Drug-induced liver injury (DILI) remains a leading cause of acute liver failure worldwide. Drugs such as isoniazid, alone or in combination with other anti-tuberculosis drugs, as well as a growing number of herbal and complementary medicines, have been implicated in most cases of acute liver failure in registry studies.

This review summarizes current knowdledge on the acute and chronic outcomes in patients with idiosyncratic DILI and discusses several of the existing prognostic models.

The reasons why some individuals progress from DILI to end-stage liver disease are still largely unknown. However, collaborative efforts over the past few decades have provided figures on the relative incidence of drug-induced acute liver failure and allowed the development of prognostic models to predict this worse outcome at the onset of the event. The outcome of chronic DILI is less well characterised due to the lack of sufficient follow-up in cohort studies, but several phenotypes of DILI can progress to chronicity, and specific drugs such as nitrofurantoin or amiodarone are classic examples of agents leading to chronic forms of DILI. Therapy for drug-induced acute liver failure and chronic DILI is mainly supportive, although some randomised clinical trials have shown beneficial effects of N-acetylcysteine and corticosteroids.

Drug induced liver injury (DILI) is a serious and potentially life-threatening condition resulting from an adverse drug reaction. Both the clinical manifestations and pathological mechanisms of DILI vary depending on drug characteristics, dose, duration of exposure as well as host specific factors. Disease onset can occur within days or months after the introduction of a drug. This has challenged identification of disease specific biomarkers and resulted in delayed and even erroneous diagnosis of patients. Apart from discontinuation of current pharmacotherapy, options for DILI patients are scarce and the condition can sometimes continue or worsen after drugs are discontinued or result in irreversible liver damage such as cirrhosis. This illustrates the need to uncover relevant pathological pathways that will pave the road for targeted interventions. In an effort to accommodate these needs, novel insights from preclinical and cellular disease modeling have allowed coupling of specific drugs to potential mechanisms of toxicity. This review outlines three signaling pathways of DILI: organelle stress, cholestasis, and immune responses, discusses their interplay with oxidative stress, and provides examples of drugs specifically targeting one or more steps in these pathways. A systematic approach identifying specific mechanisms of DILI could allow for the assembly of large databases, in turn enabling advanced computational modelling to provide accurate predictions of the DILI potential of both known drugs and future drug candidates.

Macrophages play a critical role in the progression of acute liver failure (ALF), a life-threatening clinical syndrome characterized by the rapid onset of liver injury. Recent research suggests that mechanosensation signaling may be pivotal in modulating acute inflammation. However, its involvement in ALF pathogenesis remains poorly understood. In this study, we found that Piezo1 was highly expressed in liver macrophages during liver injury in both humans and mice. Mice with macrophage-specific Piezo1 depletion were resistant to CpG-ODN/D-GalN-induced ALF, whereas mice pretreated with Yoda1 showed increased susceptibility. Furthermore, Piezo1-deficient macrophages exhibited reduced secretion of inflammatory cytokines upon CpG-ODN stimulation in vitro, while Yoda1 treatment enhanced cytokine secretion. Mechanistically, Piezo1 activation promotes the phosphorylation of CaMKII, which further enhances CpG-ODN-induced NF-κB activation. Additionally, Piezo1 activation promotes the endosomal translocation of TLR9 through the cytoskeleton remodeling. These findings suggest that Piezo1-mediated mechanosensation contributes to the development of CpG-ODN/D-GalN-induced ALF and may serve as a potential therapeutic target.

Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.

Drug-induced liver injury (DILI) is a major global health concern resulting from adverse reactions to medications, supplements or herbal medicines. The relevance of DILI has grown with an aging population, the rising prevalence of chronic diseases and the increased use of biologics, including checkpoint inhibitors. This article aims to summarise current knowledge on DILI epidemiology and risk factors.

This review critically appraises available evidence on DILI frequency, outcomes and risk determinants, focusing on drug properties and non-genetic host factors that may influence susceptibility.

DILI incidence varies across populations, with hospitalised patients experiencing notably higher rates than outpatients or the general population. Increased medication use, particularly among older adults and women, may partly explain age- and sex-based disparities in DILI incidence and reporting. Physiological changes associated with aging likely increase susceptibility to DILI in older adults, though further exposure-based studies are needed for definitive conclusions. Current evidence does not strongly support that women are inherently more susceptible to DILI than men; rather, susceptibility appears to depend on specific drugs. However, once DILI occurs, older age and female sex are associated with greater severity and poorer outcomes. Other less-studied host-related risk factors are also discussed based on available evidence.

This article summarises existing data on DILI frequency, outcomes, drug properties affecting hepatotoxicity and non-genetic host risk factors while identifying critical knowledge gaps. Addressing these gaps through future research could enhance understanding and support preventive measures.

We report the case of a patient with trigeminal neuralgia who developed cholestatic liver injury with systemic inflammation and polyserositis after starting oxcarbazepine therapy. No other causes could be identified. After discontinuation of the drug, there was a complete remission. This case shows that the more modern oxcarbazepine can also cause idiosyncratic liver damage and underlines the importance of high vigilance concerning drug reactions in clinical practice.

In this editorial, we comment on the article by Zhao et al which highlighted how patients having nonalcoholic fatty liver disease (NAFLD) were more susceptible to drug-induced lung injury (DILI). This article looked at the downstream effects of metabolic profiles and biochemical processes after medication and substance use. Although previous studies looked at how NAFLD and DILI were related, there is a lack of information on the consequences of everyday medication and substance use. NAFLD is one of the most common chronic liver diseases worldwide and it has been found to be closely related to metabolic syndrome and cardiovascular disease. The aim of this editorial is to analyze the interaction between NAFLD and DILI, what clinical manifestations can occur and what the prognosis of these patients will be.

Liver histology is the classic method for staging the severity of liver fibrosis, which in turn is an important predictor of clinical outcome. Here, we have hypothesized that the susceptibility to develop fibrosis varies among racial groups.

We examined the histology of all patients over 18 years of age who underwent liver biopsy at the Medical University of South Carolina from 1/1/2013 to 7/1/2021. Patients with malignancy, liver metastases, or missing data were excluded. Fibrosis was quantified using the Batts-Ludwig system (F0 = no fibrosis to F4 = histological cirrhosis). Racial groups were propensity matched based on age, gender, diabetes, alcohol consumption, and CDC/ATSDR Social Vulnerability Index Themes to mitigate the risk of selection bias.

We identified 1101 patients with liver biopsy histological fibrosis scores. The cohort included 23% Black patients. After propensity matching, Black patients were significantly more likely to have Hepatitis C (73/228 (32%) vs 45/228 (20%), p < 0.001) and autoimmune hepatitis (34/228 (15%) vs 6/228 (3%), p < 0.001) than White patients, while White patients were significantly more likely to have metabolic dysfunction associated steatotic liver disease (71/228 (31%) vs 18/228 (8%), p < 0.001). White patients were significantly more likely to have cirrhosis than Black patients (White - 89/228 (39%) vs Black - 68/228 (30%), p < 0.05).

White patients had a greater overall burden of advanced fibrosis (F4/cirrhosis) than Black patients, independent of etiology. The data suggest that fibrosis risk and/or progression may be worse in White than Black patients.

Drug-induced liver injury (DILI) presents unique challenges in clinical practice. While some types of DILI are mild and resolve quickly after removing the drug, other situations are more complex, with competing aetiologies or underlying liver disease. Guidelines from professional societies agree that the liver biopsy retains a role in understanding and managing DILI in certain situations. Liver biopsy allows characterization of the histological pattern of injury as well as assessment of severity. Inflammatory infiltrates, bile duct injury or loss and vascular injury are all revealed by liver biopsy. Communication between the hepatopathologist and clinical team with clinicopathological correlation of the findings is necessary for the best determination of causality and differentiation from other diseases of exclusion, like autoimmune hepatitis and graft-versus-host disease. This review highlights important aspects of the role of liver biopsy in DILI evaluation.

Hepatotoxicity is a known risk of oral and intravenous methotrexate (MTX), but whether intrathecal (IT) administration causes hepatotoxicity remains unknown. We aimed to explore whether IT-MTX causes acute hepatoxicity.

Retrospective single-centre analysis of all patients treated with IT-MTX from 2000 to 2020. We compared liver enzymes (LE) at baseline (within 7 days before IT-MTX) to post-MTX (within 7 days after IT-MTX). LE elevation was defined as ≥ 50% increase in LE from baseline and greater than upper limit of normal. Drug-induced liver injury (DILI) was defined based on established criteria.

A total of 270 patients (184 adults and 86 paediatric) received IT-MTX and had available LE data. Aminotransferase elevation was seen post-MTX in 107 (40%) patients, of whom 96 (36%) had ALT and 68 (25%) had AST elevation. DILI occurred in 16 (6%) patients. Aminotransferases peaked a median of 4 (3-5) days post-MTX, returning near baseline by day 7. Paediatric patients had higher incidence of aminotransferase elevations and DILI than adults (ALT 51% vs. 28%; AST 41% vs. 18%; DILI 11% vs. 3%; p < 0.01 for all). No significant predictors of LE elevation or DILI were identified, and no patient developed liver failure. The severity of ALT elevation after the first IT-MTX dose did not predict severity of a subsequent dose.

Acute transient aminotransferase elevation is common after IT-MTX, especially in paediatric patients. Only a fraction of patients developed DILI, which was self-limited with no sensitisation or liver failure.

The diagnosis of idiosyncratic drug-induced liver injury (DILI) is a challenging task due to the lack of specific features or definitive diagnostic tools. A minimum of clinical and pharmacological information is required, together with laboratory and imaging tests to exclude other causes of liver injury. Several standardized methods have been developed to support clinical judgement and establish causality assessment, the most widely used being the Roussel Uclaf Causality Assessment Method-RUCAM-and structured Expert Opinion. More recently, an evidence-based, revised RUCAM, Electronic Causality Assessment Method-RECAM-has been developed and, although still a work in progress, may replace RUCAM scoring in the future. International collaborative networks and ongoing research efforts are key to advancing biomarker qualification and validation and developing new in vitro patient-based methods that will help improve DILI diagnosis and move towards a personalized medicine approach.

Drug-induced liver injury (DILI) is a common clinical problem with urgent respect to demanding early diagnosis. Exosomal miRNAs are reliable and noninvasive biomarkers for the early diagnosis of DILI. However, accurate and feasible detection of exosomal miRNAs is often hampered by the low abundance of miRNAs, inefficient exosome separation techniques, and the requirement for RNA extraction from large sample volumes. Here, the multifunctional magnetic vesicles are constructed by loading a multiple signal amplification detection system and magnetic nanoparticles into virus-mimicking engineered vesicles to achieve in situ analysis of hepatogenic exosomal miRNAs, which do not require miRNA extraction or target amplification. Virus-mimicking engineered vesicles carrying large surface proteins of hepatitis B virus are designed to achieve the specific identity and fusion of hepatogenic exosomes, and the multiple signal amplification detection system assembled by catalytic hairpin assembly technology and CRISPR/Cas13a technology can achieve highly sensitive in situ detection of miRNAs in exosomes with a low limit of detection (LOD) of 1.25 × 102 particles·µL-1. This novel nanoplatforms open a promising avenue for the early clinical diagnosis of DILI.

Herbal and dietary supplements (HDS) are being used worldwide at an increasing rate. Mirroring this trend, HDS-induced liver injury, also known as HDS-induced liver injury (HILI), has increased significantly over the past three decades in the Drug-Induced Liver Injury Network (DILIN), now accounting for 20% of cases of drug-induced liver injury (DILI). There are significant challenges in the identification and prevention of HILI due to varying presentations, ability to make clear diagnosis, identification of the responsible ingredient, lack of treatment, and lack of regulatory oversight of HDS products to confirm their ingredients and ensure safety. The major implicated agents include anabolic steroids, green tea extract, garcinia cambogia, kratom, ashwagandha, turmeric and multi-ingredient nutritional supplements. Fortunately, with the formation of major DILI consortiums across the world, the last decade has seen advances in the identification of at-risk genetic phenotypes, the use of chemical analysis on multi-ingredient nutritional supplements, and the publication of data/injury patterns of potentially risky HDS.

Drug-induced liver injury (DILI) is a growing clinical problem. Antibiotics remain the most common cause of DILI in Europe. Their clinical spectrum is very broad, from asymptomatic to acute liver failure. Currently, DILI is categorized as hepatocellular (R ≥ 5), cholestatic (R ≤ 2) or mixed (R = 2-5) injury based on the serum alanine aminotransferase (ALT)/alkaline phosphatase (ALP) ratio. DILI is a diagnosis of exclusion and requires a wide differential diagnosis. The most important step in management is discontinuation of the drug suspected of causing liver damage. The list of specific antidotes that eliminate the effects of hepatotoxins is unfortunately very short. In symptomatic treatment, glucocorticosteroids and ursodeoxycholic acid have been used in selected cases. Liver transplantation is an optional treatment in patients with acute liver failure.

Drug-induced liver injury (DILI) is a harmful reaction to medications, herbs, and dietary supplements that results in liver dysfunction. Based on the distinct clinical patterns of liver damage, DILI can be categorized into hepatocellular, cholestatic, and mixed types. Hepatocellular DILI is linked to inflammation, apoptosis, and necrosis, while cholestatic DILI is commonly associated with bile plugs and, in rare cases, ductopenia. Ursodeoxycholic acid (UDCA) is the therapeutic agent most widely used for the treatment of cholestatic hepatopathies of diverse etiologies and has been mainly used as a supportive treatment in cholestatic DILI. In this review, we presented a more structured and systematic framework for the potential application of this hepatoprotective agent across a broader range of DILI scenarios. A MEDLINE search of the literature from 1995 to the present retrieved 41 preliminary clinical studies suggesting that UDCA may offer curative and preventive benefits for hepatocellular DILI as well. This aligns with preclinical studies in rodents, showing beneficial effects of UDCA in experimental DILI irrespective of the clinical patterns of injury involved. This could be due to the broad range of potentially beneficial effects of UDCA, which may address the various types of liver damage with different causes and mechanisms seen in all forms of DILI. UDCA's beneficial properties include anticholestatic, antioxidant, anti-inflammatory, anti-apoptotic, anti-necrotic, mitochondrial protective, endoplasmic reticulum stress-relieving, and immunomodulatory effects. Controlled studies with systematic use of standardized causality assessments are eagerly awaited to properly validate the use of UDCA in DILI. Meanwhile, we hope this article helps clarify and systematize the use of this versatile and safe hepatoprotective medication for different types of liver toxicity.

Acute liver injury (ALI) is associated with high mortality rates. Despite its severity, there are currently no effective interventions, underscoring the urgent need for research on the mechanisms driving ALI progression. Irisin, a hormone derived from its precursor FNDC5, has been shown to play a critical role in some chronic liver diseases. In this study we investigated the role of hepatic FNDC5/Irisin in a mouse model of AILI induced by acetaminophen (APAP, 400 mg/kg, i.p.). The mice were euthanized at 6, 12 and 24 h after APAP injection, then the blood and liver tissues were collected for analyses. By conducting transcriptome sequencing, we identified that both the expression and release of FNDC5/Irisin were significantly increased and highly correlated with AILI. We showed that knockout of Irisin significantly improved APAP-induced tissue damage and hepatocyte death in mouse liver. Conversely, preinjection of recombinant Irisin protein (1 mg·kg-1·d-1, i.p., for 3 days) exacerbated the AILI in FNDC5 knockout mice. RNA-seq analysis revealed that knockout of FNDC5/Irisin reduced inflammatory responses and JNK/NF-κB activation in APAP-treated mouse liver, while exogenous Irisin administration aggravated JNK/NF-κB-mediated inflammation. In primary mouse hepatocytes treated with APAP (15 mM), application of Irisin (100 ng/mL) activated the integrin αV/JNK/NF-κB axis, driving inflammation and oxidative stress. In summary, this study highlights Irisin as a critical regulator in AILI progression. Circulating Irisin could be a novel biomarker for AILI diagnosis, and targeting FNDC5/Irisin could hold promise for the development of novel treatments for AILI.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

Glial cell polarization plays a pivotal role in various neurological disorders. In response to distinct stimuli, glial cells undergo polarization to either mitigate neurotoxicity or facilitate neural repair following injury, underscoring the importance of glial phenotypic polarization in modulating central nervous system function. This review presents an overview of glial cell polarization, focusing on astrocytes and microglia. It explores the involvement of glial polarization in neurological diseases such as Alzheimer's disease, Parkinson's disease, stroke, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis and meningoencephalitis. Specifically, it emphasizes the role of glial cell polarization in disease pathogenesis through mechanisms including neuroinflammation, neurodegeneration, calcium signaling dysregulation, synaptic dysfunction and immune response. Additionally, it summarizes various therapeutic strategies including pharmacological treatments, dietary supplements and cell-based therapies, aimed at modulating glial cell polarization to ameliorate brain dysfunction. Future research focused on the spatio-temporal manipulation of glial polarization holds promise for advancing precision diagnosis and treatment of neurological diseases.

Pain, poor quality of life (QOL) and gastrointestinal (GI) symptoms are commonly experienced by individuals with endometriosis. Although diet and nutrition supplements are frequently used to manage endometriosis-related symptoms, there is limited understanding of the breadth and quality of research in this field. Our aim was to undertake a scoping review of diet and nutrition supplement intervention studies in people with endometriosis, diagnosed by ultrasound or surgery.

MEDLINE Complete, Embase, CINAHL and PsycINFO databases were searched for articles published in English from database inception to November 2024. Quality was assessed by two reviewers independently using the Joanna Briggs Institute appraisal tools. In total, 5130 publications were screened and 13 were included.

Among these, five evaluated the effect of diet intervention, one evaluated the effect of a combined diet-supplement intervention and seven evaluated the effect of a nutrition supplement in endometriosis. Overall, there were seven randomised controlled trials (RCTs) (n = 1 diet intervention, n = 6 nutrition supplement), two nonrandomised controlled studies (n = 1 diet intervention, n = 1 combined diet-supplement) and four uncontrolled studies (n = 3 diet intervention, n = 1 nutrition supplement). On the basis of evidence from the RCTs, the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet improved QOL and GI symptoms, whereas garlic supplements and combination trace element supplements may be beneficial for improving reduced pain symptoms related to endometriosis. The quality of most included studies was poor. Adherence to the interventions was only measured in five studies and only one diet study measured baseline diet.

High-quality RCTs of diet and nutrition supplement interventions are needed to progress the understanding of whether they should be integrated into the clinical management of endometriosis.

Immunotherapy has changed the treatment landscape for patients with cancer in the past decade. Immune checkpoint inhibitor (ICI)-based therapies have proven effective in a range of malignancies, including liver and gastrointestinal cancers, but they can cause diverse off-target organ toxicities. With the increasingly wider application of these drugs, immune-mediated liver injury from ICIs has become a commonly encountered challenge in clinical hepatology and gastroenterology. In this Review, we discuss the evidence from human and animal studies on the immunological mechanisms of immune-mediated liver injury from ICIs and summarize its clinical features and practical considerations for its management.

Over the past decade, immune checkpoint inhibitors (ICIs) have transformed the treatment of cancer, though they come with the risk of immune-related adverse (irAEs) events such as hepatotoxicity or Immune-mediated Liver Injury from Checkpoint Inhibitors (ILICI). ILICI is a serious irAE that, when severe, requires cessation of ICI and initiation of immunosuppression. Cytotoxic T Lymphocytes (CTLs) play a central role in ILICI; however, they are just part of the picture as immunotherapy broadly impacts all aspects of the immune microenvironment and can directly and indirectly activate innate and adaptive immune cells. Clinically, as our understanding of this entity grows, we encounter new challenges. The presentation of ILICI is heterogeneous with respect to latency, pattern of injury (hepatitis vs. cholangitis) and severity. This review focuses on our knowledge regarding risk factors, presentation and treatment of ILICI including ILICI refractory to steroids. An emerging topic, the possibility of rechallenge while accepting some risk, in patients who experience ILICI but require immunotherapy, is also discussed. This review provides an update on the current knowns and unknowns in ILICI and highlights several knowledge gaps where studies are needed.

Azacitidine and venetoclax are important anti-neoplastic agents used in the treatment of acute myeloid leukemia. Azacitidine has been implicated to cause nonhepatic ischemic injury. Here we report a case of severe, short latency drug-induced liver injury following the infusion of azacitidine and venetoclax in a patient which was subsequently mitigated through pretreatment with a vasodilatory agent.

Turmeric is a common spice used in traditional Chinese and Ayurvedic medicine for a variety of purported health benefits. Recent concerns have arisen regarding turmeric-induced liver injury linked to formulations with enhanced bioavailability, often including piperine found in black pepper.

We explore a case of a 40-year-old female with increasing fatigue, pruritus, and dark urine following consumption of turmeric and black pepper "wellness shots" leading to a significant drug-induced liver injury.

This case underscores the critical need to recognise herbal remedies, such as turmeric, as potential sources of hepatotoxicity. Despite a reputation of safety, limited regulation and testing of turmeric may mean potential adverse effects are under-recognised. Understanding the mechanisms behind turmeric and black pepper's hepatotoxicity, including the role of potential genetic predispositions, requires further investigation for its safe use.

While immune checkpoint inhibitors (ICIs) are revolutionising cancer therapy, checkpoint inhibitor-induced liver injury is a significant immune-related side effect of this immunotherapy. This study focuses on the severity classifications and characteristics of patients with checkpoint inhibitor-induced hepatitis.

A retrospective analysis of patients with severe Checkpoint Inhibitor-induced hepatitis grade 3 and 4 according to the recommended Common Terminology Criteria for Adverse Events (CTCAE) classification was conducted. Data on clinicobiological characteristics, treatment and outcomes were collected from 3 university hospitals, and causality was assessed by using the updated Roussel Uclaf Causality Assessment Method. The severity of hepatitis was assessed using the Model for End-stage Liver Disease score, the Drug-Induced Liver Injury Network, and the Drug-Induced Liver Injury International Expert Working Group classifications.

We retrospectively included 100 patients presenting various hepatitis patterns with a median time to onset of 20 days after checkpoint inhibitors. Severity grading varied significantly among the classifications used. A lower incidence of severe cases was observed when using the Drug-Induced Liver Injury classifications instead of the recommended CCTCAE classification, and this was correlated with outcomes.

This retrospective study challenges the efficacy of the CTCAE classification in defining the severity of Checkpoint Inhibitor-induced hepatitis and suggests that the traditional hepatology-focused scores may be more relevant. The CTCAE classification is inconsistent and gives equal weight to jaundice and elevated transaminases, which leads to steroid overtreatment and limits the rechallenge of ICIs.

Globally, nearly half of deaths from cirrhosis and chronic liver diseases (CLD) and three-quarters of deaths from hepatocellular carcinoma (HCC) occur in the Asia-Pacific region. Chronic hepatitis B is responsible for the vast majority of liver-related deaths in the region. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common form of CLD, affecting an estimated 30% of the adult population. Compared with people of European descent, people from the Asia-Pacific region carry more genetic variants associated with MASLD and its progression. Alcohol is a fast-growing cause of CLD and HCC in Asia as a result of the rising per-capita consumption of alcohol. Drug-induced liver injury is under-recognized and probably has a high prevalence in this region. The epidemiological and outcome data of acute-on-chronic liver failure are heterogeneous, and non-unified definitions across regions contribute to this heterogeneity. CLDs are severely underdiagnosed, and effective treatments and vaccinations are underutilized. In this Review, we highlight trends in the burden of CLD and HCC in the Asia-Pacific region and discuss the rapidly changing aetiologies of liver disease. We examine the multiple gaps in the care cascade and propose mitigating strategies and future directions.

Aim: Valproic acid (VPA) is a classic broad-spectrum antiepileptic drug, with significant pharmacokinetic variability. Genetic polymorphisms contribute to this variability, influencing both VPA trough serum concentration (VPA concentration) and VPA-induced liver injury. Our study aims to investigate the association between polymorphisms of uridine diphosphate glucuronyl transferase (UGT) 1A6, UGT2B7 and VPA concentration and screen for potential genetic loci affecting VPA-induced liver injury.Methods: This study included epilepsy patients treated with VPA. PCR-RFLP method was used to determine the genotypes of UGT1A6 and UGT2B7. Chemiluminescent microparticle immunoassay was used to measure VPA concentration. Multiple linear regression and logistic regression were employed to analyze factors influencing VPA concentration and VPA-induced liver injury, respectively.Results: The correlation between UGT polymorphism and VPA concentration was analyzed in 133 samples. For VPA-induced liver injury, 105 patients were analyzed, with 29 in the liver injury group and 76 in the control group. Our finding showed patients with the UGT1A6-T19G variant had significantly lower VPA concentrations compared with wild-type patients and UGT1A6-T19G, A541G, A552C and UGT2B7-C802T, G211T, A268G polymorphisms showed no impact on VPA-induced liver injury.Conclusion: This study demonstrated UGT1A6-T19G polymorphisms affected the VPA concentration, providing a theoretical basis for the individualized clinical use of VPA.

Drug-induced liver injury (DILI) is a major concern for oncology drugs in clinical practice and under development. Monitoring cancer patients for hepatotoxicity is challenging as these patients may have abnormal liver tests pre-treatment or on-study for many reasons including liver injury due to past oncology treatments, hepatic metastases, medical co-morbidities such as heart failure, and concomitant medications. At present, there are no regulatory guidelines or position papers that systematically address best practices pertaining to DILI detection, assessment and management in oncology patients.

The goals of this review are (1) to examine and interpret the available evidence and (2) to make recommendations for detection, monitoring, adjudication, and management of suspected hepatocellular DILI during oncology clinical trials.

This manuscript was developed by the IQ Consortium (International Consortium for Innovation and Quality in pharmaceutical development) DILI Initiative that consists of members from 17 pharmaceutical companies, in collaboration with academic and regulatory DILI experts. The manuscript is based on extensive literature review, expert interpretation of the literature, and several rounds of consensus discussions.

This review highlights recommendations for patient eligibility for clinical trials with or without primary/metastatic liver involvement, as well as changes in liver tests that should trigger increased monitoring and/or discontinuation of study drug. Guidance regarding causality assessment for suspected DILI events, rechallenge and dose-modification is provided.

This review brings together evidence-based recommendations and expert opinion to provide the first dedicated consensus for best practices in detection, assessment, and management of DILI in oncology clinical trials.

The Revised Electronic Causality Assessment Method (RECAM) is an updated, electronic version of the Roussel Uclaf Causality Assessment Method (RUCAM) to diagnose drug-induced liver injury (DILI). The primary aim of this study was to compare RECAM vs RUCAM in patients with suspected DILI.

Patient encounters from October 1, 2015, to September 30, 2019, were searched for suspected DILI using ICD-10 K71 codes for toxic liver disease. DILI Network (DILIN) expert opinion scores were assigned to each case (1/2/3 = probable DILI, 4/5 = non-DILI). RECAM and RUCAM scores were compared with DILIN expert opinion scores.

Among 766,930 encounters searched, 120 unique patients met inclusion criteria with 72 (60%) adjudicated as probable-DILI. The most frequent suspect drugs were antimicrobials (38.3%), antineoplastics (8.3%), and antirheumatic drugs (8.3%). The mean age was 49.2 + 15.6 years, and 50% were female with 45.8% having hepatocellular injury. RUCAM had better agreement with DILIN expert opinion for probable-DILI vs RECAM (66.7% vs 44.4%, P = 0.018). Both had 100% agreement with DILIN expert opinion for non-DILI. Frequently missing laboratory data included hepatitis C virus (HCV) RNA (64.3%) and antihepatitis E virus (HEV) immunoglobulin M (IgM) testing (70%), leading to loss of up to 6 points in RECAM scoring but not affecting RUCAM scores. A modified RECAM that made HCV RNA and anti-HEV IgM optional had better agreement with DILIN expert opinion compared with RUCAM (79.2% vs 66.7%, P = 0.09).

Among 120 suspected DILI cases, RUCAM had better agreement with DILIN expert opinion scores vs RECAM. Making HCV RNA and anti-HEV IgM testing optional significantly improved agreement between RECAM and DILIN expert opinion. Future modifications to RECAM are needed to improve causality assessment in North American patients with suspected DILI.

Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first-line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so-called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug-induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up-to-date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug-induced, autoimmune-like hepatitis (DI-AIH).

Drug-induced liver injury (DILI) is caused by various medications or herbals/nutritional supplements resulting in liver test abnormalities or hepatic dysfunction. DILI can be categorized as direct (intrinsic), idiosyncratic, or immune-mediated (indirect), and patterns of injury can be categorized as hepatocellular, cholestatic, or mixed injury. DILI is diagnosed after excluding other causes of liver injury. Cessation of the suspected drug along with supportive care is recommended for most DILI cases. In life-threatening situations, liver transplantation (LT) can be considered; however, the risks with LT and lifelong immunosuppression should be considered. In this paper, we summarize the pathophysiology, diagnosis, medical management, and LT for DILI.

In this case series, we discuss 10 cases of norethindrone-induced transaminitis and conduct a literature review of this rare adverse event. A retrospective chart review was conducted on 10 patients (median age: 33 years) with diverse endometriosis phenotypes who received norethindrone and subsequently developed transaminitis, which is defined as elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels. This condition was diagnosed in both asymptomatic and symptomatic patients, either during the work-up of acute symptoms or incidentally through routine lab tests. Our objective was to assess and characterize a case series of transaminitis associated with norethindrone use in endometriosis patients, detailing clinical presentations, management strategies, and outcomes. All cases exhibited normalization of liver function tests after discontinuation, occurring within one to 12 months with varying intervals of liver function testing. Patients receiving higher dosages (10 mg daily) demonstrated quicker resolution (average: four months). The reported adverse effects included nausea, vomiting, headache, rash, polyarthralgia, and abnormal uterine bleeding. Vigilant management, including prompt discontinuation, consistently resulted in the resolution of transaminitis. This study underscores the importance of continuous monitoring of liver function, even in asymptomatic patients on norethindrone therapy. Further investigations are imperative to identify specific groups susceptible to this adverse event.

Traditional, complementary, and integrative medicine (TCIM) modalities are widely employed. However, TCIM, specifically herbal and non-herbal dietary supplements, can pose challenges in the context of organ transplantation. In this review, we discuss common supplements used for psychiatric purposes and highlight important considerations for candidates and recipients of liver transplants.

Ashwagandha, kava kava, green tea extract, skullcap, turmeric, and valerian have known idiosyncratic hepatotoxic potential and may complicate the liver transplantation course. Multiple supplements reportedly carry a lower risk of hepatotoxicity, though evidence for widespread use in those at risk for or with hepatic impairment is limited. Psychiatrists caring for candidates and recipients of liver transplants must recognize that patients may find supplements helpful in alleviating psychiatric symptoms, despite an overall limited evidence base. Evaluating benefit versus risk ratios and reviewing drug-drug interactions is essential to promote transplant candidacy and mitigate the possibility of native or graft liver dysfunction.

Hepatitis C virus (HCV) reactivation has been reported to be caused due to several anticancer drugs and immunosuppressive agents; however, HCV reactivation after steroid monotherapy has rarely been reported. Here, we report the case of a 65-year-old Japanese man with HCV infection who developed HCV reactivation after the administration of prednisolone (PSL) for 6 days for sudden deafness. In the patient history, the positivity for anti-HCV antibody was observed, but serum level of HCV RNA was not measured. Two months after PSL administration, the patient experienced an alanine aminotransferase (ALT) flare and the serum level of HCV RNA was observed to be 6.2 log IU/mL; then, the patient was admitted to our hospital for hepatitis treatment. Based on the clinical course and laboratory findings, the patient was diagnosed with HCV reactivation. Although the ALT levels decreased spontaneously during follow-up, they did not drop to normal range; subsequently, sofosbuvir and ledipasvir treatments were started. A sustained virological response 24 weeks after the end of treatment was achieved. This case study suggests that HCV reactivation with hepatitis flare can occur even after a steroid monotherapy, and doctors should pay attention to HCV reactivation when administering PSL for patients with HCV infection.

The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR.

A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety.

Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed.

Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).

The diagnosis of drug-induced liver injury (DILI) is challenging. We modified the revised electronic version of the Roussel Uclaf Causality Assessment Method (RUCAM) for the diagnosis of DILI (RECAM), the scoring system developed in US and Spanish cohorts in 2022, and developed RECAM-J 2023 to align with the clinical practice in Japan. In the current study, we introduce RECAM-J 2023 and verify its performance in the context of Japanese patients with DILI.

After translation of RECAM into Japanese, modifications were made to develop RECAM-J 2023 without any alteration to the scores. To examine the validity and performance of RECAM-J 2023, clinical information on DILI and non-DILI cases in Japan were retrospectively collected. The diagnosis of DILI was made by expert's decision. Then we scored each case using RECAM-J 2023, and calculated area under curve (AUC) values for identification for DILI.

We collected data from 538 DILI and 128 non-DILI cases. The sum of highly probable (HP) and probable (PR) cases categorized by RECAM-J 2023 were only 206 (38%) in DILI cases. As the primary cause of low scores was the deduction with missing hepatitis virus markers, which is unlikely to be an issue in prospective applications, we rescored without these deductions. At this time, the sum of HP and PR was raised to 421 (78%). The AUCs of RECAM-J 2023 without deductions were 0.70 and 0.88 for identifying at least HP, and at least PR, respectively.

RECAM-J 2023, when prospectively used without any missing hepatitis virus markers, provides acceptable performance for identifying at least PR DILI cases in Japanese daily clinical practice.

Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests.

To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools.

Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves.

We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1).

Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.

Antidepressants are widely used to manage depression and other psychiatric diseases. A previous study revealed that hepatotoxicity was the main adverse event related to antidepressants. Therefore, drug-induced liver injury (DILI) caused by antidepressants deserves more attention.

To investigate DILI adverse events reported due to antidepressant use in the United States Food and Drug Administration Adverse Events Reporting System (FAERS) database.

A disproportionality analysis of spontaneously reported adverse events was conducted to assess the association between antidepressant drugs and DILI.

FAERS data from 1 January 2004 to 31 December 2021 were compiled and analyzed using the reporting odds ratio (ROR) and information component (IC).

As per the FAERS database, of the 324,588 cases that were administered antidepressants, 10,355 were identified as cases with DILI. Among the identified 42 antidepressants, nefazodone (n = 47, ROR = 7.79, IC = 2.91), fluvoxamine (n = 29, ROR = 4.69, IC = 2.20), and clomipramine (n = 24, ROR = 3.97, IC = 1.96) had the highest ROR for cholestatic injury; mianserin (n = 3, ROR = 21.46, IC = 3.99), nefazodone (n = 264, ROR = 18.67, IC = 3.84), and maprotiline (n = 15, ROR = 5.65, IC = 2.39) for hepatocellular injury; and nefazodone (n = 187, ROR = 12.71, IC = 0.48), clomipramine (n = 35, ROR = 2.07, IC = 0.26), and mirtazapine (n = 483, ROR = 1.96, IC = 0.94) for severe drug-related hepatic disorders. Only nefazodone elicited hepatic failure signals (n = 48, ROR = 18.64, IC = 4.16). There are limited reports on the adverse reactions of relatively new antidepressant drugs, such as milnacipran, viloxazine, esketamine, and tianeptine, and those not approved by the Food and Drugs Administration, such as reboxetine and agomelatine.

A significant association was observed between DILI and nefazodone. Duloxetine and clomipramine were associated with three DILI categories, except hepatic failure. The disproportionality analysis cannot conclude on a definite causal link between antidepressants and DILI. Additional research is required to assess new-generation antidepressants for their propensity to cause DILI.

Complementary and alternative medicines (CAM) include conventional medical treatments. Patients worldwide use CAM at alarming rates; thus, reports of CAM-related DILI have been on the rise. The clinical presentations include asymptomatic liver test abnormalities, acute hepatitis with or without jaundice, acute cholestatic liver disease (bland or with hepatitis), acute liver failure, severe hepatitis with features of portal hypertension, and acute decompensation of known or unknown cirrhosis that can lead to acute-on-chronic liver failure. Acute hepatitis with or without necrosis, hepatocellular and canalicular cholestasis, herb-induced or CAM-triggered autoimmune hepatitis, granulomatous hepatitis, severe steatohepatitis, and vanishing bile duct syndrome are common liver biopsy findings in CAM-DILI. The presence of preexisting liver disease predicts severe liver injury, risk of progression to liver failure, and decreased transplant-free survival in patients with CAM-DILI. This review discusses global epidemiology and trends in CAM-DILI, clinical presentation, assessment and outcomes, commonly emerging threats in the context of hepatotoxic herbs, pragmatic assessment of "liver beneficial" herbs and health care myths, patient communication, regulatory framework, and future directions on research in CAM.

The Revised Electronic Causality Assessment Method (RECAM), a computerized update of the Roussel Uclaf Causality Assessment Methodology (RUCAM), was recently proposed. In this study, we validated and compared the utility of the RECAM and RUCAM in Chinese patients with a single conventional or herbal agent-induced liver injury.

In this retrospective multicenter cohort of well-established DILI and non-DILI patients from 5 centers in China, the diagnostic performance of the RUCAM and RECAM was compared by AUC analysis. The consistency was evaluated by weighted kappa. The major causes of discrepancy were explored.

A total of 481 DILI and 100 non-DILI patients were included. In total, 62.6% of the DILI cases were induced by conventional agents, and 37.4% were induced by herbs. The RECAM had relatively higher AUC than RUCAM for overall [0.947 (0.926-0.964) vs. 0.867 (0.836-0.893), p=0.0016], conventional agents [0.923 (0.890-0.949) vs. 0.819 (0.775-0.858), p=0.0185], and herbs [0.972 (0.941-0.989) vs.0.911 (0.866-0.944), p=0.0199]. Latency, scores associated with hepatitis B, and hepatotoxicity information of the insulting drugs were the 3 main causes for the inconsistency between RECAM and RUCAM scores.