Drug-induced hepatotoxicity studied in a 3D, in vitro model of the liver

Drug development is a high failure rate process; too many drugs fail during clinical trials because of severe hepatotoxicity. This situation can be significantly improved by redesigning preclinical trials, and privileging the use of high-throughput in vitro models, by combining cell-based in vitro models and material-based models.

Risk Factors for Hepatotoxicity Due to Paracetamol Overdose in Adults

Background and Objectives: Over-the-counter availability and a good safety profile make paracetamol one of the most common analgesics in developed countries but also the leading cause of liver failure due to overdose. The objectives of the study were to identify modifiable risk factors for severe hepatotoxicity following paracetamol overdose in adults. Materials and Methods: A retrospective cohort study involved the consecutive adult patients hospitalized in a toxicological center over a period of seven years due to paracetamol overdose. Complete medical datasets of laboratory and anamnestic variables were analyzed and validated by means of logistic regression model. Results: A total of 185 patients entered the study, including 25 individuals who developed severe hepatotoxicity (plasma aminotransferases levels above 1000 UI/L) and 31 individuals with mild to moderate liver injury (plasma aminotransferases levels above upper normal range, but below 1000 UI/L). In the univariable analysis, significant hepatotoxicity risk factors were male gender, alcohol abuse, an ingested paracetamol dose, and a timespan from ingestion to hospital admission. The later one was the only significant risk factor in the multivariable model (adjusted odds ratio 1.08; 95% CI: 1.03–1.12). Conclusions: A delay in hospital admission, resulting in a delayed administration of disease-specific treatment outweighs any other known risk factors of paracetamol-induced hepatotoxicity.

Foodborne TiO2 Nanoparticles Induced More Severe Hepatotoxicity in Fructose-Induced Metabolic Syndrome Mice via Exacerbating Oxidative Stress-Mediated Intestinal Barrier Damage

The hazard of titanium dioxide nanoparticles (TiO2 NPs) in diseased population should be given focus due to the huge number of these NPs in foods and medicine. This study aimed to evaluate the stronger biological adverse effect of oral exposure to TiO2 NPs in a fructose-induced metabolic syndrome mouse model. Compared to the normal mice, low-dose (2 mg/kg) TiO2 NPs did not cause severe hepatotoxicity. However, high-dose (20 mg/kg) TiO2 NPs induced aggravated hepatic inflammation, fibrosis, and apoptosis, with substantial alteration of related biochemical parameters in the mouse model. Moreover, significantly increased Ti and lipopolysaccharide burden were observed in metabolic syndrome murine liver and serum, which possibly worsened the portend intestinal leakage. The expression of tight junction-related protein showed that TiO2 NPs induced further increase in serious intestinal permeability. The intestinal inflammatory and oxidative stress response in the model were also assessed. Results showed that TiO2 NPs caused more severe intestinal inflammatory injury by intensifying the oxidative stress in metabolic syndrome mice and then induced further liver injury. This work provides information on the insights into the toxic effect of TiO2 NPs in sub-healthy population.

Incidence of Hepatotoxicity in Iranian Patients With HIV on Antiretroviral Therapies and Its Correlation with Virologic Response to HIV Treatment

Objective To investigate hepatotoxicity in Iranian patients with HIV to assess the association between virologic response to HIV treatment and serum alanine aminotransferase (ALT). Methods This study was conducted with 200 control patients, 75 patients with HIV naïve to antiretroviral therapy (ART), and 443 patients who received ARTs with virologic response (≤1000 copies/mL) or virologic treatment failure (>1000 copies/mL). Serum ALT level and HIV viral load were determined in all patients. Results Patient ALT levels were significantly higher than those of control patients (45.1 ± 44.4 IU/L vs 23.8 ± 5.4 IU/L). Compared to patients who were ART-naïve, patients with ART experience had significantly higher ALT levels (38.2 ± 26.2 IU/L vs 46.3 ± 46.7 IU/L), and severe hepatotoxicity was only detected in those with ART experience (8 patients, 1.8%). Mean ALT had no significant difference between virologic response/failure groups. The ALT activity and HIV load had a negative correlation coefficient, but it was not significant. Conclusion Periodic monitoring for the possibility of hepatotoxicity is highly recommended in all patients with HIV, especially in those receiving ART treatment.

Can Nutritional Supplementation Increase the Risk Of Crizotinib-Associated Hepatotoxicity: A Clinical Case Example

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death. The identification of oncogenetic driver mutation in lung cancer led to a therapeutic revolution by the discovery of targetable genetic alterations including the anaplasic lymphoma kinase (ALK) fusion oncogene and ROS1 . The tyrosine kinase inhibitor “Crizotinib” improved clinical outcome and prolonged responses. Severe hepatotoxicity is a rare adverse event .We report a case of Crizotinib-induced acute hepatitis with a probable drug-bergamot interaction

FOXO3 polymorphisms were correlated with gefitinib-induced hepatotoxicity in patients with non-small cell lung cancer.

9578 Background: Drug-induced liver injury (DILI) is one of the most safety concern in drug development and clinical therapy. Severe hepatotoxicity of gefitinib often leads to acute/chronic liver injury, drug discontinuation and further treatment failure, however, the mechanism of gefitinib-induced hepatotoxicity remains unclear. AKT1/FOXO3 regulates expression of genes involved in multiple biological/pathological processes in liver cells, including apoptosis, oxidative stress, and cell-cycle transition, as well as expression of autophagy-related (Atg) genes. Therefore, we investigated the correlation between single nucleotide polymorphisms (SNP) in AKT1/ FOXO3 and gefitinib-induced hepatotoxicity in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 172 advanced NSCLC patients with activating EGFR mutations were enrolled and administered with gefitinib 250mg daily. 22 tag SNPs in AKT1/FOXO3 were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. The associations between polymorphisms of AKT1/FOXO3 and gefitinib-induced hepatotoxicity were analyzed by Chi square test. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: FOXO3 rs4946935 and FOXO3 rs75544369 were found to be associated with gefitinib-induced hepatotoxicity in NSCLC patients. FOXO3 rs4946935 AA carriers have higher risk of developing gefitinib-induced hepatotoxicity than those with FOXO3 rs4946935 AG/GG. ( P = 0.018, OR = 12.414, 95%CI (1.53-100.711)). Patients with FOXO3 rs75544369 GA have higher risk of developing hepatotoxicity with P of 0.0002 (OR = 5.241, CI%(1.85-14.851)), or developing severe hepatotoxicity with P of 0.033 (OR = 2.963, 95%CI (1.090-8.059)), than those with FOXO3 rs75544369 GG. Conclusions: FOXO3 rs4946935 and FOXO3 rs75544369 are predictive biomarkers for gefitinib-induced hepatotoxicity in NSCLC patients. The mechanism underlying the association between FOXO3 polymorphisms and gefitinib-induced hepatotoxicity are worth investigating in further studies. Clinical trial information: NCT01994057 .