It can be difficult to distinguish between drug-induced liver injury (DILI) and liver injury associated with sepsis (sepsis induced liver injury, SILI). The aims of the study were to compare clinical and biochemical features between DILI and SILI and identify distinguishing characteristics that might assist in diagnosing these conditions.

Retrospective cohorts of all DILI cases diagnosed in Iceland 2009-2024 and SILI 2006-2024 were divided into hepatocellular and cholestatic (CS/mixed) patterns. Patients had: > 5× upper limit of normal (ULN) of ALT and/or > 2× ULN in ALP. RUCAM and expert opinion were used in the causality assessment of DILI, and SILI patients had to fulfil international consensus criteria.

Overall 275 DILI patients (median age 59 years, 63% females), 153 with SILI (67 years, 49% females) were included. Among patients with HC type, 57% with SILI and only one (0.9%) with DILI had normal liver tests 2 weeks after the event. The peak value of AST was 1794 (IQR 931-3526) IU/L in HC type of SILI but 584 (315-1013) IU/L in DILI, p < 0.001. CS/mixed type of SILI resolved also significantly faster while CS/mixed pattern of DILI had significantly higher ALP at onset and peak ALT than SILI. SILI had 30% mortality compared to DILI (2%) p < 0.001.

Marked elevation of AST and rapid resolution with a HC pattern of liver injury favours the diagnosis of SILI. Cholestatic/mixed SILI also resolves rapidly in contrast to CS/mixed DILI that is associated with markers of more pronounced liver injury.

Drug-induced liver injury (DILI) is a drug-induced disease that not only complicates the treatment of the primary disease but may also lead to acute liver failure or even death in severe cases. Drugs commonly used in primary care, such as anti-infective agents and nonsteroidal anti-inflammatory drugs, are major causes of DILI. In addition, a large elderly population, comorbidities, and combination therapy with multiple drugs increase the risk of DILI in primary care. Therefore, primary care providers should proactively screen and monitor high-risk patients to identify potential DILI timely. Currently, diagnosis of DILI relies on the exclusion of liver diseases of other etiologies. Collection of detailed medical history of the patients and careful exclusion of other potential liver injury of other etiologies are crucial for accurate diagnosis. This guideline, developed based on evidence-based medicine from the latest research, aimed to provide primary care providers with professional guidance on the timely identification of suspected DILI cases and standardized diagnosis and management in clinical practice.

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.

Ulipristal acetate (UPA, 5 mg) demonstrated efficacy in symptom reduction for patients with symptomatic fibroids. While registration and post-marketing trials assessing UPA identified few hepatic concerns, post-marketing concerns about potential drug-induced liver injury (DILI) led to significant restrictions, including indication restriction, warning labels and mandatory liver function monitoring. These measures, along with two marketing suspensions, resulted in a decline in UPA use, ultimately leading to the withdrawal of its marketing authorization previously in Canada, Australia, as well as Singapore and in 2024, at the request of the marketing authorization holder for commercial reasons, also for the European Union.

This narrative review critically evaluates the hepatic safety considerations associated with UPA.

On reassessment, the risk of severe DILI with UPA is low at 13.5:100.000, with an incidence of 1 in 200,000 for liver transplantation. These numbers are lower than with many other widely prescribed medications, where no regular liver monitoring is recommended. UPA was subjected to strict liver test monitoring although proof of effectiveness of these measures in preventing serious DILI was lacking. While the risk of severe hepatotoxic events is important to consider, a balanced approach to safety measures is needed, particularly in light of the higher risks associated with alternative treatment options such as surgical intervention.

While UPA had a unique place in the treatment of uterine fibroids, overly cautious regulatory measures due to exceedingly rare DILI incidences led to the withdrawal of its marketing authorization in most parts of the world. There is a need for an improved understanding of DILI mechanisms and causality assessments to aid in the development of more proportional regulatory responses, balancing patient safety and sustained access to effective innovative treatment.

Drug-induced liver injury (DILI) presents a major challenge not only in new drug development but also in post-marketing withdrawals and the safety of food, cosmetics, and chemicals. Experimental model organisms such as the rodents have been widely used for preclinical toxicological testing. However, the tension exists associated with the ethical and sustainable use of animals in part because animals do not necessarily inform the human-specific ADME (adsorption, dynamics, metabolism and elimination) profiling. To establish alternative models in humans, in vitro hepatic tissue models have been proposed, ranging from primary hepatocytes, immortal hepatocytes, to the development of new cell resources such as stem cell-derived hepatocytes. Given the evolving number of novel alternative methods, understanding possible combinations of cell sources and culture methods will be crucial to develop the context-of-use assays. This review primarily focuses on 3D liver organoid models for conducting. We will review the relevant cell sources, bioengineering methods, selection of training compounds, and biomarkers towards the rationale design of in vitro toxicology testing.

Most epidemiological studies have found antibiotics to be the most common cause of drug-induced liver injury (DILI). It is unclear what the risk of DILI is associated with different antibiotics.

The aim of the study was to assess the frequency of DILI due to the most commonly used antibiotics among inpatients, in a population-based setting.

Patients who were treated with the 14 most-used antibiotics at Landspitali University Hospital Iceland 2012-2023, with concomitant: > 5 × upper limit of normal (ULN) of alanine aminotransferase (ALT) and/or > 2 × ULN of alkaline phosphatase (ALP), were identified. If DILI was a potential cause, the Revised Electronic Causality Assessment Method (RECAM) method was used to determine likelihood of DILI.

Overall 2292 patients fulfilled the inclusion criteria, 52 of whom were found to have DILI, median age 67 (range 21-93) years, 58% females, 17 (33%) with jaundice and three (5.8%) died of liver failure. The most commonly implicated agent was amoxicillin/clavulanate (n = 23) in 1:1327 users (0.075%), ceftriaxone (n = 8) 1:3779 (0.02%), cefazolin (n = 7) 1: 6363 (0.016%), cloxacillin 1:6024 (n = 4) (0.017%), piperacillin/tazobactam (n = 2) 1:1551 (0.097%), vancomycin (n = 2) 1:1966 (0.076%), trimethoprim-sulfamethoxazole (TMP/SMX) (n = 3) 1:1096 (0.091%) and ciprofloxacin (n = 1) 1:10,938 (0.009%). In two cases, more than one antibiotic was considered likely.

Drug-induced liver injury was found to be a rare adverse effect of antibiotics in a population-based setting. Overall, 33% presented with jaundice but three died of liver failure, all due to amoxicillin/clavulanate, which was the most common cause occurring in around 1 in 1300 users. However, TMP/SMX was associated with the highest proportional risk of DILI.

Pharmacogenomics, therapeutic drug monitoring, and the assessments of hepatic and renal function have made significant contributions to the advancement of individualized medicine. However, their lack of direct correlation with protein abundance/non-genetic factors, target drug concentration, and drug metabolism/excretion significantly limits their application in precision drug therapy. The primary task of precision medicine is to accurately determine drug dosage, which depends on a precise assessment of the ability to handle drugs in vivo, and drug metabolizing enzymes and transporters are critical determinants of drug disposition in the body. Therefore, accurately evaluating the functions of these enzymes and transporters is key to assessing the capacity to handle drugs and predicting drug concentrations in target organs. Recent advancements in the evaluation of enzyme and transporter functions using exogenous probes and endogenous biomarkers show promise in advancing personalized medicine. This article aims to provide a comprehensive overview of the latest research on markers used for the functional evaluation of drug-metabolizing enzymes and transporters. It also explores the application of marker omics in systematically assessing their functions, thereby laying a foundation for advancing precision pharmacotherapy.

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.

Drug-induced liver injury is an important adverse effect and can be caused by various medications, including novel therapeutic agents. The risk stratification of patients susceptible to DILI is a growing field.

The current article highlights new studies on risk stratification regarding risk factors of DILI, prediction of liver injury, and predictors of severe outcomes. Studies on patient demographic and genetic risk factors are discussed, in addition to the potential role of concomitant medications that may affect the risk of DILI.

Although much is known about patient risk factors for DILI, a better combination of these factors into risk scores is needed to predict which patients are particularly susceptible. Knowledge of these risk factors might determine drug treatment in the near future, as well as the need for routine monitoring of liver tests.

Drug-induced autoimmune-like hepatitis (DI-ALH) is a potentially life-threatening condition that can lead to acute liver failure and necessitate liver transplantation. While the association between certain drugs and DI-ALH has been documented, a comprehensive analysis of drug-related signals in a large, real-world pharmacovigilance database is lacking. This study aimed to systematically identify drugs linked to DI-ALH by analyzing adverse event reports from the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) database.

We searched the FAERS database for the term "autoimmune hepatitis" and extracted DI-ALH reports from the first quarter of 2004 to the first quarter of 2024. Positive signal drugs were identified using Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). To confirm a significant drug-adverse event association, each method had to meet predefined thresholds: for PRR and ROR, values were considered significant if the lower 95% confidence interval (CI) was greater than 1 and at least three reports were identified; for BCPNN, an Information Component (IC025) greater than 0 indicated a signal; for EBGM, a value greater than 2 for the lower 95% confidence interval (EBGM05) was used to denote a positive signal.

A total of 5,723 DI-ALH reports were extracted from the FAERS database. Disproportionality analysis identified 50 drugs with strong associations to DI-ALH, with biologics, statins, antibiotics, and antiviral drugs representing the most common categories. Among these, nitrofurantoin (ROR 94.79, CI 78.53-114.41), minocycline (ROR 77.82, CI 65.09-93.05), and nivolumab (ROR 47.12, CI 15.06-147.39) exhibited the strongest signals. Additionally, several previously unreported drugs, including mesalazine, aldesleukin, onasemnogene abeparvovec-xioi, and nefazodone, were identified as having strong associations with DI-ALH. These findings were consistent across all four signal detection methods, further validating the robustness of the associations.

This study provides a comprehensive assessment of drugs associated with DI-ALH through a rigorous analysis of the FAERS database using multiple signal detection methods. By identifying both well-known and previously underreported drugs, this study contributes to a more complete understanding of drug-induced liver injury. The findings have important implications for pharmacovigilance strategies and clinical risk assessment. However, limitations inherent in the FAERS database, such as underreporting and the potential for reporting bias, should be considered. Further clinical validation is warranted to confirm these associations.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

Drug-induced liver injury (DILI) is a leading cause of acute liver failure. Hepatotoxicity typically occurs only in a subset of individuals after prolonged exposure and constitutes a major risk factor for the termination of drug development projects.

We provide an overview of available human liver models for DILI research and discuss how they have been used to aid in early risk assessments and to mitigate the risk of project closures due to DILI in clinical stages. We summarize the different data that can be provided by such models and illustrate how these diverse data types can be interfaced with machine learning strategies to improve predictions of liver safety liabilities.

Advanced human liver models closely mimic human liver phenotypes and functions for many weeks, allowing for the recapitulation of hepatotoxicity events in vitro. Integration of the biochemical, histological, and toxicogenomic output data from these models with physicochemical compound properties using different machine learning architectures holds promise to enhance preclinical DILI predictions. However, to realize this aim, it is important to benchmark the available liver models on test sets of DILI positive and negative compounds and to carefully annotate and share the resulting data.

The incidence of drug-induced liver injury (DILI) is not known for most prescription medications. We aimed to estimate the incidence of DILI for commonly prescribed outpatient drugs.

To establish a baseline estimate of DILI incidence, we used the estimated incidence (EI) of amoxicillin/clavulanate DILI from a previous population-based study in Iceland. This was combined with the multicenter prospective DILI Network (DILIN) cohort and the US population-based Medical Expenditure Panel Survey (MEPS). From 2005 to 2019, prescription drugs with at least five bona fide DILIN cases and data from at least 10 of the 15 years from MEPS during that timeframe were included. The EI for 'drug A' was calculated as follows: EI ( drug A ) = EI AC × # DILIN cases of drug A # annual new prescriptions of drug A × # annual new prescriptions of AC # DILIN cases of AC RESULTS: In total, 30 drugs met the inclusion criteria, of which 11 were antibiotics, 4 were antiepileptic drugs (AEDs), 4 were statins, and 11 were other drug types. The highest EI was seen with azathioprine and older AEDs, with one DILI case per 349-2329 new prescriptions. The EI of antibiotics ranged greatly, with the highest risk seen for minocycline, amoxicillin/clavulanate, and nitrofurantoin (approximately 1:1000-2400 new prescriptions), and lowest risk for clindamycin, doxycycline, azithromycin, and amoxicillin (approximately 1:40,000-170,000 new prescriptions). The EI for commonly prescribed statins was approximately 1:10,000-50,000. Important medication classes with > 5 million new prescriptions from 2005 to 2019 but fewer than five DILIN cases included β-blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, selective serotonin reuptake inhibitors, and metformin, which presumably have very low DILI incidence.

The highest EI was found for azathioprine, older antiepileptics, and minocycline. In contrast, many widely used drugs are rare causes of DILI. These findings may help clinicians better weigh potential benefits of medications against hepatotoxicity risk.

Discriminating between idiosyncratic drug-induced liver injury (DILI) and autoimmune hepatitis (AIH) is critical yet challenging. We aim to develop and validate a machine learning (ML)-based model to aid in this differentiation.

This multicenter cohort study utilised a development set from Beijing Friendship Hospital, with retrospective and prospective validation sets from 10 tertiary hospitals across various regions of China spanning January 2009 to May 2023. Different ML algorithms were tested using 24 routine laboratory parameters. The Shapley Additive exPlanations (SHAP) analysis was used to evaluate the contribution of each parameter in the ML model.

A total of 2554 patients (1750 for DILI and 804 for AIH) were included. Using Gradient Boost Decision Tree algorithm, five key parameters-aspartate transaminase, globulin, prealbumin, creatinine and platelet count-were selected to construct the ML model. Consequently, a web-based tool named Beijing-AID (BJ-AID) was developed (http://43.143.153.225:5000/). The BJ-AID model demonstrated excellent discrimination performance, with an area under the receiver operating characteristic curve (AUROC) of 0.94 (95% CI, 0.902-0.975) in the development set, 0.91 (95% CI, 0.900-0.928) in all external validation sets and 0.93 (95% CI, 0.889-0.974) in a prospective validation set. Notably, the BJ-AID model also effectively discriminated atypical cases, including drug-induced autoimmune-like hepatitis and AIH with the history of drug consumption, achieving an AUROC = 0.85 (95% CI, 0.742-0.949).

We successfully developed and validated a machine learning-based model, BJ-AID, which exhibits a strong discrimination performance. BJ-AID can assist practitioners and hepatologists in diagnosing both typical and atypical cases of DILI and AIH.

ClinicalTrials.gov identifier: NCT05532345.

Statin-associated autoimmune hepatitis (AIH) is a rare but potentially life-threatening adverse event. Currently, no studies have investigated the associationbetween AIH and different statins.

This retrospective analysis of statin-associated AIH utilized the FDA Adverse Event Reporting System (FAERS) database (Q1 2004 to Q1 2024) and a systematic literature review. Disproportionality and Bayesian analyses were used to detect potential AIH signals associated with statin use.

Among 3,581 AIH reports in the FAERS database, 337 (9.41%) were associated with statins. Among all statins, fluvastatin exhibited the strongest signal, with a relative odds ratio (ROR) of 54.85 (95% CI: 32.32-93.10). Stratified analysis revealed stronger signals in patients ≥65 years (ROR 16.83 vs 9.45) and females (ROR 13.88 vs 9.00) compared to patients <65 years and males, respectively. Statins showed a higher risk of AIH compared to evolocumab, and a similar or lower risk when compared to ezetimibe and fenofibrate. Additionally, 30 cases reported in 20 independent studies were summarized.

This study demonstrates a significant association between AIH and the use of statins, particularly among older patients and females. Further research is needed to explore additional risk factors for statin-associated AIH.

Drug-induced liver injury (DILI) is an acute liver injury that poses a significant threat to human health. In severe cases, it can progress into chronic DILI or even lead to liver failure. DILI is typically caused by either intrinsic hepatotoxicity or idiosyncratic metabolic or immune responses. In addition to the direct damage drugs inflict on hepatocytes, the immune responses and liver inflammation triggered by hepatocyte death can further exacerbate DILI. Initially, we briefly discussed the differences in immune cell activation based on the type of liver cell death (hepatocytes, cholangiocytes, and LSECs). We then focused on the role of various immune cells (including macrophages, monocytes, neutrophils, dendritic cells, liver sinusoidal endothelial cells, eosinophils, natural killer cells, and natural killer T cells) in both the liver injury and liver regeneration stages of DILI. This article primarily reviews the role of innate immune regulation mediated by these immune cells in resolving inflammation and promoting liver regeneration during DILI, as well as therapeutic approaches targeting these immune cells for the treatment of DILI. Finally, we discussed the activation and function of liver progenitor cells (LPCs) during APAP-induced massive hepatic necrosis and the involvement of chronic inflammation in DILI.

Idiosyncratic hepatotoxicity induced by prescribed drugs has been known since the early 20th century. Identifying risk factors, including genetic factors, that trigger this drug-induced liver injury (DILI) has been an important priority for many years, both to prevent drugs that cause liver injury being licensed and as a potential means of preventing at-risk patients being prescribed causative drugs. Improved methods for genomic analysis, particularly the development of genome-wide association studies, have facilitated the identification of genomic risk factors for DILI, but, to date, there are only two main examples, liver injury caused by amoxicillin-clavulanate (AC) and by flucloxacillin, where genetic risk factors causing the injury have been identified and replicated with understanding of the underlying mechanism. There has also been progress on identifying genetic risk factors for liver injury caused by other anti-infective agents, herbal remedies and nonsteroidal anti-inflammatory drugs. The majority of genetic risk factors identified to date are specific human leucocyte antigen (HLA) alleles and evidence that these alleles preferentially present self-peptides inappropriately to T cells in the liver has been obtained. Non-HLA genes also contribute to genetic susceptibility, both as co-factors in T-cell responses and, in the case of isoniazid-only, drug metabolism. Polygenic risk scores to predict DILI have been developed, both a simple score that predicts AC injury and complex scores that may be applied to DILI more generally and provide evidence that additional risk factors other than HLA genes exist.

Human liver organoids are expected to be a hepatocyte source for preclinical in vitro studies of drug metabolism and disposition. Although these organoids show long-term proliferation, their hepatic functions remain low. Therefore, it is necessary to enhance the hepatic functions of primary human hepatocyte (PHH)-derived organoids. Here, we propose a novel method for two dimensional (2D)-cultured hepatic differentiation from PHH-derived organoids. PHH-derived organoids were established from cryopreserved PHHs. When cultured under a 2D condition, the single cells from PHH-derived organoids were seeded on collagen type I-coated plates. Then, optimal conditions for hepatic differentiation were screened using several compounds, cytokines and growth factors. Based on the results of the screening, we determined the 2D-cultured hepatic differentiation method from PHH-derived organoids. Hepatic gene expressions in PHH-derived organoids-derived hepatocytes (Org-HEPs) were greatly increased, compared to those in PHH-derived organoids. An RNA-seq analysis showed that gene expressions related to pharmacokinetics were upregulated in Org-HEPs compared to PHH-derived organoids. The metabolic activities of CYP1A2, CYP2C8, CYP2E1 and CYP3A4 were at levels comparable to those in PHHs. We also treated Org-HEPs and PHHs with hepatotoxic drugs, such as acetaminophen, troglitazone, amiodarone and clozapine. The cell viability of Org-HEPs was almost the same as that of PHHs. These results suggested that PHH-derived organoids could be differentiated into highly functional hepatocytes in 2D culture, and Org-HEPs could be used for hepatotoxicity tests. Thus, Org-HEPs will be useful for pharmaceutical research.

Elagolix is approved for the treatment of moderate-to-severe pain associated with endometriosis. However, the long-term safety of elagolix in a large sample of real-world patients is unknown.

The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) reports were collected and analyzed from January 2019 to June 2023. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed in data mining to quantify the signals of elagolix-related adverse events (AEs).

After removing the non-drug-related AE signals, we detected several AE signals such as hot flushes, bone pain, suicidal ideation, depression, and increased liver enzymes, which were known during the clinical trial phase. In addition to this, we detected several unexpected important AEs that were not mentioned in the drug insert, including cystitis interstitial, parosmia, and epiploic appendagitis. The median onset time of elagolix-associated AEs was 28.5 days.

Our study provides a comprehensive picture of the safety of elagolix in the post-marketing setting, while also identifying potential new AE signals. These findings emphasize the importance of continued monitoring of the potential risks of elagolix.

Drug-induced liver injury (DILI) is a leading cause of drug development failures during clinical trials and post-market introduction. Current biomarkers, such as ALT and AST, lack the necessary specificity and sensitivity needed for accurate detection. Exosomes, which protect LncRNAs from RNase degradation, could provide reliable and easily accessible options for biomarkers.

RNA-sequencing was used to identify differentially expressed LncRNAs (DE-LncRNAs), followed by isolation of LncRNAs from plasma exosomes in this study. Exosome characterization was conducted by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB). Bioinformatics analysis included functional enrichment and co-expression network analysis. Five rat models were established, and quantitative real-time PCR was used to verify the specificity and sensitivity of two candidate exosomal LncRNAs.

The APAP-induced hepatocellular injury model was successfully established for RNA-sequencing, leading to the identification of several differentially expressed exosomal LncRNAs. Eight upregulated exosomal DE-LncRNAs were selected for validation. Among them, NONRATT018001.2 (p < 0.05) and MSTRG.73954.4 (p < 0.05) exhibited a more than 2-fold increase in expression levels. In hepatocellular injury and intrahepatic cholestasis models, both NONRATT018001.2 and MSTRG.73954.4 showed earlier increases compared to serum biomarkers ALT and AST. However, no histological changes were observed until the final time point. In the fatty liver model, NONRATT018001.2 and MSTRG.73954.4 increased earlier than ALT and AST at 21 days. By the 7th day, minor steatosis was evident in liver tissue, while the expression levels of the two candidate exosomal LncRNAs exceeded 2 and 4 times, respectively. In the hepatic fibrosis model, NONRATT018001.2 and MSTRG.73954.4 showed increases at every time point. By the 49th day, hepatocellular necrosis and fibrosis were observed in the liver tissue, with NONRATT018001.2 showing an increase of more than 8 times. The specificity of the identified exosomal DE-LncRNAs was verified using a myocardial injury model and they showed no significant differences between the case and control groups.

NONRATT018001.2 and MSTRG.73954.4 hold potential as biomarkers for distinguishing different types of organ injury induced by drugs, particularly enabling early prediction of liver injury. Further experiments, such as siRNA interference or gene knockout, are warranted to explore the underlying mechanisms of these LncRNAs.

Studies evaluating the hepatic safety of medications have been limited by the inability to control for confounding from receipt of other hepatotoxic drugs.

The objective of this study was to develop an index (Hepatotoxicity Score) to adjust for concomitant hepatotoxic medication exposure within pharmacoepidemiology studies.

We identified 193 medications with ≥ 4 reports of hepatotoxicity and created cohorts of outpatient initiators in the Veterans Health Administration (2000-2021). Exposure occurred from initiation through 30 days after discontinuation or up to 1 year. We measured age-/sex-adjusted rates of hospitalization for severe acute liver injury (ALI) by chronic liver disease (CLD), identified drugs with high rates, and used these rates as weights in the score. To demonstrate real-world use, we calculated the score for proton pump inhibitor (PPI) initiators. We summed the weights of the drugs dispensed within 90 days prior to PPI initiation. Hazard ratios (HRs) of severe ALI (95% confidence intervals) were measured with and without adjustment for Hepatotoxicity Score.

Among 89 512 PPI initiators with CLD, HRs of severe ALI were higher for lansoprazole (HR = 2.17 [95% CI, 1.24-3.82]), but not pantoprazole (HR = 0.83 [95% CI, 0.61-1.13]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR = 1.99 [95% CI, 1.13-3.50]). Among 2 462 414 PPI initiators without CLD, HRs were not significantly higher for lansoprazole (HR = 1.66 [95% CI, 0.99-2.77]) but were significantly lower for pantoprazole (HR = 0.59 [95% CI, 0.37-0.95]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR = 1.52 [95% CI, 0.91-2.54]).

The Hepatotoxicity Score provides a tool to adjust for confounding due to concomitant hepatotoxic drug exposure within hepatic safety studies.

Drug-induced hepatotoxicity constitutes a major reason for non-approval and post-marketing withdrawal of pharmaceuticals. In many cases, preclinical models lack predictive capacity for hepatic damage in humans. A vital concern is the integration of immune system effects in preclinical safety assessment. The immune-related Adverse Outcome Pathway (irAOP) approach, which is applied within the Immune Safety Avatar (imSAVAR) consortium, presents a novel method to understand and predict immune-mediated adverse events elicited by pharmaceuticals and thus targets this issue. It aims to dissect the molecular mechanisms involved and identify key players in drug-induced side effects. As irAOPs are still in their infancy, there is a need for a model irAOP to validate the suitability of this tool. For this purpose, we developed a hepatotoxicity-based model irAOP for recombinant human IL-2 (aldesleukin). Besides producing durable therapeutic responses against renal cell carcinoma and metastatic melanoma, the boosted immune activation upon IL-2 treatment elicits liver damage. The availability of extensive data regarding IL-2 allows both the generation of a comprehensive putative irAOP and to validate the predictability of the irAOP with clinical data. Moreover, IL-2, as one of the first cancer immunotherapeutics on the market, is a blueprint for various biological and novel treatment regimens that are under investigation today. This review provides a guideline for further irAOP-directed research in immune-mediated hepatotoxicity.

Oleanolic acid (OA) is a naturally occurring pentacyclic triterpene compound that has been reported to cause cholestatic liver injury. However, the regulation and pathogenic role of bile acids in OA-induced development of cholestatic liver injury remains largely unclear. Farnesoid X receptor (FXR) is a metabolic nuclear receptor that plays an important role in bile acid homeostasis in the liver by regulating efflux transporters bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2). The aim of this study was to investigate the effect of OA on hepatocyte tight junction function and determine the role of FXR, BSEP, and MRP2 in the mechanism of impairment of transport of bile acids induced by OA. Both in vivo and in vitro models were used to characterize the OA-induced liver injury. The liquid chromatography-tandem mass spectrometry (LC-MS) was employed to characterize the efflux function of the transporters, and the results showed that OA caused a blockage of bile acids efflux. OA treatment resulted in decreased expression levels of the tight junction proteins zonula occludens-1 and occludin. Immunofluorescence results showed that OA treatment significantly reduced the number of bile ducts and the immunofluorescence intensity. Pretreatment with agonists of FXR and MRP2, respectively, in animal experiments attenuated OA-induced liver injury, while pretreatment with inhibitors of BSEP and MRP2 further aggravated OA-induced liver injury. These results suggest that OA inhibits FXR-mediated BSEP and MRP2, leading to impaired bile acid efflux and disruption of tight junctions between liver cells, resulting in liver damage.

Antipsychotic psychopharmacotherapy is associated with the risk of drug-induced liver injury (DILI). However, understanding specific risk factors remains challenging due to limited data. This study investigates the relationship between receptor binding affinities and occupancies of antipsychotics and their associated hepatotoxic risks.

A disproportionality analysis with calculation of the Reporting Odds Ratio (ROR) and the Information Component (IC) was conducted using data from the FDA Adverse Event Reporting System (FAERS) to identify signals related to the Standardised MedDRA Query "drug-related hepatic disorders", which served as a proxy for drug-induced hepatotoxicity. This was followed by a pharmacoepidemiologic-pharmacodynamic approach to investigate the relationship between the ROR and substance-related receptor binding affinities and occupancy, which was estimated based on in vitro receptor-binding profiles.

Significant signals were identified for several antipsychotics, including chlorpromazine, loxapine, olanzapine, and quetiapine, with chlorpromazine and loxapine showing the highest RORs for DILI. Gender-specific analysis revealed a higher frequency of signals in female patients. Statistically significant negative correlations were identified between the ROR for drug-related hepatic disorders and the affinity for serotonin receptor 5-HT1A (r (17) = -0.68, p = 0.0012), while a positive correlation was observed for cholinergic receptors (r (17) = 0.46, p = 0.048). No significant correlations were found related to other receptors or drug properties.

Our findings suggest that the serotonin and probably the cholinergic system may play a role in the development of DILI related to antipsychotic medications. The identification of antipsychotics with a higher association with DILI, such as chlorpromazine, underscores the need for careful monitoring in clinical practice. However, our findings need further longitudinal studies to confirm causality. A better understanding of the associations may inform clinical decision-making, particularly in patients with an increased susceptibility to liver damage.

Human liver organoids derived from primary human hepatocytes (PHHs) are expected to be a hepatocyte source for preclinical in vitro studies of drug metabolism and disposition. Because hepatic functions of these organoids remain low, it is necessary to enhance the hepatic functions. Here, we develop a novel method for two dimensional (2D)-cultured hepatic differentiation from PHH-derived organoids by screening several compounds, cytokines, and growth factors. Hepatic gene expressions in the hepatocyte-like cells differentiated from PHH-derived organoids (Org-HEPs) were greatly increased, compared to those in PHH-derived organoids. The metabolic activities of cytochrome P450 (CYP) 1A2, CYP2C8, CYP2C19, CYP2E1, and CYP3A4 were at levels comparable to those in PHHs. The cell viability of Org-HEPs treated with hepatotoxic drugs was almost the same as that of PHHs. Thus, PHH-derived organoids could be differentiated into highly functional hepatocytes in 2D culture. Thus, Org-HEPs will be useful for pharmaceutical research, including hepatotoxicity tests.

A limited number of drugs are used as standard or alternative therapies in autoimmune hepatitis (AIH). No specific recommendations are available for patients failing to respond to these therapies. We analyzed the efficacy and safety of infliximab in patients with AIH.

We performed a retrospective study of 42 patients with AIH who received infliximab at 21 liver centers in 12 countries. Patients were categorized according to the reason for infliximab therapy. Patients in group 1 (n=20) had failed standard, second-line (mycophenolate mofetil and 6-mercaptopurine) or third-line (tacrolimus or cyclosporine) therapy. In group 2 (n=22), infliximab was given for treatment of concomitant extrahepatic autoimmune diseases. Patients received a median of 17 (range: 3-104) infliximab infusions. Complete biochemical response (CR) was achieved or maintained in 33 (78%) patients during infliximab therapy. In group 1, infliximab induced CR in 11 of 20 (55%) patients. In group 2, 16 patients with CR prior to infliximab maintained remission, and the remaining 6 patients with active AIH (5 on standard and 1 on both second-line and third-line therapy) showed CR following infliximab therapy. Infliximab led to CR in 75% (6/8) of nonresponders to second-line and in 46% (6/13) of failing third-line therapy. Overall, 65% (17/26) of the patients with active AIH achieved CR on infliximab. Infliximab was discontinued in 3 patients of group 1. One patient had a severe allergic reaction and 2 developed anti-infliximab autoantibodies.

Our study suggests that infliximab may be an effective and safe rescue therapy in AIH.

To summarize the clinical and biochemical characteristics of patients with ceftriaxone-induced liver injury and guide the selection of safe medication.

Retrieved domestic and foreign databases from inception to October 2023, collected case data conforming to ceftriaxone-induced liver injury, and statistically analyzed the data.

A total of 617 articles were retrieved, and 16 articles with 33 cases (10 children, 23 adults) were included. Males represented 60% (18/30), with a male-to-female ratio of 1.5:1. The age of onset ranged from 2 days to 96 years, with 15 of 23 adults (65%) over 55 years old. The time from ceftriaxone use to liver injury fluctuated between 0.5 and 47 days. Only 9 patients (27.3%, 9/33) had clinical symptoms, and the clinical classification was dominated by cholestatic injury (46.2%, 12/26). There was a significant difference in the clinical classification of ceftriaxone-induced liver injury between children and adults (P = 0.0126), with hepatocellular injury predominating in children and cholestatic injury predominating in adults. The severity of liver injury was mainly mild (66.7%, 12/18). Peak values of alanine aminotransferase ranging from 228.5 to 8098 U/L, aspartate aminotransferase ranging from 86.7 to 21575 U/L, alkaline phosphatase ranging from 143 to 2434 U/L, and total bilirubin ranging from 3.35 to 66.1 mg/dL. There was a significant difference in peak values of alkaline phosphatase between children and adults (P = 0.027), with a higher peak value of alkaline phosphatase in adults (1039 ± 716.4 U/L vs. 257 ± 134.9 U/L). Patients with normal imaging examinations accounted for the majority (61.5%, 7/13). The prognosis of 32 patients (97%, 32/33) was good, and one child with sickle cell anemia who developed immune hemolysis, progressive renal failure, and acute liver injury after using ceftriaxone died in the end.

Ceftriaxone-induced liver injury can occur at any age, with a higher risk in the elderly, and age may be related to the clinical classification. Although the clinical manifestations are not specific, close monitoring of liver biochemical indicators during the use can detect liver injury early. Most cases have a good prognosis, but for people with concomitant sickle cell anemia, it is necessary to be vigilant about the occurrence of severe hemolytic anemia.

Currently, there is limited knowledge on the clinical profile of drug-induced liver injury (DILI) in Chinese children. We aimed to assess the clinical characteristics, suspected drugs, and outcomes associated with pediatric DILI in China.

This nationwide, multicenter, retrospective study, conducted between 2012 and 2014, analyzed 25,927 cases of suspected DILI at 308 medical centers using the inpatient medical register system. Utilizing the Roussel Uclaf causality assessment method score, only patients with scores ≥6 or diagnosed with DILI by three experts after scoring <6 were included in the analysis. Among them, 460 cases met the EASL biochemical criteria. The study categorized children into three age groups: toddlers (≥30 days to <6 years old), school-age children (6 to <12 years old), and adolescents (12 to <18 years old).

Hepatocellular injury was the predominant clinical classification, accounting for 63% of cases, with 34% of these cases meeting Hy's law criteria. Adolescents comprised the majority of children with moderate/severe DILI (65%). Similarly, adolescents faced a significantly higher risk of severe liver injury compared to younger children (adjusted odd ratios 4.75, p = 0.002). The top three most frequently prescribed drug classes across all age groups were antineoplastic agents (25.9%), antimicrobials (21.5%), and traditional Chinese medicine (13.7%). For adolescents, the most commonly suspected drugs were antitubercular drugs (22%) and traditional Chinese medicine (23%).

Adolescents are at a greater risk of severe and potentially fatal liver injury compared to younger children. Recognizing the risk of pediatric DILI is crucial for ensuring safe medical practices.

Drug-induced liver injury, a poorly understood yet serious cause of pediatric liver disease, encompasses a spectrum of clinical presentations, ranging from asymptomatic liver enzyme elevation to acute liver failure. This retrospective study, utilizing a large Chinese cohort of pediatric liver injury cases from 308 centers nationwide, characterized the major clinical patterns and suspected drugs in detail, revealing that adolescents are at a greater risk of severe liver injury compared to younger children. Vigilant care and careful surveillance of at-risk pediatric patients are crucial for physicians, researchers, patients, caregivers, and policymakers. Additional multicenter prospective studies are needed to evaluate the risk of hepatotoxicity in outpatients and hospitalized pediatric patients.

Drug-induced liver injury (DILI) is a prevalent adverse reaction in clinical settings. However, there is limited research on age-related differences in DILI. We performed a large-scale retrospective study to delineate the characteristics of DILI across different age groups.

We collected data on a total of 17,946 patients with confirmed DILI hospitalized at the Fifth Medical Center of the People's Liberation Army (PLA) General Hospital in Beijing, China, from January 1, 2002, to December 31, 2022. The patients were stratified based on age into the following groups: children (< 18 years), young adults (18-44 years), middle-aged individuals (45-64 years), and elderly individuals (≥ 65 years). We gathered demographic information, medical histories, laboratory results, disease severity assessments, and mortality statistics for all patients.

Overall, the distribution of DILI cases across different age groups was as follows: 6.57% were children, 24.82% were young adults, 49.06% were middle-aged individuals, and 19.54% were elderly individuals. The percentage of females increased with age, rising from 36.47% in the pediatric group to 60.51% in the elderly group. Notably, central nervous system agents (15.44%) and anti-infectious agents (21.80%) were more commonly associated with DILI in children, while cardiovascular agents (10.58%) and herbal dietary supplements or traditional medicines (H/TMs) (26.29%) were more prevalent among elderly people with DILI. Among all age groups, hepatocellular-type DILI was more common in the pediatric group (p < 0.001), whereas cholestatic-type DILI and chronic DILI were more prevalent in the elderly group (p < 0.001). Acute liver failure (ALF) and fatal outcomes were more prevalent in the pediatric and elderly groups, particularly in the pediatric group (2.04%, p = 0.041; 0.85%, p = 0.007, respectively).

Children and elderly individuals face a higher risk of adverse outcomes following DILI.

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

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.

DILI accounts for more than half of acute liver failure cases in the United States and is a major health care issue for the public worldwide. As investigative toxicology is playing an evolving role in the pharmaceutical industry, mechanistic insights into drug hepatotoxicity can facilitate drug development and clinical medication.

By integrating multisource datasets including gene expression profiles of rat livers from open TG-GATE database and DrugMatrix, drug labels from FDA Liver Toxicity Knowledge Base, and clinical reports from LiverTox, and with the employment of bioinformatic and computational tools, this study developed an approach to characterize and predict DILI based on the molecular understanding of the processes (toxicity pathways).

A panel of 11 pathways widely covering biological processes and stress responses was established using a training set of six positive and one negative DILI drugs from open TG-GATEs. An entropy weight method-based model was developed to weight responsive genes within a pathway, and an interpretable machine-learning (ML) model XGBoot-SHAP was trained to rank the importance of pathways to the panel activity. The panel activity was proven to differentiate between injured and noninjured sample points and characterize DILI manifestation using six training drugs. Next, the model was tested using an additional 89 drugs (61 positives + 28 negatives), and a precision of 86% and higher can be achieved.

This study provides a novel approach to mechanisms-driven prediction modeling, as well as big data integration for insights into pharmacology and other human biology areas.

Liver diseases have gained increasing attention due to their substantial impact on health, independently as well as in association with cardio-metabolic disorders. Studies have suggested that glutathione and adenosine assist in providing protection against oxidative stress and inflammation while glucocorticoid (GC) therapy has been associated with chronic inflammatory disorders, even in pregnancy. The implications of Glucocorticoid exposure on maternal health and fetal growth is a concern, however, the possible role of glutathione and adenosine has not been thoroughly investigated. The study therefore hypothesize that exposure to glucocorticoids leads to depletion of hepatic glutathione and adenosine levels, contributing to oxidative stress and tissue injury. Additionally, we aim to investigate whether the effects of glucocorticoids on hepatic health are pregnancy dependent in female rats. Twelve Pregnant and twelve age-matched non-pregnant rats were used for this study; an exogenous administration of glucocorticoid (Dex: 0.2 mg/kg) or vehicle (po) was administered to six pregnant and six non-pregnant rats from gestational day 14 to 19 or for a period of 6 days respectively. Data obtained showed that GC exposure led to a decrease in hepatic glucose-6-phosphate dehydrogenase, glutathione peroxidase, GSH/GSSG ratio and adenosine content in both pregnant and non-pregnant rats. In addition, increased activities of adenosine deaminase and xanthine oxidase, along with increased production of uric acid and increased levels of lactate dehydrogenase, aspartate aminotransferase, alanine transferase, alkaline phosphatase and gamma-glutamyl transferase were observed. In summary, the study indicates that GC-induced liver damage is underlined by depleted hepatic adenosine and glutathione levels as well as elevated markers of tissue inflammation and/or injury. Furthermore, the findings suggest that the effects of GC exposure on hepatic health are pregnancy independent.

Amoxicillin/clavulanate is a commonly used antibiotic. Though relatively rare, amoxicillin/clavulanate carries the highest incidence of idiosyncratic drug-induced liver disease. This case report presents an 80-year-old woman treated for simple respiratory tract infection with amoxicillin/clavulanate who was subsequently hospitalized with malaise and icterus and a biochemical cholestatic pattern with high alkaline phosphatase and bilirubin. Diagnostically challenging, ultimately, liver biopsy revealed drug-induced liver injury with a fatal course after attempt of supportive, symptomatic treatment.

Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests.

To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools.

Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves.

We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1).

Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.

Drug-induced liver injury is a prevalent severe adverse event in clinical settings, leading to increased medical burdens for patients and presenting challenges for the development and commercialization of novel pharmaceuticals. Research has revealed a close association between gut microbiota and drug-induced liver injury in recent years. However, there has yet to be a consensus on the specific mechanism by which gut microbiota is involved in drug-induced liver injury. Gut microbiota may contribute to drug-induced liver injury by increasing intestinal permeability, disrupting intestinal metabolite homeostasis, and promoting inflammation and oxidative stress. Alterations in gut microbiota were found in drug-induced liver injury caused by antibiotics, psychotropic drugs, acetaminophen, antituberculosis drugs, and antithyroid drugs. Specific gut microbiota and their abundance are associated closely with the severity of drug-induced liver injury. Therefore, gut microbiota is expected to be a new target for the treatment of drug-induced liver injury. This review focuses on the association of gut microbiota with common hepatotoxic drugs and the potential mechanisms by which gut microbiota may contribute to the pathogenesis of drug-induced liver injury, providing a more comprehensive reference for the interaction between drug-induced liver injury and gut microbiota.

Serum transaminases, alkaline phosphatase and bilirubin are common parameters used for DILI diagnosis, classification, and prognosis. However, the relevance of clinical examination, histopathology and drug chemical properties have not been fully investigated. As cholestasis is a frequent and complex DILI manifestation, our goal was to investigate the relevance of clinical features and drug properties to stratify drug-induced cholestasis (DIC) patients, and to develop a prognosis model to identify patients at risk and high-concern drugs.

DIC-related articles were searched by keywords and Boolean operators in seven databases. Relevant articles were uploaded onto Sysrev, a machine-learning based platform for article review and data extraction. Demographic, clinical, biochemical, and liver histopathological data were collected. Drug properties were obtained from databases or QSAR modelling. Statistical analyses and logistic regressions were performed.

Data from 432 DIC patients associated with 52 drugs were collected. Fibrosis strongly associated with fatality, whereas canalicular paucity and ALP associated with chronicity. Drugs causing cholestasis clustered in three major groups. The pure cholestatic pattern divided into two subphenotypes with differences in prognosis, canalicular paucity, fibrosis, ALP and bilirubin. A predictive model of DIC outcome based on non-invasive parameters and drug properties was developed. Results demonstrate that physicochemical (pKa-a) and pharmacokinetic (bioavailability, CYP2C9) attributes impinged on the DIC phenotype and allowed the identification of high-concern drugs.

We identified novel associations among DIC manifestations and disclosed novel DIC subphenotypes with specific clinical and chemical traits. The developed predictive DIC outcome model could facilitate DIC prognosis in clinical practice and drug categorization.