anti-TB 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.

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.

Magnesium Isoglycyrrhizinate Attenuates Anti-Tuberculosis Drug-Induced Liver Injury by Enhancing Intestinal Barrier Function and Inhibiting the LPS/TLRs/NF-κB Signaling Pathway in Mice.

Liver injury caused by first-line anti-tuberculosis (anti-TB) drugs accounts for a high proportion of drug-induced liver injury (DILI), and gut microbiota and intestinal barrier integrity have been shown to be involved in the development of DILI. Magnesium isoglycyrrhizinate (MgIG) is the fourth-generation glycyrrhizic acid preparation, which is well documented to be effective against anti-TB DILI, but the underlying mechanism is largely unclear. In the present study, we established a BALB/c mice animal model of the HRZE regimen (39 mg/kg isoniazid (H), 77 mg/kg rifampicin (R), 195 mg/kg pyrazinamide (Z), and 156 mg/kg ethambutol (E))-induced liver injury to investigate the protective effect of MgIG against anti-TB DILI and underlying mechanisms. The results demonstrated that intraperitoneal injection of MgIG (40 mg/kg) significantly ameliorated HRZE-induced liver injury by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), and malondialdehyde (MDA) levels and improved liver pathological changes. Species composition analysis of gut microbiota showed that Lactobacillus was the only probiotic that was down-regulated by HRZE and recovered by MgIG. In addition, MgIG attenuated HRZE-induced intestinal pathology, significantly decreased HRZE-induced intestinal permeability by increasing the protein expression of tight junction protein 1 (ZO-1) and occludin, decreased HRZE-induced high lipopolysaccharide (LPS) levels, and further markedly attenuated mRNA expression levels of TNF-α, IL-6, TLR2, TLR4, and NF-κB. Supplementation with Lactobacillus rhamnosus JYLR-005 (>109 CFU/day/mouse) alleviated HRZE-induced liver injury and inflammation in mice. In summary, MgIG effectively ameliorated HRZE-induced liver injury by restoring the abundance of Lactobacillus, enhancing intestinal barrier function, and further inhibiting the activation of the LPS/TLRs/NF-κB signaling pathway. Regulating gut microbiota and promoting the integrity of intestinal barrier function may become a new direction for the prevention and treatment of anti-TB DILI.

Hepatoprotective drugs for prevention of liver injury resulting from anti-tuberculosis treatment: A meta-analysis of cohort studies

BackgroundThe incidence of liver injury caused by anti-tuberculous (TB) drugs is very high. However, owing to a lack of sufficient evidence, preventive use of hepatoprotective drugs is not yet recommended. Therefore, we aimed to assess the protective effect of hepatoprotective drugs for anti-TB drug-induced liver injury. MethodsWe conducted a literature search in China Biology Medicine disc, China National Knowledge Infrastructure, WanFang, Chinese Scientific and Technological Journal, PubMed, Cochrane Library, Web of Science, and Embase. We performed meta-analysis using R 4.0 and Review Manager 5.3 software. ResultsA total of 18 studies involving 3589 patients from 2 groups were included. Use of hepatoprotective drugs contributed to a lower incidence of liver injury as compared with conventional anti-TB treatment alone (relative risk [RR] = 0.39, 95% confidence interval [CI]: 0.28–0.53, p < 0.001). In subgroup analysis, significant protective effects were noted for mild liver injury (RR = 0.30, 95% CI 0.15–0.58), moderate (or severe) liver injury (RR = 0.35, 95% CI 0.19–0.65), and liver injury within 2–4 weeks (RR = 0.37, 95% CI 0.19–0.71). We also found a statistically significant difference in the incidence of drug withdrawal (RR = 0.58, 95% CI 0.34–0.97, p = 0.040). ConclusionsOur results demonstrate that hepatoprotective drugs are effective in preventing liver injury in patients receiving anti-TB treatment, to some extent.

Time of Liver Function Abnormal Identification on Prediction of the Risk of Anti-tuberculosis-induced Liver Injury.

Anti-tuberculosis (anti-TB) drug-induced liver injury (AT-DILI) is the most common side effect in patients who received anti-TB therapy. AT-DILI management includes monitoring liver function until symptoms arise in patients without high-risk factors for liver damage. The present study aimed to investigate the effect of liver function test (LFT) abnormal identification on the risk of DILI, including liver failure and anti-TB drug resistance in patients without high-risk factors. A total of 399 patients without high-risk factors for liver damage at baseline and who experienced LFT abnormal during the 6 months of first-line anti-TB treatment were enrolled. The Roussel Uclaf Causal Relationship Assessment Method (RUCAM, 2016) was applied in suspected DILI. The correlations between the time of LFT abnormal identification and DILI, liver failure, and anti-TB drug resistance were analyzed by smooth curve fitting and multivariable logistic regression models. Among all study patients, 131 met the criteria for DILI with a mean RUCAM causality score of 8.86±0.63. 26/131 and 105/131 were in the probable grading and highly probable grading, respectively. The time of abnormal LFT identification was an independent predictor of DILI, liver failure, and anti-TB drug resistance in the crude model and after adjusting for other risk patient factors. The time of abnormal LFT identification was positively correlated with DILI, liver failure, and anti-TB drug resistance. The late identification group (>8 weeks) had the highest risk of DILI, followed by liver failure compared with the other two groups. The time to identification of LFT was positively correlated with DILI, liver failure, and anti-TB drug resistance. The risk of DILI and liver failure was significantly increased in the late identification group with abnormal LFT identified after 8 weeks compared with 4 and 8 weeks. Early monitoring of LFT is recommended for patients without the high-risk factor of DILI after anti-TB treatment is initiated.

Comparative effectiveness of glycyrrhizic acid preparations aimed at preventing and treating anti-tuberculosis drug-induced liver injury: A network meta-analysis of 97 randomized controlled trials

Background and objectivesClinical guidelines and expert consensus do not yet recommend glycyrrhizic acid (GA) preparations, such as compound glycyrrhizin, diammonium glycyrrhizin, magnesium isoglycyrrhizinate (MGIG), et al., for the prevention of anti-tuberculosis(anti-TB) drug-induced liver injury (DILI) due to insufficient evidence. Although these GA preparations are recommended for the treatment of anti-TB DILI, which one performs best is unclear. Previous conventional meta-analyses did not summarize the results of simultaneous comparisons of different glycyrrhizinate preparations. Therefore, we aimed to compare and rank different GA preparations on preventing and treating the anti-TB DILI by network meta-analysis (NMA). MethodsA systematic search on PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Infrastructure, SinoMed, Chongqing VIP and, the Wanfang Database was performed up to December 19, 2020. The literature was screened according to predefined inclusion and exclusion criteria to extract important information. The outcomes were the incidence of liver injury (prevention section) and treatment response rate (treatment section). The NMA was conducted with a random-effects model under the Bayesian framework to calculate risk ratios (RRs) with 95% credible intervals (95% CrIs) using R software (version 3.6.1). ResultsFrom 1,411 publications, we included 97 relevant randomized clinical trials (RCTs) (10,923 participants). In terms of preventing anti-TB DILI (33 RCTs, comprising 5,762 patients), CGC, DGC, DGEC, and DGI, but not CGI, significantly reduced the incidence of liver injury than control group (RRs ranged from 0.26 to 0.58); CGC and DGEC were superior to DGC (RRs = 0.50 and 0.58, respectively). In terms of treating anti-TB DILI (64 RCTs, comprising 5,161 patients), MGIG was most effective among all regimens (RRs ranged from 1.15 to 1.72) while DGC ranked last (RRs ranged from 0.58 to 0.83). ConclusionsAll GA preparations except for CGI were effective in preventing the incidence of anti-TB DILI and CGC was superior to DGC. MGIG seems to be the best choice among all GA preparations for the treatment of anti-TB DILI. Future clinical practice guidelines should factor in these novel findings to improve patient outcomes; however, further high-quality trials are needed to validate these results.

Gallic acid attenuates isoniazid and rifampicin-induced liver injury by improving hepatic redox homeostasis through influence on Nrf2 and NF-κB signalling cascades in Wistar Rats.

Anti-TB drugs-isoniazid and rifampicin induced hepatotoxicity present a significant clinical problem. We aimed to evaluate the beneficial effect of gallic acid in anti-TB drug-induced liver injury in vivo and for the mechanism of action, we explored the influence of gallic acid on Nrf2 and NF-κB pathways. We assessed serum liver function tests and histopathological analysis for the preventive effect of gallic acid on liver injury. For exploring the beneficial mechanism, we studied Nrf2 and NF-κB signalling pathways using molecular assays. Subsequently, we conducted in vitro cytotoxicity assays with Nrf2(ML385) and NF-κB(BAY 11-7085) antagonists. Gallic acid co-administration attenuated the elevation of liver function enzymes, hepatic necrosis and inflammation compared to the anti-TB drug treatment alone. Mechanistic investigations reveal that gallic acid increased Nrf2 activation and induction of its downstream targets, preventing cytotoxicity by isoniazid and rifampicin. The protective effect of gallic acid diminished in the presence of Nrf2 antagonists in vitro. Furthermore, we found that gallic acid treatment inhibited NF-κB/TLR-4 axis upregulated by the anti-TB drugs. Gallic acid is effective in preventing isoniazid and rifampicin induced hepatotoxicity in vivo by improving the redox homeostasis by activating Nrf2 and inhibiting NF-κB signalling pathways.

Genetic characterization of N-acetyltransferase 2 variants in acquired multidrug-resistant tuberculosis in Indonesia.

Background: Owing to the high resistance rate of tuberculosis (TB) to isoniazid, which is metabolized by N-acetyltransferase 2 (NAT2), we investigated the associations between NAT2 variants and multidrug-resistant (MDR)-TB. Materials & methods: The acetylator status based on NAT2 haplotypes of 128 patients with MDR-TB in Indonesia were compared with our published data from patients with anti-TB drug-induced liver injury (AT-DILI), TBand the general population. Results:NAT2*4 was more frequent in the MDR-TB group than in the AT-DILI group, TB controlsand general controls. NAT2*4/*4 was significantly more frequent in patients with MDR-TB than in those with AT-DILI. NAT2*5B/7B, *6A/6Aand *7B/*7B were detected at lower frequencies in patients with AT-DILI. Rapid acetylators were significantly more frequent in patients with MDR-TB than in those with AT-DILI. Conclusion: These results provide an initial data for optimizing TB treatment in the Indonesian population, and suggest that NAT2 genotyping may help to select appropriate treatment by predicting TB-treatment effect.

Global DNA hypomethylation of Alu and LINE-1 transposable elements as an epigenetic biomarker of anti-tuberculosis drug-induced liver injury

ABSTRACT Despite being highly effective, anti-tuberculosis (TB) drugs often induce adverse liver injury, anti-TB drug-induced liver injury (ATDILI), leading to treatment failure given no sensitive and selective ATDILI markers. Herein, we conducted a case–control association study to determine whether global DNA methylation of Alu and LINE-1 transposable elements responsible for genomic stability and transcriptional regulation was correlated with clinical parameters indicating ATDILI in TB patients and might serve as an ATDILI biomarker. Alu and LINE-1 methylation levels in blood leukocyte of 130 TB patients (80 ATDILI cases and 50 non-ATDILI cases) and 100 healthy controls were quantified using quantitative combined bisulfite restriction analysis. Both TB patients with and without ATDILI had significantly lower methylation levels of Alu and LINE-1 elements than healthy controls. Compared with non-ATDILI patients, Alu methylation levels were significantly decreased in ATDILI patients, commensurate with LINE-1 methylation analysis. Hypomethylation of Alu and LINE-1 measured within 1–7 days of TB treatment was independently associated with raised levels of serum aminotransferases assessed within 8–60 days of TB treatment. Receiver operating characteristic curve analysis uncovered that Alu and LINE-1 methylation levels were both more sensitive and specific for differentiating ATDILI cases from non-ATDILI cases than serum aminotransferases after starting TB treatment within 1–7 days. Kaplan-Meier analysis displayed a significant association between hypomethylation of Alu and LINE-1 elements and an increased rate of ATDILI occurrence in TB patients. Collectively, global DNA hypomethylation of Alu and LINE-1 elements would reflect ATDILI progression and might serve as novel sensitive and specific ATDILI biomarkers.

The Effect of acetyl-L-carnitine, Alpha-lipoic Acid, and Coenzyme Q10 Combination in Preventing Anti-tuberculosis Drug-induced Hepatotoxicity: A Randomized, Double-blind, Placebo-controlled Clinical Trial.

Drug-induced liver injury (DILI) is one of the most serious adverse effects of anti-tuberculosis (TB) drugs. A suggested mechanism of this adverse effect is mitochondrial dysfunction (MDF). The purpose of this study was an evaluation of the possible preventive effects of the combination of acetyl-L-carnitine (ALCAR), alpha-lipoic acid (ALA), and coenzyme Q10 (CoQ10), as mitochondrial nutrients (MNs), against anti-TB DILI. In this clinical trial, patients who met the inclusion criteria were randomly assigned to either experimental (n = 44) or placebo (n = 43) groups. The experimental group received capsules containing CoQ10 (200 mg) + ALA (250 mg) + ALCAR (250 mg) orally twice daily for two weeks, and the placebo group received oral placebo capsules with the same interval and duration. The mean serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBil) at the end of the first and second weeks as well as the incidence of DILI during the intervention were recorded and compared between the two groups. At the end of the study, the mean serum levels of AST and ALT in the experimental group were significantly lower than the placebo group (36.27 ± 36.43 vs. 86.02 ± 97.23 and 28.41 ± 27.41 vs. 78.80 ± 118.28, respectively, P = 0.003 for both). Also, the incidence of anti-TB DILI was significantly lower in the experimental group than the placebo group (6.8% vs. 25.6%, P = 0.017). In conclusion, using the combination of ALCAR, ALA, and CoQ10 may provide an effective strategy in preventing anti-TB DILI.

Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens.

Drug-induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)-containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti-TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti-TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans-ethnic meta-analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA-B*52:01 was significant (meta-analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63-4.37, P=9.4×10-5 ). For N-acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57-0.83, P=0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84-4.22, P=0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered.

GSTM1 and GSTT1 genetic polymorphisms and their association with antituberculosis drug-induced liver injury.

Antituberculosis (anti-TB) drugs are the most common cause of drug-induced liver injury (DILI). There are numerous studies revealing the associations between the polymorphisms of pharmacogenes and the risk of anti-TB DILI (ATDILI). In the present study, relevant studies regarding the pharmacogenes associated with ATDILI were systematically searched in PubMed and Scopus. A total of 24 genes associated with ATDILI were reported on and the top five reported genes in terms of frequency were revealed to be N-acetyltransferase 2, cytochrome P450 family 2 subfamily E member 1, glutathione S-transferases [glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1)] and solute carrier organic anion transporter family member 1B1. As ATDILI may be the result of direct and indirect interactions, the encoded proteins were further analysed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to observe the protein-protein interactions and the associations amongst these proteins. The results suggested that only GSTT1 and GSTM1 were central proteins associated with all the other analysed proteins. Therefore, the association between GSTT1 or GSTM1 and the risk of developing ATDILI were further analysed. The results revealed that a GSTM1 deletion genotype was significantly associated with risk of ATDILI [odds ratio (OR), 1.28; 95% confidence interval (CI), 1.08-1.51; P=0.004], whereas the GSTT1 deletion genotype and GSTM1/GSTT1 dual-deletion genotype were not significantly associated with risk of ATDILI. Subgroup analysis based on ethnicity was performed and the results demonstrated a significant association between GSTM1 and ATDILI in South Asian individuals (OR, 1.48; 95% CI, 1.12-1.95; P=0.005), which has not been reported previously, to the best of our knowledge. In conclusion, GSTM1 was associated with ATDILI in South Asian individuals.

Drug-Induced Liver Injury from Anti-Tuberculosis Treatment: A Retrospective Cohort Study.

BackgroundThe aim of this study was to investigate the clinical characteristics and the risk factors associated with anti-tuberculosis (anti-TB) drug-induced liver injury (DILI).Material/MethodsThis retrospective study enrolled 140 hospitalized patients diagnosed with anti-TB DILI during January 2009 to December 2015. We assessed the baseline characteristics and performed regular follow-up up to the 24th week to assess the possible risk factors associated with the condition.ResultsThe study population was 58.6% male and 41.4% female patients; 20.7% were diagnosed with grades 4–5 DILI and 79.3% with grades 1–3 DILI. Female patients were significantly more likely to be diagnosed with grades 4–5 DILI than with grades 1–3 DILI (58.6% vs. 36.9%, p=0.036). Patients treated with a multidrug anti-TB regimen were more commonly affected with grades 4–5 DILI (86.2% vs. 68.5%, p=0.045). A significant number of patients who reinitiated anti-TB therapy suffered severe liver injury in comparison to patients with grades 1–3 DILI (41.4% vs. 10.8%, P<.001). Laboratory examinations revealed significantly higher values for total bilirubin (TBL), International normalized ratio (INR), and Hy’s law (P<.001) in the grades 4–5 group compare to the grades 1–3 group.ConclusionsFemale gender, combination therapy for antitubercular drugs (isoniazid, rifampicin and pyrazinamide), re-challenge were the risk factors associated with the severity of anti-TB DILI.

Association between genetic polymorphisms of NRF2, KEAP1, MAFF, MAFK and anti-tuberculosis drug-induced liver injury: a nested case-control study

Reactive metabolites of anti-tuberculosis (anti-TB) drugs can result in excessive reactive oxygen species (ROS), which are responsible for drug-induced liver injury. The nuclear factor erythroid 2-related factor 2 (Nrf2) - antioxidant response elements (ARE) (Nrf2-ARE) signaling pathway plays a crucial role in protecting liver cells from ROS, inducing enzymes such as phase II metabolizing enzymes and antioxidant enzymes. Based on a Chinese anti-TB treatment cohort, a nested case-control study was performed to explore the association between 13 tag single-nucleotide polymorphisms (tagSNPs) in the NRF2, KEAP1, MAFF, MAFK genes in Nrf2-ARE signaling pathway and the risk of anti-TB drug-induced liver injury (ATLI) in 314 cases and 628 controls. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting weight and usage of hepatoprotectant. Patients carrying the TC genotype at rs4243387 or haplotype C-C (rs2001350-rs6726395) in NRF2 were at an increased risk of ATLI (adjusted OR = 1.362, 95% CI: 1.017–1.824, P = 0.038; adjusted OR = 2.503, 95% CI: 1.273–4.921, P = 0.008, respectively), whereas patients carrying TC genotype at rs2267373 or haplotype C-G-C (rs2267373-rs4444637-rs4821767) in MAFF were at a reduced risk of ATLI (adjusted OR = 0.712, 95% CI: 0.532–0.953, P = 0.022; adjusted OR = 0.753, 95% CI: 0.587–0.965, P = 0.025, respectively). Subgroup analysis also detected a significant association between multiple tagSNPs (rs4821767 and rs4444637 in MAFF, rs4720833 in MAFK) and specific clinical patterns of liver injury under different genetic models. This study shows that genetic polymorphisms of NRF2, MAFF and MAFK may contribute to the susceptibility to ATLI in the Chinese anti-TB treatment population.

Genome-Wide Analysis of DNA Methylation and Antituberculosis Drug-Induced Liver Injury in the Han Chinese Population.

Tuberculosis (TB) is one of the most prevalent infections. However, anti-TB drugs induce adverse liver injury in up to 40% of patients. Studies on candidate genes have suggested that single-nucleotide polymorphisms account for only a small contribution to the occurrence of anti-TB drug-induced liver injury (ATLI). In this study, whole-genome DNA methylation analysis was performed to systematically screen the ATLI-associated factors in a 49 vs. 51 case-control population. Next, 34 identified candidate probes were validated using MassARRAY in 296 cases and 288 controls. Our results indicated that 12 CpG sites on seven probes were positively associated with ATLI risk. Furthermore, we applied a CRISPR/Cas9-mediated methylation modifiable cell model and demonstrated that four CpGs in or near the gene region of AK2, SLC8A2, and PSTPIP2 affected the cellular response to rifampicin treatment. This study provides new biomarkers associated with ATLI occurrence.

Possible association of HMOX1 and NQO1 polymorphisms with anti-tuberculosis drug-induced liver injury: A matched case-control study.

Reactive metabolites from anti-tuberculosis (anti-TB) drugs can result in abnormal accumulation of reactive oxygen species (ROS), which plays an important role in anti-TB drug-induced liver injury (ATLI). Liver cells could keep the production of ROS in balance by antioxidant activities. The heme oxygenase 1, encoded by the HMOX1 gene and NADH:quinone oxidoreductase 1, encoded by the NQO1 gene are crucial mediators of cellular defense against ROS. The present study aimed to investigate the associations between HMOX1 and NQO1 polymorphisms and ATLI in Chinese anti-TB treatment population. A matched case-control study was conducted using 314 ATLI cases and 628 controls. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATLI by the odds ratios (ORs) with 95% confidence intervals (CIs), with weight and use of hepatoprotectant as covariates. Patients carrying the GG genotype at rs2071748 in HMOX1 were at a higher risk of ATLI than those with the AA genotype (adjusted OR=1.503, 95% CI: 1.005-2.249, P=0.047), and significant differences were also found under the recessive (P=0.015) and additive (P=0.045) models. Subgroup analysis confirmed the relationship in mild hepatotoxicity cases under the recessive and additive models (adjusted OR=1.714, 95% CI: 1.169-2.513, P=0.006; adjusted OR=1.287, 95% CI: 1.015-1.631, P=0.037, respectively). This is the first study to explore the relationship between HMOX1, NQO1 polymorphisms and ATLI in Chinese anti-TB treatment population. Based on a matched case-control study, genetic polymorphisms of HMOX1 may be associated with susceptibility to ATLI in the Chinese population.

Ursodeoxycholic acid attenuates hepatotoxicity of multidrug treatment of mycobacterial infections: A prospective pilot study.

Tuberculosis (TB) remains a global health problem. The application of rifampicin-based regimens for antimycobacterial therapy is hampered by its marked hepatotoxicity which results in poor adherence and may contribute to prolonged therapy or treatment failure. The purpose of this prospective investigation was to evaluate the hepatoprotective effectiveness of oral ursodeoxycholic acid (UDCA) (250-500 mg TID) administered to TB- or non-TB mycobacterial (NTM)-infected patients with drug-induced hepatotoxicity and ongoing therapy. Study population: During 2009-2017, 27 patients (11 women, 16 men, aged 19-90 years; median age 44 years, 16 Caucasians, 10 Africans, 1 Asian) out of 285 patients with active TB (24/261) or NTM infections (3/24) treated at our TB Center developed clinically relevant hepatotoxicity. Oral UDCA was administered to treat hepatotoxicity. Twenty-one out of 27 patients (77.8%) showed normalization of elevated enzymes (alanine transferase and aspartate aminotransferase), alkaline phosphatase, and bilirubin while continuing TB treatment and 5 patients demonstrated a significant reduction of liver enzymes (18.5%). No change was observed in 1 patient (3.7%). Drug dose was not reduced in all patients; they all showed radiological and clinical improvement. There were no significant side effects. Oral administration of UDCA to TB patients developing anti-TB drug-induced liver injury may reverse hepatotoxicity in adults.

Risk factors for acute liver failure among inpatients with anti-tuberculosis drug-induced liver injury.

ObjectiveTo analyze the clinical and laboratory features and determine the predictors of acute liver failure (ALF) among inpatients with anti-tuberculosis (TB) drug-induced liver injury (DILI).MethodPatients diagnosed with anti-TB DILI from 2010 to 2016 at The First Affiliated Hospital of Zhejiang University were retrospectively included in this study. Demographic and clinical data were collected by reviewing electronic medical records.ResultsAmong 155 inpatients with anti-TB DILI, 55 (35.48%) developed ALF, with an overall mortality of 9.68%. The median time to DILI onset was significantly longer in the ALF compared with the non-ALF group (51 versus 24 days). Eighty-three patients (53.55%) developed DILI (53.55%) within the first month of anti-TB treatment, and 60% of ALF cases occurred within 2 months. Multivariable models for ALF incorporating aspartate aminotransferase, total bilirubin, platelets, white blood cell count, and pre-existing hepatitis yielded a concordance (C-statistic) of 98.93%.ConclusionsThe results of this study suggest that approximately half of all cases of DILI occur within the first month, while 60% of ALF cases occur within 2 months. Elevated total bilirubin, aspartate aminotransferase, white blood cell count, pre-existing hepatitis, and low platelet count are independent risk factors for the development of anti-TB drug-induced ALF.

Protective Effect of Bicyclol on Anti-Tuberculosis Drug Induced Liver Injury in Rats

The present study was performed to investigate the effect of bicyclol, a synthetic anti-hepatitis drug with anti-oxidative and anti-inflammatory properties, on anti-tuberculosis (anti-TB) drug-induced liver injury and related mechanisms in rats. Bicyclol was given to rats by gavage 2 h before the oral administration of an anti-TB drug once a day for 30 days. Liver injury was evaluated by biochemical and histopathological examinations. Lipid peroxidation, mitochondrial function, and the activity of antioxidants were measured by spectrophotometric methods. Cytokines expression and CYP2E1 activity were determined by ELISA assay and liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis. The expressions of hepatic CYP2E1 and hepatocyte growth factor (HGF) were assessed by Western blotting. As a result, bicyclol significantly protected against anti-TB drug-induced liver injury by reducing the elevated serum aminotransferases levels and accumulation of hepatic lipids. Meanwhile, the histopathological changes were also attenuated in rats. The protective effect of bicyclol on anti-TB drug-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress, suppress the inflammatory cytokines and CYP2E1 expression, up-regulate the expression of HGF, and improve mitochondrial function. Furthermore, administration of bicyclol had no significant effect on the plasma pharmacokinetics of the anti-TB drug in rats.