Drug-induced liver injury (DILI) is an important medical condition. Recently, development of novel causality assessment tools has improved the diagnostic accuracy of idiosyncratic DILI, particularly RECAM (Revised Electronic Version of Roussel Uclaf Causality Assessment [RUCAM]). RECAM was found to be better than RUCAM in difficult cases and increased the precision of the DILI diagnosis but needs further refinement. In recent years, there has been an increased incidence of DILI with drugs, such as oncological drugs and herbal and dietary supplements (HDSs). DILI is commonly associated with checkpoint-induced liver injury. Treatment with corticosteroids has been the standard of care in this type of liver injury, but its use is controversial and potentially harmful. With the help of liver biopsy, 60% of subjects can avoid corticosteroids. In recent years, a number of dietary supplements have been found to lead to DILI, such as turmeric, Garcinia cambogia, kratom and ashwagandha. HLA-B*35:01 has been identified as a risk factor for green tea extract-induced liver injury. International collaborative efforts have tried to find candidate biomarkers, but no biomarker has yet demonstrated superior performance to standard liver tests. FDA has recently approved the use of serum glutamate dehydrogenase (GLDH) as a biomarker to distinguish liver injury from muscle injury. Serum GLDH should be used alongside standard liver injury monitoring in patients without pre-existing liver disease. In the current review, recent findings in DILI are presented on diagnostic strategies, new agents such as checkpoint inhibitors and HDSs leading to DILI, biomarkers and new therapies.

TLR4 knockout ameliorates acute LPS-sensitized tolvaptan-induced idiosyncratic liver injury by disrupting drug metabolism, inflammation, and bile acid homeostasis.

Integration of network pharmacology, lipidomics, and transcriptomics analysis to reveal the mechanisms underlying the synergy between susceptibility factor TNF-α and Polygonum multiflorum-induced idiosyncratic liver injury in mice.

Checkpoint inhibitor-induced liver injury (ChILI) is an immune-related adverse reaction, occurring in patients with cancer receiving immune checkpoint inhibitors (CPI). ChILI is currently managed with high doses of corticosteroids which carry their own risks and potential side effects, and the lack of available biomarkers makes monitoring patients at risk of developing ChILI a challenge. There is no specific test that distinguishes ChILI from other competing diagnoses such as acute autoimmune hepatitis (AIH) and idiosyncratic drug-induced liver injury (DILI) due to other medications. Patients with cancer taking immunotherapy who did and did not develop ChILI were recruited. Patients gave samples during the acute phase of liver injury, before CPI treatment and at 12 weeks following the start of CPI therapy if no toxicity developed. Healthy controls were recruited as well as patients with DILI and AIH. Whole blood was taken for broad immune phenotyping using mass cytometry, peripheral blood mononuclear cells were isolated for validatory flow cytometry and single-cell RNA sequencing (RNA-seq), and plasma was used for cytokine profiling. Samples from a second ChILI cohort were used for validation. Snap-frozen liver biopsies were used for bulk RNA-seq to compare the immune response in ChILI to DILI and AIH and correlate with peripheral immune signals. Formalin-fixed paraffin-embedded liver biopsies were used to visualize liver CD8+ T-cell infiltration using confocal microscopy. We have identified a circulating CD8+ effector memory T-cell subset, expressing high levels of CD38, HLA-DR and CXCR3 and significantly correlated with alanine transaminase. Flow cytometry and single-cell RNA sequencing revealed an increase in granzyme expression, the liver residency marker CD69 and exhaustion markers CTLA-4, PDCD1 and HAVCR2 relative to other CD8+ effector subsets. Liver tissue bulk RNA-seq and immune cell deconvolution showed a significant increase in resident CD8+ T cells in ChILI compared with DILI and AIH, and a significant upregulation of genes related to CXCR chemokine receptor binding. Plasma cytokine profiling highlighted soluble CD27 and PD-1 as significantly elevated in ChILI relative to controls on CPI. We have shown that circulating CD8+ T cells provide a potential biomarker to distinguish ChILI from DILI and AIH, and highlight different mechanistic pathways between ChILI and other immune-mediated liver injuries.

Systematic review on genetic polymorphisms associated with idiosyncratic drug-induced liver injury (iDILI): iDILInet as an interactive visualization tool

The role of extracellular vesicles secreted by the gut microbiota present in faeces (fEVs) is not well known in metabolic dysfunction-associated steatotic liver disease (MASLD) and idiosyncratic drug-induced liver injury (DILI). We identify the microbiome profiles of fEVs in these liver diseases, and analyse the effects of fEVs from MASLD, without (F≤2) or with (F≥3) significant liver fibrosis, and DILI patients on inflammation, steatosis and mitochondrial function. DILI patients showed a consistent pattern in fEVs, characterised by a decrease in Paraprevotella and an increase in AAP99, Acinetobacter, Actinobacillus, Aerococcus and Anaeroglobus. A higher presence of 16S rDNA was observed in plasma EVs from MASLD and DILI patients. HepG2 cells treated with DILI and MASLD F≥3 fEVs increased TLR4, TLR5, IL6 and CASP3 expression, and accumulation of lipid droplets. DILI fEVs enhanced the hepatotoxic impact of diclofenac on the response to microbial components (TLR4, TLR5), inflammatory response (IL1B, IL6), accumulation of lipid droplets and mitochondrial dysfunction (OPA1, DNM1L). In conclusion, bacterial EVs enter the bloodstream and could modulate the immune response. DILI and MASLD F≥3 fEVs are drivers of the pro-inflammatory response and hepatocyte steatosis. DILI fEVs have a distinct bacterial profile that enhances the hepatotoxic potential of diclofenac.

Idiosyncratic DILI is a complex clinical challenge requiring timely and accurate decision support. LiverTox, curated by the National Institute of Health (NIH), offers a comprehensive DILI evidence base, but its encyclopedia-like format hinders point-of-care use. Health care providers increasingly use general large language models (LLMs) for clinical care, raising safety concerns due to LLM hallucinations or misinformation. We hypothesize that retrieval-augmented generation (RAG) integration-grounding LLM responses in LiverTox content-would enable accurate DILI decision support. We processed 1343 LiverTox drug monographs into 8759 indexed segments using BioBERT embeddings. We developed a RAG pipeline that employs drug-specific prioritization, section-aware weighting, and semantic search to retrieve the most relevant content per query. Twenty-five DILI questions were evaluated across 6 models: 4 RAG-LLMs: Mistral-7B, Claude-3-Haiku, Claude-3-Opus, and GPT-4o, and 2 non-RAG GPT-4o variants (unconstrained; soft constrained with a prompt to reference LiverTox). Three hepatologists, blinded to the model, evaluated responses for accuracy, completeness, and conciseness using 5-point Likert scales. Analyses included pairwise comparisons and effect size estimation. One hundred fifty model responses were evaluated with good inter-rater reliability. GPT-4o (RAG) achieved the highest overall scores (4.47±0.10). RAG-LLMs outperformed non-RAG GPT-4o variants in accuracy (p<0.001) and completeness (p<0.01). Moderate to large effect sizes in accuracy (d=0.778) and completeness (d=0.526) were noted with RAG. No hallucinations were observed in RAG-LLM outputs, while both non-RAG GPT-4o variants produced several hallucinated responses. There were no significant differences in scoring or hallucinated response rate between the 2 non-RAG variants. We developed an RAG-LLM integrated with LiverTox for evidence-based DILI management. RAG-LLM systems outperformed non-RAG variants and produced responses without observed hallucinations in this evaluation. Our LiverTox RAG-LLM enables reliable answers to drug hepatotoxicity questions at the point of care.

ObjectiveThis project aims to employ high-performance chemical isotope labeling (HP-CIL) liquid chromatography–mass spectrometry (LC-MS) to conduct a metabolomic study on the mechanisms underlying intrinsic and idiosyncratic drug-induced liver injury (DILI). By comparing the metabolic characteristics between these two types of DILI, we seek to identify biomarkers for predicting intrinsic and idiosyncratic DILI using machine learning strategies.MethodsBased on the diagnostic criteria outlined in the EASL clinical practice guidelines on drug-induced liver injury, a review published in NEJM, enrolled DILI cases were classified according to the pathogenic mechanism into an intrinsic type (n = 17) and an idiosyncratic type (n = 27). Serum samples were collected from both groups. Metabolomic profiling was performed using high-performance chemical isotope labeling liquid chromatography–mass spectrometry (HP-CIL LC-MS) to identify differentially expressed metabolites between the two groups. Metabolites that showed significance in both univariate and multivariate statistical analyses were selected for further receiver operating characteristic (ROC) analysis. Machine learning approaches were employed to develop diagnostic models for distinguishing intrinsic and idiosyncratic DILI. These models were compared to identify potential biomarkers capable of discriminating between the two types of DILI, and the diagnostic performance of these candidate biomarkers was evaluated.ResultSerum metabolomic profiling identified four differential metabolites that distinguished intrinsic from idiosyncratic DILI through multivariate and univariate statistical analyses, followed by ROC curve analysis and machine learning-based selection. These potential biomarkers included Alanyl-Glycine (level 1),N2-Acetyl-L-Cystathionine (level 2a), Isomer 1 of 5-Hydroxyindoleacetic acid (level 2a), and Isomer 1 of 5-Hydroxyindoleacetic acid (level 2a). ROC analysis using multiple machine learning models yielded area under the curve (AUC) values greater than 0.8 for all models, indicating high diagnostic performance. Under a multivariate regression model, internal cross-validation (CV) within the training set demonstrated robust model tuning and stability, with an AUC of 0.983. Holdout validation further confirmed model reliability with an AUC of 0.935. Metabolic pathway analysis of these metabolites revealed that the most significantly associated pathways affecting intrinsic and idiosyncratic DILI were primarily related to amino acid metabolism, including tryptophan metabolism, tyrosine metabolism, cysteine and methionine metabolism, and the biosynthesis of phenylalanine, tyrosine, and tryptophan.ConclusionThis study demonstrates that machine learning-assisted serum metabolomics can effectively characterize currently well-established intrinsic and idiosyncratic drug-induced liver injury, reveal metabolic disparities between the two types, and identify differential metabolites associated with their respective pathogenesis. These findings provide a valuable reference for predicting the mechanistic type of liver injury induced by various hepatotoxic drugs in the future.

Idiosyncratic drug-induced liver injury (IDILI) is particularly problematic due to its severity and unpredictability. Various pathogenic mechanisms have been proposed for IDILI; however, these mechanisms have yet to be comprehensively elucidated. Although the hapten hypothesis has long been posited as a possible pathogenic mechanism, it is believed that other mechanisms may also elicit a strong immune response. We hypothesized that reactive metabolites generated by drug metabolism cause cellular stress and release damage-associated molecular patterns (DAMPs) that may activate antigen-presenting cells (APCs). We have shown that the metabolites of drugs such as acetaminophen, flutamide, and bicartamide activate the inflammasome response in APCs. Moreover, we confirmed that these reactions are suppressed by steroids. Meanwhile, we are also investigating drugs that are suspected to have an immune-mediated mechanism of action based on basic studies using real-world data. If the pathogenic mechanism of IDILI is indeed immune-mediated, it may be suppressed by steroid administration or activated by the concomitant use of immune checkpoint inhibitors. Additionally, we are analyzing the relative risk rates of these drugs in combination. In this review, we present the findings of our previous studies on the pathogenesis of IDILI, including those on reactive metabolites and immune activation. We also present the results of the real-world data analysis which validated the pathogenic mechanism of IDILI that was previously elucidated through basic research, showcasing our efforts to integrate basic and clinical research.

A 38-year-old Caucasian male with no significant past medical history presented to the emergency department with complaints of nausea, vomiting, abdominal pain, and jaundice of 2 days duration. He noticed this in addition to pruritus, fever, and malaise. He had severe transaminitis and hyperbilirubinemia on laboratory evaluation. He was admitted for acute liver injury of an unknown etiology. He had taken a course of ciprofloxacin days prior to presentation for UTI at an outlying facility. Serologies were also concerning possible autoimmune liver disease with elevated Anti-Nuclear Antibody and equivocal Anti Smooth Muscle Antibody. Liver biopsy was negative for any autoimmune pathology. It was determined that the patient experience Drug Induced Liver Injury (DILI) secondary to Ciprofloxacin. Although previously perceived to be a rare occurrence, providers should be aware of the possibility of DILI when prescribing Ciprofloxacin.

Idiosyncratic drug-induced liver injury (iDILI) is a rare but serious adverse reaction that occurs only in a small subset of individuals. Traditionally, drug-induced liver injury has been studied primarily through the lens of hepatocellular toxicity; however, this approach fails to explain the unpredictable nature of iDILI, which often evades detection in preclinical models. Recent studies have shifted the paradigm toward an immune-mediated mechanism, with CD8+ T cell activation restricted by specific human leukocyte antigen (HLA) class I alleles playing a central role. Nevertheless, the presence of a risk HLA allele alone is insufficient to induce disease, underscoring the importance of additional host-specific factors that regulate immune responsiveness. Among these, breakdowns in immune tolerance-such as impaired regulatory T cell function or immune checkpoint failure-appear critical in unleashing pathological T cell activity. Importantly, effective CD8+ T cell activation also requires more than antigen recognition. While HLA-mediated antigen presentation (signal 1) provides specificity, co-stimulatory signals (signal 2) from activated antigen-presenting cells are necessary to drive full activation. The convergence of these two signals, in the context of a permissive immune environment, initiates tissue-damaging immune responses. This stepwise framework offers a more accurate understanding of iDILI as an immunologically orchestrated process rather than a purely toxicological phenomenon. Although HLA-transgenic mouse models seldom reproduce overt liver injury, they serve as valuable platforms for investigating HLA-restricted immune responses in vivo and lay the foundation for improved risk prediction, mechanistic modeling, and safer therapeutic strategies.

Drug-induced liver injury with autoimmune-like features is an uncommon yet clinically significant adverse effect of several medications, including statins. Although generally considered safe, atorvastatin has been associated with rare cases of hepatotoxicity that mimic autoimmune hepatitis on histology. We describe a 53-year-old woman with recently diagnosed chronic kidney disease who developed progressive jaundice and right upper quadrant pain shortly after starting atorvastatin. Laboratory evaluation revealed a mixed pattern of liver injury with worsening liver function tests, while serologic studies for viral hepatitis, autoimmune markers, and metabolic diseases were negative. Imaging ruled out biliary or structural abnormalities. Liver biopsy showed features compatible with autoimmune hepatitis. Given the diagnostic challenge, particularly in seronegative presentations, causality and phenotype assessment tools are essential. The updated Roussel Uclaf Causality Assessment Method (RUCAM) is a validated, widely used instrument with good reproducibility in both idiosyncratic DILI and drug-induced autoimmune hepatitis (DIAIH). Similarly, although the Simplified Autoimmune Hepatitis Score was developed for idiopathic autoimmune hepatitis, it can help identify immunemediated features in DILI when interpreted in a clinical context. In this patient, a RUCAM and S-AIH score of 6, together with compatible histology and a clear temporal association with atorvastatin, supported the diagnosis of statin-induced autoimmune-like hepatitis. The patient received corticosteroids, achieving marked clinical and biochemical improvement. This case highlights the need to consider DILI with autoimmune features in patients with unexplained liver injury after recent statin exposure. When autoimmune serologies are negative, liver biopsy and structured tools such as updated RUCAM and S-AIH are crucial to establish the diagnosis and guide timely immunosuppressive therapy. Although rare, statin-induced autoimmune-like hepatitis is serious but potentially reversible.

Idiosyncratic drug-induced liver injury (iDILI) is an unpredictable and potentially severe adverse drug reaction, in which immune-mediated mechanisms are suspected to play a central role. Although eosinophilia is often considered a marker of hypersensitivity reactions, the role of eosinophils in iDILI, including drug-specific risks, remains poorly understood. We conducted a case-control study using electronic medical records to evaluate drug-specific risks associated with drug-induced liver injury with eosinophilia (DILI-Eos). Among 17129 Japanese adult patients who underwent serial liver function tests and eosinophil counts, we extracted 631 DILI-Eos cases and 16498 non-DILI-Eos controls. Multivariable logistic regression analysis was performed for 38 drugs that were newly prescribed in more than 50 DILI-Eos cases within 60 d prior to liver injury onset. Sulbactam/cefoperazone showed the strongest association with DILI-Eos (adjusted odds ratio (OR) 14.51; 95% confidence interval (CI) 10.09-20.85), followed by meropenem (OR 5.68; 95% CI 4.10-7.82) and tazobactam/piperacillin (OR 3.55; 95% CI 2.63-4.75). Several commonly used drugs, such as mosapride, lansoprazole, furosemide, and ambroxol, were also significantly associated with increased risk. These findings suggest that DILI-Eos can be triggered by a wide range of drugs across various therapeutic classes potentially via immune-mediated pathways. Notably, substantial variability in risk was observed even within the same drug classes, such as β-lactam antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), underscoring the importance of drug-specific evaluation. Further studies are needed to clarify the causality and mechanisms underlying eosinophilic responses in DILI.

Drug-induced liver injury (DILI) is a major cause of drug development failure and market withdrawal. Despite the use of animal and human-derived preclinical models, none reliably predict human hepatotoxicity. Conventional animal studies, based on group-level averages, overlook inter-individual variability critical to idiosyncratic DILI. Although several alternatives to animal testing are available, implementation of alternative methodologies into safety evaluations is very slow and to date, no standalone validated alternative models to assess systemic toxicity exist. To address this, we developed a novel serum-educated rat liver spheroid model that captures individual metabolic diversity, allowing DILI to be assessed both in vitro and in vivo within the same animal. Building on this approach, the present study aimed to validate the model’s ability to detect DILI caused by well-characterized hepatotoxic drugs, including diclofenac and bosentan, in rat models. Rats were treated orally with diclofenac or bosentan for 28 days. Blood was collected pre-dosing to generate individualized spheroids containing rat hepatocytes, stellate cells, and macrophages. These spheroids were exposed to each drug across a ten-point concentration range for 3 days and cell viability was quantified using the CellTiter-Glo ATP assay. Clinical chemistry analyses of ALT, AST, ALP, albumin, and bilirubin were performed at in vivo study termination on day 29. In vitro data were analyzed using PredictCan-MIND to derive DILI severity scores and correlate in vitro cytotoxicity with in vivo biomarkers. In vivo, diclofenac caused no significant liver enzyme elevations, although some rats, exclusively females, displayed subtle toxicity revealing sex-dependent susceptibility. Corresponding in vitro spheroids confirmed hepatocellular injury in these individuals. Bosentan produced a mild cholestatic response in vivo without consistent enzyme elevation, while in vitro analysis showed clear hepatotoxicity in 8 of 10 rats. Notably, in vitro DILI severity correlated strongly with in vivo ALP levels, consistent with bosentan’s known cholestatic mechanism. The serum-educated rat liver spheroid model captures inter-individual and sex-related differences in hepatotoxicity and demonstrates translational concordance with in vivo cholestatic markers. This approach improves DILI prediction, aligns with the 3Rs principle, and supports a potential 50%–70% reduction in animal use for preclinical liver toxicity testing.

Rationale:Idiosyncratic drug-induced liver injury is characterized by its unpredictability, lack of dose-dependence, and interindividual variability. Scutellariae Radix is a natural product widely used to treat liver diseases and has been rarely associated with liver injury in clinical settings. The report presents the case of a 50-year-old female who was hospitalized due to a Scutellariae Radix-induced liver injury.Patient concerns:The patient presented to our emergency department with a fever. And she was subsequently admitted to the hepatology department after being diagnosed with liver dysfunction.Diagnoses:Based on the exclusion of other potential causes and the patient’s prior similar episode of liver injury, a diagnosis of Scutellariae Radix-induced liver injury was established.Interventions:The patient stopped taking the herbal decoction and received hepatoprotective therapy.Outcomes:Levels of alanine transaminase and aspartate aminotransferase decreased by more than 50% on the eighth day and basically returned to normal at the time of discharge. The patient then followed up regularly, and her liver function remained within normal ranges.Lessons:The report describes a rare case of IDILI induced by Scutellariae Radix, and the presence of the rs2032582 variant in ABCB1 was revealed in this patient, which may represent an individual observation of potential relevance. Future studies are warranted to explore the potential genetic predisposition in larger cohorts.

BackgroundDrug-induced liver injury is an uncommon, idiosyncratic adverse reaction with heterogeneous clinical presentations, ranging from asymptomatic transaminase elevations to acute liver failure. Sodium-glucose cotransporter 2 inhibitors, widely prescribed for type 2 diabetes due to their glycaemic, cardiovascular, and renal benefits, are generally considered safe to the liver. Nonetheless, rare cases of cholestatic and hepatocellular drug-induced liver injury have been reported, highlighting the need for vigilance and systematic evaluation when liver dysfunction occurs in patients receiving these agents.Case reportWe describe a 56-year-old man with type 2 diabetes and chronic schizophrenia who developed cholestatic liver injury 36 days after initiating empagliflozin 10 mg od. The patient presented with jaundice, dark urine, and pale stools, with laboratory findings revealing elevated bilirubin, gamma-glutamyl transferase, and alkaline phosphatase disproportionate to alanine aminotransferase. Comprehensive work-up excluded viral, autoimmune, metabolic, and obstructive causes. Imaging confirmed intrahepatic cholestasis without biliary obstruction. Causality assessment using the Roussel Uclaf Causality Assessment Method, Maria and Victorino and Naranjo scores indicated probable adverse drug reaction. Liver biopsy demonstrated acute cholestatic injury with portal inflammatory infiltrates and ductular reaction, consistent with drug-related pathology. Empagliflozin withdrawal led to gradual clinical and biochemical recovery.ConclusionEmpagliflozin can, in rare cases, trigger idiosyncratic cholestatic drug-induced liver injury, even in patients with cirrhosis. Early recognition, prompt drug withdrawal, and systematic evaluation are essential. This case adds to the limited literature on sodium-glucose cotransporter 2 inhibitor-associated hepatotoxicity.LEARNING POINTSDrug-induced liver injury is a diagnosis of exclusion. Clinicians must rule out other causes, especially biliary obstruction, and use structured causality assessment tools to identify the offending drug.Empagliflozin and other sodium-glucose cotransporter 2 inhibitors can, in rare cases, cause liver injury. Monitoring liver function after initiating these drugs is advisable, particularly in patients with pre-existing liver disease.There is no specific treatment for idiosyncratic drug-induced liver injury. Prompt withdrawal of the offending and supportive care are usually sufficient for recovery.

Sulfamethoxazole (SMX) is associated with idiosyncratic drug-induced liver injury, which remains difficult to predict. SMX is metabolized by N-acetyltransferases (NAT1/NAT2) to form N4-acetyl sulfamethoxazole (NA-SMX), and by cytochrome P450-mediated oxidation to form SMX-hydroxylamine. This study aimed to characterize SMX metabolism in vitro and investigate how NAT1 and NAT2 variation influences NA-SMX formation, including the relationship between NAT2 protein levels and metabolite formation. Human liver microsomes, S9 fractions, and primary human hepatocytes were used to generate SMX metabolites. NA-SMX was the most abundant metabolite in primary human hepatocytes, showing 4.2-fold variability across n = 26 donors. Interestingly, NAT2 genotype-inferred acetylator phenotype did not reliably predict NA-SMX formation in 6 of 9 slow acetylators, whose formation exceeded the mean of intermediate acetylators. However, N-acetyl sulfamethazine (NA-SMZ) formation was accurately predicted using the NAT2 probe substrate, SMZ, revealing significant differences between NAT2 phenotype groups (P < .05). Activities of NAT1 and NAT2, as measured by p-aminobenzoic acid and SMZ N-acetylation, respectively, significantly correlated with NA-SMX formation (r = 0.576, P = .006; r = 0.459, P = .036). The stronger correlation with NAT1 activity supports the relationship of NAT1 to SMX metabolism. Novel targeted proteomic quantification of NAT2 showed significant correlations between NAT2 protein concentration and NAT2 activity (r = 0.823; P < .0001 and r = 0.734, P = .0002; for 2 peptides). This work demonstrates interindividual variability in SMX metabolism and highlights the importance of considering genetic and nongenetic factors in SMX-induced drug-induced liver injury risk. SIGNIFICANCE STATEMENT: This study provides new insights into sulfamethoxazole (SMX) metabolism using in vitro hepatic systems and quantifies interindividual variability in N4-acetyl SMX formation. Although NAT2 genotype did not predict SMX slow acetylator metabolism in all individuals, N4-acetyl SMX formation was significantly correlated with NAT1 and NAT2 enzyme activity. These findings show the importance of considering both genetic and phenotypic data to better understand SMX metabolism and individual risk for drug-induced liver injury.

ABSTRACTDrug‐Induced Liver Injury (DILI) is a rare but potentially serious adverse effect of many commonly used medications. DILI is a diagnosis of exclusion and requires a high index of suspicion. Amoxicillin‐Clavulanate (A‐C) is a widely prescribed antibiotic known to be one of the leading causes of idiosyncratic DILI. Though well documented in Western countries, cases of DILI are less frequently reported in our region. The usual onset of DILI varies from a few days to 8 weeks after initiation of medication. Here, we report a case of an atypically rapid onset of amoxicillin–clavulanate induced liver injury in a 32‐year‐old female following just two doses.

Abstract Temozolomide (TMZ) remains a foundational component of glioblastoma (GBM) therapy. While generally well tolerated, post-marketing surveillance has revealed rare but potentially life-threatening hepatotoxicity. Most cases of TMZ-induced liver injury are mild and self-limited, with a cholestatic or mixed pattern appearing within 2 to 8 weeks of therapy initiation. However, severe and prolonged liver injury is infrequently reported and poorly characterized. We present a case of grade 4 cholestatic hepatitis in a GBM patient receiving standard-dose TMZ. Liver injury developed after a cumulative dose of 3200 mg over four weeks and was characterized by marked transaminase and bilirubin elevation. The patient had no prior hepatic disease, no concurrent hepatotoxic medications, and no alternative etiologies, fulfilling criteria for probable idiosyncratic drug-induced liver injury. Notably, liver function recovery required approximately three months, underscoring the potential for protracted clinical courses. Our case is consistent with findings from Dixit et al., who reviewed five cases of TMZ-associated liver injury, predominantly cholestatic in pattern, with a median latency of 6.5 weeks and cumulative dose near 3,075 mg. This case contributes to the growing body of evidence emphasizing the importance of regular hepatic monitoring during TMZ therapy. Given the potential severity and delayed onset of hepatotoxicity, clinicians should remain vigilant, particularly in patients without alternative explanations for liver dysfunction. Temozolomide-induced liver injury, although rare, can be severe and prolonged. Awareness, early detection, and adherence to recommended monitoring protocols are essential to ensure patient safety.

Features and Outcomes of 280 Patients With Idiosyncratic Drug-induced Liver Injury: The REFHEPS Prospective Study.