Risk Of Liver Injury Research Articles

Protective role of resveratrol against VCM-induced hepatotoxicity in male wistar rats.

Background: Vancomycin is a glycopeptide antibiotic with a high risk of acute liver injury. Resveratrol is believed to protect the liver against toxicity. Aim: To investigate the ability of resveratrol to attenuate vancomycin-induced liver toxicity in rats injected with vancomycin. Method: Twenty-four adult male Wistar rats were distributed into three groups. The control group received only a vehicle, while the treated group received either vancomycin 200 (mg/kg, i. p.) only or vancomycin (200mg/kg, i. p.) with resveratrol (20mg/kg, oral gavage). All groups received their dose once daily for 7days. Hepatic damage was assessed by measuring biochemical parameter levels in serum, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH). Also, antioxidants and inflammation biomarkers such as Interleukin-6 (IL-6), malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) were measured. Furthermore, the vancomycin-induced pathological changes in the liver were evaluated by histopathological studies. Results: In the vancomycin-treated group, hepatic serum biomarkers such as AST, ALT, ALP, IL-6, and MDA were elevated, while NO and GSH were depleted. However, resveratrol co-treatment with vancomycin prevented the elevation of AST, ALT, ALP, IL-6, and MDA and it protected the liver from NO and GSH depletion. Also, regarding vancomycin-induced degeneration of hepatocytes, resveratrol co-treatment with vancomycin prevented such degeneration and improved mononuclear cells in the liver. Conclusion: The results showed that oral administration of resveratrol has a significant hepatoprotective effect against vancomycin-induced hepatotoxicity.

A natural history study of paediatric non-alcoholic fatty liver disease over 10 years

The long-term outcome of paediatric non-alcoholic fatty liver disease (NAFLD) has not been well established. Between 2008 and 2012, an unselected cohort of 133 children with severe obesity was screened for NAFLD. The aim of this study was to determine the 10-year natural history of NAFLD in this cohort. All 133 participants of the original study were approached. Proton magnetic resonance spectroscopy (1H-MRS) and the Enhanced Liver Fibrosis® (ELF) test were used to assess longitudinal changes in steatosis and fibrosis, respectively. Risk factors for disease progression were explored. Fifty-one of the 133 participants (38%) from the original cohort were included. The mean follow-up time was 10.3 years (range 7-13 years), 65% were female and 92% had persistent obesity. The proportion of participants with steatosis remained unchanged (47%). Nine individuals developed steatosis and in nine individuals steatosis resolved. Predefined relevant individual changes in 1H-MRS were seen in 38% of the participants. The mean ELF test did not change significantly (8.70 ± 0.58 vs. 8.51 ± 0.71, p= 0.22). However, 16% had a relevant increase in ELF test and 6% of those with NAFLD developed advanced fibrosis at follow-up. Changes in steatosis correlated with changes in established metabolic risk factors, alanine aminotransferase, and bariatric surgery. A change in the ELF test was associated with a change in triglycerides. This 10-year follow-up study shows that one-third of the young adults who had childhood obesity develop steatosis and in one-third steatosis resolves. Six percent of those with NAFLD had developed advanced fibrosis at follow-up. These data underscore the importance of screening for NAFLD and monitoring for progression to advanced NAFLD in young people with obesity. Childhood obesity accompanied by fat accumulation in the liver persists into young adulthood in the vast majority, and 6% develop serious liver injury. Worsening of metabolic disturbances increases the risk of liver injury.

Dapagliflozin: no increased risk of acute liver injury or severe UTI complications

Dapagliflozin: no increased risk of acute liver injury or severe UTI complications

Potential role of the microbiome in liver injury during COVID-19: Further research is needed.

Although different studies have associated coronavirus disease 2019 (COVID-19) with the occurrence of liver injury, the hepatic injury route during the COVID-19 course is not yet fully understood. In order to better understand the mechanisms of the disease, the human gut microbiota has been the subject of extensive discussion in the context of COVID-19 pathophysiology. However, many questions remain, including the risks of liver injury due to COVID-19 specific populations. Further research in this field could allow the discovery of new personalized treatment strategies aimed at improving the microbiota composition, thereby reducing COVID-19 severity and its complications in different populations. In this article, we discussed basic mechanisms of severe acute respiratory syndrome coronavirus 2 infection and recent evidence on the relationship between COVID-19, the gut microbiome and liver injury as well as proposed recommendations for further research.

Estimating drug-induced liver injury risk by in vitro molecular initiation response and pharmacokinetic parameters for during early drug development.

Drug-induced liver injury (DILI) is a major factor influencing new drug withdrawal; therefore, an appropriate toxicity assessment at the preclinical stage is required. Previous in silico models have been established using compound information listed in large data sources, thereby limiting the DILI risk prediction for new drugs. Herein, we first constructed a model to predict DILI risk based on a molecular initiating event (MIE) predicted by quantitative structure-activity relationships, admetSAR parameters (e.g. cytochrome P450 reactivity, plasma protein binding, and water-solubility), and clinical information (maximum daily dose [MDD] and reactive metabolite [RM]) for 186 compounds. The accuracy of the models using MIE, MDD, RM, and admetSAR alone were 43.2%, 47.3%, 77.0%, and 68.9%, while the "predicted MIE+admetSAR + MDD+RM" model's accuracy was 75.7%. The contribution of MIE to the overall prediction accuracy was little effect or rather worsening it. However, it was considered that MIE was a valuable parameter and that it contributed to detect high DILI risk compounds in the early development stage. We next examined the effect of stepwise changes in MDD on altering the DILI risk and estimating the maximum safety dose (MSD) for clinical use based on structural information, admetSAR, and MIE parameters because it is important to estimate the dose that could prevent the DILI onset in clinical conditions. Low-MSD compounds might increase the DILI risk, as these compounds were classified as "most-DILI concern" at low doses. In conclusion, MIE parameters were especially useful to check the DILI concern compounds and to prevent the underestimation of DILI risk in the early stage of drug development.

Relationship between Obstructive Sleep Apnea and Liver Abnormalities in Older Patients: A Cross-Sectional Study.

Older age is a risk factor for obstructive sleep apnea (OSA), which is associated with the development of nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the correlation between OSA and liver injury among older patients. Study Design. This is a cross-sectional study. Consecutive older (≥60 years) snoring patients were included. Subjects were divided into no OSA, mild OSA, moderate OSA, and severe OSA groups according to the apnea-hypopnea index (AHI) and were also separated into liver injury and nonliver injury groups based on liver function. Logistic regression analysis was applied to analyze the independent risk factors for liver injury. We studied 227 patients (155 male, 72 female). The prevalence of liver injury exhibited an increasing trend among groups with mild-to-severe OSA. In addition, body mass index, AHI, and TG showed significant differences between the liver injury and nonliver injury groups. Logistic regression analysis revealed that AHI and TG were the major contributing factors for liver injury in older patients (adjusted odds ratio [OR] = 1.055, p=0.013, and OR = 1.485, p=0.039, respectively). Older patients with OSA have an increased risk of liver injury and NAFLD, and sleep apnea and high TG are important factors in contributing to the development of liver injury.

Antipsychotic Safety in Liver Disease: A Narrative Review and Practical Guide for the Clinician.

Clinicians treating psychiatric disorders in medically ill patients need a comprehensive resource for comparing the risk and types of liver injury associated with antipsychotic therapy. We conducted a narrative review aimed at developing a comprehensive resource comparing antipsychotics with regard to risk of inducing or worsening liver injuries, types of liver injury, associated pharmacokinetic changes, dosing, monitoring, and patient counseling recommendations. We conducted database searches of LiverTox.nih.gov, DailyMed.nlm.nih.gov, and PubMed through June of 2022. Sources describing premarketing data, observational studies, case reports and case series of antipsychotic-induced liver injuries, types of hepatic dysfunction, interventions, recovery, and treatment for 15 antipsychotics were included. Duplicate reports were excluded. Antipsychotics were graded as low, low to moderate, moderate, moderate to high, or high risk for causing or worsening a liver disease. Of the 1861 publications, 21 papers met criteria and were included. Evidence shows antipsychotic-induced liver dysfunction is uncommon to rare. Chlorpromazine, clozapine, and olanzapine pose the greatest risk of hepatoxicity; quetiapine and risperidone pose a moderate risk with haloperidol considered to pose low to moderate risk. Paliperidone, aripiprazole, lurasidone, and loxapine are lower-risk agents with no reports of liver failure. Transaminitis that is mild and self-limiting is the most common antipsychotic-induced liver injury followed by hepatocellular disease, steatosis, and mixed liver injury. A careful risk-benefit analysis should guide the decision to discontinue the antipsychotic in cases of severe liver disease. Dose adjustments and careful monitoring are recommended for a mild to moderate disease when the benefits of treating psychosis outweigh the risks. Patients without an existing liver disease initiating a treatment with a higher-risk antipsychotic should be counseled to report symptoms of liver injuries along with regular lab monitoring. Antipsychotic selection, dosing, monitoring, and counseling should be individualized based on whether a patient has an existing liver disease and if they are receiving an agent that poses a higher risk of liver injury. The consultation-liaison psychiatry provider can guide the primary team in management through thoughtful integration of the known pathophysiologic changes in hepatic disease and risk-benefit analysis of antipsychotic safety profiles.

Experience of Using Remdesivir in Patients with Novel Coronavirus Infection

Timely, effective, and safe antiviral therapy in COVID-19 patients reduces complications, disability and mortality rates. The greatest concern with remdesivir is the risk of drug-induced liver injury, including in patients whose liver function is compromised by COVID-19.The aim of the study was to investigate the efficacy and safety of remdesivir in patients with confirmed SARS-CoV-2 infection who had been admitted to an infectious diseases hospital in the Volgograd region in March 2022. Materials and methods: the authors carried out an open, non-randomised, single-arm study using medical records of 234 patients who had been diagnosed with “U07.1 COVID-19, virus identified” and prescribed remdesivir upon admission. The effectiveness of therapy was evaluated using two criteria: the need for oxygen supplementation or ventilatory support, or mortality. The authors conducted the evaluation on days 7, 14, and 28 using the six-point ordinal severity scale by Y. Wang et al. The safety of therapy was assessed on the basis of complaints and changes in laboratory findings.Results: for the patients prescribed remdesivir at admission, the 7-day mortality rate was 3.0%, the 14-day mortality rate was 5.6%, and the 28-day mortality rate was 7.3%. With the exception of a patient with myocardial infarction, all the patients who had been hospitalised with mild COVID-19 and prescribed remdesivir did not require oxygen therapy and/or transfer to intensive care and were discharged following recovery. The patients with moderate to severe COVID-19 had the 14-day mortality rate of 6.4% and the 28-day mortality rate of 8.6%. 17 patients (7.2%) discontinued remdesivir prematurely for various reasons, including adverse drug reactions. Remdesivir therapy of 5-10 days was associated with an increase in ALT activity by 2.7 ± 0.8 times in 15.9% of patients with mild COVID-19, by 3.8 ± 1.8 times in 20.4% of patients with moderately severe COVID-19, and by 4.8 ± 2.7 times in 24% (12/50) of patients with severe COVID-19. In two patients (0.9%), the increase exceeded 10-fold the upper limit of normal.Conclusions: the obtained results support recommending remdesivir to patients with mild, moderate and severe COVID-19, including those with moderately elevated baseline activity of hepatic transaminases.

Risk of New-Onset Liver Injuries Due to COVID-19 in Preexisting Hepatic Conditions-Review of the Literature.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacted the world and caused the 2019 coronavirus disease (COVID-19) pandemic. The clinical manifestations of the virus can vary from patient to patient, depending on their respective immune system and comorbidities. SARS-CoV-2 can affect patients through two mechanisms: directly by targeting specific receptors or by systemic mechanisms. We reviewed data in the latest literature in order to discuss and determine the risk of new-onset liver injuries due to COVID-19 in preexisting hepatic conditions. The particular expression of angiotensin-converting enzyme 2 (ACE2) receptors is an additional risk factor for patients with liver disease. COVID-19 causes more severe forms in patients with non-alcoholic fatty liver disease (NAFLD), increases the risk of cirrhosis decompensation, and doubles the mortality for these patients. The coinfection SARS-CoV-2-viral hepatitis B or C might have different outcomes depending on the stage of the liver disease. Furthermore, the immunosuppressant treatment administered for COVID-19 might reactivate the hepatic virus. The high affinity of SARS-CoV-2 spike proteins for cholangiocytes results in a particular type of secondary sclerosing cholangitis. The impact of COVID-19 infection on chronic liver disease patients is significant, especially in cirrhosis, influencing the prognosis and outcome of these patients.

1431. Evaluation of Drug-induced Liver Injury in Patients Receiving Anti-tuberculosis Medications and Subsequent Management

Abstract Background For anti-tubercular medications, the risk of drug-induced liver injury (DILI) ranges from 5-33%. DILI may be asymptomatic or may present with fever, nausea, vomiting, anorexia, and lethargy. The objective of this review is to describe the incidence of hepatotoxicity occurring with anti-tuberculosis medications, management of DILI, and re-initiation of therapy. Methods Adult patients prescribed pyrazinamide during their hospital stay at Long Island Jewish Medical Center were screened for inclusion criteria of DILI (liver enzymes ≥ 3x upper limit of normal [ULN] from 7/2017 to 2/2022. IRB classified this analysis as a quality improvement project. Using the electronic medical record, retrospective data was collected for those meeting criteria for DILI which included baseline demographics, concomitant hepatotoxic medications, laboratory values (e.g., alanine aminotransferase [ALT], aspartate aminotransferase [AST], timing of drug interruption, and sequence of re-initiation. Results A total of 108 patients were screened and then 17 were included in the analysis. DILI was found in 16% of patients. The mean age was 57 years and 53% were female. None of the patients with liver injury had a history of hepatic disease, prior DILI, or alcohol consumption. Mean baseline laboratory values were total bilirubin 0.52 mg/dL, alkaline phosphatase 166 U/L, AST 54 U/L, and ALT 40 U/L. All patients were initiated on first-line treatment for drug-susceptible tuberculosis. Thirteen patients had concomitant hepatotoxic drugs (11 acetaminophen, 4 statins, 2 azole antifungals, 1 trimethoprim/sulfamethoxazole). Fourteen patients (82%) developed DILI where AST was ≥ 10 times the ULN. Drug interruption was necessary in 16 of the 17 patients (94%). Seven patients (58%) were re-initiated on treatment according to the American Thoracic Society recommendations with a mean of 8 days after drug interruption. Conclusion In conclusion, the management of DILI related to anti-tubercular medications in our institution can further be standardized to reintroduce a rifamycin analog with or without ethambutol. Education on the avoidance of concomitant hepatotoxic medications such as acetaminophen and selecting the most appropriate agents to sequentially re-initiate treatment is warranted. Disclosures All Authors: No reported disclosures.

Genetic variations in ABC transporter genes as a predictive biomarker for toxicity in North Indian lung cancer patients undergoing platinum-based doublet chemotherapy.

ATP-binding cassette (ABC) transporters are expressed in various human tissues and play a vital role in the efflux of various chemotherapeutic drugs. The current study has assessed genetic variants of ABCB1, ABCC1, ABCC2, and ABCG2 genes in 407 lung cancer patients undergoing platinum-based doublet chemotherapy. The association of ABCB1(C1236 T, C3435 T, and G2677 T/A), ABCC1(G3173 A and G2168 A),ABCC2 (G4544 A), and ABCG2(C421 A) polymorphisms with chemotherapy-induced adverse events were assessed, and statistical analysis was conducted. Our data showed that patients harboring heterozygous (GA) genotype for ABCC1 G3173 A had an increased risk of developing leukopenia (odds ratio [OR] = 1.88, p = 0.04) and anemia (adjusted odds ratio[AOR] = 2.70, p = 0.03). For ABCC2 G4544 A polymorphism, patients harboring one copy of the mutant (GA) allele showed an increased risk of developing anemia (OR = 4.24, p = 0.03). After adjusting with various confounding factors, the heterozygous (GA) genotype showed a 5.63-fold increased risk of developing anemia (AOR = 5.63, p = 0.03). The ABCB1 G2677 A (OR = 0.37, p = 0.008) and ABCC1 G3173 A (OR = 0.54, p = 0.04) polymorphism showed a lower incidence of developing nephrotoxicity. In ABCG2 C421 A polymorphism, patients harboring heterozygous (CA) genotype had a lower incidence of having diarrhea (OR = 0.25, p = 0.04). An increased risk of having diarrhea was observed in the heterozygous genotype (GA) for ABCC1 G3173 A polymorphism (AOR = 2.78, p = 0.04). An increased risk of liver injury was found in the patients carrying heterozygous genotype of the ABCC1 G3173 A (OR = 2.06, p = 0.02) and ABCB1 C1236 T (OR = 1.85, p = 0.01). This study demonstrates the role of polymorphic variations in ABCB1, ABCC1, ABCC2, and ABCG2 in predicting hematological, nephrotoxicity, gastrointestinal, and hepatotoxicity.

Statin Use and Severe Acute Liver Injury Among Patients with Elevated Alanine Aminotransferase.

While serious liver injury among statin users is extremely rare, baseline liver enzyme testing is still recommended prior to initiating therapy. The benefit of such screening should be reevaluated based on empirical evidence. This study compared the risk of severe acute liver injury (SALI) between statin initiators with an elevated ALT (>35U/L) matched to statin initiators with a normal ALT level (≤35U/L). Statin initiators with an elevated ALT were additionally compared against matched non-users. The study created cohorts from Optum and MarketScan claims data. Exposed and comparison cohorts were propensity score (PS) matched in each dataset and findings were pooled using meta-analysis. Proportional hazards regression was used to estimate hazard ratios (HRs), and a prespecified non-inferiority margin for SALI was set at a HR of 1.8. 232,889 patients with elevated ALT were PS-matched to 232,889 with normal ALT level. The overall incidence rate of SALI was about 19/100,000 person-years among statin initiators. Statin initiators with elevated ALT had no meaningfully increased risk of SALI compared to those with normal ALT (HR=1.15; 95% CI 0.75 to 1.75). Comparing statin initiators with non-initiators with elevated ALT values equally yielded no increased risk (HR=0.76; 95% CI 0.52 to 1.11). In this large population-based study, SALI in statin users was rare. Importantly, the results showed no evidence that baseline ALT status is a reliable indicator for an increased risk of severe liver injury among statin initiators.

Risk of Abemaciclib-induced Liver Injury in Hormone Receptor-positive, HER2-negative Metastatic Breast Cancer: A Retrospective Analysis.

The efficacy of endocrine therapy combined with abemaciclib for hormone receptor-positive, HER2-negative metastatic breast cancer has been established through pivotal clinical trials. However, abemaciclib-induced liver injury (AILI) can be a cause for dose reduction or discontinuation. Therefore, it is critical to understand the risk factors for AILI. This retrospective study analyzed data from patients who had received abemaciclib combined with endocrine therapy for metastatic breast cancer as first- or second-line therapy at our hospital between December 2018 and October 2021. Relevant data were extracted from their medical records. Logistic regression analysis was performed to identify characteristics associated with AILI. Of the 52 eligible patients, 12 (23%) received an aromatase inhibitor (AI), and 40 (77%) received fulvestrant, concomitantly with abemaciclib. Fifteen (29%) of the patients developed liver injury after starting abemaciclib. Univariate analysis revealed the following risk factors for AILI: age ≥65 years (p=0.047), fatty liver disease (p=0.047), and concomitant use of an AI (p=0.002). Concomitant use of an AI was identified by multivariate analysis as an independent risk factor for AILI [odds ratio (OR)=10.23, 95% confidence interval (CI)=2.02-51.91, p=0.005]. Concomitant use of an AI could be the most significant factor associated with increased risk of AILI. Future research on the mechanism by which the use of an AI plus abemaciclib can cause liver injury, and prospective studies to validate our findings regarding AILI risk factors, are warranted.

Human HepaRG liver spheroids: cold storage protocol and study on pyridinium oxime-induced hepatotoxicity in vitro

Oximes play an essential role in the therapy of organophosphorus compound (OP) poisoning by reactivating inhibited acetylcholinesterase. Impairment of liver function was observed in OP poisoning and associated with obidoxime treatment by some reports. In this study human three-dimensional HepaRG spheroids were used as complex in vitro model to investigate oxime-induced liver toxicity. In this context, cold storage of liver spheroids at 4 °C in standard culture medium and in optimized tissue preservation solutions of up to 72 h was assessed. Cold storage in standard culture medium resulted in a complete loss of viability whereas an optimized tissue preservation solution preserved viability. Separately from that liver spheroids were exposed to the four oximes pralidoxime, obidoxime, HI-6, MMB-4 and cytotoxicity (effective concentration, EC50) was determined with an ATP-based assay at several time points. The release of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin secretion was measured in supernatants. The same parameters were assessed with diclofenac as positive hepatotoxic control and with the OP pesticides malathion and malaoxon alone or in the presence of obidoxime. All individual tested oximes and OP showed a low cytotoxicity with effective concentrations mostly >2,000 μM. In contrast, the exposure to malaoxon in the presence of 1,000 μM obidoxime resulted in a marked decrease of viability and an increased release of AST indicating risk of liver injury only if oxime antidotes are strongly overdosed.

Potential risk of liver injury in epileptic patients during COVID-19 pandemic.

Most of the antiseizure medications (ASMs) are metabolized in liver and many of them particularly first-generation ASMs have the potential to increase liver enzymes or induce liver injury. Hence, treatment of new onset seizures or epilepsy by ASMs during the course of coronavirus disease 2019 (COVID-19), which could potentially be complicated by hepatic dysfunction, is a challenging clinical issue. Intravenous form of levetiracetam which has no significant hepatic metabolism or drug-drug interaction is often a favorable option to control seizures in acute phase of COVID-19. Administration of enzyme inducer ASMs and valproate with the well-known hepatotoxicity and common drug interactions is not generally recommended. In patients with epilepsy who are under control with potentially hepatotoxic ASMs, close observation and cautious dose reduction or drug switch should be considered if any evidence of hepatic impairment exists. However, risks of possible breakthrough seizures should be weighed against benefits of lowering the hazard of liver injury. In patients with epilepsy who receive polytherapy with ASMs, transient dose modification with the tendency to increase the dose of ASMs with more favorable safety profile and less drug interaction and decrease the dose of drugs with main hepatic metabolism, high protein binding, potential to cause liver injury and known drug-drug reaction should be considered. Finally, decision making should be individualized based on patients' conditions and course of illness.

Urine metabolomics and microbiome analyses reveal the mechanism of anti-tuberculosis drug-induced liver injury, as assessed for causality using the updated RUCAM: A prospective study.

Anti-tuberculosis drug-induced liver injury (ATB-DILI) is one of the most common adverse reactions that brings great difficulties to the treatment of tuberculosis. Thus, early identification of individuals at risk for ATB-DILI is urgent. We conducted a prospective cohort study to analyze the urinary metabolic and microbial profiles of patients with ATB-DILI before drug administration. And machine learning method was used to perform prediction model for ATB-DILI based on metabolomics, microbiome and clinical data. A total of 74 new TB patients treated with standard first-line anti-TB treatment regimens were enrolled from West China Hospital of Sichuan University. Only patients with an updated RUCAM score of 6 or more were accepted in this study. Nontargeted metabolomics and microbiome analyses were performed on urine samples prior to anti-tuberculosis drug ingestion to screen the differential metabolites and microbes between the ATB-DILI group and the non-ATB-DILI group. Integrating electronic medical records, metabolomics, and microbiome data, four machine learning methods was used, including random forest algorithm, artificial neural network, support vector machine with the linear kernel and radial basis function kernel. Of all included patients, 69 patients completed follow-up, with 16 (23.19%) patients developing ATB-DILI after antituberculosis treatment. Finally, 14 ATB-DILI patients and 30 age- and sex-matched non-ATB-DILI patients were subjected to urinary metabolomic and microbiome analysis. A total of 28 major differential metabolites were screened out, involving bile secretion, nicotinate and nicotinamide metabolism, tryptophan metabolism, ABC transporters, etc. Negativicoccus and Actinotignum were upregulated in the ATB-DILI group. Multivariate analysis also showed significant metabolic and microbial differences between the non-ATB-DILI and severe ATB-DILI groups. Finally, the four models showed high accuracy in predicting ATB-DILI, with the area under the curve of more than 0.85 for the training set and 1 for the validation set. This study characterized the metabolic and microbial profile of ATB-DILI risk individuals before drug ingestion for the first time. Metabolomic and microbiome characteristics in patient urine before anti-tuberculosis drug ingestion may predict the risk of liver injury after ingesting anti-tuberculosis drugs. Machine learning algorithms provides a new way to predict the occurrence of ATB-DILI among tuberculosis patients.

A high relapse risk of chronic drug-induced liver injury is correlated with a greater severity of liver fibrosis

To construct a risk prediction model for relapse of chronic drug-induced liver injury (DILI) and explore the correlation between DILI relapse risk and liver fibrosis. We retrospectively collected the clinical data of 1138 patients with chronic DILI hospitalized from January, 2017 to January, 2022, including 154 patients with and 984 without DILI relapse. Based on the results of univariable and multivariable logistic regression analyses, a risk prediction model for DILI relapse was constructed, evaluated for its discrimination and calibration using AUC value and Hosmer-Lemeshow test, and verified with a 200 times 5, 10 and 20 folds cross validation method. Spearman correlation analysis was used to evaluate the correlation between the new model and liver fibrosis, and its diagnostic efficiency for liver fibrosis was assessed by comparison with APRI and FIB-4 using ROC curve. The proportions of patients with S0, S1, S2, S3 and S4 liver fibrosis were 1.9%, 13.1%, 42.2%, 27.9% and 14.9% in the relapse group, respectively, as compared with 8.9%, 43.5%, 26.1%, 17.1% and 4.4% in the non-relapse group, respectively, showing severer liver fibrosis in patients with than those without DILI relapse. Multivariable logistic regression analysis identified LSM≥13.7 kPa (OR=4.35, 95%CI: 2.61-7.25, P < 0.001), CHE < 2500 U/L (OR=5.17, 95%CI: 2.13-12.53, P < 0.001), CHE of 2500-5000 U/L (OR=4.07, 95%CI: 2.75-6.01, P < 0.001), and AST > 2×ULN (OR=2.29, 95%CI: 1.38-3.80, P=0.001) as risk factors for relapse of chronic DILI. The ACLS model constructed based on these non-invasive indicators had an AUC value of 0.803 (95%CI: 0.78-0.83). The results of Hosmer-Lemeshow goodness of fit test (χ2=7.73, P=0.46) and the cross validation tests (average AUC of 0.803) all showed a good stability of the model. Spearman correlation analysis showed that ACLS score was positively correlated with the severity of liver fibrosis (rho=0.530, P < 0.001). At the optimal cut-off value of 3 points for diagnosing moderate liver fibrosis, the ACLS model had an AUC value of 0.78 (with specificity of 72.7% and sensitivity of 73.3%), demonstrating a better efficacy than that of APRI and FIB-4 (P < 0.001). At the cut-off value of 6 for severe liver fibrosis, the diagnostic efficacy of the model (AUC=0.83; specificity 75.7%, sensitivity 72.7%) was still better than that of APRI (P < 0.001) but comparable with that of FIB-4 (P=0.38). The patients at high risks of chronic DILI relapse have severer liver fibrosis and should be followed up regularly for timely aggressive treatment.

The association between parenteral nutrition and pancreatic injury in adult patients: a retrospective observational study

Background and objectivePatients on parenteral nutrition (PN) are at high risk of both liver and pancreatic injury. More efforts were focused on liver, however, limited data is available to evaluate the effects of PN on pancreas. Thus, we performed a retrospective observational study to evaluate the association between PN and pancreatic injury in Chinese adult patients.MethodsAdult patients (18–80 years), who received PN for a week or longer, and with repeated measurements of pancreatic enzymes, were included in the analysis. Pancreatic injury was confirmed by serum level of pancreatic amylase (P-AMYwas 53 U/L or higher) or lipase (LP was 63 U/L or higher), which were evaluated at baseline and following every week during PN duration. Age, sex, body weight, height, diagnosis of diseases, history of diseases, surgery, white blood cell, c-reactive protein, liver and renal function, fasting blood glucose, lipid profile, and daily energy supplied by PN and enteral nutrition were abstracted from medical records.ResultsA total number of 190 adult patients (125 men, 65 women) were included in the study. The average age and BMI were 61.8 ± 13.0 years and 21.7±3.3 kg/m2, while medium serum level of P-AMY and LP were 29.0 U/L (quartile range: 18.0, 47.0) and 33.0 U/L (quartile range: 19.0, 58.0), respectively at baseline. The median duration of PN was 15 days (quartile range: 11.0, 21.0). The prevalence of pancreatic injury was 42.1% (80/190) while it was 28.4% (54/190), 43.3% (77/178), 47.8% (44/92) after one-, two-, and three-week or longer PN adminstration. The proportion of daily energy supplement by PN (OR = 3.77, 95%CI: 1.87, 7.61) and history of infection were positively (OR = 3.00, 95%CI: 1.23, 7.36), while disease history for diabetes mellitus (OR = 0.38, 95%CI: 0.15, 0.98) and cancer (OR = 0.46, 95%CI: 0.23, 0.95), were negetively associated with pancreatic injury. Total bile acids were associated with the increment of P-AMY (beta = 0.98, 95%CI: 0.39, 1.56) and LP (beta = 2.55, 95%CI: 0.98, 4.12) by multi-variate linear regression.ConclusionPN was associated with pancreatic injury, as demonstrated by the increase of both serum P-AMY and LP.

Overcoming Preclinical Safety Obstacles to Discover (S)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (GDC-2394): A Potent and Selective NLRP3 Inhibitor.

Inappropriate activation of the NLRP3 inflammasome has been implicated in multiple inflammatory and autoimmune diseases. Herein, we aimed to develop novel NLRP3 inhibitors that could minimize the risk of drug-induced liver injury. Lipophilic ligand efficiency was used as a guiding metric to identify a series of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinesulfonylureas. A leading compound from this series was advanced into safety studies in cynomolgus monkeys, and renal toxicity, due to compound precipitation, was observed. To overcome this obstacle, we focused on improving the solubility of our compounds, specifically by introducing basic amine substituents into the scaffold. This led to the identification of GDC-2394, a potent and selective NLRP3 inhibitor, with an in vitro and in vivo safety profile suitable for advancement into human clinical trials.

Mechanisms of isoniazid and rifampicin-induced liver injury and the effects of natural medicinal ingredients: A review.

Isoniazid (INH) and rifampicin (RFP) are the first-line medications for tuberculosis treatment, and liver injury is the major adverse effect. Natural medicinal ingredients provide distinct benefits in alleviating patients’ symptoms, lowering the liver injury risk, delaying disease progression, and strengthening the body’s ability to heal. This paper summarises the recent research on the mechanisms of INH and RFP-induced liver injury and the effects of natural medicinal ingredients. It is believed that INH-induced liver injury may be attributed to oxidative stress, mitochondrial dysfunction, drug metabolic enzymes, protoporphyrin IX accumulation, endoplasmic reticulum stress, bile transport imbalance, and immune response. RFP-induced liver injury is mainly related to cholestasis, endoplasmic reticulum stress, and liver lipid accumulation. However, the combined effect of INH and RFP on liver injury risk is still uncertain. RFP can increase INH-induced hepatotoxicity by regulating the expression of drug-metabolizing enzymes and transporters. In contrast, INH can antagonize RFP-induced liver injury by reducing the total bilirubin level in the blood. Sagittaria sagittifolia polysaccharide, quercetin, gallic acid, and other natural medicinal ingredients play protective roles on INH and RFP-induced liver injury by enhancing the body’s antioxidant capacity, regulating metabolism, inhibiting cell apoptosis, and reducing the inflammatory response. There are still many gaps in the literature on INH and RFP-induced liver injury mechanisms and the effects of natural medicinal ingredients. Thus, further research should be carried out from the perspectives of liver injury phenotype, injury markers, in vitro and in vivo liver injury model construction, and liver-gut axis. This paper comprehensively reviewed the literature on mechanisms involved in INH and RFP-induced liver injury and the status of developing new drugs against INH and RFP-induced liver injury. In addition, this review also highlighted the uses and advantages of natural medicinal ingredients in treating drug-induced liver injury.