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Rifampicin is the most common pathogenic factor in anti-tuberculosis drug-induced liver injury (AT-DILI), the mechanisms that it promotes hepatocyte damage in AT-DILI are not yet to be thoroughly elucidated. In this study, we investigated the potential molecular mechanisms for ferroptosis involving rifampicin hepatotoxicity.Animal and cell injury models of rifampicin were constructed, and the toxicity of rifampicin was assessed by physicochemical staining and cell viability assay. Next, flow cytometry was employed to detect changes in ferroptosis-related markers, and Western blotting was used to detect protein expression. Then, the important role of autophagy and ferroptosis was verified with small molecule compound intervention.We found that ferritinophagy-induced ferroptosis participates in the toxicity of rifampicin, and the mechanism is that rifampicin precisely activates high-throughput autophagy, which leads to the massive degradation of ferritin and the increase of free iron. Moreover, rifampicin exhibited conspicuous inhibition of Human 71 kDa heat shock cognate protein (HSPA8) that is intimately associated with Microtubule-associated protein light chain 3 isoform B (LC3B) expression, in turn, HSPA8 inducer attenuated intracellular autophagy flux. Of note, inducing HSPA8 or inhibition of autophagy and ferroptosis considerably relieved the hepatotoxicity of rifampicin in mouse model.The present study highlights the crucial roles of the HSPA8 and autophagy in ferroptotic cell death driving by rifampicin, particularly illumines multiple promising regulatory nodes for therapeutic interventions in diseases involving AT-DILI.

Idisyncratic drug-induced liver injury (DILI) is a rare instance of liver injury after exposure to an otherwise safe drug or herbal or dietary supplement. DILI can be associated with significant morbidity and mortality. Furthermore, it is an important consideration in drug development due to safety concerns.To highlight pearls and pitfalls to aid clinicians in diagnosing DILI and surmising the management options. We also share the best practices from personal insights developed from decades long participation in the causality assessment committee meetings of the DILI Network.DILI lacks a diagnostic test and is currently diagnosed through a process of exclusion of competing aetiologies of liver injury. This requires a high degree of suspicion to consider the possibility of DILI, skill in ruling out the obvious and less obvious competing liver insults, and an understanding of the expected phenotypes of DILI. The facets of DILI cover multiple aspects, including the latency, liver injury pattern, course of injury, and associated autoimmune or immuno-allergic features. Care for patients with DILI is geared towards stopping the offending drug and symptom management that include the use of corticosteroids in select cases.The diagnosis of DILI is challenging and is primarily made through a carefully crafted patient interview, temporal relationship with the implicated drug or supplement, and exclusion of competing aetiology. LiverTox is a useful resource for clinicians to review the literature and recognise the likelihood of the implicated agent in causing DILI.

Patients with tuberculosis (TB) disease treated with multi-drug regimens are at risk of developing drug induced liver injury (DILI), and DILI risk might be even higher in patients with underlying liver disease. We aimed to evaluate whether underlying chronic hepatitis B virus (HBV) and TB co-infection are associated with a higher risk of TB therapy-related DILI. We conducted a systematic review and meta-analysis using MEDLINE/PubMed from inception to 31 December 2021. Primary outcome assessed was development of DILI following multi-drug TB treatment. Meta-analysis using random-effects models were utilized to evaluate whether underlying chronic HBV was associated with increased risk of DILI in patients undergoing active TB treatment. A total of 10 studies met inclusion criteria to be analysed, among which 520 patients had HBV-TB co-infection and 2988 patients had active TB disease without HBV. Prevalence of DILI was 21.9% in HBV-TB co-infected patients and 11.9% in TB patients without HBV. On meta-analysis, HBV-TB co-infected patients had significantly higher risk of DILI when treated with TB therapies compared with TB patients without HBV (pooled risk ratio 1.98, 95% CI 1.38-2.83, I

Liver depleted of hepatic stellate cells (HSCs) is resistant to ischemia/reperfusion-, concanavalin A-, and acetaminophen-induced acute injury. Whether HSCs regulate carbon tetrachloride (CCl

Exopolysaccharide biopolymers produced by microorganisms are crucial to the environment. They contribute to areas such as the health and bionanotechnology sectors, food and cosmetic industries as gelling agents, and environmental sector as flocculants owing to their biodegradability and non-toxic nature. The current study aimed to isolate the fraction of released exopolysaccharide (rEPS) by Bacillus velezensis SN-1 from Chinese Da-Jiang.The weighted average molecular weight of the major isolated component, rEPS-2, was 202 kDa, and its monosaccharide composition included mannose, glucose, and galactose at a molar ratio of 0.38:0.30:0.32. Further, the rEPS-2 was characterized using methylation analysis and one-dimensional/two-dimensional nuclear magnetic resonance (1D/2D NMR) spectroscopy. In vivo hepatoprotective effects indicated that rEPS-2 could alleviate carbon tetrachloride (CClThese results suggest that rEPS-2 has promising potential to serve as hepatoprotective agents. © 2022 Society of Chemical Industry.

© 2022 The Authors. Liver International published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., Background & aims: No multi-national prospective study of drug-induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short-term outcomes of the cases and controls is reported. Methods: Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016-2021. DILI cases or non-DILI acute liver injury controls following causality assessment were enrolled. Results: Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre-existing liver disease. DILI cases and non-DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin-clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug-induced autoimmune-like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver-related death), and another six received liver transplantation. Conclusions: In this first multi-national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI., Set up of the Prospective European Drug-Induced Liver Injury Registry (Pro-Euro-DILI Registry) was supported by an award to RJA and GPA from the EASL Registry Research Grants Programme. JIG and GPA are supported by National Institute of Health Research Nottingham Digestive Diseases Biomedical Research Unit and Nottingham Biomedical Research Centre [BRC-1215-20003]. RJA and MIL receive support from AEMPS. IAA holds a Sara Borrell contract (CD20/00083) funded by ISCiii. CIBERehd is funded by ISCiii. This article is based upon work from COST Action “CA17112 - Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology). www.cost.eu. All authors of this manuscript are members of COST Action CA17112. The Pro-Euro-DILI is a part of the Transbioline Consortium. The TransBioLine project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821283. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

Silver nanoparticles (Ag NPs or nanosilver) have pulled in expanding interest because of their novel physical, substance, and organic properties contrasted with their full scale scaled partners. The goal of this study was to investigate if Avena sativa (AVS) extract could ameliorate Ag NPs toxicity-induced alterations in liver structure and function, DNA damage, apoptosis, and oxidative stress. Twenty adult male rats were assigned randomly to four groups: control, AVS (intragastrically, 5 g/Kg body weight/day) for 2 weeks, Ag NPs (400 mg/kg body weight/day) for 1 week as acute toxicity and Ag NPs + AVS (same therapy of Ag NPs as acute toxicity with AVS). This study demonstrated a statistical significant increase in serum levels of liver function tests (AST, ALT, ALP and globulin), liver DNA damage, apoptotic P53 and Malondialdehyde after Ag NPs administration when compared to control group. Conversely, statistical significant decreases were detected in serum albumin, total proteins, liver reduced glutathione, catalase, superoxide dismutase, glutathione S-transferase and anti-apoptotic Bcl

Evidence for using bicyclol in drug-induced liver injury (DILI) is limited. This study aimed to explore the efficacy and safety of bicyclol in acute DILI.This was a multicenter, randomized, double-blinded, double-dummy, active-controlled, superiority and phase II trial. Patients with idiosyncratic acute DILI were randomized 1: 1:1 to low-dose bicyclol (25 mg times a day [TID]), high-dose bicyclol (50 mg TID) and polyene phosphatidylcholine (control) groups. The primary endpoint was the decrease from baseline in serum alanine aminotransferase (ALT) levels at post-treatment for 4 weeks.Overall, 241 patients were included in the full analysis set, with 81, 82 and 78 patients in the low-dose bicyclol, high-dose bicyclol, and control groups respectively. ALT levels decreased across groups (-249.2 ± 151.1, -273.6 ± 203.1, and -180.8 ± 218.2 U/L in the low-dose bicyclol, high-dose bicyclol and control groups, respectively; both p .001, the bicyclol-dependent groups vs. control group). The ALT normalization rates at weeks 1, 2, 4, 6 and 8 were higher in the bicyclol-dependent groups than in the control group (p = .002 at week 1 and all p .001 at weeks 2, 4, 6 and 8 respectively). The median times to ALT normalization in the low-dose bicyclol, high-dose bicyclol and control groups were 29, 16 and 43 days respectively. Adverse events, serious adverse events and adverse drug reactions were similar across groups.Bicyclol (25 and 50 mg TID) appeared efficacious and safe for treating idiosyncratic acute DILI, while bicyclol 50 mg TID showed higher efficacy.www.gov (registration no. NCT02944552).

Acetaminophen (APAP)-induced liver injury (AILI) is the most common cause of acute liver failure. Although the mechanisms that trigger AILI are well known, it is less understood how to halt AILI progression and facilitate liver recovery. Therefore, it is necessary to understand the pathophysiology of APAP hepatotoxicity in patients and to examine predictive/preventive markers. In a clinical study, we had a case in which aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels increased in a patient with a low ratio of APAP glucuronide concentration (AP-G)/APAP plasma concentration. Then a reverse translational study was conducted for clarifying this clinical question. The relationship between plasma AP-G/APAP concentration ratio and the levels of AST and ALT was examined by in vivo and in vitro experiments. In in vivo experiments, 10-week-old rats showed lower UGT activity, lower AP-G/APAP concentration ratios, and higher AST and ALT levels than 5-week-old rats. This suggests an inverse correlation between the AP-G/APAP concentration ratio and the AST, ALT levels in APAP-treated rats. Furthermore, as a result of the in vitro experiment, it was confirmed that the cell viability decreased when the AP-G/APAP concentration ratio in the culture medium decreased. Since the decrease in the plasma AP-G/APAP concentration ratio appears earlier than the increase of AST and ALT levels, the ratio might be a presymptomatic marker of AILI. When APAP is used for a long time, it is recommended to perform therapeutic drug monitoring of the AP-G/APAP concentration ratio, which is a predictive/preventive marker of AILI.

2-Amino-2-methyl-1-propanol (AMP™) is widely used as a neutralizer/pH stabilizer in personal care products (PCPs); however, the potential health implications of dermal AMP exposure remain to be fully elucidated. Consequently, an in-depth analysis was performed to determine if PCPs containing AMP pose an elevated risk in humans under the intended use conditions. Animal studies have shown that at high doses, oral AMP exposure could lead to liver steatosis; thus, this study focused on hepatotoxicity. Our assessment revealed that the derived margin of exposure (MoE) values for AMP-containing PCPs were above 100, indicating that dermal exposure to AMP is unlikely to present an elevated risk of hepatotoxicity. Further, mode of action (MOA) analysis was conducted to elucidate the potential mechanisms underlying the observed hepatotoxicity in animal studies. Our analysis proposed that AMP interferes with the CDP-choline pathway in hepatocytes via the inhibition of one or more enzymes integral to the pathway and/or the replacement of choline in the assembly of the phospholipid unit. Ultimately, these events halt the lipid export via very low-density lipoproteins, which can subsequently develop into fatty liver accompanied by hepatotoxicity and other pathological changes if AMP exposure persists at sufficiently high doses. MOA analysis corroborated that dermal exposure to AMP expected from use of PCPs is highly unlikely to result in toxicologically significant systemic concentrations of AMP and thus hepatotoxicity. We concluded that dermal exposure to AMP in PCPs is not anticipated to result in an increased risk of hepatotoxicity.

BACKGROUND: Leflunomide, a disease-modifying anti-rheumatic drug, has been associated with elevations of serum aminotransferases. Herein, we describe the clinical, laboratory features, and outcomes of 17 patients with leflunomide/teriflunomide hepatotoxicity from two large drug-induced liver injury (DILI) registries. METHODS: Consecutive, adjudicated cases of leflunomide (n=16)-or teriflunomide (n=1)-related DILI from a single center in Bangalore, India and the multicenter US Drug-Induced Liver Injury Network (DILIN) were reviewed. RESULTS: Nine (0.8%) of the 1070 Indian patients and 8 (0.5%) of the 1400 DILIN patients fulfilled criteria for DILI due to leflunomide- or teriflunomide. 89% of the Indian cases were women and all were associated with severe cutaneous adverse reaction (SCAR) and a median drug latency of 49 days, whereas 37.5% of the DILIN cases were female, none exhibited SCAR, and the median drug latency was 166 days. Hepatocellular injury (70%) was more common in women than men (92% vs. 20%) and was associated with younger mean age (41 vs. 59 years), higher peak INR (2.3 vs. 1.2), and higher mortality (58% vs. 0%). Mortality was observed in 6 patients from India (2 of the three with myocarditis) and 1 received liver transplantation from the USA CONCLUSION: Leflunomide-induced liver injury is predominantly hepatocellular. Leflunomide hepatotoxicity is more likely accompanied by SCAR, a short latency, and a higher mortality in the Indian cohort, with a predominance of females, compared to US DILIN patients. The differences in skin involvement, immunoallergic features, and outcomes among subjects from India vs. the US suggest that genetic or environmental factors are important in the pathogenesis of liver injury.

Paracetamol overdose is common in developed countries but less than 10% involve large ingestions exceeding 30 g or 500 mg/kg. High dose acetylcysteine (NAC) has been proposed in patients taking large paracetamol overdoses based on reports of hepatotoxicity despite early initiation of NAC treatment with the commonly used 300 mg/kg intravenous acetylcysteine regimen. The evidence from cohorts of patients treated with the standard NAC regimen after large paracetamol overdoses shows that it is effective in most patients. A small study in patients with paracetamol overdoses of 40 g or more and paracetamol concentrations above the 300 mg/L nomogram line showed that modification of the standard NAC regimen to provide a total of 400-500 mg/kg NAC over 21-22 h may reduce the risk of hepatotoxicity (peak ALT 1000 IU/L) but the impact on development of hepatic failure, liver transplantation and mortality with this approach is presently unknown. Better risk stratification of patients taking paracetamol overdose may allow higher dose NAC and adjunctive treatments such as CYP2E1 inhibition and extracorporeal removal of paracetamol to be targeted to those patients at the highest risk of hepatotoxicity after a large paracetamol overdose.

Tuberculosis (TB) treatment is plagued by liver damage, which often leads to treatment interruptions. Circular RNAs (circRNAs) are a special class of non-coding RNAs abundant in body fluids with important biological functions. However, the role of circRNA in anti-tuberculosis drug-induced liver injury (ADLI) is unclear. We explored ADLI-specific circRNAs in TB patients using circRNA microarrays and verified circMARS in a cohort of 300 individuals. In addition to the value assessment of circMARS in patients using a receiver operating characteristic (ROC) curve, cell experiments were also performed under the guidance of bioinformatics analyses. In particular, we found that circMARS acts as a miRNA sponge by binding to miRNAs. Compared with the blank group, the expressions of circMARS, KMT2C gene, and EGFR protein in the ADLI group were increased, while miR-6808-5p, miR-6874-3p, and miR-3157-5p were decreased. Furthermore, when si-circMARS was used in the ADLI groups, circMARS demotion manifested the opposite results. Subsequently, a self-controlled cohort of 35 participants was used to verify the circMARS-miR-6808-5p/-6874-3p/-3157-5p-KMT2C-EGFR function axis. Therefore, circMARS may participate in the compensatory repair mechanism of ADLI through the function axis, and may be a potential biomarker for ADLI diagnosis in TB patients.

Drug-induced liver injury (DILI) by acetaminophen (APAP) was one of the most challenging liver diseases. Wolfberry (Lycium barbarum L.), a traditional Chinese medicinal material and food supplement, has a potential effect on increasing the abundance of Akkermansia muciniphila (A. muciniphila) in mice colons. However, the effect and mechanism of wolfberry remain unclear in APAP-induced DILI. In this study, wolfberry promoted the proliferation of activated-A. muciniphila in vitro and in vivo. For the first time, we detected that the activated-A. muciniphila but not the killed-A. muciniphila increased the expression level of Yes-associated protein 1 (YAP1) in the liver and alleviated liver injury in APAP-induced DILI mice. Mechanically, A. muciniphila improved the intestinal mucosal barrier and reduced lipopolysaccharide (LPS) content in the liver, leading to the increased expression level of YAP1. Furthermore, wolfberry increased the A. muciniphila abundance in the colon and YAP1 expression in the liver from APAP-induced DILI mice, which promoted the recovery of APAP-induced liver injury. Meanwhile, wolfberry combination with A. muciniphila synergistically increased AKK abundance and YAP1 expression in the liver. Our research provides an innovative strategy to improve DILI.

Background and Aim: Hepatic stellate cells (HSCs) activation, a critical event in liver fibrosis, has been recently shown to be related to autophagy. Determine whether chloroquine (CQ) could affect (i) the activation of HSC in vivo and (ii) the hepatic damage in a mice acute liver injury model. Methods: The acute liver injury was induced in BALB/c mice by carbon tetrachloride (CCl4 group); 24 h before and after CCl4 administration animals were treated by CQ (CCl4 + CQ group). As control, mice treated by olive oil were considered. After 48 h from CCl4/olive oil administration, blood samples, liver tissues, and HSCs were harvested for analysis. Results: In vivo, CQ attenuates CCl4-induced acute liver damage as evidenced by (i) the reduction of liver enlargement, (ii) the reduction of liver swelling and necrosis also supported by a certain decrease of circulating transaminases level, and (iii) the reduction of liver fibrosis evaluated by collagen deposition and α-sma protein expression. In HSCs isolated from CQ treated group, we observed the inhibition of autophagy proved by the increase in p62 protein and the decrease of lc3 protein. In addition, CQ reduced the expression of the HSCs activation markers α-sma/collagen-I and down-regulated the expression of the proliferative marker ki67. Conclusion: The autophagy attenuation exerted by CQ together with the reduction of the expression of the proliferation marker in HSCs can lessen the acute liver damage potentially opening the way to novel therapeutic approaches for hepatic fibrosis.

The aim of this study was to investigate the protective effects of Nano-Se against nickel (Ni)-induced hepatotoxicity and the potential mechanism. Hence, we constructed in vivo and in vitro models of Ni-induced hepatotoxicity. Sprague-Dawley (SD) rats were exposed to nickel sulfate (NiSO4 , 5.0 mg/kg, i.p.) with or without Nano-Se (0.5, 1, and 2 mg/kg, oral gavage) co-administration for 14 days, and HepG2 cells were exposed to NiSO4 (1500 μM) with or without Nano-Se (20 μM) for 24 h. Nano-Se obviously prevented Ni-induced hepatotoxicity indicated by ameliorating pathological change and decreasing Ni accumulation in rat livers. Ni induced a significant increase in hepatic activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSH-Px), and malondialdehyde (MDA) level, decreased the glutathione (GSH) content while compared to those in the control group. Nano-Se administration improved the hepatic antioxidant capacity through increase hepatic GSH contents and GSH-Px activity, decrease the activities of SOD, CAT, and MDA level. Nano-Se improved the cell viability, decreased active oxygen (ROS) generation and ameliorated morphological changes of nuclear structures in Ni-treated HepG2 cells. In addition, Nano-Se inhibited the Ni-induced increases of cytochrome c, caspase-9, cleaved caspase-3, increased PI3K and AKT phosphorylation both in vivo and in vitro. Besides, the PI3K inhibitor Y294002 could inhibit the protective effects of Nano-Se on apoptosis. Thus, Nano-Se significantly activates PI3K/AKT signaling to ameliorate apoptosis in Ni-induced hepatotoxicity.

The identification of specific human leukocyte antigen (HLA) risk alleles in drug-induced liver injury (DILI) points towards an important role of the adaptive immune system in DILI development. In this study we aimed to corroborate the role of an adaptive immune response in DILI through immunophenotyping of leukocyte populations and immune checkpoint expressions. Blood samples were collected from adjudicated DILI (n=12), acute viral hepatitis (VH, 13), acute autoimmune hepatitis (AIH, 9) and acute liver injury of unknown etiology (UKE, 15) at day 1 (recognition), day 7 and day >30. Blood samples from non-alcoholic fatty liver disease patients (NAFLD, 20) and healthy liver controls (HLC, 54) were extracted at one time point. Leukocyte populations and immune checkpoint expressions were determined based on cell surface receptors, except for CTLA-4 that was determined intracellularly, using flow cytometry. At recognition DILI demonstrated significantly higher levels of activated helper T-cell (p

Hepatic cell death occurs in response to diverse stimuli such as chemical and physical damage. The exposure of intracellular contents such as DNA during necrosis induces a severe inflammatory response that has yet to be fully explored therapeutically. Here, we sought means to neutralize the ability of extracellular DNA to induce deleterious tissue inflammation when drug‐induced liver injury had already ensued. DNA exposure and inflammation were investigated in vivo in drug‐induced liver injury using intravital microscopy. The necrotic DNA debris was studied in murine livers in vivo and in DNA debris models in vitro by using a positively charged chemokine‐derived peptide (MIG30; CXCL9[74‐103]). Acetaminophen‐induced liver necrosis was associated with massive DNA accumulation, production of CXC chemokines, and neutrophil activation inside the injured tissue. The MIG30 peptide bound the healthy liver vasculature and, to a much greater extent, to DNA‐rich necrotic tissue. Moreover, MIG30 bound extracellular DNA directly in vivo in a charge‐dependent manner and independently of glycosaminoglycans and chemokines. Post‐treatment of mice with MIG30 reduced mortality, liver damage, and inflammation significantly. These effects were not observed with a control peptide that does not bind DNA. Mechanistically, MIG30 inhibited the interaction between DNA and histones, and promoted the dissociation of histones from necrotic debris. MIG30 also inhibited the pro‐inflammatory effect of CpG DNA, as measured by a reduction in CXCL8 production, indicating that MIG30 disturbs the ability of DNA to induce hepatic inflammation. Conclusion: The use of DNA‐binding peptides reduces necrotic liver injury and inflammation, even at late timepoints., Marques et al. used a small chemokine‐derived positively‐charged peptide (MIG30) to neutralize the deleterious effects of extracellular DNA during drug‐induced liver injury. Treatment with MIG30 rescued mice from injury, inflammation and mortality by binding DNA avidly, dissociating it from histones and reducing the pro‐inflammatory activity of CpG DNA.

Background Pegaspargase (PEG‐ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG‐ASP‐associated hepatotoxicity. Methods We collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity. Results Fifty‐two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG‐ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event‐free survival. Conclusions This real‐world data on levocarnitine supplementation during ALL induction highlights the risk of PEG‐ASP‐associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings., Patients who are adolescents or young adults and/or who are obese are at higher risk for pegaspargase‐induced hepatotoxicity. Levocarnitine supplementation may reduce the risk for hepatoxicity during induction therapy for acute lymphoblastic leukemia.

Drug-induced liver injury (DILI) is a leading cause of therapy failure in the clinic and also contributes much to acute liver failure cases. Investigations of predictive sensitivity in animal models have limitations due to interspecies differences. Previously reported in vitro models of liver injury based on primary human hepatocytes (PHHs) cannot meet the requirements of high physiological fidelity, low cost, simple operation, and high throughput with improved sensitivity. Herein, we developed an integrated biomimetic array chip (iBAC) for establishing extracellular matrix (ECM)-based models. A collagen-based 3D PHH model was constructed on the iBAC as a case for the prediction of clinical DILI at throughput. The iBAC has a three-layer structure with a core component of 3D implanting holes. At an initial cell seeding numbers of 5000-10,000, the collagen-based 3D PHH model was optimized with improved and stabilized liver functionality, including cell viability, albumin, and urea production. Moreover, basal activities of most metabolic enzymes on the iBAC were maintained for at least 12 days. Next, a small-scale hepatotoxicity screening indicated that the 3D PHH model on the iBAC was more sensitive for predicting hepatotoxicity than the 2D PHH model on the plate. Finally, a large-scale screening of liver toxicity using 122 clinical drugs further demonstrated that the collagen-based 3D PHH model on the iBAC had superior predictive sensitivity compared to all previously reported in vitro models. These results indicated the importance of 3D collagen for liver physiological functionality and hepatotoxicity prediction. We anticipant it being a promising tool for risk assessment of drug-induced hepatotoxicity with a widespread acceptance in drug industry.

Human leukocyte antigens (HLA) have been linked to adverse drug reactions. Generally, HLA association is phenotype specific and is related to either liver or skin injury. HLA-A*13:01 has been linked to dapsone-induced severe cutaneous drug reactions and its role in drug-induced liver injury (DILI) is unclear. In our series, all of the four patients with immunoallergic dapsone DILI were carrying HLA-B*13:01 compared to its prevalence of 1-12% among Indians. HLA-B*13:01 plays a role not only in dapsone-induced severe cutaneous adverse reaction (SCAR) but also in dapsone-induced liver injury with immunoallergic features and highlights the role of adaptive immune response in the pathogenesis of both liver and skin injury and associated other organ involvement.

Cancer is a lethal disease that is characterized by uncontrolled cell division and proliferation, and it results in death in many organisms. Doxorubicin (DOX) is a therapeutic agent used for treatment of many cancer types, but it induces serious hepatotoxicity. In this study, we aimed to determine possible hepato-therapeutic effects of thymoquinone (THQ) on DOX-induced hepatotoxicity in rats. Rats were divided into five groups (n = 8): Control, THQ (10 mg/kg/day/i.p for 14 days), Olive Oil (equal volume with THQ for 14 days), DOX (single dose, 15 mg/kg/i.p on 7th day) and DOX + THQ (10 mg/kg/day/i.p and DOX 15 mg/kg/i.p on 7th day). At the end of the experiment, liver tissues were extracted and evaluated histopathologically. eNOS, iNOS and Cas-3 immunostaining were performed to determine the expression levels. TUNEL method was used to determine apoptotic index. Furthermore, liver tissue total antioxidant status (TAS), total oxidant status (TOS), TNF-alpha and TGF-beta levels were measured by ELISA assay. The DOX group showed histopathological deterioration compared to Control group. Moreover, apoptotic index, eNOS, iNOS and Cas-3 expressions increased in DOX group. While TAS level of the DOX group decreased, TOS level increased. TNF-alpha and TGF-beta levels increased in DOX group. However, there was improvement in DOX + THQ group compared to DOX group. Moreover, apoptotic cell number, eNOS, iNOS and Cas-3 expressions decreased in DOX + THQ group compared to DOX group. We concluded that thymoquinone can be used as a phytotherapeutic for reducing DOX-induced liver damage.

Morinda elliptica L. (Rubiaceae) is a phytomedicinal herb, used to treat gastrointestinal complications in Peninsular Malaysia. The study evaluates the in vivo hepatoprotective activity of ethanolic extract of M. elliptica stem in thioacetamide (TAA) induced liver fibrosis in male Sprague Drawly rats. Thirty adult rats were divided into five groups of six rats each. Rats of the normal control group received intraperitoneal injections (i. p.) of vehicle 10% Tween-20, 5 ml/kg, and hepatotoxic group 200 mg/kg TAA three times per week respectively. Three supplementary groups were treated with TAA plus daily oral silymarin (50 mg/kg) or M. elliptica (250 or 500 mg/kg). After 8 weeks of treatment, all rats were sacrificed. Liver fibrosis was assessed by gross macroscopic and microscopic tissue analysis, histopathological, and biochemical analysis. The livers of the TAA treated group showed uniform coarse granules, hepatocytic necrosis with lymphocytes infiltration. Contrary, the livers of M. elliptica treated groups (250 and 500 mg/kg) were much smoother and the cell damage was much lesser. The livers of M. elliptica treated groups rats showed elevated activity of SOD and CAT with a significant decrease in MDA level at p < .0001. The level of liver damage parameters, that is, ALP, ALT, and AST, bilirubin, total protein, and albumin were restored to the normal comparable to silymarin. M. elliptica stem extract significantly promoted normal rat liver architecture with significant perfections in biochemical parameters. The molecular contents of M. elliptica with hepatoprotective influence could be discovered, is the future prospective of this study.

Objective To compare the characteristics and outcomes of drug-induced liver injury (DILI) caused by paracetamol and non-paracetamol medications, particularly herbal and dietary supplements. Design Retrospective electronic medical record data analysis. Setting, participants Adults admitted with DILI to the Gastroenterology and Liver Centre at the Royal Prince Alfred Hospital, Sydney (a quaternary referral liver transplantation centre), 2009-2020. Main outcome measures 90-day transplant-free survival; drugs implicated as causal agents in DILI. Results A total of 115 patients with paracetamol-related DILI and 69 with non-paracetamol DILI were admitted to our centre. The most frequently implicated non-paracetamol medications were antibiotics (19, 28%), herbal and dietary supplements (15, 22%), anti-tuberculosis medications (six, 9%), and anti-cancer medications (five, 7%). The number of non-paracetamol DILI admissions was similar across the study period, but the proportion linked with herbal and dietary supplements increased from 2 of 13 (15%) during 2009-11 to 9 of 19 (47%) during 2018-20 (linear trend: P = 0.011). Despite higher median baseline model for end-stage liver disease (MELD) scores, 90-day transplant-free survival for patients with paracetamol-related DILI was higher than for patients with non-paracetamol DILI (86%; 95% CI, 79-93% v 71%; 95% CI, 60-82%) and herbal and dietary supplement-related cases (59%; 95% CI, 34-85%). MELD score was an independent predictor of poorer 90-day transplant-free survival in both paracetamol-related (per point increase: adjusted hazard ratio [aHR], 1.19; 95% CI, 1.09-3.74) and non-paracetamol DILI (aHR, 1.24; 95% CI, 1.14-1.36). Conclusion In our single centre study, the proportion of cases of people hospitalised with DILI linked with herbal and dietary supplements has increased since 2009. Ninety-day transplant-free survival for patients with non-paracetamol DILI, especially those with supplement-related DILI, is poorer than for those with paracetamol-related DILI.

BACKGROUND & AIMS Severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) are high-mortality adverse drug reactions. The risk factors and prognosis of drug-induced liver injury (DILI) concomitant with SCAR warrant clarification. We aimed to evaluate the characteristics and outcomes of DILI with SCAR. METHODS We analysed the database of a 10-year multi-centre prospective study in Taiwan from 2011 to 2020. RESULTS A total of 1415 patients with DILI were enrolled, including 81 cases combined with SJS/TEN, 74 with DRESS, 3 with AGEP and 1257 with pure DILI. Approximated 11.2% of patients had SCAR, of which allopurinol was the leading incriminated drug, followed by sulphonamides and carbamazepine. The SJS/TEN group had the highest mortality (34.6%). Jaundice, acute kidney injury and SJS/TEN were independent risk factors of mortality (odds ratio: 29.54, 4.43 and 4.86, respectively, P

Drug‐induced liver injury (DILI) should be considered in all patients with recent elevation of liver tests without obvious etiology and normal hepatobiliary imaging. There is currently no biomarker that is helpful in diagnosis which relies on clinical and laboratory findings. Diagnosis is dependent on temporal relationship with a recently started drug or herbal and dietary supplement and elevated liver tests with exclusion of competing etiologies. The implicated agent should be discontinued and the patient should be observed closely. This is particularly important in patients with jaundice who have approximately 10% risk of liver related mortality and/or need for liver transplantation. There is no specific therapy for DILI which is only symptomatic such as for itching. Patients with jaundice and coagulopathy usually require hospitalization.

Liver disorders are one of the principal reasons for mortality in the world. Isotretinoin is a systemic retinoid that has been approved for therapy of acne vulgaris since 1982. This drug causes complications in the body. Evidence suggests that Isotretinoin might cause hepatotoxicity. Our research aimed to study the exact mechanism of hepatotoxicity induced by isotretinoin and the protective role of taurine in this toxicity. Biomarkers such as aspartate transaminase (AST) and alanine transaminase (ALT), superoxide dismutase, glutathione content (GSH), catalase, and malondialdehyde (MDA) were examined. Furthermore, pathological changes were evaluated. The results showed that oral administration of Isotretinoin induced hepatotoxicity as showed by elevation in ALT, AST, and MDA; also, it reduced intracellular GSH in rat liver tissue. Administration of taurine prevented the hepatotoxicity induced by isotretinoin in rats significantly.

Permethrin (PER) is a pyrethroid pesticide that is extensively used as an insecticide in world because of its high activity and its low mammalian toxicity. The current study was conducted to investigate the protective action of Fumaria officinalis against PER-induced liver injury in male rats. However, HPLC-DAD showed the richness of 6 components in F. officinalis (F) including quercetin, ferulic acid, and naringenin which were the most abundant. Total polyphenols, total flavonoids, and condensed tannins were studied by phytochemical screening. In vitro, antioxidant properties showed that F. officinalis exhibited the highest DPPH radical, FRAP, and H

The assessment in real-life conditions of the safety and efficacy of new antimalarial drugs is of greatest interest. This study aimed to monitor and evaluate both clinical and biological safety of pyronaridine-artesunate (PA) in real-life conditions in Burkina Faso's health system. This was a single-arm, open-label study, where patients attending Nanoro health facilities with uncomplicated malaria were consented to be part of a cohort event monitoring (CEM). At inclusion (day-0), PA was administered orally once a day for 3 days. Patients spontaneous reported any clinical adverse events (AEs) occurring within 28 days following the treatment. Additionally, the study focused on AEs of special interest (AESI), namely clinical signs related to hepatotoxicity and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). A nested subset of patients with blood sample collection at day-0 and day-7 were monitored to investigate the effect of PA on biochemistry parameters. From September 2017 to October 2018, 2786 patients were treated with PA. About 97.8% (2720/2786) of patients did not report any AE. The most commonly reported events were respiratory, thoracic, and mediastinal disorders (8.3 per 1000), infections and infestations (7.9 per 1000), and gastrointestinal disorders (7.2 per 1000). No clinical or biological hepatotoxicity event related to PA was reported during the follow-up. Changes in biochemistry parameters remained within laboratory reference ranges. The study showed that PA is a well-tolerated drug and should be considered as a good option by malaria control programs in countries where existing first-line antimalarial drugs are continuously threatened by the emergence of drug resistance.

Acute liver injury is a common disease without effective therapy in humans. We sought to evaluate a combination therapy of insulin-like growth factor 1 (IGF-I) and BTP-2 in a mouse liver injury model induced by lipopolysaccharide (LPS). We chose this model because LPS is known to increase the expression of the transcription factors related to systemic inflammation (i.e., NFκB, CREB, AP1, IRF 3, and NFAT), which depends on calcium signaling. Notably, these transcription factors all have pleiotropic effects and account for the other observed changes in tissue damage parameters. Additionally, LPS is also known to increase the genes associated with a tissue injury (e.g., NGAL, SOD, caspase 3, and type 1 collagen) and systemic expression of pro-inflammatory cytokines. Finally, LPS compromises vascular integrity. Accordingly, IGF-I was selected because its serum levels were shown to decrease during systemic inflammation. BTP-2 was chosen because it was known to decrease cytosolic calcium, which is increased by LPS. This current study showed that IGF-I, BTP-2, or a combination therapy significantly altered and normalized all of the aforementioned LPS-induced gene changes. Additionally, our therapies reduced the vascular leakage caused by LPS, as evidenced by the Evans blue dye technique. Furthermore, histopathologic studies showed that IGF-I decreased the proportion of hepatocytes with ballooning degeneration. Finally, IGF-I also increased the expression of the hepatic growth factor (HGF) and the receptor for the epidermal growth factor (EGFR), markers of liver regeneration. Collectively, our data suggest that a combination of IGF-I and BTP-2 is a promising therapy for acute liver injury.

Drug-induced liver injury (DILI) is a significant public health issue, but standard animal tests and clinical trials sometimes fail to predict DILI due to species differences and the relatively low number of human subjects involved in preapproval studies of a new drug, respectively. In vitro models have long been used to aid DILI prediction, with primary human hepatocytes (PHHs) being generally considered the gold standard. However, despite many efforts and decades of work, traditional culture methods have been unsuccessful in either fully preserving essential liver functions after isolation of PHHs or in emulating interactions between PHHs and hepatic nonparenchymal cells (NPCs), both of which are essential for the development of DILI under in vivo conditions. Recently, various liver-on-a-chip (Liver-Chip) systems have been developed to co-culture hepatocytes and NPCs in a three-dimensional environment on microfluidic channels, enabling better maintenance of primary liver cells and thus improved DILI prediction. The Emulate® Liver-Chip is a commercially available system that can recapitulate some in vivo DILI responses associated with certain compounds whose liver safety profile cannot be accurately evaluated using conventional approaches involving PHHs or animal models due to a lack of innate immune responses or species-dependent toxicity, respectively. Here, we describe detailed procedures for the use of Emulate® Liver-Chips for co-culturing PHHs and NPCs for the purpose of DILI evaluation. First, we describe the procedures for preparing the Liver-Chip. We then outline the steps needed for sequential seeding of PHHs and NPCs in the prepared Liver-Chips. Lastly, we provide a protocol for utilizing cells maintained in perfusion culture in the Liver-Chips to evaluate DILI, using acetaminophen as an example. In all, use of this system and the procedures described here allow better preservation of the functions of human primary liver cells, resulting in an improved in vitro model for DILI assessment. © 2022 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA. Basic Protocol 1: Liver-Chip preparation Basic Protocol 2: Seeding primary human hepatocytes and nonparenchymal cells on Liver-Chips Basic Protocol 3: Perfusion culture for the study of acetaminophen-induced liver injury.

The objective of this study was to examine the protective effects of S-methyl methionine sulfonium chloride (MMSC) against galactosamine (GalN)-induced brain and cerebellum injury in rats. A total of 22 female Sprague-Dawley rats were randomly divided into four groups as follows: Group I (n = 5), intact animals; Group II (n = 6), animals received 50 mg/kg/day of MMSC by gavage technique for 3 consecutive days; Group III (n = 5), animals injected with a single dose of 500 mg/kg of GalN intraperitoneally (ip); and Group IV (n = 6), animals injected with the same dose of GalN 1 h after MMSC treatment. After 6 h of the last GalN treatment (at the end of the experiments), all animals were killed under anesthesia, brain and cerebellum tissues were dissected out. Reduced glutathione, total antioxidant status levels, and antioxidant enzymes (catalase, superoxide dismutase, and glutathione-related enzymes), aryl esterase, and carbonic anhydrase activities remarkably declined whereas advanced oxidized protein products, reactive oxygen species, total oxidant status, oxidative stress index levels, and myeloperoxidase, acetylcholinesterase, lactate dehydrogenase, and xanthine oxidase activities were significantly elevated in the GalN group compared with intact rats. In contrast, the administration of MMSC to GalN groups reversed these alterations. In conclusion, we may suggest that MMSC has protective effects against GalN-induced brain and cerebellar toxicity in rats.

Galactosamine (GalN) is a well-known agent for inducing viral hepatitis models in rodents, but it can cause toxicity on different organs. Vitamin U (Vit U) has been proved as a powerful antioxidant on many toxicity models. The present study was designed to investigate the protective effects of Vit U on GalN-induced stomach injury. Rats were divided into four groups as follows: control (group I), Vit U given animals (50 mg/kg per day; group II), GalN administered animals (500 mg/kg at a single dose; group III), GalN + Vit U given animals (at the same dose and time, group IV). At the end of the 3rd day, animals were killed, and stomach tissues were taken. They were homogenized and centrifuged. In comparison to the control group, glutathione, total antioxidant capacity levels, catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and Na

The widespread use of atrazine, a herbicide used to control weeds, has contributed to the increased contamination of aquatic environments. To assess the toxicological effects of a xenobiotic on a nontarget organism in the laboratory, different models of toxicological exposure systems have been widely used. Therefore, the aim of this study was to evaluate and compare the action of sublethal concentrations of atrazine on the hepatic histology of Oreochromis niloticus, considering two models of exposure: static (where atrazine was only added once) and semi-static (where atrazine was periodically renewed). Fish were exposed to a concentration of 2 ppm atrazine for 15 days, which was verified by high-performance liquid chromatography. The livers were stained with hematoxylin and eosin and histopathological data were collected. In addition, they were submitted to immunohistochemistry for inducible nitric oxide synthase (iNOS). A maximum variation of 45% (static) and 12.5% (semi-static) was observed between the observed and nominal atrazine concentration. Nuclear and cytoplasmic changes were observed in both experimental models. Hepatocytes from the livers of the static system showed a degenerative appearance, while in the semi-static system, intense cytoplasmic vacuolization and necrosis were observed. iNOS positive cells were identified only in macrophages in the hepatocytes of fish in the semi-static system. These results directly showed how the choice of exposure system can influence the results of toxicological tests. However, future analysis investigating the by-products and nitrogen products should be carried out since the histopathological findings revealed the possibility of these compounds serving as secondary contamination routes.

OBJECTIVES: Paracetamol overdose is common and can lead to fulminant hepatic failure. In cases that are not improving with standard medical therapy with N-acetylcysteine, some patients may require liver transplant. The Australia and New Zealand (ANZ) referral criteria for transfer to a liver unit have not been extensively studied for its predictive value. The aim of this study was to evaluate the ANZ referral criteria for predicting mortality in paracetamol overdose. METHODS: This study involves a retrospective analysis of patients who developed hepatotoxicity post-paracetamol overdose presenting to an Australian health service with a liver transplant unit between 2010 and 2019 and were treated with N-acetylcysteine. The primary outcome was death or transplant. RESULTS: Out of 983 paracetamol overdose presentations, 81 (8.2%) cases developed hepatotoxicity. Of these, 17 cases (21%) met the composite endpoint of death or transplant. The ANZ referral criteria is highly sensitive at predicting the primary endpoint of death or transplant at time of referral 100% (95% confidence interval 81-100) but had low specificity at 30% (95% confidence interval 19-42). CONCLUSIONS: The ANZ referral criteria were highly sensitive for predicting the outcome of mortality and transplant. This is important for screening patients who may become unstable and difficult to transfer at a later stage of their admission.

Background and aims Anti-tuberculosis drugs remain as an important cause of drug-induced liver injury (DILI) worldwide. Adverse drug reactions reduce the effectiveness of treatment. We aimed to determine the incidence and risk factors associated with anti-tuberculosis DILI (ATDILI). Methods Using established criteria and causality assessment methods, risk factors for ATDILI were identified in a contemporary cohort and validated in another cohort prospectively. Independent determinants of ATDILI were identified using Cox regression analysis. Results In the derivation cohort (n = 3155), 170 (5.4%) developed ATDILI of which 27 (15.9%) developed jaundice; 9(5.3%) developed acute liver failure (ALF) and 3 died. Among HBsAg positive patients, 11/27 (40.7%) of ATDILI developed after 3 months of starting treatment. In addition, of 218 (6.9%) who developed raised alanine transferase (ALT) levels ≥3 times upper limit normal, 193 (88.5%) resolved and 25 (11.4%) progressed to DILI. Age (HR = 1.014, 95% CI: 1.005-1.023), baseline ALT (HR = 1.014, 95% CI: 1.003-1.024), haemoglobin (HR = 1.011, 95% CI: 1.002-1.020) and HBsAg positivity (HR = 1.516, 95% CI: 1.004-2.290) were independent risk factors for DILI. In the second cohort (n = 1497) of which 85 (5.7%) developed ATDILI. Age (HR = 1.029, 95% CI: 1.003-1.056), baseline AST (HR = 1.036, 95% CI: 1.010-1.062), previous TB treatment (HR = 3.894, 95% CI: 1.304-11.625) and active drinking (HR = 3.624, 95% CI: 1.147-11.454) were risk factors for developing jaundice. Conclusion Elevation of ALT of ≥3 × ULN during anti-TB treatment resolves in the vast majority without developing serious consequences. In two cohorts involving 4652 patients, incidence of ALF and death because of ATDILI are low. Age, baseline ALT, haemoglobin and HBsAg positivity are risk factors for the development of DILI and these inform monitoring and management of these patients.

N‐acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol‐APAP)‐induced acute liver injury (ALI). The 3‐bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25 h standard or 12 h modified regimen. We used liquid chromatography tandem mass spectrometry to quantify clinically important oxidative stress biomarkers and APAP metabolites in plasma samples from 45 patients who participated in a randomized controlled trial (SNAP trial). We investigated the time course response of plasma metabolites at predose, 12 h, and 20.25 h post‐start of NAC infusion. The results showed that the 12 h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12 h post‐infusion. We found no significant alteration in the metabolism of APAP, mitochondrial, amino acids, and other thiol biomarkers with the two regimens. We examined APAP and purine metabolism in overdose patients who developed ALI. We showed the major APAP‐metabolites and xanthine were significantly higher in patients with ALI. These biomarkers correlated well with alanine aminotransferase activity at admission. Receiver operating characteristic analysis showed that at admission, plasma APAP‐metabolites and xanthine concentrations were predictive for ALI. In conclusion, a significantly higher redox thiol response with the modified NAC regimen at 12 h postdose suggests this regimen may produce greater antioxidant efficacy. At baseline, plasma APAP and purine metabolites may be useful biomarkers for early prediction of APAP‐induced ALI.

Antituberculosis drug-induced liver injury (ATDILI) has received increasing attention globally, which may limit the effectiveness of the anti-tuberculosis (anti-TB) treatment. Many host genetic determinants of ATDILI have been identified, recently. Whereas, little knowledge about the association between aldehyde dehydrogenase 1 family member A1 (ALDH1A1) polymorphisms and ATDILI is currently available, so we investigated the association between their variants and the susceptibility to ATDILI. A total of 747 TB patients treated by first-line antituberculosis drugs were prospectively enrolled at West China Hospital. Genomic DNA was extracted from the peripheral blood sample of each patient and 7 single-nucleotide polymorphisms (SNPs) of ALDH1A1 gene were screened and genotyped with a custom-designed 2x48-plex SNP Scan TM Kit. The patients were followed up monthly to monitor the development of ATDILI. The C allele and the CA genotype of rs7852860 was significantly associated with an elevated risk for ATDILI (p = 0.006 and 0.005, respectively), which was consistent with the results in the dominant and additive models. No allele, genotype or genetic model of the other 6 SNPs (rs3764435, rs348471, rs63319, rs610529, rs7027604, rs8187876) were found to be associated with the susceptibility to ATDILI. Our findings firstly demonstate that rs7852860 variants in ALDH1A1 gene is associated with susceptibility to ATDILI in the Chinese Han population. Validation studies with larger sample sizes and other ethnic groups are needed to confirm our findings. This article is protected by copyright. All rights reserved.

Cyclosporine-A (CsA) is a powerful immunosuppressive agent and hepatotoxicity results from CsA treatment. This study aimed to elucidate the effectiveness of tyrosine kinase inhibitor nilotinib against CsA-induced hepatotoxicity and the underlying molecular mechanisms. Male Sprague-Dawley rats were allocated into four groups and received drugs for 28 days as follows: Control group: received vehicle, Nilotinib group: received nilotinib (20 mg/kg orally), CsA group: received CsA by subcutaneous injection (20 mg/kg daily), CsA-nilotinib: received nilotinib and CsA. Serum lactate dehydrogenase (LDH), liver function biomarkers, hepatic levels of oxidative stress biomarkers, nuclear factor erythroid-2 like-2 (Nrf2), total antioxidant capacity (TAC), interleukin-2 (IL-2), IL-1β, IL-6, and cytochrome-C were assessed. Additionally, the protein levels and mRNA expression of Bcl2 associated X protein (Bax), caspase-3, nuclear factor-κB (NF-κB), hemoxygenase-1 (HO-1) were measured. Moreover, liver tissues were assessed histopathologically using hematoxylin-eosin and Masson trichrome stain. Nilotinib treatment decreased serum LDH, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase (γ-GT), hepatic malondialdehyde, and cytochrome-C. It also increased superoxide dismutase, reduced glutathione, glutathione reductase, glutathione peroxidase, glutathione-S-transferase (GST), TAC, and Nrf2 compared to CsA-injected rats. In addition, nilotinib decreased NF-κB, IL-1β, IL-6, Bax, and caspase-3, while elevated IL-2 and immunoexpression of HO-1. Additionally, mRNA expression of Bax and caspase-3 was elevated and that of HO-1 and inhibitory protein κB-α was reduced in the nilotinib-treated group. Moreover, nilotinib significantly attenuated CsA-induced histopathological alterations. Nilotinib may have a promising role as a hepato-protective through its antiapoptotic, antioxidant, and anti-inflammatory effects.

Background and aim Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to non-alcoholic steatohepatitis, which is characterized by hepatic inflammation that can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Visfatin, an adipocytokine, was reported to induce pro-inflammatory cytokines and can be associated with liver fibrosis. We investigated the role of visfatin on hepatic inflammation and fibrosis in a methionine-choline-deficient (MCD)-diet-induced steatohepatitis mouse model. Methods Eight-week-old male C57BL/6 J mice were randomly assigned into one of three groups: (1) saline-injected control diet group; (2) saline-injected MCD diet group; and (3) visfatin-injected MCD diet group (n = 8 per group). Mice were administered intravenous saline or 10 μg/kg of recombinant murine visfatin for 2 weeks. Histologic assessment of liver and biochemical and molecular measurements of endoplasmic reticulum (ER) stress, reactive oxidative stress (ROS), inflammation, and fibrosis were performed in livers from these animals. Results Visfatin injection aggravated hepatic steatosis and increased plasma alanine aminotransferase and aspartate aminotransferase concentrations. Visfatin increased inflammatory cell infiltration (as indicated by F4/80, CD68, ly6G, and CD3 mRNA expression) and expression of chemokines in the liver. Visfatin also increased the expression of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) and activated fibrosis markers (CTGF, TIMP1, collagen 1α2, collagen 3α2, αSMA, fibronectin, and vimentin) in liver. Livers of visfatin-injected mice showed upregulation of ER stress and ROS and activation of JNK signaling. Conclusions These results suggest that visfatin aggravates hepatic inflammation together with induction of ER and oxidative stress and exacerbates fibrosis in an MCD-diet-fed mouse model of NAFLD.

Aims Early identification of patients likely to die after acetaminophen (APAP) poisoning remains challenging. We sought to compare the sensitivity and time to fulfilment (latency) of established prognostic criteria. Methods Three physician toxicologists independently classified every in-hospital death associated with APAP overdose from eight large Canadian cities over three decades using the Relative Contribution to Fatality scale from the American Association of Poison Control Centres. The sensitivity and latency were calculated for each of the following criteria: King's College Hospital (KCH), Model for End Stage Liver Disease (MELD) ≥33, lactate ≥3.5 mmol/L, phosphate ≥1.2 mmol/L 48+ hours post-ingestion, as well as combinations thereof. Results A total of 162 in-hospital deaths were classified with respect to APAP as follows: 26 Undoubtedly, 40 Probably, 27 Contributory, 14 Probably not, 25 Clearly not, and 30 Unknown. Cases from the first three classes (combined into n = 93 "APAP deaths") typically presented with supratherapeutic APAP concentrations, hepatotoxicity, acidaemia, coagulopathy and/or encephalopathy, and began antidotal treatment a median of 12 hours (IQR 3.4-30 h) from the end of ingestion. Among all patients deemed "APAP deaths", meeting either KCH or lactate criteria demonstrated the highest sensitivity (94%; 95% CI 86-98%), and the shortest latency from hospital arrival to criterion fulfilment (median 4.2 h; IQR 1.0-16 h). In comparison, the MELD criterion demonstrated a substantially lower sensitivity (55%; 43-66%) and longer latency (52 h; 4.4-∞ h, where "∞" denotes death prior to criterion becoming positive). Conclusions Meeting either KCH or serum lactate criteria identifies most patients who die from acetaminophen poisoning at or shortly after hospital presentation.

MicroRNAs (miRNA) have received considerable attention as potential biomarkers for drug-induced liver injury. We recently reported that the plasma levels of miR-143-3p and miR-218a-5p increased in severe cholestasis in rats. This study aimed to investigate whether these miRNAs increase in a severity-dependent manner and to elucidate their pathophysiological roles in cholestasis. Male Sprague-Dawley rats were orally administered different doses of α-naphthylisothiocyanate or 4,4-methylenedianiline to induce acute cholestasis. They were also orally administered acetaminophen or thioacetamide to induce hepatocellular injury. We found that plasma miR-143-3p and miR-218a-5p levels increased in a dose-dependent manner in cholestatic rats but not in hepatocellular injury. Bioinformatic analysis provided putative target genes of hsa-miR-218-5p, rno-miR-218a-5p, and mmu-miR-218-5p, among which GNAI2, PPP1CB, and PPP2R5A were experimentally validated as their direct target genes in human cholangiocyte line MMNK-1. Proliferation of MMNK-1 cells was significantly suppressed after overexpression of miR-218-5p and transduction of siRNAs for GNAI2, PPP1CB, and PPP2R5A. In the cholestatic livers of rats, Ppp1cb and Ppp2r5a expression levels decreased, whereas Gnai2 expression levels increased compared with those in vehicle-treated rats, suggesting that Ppp1cb and Ppp2r5a may be under the control of miR-218a-5p in vivo. In conclusion, our data suggest that miR-218(a)-5p is involved in the suppression of cholangiocyte proliferation by inhibiting the expression of PPP1CB and PPP2R5A, thereby contributing to the pathogenesis of cholestasis; and miR-218a-5p leaks into the plasma probably from damaged cholangiocytes in a severity-dependent manner in rats. Therefore, miR-218a-5p overexpression could be one of the underlying mechanisms of acute cholestatic liver injury in rats.

Contains fulltext : 235681.pdf (Publisher’s version ) (Open Access) AIMS: Uterine fibroids are benign tumours that cause various complaints. These complaints may significantly compromise quality of life, necessitating a clinical intervention in 25-50% of the affected women. Hysterectomy, myomectomy or embolization may offer symptomatic relief, but are costly, include a recovery period, can cause serious side-effects, sometimes fail to treat symptoms completely and are not always desired by patients. Ulipristal is a conservative long-term treatment that has a fibroid-volume decreasing effect, acceptable side-effects while preserving fertility and may be an alternative to surgical alternatives. Currently, ulipristal is investigated by the European Medicine Agency and suspended from marketing authorization because it may cause drug-induced liver injury (DILI). However, many drugs can cause severe DILI and prospective studies estimate 14-19 DILI cases/100 000 people. METHODS: This overview will discuss the risk-benefit balance between ulipristal and DILI, describe the safety-efficacy balance of ulipristal and its alternative treatments and the arguments that led to the suspension of its marketing authorization. RESULTS: Ulipristal may be associated with DILI resulting in a risk of severe liver injury in 1.5:100 000 patients and fatal liver injury in 0.1:100 000 patients. This risk needs to be weighed against the higher mortality risk of >1:1000 and higher incidence of severe complications after surgery. CONCLUSION: The DILI risk of ulipristal is considerably lower than that of other medicines that are not suspended, nor need additional safety measures. When evaluating drugs and drug safety, risks that apply to the alternative nonpharmacological treatment options should be taken into consideration.

BACKGROUND AND AIMS Reports of moderate to severe liver injury associated with tocilizumab, an interleukin-6 (IL-6) receptor antagonist, have been reported in the post-marketing setting. This case series aims to characterize cases of tocilizumab-associated clinically significant hepatic injury. METHODS We analysed cases of severe acute liver injury associated with tocilizumab reported in the FDA Adverse Event Reporting System and the medical literature. RESULTS We identified 12 cases in which tocilizumab was a suspected primary cause of liver injury and eight cases in which serious sequelae of underlying or coincident viral hepatitis were temporally associated with its use. Using the Drug-Induced Liver Injury Network (DILIN) severity scale, five of 12 cases were Grade 5 (two liver transplants, three deaths), one was Grade 4 (liver failure) and six were Grade 3 (serious events with elevated bilirubin). Two cases reported liver atrophy with low hepatocellular expression of Ki-67, a marker of cellular proliferation. Among the eight cases of tocilizumab-associated viral hepatitis exacerbation, three were scored as DILIN severity Grade 5 (one liver transplant, two deaths), one was Grade 4 (liver failure), and four were Grade 3. The reported viral hepatitis events were hepatitis B virus (HBV) reactivation (n = 3), hepatitis C virus (HCV) flare (n = 1), cytomegalovirus (CMV)-induced liver failure (n = 1), Epstein-Barr virus hepatitis (n = 1), acute hepatitis E (HEV, n = 1) and HEV-induced macrophage activation syndrome (n = 1). CONCLUSION Tocilizumab may be a primary cause of severe liver injury, as well as exacerbate underlying viral hepatitis. The disruption by tocilizumab of IL-6-mediated immune protection and hepatocyte regeneration may aggravate clinical outcomes in some cases.

Acute liver injury (ALI) is a serious syndrome that is associated with high mortality, but there are few effective treatments. The activation of NLRP3 inflammasome is associated with ALI. Oridonin is a natural substance with an anti-inflammatory effect and has been reported to be an inhibitor of NLRP3. The aim of this study was to investigate the protective effect of oridonin on d-galactosamine (d-GalN)/lipopolysaccharide (LPS)-induced ALI and whether the effect is mediated by NLRP3. Mice were pretreated with oridonin (5 or 10 mg/kg) for 3 days. Then, they were injected with d-GalN (400 mg/kg) and LPS (40 μg/kg). The levels of inflammatory factors were measured by RT-PCR, Western blot, and enzyme-linked immunosorbent assay. We confirmed that oridonin significantly alleviated ALI induced by d-GalN/LPS in mice. Oridonin markedly decreased the inflammatory response by reducing the levels of inflammatory cytokines. More importantly, oridonin markedly reduced the expression of NLRP3, caspase-1, IL-18, and IL-1β. This study showed that oridonin has a protective effect on d-GalN/LPS-induced ALI, and the underlying mechanisms may be associated with the inhibition of the NLRP3 inflammatory pathways.

Paracetamol-induced hepatotoxicity is the leading cause of acute liver failure in many countries, including North America and the United Kingdom. Among the three dominant paracetamol metabolism pathways (i.e. glucuronidation, sulfation and oxidation), the importance of sulfation is often underestimated because of the general thinking that the sulfation pathway is saturated at therapeutic doses and ultimately accounts for a limited proportion of the fate of a paracetamol dose. We illustrate that insufficient sulfation leads to a shift in biotransformation of paracetamol to toxic oxidation pathways and patients with low sulfate reserves are at higher risk of paracetamol toxicity. Here, we propose that sulfation is of critical importance in understanding the risk of liver toxicity secondary to paracetamol overdose. Serum inorganic sulfate, a measurable substrate on the causal path of paracetamol-induced liver toxicity, should be considered a biomarker for potential toxicity as well as a target for treatment.

Old patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought for the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥65 years) were categorized according to age: “young” (