Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a common adverse reaction associated with tuberculosis (TB) treatment, significantly impacting treatment adherence and therapeutic outcomes. However, large-scale studies on hospitalized patients in China remain limited.

To characterize the clinical features and liver injury patterns in hospitalized TB patients with ATB-DILI and to identify risk factors associated with severe ATB-DILI.

We retrospectively reviewed 28,753 hospitalized TB patients at Beijing Chest Hospital from 2014 to 2023. ATB-DILI was diagnosed in 567 patients (2.0%) based on serum biochemical criteria and causality assessment. Demographic, clinical, and laboratory data were analyzed to characterize liver injury types and identify risk factors for severe cases. Subgroup analyses based on liver injury patterns were performed to further evaluate the association between age and severe ATB-DILI.

Overall, 567 cases with ATB-DILI (2.0%) were analyzed. Hepatocellular injury was the most common type (71.4%), followed by cholestatic (13.8%) and mixed (14.8%) injury patterns. Most patients (68.4%) were asymptomatic and diagnosed via routine biochemical monitoring; jaundice occurred in 18.2%. Patients with hepatocellular damage were significantly younger, while those with cholestatic injury were older (p < 0.001). Severe ATB-DILI occurred in 46 patients (8.1%), with advanced age (≥60 years) identified as an independent risk factor (OR = 2.45, 95% CI: 1.33-4.52, p = 0.004). Subgroup analysis showed that this association between age and severe ATB-DILI was significant in the hepatocellular injury type (unadjusted OR = 3.59, 95% CI: 1.61-8.02, p = 0.002), while no statistically significant association was observed in cholestatic or mixed types, which may reflect limited statistical power in these subgroups.

Routine liver function monitoring and age-specific risk assessment are essential for early identification and management of ATB-DILI in hospitalized TB patients.

Rechallenge with study drug after suspected drug-induced liver injury (DILI) during drug development requires a comprehensive assessment of risks and benefits. Lack of universal consensus or societal guidelines makes this decision-making process more challenging and difficult to manage in clinical development. The sparse published literature is biased towards reporting cases of positive rechallenge (recurrent DILI), often with adverse outcomes. The heterogeneity of available data and inconsistent approaches to drug rechallenge likely lead to bias in our perception of the risks of rechallenge, ultimately leaving this topic controversial. The IQ DILI Causality Assessment Working Group, in collaboration with academic and regulatory experts, developed this manuscript with the following objectives: (1) understand and describe current practices via literature review and survey of practices and opinions among drug developers, academic experts, and regulators; (2) propose a consistent and structured approach to decision-making and managing the rechallenge process; (3) facilitate better understanding of the risks and benefits of rechallenge via a standardized approach to collecting rechallenge data, including outcomes and the importance of publishing rechallenge data; and (4) the role of obtaining a liver biopsy, guidance on when a biopsy might be considered, and what histologic findings can assist in making the rechallenge decision. Lastly, knowledge gaps in the drug rechallenge paradigm are highlighted alongside the proposal to standardize the collection and publication of rechallenge data to help address these gaps. This consensus expert opinion does not encourage rechallenge but provides guidance for drug developers to apply a consistent approach to rechallenge.

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.

 The attribution of drug-induced liver injury (DILI) to specific herbal and dietary supplements (HDS) is confounded by inaccurate labels and undisclosed ingredients. The US Drug-Induced Liver Injury Network (DILIN) determines the attribution of injury to an agent through its structured expert opinion causality assessment process, but without the use of chemical analysis data of HDS. We aimed to determine the impact of chemical analysis of HDS products on prior causality assessment scores.

Obtained samples of HDS consumed by DILIN-enrolled patients were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Chemical analysis data were compared to label accuracy and detect whether the product contained botanical and non-botanical compounds. A comparison of the causality scores reassessed with chemical analysis was compared with the original scores.

A total of 54 previously adjudicated cases with chemical analysis available were reassessed for causality with chemical analysis data; reviewers were blinded to original causality scores. Using the chemical analysis data, 37% (n = 20) of the 54 cases were scored with a higher likelihood of DILI compared with the original causality scores; 14 of the 20 (70%) moved from probable to highly likely; 52% had no change in causality score; and 11% of cases were scored as a lower likelihood of DILI.

 Our study demonstrates that there is value in using HDS chemical analysis data in the causality assessment process for DILI. In more than a third of cases, chemical analysis of products led to an increased confidence in DILI attribution to HDS. These findings suggest that chemical analysis is an important tool in causality assessment for HDS agents, specifically in challenging situations, and further studies are needed to confirm its applicability in clinical practice.

Short courses of intravenous (iv) methylprednisolone (MP) can cause drug induced liver injury (DILI). The aim of this study was to assess the clinical features and HLA associations of MP-related DILI enrolled in the US DILI Network (DILIN).

DILIN cases with MP as a suspected drug were reviewed. DILIN causality scoring was assigned on a 5-point scale (definite, highly likely, probable, possible, unlikely). All cases with MP causality scores of definite, highly likely or probable were analysed. HLA data from direct sequencing were analysed.

Eleven cases of definite, highly likely, or probable MP DILI were identified. The median age was 48 years; 73% were female; median latency to onset was 30 days; 55% were jaundiced; and all had hepatocellular injury with one patient requiring transplantation. Nine of the 11 cases were in patients with multiple sclerosis (MS). Liver biopsies in 7 cases revealed mild acute hepatitis with/without cholestasis. HLA data demonstrated that HLA-DRB1*15:01, the primary HLA class II allele associated with MS was over-represented. HLA-DQB1*06:02-HLA-DQA1*01:02 which is haplotypic with the HLA-DRB1*15 haplotype was more common in the MP DILI cases compared to other DILI controls (p = 0.03) and to DILI controls exposed to MP (p = 0.04).

MP DILI is characterised by hepatocellular injury, short latency and generally rapid recovery. There was no independent HLA haplotype associated with MP DILI.

The incidence of drug-induced liver injury (DILI) is not known for most prescription medications. We aimed to estimate the incidence of DILI for commonly prescribed outpatient drugs.

To establish a baseline estimate of DILI incidence, we used the estimated incidence (EI) of amoxicillin/clavulanate DILI from a previous population-based study in Iceland. This was combined with the multicenter prospective DILI Network (DILIN) cohort and the US population-based Medical Expenditure Panel Survey (MEPS). From 2005 to 2019, prescription drugs with at least five bona fide DILIN cases and data from at least 10 of the 15 years from MEPS during that timeframe were included. The EI for 'drug A' was calculated as follows: EI ( drug A ) = EI AC × # DILIN cases of drug A # annual new prescriptions of drug A × # annual new prescriptions of AC # DILIN cases of AC RESULTS: In total, 30 drugs met the inclusion criteria, of which 11 were antibiotics, 4 were antiepileptic drugs (AEDs), 4 were statins, and 11 were other drug types. The highest EI was seen with azathioprine and older AEDs, with one DILI case per 349-2329 new prescriptions. The EI of antibiotics ranged greatly, with the highest risk seen for minocycline, amoxicillin/clavulanate, and nitrofurantoin (approximately 1:1000-2400 new prescriptions), and lowest risk for clindamycin, doxycycline, azithromycin, and amoxicillin (approximately 1:40,000-170,000 new prescriptions). The EI for commonly prescribed statins was approximately 1:10,000-50,000. Important medication classes with > 5 million new prescriptions from 2005 to 2019 but fewer than five DILIN cases included β-blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, selective serotonin reuptake inhibitors, and metformin, which presumably have very low DILI incidence.

The highest EI was found for azathioprine, older antiepileptics, and minocycline. In contrast, many widely used drugs are rare causes of DILI. These findings may help clinicians better weigh potential benefits of medications against hepatotoxicity risk.

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.

Drug-induced liver injury (DILI) is a drug-induced disease that not only complicates the treatment of the primary disease but may also lead to acute liver failure or even death in severe cases. Drugs commonly used in primary care, such as anti-infective agents and nonsteroidal anti-inflammatory drugs, are major causes of DILI. In addition, a large elderly population, comorbidities, and combination therapy with multiple drugs increase the risk of DILI in primary care. Therefore, primary care providers should proactively screen and monitor high-risk patients to identify potential DILI timely. Currently, diagnosis of DILI relies on the exclusion of liver diseases of other etiologies. Collection of detailed medical history of the patients and careful exclusion of other potential liver injury of other etiologies are crucial for accurate diagnosis. This guideline, developed based on evidence-based medicine from the latest research, aimed to provide primary care providers with professional guidance on the timely identification of suspected DILI cases and standardized diagnosis and management in clinical practice.

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.

Marked elevation in aminotransferases (≥1000 IU/l) is typically associated with acute liver injury. Here, we hypothesized that the cause of elevation in aminotransferases ≥1000 in patients with cirrhosis is likely due to a limited number of disorders and may be associated with poor outcomes.

We aimed to investigate the most common etiologies of acute elevations in aminotransferases in patients with cirrhosis, and to examine their associated outcomes.

From May 2012 to December 2022, all hospitalized patients with cirrhosis and an aspartate aminotransferase or alanine aminotransferase ≥ 1000 IU/l were identified through Medical University of South Carolina's Clinical Data Warehouse. Complete clinical data were abstracted for each patient, and in-hospital mortality was examined.

The cohort was made up of 152 patients, who were 57 ± 12 years old, with 51 (34%) women. Underlying liver disease included mainly hepatitis C cirrhosis, alcohol-related cirrhosis, metabolic dysfunction-associated steatohepatitis cirrhosis, autoimmune cirrhosis, primary sclerosing cholangitis cirrhosis, and cryptogenic cirrhosis. The most common cause of marked elevation in aminotransferases in cirrhotic patients was ischemic hepatitis (71%), followed by chemoembolization (7%), autoimmune hepatitis (6%), drug-induced liver injury (3%), post-transjugular intrahepatic portosystemic shunt placement (3%), rhabdomyolysis (3%), and hepatitis C (2%). During hospitalization and over a 1-month follow-up period, the mortality rate in patients with ischemic hepatitis was 73% (79/108), while that for other causes of liver injury was 20% (9/44).

Ischemic hepatitis is the leading cause of marked elevation of aminotransferases in patients with cirrhosis, with distinctive clinical characteristics than other etiologies, and significantly poorer outcomes.

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.

Hyman Zimmerman observed that hepatocellular (HC) drug-induced liver injury (DILI) with jaundice had a mortality rate of ≥ 10% (Hy Law). Hy Law does not specify the timing of liver tests nor the definition of HC DILI versus cholestatic or mixed (C/M) DILI. We aimed to assess the validity of Hy Law in the prospective DILI Network (DILIN) cohort.

Drugs with ≥10 confirmed DILI cases with jaundice were analyzed. Four permutations of Hy Law were applied: R ≥ 5 using initial (1) or peak (2) alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels, and the Food and Drug Administration associated criteria of alanine aminotransferase or aspartate aminotransferase ≥ 3x upper limit of normal with alkaline phosphatase ≤ 2x upper limit of normal using initial (3) or peak values (4). Mortality was death or liver transplant adjudicated to be due to DILI.

Using initial R values, mortality was 11.1% for HC vs 2.0% for C/M ( P < 0.001); using peak R values, mortality was 10.3% vs 1.6% ( P < 0.001). Using Food and Drug Administration-associated definition, mortality was 7.9% vs 3.9% ( P = 0.04) using initial values and 7.9% vs 3.0% ( P = 0.01) using peak values. Using initial R values, drugs that frequently caused HC injury generally had mortality rates ≥ 10%, while drugs that typically caused C/M injury all had rates < 10%. Occasional agents that caused HC injury with jaundice were associated with low mortality.

Initial R values were the most reliable means of identifying Hy Law cases. There were some drugs that caused HC injury with jaundice but with mortality rates < 10%. Refinement of Hy Law is warranted.

We compared performance of the Roussel Uclaf Causality Assessment Method (RUCAM) with multidisciplinary expert panel review in identifying a drug-induced liver injury (DILI) due to antituberculosis therapy (ATT) and/or antiretroviral therapy (ART).

Cases were drawn from a prospective registry of hospitalised adults with suspected DILI due to ATT and/or ART in Cape Town, South Africa. Participants had to fulfil American Thoracic Society criteria for ATT interruption (alanine transaminase [ALT] ≥5 times upper limit of normal [ULN]/ALT ≥3 times [ULN] and symptomatic). Causality assessment by expert panel review served as reference standard. The panel ranked potentially implicated drugs as certain, probable, possible or unlikely causes guided by World Health Organization Uppsala Monitoring Centre criteria. The RUCAM was performed for each potentially implicated drug. We calculated sensitivity and specificity of the RUCAM in identifying a probable/certain drug cause for liver injury.

We included 48 participants. All were people with HIV (PWH). Twenty-seven were on concomitant ART and ATT, with a median of six potentially hepatotoxic drugs per case. Sensitivity and specificity of the RUCAM in identifying a probable/certain drug cause of liver injury compared with expert panel review was 7% and 100% respectively. Implicated drugs (times ranked probable/certain by panel) were isoniazid (18/0), pyrazinamide (17/0), rifampicin (15/1), efavirenz (6/4) and lopinavir/ritonavir (1/0).

PWH with liver injury received multiple potentially implicated drugs, which may increase liver injury risk and complicate causality assessment. Compared with expert panel review, the RUCAM had low sensitivity in detecting probable or certain drug causes of liver injury.

Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure.

To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports.

This series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023.

Outpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity.

Hospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports.

The study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports.

In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.

In April 2022, French Lentil and Leek Crumble (FLLC), a new frozen food preparation manufactured by Daily Harvest™ (containing Tara flour) was offered as a natural high-protein meal product. Soon thereafter, widespread anecdotal reports of acute gastrointestinal symptoms with liver injury were reported, leading to its voluntary withdrawal in June 2022, after shipment of 28,000 preparations.

To summarise the clinical and laboratory features of 17 patients with FLLC associated liver injury from the Drug Induced Liver Injury Network (DILIN).

Patients with FLLC-associated liver injury were enrolled into a prospective protocol and followed for 6 months. Cases were adjudicated by expert opinion causality assessment with summary statistics for data analysis.

Enrolled subjects had a mean age of 41 years, 82% were female with mean BMI of 24 kg/m2. All were Caucasian without underlying liver disease. In most cases, abdominal pain and nausea arose within hours of FLLC ingestion. Mean days from ingestion to identification of liver injury was 3.1 days (±2.8). On enrolment, 53% had jaundice, 47% nausea, 24% fever, 59% abdominal pain, 41% itching and 12% rash. The mean initial serum ALT was 475 U/L (±302), AST 315 U/L (±315), alkaline phosphatase 190 U/L (±76), with a total bilirubin of 2.6 mg/dL (±2). In this study, 63% presented with a hepatocellular pattern of liver injury, 6% cholestatic and 31% mixed as determined by the R value. In addition, 24% of patients were hospitalised, and there were no fatalities or liver transplants. Liver biopsy in one subject revealed acute hepatitis with mild ductular reaction, mild lymphocytic and eosinophilic portal inflammation, mild lobular inflammation, preserved bile ducts and absence of interface hepatitis, steatosis, granulomatous reaction or cholestasis. Phylogenetic analysis confirmed the presence of Tara spinosa, the source of Tara flour.

Natural food products are increasingly ubiquitous and may unexpectedly cause significant illness. All clinicians should inquire whether patients are consuming natural food products or herbal supplements and consider them as a potential cause of liver injury.

There are limited data on the causative agents and characteristics of drug-induced liver injury in pregnant individuals. Data from patients with drug-induced liver injury enrolled in the ongoing multicenter Drug-Induced Liver Injury Network between 2004 and 2022 and occurring during pregnancy or 6 months postpartum were reviewed and compared with cases of drug-induced liver injury in nonpregnant women of childbearing age. Among 325 individuals of childbearing age in the Drug-Induced Liver Injury Network, 16 cases of drug-induced liver injury (5%) occurred during pregnancy or postpartum. Compared with drug-induced liver injury in nonpregnant women, pregnancy-related drug-induced liver injury was more severe ( P <.05). One elective termination and three miscarriages were documented; there were no maternal deaths. We recommend that isoniazid for latent tuberculosis be deferred to the postpartum period whenever feasible and that β-blockers or calcium channel blockers rather than methyldopa be used for hypertension management during pregnancy.

Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, and antineoplastic drugs), and signal of DILI in clinical trials and its assessment.

Drug-induced liver injury (DILI) is a major problem in the United States, commonly leading to hospital admission. Diagnosing DILI is difficult as it is a diagnosis of exclusion requiring a temporal relationship between drug exposure and liver injury and a thorough work up for other causes. In addition, DILI has a very variable clinical and histologic presentation that can mimic many different etiologies of liver disease. Objective scoring systems can assess the probability that a drug caused the liver injury but liver biopsy findings are not part of the criteria used in these systems. This review will address some of the recent updates to the scoring systems and the role of liver biopsy in the diagnosis of DILI.

Drug-induced autoimmune-like hepatitis (DI-AILH) is poorly defined and more data are required to better characterise and manage this disease entity.

The aim of this study was to evaluate the clinical characteristics, histology and long-term outcomes of DI-AILH compared with idiopathic autoimmune hepatitis (AIH).

This retrospective cohort study reviewed 28 DI-AILH and 39 AIH patients in a single centre. The new (2022) and simplified (2008) AIH histology criteria were used to assess DI-AILH.

DI-AILH were more likely to present with jaundice (p = 0.004) and higher bilirubin levels (p = 0.04) than AIH. AIH patients had higher rate of immunosuppression (IS) use including second- and third-line agents, though the time to reach biochemical remission were comparable. AIH patients had more advanced fibrosis than DI-AILH (Ishak fibrosis score 3.5 vs. 1.9, p < 0.0001). DI-AILH more commonly had eosinophilic aggregates (18% vs. 3%, p = 0.031) and less commonly showed plasma cell aggregates (61% vs. 97%, p < 0.001) than AIH. The simplified AIH histology criteria identified 1 atypical histology within the DI-AILH cohort, although this patient required long-term IS. The new AIH histology criteria classified 23 (82%) as likely AIH and 5 (18%) as possible AIH. Two of the possible DI-AILH did not require IS and one patient had successful IS withdrawal. Four DI-AILH patients with fibrosis stage ≤3 had successful IS withdrawal compared with none in the AIH group. Four patients underwent liver transplantation (LT) in both cohorts with significantly shorter time to LT in DI-AILH as the indication was for (sub)acute liver failure. Two DI-AILH patients died within 60 days of LT.

The new AIH histology criteria may be better at identifying DI-AILH. Immunosuppression withdrawal in those without significant fibrosis may be considered. DI-AILH is at risk of (sub)acute liver failure and early discussions with a transplant centre would be desirable.

Liver disorders are important adverse effects associated with antifungal drug treatment. However, the accuracy of Clinical International Classification of Diseases (ICD)-10 codes in identifying liver disorders for register based research is not well-established. This study aimed to determine the positive predictive value (PPV) of the ICD-10 codes for identifying patients with toxic liver disease, hepatic failure, and jaundice among patients with systemic antifungal treatment.

Data from the Swedish Prescribed Drug Register and the National Patient Register were utilized to identify adult patients who received systemic azole antifungal drugs and had a recorded diagnosis of toxic liver disease (K71.0, K71.1, K71.2, K71.6, K71.8, K71.9), hepatic failure (K72.0, K72.9), or jaundice (R17) between 2005 and 2016. The medical records of all included patients were reviewed. Prespecified criteria were used to re-evaluate and confirm each diagnosis, serving as the gold standard to calculate PPVs with 95% confidence intervals (95% CI) for each diagnostic group.

Among the 115 included patients, 26 were diagnosed with toxic liver disease, 58 with hepatic failure, and 31 with jaundice. Toxic liver disease was confirmed in 14 out of 26 patients, yielding a PPV of 53.8% (95% CI 33.4-73.4%). Hepatic failure was confirmed in 26 out of 38 patients, resulting in a PPV of 62.1% (95% CI 48.4-74.5%). The highest PPV was found in jaundice, with 30 confirmed diagnoses out of 31, yielding a PPV of 96.8% (95% CI 83.3-99.9%).

Among patients who received azole antifungal treatment and were subsequently diagnosed with a liver disorder, the PPV for the diagnosis of jaundice was high, while the PPVs for toxic liver disease and hepatic failure were lower.

Causality assessment of suspected drug-induced liver injury (DILI) during metabolic dysfunction-associated steatohepatitis (MASH) clinical trials can be challenging, and liver biopsies are not routinely performed as part of this evaluation. While the field is moving away from liver biopsy as a diagnostic and prognostic tool, information not identified by non-invasive testing may be provided on histology.

To address the appropriate utilisation of liver biopsy as part of DILI causality assessment in this setting.

From 2020 to 2022, the Liver Forum convened a series of webinars on issues pertaining to liver biopsy during MASH trials. The Histology Working Group was formed to generate a series of consensus documents addressing these challenges. This manuscript focuses on liver biopsy as part of DILI causality assessment.

Expert opinion, guidance and recommendations on the role of liver biopsy as part of causality assessment of suspected DILI occurring during clinical trials for a drug(s) being developed for MASH are provided. Lessons learned from prior MASH programs are reviewed and gaps identified.

Although there are no pathognomonic features, histologic evaluation of suspected DILI during MASH clinical trials may alter patient management, define the pattern and severity of injury, detect findings that favour a diagnosis of DILI versus MASH progression, identify prognostic features, characterise the clinicopathological phenotype of DILI, and/or define lesions that influence decisions about trial discontinuation and further development of the drug.

Diagnosis of drug-induced liver injury (DILI) is difficult. We reviewed cases in the DILI Network prospective study that were adjudicated to have liver injury due to other causes to discover pearls for improved diagnostic accuracy.

Cases were adjudicated by expert opinion and scored from 1 (definite DILI) to 5 (unlikely DILI). Confirmed cases (1-3) were compared with unlikely cases (5).

One hundred thirty-four of the 1,916 cases (7%) were unlikely DILI. Alternative diagnoses were autoimmune hepatitis (20%), hepatitis C (20%), bile duct pathology (13%), and hepatitis E (8%).

Thorough evaluation, including follow-up, is essential to minimize incorrect diagnosis of idiosyncratic DILI.

Causality assessment is vital in patient safety and pharmacovigilance (PSPV) for safety signal detection, adverse reaction management, and regulatory submission. Large language models (LLMs), especially those designed with transformer architecture, are revolutionizing various fields, including PSPV. While attempts to utilize Bidirectional Encoder Representations from Transformers (BERT)-like LLMs for causal inference in PSPV are underway, a detailed evaluation of "fit-for-purpose" BERT-like model selection to enhance causal inference performance within PSPV applications remains absent. This study conducts an in-depth exploration of BERT-like LLMs, including generic pre-trained BERT LLMs, domain-specific pre-trained LLMs, and domain-specific pre-trained LLMs with safety knowledge-specific fine-tuning, for causal inference in PSPV. Our investigation centers around (1) the influence of data complexity and model architecture, (2) the correlation between the BERT size and its impact, and (3) the role of domain-specific training and fine-tuning on three publicly accessible PSPV data sets. The findings suggest that (1) BERT-like LLMs deliver consistent predictive power across varied data complexity levels, (2) the predictive performance and causal inference results do not directly correspond to the BERT-like model size, and (3) domain-specific pre-trained LLMs, with or without safety knowledge-specific fine-tuning, surpass generic pre-trained BERT models in causal inference. The findings are valuable to guide the future application of LLMs in a broad range of application.

Acute liver failure (ALF) describes a clinical syndrome of rapid hepatocyte injury leading to liver failure manifested by coagulopathy and encephalopathy in the absence of pre-existing cirrhosis. The hallmark diagnostic features are a prolonged prothrombin time (ie, an international normalized ratio of prothrombin time of ≥1.5) and any degree of mental status alteration (HE). As a rare, orphan disease, it seemed an obvious target for a multicenter network. The Acute Liver Failure Study Group (ALFSG) began in 1997 to more thoroughly study and understand the causes, natural history, and management of ALF. Over the course of 22 years, 3364 adult patients were enrolled in the study registry (2614 ALF and 857 acute liver injury-international normalized ratio 2.0 but no encephalopathy-ALI) and >150,000 biosamples collected, including serum, plasma, urine, DNA, and liver tissue. Within the Registry study sites, 4 prospective substudies were conducted and published, 2 interventional ( N -acetylcysteine and ornithine phenylacetate), 1 prognostic [ 13 C-methacetin breath test (MBT)], and 1 mechanistic (rotational thromboelastometry). To review ALFSG's accomplishments and consider next steps, a 2-day in-person conference was held at UT Southwestern Medical Center, Dallas, TX, entitled "Acute Liver Failure: Science and Practice," in May 2022. To summarize the important findings in the field, this review highlights the current state of understanding of ALF and, more importantly, asks what further studies are needed to improve our understanding of the pathogenesis, natural history, and management of this unique and dramatic condition.

Drug-induced liver failure is a relatively uncommon condition with a vast spectrum of clinical manifestations, and it is a leading cause of acute hepatic failure in the United States. We describe the first case of fulminant hepatic failure induced by chemotherapeutic drug daratumumab, a common FDA-approved agent. A 77-year-old male, with a history of multiple myeloma, was admitted for left lower extremity cellulitis, two weeks after receiving his first intravenous infusion of daratumumab. He developed fulminant hepatic failure in the hospital a few days later. Despite multiple doses of N-acetylcysteine, his liver function continued to decline, and he expired shortly after.

Rivaroxaban is rarely associated with drug-induced liver injury (DILI). A 57-year-old male was sent to the emergency room from an endocrine clinic for a presyncope evaluation. His exam was non-focal, and his laboratory work was remarkable for the hepatocellular pattern of liver injury. Upon detailed assessment, he was found to have DILI due to rivaroxaban. The liver function tests improved after its discontinuation. This case emphasizes the need for early recognition and timely intervention to prevent further hepatotoxicity from the culprit drug.

Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury and acute liver failure. The diagnosis, screening, and management of APAP-induced liver injury (AILI) is challenging because of the complex mechanisms involved. Starting from the current studies on the mechanisms of AILI, this review focuses on novel findings in the field of diagnosis, screening, and management of AILI. It highlights the current issues that need to be addressed. This review is supposed to summarize the recent research progress and make recommendations for future research.

Significance: Herbs are widely used worldwide. However, inappropriate use of some of the herbs can lead to herb-induced liver injury (HILI). Intriguingly, HILI incidents are on the rise, and our understanding of the underlying etiologies is in progress, and hence, an update on the current status of incidents as well as our understanding on the etiologies of HILI is appropriate. Recent Advances: HILI reports due to the use of some herbs that are traditionally considered to be safe are also on the rise. Furthermore, HILI due to the use of certain herbs in combination with other herbs (herb-herb interaction [HHI]) or non-herb components (herb-drug interaction [HDI]) has also been reported, suggesting a potentially important new type of inappropriate use of herbs. Critical Issues: Updated overviews focus on the epidemiology, etiology, phenotypes, and risk factors of HILI, as well as HDI and HHI, and analysis on several types of newly reported "toxic" effects of herbs based on types of hepatotoxicity and the HILI mechanisms. Future Directions: HILI will continue to be a significant public health challenge in the near future. In the light of the lack of broadly available guidelines and regulations for proper and safe uses of herbs worldwide, raising the public awareness of HILI will remain one of the most effective measures. In particular, it should include a better understanding of the contributing factors; a more detail subclassification and description of HILI, better characterization of the components/substances that could induce HILI; and development of HILI diagnosis based on the Roussel Uclaf Causality Assessment Method (RUCAM). Antioxid. Redox Signal. 38, 1138-1149.

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Many hepatologic pathologies mimic autoimmune hepatitis (AIH). Researchers developed the International Autoimmune Hepatitis Group (IAIHG) scoring system to compensate for the lack of specific diagnostic tests for AIH. The scoring system was not designed with pediatric patients in mind, so there are limits to its pediatric use. Additionally, there is limited information on the value of a liver biopsy in conjunction with its use.

In this retrospective study, we evaluated the effect of liver biopsy scores on the IAIHG scoring system in patients that were 0-18 years old with suspected AIH. We also analyzed demographic data and laboratory values associated with a final AIH diagnosis.

We found that interface hepatitis and predominant plasma cells found during the biopsy were significantly associated with a final AIH diagnosis. We also found that abnormal laboratory values were associated with an AIH diagnosis. We found that IAIHG scores calculated post-liver biopsy showed a greater area under the receiver operating characteristic curve (AUROC) of 0.95, which was compared to 0.88 for the scores calculated before a liver biopsy. Including biopsy metrics lowered the optimized cutoff score and test specificity.

Incorporating liver histopathological features improved the performance of the IAIHG scoring system. Further studies to identify other potential elements in liver histology may improve the performance metrics of the IAIHG test in the pediatric population.

Tolvaptan is associated with risk of drug-induced liver injury when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE trial and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted.

Analysis of safety data from prospective clinical trials of tolvaptan.

Multicenter clinical trials including more than 2,900 tolvaptan-treated participants, more than 2,300 with at least 18 months of drug exposure.

Tolvaptan administered twice daily in split-dose regimens.

Frequency of liver enzyme level increases detected by regular laboratory monitoring.

In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38 of 681 [5.6%] vs 8 of 685 [1.2%]) experienced alanine aminotransferase level increases to >3× the upper limit of normal (ULN), similar to TEMPO 3:4 (40 of 957 [4.4%] vs 5 of 484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent alanine aminotransferase level increases to >3× ULN and total bilirubin increases to >2× ULN ("Hy's Law" laboratory criteria). Based on the expanded dataset, liver enzyme increases most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Increased levels returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial drug-induced liver injury episode, with return of liver enzyme level increases in 30; 1 additional participant showed a clinical "adaptation" after the initial episode, with resolution of the enzyme level increases despite continuation of tolvaptan.

Retrospective analysis.

The absence of Hy's Law cases in REPRISE and the long-term extension trial support monthly liver enzyme monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter to detect and manage enzyme level increases, as is recommended on the drug label.

Otsuka Pharmaceutical Development & Commercialization, Inc.

Trials included in the dataset were registered at ClinicalTrials.gov with study numbers NCT00428948 (TEMPO 3:4), NCT01214421 (TEMPO 4:4), NCT02160145 (REPRISE), and NCT02251275 (long-term extension).

Acute liver injury (ALI) due to autoimmune hepatitis (AIH) can be treated by immunosuppression. In contrast, idiosyncratic drug-induced liver injury (DILI) had a poor prognosis. DILI thus needs to be distinguished from non-DILI.

Twenty-nine patients with DILI and 77 with non-DILI (42 of AIH and 35 with undetermined cause) diagnosed during 2005-2017 comprised the derivation cohort. 110 patients with ALI due to either AIH, DILI, or obscure causes at 6 liver centers during 2010-2015 were the validation cohort. Revised international AIH group scores (IAIHGs) and the Roussel-Uclaf Causality Assessment Method (RUCAM) were modified to calculate results using medical interviews and laboratory data without chronological changes. Diagnostic accuracy for the distinction of DILI and non-DILI was evaluated by receiver operating characteristic analysis and results were expressed as the area under the curve (AUC). This study received institutional institutional review board approval (MH2020-205).

The AUCs of modified IAIHGs and RUCAM scores for the diagnosis of DILI were 0.96 and 1.00 when cut-off values were set at 3 for the modified RUCAM and 5 for the modified IAIHGs in the derivation cohort. In the validation cohort, the AUCs of modified IAIHGs and RUCAM scores for the diagnosis of DILI were 0.95 and 0.97, respectively. The accuracy of the combination of the modified scores was 81% (89/110).

Modified diagnostic scores based on detailed medical interviews and routine laboratory data can distinguish DILI from non-DILI in patients with ALI.

Drug-induced liver injury (DILI) may present with autoimmune features and require immunosuppressive therapy (IST) to reach biochemical response. Discontinuation of IST without hepatitis relapse may be more frequent in these patients as compared to patients with classical autoimmune hepatitis (AIH). We aimed to determine baseline characteristics and outcome of patients with immune-mediated drug induced liver injury (IMDILI) with particular emphasis on IST during follow-up.

We performed a single-center retrospective study of consecutive patients presenting at a tertiary care center between January 2005 and December 2019 either with IMDILI or with classical AIH, for whom full baseline characteristics and a close follow-up were available over a 12-month period.

Overall, 31 patients (IMDILI n = 16, mean age 59 [34-74] years; AIH n = 15, mean age 47 [15-61] years) were included, showing similar biochemical, serological, and histological characteristics. Incriminating drugs in IMDILI patients were mostly represented by nonsteroidal antiinflammatory drugs and sartans. Initial corticosteroids combined with IST led to biochemical response in all patients. Compared to idiopathic AIH, more patients with IMDILI were weaned off corticosteroids at the end of follow-up (11/16 [68.7%] vs 4/15 [26.6%], P < 0.02). At 1 year of follow-up, more patients in the IMDILI group compared to the classical AIH group were off any type of IST (13/16 [81%] vs 15/15 [100%], P = 0.08).

Although presenting with similar baseline biochemical and histological characteristics as idiopathic AIH, patients with IMDILI may not require long-term IST.

Prior drug allergies are common and may increase susceptibility to adverse medication effects. The aim of this study was to compare the frequency, clinical features, and outcomes of DILI among patients with and without a history of prior drug allergy.

The EMR at a large liver referral center was searched for all DILI encounters using ICD-10 T-codes for drug poisoning/toxicity and K-71 codes for toxic liver injury between 10/1/2015 and 9/30/2019. Clinically significant liver injury was identified using predefined laboratory criteria, and cases were adjudicated using a 5-point expert opinion scale: 1/2/3 = probable DILI and 4/5 = non-DILI. Drug allergy was defined as a history of anaphylaxis, hives, rash, or pruritus after drug exposure.

Among 766,930 patient encounters, 127 unique patients met inclusion criteria with 72 (56.7%) cases adjudicated as probable DILI and 55 (43.3%) as non-DILI. In the probable DILI group, the most frequent suspect drug classes were: antimicrobials (41.9%), herbal and dietary supplements (9.5%), and antineoplastics (8.1%). Twenty-three of the 72 DILI patients (31.9%) had a history of drug allergy before the DILI episode compared to 16 (29.1%) of the 55 non-DILI cases (p = 0.89). However, none of the allergy drugs and suspect DILI drugs were the same although many were in the same drug class. DILI patients with a prior drug allergy were more likely to be female (73.9% vs. 44.9%, p = 0.04) and have lower serum bilirubin (4.0 vs. 7.8, p = 0.08) and INR (1.1 vs. 1.6, p = 0.043) levels at presentation. The likelihood of death or liver transplantation among probable DILI cases with prior drug allergy was lower than those without prior drug allergy (0% vs. 8.2%, p = 0.35). The suspect drug was subsequently documented in the "Drug Allergy" section of the EMR in only 23 (31.9%) of the 72 probable DILI patients, and these patients were more likely to present with a rash (7% vs. 2%, p = 0.006) and higher serum bilirubin levels (10.5 vs. 4.7, p = 0.008) compared to those in whom the suspect drug was not listed as "drug allergy."

A prior drug allergy history was not associated with a greater likelihood of developing DILI compared to other causes of acute liver injury. However, the probable DILI patients with a history of prior drug allergy tended to have less severe liver injury and clinical outcomes. The low rate of suspect drug documentation in the "Drug Allergy" section of EMR after a DILI episode is of concern and could lead to avoidable harm from inadvertent suspect drug re-challenge.