Types Of Drug-induced Liver Injury Research Articles

New finding based on Comparative Toxicogenomics Database: Hepatic YY1 mediates drug-induced liver injury

BackgroundYY1 plays a crucial part in the onset and progression of numerous liver diseases, yet the significant contribution of YY1 to drug-induced liver injury (DILI) appears to have been underestimated by researchers. PurposeTo reveal the underlying role of YY1 in DILI. MethodThe compounds that interact with YY1 were queried in the Comparative Toxicogenomics Database (CTD), with the majority found to be hepatotoxic, which includes certain widely used drugs. Molecular docking and SPR characterized the robust binding of hepatotoxic compounds to YY1. The duty of YY1 in DILI was investigated in Diosbulbin B (DIOB), a recently identified hepatotoxic compound that tightly associates with YY1, and further validated on ANIT, LCA, APAP, and CDDP. Transcriptomic analysis disclosed the underlying mechanisms involved in DIOB-induced liver injury. RT-qPCR, immunohistochemistry, immunofluorescence, western blotting, and cellular transfection techniques were employed to validate the specific mechanism. ResultsAmong the 94 compounds affecting YY1 expression in the CTD, 59 compounds exhibited hepatotoxicity, showing close interactions with YY1 and almost consistent binding sites by molecular docking. The SPR validated the tough binding of several hepatotoxic compounds to YY1, including five FDA-approved hepatotoxic drugs. Mechanistically, the involvement of YY1 in DILI was uncovered through the cholestasis lens, mice hepatic YY1 was up-regulated by hepatotoxic DIOB and transcriptionally inhibited FXR and its downstream BSEP and MRP2 expression, initiating early in cholestatic liver injury and persisting to drive the progression of cholestasis. ANIT and LCA-induced model of cholestasis provided evidence for the hypothesis that YY1 frequently mediates drug induced cholestasis (DIC). APAP and CDDP indicated that YY1 may also be involved in hepatocellular and mixed type DILI. ConclusionYY1 widely mediated the development of DIC and also might be engaged in other types of DILI. YY1 presented a common target for hepatotoxic medications and the targeting of liver YY1 for drug development may offer a novel approach for managing DILI.

Role of liver biopsy in the management of idiosyncratic DILI.

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

Glucocorticoid efficacy and treatment strategies for drug-induced liver injury: a literature review.

Drug-induced liver injury (DILI) is an adverse reaction to drugs and their metabolites. The activation of adaptive immune and inflammatory responses plays an important role in the pathogenesis of DILI. Glucocorticoids (GCs) have powerful anti-inflammatory and immunosuppressive effects and have been used to treat a variety of immune-mediated liver diseases. Due to the important role of the immune system in DILI, GCs are widely used in the clinical treatment of DILI; however, whether they are beneficial to patients remains controversial. There is no uniform standard for the timing, dosage, and population selection of GCs, which mainly depend on the clinician's experience. Therefore, elucidating whether GCs are beneficial for patients with DILI is an urgent clinical problem. Our review summarizes the recent literature and discusses the clinical efficacy, applicable population, application timing, and efficacy of GCs in special types of DILI, providing a reference for the clinical application of GCs.

Identification of reversible OATP1B1 and time-dependent CYP3A4 inhibition as the major risk factors for drug-induced cholestasis (DIC).

Hepatic bile acid regulation is a multifaceted process modulated by several hepatic transporters and enzymes. Drug-induced cholestasis (DIC), a main type of drug-induced liver injury (DILI), denotes any drug-mediated condition in which hepatic bile flow is impaired. Our ability in translating preclinical toxicological findings to human DIC risk is currently very limited, mainly due to important interspecies differences. Accordingly, the anticipation of clinical DIC with available in vitro or in silico models is also challenging, due to the complexity of the bile acid homeostasis. Herein, we assessed the in vitro inhibition potential of 47 marketed drugs with various degrees of reported DILI severity towards all metabolic and transport mechanisms currently known to be involved in the hepatic regulation of bile acids. The reported DILI concern and/or cholestatic annotation correlated with the number of investigated processes being inhibited. Furthermore, we employed univariate and multivariate statistical methods to determine the important processes for DILI discrimination. We identified time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 and reversible inhibition of the organic anion transporting polypeptide (OATP) 1B1 as the major risk factors for DIC among the tested mechanisms related to bile acid transport and metabolism. These results were consistent across multiple statistical methods and DILI classification systems applied in our dataset. We anticipate that our assessment of the two most important processes in the development of cholestasis will enable a risk assessment for DIC to be efficiently integrated into the preclinical development process.

Risk Factors for Immune Checkpoint Inhibitor-Induced Liver Injury and the Significance of Liver Biopsy.

Immune checkpoint inhibitor (ICI)-induced liver injury (LI) is a common adverse event, but the clinical characteristics based on the classification of hepatocellular injury and cholestatic types are not fully evaluated. This study aims to analyze risk factors and histological findings in relation to the classification of ICI-induced LI. In total, 254 ICI-induced LI patients among 1086 treated with ICIs between September 2014 and March 2022 were classified according to the diagnostic criteria for drug-induced LI (DILI), and their risk factors and outcomes were evaluated. Kaplan-Meier analyses showed that overall survival in patients with hepatocellular-injury-type LI was significantly longer than others (p < 0.05). Regarding pre-treatment factors, the lymphocyte count was significantly higher in patients with ICI-induced LI, especially in hepatocellular-injury-type LI. Gamma glutamyl transferase (γGTP) and alkaline phosphatase (ALP) were also significantly lower in patients with ICI-induced LI (p < 0.05). Multivariate analyses revealed that malignant melanoma, high lymphocyte count, and low ALP levels were extracted as factors contributing to hepatocellular-injury-type LI. The histological findings among 37 patients diagnosed as ICI-induced LI via liver biopsy also revealed that the spotty/focal necrosis was significantly frequent in hepatocellular-injury-type LI, whereas ductular reactions were frequently observed in cholestatic-type LI. It is suggested that the histological inflammation pattern in patients with LI is closely correlated with the type of DILI.

Significance of histological assessment in drug-induced liver injury

Liver histological assessment is of great clinical significance for the diagnosis, classification, and prognosis prediction of drug-induced liver injury (DILI). Liver histological evaluation can effectively supplement RUCAM. The clinical phenotypes of DILI are complex and diverse, including acute, chronic and severe hepatic injury. DILI has multiple insult-targets, including hepatocytes, cholangiocytes, and vascular endothelial cells and others. The pathological damage patterns are similar to many types of non-DILI liver diseases, therefore making differential diagnosis difficult. New anti-tumor drugs such as immune checkpoints inhibitors and targeted therapy are widely used in clinical antineoplastic practice, thus the growing incidence of related liver injury occurs. Liver histological examination can effectively assess the pathological phenotypes and severity of DILI, so as to guide treatment. In uncommon conditions such as special types of DILI (such as hepatic vascular disease), DILI with other competitive etiology overlapping, chronic DILI, and DILI induced liver failure, liver histological assessment can provide strong support for identifying the cause, rational treatment, and prognosis. Currently, the histological evaluation system for drug-induced liver injury seems to be a lack of consensus, and the diagnosis of DILI is short of highly specific and sensitive serological markers. All in all, liver histological assessment plays a crucial role in the diagnosis and differential diagnosis of DILI.

ГЕПАТОТОКСИЧНОСТЬ НЕСТЕРОИДНЫХ ПРОТИВОВОСПАЛИТЕЛЬНЫХ СРЕДСТВ У ПАЦИЕНТОВ С ПОДАГРОЙ

Non-steroidal anti-inflammatory drugs (NSAIDs) are the second most common group of drugs leading to the development of drug-induced liver injury (DILI). Objective: to determine the clinical features of DILI in patients with gout when using NSAIDs. Material and methods. The study is monocentric, observational, retrospective. Performed in the period from 2012-01-01 to 2020-12-31 in the Rheumatology Department of the 11th City Clinical Hospital. The study included 527 patients with gouty arthritis (GA). The type of DILI was determined in accordance with the recommendations of EASL, 2019. An updated scale RUCAM (Roussel Uclaf Causality Assessment Method) was used to assess causal relationships. Results. DILI was detected in 91 patients (14.3%), in 80 – hepatocellular, in 11 - mixed type of DILI. The 1st category of DILI severity was stated in 88, the 2nd category – in 3 patients. We observed DILI more often in younger patients without severe comorbidity, but with an alcoholic surplus preceding a GA attack and, after, during attack an excess of the average therapeutic doses of NSAIDs was registered. Conclusions. Thus, we did not observe a severe course of DILI in patients taking NSAIDs for the relief of GA. However, NSAID hepatotoxicity in this category of patients is a social and medical problem.

„Vanishing bile duct syndróm“ ako prejav poliekového poškodenia pečene u pacienta po polytraume

Summary: Vanishing bile duct syndrome is a type of drug-induced cholestatic liver injury that occurs when the body is exposed to drugs or other foreign substances. We hospitalized a 44-year-old, so far healthy, male with gradually developing painless icterus and pruritus of the whole body after severe polytrauma. The patient had previously undergone a complex treatment (antibio tics, antifungals, parenteral nutrition, LMWH). Laboratory tests revealed a several-fold elevation of total and conjugated bilirubin with a 3-fold increase in ALP levels, no signifi cant elevation of transaminases, a decrease in prothrombin time and IgG4 antibody positivity. An MRCP scan was performed revealing irregular intrahepatic bile ducts, a dilated common bile duct and characteristics of primary or secondary sclerosing cholangitis. Further examinations ruled out infectious, metabolic, toxic and oncological causes of hepatopathy. A liver bio psy ruled out both autoimmune hepatitis and IgG4 hepatopathy and displayed images of “vanishing bile duct syndrome” in drug-induced liver injury (DILI). Empirical treatment with high-dose intravenous N-acetylcysteine and other hepatoprotective agents led to a gradual decrease of bilirubin, normalization of coagulation parameters and remission of icterus and clinical complaints. This case report points to a cholestatic type of drug-induced liver injury with histologically confi rmed vanishing bile duct syndrome and the need to think of DILI as one of the causes of the otherwise unexplained hepatopathy. Key words: cholangitis – DILI – hepatopathy – IgG4 – vanishing bile duct syndrome

Silymarin Protects against Acute Liver Injury Induced by Acetaminophen by Downregulating the Expression and Activity of the CYP2E1 Enzyme.

Previous studies have shown that silymarin protects against various types of drug-induced liver injury, but whether the protective mechanism of silymarin against acetaminophen-induced liver injury is related to the CYP2E1 enzyme remains unclear. In this study, we investigated the effect of silymarin on the activity and expression of CYP2E1 in vitro and in vivo. The results of in vitro studies showed that silymarin not only inhibited the activity of CYP2E1 in human and rat liver microsomes but also reduced the expression of CYP2E1 in HepG2 cells. In vivo studies showed that silymarin pretreatment significantly reduced the conversion of chlorzoxazone to its metabolite 6-OH-CLX and significantly increased the t1/2, area under the curve (AUC) and mean residence time (MRT) of chlorzoxazone. In addition, silymarin pretreatment significantly inhibited the upregulation of Cyp2e1 expression, reduced the production of 3-cysteinylacetaminophen trifluoroacetic acid salt (APAP-CYS), and restored the liver glutathione level. The results of our study show that silymarin plays an important protective role in the early stage of acetaminophen-induced acute liver injury by reducing the activity and expression of CYP2E1, reducing the generation of toxic metabolites, and alleviating liver injury.

Recognition of specific types of drug-induced liver injury using random forest algorithm: the importance of individual serum bile acid level

Recognition of specific types of drug-induced liver injury using random forest algorithm: the importance of individual serum bile acid level

Frequency of null genotypes of glutathione S-transferase M1 and T1 in Japanese patients with drug-induced liver injury.

Previous reports suggest that the null genotype (*0/*0) of glutathione S-transferase (GST) M1 and/or GSTT1 could be risk factors for drug-induced liver injury (DILI). However, multi-institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients. Blood samples of 270 DILI patients from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp-2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week-Japan score, as well as genotypes of GSTM1 and GSTT1 in each patient with DILI. The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of the GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and Digestive Disease Week-Japan scores was not observed. The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients.

Role and Regulation of Hepatobiliary ATP-Binding Cassette Transporters during Chemical-Induced Liver Injury.

Severity of drug-induced liver injury (DILI) ranges from mild, asymptomatic, and transient elevations in liver function tests to irreversible liver damage, often needing transplantation. Traditionally, DILI is classified mechanistically as high-frequency intrinsic DILI, commonly dose dependent or DILI that rarely occurs and is idiosyncratic in nature. This latter form is not dose dependent and has a pattern of histopathological manifestation that is not always uniform. Currently, a third type of DILI called indirect hepatotoxicity has been described that is associated with the pharmacological action of the drug. Historically, DILI was primarily linked to drug metabolism events; however, the impact of transporter-mediated rates of drug uptake and excretion has gained greater prominence in DILI research. This review provides a comprehensive view of the major findings from studies examining the contribution of hepatic ATP-binding cassette transporters as key contributors to DILI and how changes in their expression and function influence the development, severity, and overall toxicity outcome. SIGNIFICANCE STATEMENT: Drug-induced liver injury (DILI) continues to be a focal point in drug development research. ATP-binding cassette (ABC) transporters have emerged as important determinants of drug detoxification, disposition, and safety. This review article provides a comprehensive analysis of the literature addressing: (a) the role of hepatic ABC transporters in DILI, (b) the influence of genetic mutations in ABC transporters on DILI, and (c) new areas of research emphasis, such as the influence of the gut microbiota and epigenetic regulation, on ABC transporters.

Prevalence and risk factors of tigecycline-induced liver injury: A multicenter retrospective study

We conducted this multicenter retrospective study to evaluate the prevalence, clinical patterns, and risk factors for tigecycline-induced liver injury, which is a type of drug-induced liver injury (DILI). Inpatients receiving intravenous tigecycline for ≥7 days were included. Patient information was collected to assess possible DILIs. The pattern and severity of tigecycline DILI were evaluated. A multivariable logistic regression model was used to identify the independent risk factors associated with tigecycline DILI. A total of 986 patients were identified and 397 patients were included in this study. The prevalence of tigecycline DILI was 10.3% (95% confidence interval [CI]=7.51-13.7%). The most common type of tigecycline DILI was cholestatic, with mild severity observed in most cases. Abnormal baseline alanine aminotransferase levels (odds ratio [OR]=3.11, 95% CI=1.55-6.24, P=0.001), intensive care unit admission (OR=2.63, 95% CI=1.32-5.36, P=0.006), and treatment length (in weeks) (OR=1.25, 95% CI=1.05-1.49, P=0.011) were independent risk factors for tigecycline DILI. Our results indicate that the prevalence of tigecycline DILI is high, and that the patients at risk should receive special attention.

Prevention and treatment of drug-induced liver injury in patients with breast cancer and ovarian cancer

Introduction: Drug-induced liver injury is one of the most serious problems in hepatology. In most cases the abolition of the “causative” drug is a sufficient condition for the reverse development of pathological changes. However, in the case of chemotherapy for cancer patients, the abolition of hepatotoxic drug is impossible without creating an immediate or delayed threat to the patient’s life. Objective: To develop optimal schemes for the prevention and treatment of drug-induced liver injury by studying of its characteristics of with various chemotherapy regimens in patients with breast cancer and ovarian cancer. Material and methods: The screening group included 291 patients who underwent chemotherapy courses for breast cancer and ovarian cancer. The diagnosis and type of drug-induced liver injury was based on laboratory data (alanine aminotransferase and/or alkaline phosphatase increased above 2 norms) and the exclusion of other etiologies of liver diseases. Chemotherapy hepatotoxicity was assessed using the Shaposhnikov scale. The degree of hepatic encephalopathy was determined using a critical flicker frequency test. Depending on chemotherapy mode, groups of the patients were divided into subgroups: cyclophosphamide + Methotrexate+ Fluorouracil, Doxorubici + Cyclophosphamide, Epirubicin + Cyclophosphamide + 5-fluorouracil, Paclitaxel + Cisplatin, Carboplatin + Cyclophosphamide. According to the type of drug-induced liver injury, patients with cholestatic type received preparations, with cytolytic type – S-adenosylmethionine for 8 weeks. Results and its discussion: It was found that the most common side effect of chemotherapy is leukopenia, anemia and increase in level of alanine aminotransferase and alkaline phosphatase. The use of ursodeoxycholic acid and S-adenosylmethionine as an accompanying therapy significantly reduces the level of alanine aminotransferase and alkaline phosphatase degree of hepatotoxicity and hepatic encephalopathy, clinical improves the quality of life of patients and contributes to a more rapid elimination of symptoms of astheno-vegetative, dyspeptic and pain syndromes. Conclusion: It has been proven that the use of a differentiated approach to the choice of a hepatoprotector: S-adenosylmethionine in hepatocellular type, ursodeoxycholic acid - in cholestatic type of drug-induced liver injury for 8 weeks in patients with oncological profile allowed to carry out the planned therapy without deviations from the protocol.

The Characteristics, Prevalence, and Risk Factors of Drug-Induced Liver Injury Among Brucellosis Inpatients in Xinjiang, China.

Background: We investigated the prevalence, demographic and clinical features, and risk factors associated with drug-induced liver injury (DILI) during the treatment of brucellosis inpatients in a retrospective study. Methods: We collected the clinical data of 782 brucellosis inpatients admitted at the Shawan County People’s Hospital, Xinjiang, from 2015–2019. All cases were re-evaluated using the international consensus of DILI criteria and RUCAM rating scale. 71 patients were confirmed as DILI cases and compared with 523 other patients with normal liver function. Results: It was indicated that DILI occurred with a prevalence of about 9.08% among brucellosis inpatients receiving drug therapy. Hepatocellular injury was the most common type of DILI (61.97%, 95% confidence interval [CI] 50.34–72.37), followed by mixed (23.94%, 95% CI 15.52–35.04) and cholestatic types (14.08%, 95% CI 7.83–24.02). In addition, 13.64% of the hepatocellular DILI cases fulfilled Hy’s law criteria and only two cases (2.82%) progressed to severe DILI. Most patients adopted the combination of rifampicin, antipyretic analgesics, anti-infective agents, and traditional Chinese medicine for the treatment of brucellosis, with all the 71 patients taking rifampicin as the drug of choice. Multivariable logistic regression analyses indicated that obesity, regular alcohol intake, and decreased serum albumin were the independent risk factors of DILI in patients with brucellosis after adjusting for gender, age, and ethnicity. Conclusion: DILI occurred in a minority of inpatients diagnosed with brucellosis receiving rifampicin-based therapeutic regimen. In addition, obesity, alcohol abuse, and decreased serum albumin were valuable predictors of the risk of DILI in patients with brucellosis.

Testing in vitro tools for the prediction of cholestatic liver injury induced by non-pharmaceutical chemicals

Bile acid accumulation and subsequent liver damage is a frequent adverse effect induced by drugs. Considerable efforts have therefore been focused on the introduction and characterization of tools that allow reliable prediction of this type of drug-induced liver injury. Among those are the cholestatic index and transcriptomic profiling, which are typically assessed in in vitro settings. The present study was set up to test the applicability of both tools to non-pharmaceutical compounds with cholestatic potential, including the industrial compound bis(2-ethylhexyl)phthalate, the cosmetic ingredients triclosan and octynoic acid, the herbicides paraquat and quizalofop-para-ethyl, and the food additives sunset yellow and tartrazine, in a human hepatoma cell culture model of cholestatic liver injury. The cholestatic index method showed cholestatic liability of sunset yellow, tartrazine and triclosan. Of those, tartrazine induced transcriptional changes reminiscent of the transcriptional profile of cholestatic drugs. Furthermore, a number of genes were found to be uniquely modulated by tartrazine, in accordance with the cholestatic drugs atazanavir, cyclosporin A and nefazodone, which may have potential as novel transcriptomic biomarkers of chemical-induced cholestatic liver injury. In conclusion, unambiguous identification of the non-pharmaceutical compounds tested in this study as inducers of cholestasis could not be achieved.

The Diagnosis of Drug-induced Liver Injury: Current Diagnostic Ability and Future Challenges of the Digestive Disease Week-Japan 2004 Scale 15 Years after Its Proposal.

Objective This study examined whether or not the Digestive Disease Week-Japan (DDW-J) 2004 scale proposed over 15 years ago can be applied to current cases of drug-induced liver injury (DILI). Methods The new patients group included 125 patients from 2012 to 2019 and was divided into 2 subgroups: 96 patients in the new DILI group and 29 patients in the new non-DILI group. Similarly, the old patients group included 105 patients from 1997 to 2002 and was divided into 2 subgroups: 59 patients in the old DILI group and 46 patients in the old non-DILI group. Patients were assessed by the DDW-J 2004 scale; those with a score ≥3 were defined as having DILI. Results The total score of the new DILI group was significantly lower than that of the old DILI group [6 (1-11) vs. 6 (3-9), p=0.004]. The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) were 94.8%, 65.6%, 90.1%, and 79.2%, respectively, in the new patients group and 100%, 91.4%, 93.7%, and 100%, respectively, in the old patients group. The specificity and NPV of the new patients group were significantly lower than those of the old patients group. Conclusion The DDW-J 2004 scale maintains a stable diagnostic ability for DILI, regardless of differences in eras and verification methods. However, differential diagnoses can affect the scoring, and new types of DILI, such as immune-related adverse events, must be addressed. Therefore, upgrading the scale should be considered.

Drug properties and host factors contribute to biochemical presentation of drug-induced liver injury: a prediction model from a machine learning approach

Drug-induced liver injury (DILI) presentation varies biochemically and histologically. Certain drugs present quite consistent injury patterns, i.e., DILI signatures. In contrast, others are manifested as broader types of liver injury. The variety of DILI presentations by a single drug suggests that both drugs and host factors may contribute to the phenotype. However, factors determining the DILI types have not been yet elucidated. Identifying such factors may help to accurately predict the injury types based on drugs and host information and assist the clinical diagnosis of DILI. Using prospective DILI registry datasets, we sought to explore and validate the associations of biochemical injury types at the time of DILI recognition with comprehensive information on drug properties and host factors. Random forest models identified a set of drug properties and host factors that differentiate hepatocellular from cholestatic damage with reasonable accuracy (69-84%). A simplified logistic regression model developed for practical use, consisting of patient's age, drug's lipoaffinity, and hybridization ratio, achieved a fair prediction (68-74%), but suggested potential clinical usability, computing the likelihood of liver injury type based on two properties of drugs taken by a patient and patient's age. In summary, considering both drug and host factors in evaluating DILI risk and phenotypes open an avenue for future DILI research and aid in the refinement of causality assessment.

Drug Induced Liver Injury in Geriatric Patients Detected by a Two-Hospital Prospective Pharmacovigilance Program: A Comprehensive Analysis Using the Roussel Uclaf Causality Assessment Method.

Background/aim: A prospective evaluation of drug-induced liver injury (DILI) in two tertiary hospitals was conducted through a pharmacovigilance program from laboratory signals at hospital (PPLSH) to determine the principal characteristics of DILI in patients older than 65 years, a growing age group worldwide, which is underrepresented in the literature on DILI. Methods: All DILI in patients older than 65 years detected by PPLSH in two hospitals were followed up for 8 years in the La Paz Hospital and 2 years in the Getafe Hospital. A descriptive analysis was conducted that determined the causality of DILI and suspected drugs, the incidence of DILI morbidities, DILI characteristics, laboratory patterns, evolution and outcomes. Results: 458 DILI cases in 441 patients were identified, 31.0% resulting in hospitalisation and 69.0% developing during hospitalisation. The mean age was 76.61 years old (SD, 7.9), and 54.4% were women. The DILI incidence was 76.33/10,000 admissions (95%CI 60.78–95.13). Polypharmacy (taking >4 drugs) was present in 86.84% of patients, 39.68% of whom took >10 drugs. The hepatocellular phenotype was the most frequent type of DILI (53.29%), a higher proportion (65%) had a mild severity index, and, in 55.2% of the evaluated drugs the RUCAM indicated that the causal relationship was highly probable. The most frequently employed drugs were paracetamol (50-cases), amoxicillin-clavulanate (42-cases) and atorvastatin (37-cases). The incidence rate of in-hospital DILI per 10,000 DDDs was highest for piperacillin-tazobactam (66.96/10,000 DDDs). A higher risk of in-hospital DILI was associated with the therapeutic chemical group-J (antiinfectives for systemic use) (OR, 2.65; 95%CI 1.58–4.46) and group-N (central nervous system drugs) (OR, 2.33; 95%CI 1.26–4.31). The patients taking >4 medications presented higher maximum creatinine level (OR, 2.01; 95%CI 1.28–3.15), and the patients taking >10 medications had a higher use of group J drugs (OR, 2.08; 95%IC 1.31–3.32). Conclusion: The incidence rate of DILI in the patients older than 65 years was higher than expected. DILI in elderly patients is mild, has a good outcome, has a hepatocellular pattern, develops during hospitalisation, and prolongs the hospital stay. Knowing the DILI incidence and explanatory factors will help improve the therapy of the elderly population.

Hepatobiliary and Pancreatic Adverse Events.

The expanded approval of immune checkpoint inhibitors (ICIs) for the treatment of multiple cancer types has offered patients more opportunities in treatment selection and survival.Hepatotoxicity is a well-recognized immune-related adverse event (irAE) associated with treatment with ICI. It is considered a type of drug-induced liver injury (DILI). Depending on the specific ICI and whether the patient receives single- or dual-drug therapy, the incidence of hepatotoxicity in general could be as high as 30%. As more patients receive treatment with ICI, more cases of hepatotoxicity are expected to occur. Clinicians must exercise close pharmacovigilance to recognize liver-related irAEs early.ICI-mediated hepatobiliary toxicity (or "IMH")generally presents as asymptomatic elevations of alanine transaminase and aspartate transaminase, with or without alkaline phosphatase elevation. Some patients may present with jaundice, fever, or malaise. Rarely, it may cause liver failure and death. The diagnosis of IMH is made after careful exclusion of other causes of acute hepatitis based on medical history, laboratory evaluation, imaging, and liver histological findings. In clinically significant cases of IMH, the management involves discontinuation of ICI followed by close monitoring and the initiationof immunosuppression. Current society guidelines, which are not based on robust evidence, specify treatment recommendations depending on the grade of liver injury, according to the Common Terminology Criteria for Adverse Events (CTCAE)version 5.0. However, our clinical experience suggests possible alternatives, including lower corticosteroid dosing with adjunct therapies. Whereas current guidelines endorse permanent cessation of future ICI treatment in patients diagnosed with grades 3-4 IMH, published clinical experience suggests potential for flexibility when assessing for candidacy of resuming ICI.Because histologic bile duct injury has been observed in cases ascribed to IMH, ICI-mediated cholangiopathic disease probably exists on a spectrum within IMH. Even extrahepatic bile duct involvement has been observed. This phenotype warrants special considerations in treatment and surveillance.ICI-related cholecystitis has been rarely reported in the literature. Management follows current standards of care for typical cases of cholecystitis. No relationship with ICI-mediated cholangiopathic disease has been observed.Assessing for and managing ICI-associated pancreatic injury remainchallenging to the clinician. Many cases of asymptomatic serum lipase elevation are detected on routine labs without clinical signs or symptoms of typical acute pancreatitis. However, symptomatic patients should be initially managed like traditional cases of acute pancreatitis requiring hospitalization for evaluation and inpatient management.