Incidence Of Drug-induced Liver Injury Research Articles

Risk and impacts of drug-induced liver injury (DILI) due to immune-checkpoint inhibitors (ICI) on overall survival in patients with newly diagnosed cancer: A retrospective cohort study.

12049 Background: The risk and impact of drug-induced liver injury (DILI) due to ICI treatment on newly diagnosed cancer patients have not been fully investigated. This study aims to assess the incidence and impact of ICI related DILI on overall survival. Methods: We included patients with newly diagnosed cancer treated with ICIs between 01/2012 and 12/2020 at the Ohio State University Comprehensive Cancer Center. DILI was defined using ICD-9 and ICD-10 codes for abnormal results of liver function, acute hepatitis, drug-induced liver injury, or toxic liver disease. History of Liver Disease (HLD) before ICI infusion was defined using ICD-9 and ICD-10 codes for any liver disease, including primary and secondary liver malignant neoplasms. To examine the causal effects of ICI-related DILI, patients who developed hepatocellular carcinoma or metastatic liver disease were excluded. Kaplan Meier method was used to estimate DILI risk post-ICI infusion in patients with and without HLD. Crude and Adjusted Cox proportional models were used to examine the association between DILI, modeled as time-dependent, and overall survival. Results: A total of 2,816 patients were included in the study, with a median age of 62 years, 58% male, and 90% white non-Hispanics. An estimated 11% of patients developed DILI during follow-up. The median (interquartile range) follow-up time from ICI infusion to DILI was 8.7 (3.0–20.1) months. The overall risk of DILI was 25.3%, which was significantly higher in patients with HLD than in those without HLD (17.8% vs. 30.8%, Log-Rank P <0.001). The median (interquartile range) survival time was 10.4 (3.7–22.7) months. During follow-up, a total of 1390 (49.4%) patients died. DILI was significantly associated with a higher risk of all-cause mortality in all regression models. The crude risk of all-cause mortality was 40% higher in patients with DILI than in those without DILI [HR: 1.40; 95% CI: 1.15–1.70]. In the fully adjusted models, DILI was associated with a 63% higher risk of all-cause mortality [adjusted HR: 1.63; 95% CI: 1.34–1.99]. DILI's effects on the overall survival risk remained significant when we further adjusted for HLD status [HR: 1.57; 95% CI: 1.29–1.93]. Conclusions: The findings from this retrospective cohort study highlight the significant risk and detrimental impact of DILI on overall survival in patients treated with ICIs. Notably, the incidence of DILI was significantly higher among patients with HLD, underscoring the elevated vulnerability of this subgroup. Furthermore, DILI was a significant predictor of increased all-cause mortality regardless of HLD status. These results underscore the need for vigilant monitoring and management of liver function in patients receiving ICIs, particularly in those with pre-existing liver conditions, to mitigate the risk of DILI and improve survival outcomes.

#1891 Evaluating the safety and effectiveness of Tolvaptan for management of adult Korean ADPKD patients (ESSENTIAL study): final report

Abstract Background and Aims Tolvaptan, a selective vasopressin V2 receptor antagonist, was first approved by Korean FDA in 2015 as a treatment option in autosomal dominant polycystic kidney disease (ADPKD). In order to prescribe Tolvaptan safely and effectively, we designed the phase 4 clinical trial among Korean ADPKD patients with chronic kidney disease (CKD) stage 1-3. Method Korean patients aged 19 to 50 with rapidly progressing ADPKD were enrolled in the study. The dose titration was performed every one week for a total of 4 weeks. The patient was prescribed Tolvaptan with the maximum tolerable dose up to 120 mg per day. A total duration of Tolvaptan prescription was 24 months. The primary outcome was the incidence of treatment emergent adverse events (TEAE) including drug-induced liver injury (DILI). The secondary outcomes were the annual mean percent change of total kidney volume (TKV) and the annual mean change of estimated glomerular filtration rate (eGFR). Results A total of 117 patients were included in the analysis. Mean age was 38.7 ± 8.4 years old and male were predominant (58.1%). The average TKV was 2066 ± 1094 mL and mean eGFR was 79.7 ± 27.7 mL/min/1.73 m2. Mean duration of Tolvaptan exposure was 1.7 ± 0.6 years and the average daily dose of Tolvaptan was 94.4 ± 24.1 mg/day. A total of 489 treatment-emergent adverse events (TEAE) occurred in 106 (90.6%) patients during study duration. The drug-induced liver injury and aquaresis-related adverse events were two most common adverse events. A total of 17 DILI cases (14.5%) occurred during the study period and mostly within 18-month period. However, liver enzymes were normalized after drug discontinuation The patients with previous history of liver disease as well as those who were prescribed higher dose of Tolvaptan demonstrated higher frequency of DILI. Mean growth rate of TKV after Tolvaptan treatment was 4.5 ± 0.5% and mean eGFR decline rate was -3.0 ± 0.39 mL/min/1.73 m2/year. Comparing with the predicted value from calculation, Tolvaptan attenuated both TKV growth and eGFR decline rate. Conclusion This study is the first post-marketing survey assessing the safety and efficacy of Tolvaptan in Korean ADPKD patients. The incidence of DILI was higher than the previous studies and especially in those with liver disease and higher Tolvaptan prescription dose. While Tolvaptan can effectively reduce TKV and attenuate eGFR decline, the clinicians should be aware of higher frequency of DILI among Korean population.

Susceptibility to Hepatotoxic Drug-Induced Liver Injury Increased After Traumatic Brain Injury in Mice.

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

Angiotensin Receptor Blockers and the Risk of Suspected Drug-Induced Liver Injury: A Retrospective Cohort Study Using Electronic Health Record-Based Common Data Model in South Korea.

Angiotensin receptor blockers are widely used antihypertensive drugs in South Korea. In 2021, the Korea Ministry of Food and Drug Safety acknowledged the need for national compensation for a drug-induced liver injury (DILI) after azilsartan use. However, little is known regarding the association between angiotensin receptor blockers and DILI. We conducted a retrospective cohort study in incident users of angiotensin receptor blockers from a common data model database (1 January, 2017-31 December, 2021) to compare the risk of DILI among specific angiotensin receptor blockers against valsartan. Patients were assigned to treatment groups at cohort entry based on prescribed angiotensin receptor blockers. Drug-induced liver injury was operationally defined using the International DILI Expert Working Group criteria. Cox regression analyses were conducted to derive hazard ratios and the inverse probability of treatment weighting method was applied. All analyses were performed using R. In total, 229,881 angiotensin receptor blocker users from 20 university hospitals were included. Crude DILI incidence ranged from 15.6 to 82.8 per 1000 person-years in treatment groups, most were cholestatic and of mild severity. Overall, the risk of DILI was significantly lower in olmesartan users than in valsartan users (hazard ratio: 0.73 [95% confidence interval 0.55-0.96]). In monotherapy patients, the risk was significantly higher in azilsartan users than in valsartan users (hazard ratio: 6.55 [95% confidence interval 5.28-8.12]). We found a significantly higher risk of suspected DILI in patients receiving azilsartan monotherapy compared with valsartan monotherapy. Our findings emphasize the utility of real-world evidence in advancing our understanding of adverse drug reactions in clinical practice.

Risk of potential hepatotoxicity from pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis: results of a retrospective analysis of a large insurance database in Taiwan.

Background: A growing population of individuals diagnosed with idiopathic pulmonary fibrosis (IPF) are receiving treatment with nintedanib and pirfenidone. The aim of our study was to assess the incidence of drug-induced liver injury (DILI) associated with the use of pirfenidone and nintedanib in patients with IPF in Taiwan. Methods: We collected a cohort of adult patients diagnosed with IPF between 2017 and 2020. The research outcomes involved assessing the incidence of DILI in patients treated with nintedanib or pirfenidone. Poisson regression analysis was employed to estimate incidence rates, with and without adjustments for covariates, to calculate and present both unadjusted and adjusted incidence rate ratios (IRRs). Results: The risk of DILI was greater in patients who received nintedanib than in those who received pirfenidone during the 1-year follow-up. Patients treated with nintedanib exhibited a heightened risk of DILI based on inpatient diagnoses using specific codes after adjusting for variables such as gender, age group, comorbidities and concomitant medications, with an adjusted incidence rate ratio (aIRR) of 3.62 (95% confidence interval (CI) 1.11-11.78). Similarly, the risk of DILI was elevated in patients treated with nintedanib according to a per-protocol Poisson regression analysis of outcomes identified from inpatient diagnoses using specific codes. This was observed after adjusting for variables including gender, age group, comorbidities, and concomitant medications, with an aIRR of 3.60 (95% CI 1.11-11.72). Conclusion: Data from postmarketing surveillance in Taiwan indicate that patients who received nintedanib have a greater risk of DILI than do those who received pirfenidone.

Antibiotic-Associated Drug-Induced Liver Injury in Critically Ill Children: A Prospective Observational Study

Scientific relevance. Drug-induced liver injury (DILI) is associated, among other things, with the use of antibiotics. Children with DILI are at risk of acute liver failure and even death. However, the literature on the subject provides little information on the possibility of distinguishing the types of hepatic lesions to diagnose potentially life-threatening DILI in time.Aim. The study aimed to describe the phenotype of new-onset DILI associated with antibiotics in critically ill children with nosocomial infection.Materials and methods. The authors conducted a prospective observational study in the resuscitation and intensive care units of the Morozov Children’s City Clinical Hospital from 1 February 2020 to 1 September 2021. The study assessed the incidence of antibiotic-associated DILI using the Global Trigger Tool. The study enrolled 100 critically ill children with nosocomial infection aged 0 to 17 years (44 boys and 56 girls).Results. Signs of hepatotoxicity were detected in 19 patients, including 8 with abnormal liver function tests but normal liver function and 11 with abnormal liver function tests and clinically apparent liver disease. Thus, the incidence of new-onset hepatotoxicity associated with antibiotics amounted to 12.9 cases per 100,000 paediatric patients, and the incidence of DILI was 7.5 cases per 100,000 children. Based on the analysis of medical records, biochemical findings, and relationships between the time of dosing and the manifestation of signs of liver disorder in 11 children, the authors characterised the phenotype of idiosyncratic cholestatic hepatitis. Critically ill children treated with antibiotics showed alanine transaminase activity up to 10 times the upper limit of normal (ULN), bilirubin levels up to 4.45 times the ULN, and gamma-glutamyl transferase activity up to 5 times the ULN. The odds of developing new-onset DILI were the highest with tigecycline (OR: 4.07; 95% CI: 1.32–12.50) and meropenem (OR: 1.84; 95% CI: 1.01–3.36). In 6 patients, clinical signs of idiosyncratic cholestatic hepatitis resolved within a few weeks after antibiotic discontinuation. The other 5 patients with clinical signs of idiosyncratic cholestatic hepatitis died.Conclusions. The authors described the phenotype of idiosyncratic cholestatic liver injury associated with antibiotics in critically ill children. The role of pharmacogenetic markers in the development of DILI associated with antibiotics in critically ill children needs to be assessed further to implement a risk-based approach and mitigate the risks.

Industry Review of Best Practices for Risk Management of Drug-Induced Liver Injury from Development to Real-World Use.

The relative treatment benefit of a drug for patients during development, marketing authorization review, or after approval includes an assessment of the risk of drug-induced liver injury (DILI). In this article, the Pharmacovigilance and Risk Mitigation Working Group of the IQ-DILI Initiative launched in June 2016 within the International Consortium for Innovation and Quality in Pharmaceutical Development presents and reviews three key topics for essential risk management activities to identify, characterize, monitor, mitigate, and communicate DILI risk associated with small molecules during drug development. The three topics are: (1) Current best practices for characterizing the DILI phenotype and the severity and incidence of DILI in the treatment population, including DILI identification, prediction and recovery. (2) Characterization of the relative treatment benefit for patients who will be exposed to a drug and the attendant risk of DILI in conjunction with existing global risk mitigation strategies. (3) Implementation of risk mitigation strategies during drug development highlighting patient factors, healthcare settings and site of product administration, and prescriber and healthcare provider factors. Industry guidance is provided for assessing whether the product labeling is sufficient to minimize the risk of DILI or whether a United States Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) or European Medicines Agency (EMA) Risk Management Plan (RMP) with additional Risk Minimization Measures (aRMM) is needed.

Integrating Liver-Chip data into pharmaceutical decision-making processes

ABSTRACT Introduction Drug-induced liver injury (DILI) is a potentially lethal condition that heavily impacts the pharmaceutical industry, causing approximately 21% of drug withdrawals and 13% of clinical trial failures. Recent evidence suggests that the use of Liver-Chip technology in preclinical safety testing may significantly reduce DILI-related clinical trial failures and withdrawals. However, drug developers and regulators would benefit from guidance on the integration of Liver-Chip data into decision-making processes to facilitate the technology’s adoption. Areas covered This perspective builds on the findings of the performance assessment of the Emulate Liver-Chip in the context of DILI prediction and introduces two new decision-support frameworks: the first uses the Liver-Chip’s quantitative output to elucidate DILI severity and enable more nuanced risk analysis; the second integrates Liver-Chip data with standard animal testing results to help assess whether to progress a candidate drug into clinical trials. Expert opinion There is now strong evidence that Liver-Chip technology could significantly reduce the incidence of DILI in drug development. As this is a patient safety issue, it is imperative that developers and regulators explore the incorporation of the technology. The frameworks presented enable the integration of the Liver-Chip into various stages of preclinical development in support of safety assessment.

Metabolic Disorders Are Associated With Drug-Induced Liver Injury During Antituberculosis Treatment: A Multicenter Prospective Observational Cohort Study in Korea.

Drug-induced liver injury (DILI) may lead to the discontinuation of antituberculosis (anti-TB) treatment (ATT). Some studies have suggested that metabolic disorders increase the risk of DILI during ATT. This study aimed to identify risk factors for DILI, particularly metabolic disorders, during ATT. A multicenter prospective observational cohort study to evaluate adverse events during ATT was conducted in Korea from 2019 to 2021. Drug-susceptible patients with TB who had been treated with standard ATT for 6 months were included. The patients were divided into 2 groups depending on the presence of 1 or more metabolic conditions, such as insulin resistance, hypertension, obesity, and dyslipidemia. We monitored ATT-related adverse events, including DILI, and treatment outcomes. The incidence of DILI was compared between individuals with and without metabolic disorders, and related factors were evaluated. Of 684 patients, 52 (7.6%) experienced DILI, and 92.9% of them had metabolic disorders. In the multivariable analyses, underlying metabolic disorders (adjusted hazard ratio [aHR], 2.85; 95% CI, 1.01-8.07) and serum albumin <3.5 g/dL (aHR, 2.26; 95% CI, 1.29-3.96) were risk factors for DILI during ATT. In the 1-month landmark analyses, metabolic disorders were linked to an elevated risk of DILI, especially significant alanine aminotransferase elevation. The treatment outcome was not affected by the presence of metabolic disorders. Patients with metabolic disorders have an increased risk of ATT-induced liver injury compared with controls. The presence of metabolic disorders and hypoalbuminemia adversely affects the liver in patients with ATT.

DRUG-INDUCED AUTOIMMUNE HEPATITIS: SYSTEMATIC REVIEW AND CASE STUDY

Drug-induced liver injury (DILI) is one of the types of adverse reactions to drugs that occur as a result of their hepatotoxic effect. The pathogenesis of drug-induced autoimmune hepatitis (LIAH) is based on the production of autoantibodies to neoantigens, which are proteins of the cytochrome P450 system, which are the result of the reaction of drug metabolites. A clinically relevant problem, such as drug-induced liver damage, affects 1-1.5 million patients almost every year. The annual incidence of DILI ranges from 2.3-13.9 per 100,000 population in population studies from Europe. The Icelandic population study recorded the highest rates of 19.1 per 100,000 population per year. And in the only study based on the US population, it was found that DILI is approximately 3 per 100,000 population. Acute hepatitis is currently a well-known manifestation, and accounts for more than 90% of liver damage caused by medications. According to studies, 2.9 - 8.8% of DILI and 2 - 18% of AIH are associated with drug-induced autoimmune hepatitis. The incidence of drug-induced liver damage with the presence of antibodies (antibodies to nuclear antigen, smooth muscle and soluble liver antigen) to AIH is 83% for nitrofurantoin, 74% for minocycline, 60% for methyldopa and 43% for hydralazine.

A nomogram model to predict the risk of drug-induced liver injury in patients receiving anti-tuberculosis treatment.

Objectives: To establish an individualized nomogram to predict the probability of drug-induced liver injury (DILI) in tuberculosis patients receiving anti-tuberculosis treatment. Methods: The clinical information of patients admitted to a tertiary hospital between January 2010 and December 2022 was retrospectively reviewed from the clinical records. Patients with baseline liver diseases (hepatis B or C infection and fatty liver) or taking liver protective drugs were excluded. The maximum values in liver function test within 180days after anti-tuberculosis treatment were collected to determine the occurrence of DILI. The candidate variables used for establishing prediction model in this study were the last results within the 30days before the treatment onset. The final variables were included after univariate and multivariate logistic regression analyses and applied to establish the nomogram model. The discrimination power and prediction accuracy of the prediction model were assessed using the area under the receiver operating characteristic (AUC) curve and a calibration chart. The clinical effectiveness was assessed via decision curve analysis (DCA). The established model was validated in two validation groups. Results: A total of 1979 patients with 25 variables were enrolled in this study, and the incidence of DILI was 4.2% (n = 83). The patients with complete variables were divided into training group (n = 1,121), validation group I (n = 492) and validation group II (n = 264). Five variables were independent factors for DILI and included in the final prediction model presented as nomogram: age (odds ratio [OR] 1.022, p = 0.023), total bilirubin ≥17.1μmol/L (OR 11.714, p < 0.001), uric acid (OR 0.977, p = 0.047), neutrophil count (OR 2.145, 0.013) and alcohol consumption (OR 3.209, p = 0.002). The AUCs of the prediction model in the training group, validation group I and validation group II were 0.833, 0.668, and 0.753, respectively. The p-values of calibration charts in the three groups were 0.800, 0.996, and 0.853. The DCA curves of the prediction model were above the two extreme curves. Conclusion: The nomogram model in this study could effectively predict the DILI risk among patients under anti-tuberculosis drug treatment.

Mapping the incidence of drug-induced liver injury: A systematic review and meta-analysis.

Drug-induced liver injury (DILI) is an increasing etiology of liver dysfunction, with various incidence worldwide. To better understand the disease burden and establish appropriate preventive and treatment strategies, a systematic review and meta-analysis was conducted. PubMed, EMBASE, Web of Science, and Cochrane Library were searched for studies on the incidence of DILI published up to June 1, 2022. According to the predefined criteria, only population-based studies were included. Incidence was presented as cases per 100 000 person-years with 95% confidence interval (CI) using a random-effects model. A total of 14 studies were included. The overall incidence of DILI was 4.94 per 100 000 person-years (95% CI 4.05-5.83). Time-based cumulative meta-analysis suggested that the incidence of DILI increased over time since 2010. The incidence varied by regions, with Asia having the highest incidence of 17.82 per 100 000 person-years (95% CI 6.26-29.38), while North America having the lowest incidence of 1.72 per 100 000 person-years (95% CI 0.48-2.95). All studies reported a higher incidence of DILI in the elderly but comparable incidences between male and female (3.42 per 100 000 person-years vs 4.64 per 100 000 person-years). The global incidence of DILI has been increasing since 2010, with the highest incidence in Asia. Understanding the epidemiological characteristics of DILI helps establish specific strategies to deal with this emerging health problems.

Retrospective analysis of risk factors for levofloxacin-induced liver injury

Levofloxacin is used as a first-line drug for the treatment of Legionella pneumonia. However, the relatively high incidence of drug-induced liver injury (DILI) remains a clinical problem. Based on the available patient data, this study aimed to identify the risk factors for DILI before levofloxacin administration. Multiple logistic regression analyses suggested that male sex (odds ratio [OR], 6.975; 95% confidence interval [CI], 1.737–28.000; p = 0.006), elevated C-reactive protein level (OR, 1.182; 95% CI, 1.089–1.283; p = 0.0006), and high haemoglobin level (OR, 1.640; 95% CI, 1.226–2.195; p = 0.001) before administration of levofloxacin were risk factors for DILI. Possible treatment with alternative drugs should be considered in male patients with elevated C-reactive protein and haemoglobin levels. Moreover, close monitoring of liver function tests when levofloxacin is administered may prevent the development and severity of DILI.

Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury.

Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver injury. Although expression of HLA-B*57:01 is associated with increased susceptibility, little is known of the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the provision of flucloxacillin-modified peptides that are presented to T-cells by the protein encoded by the risk allele. In this study, we have shown that flucloxacillin binds to multiple proteins within human primary hepatocytes, including major hepatocellular proteins (hemoglobin and albumin) and mitochondrial proteins. Inhibition of membrane transporters multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) appeared to reduce the levels of covalent binding. A diverse range of proteins with different functions was found to be targeted by flucloxacillin, including adaptor proteins (14-3-3), proteins with catalytic activities (liver carboxylesterase 1, tRNA-splicing endonuclease subunit Sen2, All-trans-retinol dehydrogenase ADH1B, Glutamate dehydrogenase 1 mitochondrial, Carbamoyl-phosphate synthase [ammonia] mitochondrial), and transporters (hemoglobin, albumin, and UTP-glucose-1-phosphate uridylyltransferase). These flucloxacillin-modified intracellular proteins could provide a potential source of neoantigens for HLA-B*57:01 presentation by hepatocytes. More importantly, covalent binding to critical cellular proteins could be the molecular initiating events that lead to flucloxacillin-induced cholestasis Data are available via ProteomeXchange with identifier PXD038581.

Hepatotoxicity and tuberculosis treatment outcomes in chronic liver disease.

The treatment of tuberculosis (TB) is known to cause liver injury, however, there is limited data to guide optimal treatment for patients with chronic liver disease. We undertook a retrospective case series of patients with chronic liver disease and TB disease. The primary objective was to determine if there was a difference in the incidence of drug-induced liver injury (DILI) in patients with cirrhosis versus those with chronic hepatitis. Additionally, we sought to compare TB treatment outcomes, type and duration of therapy, and incidence of adverse events. We included 56 patients (chronic hepatitis 40; cirrhosis 16). There were 33 patients (58.9%) who experienced DILI requiring treatment modification, with no significant difference between groups (65% versus 43.8%, p = 0.23). Patients with chronic hepatitis were more likely to receive treatment with standard first-line intensive phase therapy that included a combination of rifampin (RIF), isoniazid, and pyrazinamide (80.8% versus 19.2%, p = 0.03) and any regimen than included isoniazid (92.5% versus 68.8%, p = 0.04). The risk of DILI was higher when more hepatotoxic TB medications were used. Overall treatment success in this cohort was low (55.4%), with no significant difference between groups (62.5% versus 37.5%, p = 0.14). Most patients with treatment success (97%) were able to tolerate a rifamycin. The risk of DILI is high, especially with the use of isoniazid, in patients with TB and chronic liver disease. This risk can be effectively mitigated with no difference in treatment outcomes in the presence of cirrhosis.

Landscape of DILI-related adverse drug reaction in China Mainland.

Drug-induced liver injury (DILI) is a type of bizarre adverse drug reaction (ADR) damaging liver (L-ADR) which may lead to substantial hospitalizations and mortality. Due to the general low incidence, detection of L-ADR remains an unsolved public health challenge. Therefore, we used the dataof6.673 million of ADR reports from January 1st, 2012 to December 31st, 2016 in China National ADR Monitoring System to establish a new database of L-ADR reports for future investigation. Results showed that totally 114,357 ADR reports were retrieved by keywords searching of liver-related injuries from theoriginal heterogeneous system. By cleaning and standardizing the data fields by the dictionary ofsynonyms and English translation, we resulted 94,593 ADR records reported to liver injury andthencreated anew database ready for computer mining. The reporting status of L-ADR showed a persistent 1.62-fold change over the past five years. The national population-adjusted reporting numbers of L-ADR manifested an upward trend with age increasing and more evident in men. The annual reporting rate of L-ADR in age group over 80 years old strikingly exceeded the annual DILI incidence rate in general population, despite known underreporting situation in spontaneous ADR reporting system. The percentage of herbal and traditional medicines (H/TM) L-ADR reports in the whole number was 4.5%, while 80.60% of the H/TM reports were new findings. There was great geographical disparity of reported agents, i.e. more cardiovascular and antineoplastic agents were reported in higher socio-demographic index (SDI) regions and more antimicrobials, especially antitubercular agents, were reported in lower SDI regions. In conclusion, this study presented a large-scale, unbiased, unified, and computer-minable L-ADR database for further investigation. Age-, sex- and SDI-related risks of L-ADR incidence warrant to emphasize the precise pharmacovigilance policies within China or other regions in the world.

Identification of Drug-Induced Liver Injury Biomarkers from Multiple Microarrays Based on Machine Learning and Bioinformatics Analysis.

Drug-induced liver injury (DILI) is the most common adverse effect of numerous drugs and a leading cause of drug withdrawal from the market. In recent years, the incidence of DILI has increased. However, diagnosing DILI remains challenging because of the lack of specific biomarkers. Hence, we used machine learning (ML) to mine multiple microarrays and identify useful genes that could contribute to diagnosing DILI. In this prospective study, we screened six eligible microarrays from the Gene Expression Omnibus (GEO) database. First, 21 differentially expressed genes (DEGs) were identified in the training set. Subsequently, a functional enrichment analysis of the DEGs was performed. We then used six ML algorithms to identify potentially useful genes. Based on receiver operating characteristic (ROC), four genes, DDIT3, GADD45A, SLC3A2, and RBM24, were identified. The average values of the area under the curve (AUC) for these four genes were higher than 0.8 in both the training and testing sets. In addition, the results of immune cell correlation analysis showed that these four genes were highly significantly correlated with multiple immune cells. Our study revealed that DDIT3, GADD45A, SLC3A2, and RBM24 could be biomarkers contributing to the identification of patients with DILI.

S3259 A Case of Propofol-Induced Acute Liver Failure

Introduction: Propofol is a parenteral anesthetic routinely used for procedures given its beneficial pharmacokinetic profile of rapid onset of action and reversal. Propofol drug toxicity is rare but has been associated with idiosyncratic acute liver injury in a small number of cases. To the best of our knowledge, we present the second case of propofol-induced acute liver failure (ALF) reported in literature. Case Description/Methods: An 88-year-old male with concern for gastrointestinal bleed underwent an upper endoscopy with propofol used as the anesthetic agent. The patient tolerated the endoscopy well with no hemodynamic compromise during or afterwards. No source of bleeding was identified so the plan was to proceed with a colonoscopy the next day. Shortly after the procedure, he was noted to have altered mental status. Evaluation with routine laboratory testing revealed elevated AST of 3248 IU/L and ALT of 2411 IU/L, both increased from 35 IU/L and 24 IU/L, respectively. He was also found to have high anion gap metabolic acidosis and bicarbonate level less than 9 mEq/L. His altered mentation continued to worsen, and he became hemodynamically unstable requiring transfer to the intensive care unit. He had no history of liver disease or excessive alcohol use, no risk factors for viral hepatitis, and took no medications known to cause liver injury. Work-up was unremarkable for acute and chronic liver disease. Propofol was ultimately surmised as the cause of ALF. Unfortunately, the patient’s mental status progressively worsened despite hemodynamic stabilization and normalization of liver enzymes. His family ultimately chose to transition to comfort measures and the patient passed soon after. Discussion: The incidence of drug-induced liver injury is increasing in developed countries and is a major etiology of ALF, accounting for greater than 50% of cases. Drug toxicity secondary to an idiosyncratic reaction is unpredictable and occurs infrequently in certain individuals. While propofol is generally considered a safe agent widely used for sedation, propofol-induced acute liver injury is a rare outcome. To the best of our knowledge, it is reported to have caused five cases of acute hepatitis and one other case of ALF. We report the second case of ALF due to propofol with a lethal outcome. We recommend close monitoring of patients treated with propofol for signs of hepatitis and that ALF due to a drug insult should be considered after common causes have been excluded.

Differences in clinical characteristics among 726 patients with Chinese herbal medicine- or Western medicine-induced liver injury.

The differences between Chinese herbal medicine (CHM)- and Western medicine (WM)-induced liver injury have rarely been reported. Our aim was to investigate the clinical features of patients with drug-induced liver injury (DILI) caused by CHM or WM.The medical records of 726 DILI patients were retrospectively collected at Peking University First Hospital from January 1995 through August 2019.The number of inpatients with DILI in our hospital showed an increasing trend over time. The incidence of DILI caused by CHM exhibited a linear trend toward an increase with time (P = .0012). Of the 726 DILI patients, females accounted for 65.8%. There were 353 cases (48.6%) caused by CHM and 225 cases (40.0%) caused by WM. The 3 most common causative CHMs were Polygonum multiflorum (38 cases), Fructus Psoraleae (35 cases), and Epimedium (26 cases). The proportions of female patients, alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, total bilirubin (TBIL) levels and antinuclear antibody (ANA) positivity rates among cases caused by CHM were higher than those of cases caused by WM (P < .05). There were more patients with severe cases caused by CHM than with severe cases caused by WM (P < .05).The clinical characteristics of DILI caused by CHM differ from those caused by WM. The incidence of DILI caused by CHM is increasing yearly. The medication time of DILI caused by CHM is longer than that of DILI caused by WM, and the severity is greater. Therefore, it is necessary to scientifically and rationally use traditional CHM and monitor liver function. For DILI caused by CHM, the CHM prescription should be recorded in detail to provide detailed clinical data for scientific research on the liver toxicity of CHM.

Frequency of null genotypes of glutathione S-transferase M1 and T1 in Japanese patients with drug-induced liver injury.

Previous reports suggest that the null genotype (*0/*0) of glutathione S-transferase (GST) M1 and/or GSTT1 could be risk factors for drug-induced liver injury (DILI). However, multi-institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients. Blood samples of 270 DILI patients from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp-2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week-Japan score, as well as genotypes of GSTM1 and GSTT1 in each patient with DILI. The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of the GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and Digestive Disease Week-Japan scores was not observed. The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients.