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Background: Glecaprevir/pibrentasvir (G/P; 300 mg/120 mg) is a new direct-acting antiviral (DAA) that exhibits anti-hepatitis C virus (HCV) pan-genotype (GT) activity for 8, 12, or 16 weeks. However, the U.S. Food and Drug Administration have received reports that using G/P causes moderate to severe liver impairment. In some cases, isolated hyperbilirubinemia and jaundice have been reported without concomitant evidence of increased transaminase levels or other hepatic decompensation events. Objective: This study aimed to analyze the incidence of drug-induced liver injury of G/P for chronic hepatitis C virus. Materials and methods: We searched databases from the inception of each database until March 2021. Data were pooled using a random-effects model. The Cochrane Risk of Bias Tool (RoB 2.0) and the OpenMeta [Analyst] software were performed for quality assessment and quantitative studies, respectively. The primary outcome was grade 3 level of drug-induced liver injury (DILI). Results: The nine studies included in the meta-analysis involved a total of 7,650 participants, and the overall sustained virologic response rate was above 95%. The most frequent drug-related laboratory abnormalities in DILI involved total bilirubin, alanine aminotransferase, aspartate aminotransferase, and hemoglobin, but these abnormalities were minimal. The cirrhosis–without cirrhosis incidence risk ratio (IRR) was 2.724 (95% confidence interval: 1.182–6.276) in the grade 3 hyperbilirubinemia subgroup analysis. No significant differences were found within the other subgroups, in HCV GTs, and in treatment duration. Conclusions: DILI was found to occur frequently with G/P treatment. Hyperbilirubinemia occurred most frequently, especially, in patients with cirrhosis. However, G/P is still the primary therapy of choice for CKD and end-stage renal disease (ESRD) patients due to a superior safety rate.

Background: The intake of dietary supplements and medicinal plants is very popular worldwide. However, these products are not innocuous, and their intake can cause severe damage to health, especially liver injury. Objective: This study aims to describe the clinical cases of dietary supplements-induced liver injury (DSILI) and herb-induced liver injury (HILI), identifying the main products involved and the clinical outcomes related to them. Method: A literature search was performed in PubMed, EMBASE, Google Scholar, and LILACS databases, using the search terms: “Chemical and Drug-Induced Liver Injury”, “Dietary Supplements” and “Herbal” and their synonyms. Results: 189 articles were included in the study, totaling 428 clinical cases of drug-induced liver injury. The most frequent agents of liver injury were Herbalife® products, associated with 50 cases, Polygonum multiflorum, with 25 cases, Hydroxycut® products, and green tea, both associated in 19 cases, and Oxyelite Pro® and kava tea, both associated with 16 cases. Most individuals required hospitalization (82.6%) and an important number of cases evolved to death (3.6%), liver transplantation (8.9%), or chronic liver disease (1.9%). Conclusion: The indiscriminate use of dietary supplements and herbal products was associated with an alarming number of cases of liver injury. The mechanisms through which each of the products causes liver damage still need to be better understood, but this review is a warning about the risk associated with the use of products considered harmless by a large part of the population.

The central function of the liver in the regulation of the metabolisms of hormones and nutrients makes it an integral part of the endocrine system. In everyday clinical practice, the endocrinologist usually encounters patients with altered liver function tests. This condition might be a cause or a consequence of the endocrine disease (e.g. type 2 diabetes mellitus, polycystic ovary syndrome), an associated condition as in the case of concomitant autoimmune diseases, a consequence of a specific pharmacological treatment, or an unrelated condition. In this chapter, we focus on the most common causes of alteration of liver function tests and provide indications on how to perform the first assessment of liver disease and when to refer patients to a hepatologist.

© 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.

Tyrosine kinase inhibitors (TKIs) are increasingly popular drugs used to treat more than a dozen different diseases including some forms of cancer. Despite having fewer adverse effects than traditional chemotherapies, they are not without risks. Liver injury is a particular concern. Of the FDA-approved TKIs, approximately 40% cause hepatotoxicity. However, little is known about the underlying pathophysiology. The leading hypothesis is that TKIs are converted by cytochrome P450 3A4 (CYP3A4) to reactive metabolites that damage proteins. Indeed, there is strong evidence for this bioactivation of TKIs in in vitro reactions. However, the actual toxic effects are underexplored. Here, we measured the cytotoxicity of several TKIs in primary mouse hepatocytes, HepaRG cells and HepG2 cells with and without CYP3A4 modulation. To our surprise, the data indicate that CYP3A4 increases resistance to sorafenib and lapatinib hepatotoxicity. The results have implications for the mechanism of toxicity of these drugs in patients and underline the importance of selecting an appropriate experimental model.

Objective: the study was to find a suitable treatment for acute drug-induced liver injury. The use of nanocarriers can improve the therapeutic effect of natural drugs by targeting hepatocytes and higher loads. Methods: firstly, uniformly dispersed three-dimensional dendritic mesoporous silica nanospheres (MSNs) were synthesized. Glycyrrhetinic acid (GA) was covalently modified on MSN surfaces through amide bond and then loaded with COSM to form drug-loaded nanoparticles (COSM@MSN-NH2-GA). The constructed drug-loaded nano-delivery system was determined by characterization analysis. Finally, the effect of nano-drug particles on cell viability was evaluated and the cell uptake in vitro was observed. Results: GA was successfully modified to obtain the spherical nano-carrier MSN-NH2-GA (≤200 nm). The neutral surface charge improves its biocompatibility. MSN-NH2-GA has high drug loading (28.36% ± 1.00) because of its suitable specific surface area and pore volume. In vitro cell experiments showed that COSM@MSN-NH2-GA significantly enhanced the uptake of liver cells (LO2) and decreased the AST and ALT indexes. Conclusion: this study demonstrated for the first time that formulation and delivery schemes using natural drug COSM and nanocarrier MSN have a protective effect on APAP-induced hepatocyte injury. This result provides a potential nano-delivery scheme for the targeted therapy of acute drug-induced liver injury.

Human colon microbiota produce a metabolite called urolithin A (URO A) from ellagic acid and linked compounds, and this metabolite has been demonstrated to have antioxidant, anti-inflammatory, and antiapoptotic activities. The current work examines the various mechanisms through which URO A protects against doxorubicin (DOX)-induced liver injury in Wistar rats. In this experiment, Wistar rats were administered DOX intraperitoneally (20 mg kg−1) on day 7 while given URO A intraperitoneally (2.5 or 5 mg kg−1 d−1) for 14 days. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transferase (GGT) were measured. Hematoxylin and eosin (HE) staining was used to evaluate histopathological characteristics, and then antioxidant and anti-inflammatory properties were evaluated in tissue and serum, respectively. We also looked at how active caspase 3 and cytochrome c oxidase were in the liver. The findings demonstrated that supplementary URO A therapy clearly mitigated DOX-induced liver damage. The antioxidant enzymes SOD and CAT were elevated in the liver, and the levels of inflammatory cytokines, such as TNF-α, NF-kB, and IL-6, in the tissue were significantly attenuated, all of which complemented the beneficial effects of URO A in DOX-induced liver injury. In addition, URO A was able to alter the expression of caspase 3 and cytochrome c oxidase in the livers of rats that were subjected to DOX stress. These results showed that URO A reduced DOX-induced liver injury by reducing oxidative stress, inflammation, and apoptosis.

Drug-induced liver injury (DILI) is a major challenge in clinical medicine and drug development. There is a need for rapid diagnostic tests, ideally at point-of-care. MicroRNA 122 (miR-122) is an early biomarker for DILI which is reported to increase in the blood before standard-of-care markers such as alanine aminotransferase activity. We developed an electrochemical biosensor for diagnosis of DILI by detecting miR-122 from clinical samples. We used electrochemical impedance spectroscopy (EIS) for direct, amplification free detection of miR-122 with screen-printed electrodes functionalised with sequence specific peptide nucleic acid (PNA) probes. We studied the probe functionalisation using atomic force microscopy and performed elemental and electrochemical characterisations. To enhance the assay performance and minimise sample volume requirements, we designed and characterised a closed-loop microfluidic system. We presented the EIS assay's specificity for wild-type miR-122 over non-complementary and single nucleotide mismatch targets. We successfully demonstrated a detection limit of 50 pM for miR-122. Assay performance could be extended to real samples; it displayed high selectivity for liver (miR-122 high) comparing to kidney (miR-122 low) derived samples extracted from murine tissue. Finally, we successfully performed an evaluation with 26 clinical samples. Using EIS, DILI patients were distinguished from healthy controls with a ROC-AUC of 0.77, a comparable performance to qPCR detection of miR-122 (ROC-AUC: 0.83). In conclusion, direct, amplification free detection of miR-122 using EIS was achievable at clinically relevant concentrations and in clinical samples. Future work will focus on realising a full sample-to-answer system which can be deployed for point-of-care testing.

Background Adverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients. TB endemic settings have limited capacity to conduct clinical trials. We designed a proof-of-concept clinical trial primarily to explore the preliminary evidence on the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications. Methods This is a proof-of-concept randomized open label clinical trial with 3 treatment arms including a control arm, an interventional arm of NAC 900 mg daily, and an interventional arm of NAC 900 mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong’oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania. The minimum anticipated sample size is 66; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24 weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis. Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model. Discussion Given that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress, it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney, and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Conduct of this trial will set the needed infrastructure for clinical trials. Trial registration PACTR202007736854169 Registered 03 July 2020

アセトアミノフェン（acetaminophen:AAP）は，一般に非ステロイド性抗炎症薬（non-steroidal anti-inflammatory drugs:NSAIDs）と比較して副作用が少ない解熱鎮痛薬として，高齢者や肝腎機能障害を有する患者にも頻用されている。一方で肝障害の副作用が知られ，肝疾患のある患者では1,500 mg/日以下とすべきであると記載されている。今回，常用量AAPによる昏睡型肝不全の一例を経験したので報告する。症例は意識障害を主訴に当院へ救急搬送された73歳の女性。左変形性膝関節症に対して，左膝関節全置換術施行後もAAP 1,200 mg/日の内服を2カ月間継続していた。搬送時にJapan Coma Score （JCS） 200の意識障害と黄疸，全身性浮腫を認めた。高度の肝機能障害と凝固障害，肝萎縮があり，昏睡型急性肝不全と診断し加療を開始した。集学的に加療を行ったものの，第7病日に痙攣が出現し呼吸状態悪化に伴い亡くなった。本症例はAAPによる薬物性肝障害（drug-induced liver injury:DILI） であったと判断した。以前より指摘されていた非アルコール性脂肪性肝疾患（nonalcoholic fatty liver disease:NAFLD）と高齢により，DILIのリスクが高かったと考えた。本症例のようにDILIの危険性のある症例では，定期的な肝機能検査の施行や，症状改善に伴う頓服への変更または減量が推奨される。, Acetaminophen (AAP) is an antipyretic and analgesic drug with fewer side effects than NSAIDs, and is frequently prescribed for the elderly and patients with hepatic and renal dysfunction. On the other hand, known side effects of AAP include hepatic damage, for which reason its dose is recommended to be less than 1,500 mg/day in patients with hepatic disease. Herein, we describe a case of acute hepatic failure with hepatic coma attributed to regular doses of AAP. A 73-year-old woman in a coma was brought to our hospital. She had been taking 1,200 mg/day of AAP for 2 months after a total knee arthroplasty for left knee osteoarthritis. At the time of admission, the patient’s Japan Coma Scale (JCS) score was 200; she had jaundice and generalized edema. With severe liver dysfunction, coagulopathy, and hepatic atrophy, she was diagnosed with acute hepatic failure and hepatic coma. Despite aggressive multidisciplinary treatment, the patient died on the seventh day of hospitalization, with convulsions and worsening of respiratory status. We concluded that this was a case of drug-induced liver injury (DILI) caused by AAP. The risk of DILI was considered to be high due to the presence of nonalcoholic fatty liver disease (NAFLD), previously diagnosed, and advanced age. In patients at risk of DILI, as in the present case, periodic liver function tests should guide the cessation or dose reduction of AAP to minimize risks of hepatic dysfunction and possible mortality.

International audience; The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity.

Background: There are limited data on the outcomes of rechallenge with anti-tuberculosis therapy (ATT) following anti-tuberculosis drug-induced liver injury (AT-DILI) in a high HIV prevalence setting. Objectives: To describe the outcomes of rechallenge with first-line ATT. Method: Hospitalised participants with AT-DILI who were enrolled into a randomised controlled trial of N-acetylcysteine in Cape Town, South Africa, were followed up until completion of ATT rechallenge. We described rechallenge outcomes, and identified associations with recurrence of liver injury on rechallenge (positive rechallenge). Results: Seventy-nine participants were rechallenged of whom 41 (52%) were female. Mean age was 37 years (standard deviation [s.d.] ±10). Sixty-eight (86%) were HIV-positive, of whom 34 (50%) were on antiretroviral therapy (ART) at time of AT-DILI presentation. Five participants had serious adverse reactions to an aminoglycoside included in the alternate ATT regimen given after first-line ATT interruption: acute kidney injury in three and hearingloss in two. The median time from first-line ATT interruption to start of first-line ATT rechallenge was 13 days (interquartile range [IQR]: 8–18 days). Antiretroviral therapy was interrupted for a median of 32 days (IQR: 17–58) among HIV-positive participants on ART before AT-DILI. Fourteen participants had positive rechallenge (18%). Positive rechallenge was associated with pyrazinamide rechallenge (P = 0.005), female sex (P = 0.039) and first episode of tuberculosis (TB) (P = 0.032). Conclusion: Rechallenge was successful in most of our cohort. Pyrazinamide rechallenge should be carefully considered.

Drug-induced liver injury (DILI) is one of the leading causes of acute liver injury. While many factors may contribute to the susceptibility to DILI, obese patients with hepatic steatosis are particularly prone to suffer DILI. The secretome derived from mesenchymal stem cell has been shown to have hepatoprotective effects in diverse in vitro and in vivo models. In this study, we evaluate whether MSC secretome could improve DILI mediated by amiodarone (AMI) or tamoxifen (TMX). Hepatic HepG2 and HepaRG cells were incubated with AMI or TMX, alone or with the secretome of MSCs obtained from human adipose tissue. These studies demonstrate that coincubation of AMI or TMX with MSC secretome increases cell viability, prevents the activation of apoptosis pathways, and stimulates the expression of priming phase genes, leading to higher proliferation rates. As proof of concept, in a C57BL/6 mouse model of hepatic steatosis and chronic exposure to AMI, the MSC secretome was administered endovenously. In this study, liver injury was significantly attenuated, with a decrease in cell infiltration and stimulation of the regenerative response. The present results indicate that MSC secretome administration has the potential to be an adjunctive cell-free therapy to prevent liver failure derived from DILI caused by TMX or AMI.

Drug-induced liver injury (DILI) is one of the main reasons for drug attrition during pre-clinical and clinical phases of drug development as well as for drug withdrawal post-marketing. The development of DILI can result in severe outcomes giving high risk for liver failure. The activation of adaptive stress response pathways is a way for cells to cope with drug-induced stress and is one of the early key events in the development of DILI. In this thesis, the regulation of the activation of adaptive stress responses has been studied using high content imaging, gene silencing and high throughput transcriptomics approaches to improve the understanding and prediction of DILI. The tight regulation of the unfolded stress response was dissected by combining computational modelling and RNA interference screening. Improved insight in the crosstalk between oxidative stress and DNA damage response during chemical exposure was obtained. Different liver test systems were compared for their capability to identify stress response activation, which allows for well-considered selection of models fit-for-purpose for drug screening. Furthermore, the inter-individual variability in stress response activation was mapped to enable the usage of accurately defined uncertainty factors to account for human population variability for DILI liabilities during safety testing.

In drug discovery, it is crucial to understand how drugs relate to complex phenotypes. This includes understanding how a drug can help to treat a condition, but also how it can result in adverse effects so that safety risks can be mitigated earlier. How effects propagate from the molecular to the systems scale is, however, in many cases not fully clear, in particular for complex phenotypes which cannot be narrowed down to individual causes. In this thesis, transcriptomics data was used as intermediate layer alongside additional data sources to study links between compounds and phenotypes. First, safety biomarker candidates in Drug-Induced Vascular Injury were identified based on changes in tissue expression across adverse and non-adverse treatments. Further characterization of their biological role and predictive performance thereby identified multiple secreted proteins as most promising candidates. Secondly, pathways and transcription factors involved in the pathogenesis of Drug-Induced Liver Injury, another safety-related endpoint, were identified and characterised based on time concordance in repeat-dose studies in rats. In Chapter 3, it is demonstrated how time concordance can be combined with other streams of evidence towards causal hypothesis and mechanistic biomarkers. In order to make time concordance analysis on the Open TG-GATEs liver data also accessible to researchers in an interactive manner, the R/Shiny app “DILI Cascades” is presented in Chapter 4. Instead of drug toxicity, the last chapter then focusses on efficacy and aims to prioritise repurposing candidates, direct targets and downstream effectors which may promote alveolar regeneration in Idiopathic Pulmonary Fibrosis. This demonstrates how single-cell RNA-Seq data can be leveraged for drug repurposing through better characterization of cell transitions followed by signature matching. In summary, data-driven approaches with transcriptomics as key modality were used to derive insights on how drug perturbations are linked to adverse effects and fibrotic disease. Thereby, the presented work did not only aim at better mechanistic understanding but also provides actionable starting points for the discovery of new biomarkers and drug indications., GlaxoSmithKline (GSK)

This review focuses on the study of drug-induced liver injury (DILI), a disease that consists of adverse reactions to drugs and herbal and dietary supplements (HDS), with important industry and clinical implications, as it has been responsible for a considerable fraction of drug withdrawals from the market and during drug development. DILI has been traditionally classified into two different entities: intrinsic and idiosyncratic DILI. The first one refers to the predictable, dose-dependent toxicity and it occurs shortly after the patient exceeds a threshold dose. Idiosyncratic DILI is unpredictable, has a longer latency period, and, although a threshold dose is necessary to induce the cascade of events leading to liver damage, it is considered to be non-dose dependent. The uncertainty in the diagnosis of DILI and the lack of complete knowledge about its pathophysiology highlight the need for the establishment and characterization of appropriate DILI models in preclinical research. In this systematic review we aim to list the drugs to be used as positive/negative controls in in vitro hepatotoxicity assays.

Although the relationship between androgens and hepatocellular tumor development has been noted since 1975, cases involving hepatocellular carcinoma (HCC) or cholangiocarcinoma development in patients on chronic androgen therapy or anabolic androgenic steroid (AAS) use are few, and far between. We present three cases of patients who developed hepatic and bile duct malignancies in the setting of AAS use and testosterone supplementation, arising from a single tertiary referral center. Additionally, we review the literature for the mechanisms behind the possible androgen-mediated malignant transformation of these liver and bile duct tumors.

Drug-induced liver injury (DILI) is the principal reason for failure in developing drug candidates. It is the most common reason to withdraw from the market after a drug has been approved for clinical use. In this context, data from animal models, liver function tests, and chemical properties could complement each other to understand DILI events better and prevent them. Since the chemical space concept improves decision-making drug design related to the prediction of structure–property relationships, side effects, and polypharmacology drug activity (uniquely mentioning the most recent advances), it is an attractive approach to combining different phenomena influencing DILI events (e.g., individual “chemical spaces”) and exploring all events simultaneously in an integrated analysis of the DILI-relevant chemical space. However, currently, no systematic methods allow the fusion of a collection of different chemical spaces to collect different types of data on a unique chemical space representation, namely “consensus chemical space.” This study is the first report that implements data fusion to consider different criteria simultaneously to facilitate the analysis of DILI-related events. In particular, the study highlights the importance of analyzing together in vitro and chemical data (e.g., topology, bond order, atom types, presence of rings, ring sizes, and aromaticity of compounds encoded on RDKit fingerprints). These properties could be aimed at improving the understanding of DILI events.

Emerging advances in the field of in vitro toxicity testing attempt to meet the need for reliable human-based safety assessment in drug development. Intrahepatic cholangiocyte organoids (ICOs) are described as a donor-derived in vitro model for disease modelling and regenerative medicine. Here, we explored the potential of hepatocyte-like ICOs (HL-ICOs) in in vitro toxicity testing by exploring the expression and activity of genes involved in drug metabolism, a key determinant in drug-induced toxicity, and the exposure of HL-ICOs to well-known hepatotoxicants. The current state of drug metabolism in HL-ICOs showed levels comparable to those of PHHs and HepaRGs for CYP3A4; however, other enzymes, such as CYP2B6 and CYP2D6, were expressed at lower levels. Additionally, EC50 values were determined in HL-ICOs for acetaminophen (24.0–26.8 mM), diclofenac (475.5–>500 µM), perhexiline (9.7–>31.5 µM), troglitazone (23.1–90.8 µM), and valproic acid (>10 mM). Exposure to the hepatotoxicants showed EC50s in HL-ICOs comparable to those in PHHs and HepaRGs; however, for acetaminophen exposure, HL-ICOs were less sensitive. Further elucidation of enzyme and transporter activity in drug metabolism in HL-ICOs and exposure to a more extensive compound set are needed to accurately define the potential of HL-ICOs in in vitro toxicity testing.

Small molecule protein kinase inhibitors (PKIs) have become an effective strategy for cancer patients. However, hepatotoxicity is a major safety concern of these drugs, since the majority are reported to increase transaminases, and few of them (Idelalisib, Lapatinib, Pazopanib, Pexidartinib, Ponatinib, Regorafenib, Sunitinib) have a boxed label warning. The exact rate of PKI-induced hepatoxicity is not well defined due to the fact that the majority of data arise from pre-registration or registration trials on fairly selected patients, and the post-marketing data are often based only on the most severe described cases, whereas most real practice studies do not include drug-related hepatotoxicity as an end point. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing PKIs should be carefully pre-evaluated and monitored. The management of this complication requires an individually tailored reappraisal of the risk/benefit ratio, especially in patients who are responding to therapy. This review reports the currently available data on the risk and management of hepatotoxicity of all the approved PKIs.

Sphingolipids are exceptionally diverse, comprising hundreds of unique species. The bulk of circulating sphingolipids are synthesized in the liver, thereby plasma sphingolipid profiles represent reliable surrogates of hepatic sphingolipid metabolism and content. As changes in plasma sphingolipid content have been associated to exposure to drugs inducing hepatotoxicity both in vitro and in rodents, in the present study the translatability of the preclinical data was assessed by analyzing the plasma of patients with suspected drug-induced liver injury (DILI) and control subjects. DILI patients, whether intrinsic or idiosyncratic cases, had no alterations in total sphingoid base levels and profile composition compared to controls, whereby cardiovascular disease (CVD) was a confounding factor. Upon exclusion of CVD individuals, elevation of 1-deoxysphingosine (1-deoxySO) in the DILI group emerged. Notably, 1-deoxySO values did not correlate with ALT values. While 1-deoxySO was elevated in all DILI cases, only intrinsic DILI cases concomitantly displayed reduction of select shorter chain sphingoid bases. Significant perturbation of the sphingolipid metabolism observed in this small exploratory clinical study is discussed and put into context, in the consideration that sphingolipids might contribute to the onset and progression of DILI, and that circulating sphingoid bases may function as mechanistic markers to study DILI pathophysiology.

Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases (IBD), both in Crohn’s disease and ulcerative colitis (UC), and therefore represent a diagnostic challenge. Immune-mediated conditions include primary sclerosing cholangitis (PSC) as the main form, variant forms of PSC (namely small-duct PSC, PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis) and granulomatous hepatitis. PSC is by far the most common, presenting in up to 8% of IBD patients, more frequently in UC. Several genetic foci have been identified, but environmental factors are preponderant on disease pathogenesis. The course of the two diseases is typically independent. PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies. Risk of cholangiocarcinoma is significantly increased in PSC, as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis. No disease-modifying drugs are approved to date. Thus, PSC management is directed against symptoms and complications and includes medical therapies for pruritus, endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease. Other non-immune-mediated hepatobiliary disorders are gallstone disease, whose incidence is higher in IBD and reported in up to one third of IBD patients, non-alcoholic fatty liver disease, pyogenic liver abscess and portal vein thrombosis. Drug-induced liver injury (DILI) is an important issue in IBD, since most IBD therapies may cause liver toxicity; however, the incidence of serious adverse events is low. Thiopurines and methotrexate are the most associated with DILI, while the risk related to anti-tumor necrosis factor-α and anti-integrins is low. Data on hepatotoxicity of newer drugs approved for IBD, like anti-interleukin 12/23 and tofacitinib, are still scarce, but the evidence from other rheumatic diseases is reassuring. Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD, and adequate screening and vaccination is warranted. On the other hand, hepatitis C reactivation does not seem to be a real risk, and hepatitis C antiviral treatment does not influence IBD natural history. The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis, but it is of paramount importance to make a quick and accurate diagnosis, as it may influence the therapeutic management.

Circulating biomarkers of drug-induced liver injury (DILI) have been a focus of research in hepatology over the last decade, and several novel DILI biomarkers that hold promise for certain applications have been identified. For example, glutamate dehydrogenase holds promise as a specific biomarker of liver injury in patients with concomitant muscle damage. It may also be a specific indicator of mitochondrial damage. In addition, microRNA-122 is sensitive for early detection of liver injury in acetaminophen overdose patients. However, recent events in the field of DILI biomarker research have provided us with an opportunity to step back, consider how biomarker discovery has been done thus far, and determine how to move forward in a way that will optimize the discovery process. This is important because major challenges remain in the DILI field and related areas that could be overcome in part by new biomarkers. In this short review, we briefly describe recent progress in DILI biomarker discovery and development, identify current needs, and suggest a general approach to move forward.

Drug-induced liver injury (DILI) is one of the leading causes of liver failure and withdrawal of drugs from the market. A poor understanding of the precipitating event aetiology and mechanisms of disease progression has rendered the prediction and subsequent treatment intractable. Recent literature suggests that some drugs can alter the liver's repair systems resulting in injury. The pathophysiology of DILI is complex, and immune dysfunction plays an important role in determining the course and severity of the disease. Immune dysfunction is influenced by the host response to drug toxicity. A deeper understanding of these processes may be beneficial in the management of DILI and aid in drug development. This review provides a structured framework presenting DILI in three progressive stages that summarize the interplay between drugs and the host defence networks.

Introduction and aim: Drug-induced liver injury (DILI) manifests as a spectrum of clinical presentations that carries morbidity and mortality. Patients with chronic liver disease (CLD), particularly hospitalized, are at high risk for developing DILI. We aimed to investigate the use of potentially hepatotoxic drugs (PHD) in patients with CLD in a tertiary university hospital. Materials and methods: Adult (≥ 18 years-old) with CLD admitted to the hospital from January 2016 to December 2018 were evaluated regarding PHD, assessing the risk of DILI and liver enzymes behavior after exposure. Results: From 931 hospitalized patients with CLD, 291 (31.3%) were exposed to hepatotoxic drugs during their hospitalization. Of those, 244 (83.8%) were cirrhotic. The most frequent causes of liver disease were hepatitis C (41.2%), followed by alcohol (13.2%), hepatitis C/alcohol (11.7%) and non-alcoholic fatty liver disease (5.8%). Decompensated cirrhosis (46.7%) was the main reason for hospital admission. The most often prescribed PHD were antibiotics (67.7%), cardiovascular drugs (34.4%), neuromodulators (26.1%) and anesthetics (19.9%). After exposure, 113 patients (38.8%) presented significant elevated liver enzymes. Surprisingly, PHD were more often prescribed in GI/Liver unit (48.8%) followed by emergency/intensive care unit (28.5%). A total of 65 patients (22%) died, however in neither case was it possible to safely infer causal relationship among PHD, liver enzymes and death. Conclusion: PHD prescription is frequent in patients with CLD even in a tertiary university hospital and in the gastroenterology and hepatology department, exposing these patients to an additional risk.

Background Drug-induced liver injury (DILI) is the leading cause of acute liver failure in the United States. DILI is mainly caused by painkillers and fever reducers, and it is often characterized by the type of hepatic injury (hepatocellular or cholestatic). This report presents a case of fenofibrate-induced severe jaundice in a 65-year-old Korean male with no prior history of liver disease. We offer a strategy for patients who present signs of severe liver injury with jaundice and high elevations in serum transaminases. Case summary A 65-year-old male visited the gastroenterology outpatient clinic of a tertiary hospital due to increased levels of liver enzyme and total bilirubin which were incidentally detected through a preoperative screening test. Abdominal ultrasound and computed tomography showed no biliary obstruction or non-specific findings in the liver. Liver biopsy was performed and the patient was finally diagnosed with acute cholestatic hepatitis. Following the biopsy, steroid therapy was initiated and after 3 wk of treatment, the total bilirubin level was reduced to 7.22 mg/dL. Conclusion In patients with hyperlipidemia, treatment including fenofibric acid induces rare complications such as severe jaundice and acute cholestatic hepatitis, warranting clinical attention.

Purpose of review Liver test abnormalities in children with inflammatory bowel disease (IBD) are usually insidious in onset. By the time that symptoms referable to liver disease have appeared, the liver injury may be well advanced. It is, therefore, important that children with an incidental finding of abnormal liver tests are investigated in an appropriate and timely manner.Recent findings The most prevalent cause of liver test elevations in paediatric IBD is immune-related liver disease, including primary sclerosing cholangitis, autoimmune sclerosing cholangitis, and autoimmune hepatitis. Although less common, drugs used in the treatment of IBD can also cause liver injury. The diagnosis of drug-induced liver injury relies largely on excluding other causes of liver injury, such as viral hepatitis, nonalcoholic fatty liver disease, and biliary and vascular complications.Summary This review highlights an avenue to a step-wise approach for investigating children with IBD and silent liver test elevations. Central to the timing of diagnostic actions is grading the severity of liver test elevations.

In recent years, microphysiological systems (MPS) have been developed to shorten the test period and reduce animal experiments for drug development. We examined cell sources for the liver-MPS, i.e., MPS mimicking liver function. For liver-MPS, liver-like cells with high liver functions are required. Cryo-preserved hepatocytes (cryoheps), the gold standard hepatocytes for in vitro drug development, present several disadvantages, including differences between lots due to individual donor variations or a limited cell supply from the same donor. As such, alternatives for cryoheps are sought. Hepatocyte-like cells derived from human induced pluripotent stem cells (hiPSC-Heps), hepatocytes derived from liver-humanized mice (PXB-cells), and human liver cancer cells (HepG2 cells) were examined as source candidates for liver-MPS. Gene expression levels of the major cytochrome P450 of hiPSC-Heps, PXB cells, and HepG2 cells were compared with 22 lots of cryoheps, and the activities of hiPSC-Heps were compared with 8 lots of cryopreserved hepatocytes. A focused DNA microarray was used for the global gene analysis of the liver-like characteristics of hiPSC-Heps, PXB-cells, cryoheps, and HepG2 cells. Gene expression data from the focused microarray were analyzed by principal component analysis, hierarchical clustering, and enrichment analysis. The results indicated the characteristics of individual hepatocyte cell source and raised their consideration points as an alternative cell source candidate for liver-MPS. The study contributes to the repetitive utilization of a robust in vitro hepatic assay system over long periods with stable functionality.

Background: Drug-induced liver injury (DILI), represented by acetaminophen (APAP), is a common cause of acute liver failure in clinics. Paeoniflorin (PF) has been proven to demonstrate a significant hepatoprotective effect. However, it is still unclear whether it can be a potential agent against hepatotoxicity induced by APAP. This study aimed to explore the preventive and therapeutic effects and mechanisms of PF on APAP-induced liver injury. Methods: Different doses of PF (50, 100, and 200 mg/kg) were given to C57BL/6 male mice for five consecutive days. After 12 h of APAP (250 mg/kg i.p.) treatment, blood and liver tissues were collected and isolated for detection. Results: The results showed that the therapeutic effects of PF on APAP mice were presented in the downregulation of the content of serum indices and significantly improved hepatic tissue edema and inflammatory infiltration. Meanwhile, PF reduces the level of the mitochondrial metabolic enzyme. Ulteriorly, it was found that PF has a downregulating effect on the apoptotic reaction and could inhibit the protein expression of CYP2E1/JNK signaling, which in turn reduces the damage of APAP. Conclusion: Our findings showed that PF acted as a protective agent against APAP-induced hepatotoxicity by inhibiting JNK-related signals, suggesting a novel insight into treating APAP-induced liver injury.

Inherited chromosomally integrated (ici) human herpes virus 6 (HHV-6) is estimated to occur in 0.6–2.7% of people worldwide. HHV-6 comprises two distinct species: HHV-6A and HHV-6B. Both HHV-6A and HHV-6B integration have been reported. Several drugs are capable of activating iciHHV-6 in tissues, the consequences of which are poorly understood. We report herein a case of a woman with iciHHV-6A+ and iciHHV-6B+, who developed ulipristal acetate (a selective progesterone receptor modulator)-induced fulminant hepatic failure that required liver transplantation. We confirmed the presence of ~one copy per cell of both HHV-6A and HHV-6B DNA in her hair follicles using multiplex HHV-6A/B real-time PCR and demonstrated the Mendelian inheritance of both iciHHV-6A and iciHHV-6B in her family members over three generations. Because of the rarity of this presentation, we discuss herein the possible links between reactivated HHV-6 from iciHHV-6A and/or iciHHV-6B and adverse drug reactions, suggesting that iciHHV-6 could be screened before the introduction of any hepatotoxic drugs to exclude HHV-6 active disease or combined idiosyncratic drug-induced liver injury in these patients.

(1) Antibiotics are an important weapon in the fight against serious bacterial infections and are considered a common cause of drug-induced liver injury (DILI). The hepatotoxicity of many drugs, including antibiotics, is poorly analyzed in human in vitro models. (2) A standardized assay with a human hepatoma cell line was used to test the hepatotoxicity of various concentrations (Cmax, 5× Cmax, and 10× Cmax) of antibiotics. In an ICU, the most frequently prescribed antibiotics, ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, meropenem, rifampicin, tigecycline, and vancomycin, were incubated with HepG2/C3A cells for 6 days. Cell viability (XTT assay, LDH release, and vitality), albumin synthesis, and cytochrome 1A2 activity were determined in cells. (3) In vitro, vancomycin, rifampicin, and tigecycline showed moderate hepatotoxic potential. The antibiotics ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, and meropenem were associated with mild hepatotoxic reactions in test cells incubated with the testes Cmax concentration. Rifampicin and cefuroxime showed significantly negative effects on the viability of test cells. (4) Further in vitro studies and global pharmacovigilance reports should be conducted to reveal underlying mechanism of the hepatotoxic action of vancomycin, rifampicin, tigecycline, and cefuroxime, as well as the clinical relevance of these findings.

Herbal-induced liver injury (HILI) is an important and increasingly concerning cause of liver toxicity, and this study presents recent updates to the literature. An extensive literature review was conducted encompassing September 2019 through March 2021. Studies with clinically significant findings were analyzed and included in this review. We emphasized those studies that provided a causality assessment methodology, such as Roussel Uclaf Causality Assessment Method scores. Our review includes reports of individual herbals, including Garcinia cambogia, green tea extract, kratom as well as classes such as performance enhancing supplements, Traditional Chinese medicine, Ayurvedic medicine and herbal contamination. Newly described herbals include ashwagandha, boldo, skyfruit, and ‘Thermo gun’. Several studies discussing data from national registries, including the United States Drug-Induced Liver Injury (DILI) Network, Spanish DILI Registry, and Latin American DILI Network were incorporated. There has also been a continued interest in hepatoprotection, with promising use of herbals to counter hepatotoxicity from anti-tubercular medications. We also elucidated the current legal conversation surrounding use of herbals by presenting updates from the Federal Drug Administration. The highlights of the literature over the past year indicate interest in HILI that will continue as the supplement industry in the United States grows.

Yi-Hui Liu,1 Yan Guo,2 Hong Xu,1 Hui Feng,1 Dong-Ya Chen1 1Department of Digestive Hepatology, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, 310003, People’s Republic of China; 2Department of Gastroenterology, Hangzhou Third Hospital, Hangzhou, Zhejiang, 310009, People’s Republic of ChinaCorrespondence: Yi-Hui LiuDepartment of Digestive Hepatology, Hangzhou Red Cross Hospital, No. 208 of Huancheng East Road, Xiacheng District, Hangzhou, Zhejiang, 310003, People’s Republic of ChinaTel +8613588227972Email yhl_123drsea@163.comObjective: To observe the effect of non-alcoholic simple fatty liver disease on drug-induced liver injury caused by tuberculosis.Methods: We retrospectively analyzed the incidence, characteristics, and risk factors of antituberculosis drug-induced liver injury in 104 patients with initial treatment of tuberculosis complicated with non-alcoholic simple fatty liver disease. The patients were divided into two groups according to whether there was liver injury or not. The differences in age, gender, body mass index (BMI), cholesterol, and triglycerides were studied between the two groups.Results: Among the 104 patients with initial treatment of tuberculosis complicated with non-alcoholic fatty liver disease, 24 (23%) patients developed a drug-induced liver injury. The remaining 80 (77%) patients did not develop drug-induced liver injury (χ2 = 60.308, P < 0.05). In the liver injury group, there were 20 cases of mild liver injury, two cases of moderate liver injury, two cases of severe liver injury, 22 cases of hepatocellular injury, two cases of cholestasis, and no cases of mixed liver injury. The time of abnormal liver function in antituberculosis treatment was 16.42 ± 9.18 days from the beginning of the antituberculosis treatment. There were no significant differences in gender, age, BMI, or triglyceride between the liver injury group and the non-liver injury group (χ2 = 2.063, t = 0.179, t = 0.703, t = 1.12, P > 0.05 in all), but there were significant differences in cholesterol (t = 3.08, P < 0.05). By logistic regression analysis, cholesterol was a high-risk factor for liver injury.Conclusion: Non-alcoholic simple fatty liver disease may increase the risk of antituberculosis drug-induced liver injury.Keywords: non-alcoholic simple fatty liver disease, antituberculosis drugs, drug-induced liver injury

Yi-Hui Liu,1 Yan Guo,2 Hong Xu,1 Hui Feng,1 Dong-Ya Chen1 1Department of Digestive Hepatology, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang, 310003, People’s Republic of China; 2Department of Gastroenterology, Hangzhou Third Hospital, Hangzhou, Zhejiang, 310009, People’s Republic of ChinaCorrespondence: Yi-Hui LiuDepartment of Digestive Hepatology, Hangzhou Red Cross Hospital, No. 208 of Huancheng East Road, Xiacheng District, Hangzhou, Zhejiang, 310003, People’s Republic of ChinaTel +8613588227972Email yhl_123drsea@163.comObjective: To observe the effect of non-alcoholic simple fatty liver disease on drug-induced liver injury caused by tuberculosis.Methods: We retrospectively analyzed the incidence, characteristics, and risk factors of antituberculosis drug-induced liver injury in 104 patients with initial treatment of tuberculosis complicated with non-alcoholic simple fatty liver disease. The patients were divided into two groups according to whether there was liver injury or not. The differences in age, gender, body mass index (BMI), cholesterol, and triglycerides were studied between the two groups.Results: Among the 104 patients with initial treatment of tuberculosis complicated with non-alcoholic fatty liver disease, 24 (23%) patients developed a drug-induced liver injury. The remaining 80 (77%) patients did not develop drug-induced liver injury (χ2 = 60.308, P < 0.05). In the liver injury group, there were 20 cases of mild liver injury, two cases of moderate liver injury, two cases of severe liver injury, 22 cases of hepatocellular injury, two cases of cholestasis, and no cases of mixed liver injury. The time of abnormal liver function in antituberculosis treatment was 16.42 ± 9.18 days from the beginning of the antituberculosis treatment. There were no significant differences in gender, age, BMI, or triglyceride between the liver injury group and the non-liver injury group (χ2 = 2.063, t = 0.179, t = 0.703, t = 1.12, P > 0.05 in all), but there were significant differences in cholesterol (t = 3.08, P < 0.05). By logistic regression analysis, cholesterol was a high-risk factor for liver injury.Conclusion: Non-alcoholic simple fatty liver disease may increase the risk of antituberculosis drug-induced liver injury.Keywords: non-alcoholic simple fatty liver disease, antituberculosis drugs, drug-induced liver injury

The application of immune checkpoint inhibitors (ICI) in advanced cancer has been a major development in the last decade. The indications for ICIs are constantly expanding into new territory across different cancers, disease stages and lines of therapy. With this increased use, adverse events including immune checkpoint inhibitor-related hepatotoxicity (ICH) have emerged as an important clinical problem. This along with the introduction of ICI as first- and second-line treatments for advanced hepatocellular carcinoma makes ICH very relevant to gastroenterologists and hepatologists. The incidence of ICH varies between 1%-20% depending on the number, type and dose of ICI received. Investigation and management generally involve excluding differential diagnoses and following a stepwise escalation of withholding or ceasing ICI, corticosteroid treatment and adding other immunosuppressive agents depending on the severity of toxicity. The majority of patients with ICH recover and some may even safely recommence ICI therapy. Guideline recommendations are largely based on evidence derived from retrospective case series which highlights a priority for future research.

As practice shows, there are many alternative drugs that cause drug damage to the liver. A case of medicinal damage to the liver with an immunomodulatory herbal preparation Immunostimulating collection, which included St. John's wort, Elecampane, Kopeichnik, Echinacea, Licorice, Rosehip, is presented. A 39-year-old patient came to the clinic with complaints of yellowing of the skin, whites of the eyes, heaviness in the epigastrium after eating, lightening of feces, dark urine, sour taste in the mouth, bloating, pruritus, decreased appetite, pronounced general weakness, drowsiness 10 days after you start taking herbal immunostimulant. The diagnosis of drug damage to the liver was made taking into account the history and laboratory parameters, since the patient had negative markers of viral hepatitis and increasing of biochemical blood tests: alanine transferase up to 2800 U/l (norm up to 32 U/L), aspartate transferase up to 1776 U/l (norm up to 31 U/l), total bilirubin up to 577 U/l (norm up to 21 U/l), direct bilirubin up to 116 U/l (norm up to 4.3 U/l), alkaline phosphatase up to 112 U/l (norm up to 98 U/l). After the withdrawal of the immunomodulator and the appointment of therapy, including diet, enzyme replacement therapy, drugs clinical and laboratory manifestations of liver drug damage completely disappeared. This confirms the leading role of the immunoactive drug, which the patient took in the toxic effect on the liver.Как показывает практика, существует немало биологически активных добавок и средств народной медицины, которые вызывают лекарственное поражение печени. Представлен случай лекарственного поражения печени иммуномодулирующим препаратом растительного происхождения Иммуностимулирующий сбор трав, в состав которого входили зверобой, девясил, копеечник, эхинацея, солодка, шиповник. Пациентка 39 лет обратилась в поликлинику с жалобами на пожелтение кожных покровов, склер, тяжесть в эпигастрии после приема пищи, осветление окраски кала, темный цвет мочи, кислый привкус во рту, вздутие живота, кожный зуд, снижение аппетита, выраженную общую слабость, сонливость через 10 дней после начала приема иммуностимулятора растительного происхождения. Диагноз лекарственное поражение печени поставлен с учетом анамнеза и лабораторных показателей, так как у пациентки отсутствовали маркеры вирусных гепатитов, отмечалось повышение в биохимическом анализе крови аланинаминотрансферазы до 2800 ед/л (норма до 32 Ед/л), аспартатаминотрансферазы до 1776 Ед/л (норма до 31 Ед/л), билирубина общего до 577 Ед/л (норма до 21 Ед/л), билирубина прямого до 116 Ед/л (норма до 4,3 Ед/л), щелочной фосфатазы до 112 Ед/л (норма до 98 Ед/л). На фоне отмены иммуностимулятора, проведения инфузионной дезинтоксикационной терапии, назначения гепатопротектора, приема сорбентов, диетотерапии с использованием специализированного питания клинико-лабораторные проявления лекарственного острого гепатита полностью исчезли. Это подтверждает ведущую роль фитосбора с иммуностимулирующим действием, который принимала пациентка, в токсическом действии на печень.

Autoimmune hepatitis (AIH) is a chronic progressive liver disease whose etiology and pathogenesis are not yet clear. It is currently believed that the occurrence of AIH is closely related to genetic susceptibility and immune abnormalities, and other factors such as environment, viral infection and drugs that may cause immune dysfunction. This article reviews the pathogenesis of AIH and describes the latest research results in the past 5 years.

Drug-induced liver injury (DILI) is an adverse toxic hepatic clinical reaction associated to the administration of a drug that can occur both at early clinical stages of drug development, as well after normal clinical usage of approved drugs. Because of its unpredictability and clinical relevance, it is of medical concern. Three DILI phenotypes (hepatocellular, cholestatic, and mixed) are currently recognized, based on serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) values. However, this classification lacks accuracy to distinguish among the many intermediate mixed types, or even to estimate the magnitude and progression of the injury. It was found desirable to have additional elements for better evaluation criteria of DILI. With this aim, we have examined the serum metabolomic changes occurring in 79 DILI patients recruited and monitored using established clinical criteria, along the course of the disease and until recovery. Results revealed that free and conjugated bile acids, and glycerophospholipids were among the most relevant metabolite classes for DILI phenotype characterization. Using an ensemble of PLS–DA models, metabolomic information was integrated into a ternary diagram to display the disease phenotype, the severity of the liver damage, and its progression. The modeling implemented and the use of such compiled information in an easily understandable and visual manner facilitates a straightforward DILI phenotyping and allow to monitor its progression and recovery prediction, usefully complementing the concise information drawn out by the ALT and ALP classification. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03114-z.

The zebrafish embryo (ZFE) is a promising alternative non-rodent model in toxicology, and initial studies suggested its applicability in detecting hepatic responses related to drug-induced liver injury (DILI). Here, we hypothesize that detailed analysis of underlying mechanisms of hepatotoxicity in ZFE contributes to the improved identification of hepatotoxic properties of compounds and to the reduction of rodents used for hepatotoxicity assessment. ZFEs were exposed to nine reference hepatotoxicants, targeted at induction of steatosis, cholestasis, and necrosis, and effects compared with negative controls. Protein profiles of the individual compounds were generated using LC-MS/MS. We identified differentially expressed proteins and pathways, but as these showed considerable overlap, phenotype-specific responses could not be distinguished. This led us to identify a set of common hepatotoxicity marker proteins. At the pathway level, these were mainly associated with cellular adaptive stress-responses, whereas single proteins could be linked to common hepatotoxicity-associated processes. Applying several stringency criteria to our proteomics data as well as information from other data sources resulted in a set of potential robust protein markers, notably Igf2bp1, Cox5ba, Ahnak, Itih3b.2, Psma6b, Srsf3a, Ces2b, Ces2a, Tdo2b, and Anxa1c, for the detection of adverse responses.

Aims: N-Acetylcysteine (NAC) is used as an antidote in acetaminophen (APAP) overdose to prevent and mitigate drug-induced liver injury (DILI). Our objective was to systematically review evidence of the use of NAC as a therapeutic option for APAP overdose and APAP-related DILI in order to define the optimal treatment schedule and timing to start treatment.Methods: Bibliographic databases (PubMed, Web of Science, Embase, and MEDLINE) were searched for retrospective and prospective cohort studies, case series, and clinical trials. The prespecified primary outcomes were DILI-related mortality, hepatotoxicity, and adverse events (AEs).Results: In total, 34 studies of NAC usage in APAP-related DILI cases with 19,580 patients were identified, of which 2,376 patients developed hepatotoxicities. The mortality rate across different studies ranged from 0 to 52%. Large variability of NAC regimens was found, i.e., intravenous (I.V.) (100–150 mg/kg) and oral (70–140 mg/kg), and length of treatment varied—12, 24, or 48 h for I.V. regimen and 72 h for oral administration. The timing of initiation of NAC treatment showed different results in terms of occurrence of hepatotoxicity and mortality; if started within 8 h and no more than 24 h from APAP overdose, either intravenously or orally, NAC administration was efficacious in terms of mortality. The most frequent AEs reported were anaphylactic reactions, followed by cutaneous AEs for the IV route and intestinal AEs for the oral one.Conclusion: NAC improves hepatotoxicity and reduces mortality. Timing of treatment, ranging from 8 to 24 h from APAP overdose, regardless of the regimen or route of administration, is important to prevent or minimize liver damage, particularly in children and in elderly and obese patients.

Among adverse drug reactions, drug-induced liver injury presents particular challenges because of its complexity, and the underlying mechanisms are still not completely characterized. Our knowledge of the topic is limited and based on the assumption that a drug acts on one molecular target. We have leveraged drug polypharmacology, i.e., the ability of a drug to bind multiple targets and thus perturb several biological processes, to develop a systems pharmacology platform that integrates all drug–target interactions. Our analysis sheds light on the molecular mechanisms of drugs involved in drug-induced liver injury and provides new hypotheses to study this phenomenon.

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.

BACKGROUND Sodium valproate is widely used in the treatment of epilepsy in clinical practice. Most adverse reactions to sodium valproate are mild and reversible, while serious idiosyncratic side effects are becoming apparent, particularly hepatotoxicity. Herein, we report a case of fatal acute liver failure (ALF) with thrombotic microangiopathy (TMA) caused by treatment with sodium valproate in a patient following surgery for meningioma. CASE SUMMARY A 42-year-old man who received antiepileptic treatment with sodium valproate after surgery for meningioma exhibited extreme fatigue, severe jaundice accompanied by oliguria, soy sauce-colored urine, and ecchymosis. His postoperative laboratory values indicated a rapid decreased platelet count and hemoglobin level, severe liver and kidney dysfunction, and disturbance of the coagulation system. He was diagnosed with drug-induced liver failure combined with TMA. After plasma exchange combined with hemoperfusion, pulse therapy with high-dose methylprednisolone, and blood transfusion, his liver function deteriorated, and finally, he died. CONCLUSION ALF with TMA is a rare and fatal adverse reaction of sodium valproate which needs to be highly valued.

Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury.

Drug-induced liver injury (DILI) is a leading reason for preclinical safety attrition and post-market drug withdrawals. Drug-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI, especially in idiosyncratic liver injury. This study examined liver injury reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of toxicity. The frequency of hepatotoxicity was determined at a group level and individual drug level. A reporting odds ratio (ROR) was calculated as the measure of effect. Between the two DILI groups, reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43 (95% CI 1.42–1.45; P 18: benzbromarone, troglitazone, isoniazid, rifampin) were associated with mitochondrial mechanisms of toxicity. The major demographic influence for DILI risk was also examined. There was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1 ± 18.33 (SD)] compared to non-mitochondrial mechanisms [48 ± 19.53 (SD)] (P, Graphical abstract In this study, we investigated liver injury reports submitted to the FAERS database and compared the frequency of reports between drugs that can cause hepatotoxicity via mitochondrial mechanisms and those without mitochondrial mechanisms of toxicity.Image 1

Objectives Statins have proved to reduce cardiovascular morbidity and mortality in high-risk population and are generally well tolerated, although adverse events can occur. Up to 3% of patients develop aminotransferases elevation, which usually normalizes with continued treatment and hardly is associated with clinical symptoms. Serious statin-related liver injury is exceedingly rare. Furthermore, literature regarding rechallenge with a second statin is extremely poor. Some authors caution that re-exposure to these drugs is associated with a more serious liver injury but safe switching to a second statin after drug-induced liver injury (DILI) is also reported. Case presentation We describe a case of a middle-aged woman who developed hepatocellular liver injury after simvastatin dose escalation; a rechallenge with low dose rosuvastatin caused rapid recurrence of DILI. Conclusions In our opinion, clinicians should be very cautious upon rechallenge and closely follow-up patients who experienced statin-induced liver injury when trying re-exposure to another statin.

In this review, we discussed the epidemiological and pathogenetic aspects of mixed steatohepatitis (SH), developed due to non-alcoholic fatty liver disease, metabolic associated fatty liver disease, drug-induced liver injury. We discussed the mechanisms of the mutually aggravating influence of etiological factors. Drugs can cause steatosis and SH, as well as contribute to the progressive course of existing SH, primarily of metabolic origin. The issues of interaction of pathogenetic factors, peculiarities of diagnostics and perspectives of pathogenetic and symptomatic treatment are considered. Therapy of mixed SH is based on avoidance of hepatotoxic drugs and lifestyle modification, medications with demonstrated efficacy (such as ademetionine) in certain SH might be used.В обзоре обсуждаются эпидемиологические и патогенетические аспекты сочетания стеатогепатитов (СГ) смешанного генеза, обусловленных неалкогольной жировой болезнью печени (метаболически ассоциированная жировая болезнь печени), алкогольной болезнью печени, лекарственным поражением печени. Проанализированы патогенетические механизмы взаимоотягчающего влияния этиологических факторов. Лекарственные средства могут вызывать стеатоз и СГ, а также способствовать прогрессирующему течению уже имеющегося СГ, прежде всего метаболического характера. Рассмотрены вопросы взаимодействия патогенетических факторов, особенности диагностики и перспективные возможности патогенетического и симптоматического лечения. Основой терапии СГ смешанного генеза являются отмена гепатотоксических лекарственных препаратов и модификация образа жизни, в качестве медикаментозного лечения следует использовать препараты, показавшие свою эффективность при отдельных вариантах СГ (такие как адеметионин).

Corona virus disease (COVID)-19 is caused by the novel severe acute respiratory syndrome coronavirus-2 (commonly referred to as SARS-CoV-2). In March 2020, the World Health Organization declared the COVID-19 outbreak a pandemic. Though the target organ for the virus is primarily the lungs, with the recent understanding of the pathobiology of this disease and the immune dysregulation associated with it, it is now clear that COVID-19 affects multiple organ systems. Several drugs and therapies have been tried or repurposed to combat the wrath posed by this disease. On October 22, 2020, the USA Food and Drug Administration approved remdesivir for use in adults and pediatric patients (12 years of age and older). Several of the drugs being tried against COVID-19 have hepatotoxicity as their potential side effect. This review aims to provide the latest insights on various drugs being used in the treatment of COVID-19 and their effects on the liver.

Drug-induced liver injury (DILI), which refers to liver damage caused by a drug or its metabolites, has emerged as an important cause of acute liver failure (ALF) in recent years. Chemically-induced ALF in animal models mimics the pathology of DILI in humans; thus, these models are used to study the mechanism of potentially effective treatment strategies. Mesenchymal stromal cells (MSCs) possess immunomodulatory properties, and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF. Here, we summarize some of the existing research on the interaction between MSCs and immune cells, and discuss the possible mechanisms underlying the immuno-modulatory activity of MSCs in chemically-induced ALF. We conclude that MSCs can impact the phenotype and function of macrophages, as well as the differentiation and maturation of dendritic cells, and inhibit the proliferation and activation of T lymphocytes or B lymphocytes. MSCs also have immuno-modulatory effects on the production of cytokines, such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6, in animal models. Thus, MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.