Roussel Uclaf Causality Assessment Method Research Articles

RECAM-J 2023-Validation and development of the Japanese version of RECAM for the diagnosis of drug-induced liver injury.

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.

Acute liver failure caused by high-dose tigecycline: A case report.

High-dose tigecycline is gradually being introduced for the treatment of serious infectious diseases due to the increasing difficulty in treating pan-resistant bacterial infections. However, the safety of high-dose tigecycline is controversial. We report the case of a 76-year-old female patient with cerebral hemorrhage who received high-dose tigecycline (100 mg q12h) with other drugs for ventilator-associated pneumonia. 25 days after admission, she developed acute liver failure, mainly manifested by abnormally high bilirubin, coagulation dysfunction, and gastrointestinal hemorrhage with hemorrhagic shock. According to the updated Roussel Uclaf causality assessment method, the patient's acute liver injury was most likely caused by tigecycline.

Human Leucocyte Antigen Genetics in Idiosyncratic Drug-Induced Liver Injury with Evidence Based on the Roussel Uclaf Causality Assessment Method.

The human leucocyte antigen (HLA) allele variability was studied in cohorts of patients with idiosyncratic drug-induced liver injury (iDILI). Some reports showed an association between HLA genetics and iDILI, proposing HLA alleles as a potential risk factor for the liver injury. However, the strength of such assumptions heavily depends on the quality of the iDILI diagnosis, calling for a thorough analysis. Using the PubMed database and Google Science, a total of 25 reports of case series or single cases were retrieved using the terms HLA genes and iDILI. It turned out that in 10/25 reports (40%), HLA genetics were determined in iDILI cases, for which no causality assessment method (CAM) was used or a non-validated tool was applied, meaning the findings were based on subjective opinion, providing disputable results and hence not scoring individual key elements. By contrast, in most iDILI reports (60%), the Roussel Uclaf Causality Assessment Method (RUCAM) was applied, which is the diagnostic algorithm preferred worldwide to assess causality in iDILI cases and represents a quantitative, objective tool that has been well validated by both internal and external DILI experts. The RUCAM provided evidence-based results concerning liver injury by 1 drug class (antituberculotics + antiretrovirals) and 19 different drugs, comprising 900 iDILI cases. Among the top-ranking drugs were amoxicillin-clavulanate (290 cases, HLA A*02:01 or HLA A*30:02), followed by flucloxacillin (255 cases, HLA B*57:01), trimethoprim-sulfamethoxazole (86 cases, HLA B*14:01 or HLA B*14:02), methimazole (40 cases, HLA C*03:02), carbamazepine (29 cases, HLA A*31:01), and nitrofurantoin (26 cases, HLA A*33:01). In conclusion, the HLA genetics in 900 idiosyncratic drug-induced liver injury cases with evidence based on the RUCAM are available for studying the mechanistic steps leading to the injury, including metabolic factors through cytochrome P450 isoforms and processes that activate the innate immune system to the adaptive immune system.

Safety of naltrexone in patients with cirrhosis

BackgroundTreatment of alcohol use disorder (AUD) improves survival in patients with alcohol-related cirrhosis. However, medications for alcohol use disorder (MAUD) are underutilized in this population, partially due to concerns for drug-induced liver injury (DILI). Our aim was to evaluate the safety of naltrexone in patients with cirrhosis. MethodsThis was a retrospective study of patients with cirrhosis who were prescribed naltrexone using the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) database. Patients with new initiation of naltrexone after diagnosis of cirrhosis who had liver enzymes checked within a 3-month time frame were included. A chart review was performed on patients who developed alanine transaminase or alkaline phosphatase elevations to more than 2 times or 5 times the upper limit of normal, respectively. The Roussel Uclaf Causality Assessment Method (RUCAM) was used to determine if DILI occurred. ResultsA total of 3285 patients with cirrhosis were initiated on naltrexone and 2940 of these had laboratory testing during the high-risk DILI period. Only 2% of patients had liver enzyme elevations, and among those, 30 (48%) were classified as “DILI excluded” and 32 (52%) were classified as “DILI unlikely”. No patients were classified as possible, probable, or highly probable DILI. No deaths or new decompensations were attributed to naltrexone. ConclusionsNaltrexone in patients with cirrhosis was not associated with development of DILI using RUCAM scoring. Naltrexone appears to be safe in patients with compensated and decompensated cirrhosis. Impact and ImplicationsNaltrexone is an effective medication for treating alcohol use disorder but is underutilized in patients with underlying liver disease due to historical concerns for hepatotoxicity. This retrospective study shows no drug induced liver injury in a large cohort of patients with cirrhosis with new initiation of naltrexone. This study may encourage providers to prescribe naltrexone to patients with existing liver disease with ongoing alcohol use disorder.

Drug Induced Liver Injury in Children: A Nationwide Cohort Study from China

Background & AimsCurrently, there is limited knowledge on the clinical profile of drug induced liver injury (DILI) in Chinese children. We aimed to assess the clinical characteristics, suspected drugs, and outcomes associated with pediatric DILI in China. MethodsThis nationwide, multi-center, retrospective study, conducted between 2012 and 2014, analyzed 25,927 cases of suspected DILI at 308 medical centers using the inpatient medical register system. Utilizing the Roussel Uclaf Causality Assessment Method (RUCAM) score, only patients with scores>6 or diagnosed with DILI by at least two experts after scoring <6 were included in the analysis. Among them, 460 cases met the European Association for the Study of Liver (EASL) biochemical criteria. The study categorized children into three age groups: toddlers (≥30 days to <6 years old), school-age children (6 to <12 years old), and adolescents (12 to <18 years old). ResultsHepatocellular injury was the predominant clinical classification, accounting for 63% of cases, with 34% of these cases meeting Hy's law criteria. Adolescents comprised the majority of children with moderate/severe DILI (65%). Similarly, adolescents faced a significantly higher risk of severe liver injury compared to younger children (adjusted odd ratio [aOR]=4.75, p =.002). The top three most frequently prescribed drug classes across all age groups were antineoplastic agents (25.9%), antimicrobials (21.5%), and traditional Chinese medicine (TCM, 13.7%). For adolescents, the most commonly suspected drugs were antituberculosis drugs (22%) and TCM (23%). ConclusionAdolescents are at a greater risk of severe and potentially fatal liver injury compared to younger children. Recognizing the risk of pediatric DILI is crucial for ensuring safe medical practices.

Exploring Individual Variability in Drug-Induced Liver Injury (DILI) Responses through Metabolomic Analysis.

Drug-induced liver injury (DILI) is a serious adverse hepatic event presenting diagnostic and prognostic challenges. The clinical categorization of DILI into hepatocellular, cholestatic, or mixed phenotype is based on serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) values; however, this classification may not capture the full spectrum of DILI subtypes. With this aim, we explored the utility of assessing changes in the plasma metabolomic profiles of 79 DILI patients assessed by the RUCAM (Roussel Uclaf Causality Assessment Method) score to better characterize this condition and compare results obtained with the standard clinical characterization. Through the identification of various metabolites in the plasma (including free and conjugated bile acids and glycerophospholipids), and the integration of this information into predictive models, we were able to evaluate the extent of the hepatocellular or cholestatic phenotype and to assign a numeric value with the contribution of each specific DILI sub-phenotype into the patient's general condition. Additionally, our results showed that metabolomic analysis enabled the monitoring of DILI variability responses to the same drug, the transitions between sub-phenotypes during disease progression, and identified a spectrum of residual DILI metabolic features, which can be overlooked using standard clinical diagnosis during patient follow-up.

Herb induced liver injury by Xianling Gubao Tablets: A case assessed for causality using updated RUCAM and integrated evidence chain

ObjectiveA typical case of Xianling Gubao (XLGB) Tablets-induced liver injury was systematically studied in the clinic and the laboratory. MethodsA patient with herb-induced liver injury (HILI) and a history of taking XLGB Tablets before disease onset was engaged as the study subject, and the case was diagnosed according to the updated Roussel Uclaf Causality Assessment Method (RUCAM) and the integrated evidence chain (iEC) method recommended by the Guidelines for Diagnosis and Treatment of Herb-induced Liver Injury (HILI Guidelines). ResultsClinical history, biochemical indexes and imaging tests were used to exclude the influence of fundamental diseases and confusing liver diseases such as viral, alcoholic and autoimmune liver diseases on the diagnosis. Based on an investigation of the patient’s medication history, she was suspected to have HILI caused by XLGB Tablets, as the patient was only taking an oral preparation of XLGB Tablets, and the influence of other drugs on the diagnosis was excluded. This patient with alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) and a calculated R of 6 was diagnosed with possible acute drug-induced hepatocellular injury. The relationship was considered “highly probable” (score of 9) using the updated RUCAM of 2016. Moreover, the fingerprint similarity between the preparation taken by the patient and a commercially available preparation was 0.99, suggesting that the patient was consuming XLGB Tablets rather than another drug. LC-MS technology and the Agilent Fake TCM-Drugs database were used to investigate the drug, and no chemical additions were found. Examination of the drug for pesticide residues, heavy metals, aflatoxins and other exogenous substances indicated compliance with the content limits of the Chinese Pharmacopoeia. ConclusionIn summary, the final diagnosis of XLGB-induced liver injury reached the clinical diagnosis of HILI and was acute severe hepatocellular injury type by the updated RUCAM and iEC. Therefore, this study provides scientific evidence regarding the causality evaluation of compound preparations of traditional Chinese medicines-induced liver injury.

Drug-induced liver injury from selective androgen receptor modulators, anabolic-androgenic steroids and bodybuilding supplements in Australia.

Reports of DILI due to herbal and dietary supplements have been increasing over time. To characterise clinical, laboratory and histopathological phenotypes and outcomes of drug-induced liver injury (DILI) due to anabolic-androgenic steroids (AAS), selective androgen receptor modulators (SARMs), and bodybuilding supplements (BBS) in Australia. Retrospective case series. Patients presented to nine Australian tertiary hospitals, 2017-2023. DILI was defined biochemically and patients were included if their treating physician attributed DILI to preceding use of AAS, SARMs or BBS. Primary endpoint was time to normalisation of liver biochemistry. Secondary endpoints were hospitalisation for investigation or management of DILI, death attributable to liver injury, and liver transplantation. Twenty-three cases of DILI were identified, involving 40 drugs: 18 AAS, 14 SARMs and eight BBS. Patients were predominantly male (22/23), with median age 30 years (IQR 26-42). Most were symptomatic (21/23). Median latency of onset was 58 days (IQR 28-112 days) from drug commencement. Most patients (17/23) were admitted to hospital. Based on updated Roussel Uclaf Causality Assessment Method, DILI was possible in 17/23, probable in 2/23 and unlikely in 4/23. Median time to normalisation of liver biochemistry was 175 days (IQR 70-292 days) from presentation. Three (3/23) were treated with corticosteroids, 14/23 were treated for itch, and one (1/23) underwent liver transplantation. There were no deaths. The prognosis of DILI from AAS, SARMs and BBS is good although liver transplantation may rarely be required. A detailed drug history is important in uncovering DILI due to these supplements.

Steroid-responsive intractable pruritus in drug-induced liver injury: a case series

Background: Drug-induced liver injury (DILI) is commonly caused by modern medications, complementary and alternative medicines (CAMs), and other toxins. DILI is an umbrella term encompassing herb-induced liver injury (HILI) caused by herbs and CAMs, in addition to other medications. Apart from the cessation of the culprit drug and the supportive management, there are no definite treatment options for DILI. Although being used in DILI, steroids are not the standard medications for DILI, except that they are indicated for a few specific conditions. Materials and Methods: We report five cases of DILI with pruritus who responded well to steroids used as rescue therapy. DILI in these five cases was caused by CAMs (1), anabolic steroids (2), dapsone (1), and antifungal drug itraconazole (1). All patients presented with jaundice and pruritus, and their conditions did not improve following the discontinuation of offending agents and the implementation of supportive care. We used the Roussel UCLAF Causality Assessment Method 2016 for causality assessment. R-value was used to describe the pattern of liver injury. All patients underwent comprehensive work-up including liver biopsy as part of the procedure to rule out other potential etiologies. Steroids were used as a last resort, and both clinical and biochemical measurements were conducted. Results: The mean age of patients was 28.8 years, and the majority of them were males (80%). The median duration from symptom onset to presentation at our hospital was 4 weeks. The mean durations for pruritus improvement and complete biochemical improvement after steroid treatment were 3.2 weeks and 11.2 weeks, respectively. Extended follow-up was done for a mean period of 29.6 weeks from symptom presentation, and none of the patients had recurrence of liver injury after discontinuation of steroids. Conclusions: Ssteroids can be used to treat as rescue therapy for severe DILI with intractable pruritus in patients with worsening liver function. Relevance for Patients: DILI in selected cases can be therapeutically managed using steroids, which, however, should not be indicated as a first-line treatment.

Incidence of amoxycillin-clavulanic acid associated hepatotoxicity in an Australian children's hospital.

Amoxycillin/clavulanic acid is the most common antimicrobial cause of drug-induced liver injury in adults. It is a less common cause of severe drug-related hepatotoxicity in children despite its frequent use. We studied the incidence, characteristics and predictive factors for amoxycillin/clavulanic acid hepatoxicity in children. Retrospective cohort study of children who received oral or intravenous amoxycillin/clavulanic acid at a quaternary children's hospital over a 5-year period. Children were included if they had liver function tests (LFTs) determined at baseline, during and within 3 months after the treatment course. Causality was assessed using the Naranjo criteria for adverse drug reactions and Roussel Uclaf Causality Assessment Method. Of 3271 children prescribed amoxycillin/clavulanic acid, 374 were included. Forty-nine (13%) had LFT abnormalities related to amoxycillin/clavulanic acid. Fourteen (3.6%) fulfilled Common Terminology Criteria for Adverse Events (CTCAE) grade 2 criteria with clinically significant hepatotoxicity. Age <2 years, sepsis, post-gastrointestinal surgical indications, prolonged treatment course of >7 days and higher cumulative amoxycillin (>10 g) and clavulanic acid dose (>1 g) were predictive of hepatotoxicity. The median time to resolution of LFT abnormalities was 4 weeks (range 3-7). The incidence of amoxycillin/clavulanic acid related LFT abnormalities (CTCAE Grade 2 or above) in children was 3.6%. A prolonged treatment course >7 days, high cumulative amoxycillin (10 g) and clavulanic acid (>1 g) doses, those aged <2 years, and patients with sepsis or post-gastrointestinal surgery were predictive of a higher likelihood of abnormal LFTs. LFT monitoring should be considered in children receiving ≥7 days of treatment, particularly in those with other predisposing factors.

Predictive Model of Oxaliplatin-induced Liver Injury Based on Artificial Neural Network and Logistic Regression.

Identifying potential high-risk groups of oxaliplatin-induced liver injury (OILI) is valuable, but tools are lacking. So artificial neural network (ANN) and logistic regression (LR) models will be developed to predict the risk of OILI. The medical information of patients treated with oxaliplatin between May and November 2016 at 10 hospitals was collected prospectively. We used the updated Roussel Uclaf causality assessment method (RUCAM) to identify cases of OILI and summarized the patient and medication characteristics. Furthermore, the ANN and LR models for predicting the risk of OILI were developed and evaluated. The incidence of OILI was 3.65%. The median RUCAM score with interquartile range was 6 (4, 9). The ANN model performed similarly to the LR model in sensitivity, specificity, and accuracy. In discrimination, the area under the curve of the ANN model was larger (0.920>0.833, p=0.019). In calibration, the ANN model was slightly improved. The important predictors of both models overlapped partially, including age, chemotherapy regimens and cycles, single and total dose of OXA, glucocorticoid drugs, and antihistamine drugs. When the discriminative and calibration ability was given priority, the ANN model outperformed the LR model in predicting the risk of OILI. Other chemotherapy drugs in oxaliplatin-based chemotherapy regimens could have different degrees of impact on OILI. We suspected that OILI may be idiosyncratic, and chemotherapy dose factors may be weakly correlated. Decision making on prophylactic medications needs to be carefully considered, and the actual preventive effect needed to be supported by more evidence.

Development and Validation of a Clinical Risk Score to Predict Immune-mediated Liver Injury Caused by Sintilimab: Assessed for Causality Using Updated RUCAM.

Immune-mediated liver injury is a fatal side effect of sintilimab. This study aimed to shed light on the associated risk factors and characteristics of this adverse event. The clinical records of 772 patients treated with sintilimab were retrospectively reviewed to investigate risk factors associated with sintilimab immune-related hepatotoxicity, as well as its incidence and outcome. The Roussel Uclaf Causality Assessment Method was used to identify cases of sintilimab-induced hepatotoxicity. Furthermore, logistic regressions were performed to compare the clinical and bloodwork characteristics of patients with and without immune-mediated liver injury caused by checkpoint inhibitors. Of the 585 patients included in the study, 71 (12.1%) developed liver injury during sintilimab use. The median RUCAM score with interquartile range was 7 (6, 8). Hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were risk factors for sintilimab-related hepatotoxicity. A nomogram model was constructed for sintilimab-induced immune-mediated liver injury based on these risk factors, which had a C-index value of 0.713 and a good calibration curve. When applied to patients with grade ≥3 and ≥4 sintilimab-induced immune-mediated liver injury, it achieved C-index values of 0.752 and 0.811, respectively. The nomogram model also showed a good prediction potential in patients ≥65 years and males. Six of the patients with sintilimab-related hepatotoxicity showed improved liver function upon treatment with steroids. This study demonstrated that hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were clinically feasible prognostic biomarkers to predict liver injury in patients treated with sintilimab.

Aetiology of Significant Liver Test Abnormalities in a Single-Centre Cohort of People with Cystic Fibrosis Exposed to Elexacaftor/Tezacaftor/Ivacaftor, Utilizing the Updated RUCAM.

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) has been associated with substantial multisystem benefits for people with CF eligible for therapy. In a minority, tolerance has been limited by hepatic toxicity. It is unknown whether there may be particular risk factors for significant drug-induced elevation in transaminases. We aimed to determine the cause of raised transaminases following the introduction of E/T/I, and whether E/T/I can safely be continued in some individuals with elevated transaminases. At a large, single, adult CF centre, individuals with transaminases >3×the upper limit of normal (ULN) since commencing E/T/I underwent clinical assessment to exclude known causes of raised transaminases. Where an alternative cause could not be identified, individuals were discussed with hepatology to advise on further investigations to establish aetiology in addition to calculation of the updated Roussel Uclaf Causality Assessment Method (RUCAM) score to assess causality grading of drug-induced liver injury (DILI) due to E/T/I, and to guide management of ongoing CFTR modulator therapy. Of 337 adults taking E/T/I for a median of 27 months, 19 (5.6%) had transaminases >3×ULN. In 12 individuals, there was clear evidence of an aetiology unrelated to E/T/I (RUCAM scores -2 to 1 [excluded-unlikely]). Of the remaining cases, two had RUCAM scores in the 'possible' range and one had a RUCAM score in the 'probable' range. Liver biopsy was performed in four individuals, showing hepatic steatosis in one individual, normal histology in one individual, and hepatocyte necrosis suggestive of DILI in two individuals. E/T/I was suspended in those with hepatocyte necrosis, with one permanent discontinuation due to synthetic dysfunction. One individual with hepatocyte necrosis on histology was successfully re-established on E/T/I therapy. Alternative causes were identified in the majority of patients with clinically significant increases in transaminases following E/T/I, highlighting the importance of thorough investigation. Multidisciplinary assessment involving an experienced hepatologist is crucial in cases of diagnostic uncertainty or suggestion of significant DILI, as discontinuation of therapy can have significant consequences for individuals.

Incidence and predisposing factors for flucloxacillin-related hepatotoxicity in children.

Flucloxacillin-induced hepatotoxicity is well established in adults. However, there are few paediatric studies of flucloxacillin-induced hepatotoxicity despite this drug being among the most commonly prescribed in children. We aimed to determine the incidence of flucloxacillin-induced hepatotoxicity in children receiving IV therapy as well as identify risk factors for this adverse drug reaction. We undertook a 2 year retrospective audit of children aged 0-18 years admitted to the Royal Children's Hospital (March 2019 to March 2021) who had liver function tests determined before and after receiving IV flucloxacillin for at least 24 hours duration. Causality was assessed using the Roussel Uclaf Causality Assessment Method and Naranjo criteria. Overall, the incidence of hepatotoxicity was 66/393 (17%). The median age of children with hepatotoxicity was 1.1 years (IQR 0.3-11.9), 43 (65%) received two or more concomitant hepatotoxic medications and 23 (35%) were receiving total parenteral nutrition. The median timing of onset of hepatotoxicity after commencement of flucloxacillin was 4 days (range 2-7). Severe hepatotoxicity (Common Terminology Criteria for Adverse Events grade 3 or above) occurred in 9/66 (14%) for bilirubin, 13/66 (20%) for ALT and 10/66 (15%) for GGT. Predisposing factors for hepatotoxicity were increasing age (OR 1.06 per additional year, 95% CI 1.01-1.10, P = 0.02), with adolescents aged 12-18 years having the highest risk (OR 5.10, 95% CI 2.02-12.85, P = 0.001), and two or more concomitant hepatotoxic medications (OR 2.51, 95% CI 1.02-6.18, P = 0.05). The median time to resolution of hepatotoxicity after cessation of flucloxacillin was 5 days (range 2-10). In children, older patients and those receiving two or more concomitant hepatotoxic medications are at greater risk of flucloxacillin-induced hepatotoxicity.

Drug-induced liver injury and COVID-19: Use of artificial intelligence and the updated Roussel Uclaf Causality Assessment Method in clinical practice

The application of artificial intelligence (AI) in gastrointestinal endoscopy has gained significant traction over the last decade. One of the more recent applications of AI in this field includes the detection of dysplasia and cancer in Barrett’s esophagus (BE). AI using deep learning methods has shown promise as an adjunct to the endoscopist in detecting dysplasia and cancer. Apart from visual detection and diagnosis, AI may also aid in reducing the considerable interobserver variability in identifying and distinguishing dysplasia on whole slide images from digitized BE histology slides. This review aims to provide a comprehensive summary of the key studies thus far as well as providing an insight into the future role of AI in Barrett’s esophagus.

Combination vardenifil and tadalifil drug induced liver injury; case report and review of the literature of liver injury associated with phosphodiesterase type 5 inhibitors.

Phosphodiesterase type 5 inhibitors (PDE5I) are prescribed for erectile dysfunction and pulmonary hypertension. Despite its widespread use, there are only seven cases of drug-induced liver injury (DILI) associated with PDE5I, none associated with vardenafil or avanafil. We report a patient who had taken vardenafil and tadalafil individually for several years without developing symptoms of liver injury. However, after taking vardenafil and tadalafil together on 2 consecutive days, he developed severe cholestasis. Causality was determined using Roussel Uclaf causality assessment method (RUCAM). The patient is a 72-year-old White man in excellent health who drank 2 units of alcohol, three times/week. Previously, he had used vardenafil for more than 2 years and tadalafil for 3 months as single agent for erectile dysfunction without any complications. He took vardenafil and tadalafil for 2 consecutive days and 5 days later, he developed dyspepsia, loss of appetite, jaundice, and intense itching. Liver tests showed mixed cholestatic/hepatocellular pattern of injury. Histology showed marked cholestasis with minimal inflammation. He remained cholestatic for 5 weeks before a full recovery 2 months later. The patient then resumed vardenafil monotherapy with no recurrent liver dysfunction. RUCAM causality score 7 indicates that the combination of PDE5I is probable cause of liver injury. The similarities among the eight cases of PDE5I DILI include a relatively short latency, cholestatic histological features, and complete recovery. Biochemical pattern of liver injury is variable. PDE5I DILI is a rare event that can result in severe acute liver injury.

Idiosyncratic DILI and RUCAM under One Hat: The Global View

Drugs are prescribed worldwide to treat diseases but with the risk of idiosyncratic drug-induced liver injury (iDILI). The most important difficulty is how best to establish causality. Based on strong evidence and principles of artificial intelligence (AI) to solve complex processes through quantitative algorithms using scored elements, progress was achieved with the Roussel Uclaf Causality Assessment Method (RUCAM) in its original and updated versions, often viewed now as the gold standard. As a highly appreciated diagnostic algorithm, the RUCAM is in global use with around 100,000 iDILI cases published worldwide using RUCAM to assess causality, largely outperforming any other specific causality assessment tool in terms of case numbers. Consequently, the RUCAM helps to establish a list of top-ranking drugs worldwide implicated in iDILI and to describe clinical and mechanistic features of iDILI caused by various drugs. In addition, the RUCAM was recently applied in iDILI cases of patients treated for coronavirus disease 2019 (COVID-19) infections or cancer patients treated with immune checkpoint inhibitors (ICIs), as well as in the search for new treatment options with conventional drugs in iDILI. Analyses of RUCAM-based iDILI cases are helpful to support pathogenetic steps like immune reactions, genetic predisposition as evidenced by human leucocyte antigens (HLA) genotypes for selected drugs, and the role of the gut microbiome. To achieve consistency in data collection, analysis, and specific clinical and pathogenetic presentation, researchers, regulatory agencies, and pharmaceutical firms should place iDILI and the updated RUCAM as the causality tool under one and the same hat in review articles and clinical guidelines for the diagnosis and treatment of iDILI.

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.

Drug toxic hepatopathy - an underestimated danger

Drug-induced toxic hepatopathies and drug-induced liver injury, DILI, are characterized by a variety of clinical manifestations and therefore represent a significant diagnostic challenge. This article shows how DILI is diagnosed and what therapy options exist. Current special cases of DILI genesis are also discussed (DOACs, IBD drugs, tyrosine kinase inhibitors). These newer substances and corresponding hepatotoxic effects are not yet fully understood. The internationally recognized and online available RUCAM score (Roussel Uclaf Causality Assessment Method) helps to assess the probability of drug-related toxic liver damage.

Analysis of medical malpractice liability disputes related to novel antineoplastic drugs and research on risk prevention and control strategies.

To investigate the general characteristics of litigation cases of medical malpractice liability disputes (MMLDs) related to novel antineoplastic drugs (NADs), the drugs involved, as well as the common types of medical errors related to NADs and their damages in the process of diagnosis and treatment, with the aims of improving the level of rational medication use in the clinical application of NADs and actively prevent medical disputes. The China Judgments Online was searched for the cause of action using the key word "MMLDs" along with the name of 77 kinds of NADs. A total of 39 NAD litigation cases meeting the inclusion criteria from 1 January 2009 to 31 December 2021 were analyzed, and each potential adverse drug reaction (ADR) was reviewed to determine a causality assessment using the Naranjo algorithm for non-drug-induced liver injury (DILI) cases and the updated Roussel Uclaf Causality Assessment Method (RUCAM) for the DILI cases. Risk prevention and control strategies were recommended. Cases that met the inclusion criteria increased substantially each year during the last six years, from three cases in 2009-2015 to 36 cases in 2016-2021. There were more cases in Eastern China than in other geographic regions. Most cases involved tertiary hospitals, patients between 25 and 60 years of age, and patients who were predominately male. There were 18 kinds of NADs involved in medical errors. The most common consequences of NADs were closely related to the death, disability, and increased treatment costs caused by ADRs, inadequate indications, delayed diagnosis and treatment, and misdiagnosis and mistreatment. The most frequent medical errors were medical technology errors, medical ethics errors and medical record writing/safekeeping errors. In two cases involving DILI, one case was unable to undergo further RUCAM scoring because the liver function indicators of the patient before and after treatment were not published. The establishment of mechanisms to reduce the risks associated with the clinical application of NADs is warranted. Healthcare services must maintain strict adherence to the specific requirements of GPCANADs and drug instructions and strictly grasp the indications, contraindications, usage, and dosage of drugs, and strengthen the notification and management of off-label drug use. Monitoring patients for ADRs and preparing rescue and treatment measures for high-risk drugs may serve to reduce damages related to NADs. For DILI cases, medical and appraisal institutions should use RUCAM score to assess causal relationships.