A possible cause is represented by the formation of toxic metabolites, which in some patients may be increased due to alterations in the enzymatic apparatus involved in drug metabolism. Various studies have shown that the drugs that can most frequently cause hepatotoxicity are immunosuppressants, while mesalazine and biological drugs are, for the most part, less associated with such complications. Therefore, it is possible to assume that in the future, biological therapies could become the first line for the treatment of IBD. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Different patterns of liver injury have been reported in association with the SARSCoV-2 vaccines. The aim of this study was to describe a nationwide cohort of patients with SARS CoV-2 vaccine-induced liver injury, focusing on treatment and the evolution after further booster administration. Patients and Methods: multicentre, retrospective-prospective study, including subjects who developed abnormal liver tests within 90 days after administration of SARS-CoV-2 vaccination. Results: 47 cases were collected: 17 after prime dose and 30 after booster. Age was 57 years, 30 (63.8 %) were female, and 7 (14.9 %) had a history of prior autoimmune hepatitis (AIH). Most cases were non-severe, though 9 (19.1 %) developed acute liver injury or failure (ALF). Liver injury tended to be more severe in those presenting after a booster (p=0.084). Pattern of liver injury was hepatocellular (80.9 %), mixed (12.8 %) and 3 (6.4 %) cholestatic. Liver biopsy was performed on 33 patients; 29 showed findings of AIH. Forty-one (87.2 %) patients received immunosuppressants, mostly corticosteroids (35/41). One required liver transplantation and another died due to ALF. Immunosuppression was discontinued in 6/41 patients without later rebound. Twenty-five subjects received at least one booster and 7 (28.0 %) relapsed from the liver injury, but all were non-severe. Recurrence was less frequent among patients on immunosuppressants at booster administration (28.6 % vs. 88.9 %, p=0.007). Conclusions: SARS CoV-2 vaccine-induced liver injury is heterogeneous but mostly immune-mediated. Relapse of liver injury after re-exposure to vaccine is frequent (28.0 %) but mild. Immunosuppression at booster administration is associated with a lower risk of liver injury. [ABSTRACT FROM AUTHOR]

Background: Cyproheptadine is an easily available over-the-counter first-generation antihistaminic that is often used as an appetite stimulant. Although it is usually a safe drug, rare instances of drug-induced liver injury may occur. Case presentation: We report a case of cholestatic liver injury secondary to cyproheptadine in a young pharmacy student with chronic hepatitis B and review the literature of cyproheptadine-induced liver injury. Conclusion: Although cyproheptadine is largely a safe drug, its potential for significant liver toxicity cannot be ignored. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The objective of this research was to create and validate an interpretable prediction model for drug-induced liver injury (DILI) during tuberculosis (TB) treatment. Methods: A dataset of TB patients from Ningbo City was used to develop models employing the eXtreme Gradient Boosting (XGBoost), random forest (RF), and the least absolute shrinkage and selection operator (LASSO) logistic algorithms. The model's performance was evaluated through various metrics, including the area under the receiver operating characteristic curve (AUROC) and the area under the precision recall curve (AUPR) alongside the decision curve. The Shapley Additive exPlanations (SHAP) method was used to interpret the variable contributions of the superior model. Results: A total of 7,071 TB patients were identified from the regional healthcare dataset. The study cohort consisted of individuals with a median age of 47 years, 68.0% of whom were male, and 16.3% developed DILI. We utilized part of the high dimensional propensity score (HDPS) method to identify relevant variables and obtained a total of 424 variables. From these, 37 variables were selected for inclusion in a logistic model using LASSO. The dataset was then split into training and validation sets according to a 7:3 ratio. In the validation dataset, the XGBoost model displayed improved overall performance, with an AUROC of 0.89, an AUPR of 0.75, an F1 score of 0.57, and a Brier score of 0.07. Both SHAP analysis and XGBoost model highlighted the contribution of baseline liver-related ailments such as DILI, drug-induced hepatitis (DIH), and fatty liver disease (FLD). Age, alanine transaminase (ALT), and total bilirubin (Tbil) were also linked to DILI status. Conclusion: XGBoost demonstrates improved predictive performance compared to RF and LASSO logistic in this study. Moreover, the introduction of the SHAP method enhances the clinical understanding and potential application of the model. For further research, external validation and more detailed feature integration are necessary. [ABSTRACT FROM AUTHOR]

Acetaminophen overdose is a leading cause of acute liver failure (ALF). Despite the pivotal role of the inflammatory microenvironment in the progression of advanced acetaminophen‐induced liver injury (AILI), a comprehensive understanding of the underlying cellular interactions and molecular mechanisms remains elusive. Mas is a G protein‐coupled receptor highly expressed by myeloid cells; however, its role in the AILI microenvironment remains to be elucidated. A multidimensional approach, including single‐cell RNA sequencing, spatial transcriptomics, and hour‐long intravital imaging, is employed to characterize the microenvironment in Mas1 deficient mice at the systemic and cell‐specific levels. The characteristic landscape of mouse AILI models involves reciprocal cellular communication among MYC+CD63+ endothelial cells, MMP12+ macrophages, and monocytes, which is maintained by enhanced glycolysis and the NF‐κB/TNF‐α signaling pathway due to myeloid‐Mas deficiency. Importantly, the pathogenic microenvironment is delineated in samples obtained from patients with ALF, demonstrating its clinical relevance. In summary, these findings greatly enhance the understanding of the microenvironment in advanced AILI and offer potential avenues for patient stratification and identification of novel therapeutic targets. [ABSTRACT FROM AUTHOR]

The incidence and prevalence of drug-induced liver injury appear to be increasing globally, for example, with the introduction of checkpoint inhibitors. Several reviews have been published in the last decade on the epidemiology of DILI, both among hospitalized patients and in the general population, as well as from retrospective and prospective studies on DILI. Most of these reviews have not focused on newly recognized agents that have recently changed the landscape of DILI. Apart from liver injury associated with antibiotics, oncological agents, particularly checkpoint inhibitors, are increasingly being recognized as causing liver injury. The type of liver injury associated with these agents is not idiosyncratic but rather an indirect type of injury. Furthermore, recently, COVID-19 vaccines and green tea extract have been found to lead to liver injury. Checkpoint inhibitors have revolutionized the treatment of many malignancies, such as malignant melanoma, lung cancer, and renal cancer. Via the activation of T cells, they can increase immune activity against malignant cells, but at the same time, they can decrease immune tolerance and therefore lead to immune-related adverse effects in many organs. The most common adverse effect in clinical practice is liver injury. A recent prospective study demonstrated an 8% frequency of DILI due to the use of checkpoint inhibitors among patients with malignant melanoma and renal cancer. This rate is much higher than observed with drugs, leading to idiosyncratic liver injury. Shortly after the implementation of the worldwide vaccination program against COVID-19, several case reports were published on suspected vaccination-induced autoimmune-like hepatitis occurring shortly after the vaccination. At first, these reports were met with skepticism, but currently, around 100 reports have been published, and cases of positive recurrence have been reported. The clinical, biochemical, immunological, and histological features are indistinguishable from classic autoimmune hepatitis (AIH). These reactions are very similar to drug-induced autoimmune-like hepatitis (DI-ALH) due to drugs such as nitrofurantoin, minocycline, and infliximab, which do not relapse after a short course of corticosteroids, which is the general rule in classic autoimmune hepatitis (AIH). Green tea extract has been found to be a well-documented cause of acute hepatocellular liver injury with jaundice. A strong HLA association has been reported, showing a high prevalence of HLA-B*35:01 among patients suffering from green tea-induced liver injury. Overall, 3% of patients recruited in the DILIN study were supplemented with green tea extract as one of the ingredients. In a prospective population-based study from Iceland, green tea was implicated in approximately 8% of patients with DILI. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP)-induced liver injury is one of the most frequent causes of acute liver failure worldwide. Significant increases in the levels of miRNA-21 in both liver tissues and plasma have been observed in APAP-overdosed animals and humans. However, the mechanistic effect of miRNA-21 on acute liver injury remains unknown. In this study, we generated a new hepatocyte-specific miRNA-21 knockout (miR-21-HKO) mouse line. miR-21-HKO and the background-matched sibling wild-type (WT) mice were treated with a toxic dose of APAP. Compared with WT mice, miR-21 HKO mice showed an increased survival, a reduction of necrotic hepatocytes, and an increased expression of light chain 3 beta, which suggested an autophagy activation. The expression of PPARγ was highly induced in the livers of miR-21-HKO mice after a 2-h APAP treatment, which preceded the activation of LC3B at the 12 h APAP treatment. miR-21 negatively regulated PPARγ protein expression by targeting its 3′-UTR. When PPARγ function was blocked by a potent antagonist GW9662 in miR-21-HKO mice, the autophage activation was significantly diminished, suggesting an indispensable role of PPARγ signaling pathway in miR-21-mediated hepatotoxicity. Taken together, hepatocyte-specific depletion of miRNA-21 alleviated APAP-induced hepatotoxicity by activating PPARγ and autophagy, demonstrating a crucial new regulatory role of miR-21 in APAP-mediated liver injury. [ABSTRACT FROM AUTHOR]

Genetic polymorphisms can exert a considerable impact on drug pharmacokinetics (PK) and the development of adverse drug reactions (ADR). However, the effect of genetic polymorphisms on the anti-tuberculosis (anti-TB) drug, and particularly rifampicin (RIF), exposure or anti-TB drug-induced liver injury (DILI) remains uncertain. Here, we evaluated the relationship between single nucleotide polymorphisms (SNPs) detected in the RIF pharmacogenes (AADAC, SLCO1B1, SLCO1B3, ABCB1, and NR1I2) and RIF PK parameters, as well as anti-TB treatment-associated DILI. In total, the study enrolled 46 patients with drug-susceptible pulmonary TB. The RIF plasma concentration was measured using the LC-MS/MS method in the blood samples collected pre-dose and 2 and 6 h post-dose, whilst the DILI status was established using the results from blood biochemical analysis performed before and 10–12 days after treatment onset. The genotyping was conducted using a targeted NGS approach. After adjustment for confounders, the patients carrying the rs3732357 GA/AA genotype of the NR1I2 gene were found to have significantly lower RIF plasma AUC0–6 h in comparison to those with GG genotype, while the difference in RIF plasma Cmax was insignificant. None of the analyzed SNPs was related to DILI. Hence, we are the first to report NR1I2 intronic SNP rs3732357 as the genetic component of variability in RIF exposure. Regarding anti-TB treatment-associated DILI, the other preexisting factors promoting this ADR should be considered. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Clinicians in tuberculosis and dengue endemic regions should have heightened vigilance for drug‐induced liver injury (DILI) overlapping with active infections, enabling prompt recognition and life‐saving conservative management. Severe dengue and drug‐induced liver injury (DILI) are significant independent risk factors for acute liver failure. The co‐occurrence of these conditions significantly complicates clinical management. Here, we describe the case of a 21‐year‐old Nepali female who developed acute liver failure during antitubercular therapy (ATT). The patient, presenting with fever and nausea after 3 weeks of ATT, subsequently received a diagnosis of severe dengue. Laboratory evidence indicated markedly elevated transaminases (AST 4335 U/L, ALT 1958 U/L), total bilirubin (72 μmol/L), and INR (>5). Prompt discontinuation of first‐line ATT, initiation of a modified ATT regimen, and N‐acetylcysteine (NAC) infusion facilitated the patient's recovery after a week of intensive care. This case underscores the potential for synergistic hepatotoxicity in regions where multiple endemic illnesses coincide. Early recognition of DILI, cessation of offending agents, and comprehensive intensive care are crucial interventions. While the definitive efficacy of NAC remains under investigation, its timely administration in these complex cases warrants exploration for its potential lifesaving benefits. [ABSTRACT FROM AUTHOR]

A hypo-enhancement of the liver in contrast-enhanced ultrasound (CEUS), pathologic one-minute hepatic enhancement (pOMHE), was recently observed in 70% of allogeneic hematopoietic stem cell transplantation patients with a high-risk profile for veno-occlusive disease (VOD). Whether pOMHE was a pre-clinical sign of VOD or an unspecific feature of liver damage secondary to intensive chemotherapy is unclear. To investigate this, we studied CEUS patterns in patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (auto-HSCT) or intensive induction therapy (IT) for the treatment of acute leukemia. From April 2020 to May 2021, patients undergoing auto-HSCT (n = 20) or acute leukemia patients prior to IT (n = 20) were included. All patients underwent a B-mode ultrasound and CEUS of the liver and spleen before treatment (d0) and on day 10 (d10) after therapy start. The one-minute hepatic enhancement was quantified. An optical density of liver enhancement less than 90% compared with the spleen was considered pathologic (pOMHE). Clinical and laboratory parameters used to assess a drug-induced liver injury (DILI) were documented. The OMHE was normal (d0 and d10) in 36 (90%) patients. After IT, 2 of 20 patients had a pOMHE. A DILI grade IV was diagnosed in one case and hyperfibrinolysis in the second case. In 2 of 20 (5%) auto-HSCT patients a pOMHE was observed at d10 without clinical symptoms. Chemotherapy-induced effects are not the cause of a pathologic liver enhancement. In contrast, severe DILI or hyperfibrinolysis can be associated with pOMHE. [ABSTRACT FROM AUTHOR]

Background: The antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients. Objectives: This study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells. Methods: Neutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out. Results: Busulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan‐induced steatosis might be linked to the high expression of glutathione S‐transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan‐induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis. Conclusion: While the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug‐induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics. [ABSTRACT FROM AUTHOR]

Background: Drug-induced liver injury (DILI) is a significant cause of morbidity and mortality worldwide. Understanding the spectrum of DILI in tertiary hospitals is essential for effective management and prevention strategies. Materials and Methods: A retrospective analysis was conducted on patients diagnosed with DILI admitted to a tertiary hospital between January 2018 and November 2023. Demographic data, implicated drugs, clinical presentation, laboratory findings, and outcomes were analyzed. Results: Among 250 patients diagnosed with DILI, the mean age was 52 years, with a slight male predominance (55%). The most commonly implicated drug classes were antibiotics (32%), nonsteroidal anti-inflammatory drugs (NSAIDs) (25%), and herbal supplements (18%). Clinical presentation varied widely, with jaundice (65%), fatigue (52%), and abdominal pain (45%) being the most common symptoms. Laboratory investigations revealed elevated alanine transaminase (ALT) (mean: 856 U/L), aspartate transaminase (AST) (mean: 724 U/L), and total bilirubin (mean: 8.5 mg/dL). Liver biopsy was performed in 40% of cases, showing patterns consistent with hepatocellular injury (45%), cholestatic injury (35%), and mixed injury (20%). Management included discontinuation of the offending agent (100%), supportive care, and, in severe cases, liver transplantation (5%). Mortality rate was 8%. Conclusion: DILI presents with diverse clinical manifestations and laboratory findings. Prompt recognition, withdrawal of the offending agent, and supportive care are crucial in management. A multidisciplinary approach involving hepatologists, pharmacists, and clinicians is necessary for optimal patient outcomes. [ABSTRACT FROM AUTHOR]

Oltipraz (OPZ) is a synthetic dithiolethione with potential as a cancer chemopreventive agent, which can work by inducing detoxification enzymes. OPZ is an activator of nuclear factor erythroid 2-related factor 2 (Nrf2), suggesting its involvement in enzyme induction and possible protection against drug-induced liver injury. In this study, we present OPZ-mediated protection of mice against acetaminophen (APAP)-induced liver injury and discuss its possible contributing factors. Overnight-fasted male CD-1 mice were administered APAP intraperitoneally, and some mice were administered OPZ 16 h before APAP. Hepatotoxicity was assessed by measuring serum alanine aminotransferase leakage and histopathological evaluation. The hepatic mRNA expressions of CYP2E1, glutamate cysteine ligase (GCL), and NAD(P)H:quinone oxidoreductase (NQO1) were measured by real-time reverse-transcription polymerase chain reaction. OPZ protected mice from APAP-induced liver injury in a dose-dependent manner, but did not alter hepatic glutathione (GSH) content or GCL expression in control mice, indicating that its hepatoprotective effect is not due to changes in basal GSH levels. OPZ did not affect CYP2E1 expression or APAP-induced early GSH depletion, suggesting it does not inhibit the metabolic activation of APAP to produce N-acetyl-p-benzoquinone imine. In contrast, after GSH depletion, OPZ accelerated hepatic GSH recovery. APAP significantly increased GCL expression during liver injury, but OPZ treatment only led to additional NQO1 expression. This suggests that NQO1 is responsible for the enhanced GSH recovery and protection against APAP-induced liver injury seen in OPZ-treated mice. In summary, OPZ protects against APAP-induced liver injury by inducing NQO1 expression and resulting in improved GSH recovery. [ABSTRACT FROM AUTHOR]

Summary: Background: Causality assessment of suspected drug‐induced liver injury (DILI) during metabolic dysfunction‐associated steatohepatitis (MASH) clinical trials can be challenging, and liver biopsies are not routinely performed as part of this evaluation. While the field is moving away from liver biopsy as a diagnostic and prognostic tool, information not identified by non‐invasive testing may be provided on histology. Aim: To address the appropriate utilisation of liver biopsy as part of DILI causality assessment in this setting. Methods: From 2020 to 2022, the Liver Forum convened a series of webinars on issues pertaining to liver biopsy during MASH trials. The Histology Working Group was formed to generate a series of consensus documents addressing these challenges. This manuscript focuses on liver biopsy as part of DILI causality assessment. Results: Expert opinion, guidance and recommendations on the role of liver biopsy as part of causality assessment of suspected DILI occurring during clinical trials for a drug(s) being developed for MASH are provided. Lessons learned from prior MASH programs are reviewed and gaps identified. Conclusions: Although there are no pathognomonic features, histologic evaluation of suspected DILI during MASH clinical trials may alter patient management, define the pattern and severity of injury, detect findings that favour a diagnosis of DILI versus MASH progression, identify prognostic features, characterise the clinicopathological phenotype of DILI, and/or define lesions that influence decisions about trial discontinuation and further development of the drug. [ABSTRACT FROM AUTHOR]

Safety is one of the important factors constraining the distribution of clinical drugs on the market. Drug-induced liver injury (DILI) is the leading cause of safety problems produced by drug side effects. Therefore, the DILI risk of approved drugs and potential drug candidates should be assessed. Currently, in vivo and in vitro methods are used to test DILI risk, but both methods are labor-intensive, time-consuming, and expensive. To overcome these problems, many in silico methods for DILI prediction have been suggested. Previous studies have shown that DILI prediction models can be utilized as prescreening tools, and they achieved a good performance. However, there are still limitations in interpreting the prediction results. Therefore, this study focused on interpreting the model prediction to analyze which features could potentially cause DILI. For this, five publicly available datasets were collected to train and test the model. Then, various machine learning methods were applied using substructure and physicochemical descriptors as inputs and the DILI label as the output. The interpretation of feature importance was analyzed by recognizing the following general-to-specific patterns: (i) identifying general important features of the overall DILI predictions, and (ii) highlighting specific molecular substructures which were highly related to the DILI prediction for each compound. The results indicated that the model not only captured the previously known properties to be related to DILI but also proposed a new DILI potential substructural of physicochemical properties. The models for the DILI prediction achieved an area under the receiver operating characteristic (AUROC) of 0.88–0.97 and an area under the Precision-Recall curve (AUPRC) of 0.81–0.95. From this, we hope the proposed models can help identify the potential DILI risk of drug candidates at an early stage and offer valuable insights for drug development. [ABSTRACT FROM AUTHOR]

A liver injury was recently reported for saxagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor. However, the underlying mechanisms of saxagliptin-induced liver injury remain unknown. This study aimed to evaluate whether saxagliptin, a potent and selective DPP-4 inhibitor that is globally used for treating type 2 diabetes mellitus, binds to the nucleophiles in vitro. Four DPP-4 inhibitors, including vildagliptin, were evaluated for comparison. Only saxagliptin and vildagliptin, which both contain a cyanopyrrolidine group, quickly reacted with L-cysteine to enzyme-independently produce thiazolinic acid metabolites. This saxagliptin–cysteine adduct was also found in saxagliptin-administered male Sprague–Dawley rats. In addition, this study newly identified cysteinyl glycine conjugates of saxagliptin and 5-hydroxysaxagliptin. The observed metabolic pathways were hydroxylation and conjugation with cysteine, glutathione, sulfate, and glucuronide. In summary, we determined four new thiazoline-containing thiol metabolites (cysteine and cysteinylglycine conjugates of saxagliptin and 5-hydroxysaxagliptin) in saxagliptin-administered male rats. Our results reveal that saxagliptin can covalently bind to the thiol groups of cysteine residues of endogenous proteins in vivo, indicating the potential for saxagliptin to cause drug-induced liver injury. [ABSTRACT FROM AUTHOR]

Isoniazid is a first-line drug in antitubercular therapy. Isoniazid is one of the most commonly used drugs that can cause liver injury or acute liver failure, leading to death or emergency liver transplantation. Therapeutic approaches for the prevention of isoniazid-induced liver injury are yet to be established. In this study, we identified the gene expression signature for isoniazid-induced liver injury using a public transcriptome dataset, focusing on the differences in susceptibility to isoniazid in various mouse strains. We predicted that lansoprazole is a potentially protective drug against isoniazid-induced liver injury using connectivity mapping and an adverse event reporting system. We confirmed the protective effects of lansoprazole against isoniazid-induced liver injury using zebrafish and patients' electronic health records. These results suggest that lansoprazole can ameliorate isoniazid-induced liver injury. The integrative approach used in this study may be applied to identify novel functions of clinical drugs, leading to drug repositioning. [ABSTRACT FROM AUTHOR]

Introduction: Drug-induced liver injury (DILI) associated with 5-aminosalicylic acid (5-ASA) is a rare but potentially life-threatening adverse event. Case Presentation: We report the case of a 58-year-old woman with ulcerative colitis who developed DILI after initiating maintenance therapy with the multimatrix system 5-ASA. The patient presented with grade 4 liver enzyme elevation on day 98 after initiating 5-ASA and was admitted to the hospital. Blood tests revealed the mixed liver injury, and imaging studies showed no abnormalities except for mild lymph node enlargement. Liver biopsy revealed acute lobular hepatitis with interfacial activity. The patient's score on the International Autoimmune Hepatitis Group 1999 revised scoring system was a total score of 10, causing a suspicion for the diagnosis of autoimmune hepatitis. The DDW-J 2004 scale calculated a total score of six, indicating a high probability of DILI. We suspected DILI due to 5-ASA, and the 5-ASA formulations were discontinued. The patient was treated with ursodeoxycholic acid and neominophagen C, and her liver function gradually improved without steroid treatment. Finally, we definitively diagnosed DILI based on the pathological findings and clinical course after discontinuation of 5-ASA. Conclusion: This case highlights the importance of monitoring liver function in patients receiving 5-ASA therapy. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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). Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

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. 53 years, 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. [ABSTRACT FROM AUTHOR]

• This research introduces a new deep learning model called DMFPGA for predicting DILI positivity. • DMFPGA fuses multiple features and finally channels them into a fully connected neural network to achieve classification. • We take into account complementary features at both atomic and molecular levels through the extraction and processing of various distinct molecular attributes. • The amalgamation of multiple features is employed to represent each molecule. Drug-induced liver injury (DILI) is a significant issue in drug development and clinical treatment due to its potential to cause liver dysfunction or damage, which, in severe cases, can lead to liver failure or even fatality. DILI has numerous pathogenic factors, many of which remain incompletely understood. Consequently, it is imperative to devise methodologies and tools for anticipatory assessment of DILI risk in the initial phases of drug development. In this study, we present DMFPGA, a novel deep learning predictive model designed to predict DILI. To provide a comprehensive description of molecular properties, we employ a multi-head graph attention mechanism to extract features from the molecular graphs, representing characteristics at the level of compound nodes. Additionally, we combine multiple fingerprints of molecules to capture features at the molecular level of compounds. The fusion of molecular fingerprints and graph features can more fully express the properties of compounds. Subsequently, we employ a fully connected neural network to classify compounds as either DILI-positive or DILI-negative. To rigorously evaluate DMFPGA's performance, we conduct a 5-fold cross-validation experiment. The obtained results demonstrate the superiority of our method over four existing state-of-the-art computational approaches, exhibiting an average AUC of 0.935 and an average ACC of 0.934. We believe that DMFPGA is helpful for early-stage DILI prediction and assessment in drug development. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) remains a challenging diagnosis due to an absence of specific biomarkers. DILI due to volatile anaesthetics (VA-DILI) is characterised by trifluoroacetyl and CYP2E1 antibodies, but may not be seen for weeks after injury. Interleukin-4 (IL-4) may be involved in the production of these antibodies and may serve as a clinically useful early biomarker of VA-DILI. To prospectively compare serum IL-4 levels between patients who develop VA-DILI and controls following exposure to the volatile anaesthetic. A nested case-control study of patients exposed to VA during surgery was conducted. Thirteen DILI cases were identified from the original cohort, and 26 controls were matched according to age, sex and VA agent. Serum samples were collected before and 48-96 h after VA exposure, and analysed for IL-4 using quantitative enzyme-linked immunosorbent assay techniques. There was a statistically significant difference in serum IL-4 in post-VA samples between DILI cases and controls (control: 0.030 pg/mL, IQR: 0.030 − 0.030 pg/mL vs DILI: 0.044 pg/mL, IQR: 0.030 − 0.061 pg/mL; p = 0.039). A greater proportion of DILI cases had post-VA IL-4 levels above the assay lower limit of detection compared to controls (control: 23% vs DILI: 69%; p = 0.013). IL-4 is a potential biomarker of DILI. Clinical diagnosis and understanding of DILI disease mechanisms may be improved by further investigation of novel biomarkers, and this IL-4 signal in serum is important as proof of concept for prospective study designs. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Diagnosis of drug-induced liver injury (DILI) is difficult. We reviewed cases in the DILI Network prospective study that were adjudicated to have liver injury due to other causes to discover pearls for improved diagnostic accuracy. METHODS: Cases were adjudicated by expert opinion and scored from 1 (definite DILI) to 5 (unlikely DILI). Confirmed cases (1-3) were compared with unlikely cases (5). RESULTS: One hundred thirty-four of the 1,916 cases (7%) were unlikely DILI. Alternative diagnoses were autoimmune hepatitis (20%), hepatitis C (20%), bile duct pathology (13%), and hepatitis E (8%). DISCUSSION: Thorough evaluation, including follow-up, is essential to minimize incorrect diagnosis of idiosyncratic DILI. [ABSTRACT FROM AUTHOR]

Background & Aims: Immune checkpoint inhibitors may cause various types of organ damage as immunerelated adverse events, of which, liver damage is the most common. Herein, we evaluated the clinicopathological features of immune checkpoint inhibitor-related liver injury and investigated the differences between immune checkpoint inhibitor-related liver injury and drug-induced liver injury or autoimmune hepatitis. Methods: We selected patients with = grade 3 liver injury who were diagnosed with immune checkpoint inhibitor-related liver injury (n=15). Liver biopsies were performed in 10 of the 15 cases. We also selected cases in which a liver biopsy was performed and drug-induced liver injury (n=7) or autoimmune hepatitis [n=21: acute exacerbation (n=13) was diagnosed and cases of acute onset (n=8), in which liver function test results corresponded to = grade 3]. Results: Portal fibrosis and periportal activity scores were significantly higher in the acute exacerbation autoimmune hepatitis group than in the other groups. Portal and lobular activity were not different between the groups. Plasma cell infiltration showed a higher trend in the autoimmune hepatitis group than in the other groups. Granuloma formations were seen in 90% of immune checkpoint inhibitor-related liver injury cases. The CD4/8 ratio was significantly lower in the immune checkpoint inhibitor-related liver injury group than in the other groups. Patients with bile duct injury had poorer response to corticosteroid therapy than those without. Conclusions: There are some obvious differences among immune checkpoint inhibitor-related liver injury, drug-induced liver injury, and autoimmune hepatitis in liver histology. Liver biopsy is helpful for the diagnosis and severity evaluation of liver injury. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is an unwarranted problem and has been a scourge in the treatment of tuberculosis (TB) infection in general and children in particular. Usually, when the Antituberculosis treatment (ATT) regime is temporarily interrupted and modified, DILI subsides, and the whole treatment can be completed under supervision. We report a case of ATT-induced DILI not improving despite modification in the ATT regime, which ultimately led to the revealing of a yet unreported constellation of syndromes that included Wilson Disease, 46 XX gonadal dysgenesis, and Mayer Rokitansky Kuster Hauser (MRKH) Syndrome. [ABSTRACT FROM AUTHOR]

Drug-Induced Liver Injury (DILI) constitutes hepatic damage attributed to drug exposure. DILI may be categorized as hepatocellular, cholestatic or mixed and might also involve immune responses. When DILI occurs in dose-dependent manner, it is referred to as intrinsic, while if the injury occurs spontaneously, it is termed as idiosyncratic. This review predominately focused on idiosyncratic liver injury. The established molecular mechanisms for DILI include (1) mitochondria dysfunction, (2) increased reactive oxygen species levels, (3) presence of elevated apoptosis and necrosis, (4) and bile duct injuries associated with immune mediated pathways. However, it should be emphasized that the underlying mechanisms responsible for DILI are still unknown. Prevention strategies are critical as incidences occur frequently, and treatment options are limited once the injury has developed. The aim of this review was to utilize retrospective cohort studies from across the globe to gain insight into epidemiological patterns. This review considers (1) what is currently known regarding the mechanisms underlying DILI, (2) discusses potential risk factors and (3) implications of the coronavirus pandemic on DILI presentation and research. Future perspectives are also considered and discussed and include potential new biomarkers, causality assessment and reporting methods. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury and acute liver failure. The diagnosis, screening, and management of APAP induced liver injury (AILI) is challenging because of the complex mechanisms involved. Starting from the current studies on the mechanisms of AILI, this review focuses on novel findings in the field of diagnosis, screening, and management of AILI. It highlights the current issues that need to be addressed. This review is supposed to summarize the recent research progress and make recommendations for future research. [ABSTRACT FROM AUTHOR]

Aims: To explore the potential value of serum glutamate dehydrogenase (GLDH), ferrochelatase (FECH), heme oxygenase‐1 (HO‐1) and glutathione‐S‐transferase‐α (GST‐α) as diagnostic biomarkers for liver injury caused by antituberculosis drugs. Methods: We established a rat model of isoniazide‐induced liver injury and recruited 122 hospitalized tuberculosis patients taking antituberculosis drugs. We detected the concentration of GLDH, FECH, HO‐1 and GST‐α by enzyme‐linked immunosorbent assay. GraphPad Prism8 and SPSS 26.0 were used for statistical analysis. Results: In the rat model, serum GLDH concentration gradually increased during isoniazid (INH) administration, while serum FECH, HO‐1 and GST‐α concentrations significantly increased after INH administration was stopped. The receiver operating characteristic curve showed that the areas under the curve (AUCs) of serum GLDH and FECH for the diagnosis of anti‐tuberculosis (TB) drug‐induced liver injury (anti‐TB‐DILI) were 0.7692 (95% confidence interval [CI] 0.5442‐0.9943) and 0.7284 (95% CI 0.4863‐0.9705) and the diagnostic accuracies were 81.25% and 78.79%, respectively. In clinical research, the AUCs of GLDH and FECH were 0.9124 (95% CI 0.8380‐0.9867) and 0.6634 (95% CI 0.5391‐0.7877), and the optimal thresholds were 10.40 mIU/mL and 1.304 ng/mL, respectively. The diagnostic accuracy, specificity and positive predictive value (PPV) of GLDH were 82.61%, 79.38% and 47.22%. We performed a joint diagnostic test for GLDH and FECH. The diagnostic accuracy (90.43%), specificity (91.75%) and PPV (65.21%) of serial tests were better than for GLDH and FECH alone. Conclusions: GLDH in the diagnosis of liver injury induced by anti‐TB drugs has high sensitivity, but low specificity and low PPV. The combination of GLDH and FECH could significantly improve the specificity, PPV and diagnostic accuracy, and reduce the false‐positive rate of anti‐TB‐DILI. [ABSTRACT FROM AUTHOR]