Risk Of Liver Injury Research Articles

Risk and impacts of drug-induced liver injury (DILI) due to immune-checkpoint inhibitors (ICI) on overall survival in patients with newly diagnosed cancer: A retrospective cohort study.

12049 Background: The risk and impact of drug-induced liver injury (DILI) due to ICI treatment on newly diagnosed cancer patients have not been fully investigated. This study aims to assess the incidence and impact of ICI related DILI on overall survival. Methods: We included patients with newly diagnosed cancer treated with ICIs between 01/2012 and 12/2020 at the Ohio State University Comprehensive Cancer Center. DILI was defined using ICD-9 and ICD-10 codes for abnormal results of liver function, acute hepatitis, drug-induced liver injury, or toxic liver disease. History of Liver Disease (HLD) before ICI infusion was defined using ICD-9 and ICD-10 codes for any liver disease, including primary and secondary liver malignant neoplasms. To examine the causal effects of ICI-related DILI, patients who developed hepatocellular carcinoma or metastatic liver disease were excluded. Kaplan Meier method was used to estimate DILI risk post-ICI infusion in patients with and without HLD. Crude and Adjusted Cox proportional models were used to examine the association between DILI, modeled as time-dependent, and overall survival. Results: A total of 2,816 patients were included in the study, with a median age of 62 years, 58% male, and 90% white non-Hispanics. An estimated 11% of patients developed DILI during follow-up. The median (interquartile range) follow-up time from ICI infusion to DILI was 8.7 (3.0–20.1) months. The overall risk of DILI was 25.3%, which was significantly higher in patients with HLD than in those without HLD (17.8% vs. 30.8%, Log-Rank P <0.001). The median (interquartile range) survival time was 10.4 (3.7–22.7) months. During follow-up, a total of 1390 (49.4%) patients died. DILI was significantly associated with a higher risk of all-cause mortality in all regression models. The crude risk of all-cause mortality was 40% higher in patients with DILI than in those without DILI [HR: 1.40; 95% CI: 1.15–1.70]. In the fully adjusted models, DILI was associated with a 63% higher risk of all-cause mortality [adjusted HR: 1.63; 95% CI: 1.34–1.99]. DILI's effects on the overall survival risk remained significant when we further adjusted for HLD status [HR: 1.57; 95% CI: 1.29–1.93]. Conclusions: The findings from this retrospective cohort study highlight the significant risk and detrimental impact of DILI on overall survival in patients treated with ICIs. Notably, the incidence of DILI was significantly higher among patients with HLD, underscoring the elevated vulnerability of this subgroup. Furthermore, DILI was a significant predictor of increased all-cause mortality regardless of HLD status. These results underscore the need for vigilant monitoring and management of liver function in patients receiving ICIs, particularly in those with pre-existing liver conditions, to mitigate the risk of DILI and improve survival outcomes.

SAT-314 Impact of hepatic steatosis on risk of acute liver injury among people with chronic hepatitis B and SARS-CoV-2 infection

SAT-314 Impact of hepatic steatosis on risk of acute liver injury among people with chronic hepatitis B and SARS-CoV-2 infection

Discovery, evaluation, prevention, and control of liver injury risk by Polygoni Multiflori Radix

In recent years, adverse reactions and events associated with traditional Chinese medicines (TCMs) and herbal medicines (HMs) have frequently occurred. In particular, with regard to the safety of newly discovered TCMs that have been deemed “toxic,” providing a scientifically based answer and developing effective solutions is challenging. Owing to the complexity of TCM/HM products and lack of systematic research, our understanding of the potential causes of TCM/HM-induced liver injury is limited. Therefore, significant advancements in understanding the toxicity of TCM and preventing and managing safety risks are urgently needed to address the safety concerns associated with TCMs/HMs. Using Polygoni Multiflori Radix (PMR) hepatotoxicity as a typical example, we evaluated the “integrated evidence chain” based on the causality evaluation of TCM-induced liver injury, and confirmed the objective authenticity of PMR hepatotoxicity. Furthermore, we first proposed and established a disease-syndrome-combined toxicology model that was applied to the objective evaluation and analysis of the mechanism of PMR-induced hepatotoxicity. The mechanism hypothesis of “three-factor-induced toxicity” of idiosyncratic hepatotoxicity of TCM was proposed and confirmed. Based on this, the disease characteristics of the population susceptible to PMR idiosyncratic hepatotoxicity were elucidated, and various biomarkers were screened and identified, including the genetic marker HLA-B*35:01 and immunological and metabolomic markers. Finally, the study explored and established a safe medication strategy and method for “host-drug-use” three-dimensional risk prevention and control based on identifying susceptible individuals, controlling susceptible substances, and clinical precision medication. This study provides a foundation for comprehensively understanding the scientific implications of TCM/HM toxic side reactions and establishing scientific and effective risk prevention and control strategies.

Comparison of the safety profiles for pirfenidone and nintedanib: a disproportionality analysis of the US food and drug administration adverse event reporting system.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. Pirfenidone (PFD) and nintedanib (NDN) were both conditionally recommended in the clinical practice guideline published in 2015. Safety and tolerability are related to the risk of treatment discontinuation. Therefore, this study evaluated and compared the adverse events (AEs) of PFD and NDN in a large real-world population by analyzing data from the FDA Adverse Event Reporting System (FAERS) to provide a reference for their rational and safe use. The AEs of PFD and NDN were extracted from the FAERS database. The pharmacovigilance online analysis tool OpenVigil 2.1 was used to retrieve data from the FAERS database from the first quarter of 2012 to the second quarter of 2022. The reporting odds ratio (ROR) and proportional reporting ratio were used to detect the risk signals. The database included 26,728 and 11,720 reports for PFD and NDN, respectively. The most frequent AEs of PFD and NDN were gastrointestinal disorders. The RORs for these drugs were 5.874 and 5.899, respectively. "Cardiac disorders" was the most statistically significant system order class for NDN with an ROR of 9.382 (95% confidence interval = 8.308-10.594). Furthermore, the numbers of designated medical events of PFD and NDN were 552 and 656, respectively. Notably, liver injury was reported more frequently for NDN (11.096%) than for PFD (6.076%). This study revealed differences in the reporting of AEs between PFD and NDN. The findings provide reference for physicians in clinical practice. Attention should be paid to the risks of cardiac disorders and liver injury associated with NDN.

Guidelines for safe use of Polygoni Multiflori Radix

Polygoni Multiflori Radix is a Chinese medicine widely used in clinical treatment and preventive healthcare. However, recently there have been frequent reports of liver injury caused by Polygoni Multiflori Radix and its related preparations, and some patients have serious adverse outcomes, attracting wide attention worldwide. The risk of liver damage caused by preparations containing Polygoni Multiflori Radix or Polygoni Multiflori Caulis has been repeatedly reported by the Chinese Food and Drug Administration. Fortunately, substantial progress has recently been made in revealing the basic properties, main causes, material basis, and molecular mechanism of Polygoni Multiflori Radix-related liver injury. The basic characteristics and biomarkers of susceptible people have been identified, indicating that Polygoni Multiflori Radix has the risk of inducing liver injury only in a few specific populations and is safe for most populations. This study provides a scientific basis for a correct and objective understanding of liver injury caused by Polygoni Multiflori Radix, and a reasonable formulation of safe medication measures for Polygoni Multiflori Radix and related preparations. The China Association of Chinese Medicine organized experts in relevant fields across the country to draft and formulate the “Guidelines for Safe Use of Polygoni Multiflori Radix,” with the aim of helping the public and relevant institutions at home and abroad to scientifically understand, evaluate, and avoid the risk of liver injury; guide the rational use; protect the health rights and interests of consumers; and promote the healthy and sustainable development of Polygoni Multiflori Radix and related preparations. These guidelines were issued by the China Association of Chinese Medicine (No.T/CACM 1328-2019).

The use of PD-1 functional knockout rats to study idiosyncratic adverse reactions to nevirapine.

Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine is associated with a relatively high risk of serious skin rash and liver injury. We previously found that nevirapine causes a similar skin rash in female Brown Norway rats, but these animals do not develop significant liver injury. Programmed cell death protein-1 (PD-1) is an immune checkpoint involved in immune tolerance, and anti-PD-1 antibodies have been used to treat cancer. However, they increase the risk of liver injury caused by co-administered drugs. We found that PD-1-/- mice are more susceptible to drug-induced liver injury, but PD-1-/- mice are not a good model for all drugs. In particular, they do not develop a skin rash when treated with nevirapine, at least in part because they lack the sulfotransferase in their skin that forms the reactive metabolite responsible for the rash. Therefore, we developed a PD-1 mutant (PD-1m/m) rat, with an excision in the ligand-binding domain of PD-1, to test whether nevirapine would cause a more serious skin rash in these animals. The PD-1m/m rat was based on a Sprague Dawley background, which has a lower incidence of skin rash than Brown Norway rats. The treated PD-1m/m rats developed more severe liver injury than PD-1-/- mice, but in contrast to expectations, they did not develop a skin rash. Functional knockouts provide a unique tool to study the mechanisms of IDRs.

Safety of Combined Statin and Fibrate Therapy: Risks of Liver Injury and Acute Kidney Injury in a Cohort Study from the Shizuoka Kokuho Database.

Statins and fibrates are important means of preventing cardiovascular diseases, particularly when administered in combination as part of various therapeutic strategies. In this study, we explored the risks associated with various combinations of these drugs. We aimed to evaluate the risk of 1-year hospitalization with acute kidney injury, liver injury, pancreatitis, or rhabdomyolysis related to the concurrent administration of statins and fibrates. We performed a retrospective cohort study using data from the Shizuoka Kokuho Database, focusing on patients prescribed statins, fibrates, or a combination. Four drug exposure patterns were evaluated: adding statins to fibrates (exposure 1), switching from fibrates to statins (exposure 2), adding fibrates to statins (exposure 3), and switching from statins to fibrates (exposure 4). Hospitalization for the specified conditions within 1year was the outcome. Propensity score matching was used to create balanced cohorts for comparison. We studied 269,226 statin users and 16,282 fibrate users. After propensity score matching, there were 498 participants in the group of exposure 1, matched with 2988 in the fibrate-only group; 1180 in the group of exposure 2, matched with 7080 in the fibrate-only group; 1183 in group of exposure 3, matched with 11,830 in the statin only group; and 1356 in group of exposure 4, matched with 13,560 in the statin only group. The 1-year hospitalization rate with liver injury was higher in the group of exposure 1 than in the fibrate-only group (1.2% vs 0.3%, p < 0.01), in the group of exposure 2 than in the fibrate-only group (0.9% vs 0.3%, p < 0.01), and in the group of exposure 4 than in the statin-only group (0.6% vs 0.2%, p = 0.02). There was also a higher risk of 1-year hospitalization with acute kidney injury in group of exposure 1 than in the fibrate-only group (1.3% vs 0.3%, p = 0.01) but not in evaluations of exposure 2, 3, and 4. However, there were no differences in the risks of 1-year hospitalization with pancreatitis or rhabdomyolysis among the matched groups. We have demonstrated higher risks of 1-year hospitalization with liver injury or acute kidney injury associated with the use of combinations of statins and fibrates. This underscores the need for a cautious approach to the prescribing of such drug combinations and the importance of monitoring patients for potential adverse events.

Analysis of the Consumption of Medicinal Products Associated with a High Risk of Drug-Induced Liver Injury in Patients with COVID-19

INTRODUCTION. The risk of liver damage correlates with the severity of COVID-19. However, a growing number of studies have shown an association between liver function impairment and combinations of medicinal products used to treat COVID-19.AIM. The study aimed to analyse the annual consumption of medicinal products associated with a high risk of drug-induced liver injury (DILI) used as part of combination therapy in COVID-19 patients and to review a number of medication administration records in order to develop measures to prevent DILI.MATERIALS AND METHODS. The study used the ATC/DDD methodology to study consumption data for 2020, 2021, and 2022 and analysed a sample of 1250 inpatient medical records and medication administration records of COVID-19 patients treated in a Volgograd region hospital converted into a COVID-19 care centre. For genetically engineered biologicals and cyclophosphamide, which were lacking DDDs, the authors calculated the volume of consumption using the average dose per treatment course. The authors identified medicines capable of causing clinically apparent liver damage (according to the LiverTox database and Russian clinical practice guidelines) and/or elevated liver enzymes in ≥1% of patients (according to safety reports).RESULTS. The study found that 28% of the medicinal products used in combination for inpatient treatment of COVID-19 were associated with a high risk of DILI. In 2020, 2021, and 2022, the total consumption of medicinal products associated with a high risk of DILI was 342.3, 425.3, and 402.3 DDDs per 100 bed days, and the total consumption of genetically engineered biologicals (administered as a single dose) and cyclophosphamide was 3.5, 16.9, and 29.7 average course doses per 100 patients, respectively. According to the selective analysis of medical records, 19.8% (247/1250) reported concomitant use of 5 or more medicinal products associated with a high risk of DILI, which increased the risk of adverse drug interactions leading to DILI. In 2022, the most prescribed medicinal products with a high risk of DILI were omeprazole (188.7 DDDs per 100 bed days), non-steroidal anti-inflammatory drugs and paracetamol (54.4 DDDs per 100 bed days), atorvastatin (46.2 DDDs per 100 bed days), levofloxacin (26.4 DDDs per 100 bed days), ceftriaxone (20.5 DDDs per 100 bed days), favipiravir (17.3 DDDs per 100 bed days), and genetically engineered biologicals (24.0 DDDs per 100 bed days).CONCLUSIONS. To reduce the risk of DILI in COVID-19 patients admitted to infectious disease units, including the risk of DILI due to drug interactions, it is necessary to limit the use of hepatotoxic antibacterial agents, proton-pump inhibitors, and non-steroidal anti-inflammatory drugs, or consider alternative medicinal products with a lower risk of hepatotoxicity.

Management of Hepatitis B Virus and Hepatitis C Virus Infections in Patients with Cancer Receiving Immune Checkpoint Inhibitors.

Patients with cancer with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are excluded from many cancer clinical trials of immune checkpoint inhibitors (ICIs). Therefore, data are limited regarding the management of HBV and HCV infections in patients with cancer treated with ICIs. To address this gap, we reviewed the literature on management of HBV and HCV infections in patients with cancer receiving ICIs. We searched MEDLINE and PubMed for all original research articles, case reports, and systematic reviews published in English between Jul 2013 and Jul 2023 on patients with cancer with HBV or HCV infection receiving ICIs. We found 28 studies (three prospective clinical trials, seven retrospective cohort studies, nine retrospective case series, and nine case reports) that evaluated the safety of ICI therapy in patients with HBV infection and cancer. The overall rate of HBV reactivation was 1.4% (38/2799), and no HBV-related deaths were reported. The frequency of HBV reactivation in patients with chronic and past HBV infections was 2% (35/1667) and 0.3% (3/1132), respectively. The risk of HBV reactivation was significantly higher among patients with chronic HBV infection not receiving antiviral prophylaxis than among those receiving antivirals (17% vs 1%, p < 0.05). Based on high-quality evidence, for patients with chronic HBV infection, antiviral prophylaxis is recommended before ICI therapy initiation. For patients with past HBV infection, monitoring and on-demand antiviral treatment are sufficient. We found 11 studies (five clinical trials, five retrospective studies, and one prospective observational study) that evaluated the safety of ICI therapy in patients with HCV infection and cancer. The overall rate of HCV reactivation was 0.5% (2/387), and no HCV-related deaths were reported. HCV reactivation occurs primarily in patients receiving immunosuppressants for ICI-related toxic effects. ICIs are safe for HCV-infected patients with solid tumors. Chronic HBV or HCV infection should not be considered a contraindication for ICI therapy. Specific risk assessment, monitoring, and management strategies are necessary to reduce the risk of ICI-related liver injury in patients with cancer and chronic HBV or HCV infection.

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.

Acrylamide-Aggravated Liver Injury by Activating Endoplasmic Reticulum Stress in Female Mice with Diabetes.

Acrylamide (ACR) is a common industrial contaminant with endocrine-disrupting toxicity. Numerous studies have indicated that females and diabetics are more sensitive to environmental contaminants. However, it remains unknown whether female diabetics are susceptible to ACR-induced toxicity and its potential mechanisms. Thus, the female ACR-exposure diabetic Balb/c mice model was established to address these issues. Results showed that ACR could induce liver injury in normal mice and cause more serious inflammatory cell infiltration, hepatocyte volume increase, and fusion in diabetic mice liver. Meanwhile, ACR could lead to exacerbation of diabetic symptoms in diabetic mice by disturbing the glucose and lipid metabolism in the liver, which mainly manifests as the accumulation of liver glycogen and liver lipids, the reduction of the activity/content of glycolytic and metabolizing enzyme as well as pentose phosphatase, upregulation of the gene expression in fatty acid transporter and gluconeogenesis, and downregulation of the gene expression in fatty acid synthesis and metabolism. Moreover, ACR exposure could induce oxidative stress, inflammation, and endoplasmic reticulum stress in the liver by a decrease in hepatic antioxidant enzyme activity and antioxidant content, an increase in inflammatory factor levels, and a change in the related protein expression of endoplasmic reticulum stress (ERS) and apoptosis-related pathways in diabetic mice. Statistical analysis results revealed that ACR-induced liver injury was highly correlated with inflammation and oxidative stress, and ERS and diabetic mice had a higher risk of liver injury than normal mice. Overall results suggested that female diabetic mice easily suffer from ACR-induced toxicity, and the reason was that ACR could induce further damage to the liver by worsening the condition of inflammation, oxidative stress, and ERS in the liver.

The effect of statins on the risk of anti-tuberculosis drug-induced liver injury among patients with active tuberculosis: A cohort study

BackgroundTuberculosis (TB) remains prevalent worldwide, and anti-TB drugs are associated with drug-induced liver injury (DILI). Statins have pleiotropic effects which may decrease inflammation and achieve immunomodulation. However, few studies have investigated the pleiotropic effects of statins on the risk of DILI. The purpose of this study was to investigate whether statins prevent anti-tuberculosis DILI among active TB patients on standard anti-TB drug therapy. MethodsWe conducted a hospital-based retrospective cohort study using claims data from the Integrated Medical Database of National Taiwan University Hospital (NTUH-iMD). Patients with a positive TB culture were included. The use of statins was defined as a daily equivalent dose >0.5 mg of pitavastatin. Deterioration in liver function was evaluated according to elevated liver enzyme levels. The primary and secondary endpoints were the DILI and the severe DILI. The prognostic value of statins was evaluated by Kaplan–Meier analysis, and Cox proportional hazards models. ResultsA total of 1312 patients with a diagnosis of TB and receiving anti-TB treatment were included. During the study period, 193 patients had the DILI and 140 patients had the severe DILI. Kaplan–Meier analysis showed a significant difference between the usual statin users and controls in the DILI. In multivariable Cox proportional hazards analysis, statins showed a protective effect against the primary and secondary endpoints. In addition, the protective effect of statins showed a dose–response relationship against the DILI. ConclusionStatin treatment had a protective effect against the risk of anti-TB DILI with a positive dose–response relationship.

CDK4/6 inhibitors in drug-induced liver injury: a pharmacovigilance study of the FAERS database and analysis of the drug-gene interaction network.

The aim of this study was to investigate the potential risk of drug-induced liver injury (DILI) caused by the CDK4/6 inhibitors (CDK4/6is abemaciclib, ribociclib, and palbociclib by comprehensively analyzing the FDA Adverse Event Reporting System (FAERS) database. Moreover, potential toxicological mechanisms of CDK4/6is-related liver injury were explored via drug-gene network analysis. In this retrospective observational study, we collected reports of DILI associated with CDK4/6i use from the FAERS dated January 2014 to March 2023. We conducted disproportionality analyses using the reporting odds ratio (ROR) with a 95% confidence interval (CI). Pathway enrichment analysis and drug-gene network analyses were subsequently performed to determine the potential mechanisms underlying CDK4/6i-induced liver injury. We found positive signals for DILI with ribociclib (ROR = 2.60) and abemaciclib (ROR = 2.37). DILIs associated with liver-related investigations, signs, and symptoms were confirmed in all three reports of CDK4/6is. Moreover, ascites was identified as an unlisted hepatic adverse effect of palbociclib. We isolated 189 interactive target genes linking CDK4/6 inhibitors to hepatic injury. Several key genes, such as STAT3, HSP90AA1, and EP300, were revealed via protein-protein analysis, emphasizing their central roles within the network. KEGG pathway enrichment of these genes highlighted multiple pathways. Our study revealed variations in hepatobiliary toxicity among the different CDK4/6 inhibitors, with ribociclib showing the highest risk of liver injury, followed by abemaciclib, while palbociclib appeared relatively safe. Our findings emphasize the need for cautious use of CDK4/6 inhibitors, and regular liver function monitoring is recommended for long-term CDK4/6 inhibitor use.

Hepatitis after gene therapy, what are the possible causes?

Hepatitis is a common adverse event following gene therapy for haemophilia, often associated with a loss of transgene expression. Investigating the potential causes and implications of this is crucial for the overall success of treatment. Gene therapy trials using adeno-associated virus (AAV) vectors have demonstrated promising results marked by increases in factor FVIII and FIX levels and reductions in episodes of bleeding. However, hepatocellular injury characterised by elevations in alanine aminotransferases (ALT) has been noted. This liver injury is typically transient and asymptomatic, posing challenges in determining its clinical significance. Proposed causes encompass immune-mediated responses, notably T cell cytotoxicity in response to the AAV vector, direct liver injury from the viral capsid or transcribed protein via the unfolded protein response and pre-existing liver conditions. Liver biopsy data conducted years post-gene therapy infusion has shown sinusoidal infiltration without significant inflammation. The overall safety profile of gene therapy remains favourable with no evidence drug-induced liver injury (DILI) based on Hy's Law criteria. Essential pre-therapy monitoring and identifying patients at high risk of liver injury should involve liver function tests and non-invasive fibroscans, while novel blood-based biomarkers are under exploration. Further research is required to comprehend the mechanisms underlying transaminitis, loss of transgene expression and long-term effects on the liver, providing insights for optimising gene therapy for haemophilia.

Optimized therapeutic potential of Yinchenhao decoction for cholestatic hepatitis by combined network meta-analysis and network pharmacology

BackgroundCholestatic hepatitis is recognized as a significant contributor to the development of liver fibrosis and cirrhosis. As a well-known classic formula for the treatment of cholestatic hepatitis, Yinchenhao decoction (YCHD) is widely used in countries in Asia, including China, Japan, and Korea. However, in recent years, a risk of liver injury has been reported from Rheum palmatum L. and Gardenia jasmonoides J.Ellis which are the main ingredients of YCHD. Therefore, the question arises whether YCHD is still safe enough for the treatment of cholestatic hepatitis or whether an optimized ratio of ingredients should be applied. These is inevitable questions for the clinical application of YCHD. PurposeTo provide a scientific basis for the clinical application of YCHD through a combination of meta-analysis and network pharmacology and to find the best ratio of components to ensure optimal therapeutic efficacy and safety. At the same time, a deeper understanding of the mechanisms of YCHD was explored. MethodsWe retrieved relevant trials from various databases including PubMed, Web of Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP and Wanfang databases up to August 2023. After screening for inclusion and exclusion criteria, we assessed efficiency, ALT, AST, and TBIL as outcome parameters. The relevant data underwent a network meta-analysis using STATA 16.0 software. Based on network pharmacology, we screened the disease targets, active ingredients, and targets related to YCHD. The targets were visualized using Cytoscape 3.9.1. Then, potential mechanisms were explored based on bioinformatic techniques. ResultsTwenty eligible studies were finally screened and a total of 1,591 patients who fulfilled the inclusion criteria were enrolled in the study. The meta-analysis results indicated that TG-c (treatment group c) [(Artemisia capillaris Thunb. : Gardenia jasminoides J.Ellis : Rheum palmatum L. = 10:5:2–10:5:3) + CT] was the most promising therapeutic approach, demonstrating superior efficacy and notable improvements in both AST and TBIL levels. For ALT, TG-d [(Artemisia capillaris : Gardenia jasminoides : Rheum palmatum = 5:1:1–5:2:1) + CT] exhibited the greatest potential as optimal therapy option. Based on the surface under the cumulative ranking curve (SUCRA) values, TG-c was the best therapy in terms of efficiency and improvement in TBIL levels, while TG-d was the most effective in reducing ALT levels. For AST levels, TG-e [(Artemisia capillaris : Gardenia jasminoides : Rheum palmatum = 5:2:2–5:3:3) + CT] was the most effective therapy. The comprehensive analysis revealed that TG-c exhibited the most pronounced efficacy. Combined network pharmacology, GO enrichment analysis and KEGG pathway enrichment analysis displayed that the key target genes of Artemisia capillaris, Rheum palmatum, and Gardenia jasminoides were closely involved in inflammation response, bile transport, apoptosis, oxidative stress, and regulation of leukocyte migration. Notably, bile secretion dominated the common pathway of the three herbs. On the other hand, Artemisia capillaris exhibited a unique mode of action by regulating the IL-17 signaling pathway, which may play a crucial role in its effectiveness. ConclusionBased on our findings, the optimal TG-C demonstrated the most favorable overall therapeutic efficacy by increasing the dosage of Artemisia capillaris while reducing the dosage of Gardenia jasminoides and Rheum palmatum. This is attributed to the potent ability of Artemisia capillaris. to effectively modulate the IL-17 signaling pathway, thereby exerting a beneficial therapeutic effect. Conversely, Gardenia jasminoides and Rheum palmatum may potentially enhance the activation of the NF-кB signaling pathway, thereby elevating the risk of hepatotoxicity.

Angiotensin Receptor Blockers and the Risk of Suspected Drug-Induced Liver Injury: A Retrospective Cohort Study Using Electronic Health Record-Based Common Data Model in South Korea.

Angiotensin receptor blockers are widely used antihypertensive drugs in South Korea. In 2021, the Korea Ministry of Food and Drug Safety acknowledged the need for national compensation for a drug-induced liver injury (DILI) after azilsartan use. However, little is known regarding the association between angiotensin receptor blockers and DILI. We conducted a retrospective cohort study in incident users of angiotensin receptor blockers from a common data model database (1 January, 2017-31 December, 2021) to compare the risk of DILI among specific angiotensin receptor blockers against valsartan. Patients were assigned to treatment groups at cohort entry based on prescribed angiotensin receptor blockers. Drug-induced liver injury was operationally defined using the International DILI Expert Working Group criteria. Cox regression analyses were conducted to derive hazard ratios and the inverse probability of treatment weighting method was applied. All analyses were performed using R. In total, 229,881 angiotensin receptor blocker users from 20 university hospitals were included. Crude DILI incidence ranged from 15.6 to 82.8 per 1000 person-years in treatment groups, most were cholestatic and of mild severity. Overall, the risk of DILI was significantly lower in olmesartan users than in valsartan users (hazard ratio: 0.73 [95% confidence interval 0.55-0.96]). In monotherapy patients, the risk was significantly higher in azilsartan users than in valsartan users (hazard ratio: 6.55 [95% confidence interval 5.28-8.12]). We found a significantly higher risk of suspected DILI in patients receiving azilsartan monotherapy compared with valsartan monotherapy. Our findings emphasize the utility of real-world evidence in advancing our understanding of adverse drug reactions in clinical practice.

CYP7A1 Gene Induction via SHP-Dependent or Independent Mechanisms can Increase the Risk of Drug-Induced Liver Injury Independently or in Synergy with BSEP Inhibition.

Drug-induced liver injury (DILI) is a frequent cause of clinical trial failures during drug development. While inhibiting bile salt export pump (BSEP) is a well-documented DILI mechanism, interference with genes related to bile acid (BA) metabolism and transport can further complicate DILI development. Here, the effects of twenty-eight compounds on genes associated with BA metabolism and transport were evaluated, including those with discontinued development or use, boxed warnings, and clean labels for DILI. The study also included rifampicin and omeprazole, pregnane X receptor and aryl hydrocarbon receptor ligands, and four mitogen-activated protein kinase kinase (MEK1/2) inhibitors. BSEP inhibitors with more severe DILI, notably pazopanib and CP-724714, significantly upregulated the expression of 7 alpha-hydroxylase (CYP7A1), independent of small heterodimer partner (SHP) expression. CYP7A1 expression was marginally induced by omeprazole. In contrast, its expression was suppressed by mometasone (10-fold), vinblastine (18-fold), hexachlorophene (2-fold), bosentan (2.1-fold), and rifampin (2-fold). All four MEK1/2 inhibitors that show clinical DILI were not potent BSEP inhibitors but significantly induced CYP7A1 expression, accompanied by a significant SHP gene suppression. Sulfotransferase 2A1 and BSEP were marginally upregulated, but no other genes were altered by the drugs tested. Protein levels of CYP7A1 were increased with the treatment of CYP7A1 inducers and decreased with obeticholic acid, an farnesoid X receptor ligand. CYP7A1 inducers significantly increased bile acid (BA) production in hepatocytes, indicating the overall regulatory effects of BA metabolism. This study demonstrates that CYP7A1 induction via various mechanisms can pose a risk for DILI, independently or in synergy with BSEP inhibition, and it should be evaluated early in drug discovery. SIGNIFICANCE STATEMENT: Kinase inhibitors, pazopanib and CP-724714, inhibit BSEP and induce CYP7A1 expression independent of small heterodimer partner (SHP) expression, leading to increased bile acid (BA) production and demonstrating clinically elevated drug-induced liver toxicity. MEK1/2 inhibitors that show BSEP-independent drug-induced liver injury (DILI) induced the CYP7A1 gene accompanied by SHP suppression. CYP7A1 induction via SHP-dependent or independent mechanisms can pose a risk for DILI, independently or in synergy with BSEP inhibition. Monitoring BA production in hepatocytes can reliably detect the total effects of BA-related gene regulation for de-risking.

Changing Trajectories of Alanine Aminotransferase and Risk of Antituberculosis Drug-Induced Liver Injury in Chinese Patients: A Cohort Study.

Antituberculosis drug-induced liver injury (ATLI) is a major adverse effect during antituberculosis treatment. Early detection or prediction is essential to prevent ATLI in antituberculosis treatment patients. The purpose of this work is to explore the relationship between alanine aminotransferase (ALT) trajectories within 15 days of initial treatment and the risk of ATLI. Based on a historical cohort of patients hospitalized for antituberculosis treatment and group-based trajectory modeling analysis, ALT trajectories within 15 days of initial treatment were determined. Conditional logistic regression model was used to estimate the association between different ALT trajectories and the risk of ATLI, and the corresponding odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated with covariates. Based on the ALT levels within 15 days of initial treatment, a total of 853 patients were divided into four ALT trajectories. The incidence of ATLI significantly increased with the increase of ALT trajectories (2.33%, 4.38%, 5.90%, and 2.44%, respectively). Compared with trajectory 1, the adjusted OR for ATLI in trajectory 2, trajectory 3, and trajectory 4 were 2.448 (95% CI: 0.302-19.856, P = 0.402), 5.373 (95% CI: 0.636-45.411, P = 0.123), 11.010 (95% CI: 0.720-168.330, P = 0.085), respectively, and there was an increasing trend of ATLI risk (Ptrend = 0.015). Different ALT trajectories within 15 days of initial treatment were associated with different risk of ATLI, and it is necessary to pay attention to the ALT trajectory within 15 days of initial treatment to predict the occurrence of ATLI.

Impact of hepatic steatosis on risk of acute liver injury in people with chronic hepatitis B and SARS‐CoV‐2 infection

AbstractBackgroundSARS‐CoV‐2 infection was known to be associated with higher risk of liver impairment in people with chronic hepatitis B infection (CHB). However, evidence regarding the impact of concomitant hepatic steatosis (HS) on the risk of liver disease among people with CHB and SARS‐CoV‐2 infection is lacking. We investigated the impact of concomitant HS on people with CHB suffering from SARS‐CoV‐2 infection.MethodsThis retrospective cohort study was performed using an electronic health database for people in Hong Kong with CHB and confirmed SARS‐CoV‐2 infection between 21 January 2020 and 31 January 2023. People with HS diagnosis (HS + CHB + COVID‐19) were identified and matched 1:1 by propensity score with those without (CHB + COVID‐19). Each person was followed up until death, outcome event, or 31st January 2023. Study outcome was incidence of acute liver injury (ALI) within first 28 days since COVID‐19 diagnosis. Severity of ALI and comparison of ALI risk stratified by the presence of CHB infection and HS were also analysed. Incidence rate ratios (IRRs) were estimated by Poisson regression models.ResultsOf 52 259 COVID‐19 patients with CHB infection in the cohort, 15 391 people with HS + CHB + COVID‐19 and 15 391 people with CHB + COVID‐19 were included after matching. HS + CHB + COVID‐19 was associated with increased risk of ALI (IRR: 1.41, 95% CI:1.05–1.90, p = 0.023), compared to CHB + COVID‐19. Over 99% ALI cases were mild to moderate severity, and there were no differences in the severity of ALI between HS + CHB + COVID‐19 and CHB + COVID‐19 (p = 0.127).ConclusionsConcomitant HS was associated with increased risk of ALI among people with CHB infection suffering from SARS‐CoV‐2 infection.

Impact of statins in the liver: A bane or a boon?

Treatment of hypercholesterolemia with statins is considered one of the cornerstones in the management of atherosclerotic cardiovascular diseases. Statins exert their hypolipidemic effects by inhibiting HMG-CoA reductase, the key enzyme in cholesterol biosynthesis. Beyond cholesterol reduction, statins exhibit pleiotropic effects, including anti-inflammatory, antioxidant, and antiproliferative actions, making them valuable in mitigating atherosclerotic and non-atherosclerotic diseases. Though concerns of hepatotoxicity have been associated with the use of statins, extensive evidence suggests that the risk of statin-induced liver injury (SILI) is rare, with an incidence of &lt;1%. Hepatic adverse effects include reversible asymptomatic transaminase elevation (most frequent), hepatitis, cholestasis, and rarely acute liver failure. While hepatotoxicity concerns should not be dismissed, the evidence overwhelmingly supports the safety of statins. Contrary to the myth of statin hepatotoxicity, real-world data and extensive research emphasize the safety and benefits of statins. They are therapeutic in various liver-related conditions, mainly non-alcoholic fatty liver disease. This scientific review aims to provide a comprehensive overview of statins, shedding light on their mechanism of action, hepatotoxicity concerns, and therapeutic potential in various liver-related conditions.