Roles of X-box binding protein 1 in liver pathogenesis.

The prevalence of drug-induced liver injury (DILI) and viral liver infections presents significant challenges in modern healthcare and contributes to considerable morbidity and mortality worldwide. Concurrently, metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a major public health concern, reflecting the increasing rates of obesity and leading to more severe complications such as fibrosis and hepatocellular carcinoma. X-box binding protein 1 (XBP1) is a distinct transcription factor with a basic-region leucine zipper structure, whose activity is regulated by alternative splicing in response to disruptions in endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR) activation. XBP1 interacts with a key signaling component of the highly conserved UPR and is critical in determining cell fate when responding to ER stress in liver diseases. This review aims to elucidate the emerging roles and molecular mechanisms of XBP1 in liver pathogenesis, focusing on its involvement in DILI, viral liver infections, MAFLD, fibrosis/cirrhosis, and liver cancer. Understanding the multifaceted functions of XBP1 in these liver diseases offers insights into potential therapeutic strategies to restore ER homeostasis and mitigate liver damage.

Acute Liver Failure Induced by Provitalize: A Menopause Supplement Concocted From Herbs & Probiotics.

Drug-induced liver injury is one of the most common causes of acute liver failure in the Western world. Despite discontinuation of the offending agent, it can still tax a grim prognosis. We describe a case of a menopausal woman taking a herbal supplement called "Provitalize" to relieve hot flashes and bloating. This is the first case report of liver injury from this supplement. She initially presented with mild jaundice and elevated transaminases. Unfortunately, she rapidly progressed to encephalopathy, experienced multiorgan failure, and then died.

Sertraline-Induced Hypoglycemia in Drug-Induced Liver Injury.

Sertraline, a selective serotonin reuptake inhibitor, is a medication recommended as a third line treatment of cholestatic liver injury pruritis. We report a case of a young male who developed liver injury secondary to self-administration of anabolic steroids and who complained of persistent pruritis leading to a treatment by sertraline. Two days later, the patient was admitted to the hospital with a severe hypoglycemia, while the liver function tests were in amelioration. Clinical and biological evaluation were in favor of sertraline-induced hypoglycemia, a side effect rarely reported in non-diabetic patients, and in the context of hepatic injury.

Propensity score matching-based analysis of the effect of corticosteroids in treating severe drug-induced liver injury.

BACKGROUND AND AIM: There is no conventional treatment for patients with severe drug-induced liver injury (DILI) except for discontinuation of liver injury drugs and symptomatic supportive therapy. Opinions on whether corticosteroids can be used to treat severe DILI are conflicting, and most of the relevant clinical studies are case reports or retrospective studies, which still need to be supported by high-level evidence-based medical studies. This study aimed to evaluate the effect and tolerance of corticosteroids in patients with severe DILI. Risk factors associated with patient failure to cure were also explored. METHODS: Propensity score matching based on nearest-neighbor 1:1 matching was used to screen severe DILI patients in the corticosteroids and control groups. Severe DILI was defined as elevated serum ALT and/or ALP with TBIL≥5 ULN (5 mg/dL or 85.5 µmol/L) with or without INR ≥1.5. Patients were treated with conventional therapy combined with corticosteroids in the corticosteroids group and only conventional therapy in the control group. RESULTS: A total of 146 patients, 73 each in the corticosteroids and control groups, were included in this study. By analyzing the entire cohort, we found no significant difference in cure rates between patients in the corticosteroid group and control group (34.2% vs. 20.5%, p=0.095), and there was no significant difference in the incidence of adverse effects between the two groups (20.5% vs. 20.5%, p=1.000). However, TBIL decreased more in the corticosteroids group on day 7 (89.2 ± 107.6 µmol/L vs. 58.8 ± 70.7 µmol/L, p=0.046). In subgroup analyses, patients whose TBIL remained elevated despite conventional treatment had a higher TBIL decline on day 7,14 after use of corticosteroid (99.2 ± 98.5µmol/L vs. -23.3 ± 50.4µmol/L, p<0.001; 120 ± 119.1µmol/L vs. 61.2 ± 98.5µmol/L, p=0.047). The cure rate of patients in the corticosteroid group was significantly higher than that of the control group (36.1% versus 4.5%, p=0.016). The proportion of patients with TBIL <85.5 µmol/L was also significantly higher in the corticosteroid group than in the control group at day 7 (p=0.016) and day 14 (p=0.004) after treatment. In the subgroup analysis of patients with different clinical phenotypes, the causative agent was herbal, autoimmune antibody-positive and 40% < PTA ≤ 50% of patients, corticosteroid use did not increase the cure rate of the patients. Univariate and multifactorial analyses found corticosteroid use to be a protective factor for failure to cure in patients with severe DILI (p<0.001, OR:0.191,95% CI:0.072-0.470), and peak TBIL to be a risk factor (p=0.003, OR:1.016,95% CI:1.007-1.028). CONCLUSIONS: The addition of corticosteroids could not increase the cure rate in patients with severe DILI, but it could rapidly reduce the patient's TBIL at an earlier stage. Corticosteroids could also promote curing in patients with elevated TBIL after conventional treatment. Corticosteroid use was a protective factor for failure to cure in patients with severe DILI and peak TBIL was a risk factor.

Triptolide-induced acute liver injury and its mechanism with estradiol in regulating macrophage-mediated inflammation and hepatocyte function.

Triptolide (TP), a diterpene from Tripterygium wilfordii, exhibits potent anti-inflammatory, immunomodulatory, and antitumor properties but is limited by severe hepatotoxicity. This study investigates sex differences in TP-induced liver injury and the protective role of estradiol (E2) in modulating macrophage-mediated inflammation and hepatocyte function. An acute liver injury model was established in male and female Balb/c mice using intraperitoneal TP injection. Liver function tests, histological analyses, and immunohistochemical staining were performed. THP-1 macrophage and various liver cell lines were used to study the effects of TP and E2 in vitro. Virtual screening, molecular docking, luciferase assays, and qPCR were employed to identify potential targets and elucidate underlying mechanisms. TP caused more severe liver injury in female mice, evidenced by increased liver indices, aspartate aminotransferase (AST) levels, and extensive hepatocyte damage. TP promoted M1 macrophage polarization, enhancing inflammation, particularly in female mice. E2 mitigated TP-induced inflammatory responses by downregulating pro-inflammatory cytokines and macrophage activation markers. Molecular docking and functional assays identified Nuclear receptor subfamily 1 group I member 2 (NR1I2) as a key target mediating the protective effects of E2. The study highlights significant sex differences in TP-induced hepatotoxicity, with females being more susceptible. E2 exerts protective effects against TP-induced liver injury by modulating immune responses, presenting a potential therapeutic approach to mitigate drug-induced liver injury (DILI). Further research on NR1I2 could lead to targeted therapies for reducing drug-induced liver damage.

Assessing hepatotoxicity in novel and standard short regimens for rifampicin-resistant tuberculosis: Insights from the TB-TRUST and TB-TRUST-plus trials.

OBJECTIVES: Efforts to shorten rifampicin-resistant tuberculosis (RR-TB) treatment have led to concerns about hepatotoxicity in shorter regimens. We evaluated hepatotoxicity in two novel regimens against the standard shorter regimen recommended by the World Health Organization (WHO). METHODS: Participants from the TB-TRUST and TB-TRUST plus trials were assigned to the WHO shorter regimen, a levofloxacin (Lfx)-based regimen, or a bedaquiline (Bdq)-based regimen. Liver function was tested bi-weekly in the first month, then monthly until treatment ended. Eligibility required receiving at least one drug dose and undergoing at least two liver function tests. RESULTS: Of 429 patients, hepatotoxicity was most prevalent in the WHO shorter group (26.7% of 169), compared to 4.7% in the Lfx group (172 patients), and 5.7% in the Bdq group (88 patients). The median peak alanine aminotransferase levels were 1.67 × upper limit of normal (ULN) for WHO, 0.82 × ULN for Lfx, and 0.88 × ULN for Bdq groups. The incidence of drug-induced liver injury was significantly higher in the WHO group (18.3%) than in the Lfx (3.5%) and Bdq (4.6%) groups. The time to significant alanine aminotransferase elevation was about 2.8 months, with no differences between groups. CONCLUSIONS: Two novel regimens demonstrated lower hepatotoxicity compared to the WHO's shorter regimen. Entire course management monitoring is recommended in RR-TB treatment.

Inhibitory effects of flavonoids on organic cation transporter 1: Implications for food/herb-drug interactions and hepatoprotective effects.

Organic cation transporter 1 (OCT1, gene symbol: SLC22A1) is mainly responsible for the hepatic uptake of various cationic drugs, closely associated with drug-induced liver injury (DILI). Screening and identifying potent OCT1 inhibitors with little toxicity in natural products is of great value in alleviating OCT1-mediated liver injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions (FDIs). Our objective was to investigate potential inhibitors of OCT1 from 96 flavonoids, evaluate the hepatoprotective effects on retrorsine-induced liver injury, and clarify the structure-activity relationships of flavonoids with OCT1. Thirteen flavonoids exhibited significant inhibition (>50%) on OCT1 in OCT1-HEK293 cells. Among them, the five strongest flavonoid inhibitors (IC50 < 10 µM), including α-naphthoflavone, apigenin, 6-hydroxyflavone, luteolin, and isosilybin markedly decreased oxaliplatin-induced cytotoxicity. In retrorsine-induced liver injury models, they also reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to different levels, the best of which was 6-hydroxyflavone. The pharmacophore model clarified that hydrogen bond acceptors at the 4,8,5' position might play a vital role in the inhibitory effect of flavonoids on OCT1. Taken together, our findings would pave the way to predicting the potential risks of flavonoid-related FDIs in humans and optimizing flavonoid structure to alleviate OCT1-mediated liver injury.

Newer formulations of oral testosterone undecanoate: development and liver side effects.

INTRODUCTION: Testosterone deficiency is a clinical disorder due to either failure of the testes to produce testosterone or failure of the hypothalamus or pituitary to produce sufficient gonadotropins. Previous formulations of oral testosterone therapy, particularly methyltestosterone, have been associated with adverse liver effects. Many different routes of testosterone delivery have been developed, each with their own administrative benefits and challenges. Newer formulations of oral testosterone undecanoate (TU) provide a convenient administration option, although their use has been limited by hepatotoxicity concerns based on older methyltestosterone data, and prescribing physicians may still be concerned about adverse liver effects. OBJECTIVES: In this review, we discuss the history of oral testosterone development, clarify the mechanism of action of oral TU, and describe the relevant liver safety findings. METHODS: Relevant literature was allocated to present a review on the history of oral TU development and the mechanism of action of oral TU. We pooled data from individual studies of oral TU products to present a safety summary. RESULTS: Overall, safety results from studies of the newer formulations of oral TU showed that increased liver function test values are not generally associated with oral TU formulations and that no clinically significant liver toxicities were noted in clinical trials of oral TU. CONCLUSION: Continued research into the safety of oral TU will contribute to a better understanding of the potential risks in patients receiving this therapy, an outcome that highlights the importance of providing patient education and reassurance regarding oral TU safety.

Paeoniflorin protects hepatocytes from APAP-induced damage through launching autophagy via the MAPK/mTOR signaling pathway.

BACKGROUND: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies. PURPOSE: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms. METHODS: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques. RESULTS: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury. CONCLUSIONS: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin.

Certolizumab-Induced Liver Injury in Ankylosing Spondylitis: A Case Report and Causality Assessment.

Certolizumab-induced liver injury is exceptionally rare, with only a few cases reported in the literature. We present the case of a 34-year-old man with axial ankylosing spondylitis (AS) who developed a drug-induced liver injury following treatment with certolizumab. Despite the initial ineffectiveness of non-steroidal anti-inflammatory drugs and an inadequate response to infliximab, the patient achieved remission of AS symptoms with certolizumab. However, he subsequently developed elevated liver enzymes indicative of hepatocellular injury. Investigations excluded viral hepatitis and autoimmune liver diseases, pointing to certolizumab as the likely cause. The updated Roussel Uclaf Causality Assessment Method confirmed a probable causal relationship between certolizumab and hepatotoxicity. Discontinuation of certolizumab led to normalization of liver enzymes without recurrence of liver injury. This case highlights the need for vigilant monitoring for hepatotoxicity in patients receiving tumor necrosis factor inhibitors.

Inhibition of 15-prostaglandin dehydrogenase attenuates acetaminophen-induced liver injury via suppression of apoptosis in liver endothelial cells.

Hepatic microvascular disruption caused by injury to liver sinusoidal endothelial cells (LSECs) is an aggravating factor for drug-induced liver injury (DILI). It is suggested that prostaglandin E2 (PGE2) may be able to attenuate LSEC injury. However, it is also known that 15-keto PGE2, a metabolite of PGE2 produced by 15-prostaglandin dehydrogenase (15-PGDH) that is not a ligand of PGE2 receptors, suppresses inflammatory acute liver injury as a ligand of peroxisome proliferator-activated receptor γ. In this study, we aimed to understand whether 15-PGDH activity is essential for preventing DILI by suppressing hepatic microvascular disruption in a mouse model of acetaminophen (APAP)-induced liver injury. To inhibit 15-PGDH activity prior to APAP-induced LSEC injury, we administered the 15-PGDH inhibitor, SW033291, 1 h before and 3 h after APAP treatment. We observed that LSEC injury preceded hepatocellular injury in APAP administered mice. Hepatic endogenous PGE2 levels did not increase up till the initiation of LSEC injury but rather increased after hepatocellular injury. Moreover, hepatic 15-PGDH activity was downregulated in APAP-induced liver injury. The inhibition of 15-PGDH attenuated LSEC injury and subsequently hepatic injury by inhibiting apoptosis in APAP administered mice. Our in vitro studies also suggested that PGE2 inhibited APAP-induced apoptosis via the EP4/PI3K pathway in endothelial cells. Therefore, a decrease in 15-PGDH activity would be beneficial for preventing APAP-induced liver injury by attenuating LSEC injury.

Drug-induced liver injury related to gene therapy: A new challenge to be managed.

Gene therapy is being successfully developed for the treatment of several genetic disorders. Various methods of gene transfer have been developed to enable the production of the deficient enzyme or protein. One of the most important is adeno-associated virus vectors, which have been shown to be viable for use in in vivo gene therapy. Several gene therapies have already been approved. They are also promising for acquired diseases. Important examples include gene therapy for haemophilia A and B, X-linked myotubular myopathy, spinal muscular atrophy and several liver diseases such as Criggler-Najjar disease, alpha-1 antitrypsin deficiency and Fabry disease. However, the introduction of a foreign compound into hepatocytes leads to hepatic reactions with heterogeneous phenotypic expression and a wide spectrum of severity, ranging from mild transaminase elevation to acute liver failure. Several mechanisms appear to be involved in liver injury, including an immune response, but also direct toxicity depending on the method of gene transfer. As a result, the incidence, expression and severity of liver injury vary from indication to indication and from patient to patient. Patients treated for haemophilia A are more prone to transaminase elevation than those treated for haemophilia B. Corticosteroids are successfully used to correct liver reactions but also to prevent degradation of the transferred gene and loss of therapeutic activity. The aim of this review is to describe the risk of liver injury according to the indication for gene therapy and the short- and long-term management currently proposed to prevent or correct liver reactions in clinical practice.

Novel reduced heteropolyacid nanoparticles for effective treatment of drug-induced liver injury by manipulating reactive oxygen and nitrogen species and inflammatory signals.

With the rapid advancements in biomedicine, the use of clinical drugs has surged sharply. However, potential hepatotoxicity limits drug exploitation and widespread usage, posing serious threats to patient health. Hepatotoxic drugs disrupt liver enzyme levels and cause refractory pathological damage, creating a challenge in the application of diverse first-line drugs. The activation and deterioration of reactive oxygen and nitrogen species (RONS) and inflammatory signals are key pathological mechanisms of drug-induced liver injury (DILI). Herein, a novel reduced heteropolyacid nanoparticle (RNP) has been developed, possessing high RONS-scavenging ability, strong anti-inflammatory activity, and excellent biosafety. These features enable it to swiftly restore the redox and immune balance of the liver. Intravenous administration of RNP effectively scavenged RONS storm, reversing liver oxidative stress and restoring normal mitochondrial membrane potential and function. Furthermore, by inhibiting c-Jun-N-terminal kinase phosphorylation, RNP facilitated the restoration of nuclear factor erythroid 2-related factor 2-mediated endogenous antioxidant signaling, ultimately rescuing the liver function and tissue morphology in acetaminophen-induced DILI mice. Crucially, the high biocompatible RNP exhibited superior efficacy in the DILI mouse model compared to the clinical antioxidant N-acetylcysteine. This targeted therapeutic approach, tailored to address the onset and progression of DILI, offers valuable new insights into controlling the condition and restoring liver structure and function.

A hemicyanine-modified upconversion nanoprobe for NIR-excited evaluating superoxide signaling in drug-induced liver injury.

BACKGROUND: Drug-induced liver injury (DILI) is the most important standard for the entrance of clinical drugs into the pharmaceutical market. The elevation of superoxide anion (O2•-) during drug metabolism can mediate apoptosis of hepatocytes and further generation of liver damage. Therefore, developing an effective imaging method for evaluating O2•- levels during DILI is of great importance. However, current reported O2•- fluorescent probes either use short excitation wavelengths or a single intensity detection system, limiting the accurate quantification of O2•- in deep tissue in vivo. RESULTS: We developed a NIR-excited ratiometric nanoprobe (CyD-UCNPs) by assembly of O2•--sensitive hemicyanine dyes (CyD) on the surface of Tm/Er-codoped upconversion nanoparticles (UCNPs) with the assistance of α-cyclodextrin, which exhibited a robust "turn-on" ratiometric sensing signal. In vitro experiments indicated that CyD-UCNPs respond well to O2•- with high selectivity. Furthermore, by taking advantage of the outstanding optical properties produced by the luminescent resonance energy transfer between the UCNPs and CyD upon the excitation of 980 nm, the ratiometric upconversion luminescence signal of CyD-UCNPs was successfully utilized to monitor the fluctuation of O2•- levels under phorbol-12-myristate-13-acetate (PMA)/cisplatin-induced oxidative stress in living cells, liver tissues, and zebrafish. More importantly, endogenous change in O2•- levels in the liver sites of mice during DILI and its prevention with L-carnitine was visualized using CyD-UCNPs. SIGNIFICANCE: This study provides a ratiometric NIR-excited imaging strategy for investigating the correlation between O2•- levels and DILI and its prevention, which is significant for early diagnosis of DILI and preclinical screening of anti-hepatotoxic drugs in vivo.

Shenqi Pill alleviates acetaminophen-induced liver injury: a comprehensive strategy of network pharmacology and spectrum-effect relationship reveals mechanisms and active components.

BACKGROUND: Acetaminophen (APAP), commonly used for its antipyretic and analgesic properties, can cause severe liver injury or even acute liver failure when overdosed. However, the options for treating APAP-induced liver toxicity are limited. Shenqi Pill (SQP), a traditional Chinese herbal formula, has shown effectiveness in treating various liver ailments. SQP consists of cinnamon, aconite, rehmannia, cornus, peony bark, Chinese yam, poria, and alisma in a ratio of 1:1:8:4:3:4:3:3. However, the mechanisms and active components of SQP that counteract drug-induced liver injury (DILI) are not well understood. PURPOSE: This study aimed to explore the protective effects of SQP against APAP-induced liver injury in both laboratory and animal settings. It seeks to identify the active components and potential mechanisms by which SQP targets mitochondria to alleviate liver damage. METHODS: A mouse model with APAP-induced liver injury was established to assess SQP's therapeutic impact. This study then analyzed the components of SQP using UPLC-Q-TOF-MS in both in vivo and in vitro environments. Network pharmacology and the GEO database helped predict potential pathways and targets. Potential active components were identified through spectrum-effect relationship analysis and validated their efficacy using Seahorse assays and molecular docking. RESULTS: Treatment with SQP significantly reduced liver dysfunction, tissue damage, lipid metabolic disruptions, and inflammation caused by APAP in mice. In cellular tests, SQP-treated serum notably enhanced mitochondrial function, maintained membrane potential, decreased ROS levels, and prevented mitochondrial permeability transition pore opening. Biochemically, SQP reversed the suppression of p-AMPK, p-ACC, CPT1, and ACADM expression caused by APAP overdose. This study identified 97 in vitro and 24 in vivo components of SQP, with eight showing significant mitochondrial benefits. Molecular docking studies suggest that fuziline and paeoniflorin could activate AMPK. CONCLUSION: SQP effectively mitigates APAP-induced liver injury by enhancing mitochondrial function via the AMPK-ACC-CPT1-ACADM pathway. Moreover, this study introduces a novel strategy for analyzing the relationship between the chemical and pharmacological properties of drug-containing serum, successfully identifying compounds with mitochondrial activity. Fuziline and paeoniflorin, in particular, emerge as promising mitochondrial protectants and warrant further investigation. This research underpins the development of innovative treatments for DILI using SQP and its components.

Association of Gene Polymorphisms and Serum Levels of ALAS1 with the Risk of Anti-Tuberculosis Drug-Induced Liver Injury.

The accumulation of protoporphyrin IX in the liver caused by isoniazid and rifampicin through the disorder of heme biosynthesis was considered an important mechanism of anti-tuberculosis drug-induced liver injury (ATLI). Alanine synthase 1 (ALAS1) is a rate-limiting enzyme in the process of heme synthesis. This study aimed to investigate the association between ALAS1 gene polymorphism, serum ALAS1 level, and the risk of ATLI. This study was a case-control study including 58 ATLI cases and 192 controls. Four single nucleotide polymorphisms (SNPs) of the ALAS1 gene were selected for genotyping and serum ALAS1 concentrations were detected using ELISA kits. There was no significant difference in the genotype distribution of four SNPs between the ATLI cases and the controls under different genetic models. Patients carrying the GG genotype of SNP rs352163 in controls had higher baseline ALAS1 levels than those in ATLI cases (243.6 vs 290.2 ng/L, P = .034), and patients with baseline ALAS1 < 337.85 ng/L had a higher risk of ATLI than those with ALAS1 ≥ 337.85 ng/L (HR = 2.679, 95% CI: 1.360-5.278, P = .004). Our findings indicated that the serum ALAS1 concentrations in the ATLI cases were lower than those in the controls, and the lower baseline ALAS1 levels can be associated with higher ATLI risk.

Pirfenidone-induced liver injury, a case report of a rare idiosyncratic reaction.

Nearly all medications carry the risk of drug-induced liver injury (DILI). Idiosyncratic reactions are rare and poorly predictable, and the mechanisms are not always well understood. Pirfenidone is an oral antifibrotic drug used to treat idiopathic pulmonary fibrosis. While elevation of liver enzymes is a common adverse reaction during therapy, it rarely leads to discontinuation or reduction of the drug. Although isolated cases of liver damage or liver failure have been reported, they are infrequent. This report presents the case of a 70-year-old woman with known idiopathic pulmonary fibrosis, depression, hypothyroidism, and hypercholesterolemia who presented at our emergency department with jaundice, anorexia, and asthenia. The patient's medication regimen included lamotrigine, simvastatin, levothyroxine, and pirfenidone, which had been introduced 6 months prior. Laboratory testing revealed elevated liver enzyme levels consistent with acute hepatocellular hepatitis. Following a medical workup, which included anamnesis, laboratory testing, iconographic investigations, and liver biopsy, we concluded that the patient had suffered from pirfenidone-induced liver injury. Pirfenidone was withdrawn, and liver tests gradually improved. The purpose of this clinical case report is to highlight this rare adverse reaction and to make clinicians aware of its assessment and management. In 2018, only one other case of severe liver failure leading to the death of the patient was reported. Early detection of potential DILI during the workup is crucial to discontinue the suspected medication promptly. Any drug-induced hepatitis must be reported for registration.

A case report of toxic hepatitis induced by drug (pirfenidone) in a patient with idiopathic pulmonary fibrosis • Drug-induced liver injury (DILI) is a type of hepatitis caused by medication, drugs, or even herbal and dietary supplements. • There are two types of DILI reactions: intrinsic and idiosyncratic. ○ The intrinsic reaction, such as acute hepatotoxicity due to acetaminophen overdose, is easily predictable and well-known. ○ The idiosyncratic reaction is more complex, unpredictable, and not well-understood. Therefore, diagnosing an idiosyncratic reaction can be challenging. • Pirfenidone is an immunosuppressive drug used to treat idiopathic pulmonary fibrosis by inhibiting collagen formation through anti-fibrotic and anti-inflammatory mechanisms. • Several adverse reactions of pirfenidone are well described, including temporary elevation of liver enzymes during treatment. This adverse reaction is mostly asymptomatic and resolves spontaneously with or without dose adjustment. • However, few cases of severe DILI due to pirfenidone have been reported, which may lead to liver dysfunction. • This paper reports on a rare idiosyncratic reaction related to pirfenidone that resulted in hepatic adverse reactions.

Selective Androgen Receptor Modulators Leading to Liver Injury: A Case Report.

Selective androgen receptor modulators (SARMs) have gained popularity for their alleged ability to selectively target androgen receptors, potentially offering muscle-building benefits with fewer side effects than traditional steroids. However, the safety profile of SARMs, including RAD-140, is not fully understood. This case report presents a 29-year-old male who developed liver injury after taking RAD-140. The patient experienced jaundice and elevated liver enzymes after three months of RAD-140 use. A liver ultrasound revealed hepatic steatosis and a hyperechoic lesion. Symptoms resolved after discontinuing RAD-140. Similar cases of liver injury associated with RAD-140 have been reported, highlighting the potential hepatotoxicity of this SARM. Discontinuation of RAD-140 appears to reverse liver injury, but the long-term effects and risks of SARM use remain unclear. This case highlights the need for caution and monitoring when considering SARMs for performance enhancement.

Naproxen-induced liver injury in a case of adult-onset Still's disease.

We present the case of a young female with fever, rash, and joint pain without any other history of connective tissue disorder, who was found on evaluation to have neutrophilic leucocytosis, elevated inflammatory markers and lymphadenopathy with hepatosplenomegaly. After extensive workup, the possibility of adult onset Still's disease was suggested by Yamaguchi criteria. She was started on naproxen, but later on developed drug-induced liver injury. She already had central serous retinopathy due to steroid use, and it was difficult to treat the adult-onset Stills disease due to the liver injury in view of contraindication to use of anti-inflammatory drugs but her illness was monocyclic and did not require further immunosuppression.

Uncovering the mechanism of troglitazone-mediated idiosyncratic drug-induced liver injury with individual-centric models.

Idiosyncratic drug-induced liver injury is a rare and unpredictable event. Deciphering its initiating-mechanism is a hard task as its occurrence is individual dependent. Thus, studies that utilize models that are not individual-centric might drive to a general mechanistic conclusion that is not necessarily true. Here, we use the individual-centric spheroid model to analyze the initiating-mechanism of troglitazone-mediated iDILI risk. Individual-centric spheroid models were generated using a proprietary cell educating technology. These educated spheroids contain hepatocytes, hepatic stellate cells, activated monocyte-derived macrophages, and dendritic cells under physiological conditions. We show that phases 1 and 2 drug-metabolizing enzymes were induced in an individual-dependent manner. However, we did not observe any association of DEMs induction and troglitazone (TGZ)-mediated iDILI risk. We analyzed TGZ-mediated iDILI and found that a 44-year-old male showed iDILI risk that is associated with TGZ-mediated suppression of IL-12 expression by autologous macrophages and dendritic cells. We performed a rescue experiment and showed that treatment of spheroids from this 44-year-old male with TGZ and recombinant IL-12 suppressed iDILI risk. We confirmed the mechanism in another 31-year-old female with iDILI risk. We demonstrate here that individual-centric spheroid are versatile models that allow to predict iDILI risk and to analyze a direct effect of the drug on activated macrophages and dendritic cells to uncover the initiating-mechanism of iDILI occurrence. This model opens perspectives for a personalized strategy to mitigate iDILI risk.