Hepatotoxicity Research Articles

Analysis of Clinical Differences in Drug-Induced Hepatitis in Elderly Patients Caused by Various Drugs

Background: This study aimed to analyze the clinical differences in drug-induced hepatitis among elderly patients caused by various medications. Methods: We conducted a retrospective analysis of clinical data from 140 elderly patients with drug-induced hepatitis admitted to our hospital between June 2021 and June 2023. We examined overall clinical features, identified drugs causing hepatitis, analyzed differences in symptoms, severity, and liver function indicators among patients exposed to various drugs, and investigated factors influencing prognosis. Results: The primary drugs inducing drug-induced liver injury were traditional Chinese medicine (34.29%), antituberculosis drugs (27.86%), and antibiotics (23.57%). Hepatocellular injury was the most prevalent clinical type (72.86%). The incidence of jaundice was significantly higher with antituberculosis drugs. Grade 1 hepatitis incidence was lower with traditional Chinese medicine but higher with Grade 3 hepatitis. Liver function indicators did not significantly differ across groups. Effective treatment was observed in 90.71% of patients. Significant differences were noted in TBIL, ALT, ALP, AST, and severity between patients with effective and ineffective treatment (P < 0.05). Conclusions: Traditional Chinese medicine, antituberculosis drugs, and antibiotics are common causes of drug-induced hepatitis in elderly patients, with hepatocellular injury being the predominant clinical type. Prognosis is influenced by liver function and the severity of the condition.

Clinical characteristics and HLA associations of azithromycin-induced liver injury.

Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug-induced liver injury (DILI) due to AZ. The clinical characteristics of individuals with definite, highly likely, or probable AZ-DILI enrolled in the US Drug-Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ-DILI cases was compared to population controls, other DILI cases, and other antibiotic-associated DILI cases. Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ-DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA-DQA1*03:01 was significantly more common in AZ-DILI versus population controls and amoxicillin-clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively). Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA-DQA1*03:01 was significantly more common in AZ cases compared to controls.

Improved Detection of Drug-Induced Liver Injury by Integrating Predicted In Vivo and In Vitro Data.

Drug-induced liver injury (DILI) has been a significant challenge in drug discovery, often leading to clinical trial failures and necessitating drug withdrawals. Over the last decade, the existing suite of in vitro proxy-DILI assays has generally improved at identifying compounds with hepatotoxicity. However, there is considerable interest in enhancing the in silico prediction of DILI because it allows for evaluating large sets of compounds more quickly and cost-effectively, particularly in the early stages of projects. In this study, we aim to study ML models for DILI prediction that first predict nine proxy-DILI labels and then use them as features in addition to chemical structural features to predict DILI. The features include in vitro (e.g., mitochondrial toxicity, bile salt export pump inhibition) data, in vivo (e.g., preclinical rat hepatotoxicity studies) data, pharmacokinetic parameters of maximum concentration, structural fingerprints, and physicochemical parameters. We trained DILI-prediction models on 888 compounds from the DILI data set (composed of DILIst and DILIrank) and tested them on a held-out external test set of 223 compounds from the DILI data set. The best model, DILIPredictor, attained an AUC-PR of 0.79. This model enabled the detection of the top 25 toxic compounds (2.68 LR+, positive likelihood ratio) compared to models using only structural features (1.65 LR+ score). Using feature interpretation from DILIPredictor, we identified the chemical substructures causing DILI and differentiated cases of DILI caused by compounds in animals but not in humans. For example, DILIPredictor correctly recognized 2-butoxyethanol as nontoxic in humans despite its hepatotoxicity in mice models. Overall, the DILIPredictor model improves the detection of compounds causing DILI with an improved differentiation between animal and human sensitivity and the potential for mechanism evaluation. DILIPredictor required only chemical structures as input for prediction and is publicly available at https://broad.io/DILIPredictor for use via web interface and with all code available for download.

Modulation of keap-1/Nrf2/HO-1 and NF-ĸb/caspase-3 signaling pathways by dihydromyricetin ameliorates sodium valproate-induced liver injury

Nuclear factor erythroid factor 2 (Nrf2) is the key regulatory of the antioxidant response elements. Also, Nrf2 interacts with nuclear factor kappa B (NF-ĸB) to inhibit subsequent inflammatory cascade. Activation of Nrf2 signaling ameliorates drug-induced liver injury. Sodium valproate (SVP) is an anti-epilepsy drug with a hepatotoxic adverse effect that restricts its clinical use. In this study, coadministration of Dihydromyricetin (DHM), a natural flavonoid, with SVP to rats upregulated gene expression of Nrf2 and its downstream gene, heme oxygenase 1 (HO-1), while suppressed the Nrf2 repressor, Keap-1. Additionally, DHM led to downregulation of proinflammatory factors in liver tissues, including NF-ĸB, interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α). This was accompanied by a decrease in the proapoptotic protein (cleaved caspase-3) expression level. Furthermore, biochemical and histopathological studies showed that DHM treatment improved liver function and lipid profile while decreased inflammatory cell infiltration, congestion, and hepatocellular damage. According to our knowledge, prior research has not examined the protective effect of DHM on the liver injury induced by SVP. Consequently, this study provides DHM as a promising herbal medication that, when used with SVP, can prevent its induced hepatotoxicity owing to its potential anti-oxidative, anti-inflammatory, and anti-apoptotic properties.

Drug-induced Liver Injury in Latin America: 10-year Experience of the Latin American DILI (LATINDILI) Network

Background and aimsLatin America is a region of great interest for studying the clinical presentation of idiosyncratic drug-induced liver injury (DILI). A comprehensive analysis of patients enrolled into the LATINDILI Network over a decade is presented. MethodsDemographics, clinical presentation, histological findings and outcome of prospectively recruited DILI cases in the LATINDILI Network were analyzed. Suspected culprit drugs were classified according to the Anatomical Therapeutic Chemical classification. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) scale. ResultsOverall, 468 idiosyncratic DILI cases were analyzed (62% women, mean age 49 years). Hepatocellular injury predominated (62%), jaundice was present in 60% of patients and 42% were hospitalized. 4.1% of the cases had a fatal outcome, and 24 (12%) patients developed chronic DILI. The most common drug classes were systemic anti-infectives (31%), musculoskeletal agents (12%), antineoplastic and immunomodulating agents (11%), and herbal and dietary supplements (HDS, 9%). Notably, none of the patients with DILI due to antibacterials or immunosuppressants had a fatal outcome. In fact, Hy's law showed to have drug-specific predictive value, with anti-tuberculosis drugs, nimesulide and HDS associated with the worst outcome, whereas DILI caused by amoxicillin-clavulanate, nitrofurantoin and diclofenac that fulfilled Hy's law did not have a fatal outcome. ConclusionFeatures of DILI in Latin America are comparable to other prospective registries. However, the pattern of drugs responsible for DILI differs. An increasing incidence of HDS, with high mortality rate, and likewise nimesulide and nitrofurantoin was noted. Thus, public health policies should raise awareness of the potential adverse effects of these compounds.

Drug-induced Liver Injury from Intravenous Immunoglobulin for Prevention of Recurrent Gestational Alloimmune Liver Disease: A Clinical Catch-22

Gestational alloimmune liver disease (GALD) is a rare autoimmune syndrome in which maternal antibodies lead to in utero fetal hepatocyte destruction, often presenting as neonatal liver failure and hemochromatosis. Antenatal intravenous immunoglobulin (IVIG) is generally accepted to be safe in pregnancy with demonstrable benefits for reducing GALD recurrence risk in subsequent pregnancies. Here we present a case of a 33-year-old woman with a prior neonatal demise due to GALD who received multiple prophylactic IVIG infusions in a subsequent twin pregnancy complicated by maternal jaundice and acute hepatitis. A liver biopsy demonstrated hepatocellular injury with bridging necrosis and cholestatic features consistent with drug-induced liver injury. This case demonstrates the importance of close clinical monitoring during IVIG therapy and the need for further research into alternative prophylaxis options for GALD. Key Points

Turmeric-Induced Liver Injury in a Patient with Concurrent Semaglutide Use

Turmeric has surged in popularity as one of the most widely used dietary supplements in the United States. Recognized for its antiinflammatory and antioxidant properties, it has traditionally been regarded as safe. Recent literature and reports in LiverTox have documented over a dozen cases of acute liver injury associated with the use of turmeric supplements. However, potential drug interactions with turmeric have been described but not well-documented. Thus, we present a case of drug-induced liver injury (DILI) correlated with turmeric supplement use and the concurrent use of semaglutide. INTRODUCTION Drug-induced liver injury (DILI) from herbal and dietary supplements (HDS) in the United States has increased as the usage of HDS has become more popular. According to the United States Drug-Induced Liver Injury Network (DILIN), approximately 20% of cases of DILI can be attributed to HDS, an increase from 7% in 2004.1 Turmeric supplements have become one of the top selling HDS in the United States. It is promoted for arthritis, pain, and digestive disorders. Common side effects include dermatitis and gastrointestinal upset, while instances of hepatotoxicity are rare. Different formulations that increase the bioavailability of curcumin, the active ingredient in turmeric, have been linked to cases of liver injury and acute hepatitis outbreaks outside of the United States.2 Possible interactions between turmeric and other drugs, such as anticoagulants, antiplatelets, antidiabetics, and chemotherapeutic agents, have been described in in vitro and animal studies, but have not been well studied in humans.3 In this report, we describe a possible drug interaction in a patient who had been using turmeric supplements and semaglutide injections and presented with elevated liver transaminases and bilirubin, with improvement upon cessation of the supplement.

Drug-induced Liver Injury Caused by Levetiracetam

Levetiracetam, known as Keppra, is an antiepileptic drug that is commonly used due to its rare side effects, particularly on the liver. It is mainly excreted by the kidneys with minimal hepatic metabolism. Drug-induced liver injury associated with Levetiracetam is extremely rare. Few cases of Levetiracetam-induced liver toxicity and failure were declared. Until now, there are no previously reported cases of mixed pattern liver injury related to this drug. We report a case of a patient taking Levetiracetam, that was found to have mixed pattern liver injury. Our patient experienced important rapid improvement of hepatocellular injury and a delayed improvement of cholestatic pattern after Levetiracetam discontinuation, suggesting the mentioned association. This case report is the first to establish both hepatocellular and cholestatic injury associated with Levetiracetam. We would like to highlight this side effect, though rare, of this frequently used drug in medical practice.

The Role of Pharmacogenomics Studies for Precision Medicine Among Ethiopian Patients and Their Clinical Implications: A Scoping Review.

Pharmacogenomics research is currently revolutionizing treatment optimization by discovering molecular markers. Medicines are the cornerstone of treatment for both acute and chronic diseases. Pharmacogenomics associated treatment response varies from 20% to 95%, resulting in from lack of efficacy to serious toxicity. Pharmacogenomics has emerged as a useful tool for therapy optimization and plays a bigger role in clinical care going forward. However, in Africa, in particular in Ethiopia, such studies are scanty and not generalizing. Therefore, the objective of this review was to outline such studies, generating comprehensive evidence and identify studied variants' association with treatment responses in Ethiopian patients. The Joanna Briggs Institute's updated 2020 methodological guidelines for conducting and guidance for scoping reviews were used. We meticulously adhered to the systemic review reporting items checklist and scoping review meta-analyses extension. Two hundred twenty-nine possibly relevant studies were searched. These include: 64, 54, 21, 48 and 42 from PubMed, Scopus, Google Scholar, EMBASE, and manual search, respectively. Seventy-seven duplicate studies were removed. Thirty-nine papers were rejected with justification, whereas 58 studies were qualified for full-text screening. Finally 19 studies were examined. The primary pharmacogene that was found to have a significant influence on the pharmacokinetics of efavirenz was CYP2B6. Drug-induced liver injury has frequently identified toxicity among studied medications. Pharmacogenomics studies in Ethiopian populations are less abundant. The studies conducted focused on infectious diseases, specifically on HAART commonly efavirenz and backbone first-line anti-tuberculosis drugs. There is a high need for further pharmacogenomics research to verify the discrepancies among the studies and for guiding precision medicine. Systematic review and meta-analysis are also recommended for pooled effects of different parameters in pharmacogenomics studies.

Suppression of the Epithelial-Mesenchymal Transition and Maintenance of the Liver Functions in Primary Hepatocytes through Dispersion Culture within a Dome-Shaped Collagen Matrix.

Primary hepatocytes are valuable for studying liver diseases, drug-induced liver injury, and drug metabolism. However, when cultured in a two-dimensional (2D) environment, primary hepatocytes undergo rapid dedifferentiation via an epithelial-mesenchymal transition (EMT) and lose their liver-specific functions. On the other hand, a three-dimensional (3D) culture of primary hepatocyte organoids presents challenges for analyzing cellular functions and molecular behaviors due to strong cell-cell adhesion among heterogeneous cells. In this study, we developed a novel dispersion culture method of hepatocytes within a dome-shaped collagen matrix, overcoming conventional limitations. The expression levels of EMT-related genes were lower in rat primary hepatocytes cultured using this method for 4 d than in cells cultured using the 2D method. Furthermore, albumin production, a marker of liver function, declined sharply in rat primary hepatocytes cultured in two dimensions from 6.40 µg/mL/48 h on day 4 to 1.35 µg/mL/48 h on day 8, and declined gradually from 4.92 µg/mL/48 h on day 8 to 3.89 µg/mL/48 h on day 14 in rat primary hepatocytes cultured using our new method. These findings indicate that the newly developed culture method can suppress EMT and maintain liver functions for 14 d in rat primary hepatocytes, potentially expanding the utility of primary hepatocyte cultured by using conventional 3D methods.

Multidisciplinary Management of Lipoprotein X-Induced Hyperlipidemia Secondary to Drug-Induced Liver Injury

Multidisciplinary Management of Lipoprotein X-Induced Hyperlipidemia Secondary to Drug-Induced Liver Injury

Efficacy and Safety of Rimegepant 75 mg Oral Tablet, a CGRP Receptor Antagonist, for the Acute Treatment of Migraine: A Randomized, Double-Blind, Placebo-Controlled Trial.

This study compared the efficacy, tolerability, and safety of rimegepant 75 mg oral tablet - a small molecule calcitonin-gene receptor peptide (CGRP) receptor antagonist - with placebo in the acute treatment of migraine. This double-blind, randomized, placebo-controlled trial enrolled adults aged ≥18 years with at least a 1-year history of migraine. Participants randomized to rimegepant 75 mg oral tablet or placebo treated a single migraine attack of moderate or severe pain intensity. The coprimary endpoints, pain freedom and freedom from the most bothersome symptom ([MBS] nausea, photophobia, or phonophobia) at 2 hours postdose, were evaluated using Mantel-Haenszel risk estimation. Of the 1485 participants enrolled, 1162 (78.2%) were randomized to rimegepant (n = 582) or placebo (n = 580). Most participants (85.5%) were female; the population had a mean (SD) age of 41.6 (12.2) years and a history of 4.7 (1.8) migraine attacks per month. At 2 hours postdose, rimegepant-treated participants had higher pain freedom rates (19.2% [104/543] vs 14.2% [77/541]; risk difference 4.9; 95% confidence interval [CI] 0.5 to 9.3; P=0.0298) and MBS freedom rates (36.6% [199/543] vs 27.7% [150/541]; risk difference 8.9; 95% CI 3.4 to 14.4; P=0.0016) than placebo-treated participants. Rimegepant-treated participants also had higher rates of pain relief (56.0% [304/543] vs 45.7% [247/541]; risk difference 10.3; 95% CI 4.4 to 16.2, P=0.0006) at 2 hours postdose. The most common adverse events were nausea (0.9% [5/546] vs 1.1% [6/549]) and dizziness (0.7% [4/546] vs 0.4% [2/549]). No signal of drug-induced liver injury due to rimegepant was identified. Rimegepant 75 mg oral tablet was effective in the acute treatment of migraine. Tolerability and safety were similar to placebo, with no evidence of hepatotoxicity. Clinicaltrials.gov Identifier: NCT03235479.

A dual-response fluorescent probe to reveal the role of ferroptosis in drug-induced liver injury

Drug-induced liver injury (DILI) has already been recognized as a formidable obstacle in global health issues. Despite the proposed common cellular death types in DILI, exploration of alternative mechanisms such as ferroptosis for prevention and therapy remains limited. Visualization of the role of ferroptosis in DILI holds profound promise in advancing diagnostic and therapeutic strategies for DILI. To address this, herein, a unique multi-functional fluorescent probe, VIS-HNO, was elaborately built up and endowed with the extraordinary performance of excellent selectivity and high sensitivity toward HNO and viscosity. Employing the probe VIS-HNO with the confocal fluorescence imaging, the up-regulations of HNO and viscosity in the process of DILI and ferroptosis were disclosed. Then the remediation of DILI was achieved by VIS-HNO under the treatment of ferrostatin1 (Fer-1), indicating its therapeutic value for DILI. In addition, taking into account the significance of HNO in determining the role of ferroptosis in DILI, the pathway of HNO production in DILI was further explored, which presented essential insights into the role of ferroptosis in DILI. Overall, these findings demonstrated that VIS-HNO may be a potent tool to aid in diagnosing ferroptosis and DILI, more importantly, to understand the role of ferroptosis in DILI by evaluating HNO and viscosity level, which will facilitate the exploration of unique strategies for DILI treatment.

Effects of drug-induced liver injury on the in vivo fate of liposomes

Liposomes represent one of the most extensively studied nano-carriers due to their potential in targeted drug delivery. However, the complex in vivo fate, particularly under pathological conditions, presents challenges for clinical translation of liposomal therapeutics. Liver serves as the most important organ for liposome accumulation and metabolism. Unfortunately, the fate of liposomes under pathological liver conditions has been significantly overlooked. This study aimed to investigate the in vivo pharmacokinetic profile and biodistribution profile of liposomes under drug-induced liver injury (DILI) conditions. Two classic DILI animal models, i.e. acetaminophen-induced acute liver injury (AILI) and triptolide-induced subacute liver injury (TILI), were established to observe the effect of pathological liver conditions on the in vivo performance of liposomes. The study revealed significant changes in the in vivo fate of liposomes following DILI, including prolonged blood circulation and enhanced hepatic accumulation of liposomes. Changes in the composition of plasma proteins and mononuclear phagocyte system (MPS)-related cell subpopulations collectively led to the altered in vivo fate of liposomes under liver injury conditions. Despite liver injury, macrophages remained the primary cells responsible for liposomes uptake in liver, with the recruited monocyte-derived macrophages exhibiting enhanced ability to phagocytose liposomes under pathological conditions. These findings indicated that high capture of liposomes by the recruited hepatic macrophages not only offered potential solutions for targeted delivery, but also warned the clinical application of patients under pathological liver conditions.

Clinical Case Of Rare Mitochondrial Disease In A Child

We describe a clinical case of Alpers-Huttenlocher syndrome in a child with polyneuropathy, myopathy and epileptic seizures, the development of toxic hepatitis with a fatal outcome after the use of valproic acid as an antiepileptic drug. The need for early differential diagnosis of Alpers syndrome and molecular genetic testing in cases of damage to the nervous system with various symptoms in order to select optimal therapy is shown.

The potential liver injury induced by metronidazole-provoked disturbance of gut microbiota: modulatory effect of turmeric supplementation.

It has been reported that the gut-liver axis and intestinal microbiome contribute crucially to different liver diseases. So, targeting this hepato-intestinal connection may provide a novel treatment modality for hepatic disorders such as drug-induced liver injury (DILI). The present study thought to investigate the protective effect of turmeric (TUR) on metronidazole (MNZ)-induced liver damage and the possible association of the gut-liver axis and gut microbiota as a suggested underlying mechanism. In the first experiment, a MNZ-induced liver injury rat model was reproduced after 130mg/kg oralMNZ administration for 30days. Meanwhile, the treatment group was orallytreated with 100mg/kg turmeric daily. In the second experiment, fecal microbiome transplantation (FMT) was conducted, in which the fecal microbiome of each group in the first experiment was transplanted to a healthy corresponding group in the second experiment. The liver enzymes (aminotransferase (ALT) and aspartate aminotransferase (AST)) and histopathological examination were estimated to assess liver function. Inflammatory cytokines and oxidative markers were evaluated in the liver tissues. Histological analysis, intestinal barrier markers, and expression of tight junction proteins were measured for assessment of the intestinal injury. Changes in the gut microbial community and possible hepatic bacterial transmission were analyzed using 16S rRNA sequencing. MNZ induced intestinal and liver injuries which were significantly improved by turmeric. Increased firmicutes/bacteroidetes ratio and bacterial transmission due to gut barrier disruption were suggested. Moreover, TUR has maintained the gut microbial community by rebalancing and restoring bacterial proportions and abundance, thereby repairing the gut mucosal barrier and suppressing bacterial translocation. TUR protected against MNZ-induced gut barrier disruption. Reshaping of the intestinal bacterial composition and prohibition of the hepatic microbial translocation were suggested turmeric effects, potentially mitigating MNZ-related liver toxicity.

Isolation and characterization of a hepatoprotective polysaccharide from Lonicera caerulea L. var. edulis Turcz. ex Herd. fruit against APAP-induced acute liver injury mice

The structure and bioactivities of a novel polysaccharide from Lonicera caerulea L. var. edulis Turcz. ex Herd. fruit (THP-3) were investigated. The crude polysaccharides of Turcz. ex Herd. (THP) were extracted by hot water extraction. After purification, the chemical structure of polysaccharides was identified. Then, a mouse model of acute drug-induced liver injury was constructed using 4-acetamidophenol (APAP) and pretreated with THP. The number-average molecular weight of THP-3 was 48.89 kDa and the mass average molar mass was 97.87 kDa. THP-3 was mainly composed of arabinose (42.54 %), glucose (27.62 %), galacturonic acid and galactose (29.84 %). The main linkage types of THP-3 were 1-linked Araf, 1,4-linked Glcp, and 1,3,6-linked Galp. In addition, after THP treatment, serum Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and γ-glutamyl transpeptidase (γGT) in AILI mice were successfully down-regulated. The results showed that THP could prevent the characteristic morphological changes of hepatic lobular injury and lipid depletion caused by APAP, reduced the level of oxidative damage in mice, increased the expression of APAP-induced hypolipidemia and related inflammatory indicators, and improved the detoxification function of liver. In general, the newly extracted THP polysaccharide has a good liver protection effect and is an ideal natural medicine for the treatment of liver diseases.

The developmental stage is a critical parameter for accurate assessment of the drug-induced liver injury (DILI) potentials of drugs with the zebrafish larval liver model

Prediction of drug-induced liver injury (DILI) potential of drugs is one of the most challenging issues of drug development. Zebrafish larvae provide an in vivo and robust test platform. Due to the ease of handling developing larvae between 2 - 5 days post fertilization (dpf) has been extensively used as a DILI test model. However, the liver is not fully functional at this stage. Here, the importance of larval liver maturation was tested by applying selected known DILI-rank drugs to liver reporter zebrafish between 2-5 dpf and 5-7 dpf. Acetaminophen (most-DILI) treatment caused a significant dose-dependent reduction in liver size only at the early stage. Isoniazid (most-DILI) administration after liver maturation induced hepatomegaly, while it induced liver size reduction between 2-5 dpf. Chlorambucil (less-DILI) treatment induced opposing effects on liver size, in the two stages tested. A non-DILI agent chloramphenicol did not induce any liver size change in either larval stage. Clinical observations were better reproduced when isoniazid and chlorambucil were administered after liver maturation. Our findings show that often-overlooked liver maturity status is a critical parameter for the evaluation of DILI.

Rethinking Drug-Induced Liver Injury—A New Era of Pharmacovigilance

Rethinking Drug-Induced Liver Injury—A New Era of Pharmacovigilance

Idiosyncratic Drug-Induced Liver Injury and Amoxicillin-Clavulanate: Spotlight on Gut Microbiota, Fecal Metabolome and Bile Acid Profile in Patients.

Several hepatic disorders are influenced by gut microbiota, but its role in idiosyncratic drug-induced liver injury (iDILI), whose main causative agent is amoxicillin-clavulanate, remains unknown. This pioneering study aims to unravel particular patterns of gut microbiota composition and associated metabolites in iDILI and iDILI patients by amoxicillin-clavulanate (iDILI-AC). Thus, serum and fecal samples from 46 patients were divided into three study groups: healthy controls (n = 10), non-iDILI acute hepatitis (n = 12) and iDILI patients (n = 24). To evaluate the amoxicillin-clavulanate effect, iDILI patients were separated into two subgroups: iDILI non-caused by amoxicillin-clavulanate (iDILI-nonAC) (n = 18) and iDILI-AC patients (n = 6). Gut microbiota composition and fecal metabolome plus serum and fecal bile acid (BA) analyses were performed, along with correlation analyses. iDILI patients presented a particular microbiome profile associated with reduced fecal secondary BAs and fecal metabolites linked to lower inflammation, such as dodecanedioic acid and pyridoxamine. Moreover, certain taxa like Barnesiella, Clostridia UCG-014 and Eubacterium spp. correlated with significant metabolites and BAs. Additionally, comparisons between iDILI-nonAC and iDILI-AC groups unraveled unique features associated with iDILI when caused by amoxicillin-clavulanate. In conclusion, specific gut microbiota profiles in iDILI and iDILI-AC patients were associated with particular metabolic and BA status, which could affect disease onset and progression.