Detection Of Drug-induced Liver Injury Research Articles

Salivary metabolites are promising noninvasive biomarkers of drug-induced liver injury.

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.

Ultrasensitive upconverting nanoprobes for in situ imaging of drug-induced liver injury using miR-122 as the biomarker

Drug-induced liver injury (DILI) is a frequent adverse drug reaction. The current clinical diagnostic methods are inadequate for accurate and early detection of DILI due to the lack of effective diagnostic biomarkers. Hepatocyte-specific miR-122 is released from injured hepatocytes promptly and its efflux is significantly correlated with the progression of DILI. Therefore, achieving precise in situ detection of miR-122 with high sensitivity is vital for early visualization of DILI. Herein, a new nanoprobe, consisting of miR-122 aptamer, upconversion nanoparticles (UCNPs) and Prussian blue nanoparticles (PBNPs) was introduced for the early and sensitive detection of DILI in situ. As the nanoprobes reached in the liver, miR-122 aptamer-based entropy-driven strand displacement (ESDR) signal amplification reaction was triggered and luminescence resonance energy transfer (LRET) between UCNPs and PBNPs was responded to achieve the high-fidelity detection of DILI. A negative correlation was observed between the intensity of upconversion luminescence (UCL) and the concentration of miR-122. UCL imaging conducted both in vivo and ex vivo indicated that a reduction in miR-122 concentration led to an increase in UCL intensity, revealing a precise state of DILI. The detection technique demonstrated a positive correlation between signal intensity and severity, offering a more straightforward and intuitive method of visualizing DILI.

P16-37: Comparative assessment of hepatic in vitro systems for detection of drug-induced liver injury

P16-37: Comparative assessment of hepatic in vitro systems for detection of drug-induced liver injury

Investigation of TGF-α-overexpressing mouse hepatocytes (TAMH) cultured as spheroids for use in hepatotoxicity screening of drug candidates.

The immortalized mouse liver cell line TAMH has been described as a valuable tool for studying hepatotoxic mechanisms, but until now, it has only been reported to grow as a monolayer in culture. However, culturing hepatocytes as three-dimensional (3D) spheroids has been shown to result in improved liver-specific functions (e.g., metabolic capacity) by better mimicking the in vivo environment. This approach may lead to more reliable detection of drug-induced liver injury (DILI) in the early phase of drug discovery, preventing post-marketing drug withdrawals. Here, we investigated the cultivation of TAMH as 3D spheroids, characterizing them with optical and transmission electron microscopy as well as analyzing their gene expression at mRNA level (especially drug-metabolizing enzymes) compared to TAMH monolayer. In addition, comparisons were made with spheroids grown from the human hepatoblastoma cell line HepG2, another current spheroid model. The results indicate that TAMH spheroids express hepatic structures and show elevated levels of some of the key phase I and II drug-metabolizing enzymes, in contrast to TAMH monolayer. The in vitro hepatotoxic potencies of the drugs acetaminophen and flupirtine maleate were found to be very similar between TAMH spheroidal and the monolayer cultures. Both the advantages and disadvantages of TAMH spheroids as an in vitro hepatotoxicity model compared to monolayer model are discussed.

Causal Evaluation of Post-Marketing Drugs for Drug-induced Liver Injury from Electronic Health Records.

Drug-induced liver injury (DILI) is one of the most common and serious adverse drug reactions that can lead to acute liver failure and death. Detection of DILI and causal estimation of drug-hepatotoxicity association are of great importance for patient safety. This paper proposes a framework for causal estimation of post-marketing drugs for DILI from real-world electronic health record (EHR) data. Randomized clinical trials were replicated at scale by automatically generating different user and non-user cohorts for each potential drug, and average treatment effects (ATEs) of drugs were estimated using targeted maximum likelihood estimation. Ten years of real-world EHRs were used to validate the framework. Of all 1199 single-ingredient drugs analyzed, 7 novel and 7 known drug-hepatotoxicity associations were found to be causal.

Screening and optimization of a water-soluble near-infrared fluorescent probe for drug-induced liver injury monitoring

Peroxynitrite (ONOO−) is a potential biomarker of drug-induced liver injury (DILI) and is involved in the process of DILI. Therefore, developing a reliable detection method for ONOO− will greatly contribute to ensuring drug safety and improving treatment efficiency. Here, based on the previous work, two kinds of NIR fluorescence probes PN and SPN were developed with phenyl-hydrazine as the ONOO− recognition group, which based on two fluorophores RN and SRN that are stable to ONOO−. A sensitive NIR probe SPN with good water solubility, low detection limit and good biocompatibility was selected through in vitro spectral property screening. Further experimental results show that there is a good linear relationship between the response intensity of probe SPN to ONOO− and the concentration of ONOO−, and the detection limit can reach 19.7 nM. At the cellular level, probe SPN can achieve a good and specific response to endogenous and exogenous ONOO−. Also, the probe SPN can be used for imaging and detection of DILI in zebrafish level and small animal level, indicating that probe SPN can be used as a powerful tool for diagnosis of DILI and efficacy evaluation of therapeutic drugs.

A review of challenges and prospects of 3D cell-based culture models used for studying drug induced liver injury during early phases of drug development.

Drug-induced liver injury (DILI) is the leading cause of compound attrition during drug development. Over the years, a battery of in-vitro cell culture toxicity tests is being conducted to evaluate the toxicity of compounds prior to testing in laboratory animals. Two-dimensional (2D) in-vitro cell culture models are commonly used and have provided a great deal of knowledge; however, these models often fall short in mimicking natural structures of tissues in-vivo. Testing in humans is the most logical method, but unfortunately there are ethical limitations associated with human tests. To overcome these limitations better human-relevant, predictive models are required. The past decade has witnessed significant efforts towards the development of three-dimensional (3D) in-vitro cell culture models better mimicking in-vivo physiology. 3D cell culture has advantages in being representative of the interactions of cells in-vivo and when validated can act as an interphase between 2D cell culture models and in-vivo animal models. The current review seeks to provide an overview of the challenges that make biomarkers used for detection of DILI not to be sensitive enough during drug development and explore how 3D cell culture models can be used to address the gap with the current models.

The Potential Role of Metabolomics in Drug-Induced Liver Injury (DILI) Assessment.

Drug-induced liver injury (DILI) is one of the most frequent adverse clinical reactions and a relevant cause of morbidity and mortality. Hepatotoxicity is among the major reasons for drug withdrawal during post-market and late development stages, representing a major concern to the pharmaceutical industry. The current biochemical parameters for the detection of DILI are based on enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP)) and bilirubin serum levels that are not specific of DILI and therefore there is an increasing interest on novel, specific, DILI biomarkers discovery. Metabolomics has emerged as a tool with a great potential for biomarker discovery, especially in disease diagnosis, and assessment of drug toxicity or efficacy. This review summarizes the multistep approaches in DILI biomarker research and discovery based on metabolomics and the principal outcomes from the research performed in this field. For that purpose, we have reviewed the recent scientific literature from PubMed, Web of Science, EMBASE, and PubTator using the terms “metabolomics”, “DILI”, and “humans”. Despite the undoubted contribution of metabolomics to our understanding of the underlying mechanisms of DILI and the identification of promising novel metabolite biomarkers, there are still some inconsistencies and limitations that hinder the translation of these research findings into general clinical practice, probably due to the variability of the methods used as well to the different mechanisms elicited by the DILI causing agent.

Evaluation of a Three-Dimensional Primary Human Hepatocyte Spheroid Model: Adoption and Industrialization for the Enhanced Detection of Drug-Induced Liver Injury.

Drug-induced liver injury is a leading cause of compound attrition during both preclinical and clinical drug development, and early strategies are in place to tackle this recurring problem. Human-relevant in vitro models that are more predictive of hepatotoxicity hazard identification, and that could be employed earlier in the drug discovery process, would improve the quality of drug candidate selection and help reduce attrition. We present an evaluation of four human hepatocyte in vitro models of increasing culture complexity (i.e., two-dimensional (2D) HepG2 monolayers, hepatocyte sandwich cultures, three-dimensional (3D) hepatocyte spheroids, and precision-cut liver slices), using the same tool compounds, viability end points, and culture time points. Having established the improved prediction potential of the 3D hepatocyte spheroid model, we describe implementing this model into an industrial screening setting, where the challenge was matching the complexity of the culture system with the scale and throughput required. Following further qualification and miniaturization into a 384-well, high-throughput screening format, data was generated on 199 compounds. This clearly demonstrated the ability to capture a greater number of severe hepatotoxins versus the current routine 2D HepG2 monolayer assay while continuing to flag no false-positive compounds. The industrialization and miniaturization of the 3D hepatocyte spheroid complex in vitro model demonstrates a significant step toward reducing drug attrition and improving the quality and safety of drugs, while retaining the flexibility for future improvements, and has replaced the routine use of the 2D HepG2 monolayer assay at GlaxoSmithKline.

Diketopyrrolopyrrole-based sensor for over-expressed peroxynitrite in drug-induced hepatotoxicity via ratiometric fluorescence imaging

Early diagnosis and detection of drug-induced liver injury (DILI) is great significance for the effective prevention and treatment of patients with liver injury. Studies indicate that the up-regulation of peroxynitrite (ONOO−) levels in liver is profoundly involved in acetaminophen (APAP)-induced liver injury. Herein, we constructed diketopyrrolopyrrole (DPP)-based ratiometric fluorescent probes (DPP-DH-P and DPP-DEG-P) for detecting and imaging ONOO−. Comparing two probes, DPP-DEG-P exhibited higher signal-to-noise ratio (2750-fold) and lower detection limit (3.5 nM) for tracking ONOO− in solution. DPP-DH-P possessing better biocompatibility had been successfully applied to monitor the fluctuation of ONOO− in LPS/IFN-γ or APAP-treated hepatocytes with a high signal-to-noise ratio (20-fold) by ratiometric imaging. Moreover, the probe was used to evaluate the repair effect of glutathione on DILI. We unexpectedly discovered that DPP-DH-P and DPP-DH targeted lysosomes and mitochondria, respectively. Based on the change of ONOO− induced by APAP, we observed that DPP-DH-P and the generated DPP-DH diffused from lysosome into cytoplasm, and DPP-DH did not target mitochondria due to the effect of endogenous ONOO−, these indirectly reflected the dysfunction of organelles. Observably, this work will accelerate a deeper comprehending for the pathogenesis of DILI, and furnish an effective tool for the diagnosis and treatment of DILI.

MiR122-controlled all-in-one nanoplatform for in situ theranostic of drug-induced liver injury by visualization imaging guided on-demand drug release.

Drug-induced liver injury (DILI) is a challenging clinical problem with respect to both diagnosis and management. As a newly emerging biomarker of liver injury, miR122 shows great potential in early and sensitive in situ detection of DILI. Glycyrrhetinic acid (GA) possesses desirable therapeutic effect on DILI, but its certain dose-dependent side effects after long-term and/or high-dose administration limit its clinical application. In this study, in order to improve the precise diagnosis and effective treatment of DILI, GA loaded all-in-one theranostic nanoplatform was designed by assembling of upconversion nanoparticles and gold nanocages. As a proof of concept, we demonstrated the applicability of this single-wavelength laser-triggered theranostic nanoplatform for the spatiotemporally controllable in situ imaging of DILI and miR122-controlled on-demand drug release in vitro and in vivo. This novel nanoplatform opens a promising avenue for the clinical diagnosis and treatment of DILI.

Correction to: Exosomal microRNAs Release as a Sensitive Marker for Drug-Induced Liver Injury In Vitro by Messner CJ, et al. Appl In Vitro Toxicol 2020:6;77–89. DOI: 10.1089/aivt.2020.0008

Applied In Vitro ToxicologyVol. 6, No. 4 CorrectionOpen AccessCorrection to: Exosomal microRNAs Release as a Sensitive Marker for Drug-Induced Liver Injury In Vitro by Messner CJ, et al. Appl In Vitro Toxicol 2020:6;77–89. DOI: 10.1089/aivt.2020.0008is erratum ofExosomal microRNAs Release as a Sensitive Marker for Drug-Induced Liver Injury In VitroPublished Online:16 Dec 2020https://doi.org/10.1089/aivt.2020.0008.correxAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail In the September 2020 issue of Applied In Vitro Toxicology (vol. 6, no. 3; 77–89), the article entitled “Exosomal microRNAs Release as a Sensitive Marker for Drug-Induced Liver Injury In Vitro” by Messner et al. requires correction.An error was inadvertently introduced to the Abstract.The original text read:“Introduction: In vitro models for liver disease suffer from the lack of well-established and sensitive biomarkers of cellular damage. MicroRNAs (miRNAs; small noncoding RNAs) represent potential biomarkers for the detection of drug-induced liver injury in vitro and in vitro. Altered physiological state caused by disease or tissue damage results in altered release of exosomal- or protein-bound miRNAs, detectable in body fluids and cell culture media.”The revised text now reads:“Introduction: In vitro models for liver disease suffer from the lack of well-established and sensitive biomarkers of cellular damage. MicroRNAs (miRNAs; small noncoding RNAs) represent potential biomarkers for the detection of drug-induced liver injuryin vivoand in vitro. Altered physiological state caused by disease or tissue damage results in altered release of exosomal- or protein-bound miRNAs, detectable in body fluids and cell culture media.”The online version of the article has been corrected to reflect this change.The publisher apologizes for this error.FiguresReferencesRelatedDetailsRelated articlesExosomal microRNAs Release as a Sensitive Marker for Drug-Induced Liver Injury In Vitro16 Sep 2020Applied In Vitro Toxicology Volume 6Issue 4Dec 2020 InformationCopyright 2020, Mary Ann Liebert, Inc., publishersTo cite this article:Correction to: Exosomal microRNAs Release as a Sensitive Marker for Drug-Induced Liver Injury In Vitro by Messner CJ, et al. Appl In Vitro Toxicol 2020:6;77–89. DOI: 10.1089/aivt.2020.0008.Applied In Vitro Toxicology.Dec 2020.156-156.http://doi.org/10.1089/aivt.2020.0008.correxcreative commons licensePublished in Volume: 6 Issue 4: December 16, 2020Online Ahead of Print:October 6, 2020PDF download

Identification of Translational microRNA Biomarker Candidates for Ketoconazole-Induced Liver Injury Using Next-Generation Sequencing.

Drug-induced liver injury (DILI) is a leading cause of acute liver failure. Reliable and translational biomarkers are needed for early detection of DILI. microRNAs (miRNAs) have received wide attention as a novel class of potential DILI biomarkers. However, it is unclear how DILI drugs other than acetaminophen may influence miRNA expression or which miRNAs could serve as useful biomarkers in humans. We selected ketoconazole (KCZ), a classic hepatotoxin, to study miRNA biomarkers for DILI as a proof of concept for a workflow that integrated in vivo, in vitro, and bioinformatics analyses. We examined hepatic miRNA expression in KCZ-treated rats at multiple doses and durations using miRNA-sequencing and correlated our results with conventional DILI biomarkers such as liver histology. Significant dysregulation of rno-miR-34a-5p, rno-miR-331-3p, rno-miR-15b-3p, and rno-miR-676 was associated with cytoplasmic vacuolization, a phenotype in rat livers with KCZ-induced injury, which preceded the elevation of serum liver transaminases (ALT and AST). Between rats and humans, miR-34a-5p, miR-331-3p, and miR-15b-3p were evolutionarily conserved with identical sequences, whereas miR-676 showed 73% sequence similarity. Using quantitative PCR, we found that the levels of hsa-miR-34a-5p, hsa-miR-331-3p, and hsa-miR-15b-3p were significantly elevated in the culture media of HepaRG cells treated with 100 µM KCZ (a concentration that induced cytotoxicity). Additionally, we computationally characterized the miRNA candidates for their gene targeting, target functions, and miRNA/target evolutionary conservation. In conclusion, we identified miR-34a-5p, miR-331-3p, and miR-15b-3p as translational biomarker candidates for early detection of KCZ-induced liver injury with a workflow applicable to computational toxicology studies.

Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives.

Drug-induced liver injury (DILI) is one among the common adverse drug reactions and the leading causes of drug development attritions, black box warnings, and post-marketing withdrawals. Despite having relatively low clinical incidence, its potentially severe adverse events should be considered in the individual patients due to the high risk of acute liver failure. Although traditional liver parameters have been applied to the diagnosis of DILI, the lack of specific and sensitive biomarkers poses a major limitation, and thus accurate prediction of the subsequent clinical course remains a significant challenge. These drawbacks prompt the investigation and discovery of more effective biomarkers, which could lead to early detection of DILI, and improve its diagnosis and prognosis. Novel promising biomarkers include glutamate dehydrogenase, keratin 18, sorbitol dehydrogenase, glutathione S-transferase, bile acids, cytochrome P450, osteopontin, high mobility group box-1 protein, fatty acid binding protein 1, cadherin 5, miR-122, genetic testing, and omics technologies, among others. Furthermore, several clinical scoring systems have gradually emerged for the diagnosis of DILI including the Roussel Uclaf Causality Assessment Method (RUCAM), Clinical Diagnostic Scale (CDS), and Digestive Disease Week Japan (DDW-J) systems. However, currently their predictive value is limited with certain inherent deficiencies. Thus, perhaps the greatest benefit would be achieved by simultaneously combining the scoring systems and those biomarkers. Herein, we summarized the recent research progress on molecular biomarkers for DILI to improved approaches for its diagnosis and clinical management.

Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis: Implications for Drug Hepatotoxicity Monitoring.

Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy's law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34-299) and 56 U/L (47-85)] than for those with normal baseline values [median 26.5 U/L (range 18-33) and 29 U/L (25.5-30.5)] in both studies, respectively, with p < 0.001. Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.

Consensus guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease.

SummaryBackgroundImproved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug‐induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients.AimsTo outline best practices for detection, assessment and management of suspected acute DILI during clinical trials in adults with the cholestatic liver diseases – Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC).MethodsThis is one of the several papers developed by the IQ DILI Initiative, which is comprised of members from 16 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. The contents are the result of an extensive literature review, as well as in‐depth discussions among industry, regulatory and academic DILI experts, to achieve consensus recommendations on DILI‐related issues occurring during clinical trials for cholestatic liver diseases.ResultsRecommended best practices are outlined pertaining to hepatic eligibility criteria, monitoring of liver tests, approach to a suspected DILI signal, and hepatic discontinuation rules.ConclusionsThis paper provides a framework for the approach to detection, assessment and management of suspected acute DILI occurring during clinical trials in adults with cholestatic liver disease.

Roussel Uclaf Causality Assessment Method for Drug-Induced Liver Injury: Present and Future.

Among the causality assessment methods used for the diagnosis of drug-induced liver injury (DILI), Roussel Uclaf Causality Assessment Method (RUCAM) remains the most widely used not only for individual cases but also for prospective and retrospective studies worldwide. This first place is justified by the characteristics of the method such as precise definition and classification of the liver injury, which determines the right scale in the scoring system, precise definition of the seven criteria, and the validation approach based on cases with positive rechallenge. RUCAM is used not only for any types of drugs but also for herbal medicines causing herb-induced liver injury, (HILI) and dietary supplements. In 2016, the updated RUCAM provided further specifications of criteria and instructions to improve interobserver variability. Although this method was criticized for criteria such as the age and alcohol consumption, recent consensus meeting of experts has recognized their value and recommended their incorporation into any method. While early studies searching for DILI in large databases especially in electronic medical records were based on codes of diseases or natural language without causality assessment, the recommendation is now to include RUCAM in the search for DILI/HILI. There are still studies on DILI detection or the identification of biomarkers that take into consideration the cases assessed as “possible,” although it is well known that these cases reduce the strength of the association between the cases and the offending compound or the new biomarker to be validated. Attempts to build electronic RUCAM or automatized application of this method were successful despite some weaknesses to be corrected. In the future, more reflections are needed on an expert system to standardize the exclusion of alternative causes according to the clinical context. Education and training on RUCAM should be encouraged to improve the results of the studies and the day-to-day work in pharmacovigilance departments in companies or in regulatory agencies. It is also expected to improve RUCAM with biomarkers or other criteria provided that the validation process replaces expert opinion by robust standards such as those used for the original method.

Automated Machine Learning Diagnostic Support System as a Computational Biomarker for Detecting Drug-Induced Liver Injury Patterns in Whole Slide Liver Pathology Images.

Drug-induced liver injury (DILI) is a challenging disease to diagnose, a leading cause of acute liver failure, and responsible for drug withdrawal from the market. There is no symptom, no biomarker or test for detection, no therapy, but discontinuation of the drug. Pharmaceutical companies spend huge money, time, and scientific research efforts to test DILI effects and drug efficacy. A preclinical diagnostic support system is designed and proposed for DILI detection and classification on liver biopsy histopathology images. Heterogeneity features and automated machine learning (AutoML) models were tested to classify DILI injury patterns on whole slide image. Fractal and lacunarity values were used to detect hepatocellular necrotic injury patterns caused on a rat liver (in vivo) by 10 drugs at four dose levels. Correlations between fractal and lacunarity values were statistically analyzed for the 10 drugs; the Pearson correlation (r = 0.9809), p-value (1.6612E-06), and R2 (0.9582) were found to be high in the case of carbon tetrachloride. The AutoML model was tested to understand the injury patterns on a subset of 1,277 histology images. The AutoML algorithm was able to classify necrotic injury patterns accurately with an average precision of 98.6% on a score threshold of 0.5.

Consensus: guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis.

SummaryBackgroundThe last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug‐induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials.AimsThis publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH.MethodsThis is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic.ResultsRecommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules.ConclusionsThis paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH.

A novel near-infrared fluorescent light-up probe for tumor imaging and drug-induced liver injury detection.

A novel near-infrared fluorescent light-up probe with a tumor-homing pentapeptide, CREKA (Cys-Arg-Glu-Lys-Ala), specifically binds to fibrin-fibronectin complexes was rationally designed and developed for biomedical imaging. Its superior practical applications in tumor imaging and drug-induced liver injury detection are well demonstrated for the first time.