Anti-tuberculosis Drug-induced Liver Injury Research Articles

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.

Exploring Variability in Rifampicin Plasma Exposure and Development of Anti-Tuberculosis Drug-Induced Liver Injury among Patients with Pulmonary Tuberculosis from the Pharmacogenetic Perspective.

Genetic polymorphisms can exert a considerable impact on drug pharmacokinetics (PK) and the development of adverse drug reactions (ADR). However, the effect of genetic polymorphisms on the anti-tuberculosis (anti-TB) drug, and particularly rifampicin (RIF), exposure or anti-TB drug-induced liver injury (DILI) remains uncertain. Here, we evaluated the relationship between single nucleotide polymorphisms (SNPs) detected in the RIF pharmacogenes (AADAC, SLCO1B1, SLCO1B3, ABCB1, and NR1I2) and RIF PK parameters, as well as anti-TB treatment-associated DILI. In total, the study enrolled 46 patients with drug-susceptible pulmonary TB. The RIF plasma concentration was measured using the LC-MS/MS method in the blood samples collected pre-dose and 2 and 6 h post-dose, whilst the DILI status was established using the results from blood biochemical analysis performed before and 10-12 days after treatment onset. The genotyping was conducted using a targeted NGS approach. After adjustment for confounders, the patients carrying the rs3732357 GA/AA genotype of the NR1I2 gene were found to have significantly lower RIF plasma AUC0-6 h in comparison to those with GG genotype, while the difference in RIF plasma Cmax was insignificant. None of the analyzed SNPs was related to DILI. Hence, we are the first to report NR1I2 intronic SNP rs3732357 as the genetic component of variability in RIF exposure. Regarding anti-TB treatment-associated DILI, the other preexisting factors promoting this ADR should be considered.

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.

Efficacy and safety of bicyclol for treating patients with antituberculosis drug-induced liver injury.

BACKGROUND: Bicyclol was used for treating idiosyncratic acute drug-induced liver injury (DILI) in a phase II trial. This study was aimed at evaluating the efficacy and safety of bicyclol 25 and 50 mg thrice a day (TID) for treating acute DILI caused by anti-TB drugs in the light of the trial results.METHODS: We analysed clinical data of patients with TB drug-induced DILI in the trial database. The primary endpoint was reduction in serum alanine aminotransferase (ALT) levels after 4 weeks of treatment compared to baseline.RESULTS: Overall, 148 patients were included, with respectively 48, 52 and 48 patients included in the control (456 mg polyene phosphatidylcholine TID), high-dose (50 mg bicyclol TID) and low-dose (25 mg bicyclol TID) groups. ALT levels decreased by respectively â-"149.0 (IQR â-"299.3 to â-"98.3 (), â-"225.5 (IQR â-"309.3 to â-"181.8 ) and â-"242.5 (IQR â-"364.8 to â-"153.8) U/L in the control, high-dose and low-dose groups (P < 0.001). The ALT normalisation rates at weeks 1, 2, 4, 6 and 8 were higher in the high- and low-dose groups, while adverse events and serious adverse events were similar across groups.CONCLUSIONS: Bicyclol (25 and 50 mg TID) is effective and safe in treating anti-TB DILI, and bicyclol 50 mg TID showed higher efficacy.

Relevance of NAT2 genotype and clinical factors to risk for antituberculosis drug-induced liver injury.

The study analyzes the risk factors associated with antituberculosis drug-induced liver injury (ATB-DILI), and the relationship between ATB-DILI and NAT2 gene polymorphisms. Out of the 324 included patients, 57 (17.59%) developed ATB-DILI. Age, history of liver disease, alcohol consumption and timing ofantituberculosis(ATB) treatment were independent risk factors for ATB-DILI in the patients with tuberculosis (TB;p<0.05). There was a significant difference in the distribution of NAT2 metabolic phenotypes between the study group and the control group (p<0.05). The ATB drug treatment for pulmonary TB can cause a high incidence of ATB-DILI. Age, history of liver disease, alcohol consumption and timing of ATB treatment are independent risk factors for ATB-DILI in patients with TB.

Systematic review and network meta-analysis of efficacy and safety of interventions for preventing anti-tuberculosis drug induced liver injury

Anti-tuberculosis drug induced liver injury (Anti-TB DILI) is the most common adverse events (AEs) necessitating therapy interruption but there is no preventing regimen. This study aimed to examine the efficacy and safety of herbs/alternative medicines for preventing anti-TB DILI. Relevant articles were identified through a systematic search in 5 international databases from inception till March 2022. All randomized controlled trials (RCT) assessing the effects of herbal or alternative medicines against anti-TB DILI were included. The network meta-analysis (NMA) was used to synthesize the evidence for preventing hepatotoxicity using a random-effects model. A total of 3423 patients from 14 RCTs were included. The NMA indicated that supplementation of Turmeric plus Tinospora cordifolia (RR 0.07; 95% CI 0.02 to 0.28), and N-acetyl cysteine (NAC) (RR 0.09; 95% CI 0.01 to 0.75) significantly reduced the incidence of anti-TB DILI compared with placebo. In addition, poly herbal product significantly reduced alkaline phosphatase (ALP) (MD − 21.80; 95% CI − 33.80 to − 9.80) and total bilirubin (Tbil) compared with placebo (MD − 0.51; 95% CI − 0.76 to − 0.26). There was no statistically significant difference in the occurrence of AEs in any intervention. In conclusion, Turmeric plus Tinospora cordifolia, NAC and poly-herbal product may provide benefit for preventing anti-TB DILI in TB patients. However, these findings are based on a small number of studies. Additional studies are warranted to confirm the findings.

Genetic Polymorphisms of UDP-Glucuronosyltransferases and Susceptibility to Antituberculosis Drug-Induced Liver Injury: A Systematic Review and Meta-Analysis.

The PRISMA statement was strictly followed, and the protocol was registered in PROSPERO (CRD42022339317). The PICOS framework was used: patients received antituberculosis treatment, UGTs polymorphisms (mutants), UGTs polymorphisms (wild), AT-DILI, and case-control studies. Eligible studies were searched through nine databases up to April 27, 2022. The study's qualities were assessed by the revised Little's recommendations. Meta-analysis was conducted with a random-effects model using odds ratios (ORs) with 95% confidence intervals (95% CIs) as the effect size. Twelve case-control studies with 2128 cases and 4338 controls were included, and 32 single nucleotide polymorphisms (SNPs) in the seven UGT genes have been reported in Chinese and Korean. All studies were judged as high quality. The pooled results indicated that UGT1A1 rs3755319 (AC vs. AA, OR = 1.454, 95% CI: 1.100-1.921, P = 0.009), UGT2B7 rs7662029 (G vs. A, OR = 1.547, 95% CI: 1.249-1.917, P < 0.0001; GG + AG vs. AA, OR = 2.371, 95% CI: 1.779-3.160, P < 0.0001; AG vs. AA, OR = 2.686, 95% CI: 1.988-3.627, P < 0.0001), and UGT2B7 rs7439366 (C vs. T, OR = 0.585, 95% CI: 0.477-0.717, P < 0.0001; CC + TC vs. TT, OR = 0.347, 95% CI: 0.238-0.506, P < 0.0001; CC vs. TC + TT, OR = 0.675, 95% CI: 0.507-0.898, P = 0.007) might be associated with the risk of AT-DILI. The polymorphisms of UGT1A1 rs3755319, UGT2B7 rs7662029, and UGT2B7 rs7439366 were significantly associated with AT-DILI susceptibility. However, this conclusion should be interpreted with caution due to the low number of studies and the relatively small sample size.

HLA-DQB1*05:02 Allele Association with Anti-Tuberculosis Drug Induced Liver Injury: A Single-Hospital Based Study in Jakarta, Indonesian Population

Past studies have delved into the genetic factors underlying anti-tuberculosis drug-induced liver injury (AT-DILI), primarily concentrating on polymorphisms in genes responsible for drug-metabolizing enzymes. However, the immune system's potential impact on drug adverse effects, specifically through genes such as HLA, has received limited attention. Previous research has notably revealed an association between HLA-DQB1*05 and AT-DILI, specifically the prevalence of the HLA-DQB*05:02 allele in AT-DILI patients. In light of this, our study aimed to investigate a potential link between HLA-DQB1*05:02 alleles and AT-DILI. In this study, we included 51 AT-DILI cases and 59 controls belonging to the Javanese ethnic group. The HLA-DQB1*05:02 genotypes were determined using a customized PCR-based typing method, and the results were further confirmed by analyzing five samples via the Luminex assay. Our findings revealed a significant association between HLA-DQA1*05: 02 and the risk of AT-DILI (P = 0.022; OR (95% CI) = 6.11 (1.25-29.74)). Moreover, the consistent results obtained from the Luminex assay validated the reliability of the custom PCR-based genotyping approach. This preliminary study sheds light on the relationship between the HLA-DQB1*05:02 allele and AT-DILI within the Indonesian population. Furthermore, our study demonstrates the dependability of custom PCR-based genotyping in detecting HLA-DQB1*05:02 alleles. Nevertheless, further research is imperative to corroborate and expand upon our findings.

Anti-tuberculosis treatment-induced hepatotoxicity in a post-operative setting

The most frequent cause of infectious disease-related mortality globally is tuberculosis (TB), a multisystemic disease with a wide range of presentations and symptoms. Around 12% of extrapulmonary TB cases and 1–3% of all TB cases are caused by abdominal TB. The issue of antituberculosis drug-induced liver injury (ATLI), which has long been a challenge in the management of TB infection, is one of increased significance. The major steps to reduce the occurrence of ATLI are to identify the possible risk factors of hepatotoxicity and to provide an appropriate weight-based anti-tuberculosis treatment (ATT). This case report clarifies the significance of appropriate weight-based dosing of ATT, particularly in a post-operative environment as evidenced in this instance where the patient experienced considerable post-operative weight loss.

Serum levels of IL-6/IL-10/GLDH may be early recognition markers of anti-tuberculosis drugs (ATB) -induced liver injury

To explore the potential value of serum glutamate dehydrogenase (GLDH) combined with inflammatory cytokines as diagnostic biomarkers for anti-tuberculosis drug -induced liver injury (ATB-DILI). We collected the residual serum from the patients who met the criteria after liver function tests. We have examined these parameters including GLDH which were determined by enzyme-linked immunosorbent assay and cytokines which were determined by cytokine combination detection kit. Multivariate logistics stepwise forward regression was applied to establish regression models. A total of 138 tuberculosis patients were included in the diagnostic markers study of ATB-DILI, including normal liver function group (n = 108) and ATB-DILI group(n = 30). Serum GLDH, IL-6 and IL-10 levels were significantly increased in the ATB-DILI group. Receiver operating characteristic curve (ROC) curve showed that the area under curve (AUC) of serum GLDH, IL-6 and IL-10 for the diagnosis of ATB-DILI were 0.870, 0.714 and 0.811, respectively. In logistic regression modeling, the AUC of GLDH combined with IL-10 as an ATB-DILI marker is 0.912. Serum IL-6、IL-10 and GLDH levels began to rise preceded the increase in ALT by 7 days, with significant differences in IL-6 compared with 7 days. Serum GLDH, IL-6 and IL-10 levels were correlated with the severity of liver injury. In conclusion, we found that GLDH, IL-6 and IL-10 alone as diagnostic markers of ATB-DILI had good diagnostic efficacy. Logistic regression model established by GLDH and IL-10 had better diagnostic efficacy and IL-6 may be an early predictor of liver injury in the setting of ATB poisoning.

Glutamate dehydrogenase combined with ferrochelatase as a biomarker of liver injury induced by antituberculosis drugs.

To explore the potential value of serum glutamate dehydrogenase (GLDH), ferrochelatase (FECH), heme oxygenase-1 (HO-1) and glutathione-S-transferase-α (GST-α) as diagnostic biomarkers for liver injury caused by antituberculosis drugs. We established a rat model of isoniazide-induced liver injury and recruited 122 hospitalized tuberculosis patients taking antituberculosis drugs. We detected the concentration of GLDH, FECH, HO-1 and GST-α by enzyme-linked immunosorbent assay. GraphPad Prism8 and SPSS 26.0 were used for statistical analysis. In the rat model, serum GLDH concentration gradually increased during isoniazid (INH) administration, while serum FECH, HO-1 and GST-α concentrations significantly increased after INH administration was stopped. The receiver operating characteristic curve showed that the areas under the curve (AUCs) of serum GLDH and FECH for the diagnosis of anti-tuberculosis (TB) drug-induced liver injury (anti-TB-DILI) were 0.7692 (95% confidence interval [CI] 0.5442-0.9943) and 0.7284 (95% CI 0.4863-0.9705) and the diagnostic accuracies were 81.25% and 78.79%, respectively. In clinical research, the AUCs of GLDH and FECH were 0.9124 (95% CI 0.8380-0.9867) and 0.6634 (95% CI 0.5391-0.7877), and the optimal thresholds were 10.40 mIU/mL and 1.304 ng/mL, respectively. The diagnostic accuracy, specificity and positive predictive value (PPV) of GLDH were 82.61%, 79.38% and 47.22%. We performed a joint diagnostic test for GLDH and FECH. The diagnostic accuracy (90.43%), specificity (91.75%) and PPV (65.21%) of serial tests were better than for GLDH and FECH alone. GLDH in the diagnosis of liver injury induced by anti-TB drugs has high sensitivity, but low specificity and low PPV. The combination of GLDH and FECH could significantly improve the specificity, PPV and diagnostic accuracy, and reduce the false-positive rate of anti-TB-DILI.

OS-009 - Efficacy of N-acetylcysteine to prevent anti-tuberculosis drug-induced liver injury: a randomized controlled trial

OS-009 - Efficacy of N-acetylcysteine to prevent anti-tuberculosis drug-induced liver injury: a randomized controlled trial

Regulation of Gut Microflora by Lactobacillus casei Zhang Attenuates Liver Injury in Mice Caused by Anti-Tuberculosis Drugs.

The gut-liver axis may provide a new perspective for treating anti-tuberculosis drug-induced liver injury (ATDILI). Herein, the protective effect of Lactobacillus casei (Lc) was investigated by modulating gut microflora (GM) and the toll like receptor 4 (TLR4)-nuclear factor (NF)-κB-myeloiddifferentiationfactor 88 (MyD88) pathway. C57BL/6J mice were given three levels of Lc intragastrically for 2 h before administering isoniazid and rifampicin for 8 weeks. Blood, liver, and colon tissues, as well as cecal contents, were collected for biochemical and histological examination, as well as Western blot, quantitative real time polymerase chain reaction (qRT-PCR), and 16S rRNA analyses. Lc intervention decreased alkaline phosphatase (ALP), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and tumor necrosis factor (TNF)-α levels (p < 0.05), recovered hepatic lobules, and reduced hepatocyte necrosis to alleviate liver injury induced by anti-tuberculosis drugs. Moreover, Lc also increased the abundance of Lactobacillus and Desulfovibrio and decreased Bilophila abundance, while enhancing zona occludens (ZO)-1 and claudin-1 protein expression compared with the model group (p < 0.05). Furthermore, Lc pretreatment reduced the lipopolysaccharide (LPS) level and downregulated NF-κB and MyD88 protein expression (p < 0.05), thus restraining pathway activation. Spearman correlation analysis indicated that Lactobacillus and Desulfovibrio were positively correlated with ZO-1 or occludin protein expression and negatively correlated with pathway protein expression. Desulfovibrio had significant negative relationships with alanine aminotransferase (ALT) and LPS levels. In contrast, Bilophila had negative associations with ZO-1, occludin, and claudin-1 protein expressions and positive correlations with LPS and pathway proteins. The results prove that Lactobacillus casei can enhance the intestinal barrier and change the composition of the gut microflora. Moreover, Lactobacillus casei may also inhibit TLR4-NF-κB-MyD88 pathway activation and alleviate ATDILI.

Immune Thrombocytopenic Purpura Secondary to Peritoneal Tuberculosis Patient with Anti-Tuberculosis Drug-Induced Liver Injury. A Case Report

Introduction: Various haematological abnormalities commonly occur in active tuberculosis (TB) but immune thrombocytopenic purpura (ITP) secondary to extrapulmonary TB is exceedingly rare. Case presentation: We reported an 18-year-old male patient who presented with fever, abdominal pain, and thrombocytopenia. From the physical examination, there was found slight abdominal distention and diffuse tenderness. Peripheral blood smear and Immature Platelet Fraction (IPF) investigations were suggestive of ITP.

Genetic variants of the nuclear factor erythroid 2-related factor 2/antioxidant reaction element pathway on the risk of antituberculosis drug-induced liver injury: a systematic review.

Aim: To evaluate the effects of genetic variants in the nuclear factor erythroid 2-related factor 2/antioxidant reaction element signaling pathway on antituberculosis drug-induced liver injury (AT-DILI) susceptibility. Methods: The PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure and Wanfang databases were searched from inception to April 2022. Results: Seven case-control studies with 4676 patients were included. Six genes with 35 SNPs in the pathway have been reported. Among 17 SNPs reported in two or more studies, the meta-analysis indicated that only one SNP (rs3735656 in MAFK) was significantly associated with a decreased risk for AT-DILI under the dominant model (odds ratio: 0.636; 95% CI: 0.519-0.780; p<0.001). Conclusion: SNP rs3735656 in the MAFK gene was significantly associated with the risk of AT-DILI.

Gut microbiota characteristics of Mongolian and Han populations in anti-tuberculosis drug-induced liver injury: a population-based case–control study

BackgroundThe pathogenesis of anti-tuberculosis (TB) drug-induced liver injury (ADLI) is complicated and remains unclear. We aimed to analyse the relationship between the characteristics of gut microbiota and ADLI in Mongolian and Han patients with pulmonary TB and identify the most notable bacteria related to the occurrence of liver injury in those populations.MethodsPatients with concurrent liver injury (LI) and no liver injury (ULI) before receiving first-line anti-TB drug treatment (T1) from the Han population in Tangshan and the Mongolian population in Inner Mongolia were selected as research subjects. At the time of liver injury (T2), stool samples were measured by bacterial 16S rRNA gene high-throughput sequencing to analyse and compare the differences in the gut microbiota of the LI and ULI Mongolian and Han patients at T1 and T2 and identify the differences between those patients.ResultsA total of 45 Mongolian and 37 Han patients were enrolled in our study. A dynamic comparison from T1 to T2 showed that the microbiota of the LI and ULI groups changed significantly from T1 to T2 in both the Mongolian and Han populations. However, there were commonalities and personality changes in the microbiota of the two ethnic groups.ConclusionDifferences in gut microbes in ADLI were found among the Han and Mongolian patients in our study. Ekmania and Stenotrophomonas were related to the occurrence of ADLI in Mongolian patients, while Ekmania and Ruminococcus__gnavus_group were related to the occurrence of ADLI in the Han population.

Hepatocyte ferroptosis contributes to anti-tuberculosis drug-induced liver injury: Involvement of the HIF-1α/SLC7A11/GPx4 axis

Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a common serious adverse event observed during the clinical treatment of tuberculosis. However, the molecular mechanisms underlying ATB-DILI remain unclear. A recent study has indicated that ferroptosis and lipid peroxidation may be involved in liver injury. Therefore, this study aimed to investigate the role of ferroptosis in the molecular mechanisms underlying ATB-DILI. Our results showed that anti-TB drugs induced hepatocyte damage in vivo and in vitro and inhibited BRL-3A cell activity in a dose-dependent manner, accompanied by increased lipid peroxidation and reduced antioxidant levels. Moreover, ACSL4 expression and Fe2+ concentration significantly increased following anti-TB drug treatment. Interestingly, anti-TB drug-induced hepatocyte damage was reversed by ferrostatin-1 (Fer-1, a specific ferroptosis inhibitor). In contrast, treatment with erastin (a ferroptosis inducer) resulted in further elevation of ferroptosis indicators. Additionally, we also found that anti-TB drug treatment inhibited HIF-1α/SLC7A11/GPx4 signaling in vivo and in vitro. Notably, HIF-1α knockdown significantly enhanced anti-TB drug-induced ferroptotic events and the subsequent exacerbation of hepatocyte damage. In conclusion, our findings indicated that ferroptosis plays a crucial role in the development of ATB-DILI. Furthermore, anti-TB drug-induced hepatocyte ferroptosis was shown to be regulated by HIF-1α/SLC7A11/GPx4 signaling. These findings shed new light on the mechanisms underlying ATB-DILI and suggest novel therapeutic strategies for this disease.

Polymorphisms in drug metabolism genes as a risk factor for first-line anti-tuberculosis drug-induced liver injury.

Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common side effects in TB patients during treatment. The prime cause of liver injury during TB treatment is reported to be isoniazid and its metabolites. Different factors influenced the development of AT-DILI, and genetic factors are one of the major factors. Polymorphisms in drug metabolism genes like NAT2, CYP2E1, PXR, and GST have been reported to be associated with AT-DILI, and they are one of the major areas of focus at present. Attempts are met in this review to analyse the different markers in these drug metabolism genes for their association with AT-DILI. A better understanding of the polymorphisms in these genes and their functional effects will give better insights into the development of AT-DILI, and it could facilitate in designing and developing more effective personalized treatment for TB.

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.

Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy.

Rifampicin is the most common pathogenic factor in anti-tuberculosis drug-induced liver injury (AT-DILI), the mechanisms that it promotes hepatocyte damage in AT-DILI are not yet to be thoroughly elucidated. In this study, we investigated the potential molecular mechanisms for ferroptosis involving rifampicin hepatotoxicity. Animal and cell injury models of rifampicin were constructed, and the toxicity of rifampicin was assessed by physicochemical staining and cell viability assay. Next, flow cytometry was employed to detect changes in ferroptosis-related markers, and Western blotting was used to detect protein expression. Then, the important role of autophagy and ferroptosis was verified with small molecule compound intervention. We found that ferritinophagy-induced ferroptosis participates in the toxicity of rifampicin, and the mechanism is that rifampicin precisely activates high-throughput autophagy, which leads to the massive degradation of ferritin and the increase of free iron. Moreover, rifampicin exhibited conspicuous inhibition of Human 71 kDa heat shock cognate protein (HSPA8) that is intimately associated with Microtubule-associated protein light chain 3 isoform B (LC3B) expression, in turn, HSPA8 inducer attenuated intracellular autophagy flux. Of note, inducing HSPA8 or inhibition of autophagy and ferroptosis considerably relieved the hepatotoxicity of rifampicin in mouse model. The present study highlights the crucial roles of the HSPA8 and autophagy in ferroptotic cell death driving by rifampicin, particularly illumines multiple promising regulatory nodes for therapeutic interventions in diseases involving AT-DILI.