Drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method following mild COVID-19 in a patient under anastrozole therapy-A case report.

BACKGROUND: Anastrozole is a selective aromatase inhibitor used for the treatment of postmenopausal hormone-sensitive breast cancer. The major side effects include osteoporosis, hypercholesterolemia, and musculoskeletal events, such as arthralgia and myalgia. Other adverse events are rare, including symptoms of acne, masculinization, and drug-induced liver injury, with the latter reported in a few cases only. CASE: Here, we report on a patient under anastrozole therapy who developed drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method 5 weeks after a mild SARS-CoV-2 infection, which is, to the best of our knowledge, the first report of its kind involving anastrozole. Discontinuation of anastrozole resulted in a marked improvement of the alanine aminotransaminase, and aspartate aminotransaminase as well as normalized lactate dehydrogenase serum levels already seen after 26 days. Surprisingly, however, the cholestatic serum markers gamma-glutamyl transpeptidase and alkaline phosphatase showed a further rise, and took another 4 weeks to drop significantly. CONCLUSION: The presentation of this case is meant to alert physicians to a potential drug-induced liver injury following mild SARS-CoV-2 infection in patients under anastrozole medication.

Drug-drug interaction assessment based on a large-scale spontaneous reporting system for hepato- and renal-toxicity, and thrombocytopenia with concomitant low-dose methotrexate and analgesics use.

BACKGROUND: Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment. METHODS: We used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA. RESULTS: After identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω025 = 0.08) and piroxicam (Ω025 = 0.46), and ibuprofen (Ω025 = 0.74) and ketorolac (Ω025 = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs. CONCLUSIONS: Studies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment.

Liver biopsy for assessment of suspected drug-induced liver injury in metabolic dysfunction-associated steatohepatitis clinical trials: Expert consensus from the Liver Forum.

BACKGROUND: 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. AIM: To address the appropriate utilisation of liver biopsy as part of DILI causality assessment in this setting. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Industry Review of Best Practices for Risk Management of Drug-Induced Liver Injury from Development to Real-World Use.

The relative treatment benefit of a drug for patients during development, marketing authorization review, or after approval includes an assessment of the risk of drug-induced liver injury (DILI). In this article, the Pharmacovigilance and Risk Mitigation Working Group of the IQ-DILI Initiative launched in June 2016 within the International Consortium for Innovation and Quality in Pharmaceutical Development presents and reviews three key topics for essential risk management activities to identify, characterize, monitor, mitigate, and communicate DILI risk associated with small molecules during drug development. The three topics are: (1) Current best practices for characterizing the DILI phenotype and the severity and incidence of DILI in the treatment population, including DILI identification, prediction and recovery. (2) Characterization of the relative treatment benefit for patients who will be exposed to a drug and the attendant risk of DILI in conjunction with existing global risk mitigation strategies. (3) Implementation of risk mitigation strategies during drug development highlighting patient factors, healthcare settings and site of product administration, and prescriber and healthcare provider factors. Industry guidance is provided for assessing whether the product labeling is sufficient to minimize the risk of DILI or whether a United States Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) or European Medicines Agency (EMA) Risk Management Plan (RMP) with additional Risk Minimization Measures (aRMM) is needed.

The relative treatment benefit of a drug for patients during development, marketing authorization review or after approval includes an assessment of the risk of drug-induced liver injury (DILI). Reported incidences of DILI range from 0.74 to 19 per 100,000, and laboratory criteria and/or clinical outcome determine the severity of DILI. At least 10% of patients who develop jaundice caused by DILI (Hy's Law cases) develop liver failure (i.e., severe DILI). A drug's liver safety profile can be assessed using Evaluation of Drug-Induced Serious Hepatotoxicity Plots. Specific recommendations for monitoring DILI in the post-marketing setting depend on characterization of the phenotype during drug development. Risk mitigation tools include additional educational mechanisms, and risk minimization measures include Elements To Assure Safe Use (ETASU) for healthcare professionals, administration sites, and patients. The overall aim of risk management is to ensure that the benefit of a particular product exceeds the risks as far as possible for the individual patient and for the target population.

Human Hepatic Spheroid Coculture Model for the Assessment of Drug-Induced Liver Injury.

Accurate evaluation of potential drug risks such as drug-induced liver injury (DILI) continues to be a challenge faced by pharmaceutical industry and regulatory agencies. Preclinical testing has served as a foundation for the evaluation of the potential risks and effectiveness of investigational new drug (IND) products in humans. However, current two-dimensional (2D) in vitro human primary hepatocyte (HPH) culture systems cannot accurately depict and simulate the rich environment and complex processes observed in vivo, while animal studies present inherited species-specific differences and low throughput scales. Thus, there is a continued demand to establish new approaches that can better characterize DILI during drug discovery and development. Among others, the three-dimensional (3D) hepatic spheroid model comprising self-aggregated primary human hepatocytes cocultured with non-parenchymal cells (NPCs) appears to be a more accurate representation of the natural hepatic microenvironment with intercellular interactions between hepatocytes, stellate cells, Kupffer cells, liver sinusoidal endothelial cells (LSECs), and other cell types. This model holds the potential to improve the ability for long-term functional and toxicological studies. Here, we provide methodological details for this human hepatic spheroid coculture model system.

New insight into PAH4 induced hepatotoxicity and the dose-response assessment in rats model.

PAH4 (sum of benzo[a]pyrene, chrysene, benz[a]anthracene and benzo[b]fluoranthene) has been proposed as better marker than benzo[a]pyrene to assess total PAHs exposure in foodstuffs. However, the toxicological behaviors of PAH4 combined exposure remain unclear. This study aimed to investigate PAH4 toxicity effects with non-targeted metabolomics approach and evaluate the external and internal dose-response relationships based on benchmark dose (BMD) analysis. Male Sprague-Dawley rats were treated by gavage with vehicle (corn oil) or four doses of PAH4 (10, 50, 250, 1000 µg/kg·bw) for consecutive 30 days. After the final dose, the liver, blood and urine samples of rats were subsequently collected for testing. The concentrations of urinary mono-hydroxylated PAHs metabolites (OH-PAHs) including 3-hydroxybenzo[a]pyrene (3-OHB[a]P), 3-hydroxychrysene (3-OHCHR) and 3-hydroxybenz[a]anthracene (3-OHB[a]A) were determined to reflect internal PAH4 exposure. Our results showed PAH4 exposure increased relative liver weight and serum aspartate aminotransferase (AST) activity and caused hepatocyte swelling and degeneration, implying hepatotoxicity induced by PAH4. Serum metabolomics suggested PAH4 exposure perturbed lipid metabolism through upregulating the expression of glycerolipids metabolites, which was evidenced by markedly increased serum triglyceride (TG) level and hepatic TG content. Additionally, urinary OH-PAHs concentrations presented strong positive correlations with the external dose, indicating they were able to reflect PAH4 exposure. Furthermore, PAH4 exposure led to a dose-response increase of hepatic TG content, based on which the 95% lower confidence value of BMDs for external and internal doses were estimated as 5.45 µg/kg·bw and 0.11 µmol/mol·Cr, respectively. In conclusion, this study suggested PAH4 exposure could induce hepatotoxicity and lipid metabolism disorder, evaluating the involved dose-response relationships and providing a basis for the risk assessment of PAHs.

A blinded in vitro analysis of the intrinsic immunogenicity of hepatotoxic drugs: implications for preclinical risk assessment.

In vitro preclinical drug-induced liver injury (DILI) risk assessment relies largely on the use of hepatocytes to measure drug-specific changes in cell function or viability. Unfortunately, this does not provide indications toward the immunogenicity of drugs and/or the likelihood of idiosyncratic reactions in the clinic. This is because the molecular initiating event in immune DILI is an interaction of the drug-derived antigen with MHC proteins and the T-cell receptor. This study utilized immune cells from drug-naïve donors, recently established immune cell coculture systems and blinded compounds with and without DILI liabilities to determine whether these new methods offer an improvement over established assessment methods for the prediction of immune-mediated DILI. Ten blinded test compounds (6 with known DILI liabilities; 4 with lower DILI liabilities) and 5 training compounds, with known T-cell-mediated immune reactions in patients, were investigated. Naïve T-cells were activated with 4/5 of the training compounds (nitroso sulfamethoxazole, vancomycin, Bandrowski's base, and carbamazepine) and clones derived from the priming assays were activated with drug in a dose-dependent manner. The test compounds with DILI liabilities did not stimulate T-cell proliferative responses during dendritic cell-T-cell coculture; however, CD4+ clones displaying reactivity were detected toward 2 compounds (ciprofloxacin and erythromycin) with known liabilities. Drug-responsive T-cells were not detected with the compounds with lower DILI liabilities. This study provides compelling evidence that assessment of intrinsic drug immunogenicity, although complex, can provide valuable information regarding immune liabilities of some compounds prior to clinical studies or when immune reactions are observed in patients.

The hepatotoxicity assessment of micro/nanoplastics: A preliminary study to apply the adverse outcome pathways.

Plastic pollution has become a significant global problem over the years, leading to the continuous decomposition and accumulation of micro/nanoplastics (MNPLs) in the environment. As a result, human exposure to these MNPLs is inevitable. The liver, in particular, is highly susceptible to potential MNPL toxicity. In this study, we systematically reviewed the current literature on MNPLs-induced hepatotoxicity and collected data on toxic events occurring at different biological levels. Then, to better understand the cause-mechanism causality, we developed an Adverse Outcome Pathway (AOP) framework for MNPLs-induced hepatotoxicity. The AOP framework provided insights into the mechanism of MNPL-induced hepatotoxicity and highlighted potential health risks such as liver dysfunction and inflammation, metabolism disorders and liver fibrosis. Moreover, we discussed the potential application of emerging toxicological models in the hepatotoxicity study. Liver organoids and liver-on-chips, which can simulate the structure and function of the liver in vitro, offer a promising alternative platform for toxicity testing and risk assessment. We proposed combining the AOP framework with these emerging toxicological models to improve our understanding of the hepatotoxic effects of MNPLs. Overall, this study performed a preliminary exploration of novel toxicological methodologies to assess the hepatotoxicity of MNPLs, providing a deeper understanding of environmental toxicology.

Advances in Idiosyncratic Drug-Induced Liver Injury Issues: New Clinical and Mechanistic Analysis Due to Roussel Uclaf Causality Assessment Method Use.

Clinical and mechanistic considerations in idiosyncratic drug-induced liver injury (iDILI) remain challenging topics when they are derived from mere case narratives or iDILI cases without valid diagnosis. To overcome these issues, attempts should be made on pathogenetic aspects based on published clinical iDILI cases firmly diagnosed by the original RUCAM (Roussel Uclaf Causality Assessment Method) or the RUCAM version updated in 2016. Analysis of RUCAM-based iDILI cases allowed for evaluating immune and genetic data obtained from the serum and the liver of affected patients. For instance, strong evidence for immune reactions in the liver of patients with RUCAM-based iDILI was provided by the detection of serum anti-CYP 2E1 due to drugs like volatile anesthetics sevoflurane and desflurane, partially associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates that form protein adducts and may generate reactive oxygen species (ROS). This is accompanied by production of anti-TFA antibodies detected in the serum of these patients. Other RUCAM-based studies on serum ANA (anti-nuclear antibodies) and SMA (anti-smooth muscle antibodies) associated with AIDILI (autoimmune DILI) syn DIAIH (drug-induced autoimmune hepatitis) provide additional evidence of immunological reactions with monocytes as one of several promoting immune cells. In addition, in the blood plasma of patients, mediators like the cytokines IL-22, IL-22 binding protein (IL-22BP), IL-6, IL-10, IL 12p70, IL-17A, IL-23, IP-10, or chemokines such as CD206 and sCD163 were found in DILI due to anti-tuberculosis drugs as ascertained by the prospective updated RUCAM, which scored a high causality. RUCAM-based analysis also provided compelling evidence of genetic factors such as HLA (human leucocyte antigen) alleles contributing to initiate iDILI by a few drugs. In conclusion, analysis of published RUCAM-based iDILI cases provided firm evidence of immune and genetic processes involved in iDILI caused by specific drugs.

Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease.

INTRODUCTION: Paracetamol is one of the most used medicines worldwide and is the most common important poisoning in high-income countries. In overdose, paracetamol causes dose-dependent hepatotoxicity. Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur. AREAS COVERED: This review summarizes paracetamol overdose and toxicity (including mechanisms, risk factors, risk assessment, and treatment). In addition, we summarize the epidemiology of paracetamol overdose worldwide. A literature search on PubMed for poisoning epidemiology and mortality from 1 January 2017 to 26 October 2022 was performed to estimate rates of paracetamol overdose, liver injury, and deaths worldwide. EXPERT OPINION: Paracetamol is widely available and yet is substantially more toxic than other analgesics available without prescription. Where data were available, we estimate that paracetamol is involved in 6% of poisonings, 56% of severe acute liver injury and acute liver failure, and 7% of drug-induced liver injury. These estimates are limited by lack of available data from many countries, particularly in Asia, South America, and Africa. Harm reduction from paracetamol is possible through better identification of high-risk overdoses, and better treatment regimens. Large overdoses and those involving modified-release paracetamol are high-risk and can be targeted through legislative change.

Relationship between common telomere length-related genetic variations, telomere length, and risk of antituberculosis drug-induced hepatotoxicity in Chinese Han population: As assessed for causality using the updated Roussel Uclaf Causality Assessment Method.

Antituberculosis drug-induced hepatotoxicity (ATDH) is a significant threat to tuberculosis control, and two recent studies indicated that leukocyte telomere length (LTL) might be a potential biomarker for ATDH. This study aimed to investigate the relationship between common telomere length-related genetic variations, LTL, and risk of ATDH in Eastern Chinese antituberculosis treatment patients. A 1:4 matched case-control study was conducted among 79 ATDH cases assessed for causality using the updated RUCAM and 316 controls. LTL was determined by quantitative real-time PCR, and nine SNPs involved in telomere biology reported by previous GWAS were assessed. Conditional logistic regression model was used to estimate the association between genotypes and risk of ATDH with odds ratios (ORs) and 95% confidence intervals (CIs). The average RUCAM score of cases was 7.1. The average LTL in cases was significantly shorter than that in controls (median = 1.239 vs. 1.481, P = 0.032). Differences in the distribution of LTL were statistically significant among three genotypes of SNP rs2736098 (CC vs. CT vs. TT, median = 1.544 vs. 1.356 vs. 1.337, P = 0.026) and rs2853677 (AA vs. AG vs. GG, median = 1.511 vs. 1.544 vs. 1.159, P = 0.005) in TERT. SNP rs7675998 in NAF1 was statistically associated with the risk of ATDH under the dominant model (adjusted OR = 1.725, 95% CI: 1.021-2.913, P = 0.042). This is the first study to investigate the relationship of LTL, common telomere length-related variations, and risk of ATDH. SNP rs2736098 and rs2853677 in TERT were significantly associated with LTL, and SNP rs7675998 in NAF1 may be associated with ATDH in Chinese population.

Establishment of an in vitro cholestasis risk assessment system using two-dimensional cultured HepaRG cells and 12 bile acids.

Drug-induced liver injury (DILI) is a major cause of market withdrawal or drug-development discontinuation because of safety concerns. In this study, we focused on drug-induced cholestasis (DIC) to establish an in vitro cytotoxicity test system and analyze its sensitivity using two-dimensional (2-D) cultured HepaRG cells and 12 types of bile acids (BAs) present in the human serum. First, to detect the cytotoxicity associated with cholestasis effectively, non-toxic BA concentrations were investigated and determined to be 100-fold the human serum value (455 µM total BAs). Next, the cytotoxicity of 31 compounds that can inhibit the bile acid export pump (BSEP) and were categorized as no-DILI-concern, less-DILI-concern, and most-DILI-concern was examined. None of the no-DILI-concern compounds yielded cytotoxicity, whereas almost all less-DILI-concern compounds (with the exception of simvastatin) and most-DILI-concern compounds (with the exception of bosentan) exhibited cytotoxicity. An investigation of the cause of cytotoxicity using 3H-taurocholic acid revealed that most-DILI-concern and less-DILI-concern compounds, but not no-DILI-concern compounds, triggered the accumulation of radioactivity in the cell lysates. Thus, the onset of cytotoxicity seemed to be associated with cholestasis. The established HepaRG cytotoxicity assessment system (sensitivity of 89%, specificity of 100%, and accuracy of 97%) was mostly superior to the Css/BSEP IC50 (> 0.1) assessment system (sensitivity of 83%, specificity of 100%, and accuracy of 72%). Therefore, the assay method using 2-D cultured HepaRG cells and 12 BAs established here can be widely applicable as a model for the in vitro potential assessment of DIC.

Assessment of the Frequency, Phenotypes, and Outcomes of Acute Liver Injury Associated with Amoxicillin/Clavulanate in 1.4 Million Patients in the Veterans Health Administration.

INTRODUCTION: Drug-induced liver injury is a significant health issue, yet the exposure-based incidence remains to be characterized. OBJECTIVE: We aimed to assess the frequency, phenotypes, and outcomes of acute liver injury associated with amoxicillin/clavulanate using a large electronic health record system. METHODS: Using the Veterans Health Administration electronic health record system, we developed the framework to identify unexplained acute liver injury, defined by alanine aminotransferase and/or alkaline phosphatase elevation temporally linked to prescription records of amoxicillin/clavulanate, a major culprit of clinically significant drug-induced liver injury, excluding other competing causes. The population was subcategorized by pre-existing liver conditions and inpatient status at the time of exposure for the analysis. RESULTS: Among 1,445,171 amoxicillin/clavulanate first exposures in unique individuals [92% men; mean age (standard deviation): 59 (15) years], 6476 (incidence: 0.448%) acute liver injuries were identified. Of these, 4427 (65%) had alternative causes, yielding 2249 (incidence: 0.156%) with unexplained acute liver injuries. The incidence of unexplained acute liver injury was lowest in outpatients without underlying liver disease (0.067%) and highest in inpatients with pre-existing liver conditions (0.719%). Older age, male sex, and American Indian or Alaska Native (vs White) were associated with a higher incidence of unexplained acute liver injury. Cholestatic injury affected 74%, exhibiting a higher frequency with advanced age, inpatient exposure, and pre-existing liver conditions. Hepatocellular injury with bilirubin elevation affected 0.003%, with a higher risk at age >45 years. During a 12-month follow-up, patients with unexplained acute liver injury had a higher adjusted overall mortality risk than those without evident acute liver injury. CONCLUSIONS: This framework identifies unexplained acute liver injury following drug exposure in large electronic health record datasets. After validating in other systems, this framework can aid in deducing drug-induced liver injury in the general patient population and regulatory decision making to promote drug safety and public health.

Decision tree algorithm can determine the outcome of repeated supratherapeutic ingestion (RSTI) exposure to acetaminophen: review of 4500 national poison data system cases.

This study is aimed at establishing the outcome of RSTI exposure to acetaminophen based on a decision tree algorithm for the first time. This study used the National Poison Data System (NPDS) to conduct a six-year retrospective cohort analysis, which included 4522 individuals. The patients had a mean age of 26.75 ± 16.3 years (1-89). 3160 patients (70%) were females. Most patients had intentional exposure to acetaminophen. Almost all the patients had acetaminophen exposure via ingestion. In addition, 400 (8.8%) experienced major outcomes, 1500 (33.2%) experienced moderate outcomes, and 2622 (58%) of the patients experienced mild ones. The decision tree model performed well in the training and test groups. In the test group, the accuracy was 0.813, precision of 0.827, recall being 0.798, specificity 0.898, and an F1 score 0.80. In the training group, accuracy was 0.831, recall was 0.825, precision was 0.837, specificity was 0.90, and F1 score was 0.829. Our results showed that serum liver enzymes being present at elevated levels (Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) greater than 1000 U/L followed by ALT, AST between 100 and 1000 U/L), prothrombin time (PT) prolongation, bilirubin increase, renal failure, confusion, age, hypotension, other coagulopathy (such as partial thromboplastin time (PTT) prolongation), acidosis, and electrolyte abnormality were the effective factors in determining the outcomes in these patients. The decision tree algorithm is a dependable method for establishing the prognosis of patients who have been exposed to RSTI acetaminophen and can be used throughout the patients' hospitalization period.

Failure of Risk Assessment After Paracetamol Overdose-A Short Communication.

BACKGROUND: The accepted treatment for patients with acetaminophen/paracetamol overdose includes risk assessment based on the Rumack-Matthew (R-M) nomogram. An inaccurate use of the nomogram may result in improper treatment. Clinicians were surveyed to determine their understanding and proper use of this risk assessment tool in practice. METHODS: Differences between visual risk assessment using the same depiction of the R-M nomogram and calculated risk assessment were determined using an online calculator developed based on the Rumack equation. An online survey was administered in French between August 25, 2021, and November 25, 2021, as a Google Form with 14 questions (the paracetamol concentration and time postingestion were stated). A total of 147 respondents with an average age of 32 years (range 23-61 years) performed risk assessment (low/possible/probable/not assessable). The mean assessment accuracy was 66.2 ± 26.7% (12.3-99.3). The sensitivity, specificity, positive predictive value, and negative predictive value were 93%, 55%, 71%, and 89%, respectively. A subcohort of n = 31 senior clinicians showed the same trends (91%, 52%, 69%, and 84%). RESULTS: Approximately 7% of patients who are at risk of hepatotoxicity based on the R-M nomogram would not be treated. By contrast, N-acetylcysteine was not recommended by the R-M nomogram but would be administered to approximately 50% of patients. A concern for the latter group is that anaphylactoid reactions occur in up to 25% of patients with low paracetamol concentrations. CONCLUSIONS: Some patients may be undertreated, resulting in possible hepatotoxicity, and many patients may be overtreated, resulting in a high percentage of anaphylaxis. Rather than relying on visual risk assessment, physicians should use an online calculator ( www.hopitox.com/?lang=en ) or consult with a toxicologist or poison center to substantially improve patient care after acetaminophen/paracetamol overdose.

Fifty years of paracetamol (acetaminophen) poisoning: the development of risk assessment and treatment 1973-2023 with particular focus on contributions published from Edinburgh and Denver.

INTRODUCTION: Fifty years ago, basic scientific studies and the availability of assay methods made the assessment of risk in paracetamol (acetaminophen) poisoning possible. The use of the antidote acetylcysteine linked to new methods of risk assessment transformed the treatment of this poisoning. This review will describe the way in which risk assessment and treatments have developed over the last 50 years and highlight the remaining areas of uncertainty. METHODS: A search of PubMed and its subsidiary databases revealed 1,166 references published in the period 1963-2023 using the combined terms "paracetamol", "poisoning", and "acetylcysteine". Focused searches then identified 170 papers dealing with risk assessment of paracetamol poisoning, 141 with adverse reactions to acetylcysteine and 114 describing different acetylcysteine regimens. To manage the extensive literature, we focused mainly on contributions made by the authors during their time in Edinburgh and Denver. DOSE AND CONCENTRATION RESPONSE: The key relationship between paracetamol dose and toxicity risk was established in 1971 and led to the development of the Rumack-Matthew nomogram from data collected in Edinburgh. MECHANISMS OF TOXICITY: A series of papers on the mechanisms of toxicity were published in 1973, and these showed that paracetamol hepatotoxicity was caused by the formation of a toxic intermediate epoxide metabolite normally detoxified by glutathione but which, in excess, was bound covalently to hepatic enzymes and proteins. An understanding of the relationship between the rate of paracetamol metabolism, paracetamol concentration, and toxic hazard in humans soon followed. ANTIDOTE DEVELOPMENT AND EFFICACY IN PATIENTS: These discoveries were followed by the testing of a range of sulfhydryl-donors in animals and "at risk" patients. Acetylcysteine was developed as the lead intravenous antidote in the United Kingdom. The license holder in the United States refused to make an intravenous formulation. Thus, oral acetylcysteine became the antidote trialed in the United States National Multicenter Study. Intravenous acetylcysteine regimens used initially in the United Kingdom and subsequently in the United States used loading doses of 150 mg/kg over 15 minutes or one hour, 50 mg/kg over four hours, and 100 mg/kg over 16 hours. These regimens were associated with adverse drug reactions (nausea, vomiting and anaphylactoid reactions) and hence, treatment interruption. Newer dosing regimens now give loading doses more slowly. One, the Scottish and Newcastle Anti-emetic Pretreatment protocol, using an acetylcysteine regimen of 100 mg/kg over two hours followed by 200 mg/kg over 10 hours, has been widely adopted in the United Kingdom. A cohort comparison study suggests this regimen has comparable efficacy to standard regimens and offers opportunities for selective higher acetylcysteine dosing. RISK ASSESSMENT AT PRESENTATION: No dose-ranging studies with acetylcysteine were done, and no placebo-controlled studies were performed. Thus, there is uncertainty regarding the optimal dose of acetylcysteine, particularly in patients ingesting very large overdoses of paracetamol. The choice of intervention concentration on the Rumack-Matthew nomogram has important consequences for the proportion of patients treated. The United States National Multicenter Study used a "treatment" line starting at 150 mg/L (992 µmol/L) at 4 hours post overdose, extending to 24 hours with a half-life of 4 hours, now standard there, and subsequently adopted in Australia and New Zealand. In the United Kingdom, the treatment line was initially 200 mg/L (1,323 µmol/L) at 4 hours (the Rumack-Matthew "risk" line). In 2012, the United Kingdom Medicines and Healthcare products Regulatory Agency lowered the treatment line to 100 mg/L (662 µmol/L) at 4 hours for all patients, increasing the number of patients admitted and treated at a high cost. Risk assessment is a key issue for ongoing study, particularly following the development of potential new antidotes that may act in those at greatest risk. The development of biomarkers to assess risk is ongoing but has yet to reach clinical trials. CONCLUSION: Even after 50 years, there are still areas of uncertainty. These include appropriate acetylcysteine doses in patients who ingest different paracetamol doses or multiple (staggered) ingestions, early identification of at-risk patients, and optimal treatment of late presenters.

Review article: clinical assessment of suspected drug-induced liver injury and its management.

BACKGROUND: Idisyncratic drug-induced liver injury (DILI) is a rare instance of liver injury after exposure to an otherwise safe drug or herbal or dietary supplement. DILI can be associated with significant morbidity and mortality. Furthermore, it is an important consideration in drug development due to safety concerns. AIMS AND METHODS: To highlight pearls and pitfalls to aid clinicians in diagnosing DILI and surmising the management options. We also share the best practices from personal insights developed from decades long participation in the causality assessment committee meetings of the DILI Network. RESULTS: DILI lacks a diagnostic test and is currently diagnosed through a process of exclusion of competing aetiologies of liver injury. This requires a high degree of suspicion to consider the possibility of DILI, skill in ruling out the obvious and less obvious competing liver insults, and an understanding of the expected phenotypes of DILI. The facets of DILI cover multiple aspects, including the latency, liver injury pattern, course of injury, and associated autoimmune or immuno-allergic features. Care for patients with DILI is geared towards stopping the offending drug and symptom management that include the use of corticosteroids in select cases. CONCLUSION: The diagnosis of DILI is challenging and is primarily made through a carefully crafted patient interview, temporal relationship with the implicated drug or supplement, and exclusion of competing aetiology. LiverTox is a useful resource for clinicians to review the literature and recognise the likelihood of the implicated agent in causing DILI.

A novel quantitative computer-assisted drug-induced liver injury causality assessment tool (DILI-CAT).

BACKGROUND AND AIMS: We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug. METHODS: Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets. RESULTS: The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated. CONCLUSIONS: DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.