Antituberculosis Drug-induced Hepatotoxicity Research Articles

Fulminant Hepatitis Secondary to Anti-tuberculosis Drug-induced Hepatotoxicity Complication, Its Prevention Strategies and Management: A Case Report

Aim: Tuberculosis remains a public health problem around the world. Hepatotoxicity is a serious side effect of anti-tuberculosis treatment. Fulminant hepatitis is a rare form but considered very serious outside of liver transplantation. It can occur several weeks or months after the start of treatment.
 Presentation of Case: We report the case of a 34-year-old single male patient treated for pleural tuberculosis in whom fulminant hepatitis appeared after four months of treatment with Isoniazid and Rifampicin. Despite a treatment in intensive care unit He had a fatal outcome because of lack of liver transplantation.
 Discussion: Hepatotoxicity varies from biological hepatitis to fulminant hepatitis. Application of personalized strategy of genetic analysis and pharmacological drug monitoring to optimize treatment is the most safe to avoid antituberculosis drug induced hepatotoxicity but not available in all healthcare centers of developing countries. There was any change of anti-tuberculosis protocol because of the risk of bacterial resistance. The protocol includes association between several medicines potentially toxics for a long duration. For some moderate forms of tuberculosis (nodals, pleural), it’s necessary to ask if duration of antiviotherapy can be reduced.
 Conclusion: Prevention of hepatotoxicity starts with identifying risk factors, regular clinical and biological assessment and informing patients of symptom that can indicate toxicity to react early.

SLCO1B1 variants and the risk of antituberculosis drug-induced hepatotoxicity: a systematic review and meta-analysis.

Aims: To evaluate the association between SLCO1B1 gene polymorphisms and susceptibility of antituberculosis drug-induced hepatotoxicity (ATDH). Methods: We searched the PubMed, Cochrane Library, Embase, Web of Science, Wan Fang and China National Knowledge Infrastructure database from inception to 2022. Results: Nine case-control studies with 1129 cases and 2203 controls were included. Among four SNPs reported in two or more studies, the final results indicated that SNP rs4149014 was significantly associated with decreased ATDH risk (dominant model, odds ratio:0.73; 95% CI: 0.55-0.97; p=0.03; allele model,odds ratio:0.69;95% CI: 0.55-0.86;p=0.001), and the trial sequential analysis also confirmed this significant association. Conclusion: SLCO1B1 gene SNP rs4149014 was significantly associated with lower risk of ATDH susceptibility.

Association of Cytochrome P450 2E1 and N-Acetyltransferase 2 Genotypes with Serum Isoniazid Level and Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Cross-Sectional Study.

Anti-tuberculosis drug-induced hepatotoxicity can result from genetic polymorphism of the isoniazid (INH) metabolizing enzyme. This study aimed to determine the effect of genetic polymorphism of N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genes on serum isoniazid level and drug-induced hepatotoxicity. A cross-sectional study was conducted on 120 patients (with and without hepatotoxicity) with pulmonary tuberculosis from June 2019 to April 2022 in Tehran (Iran). High-performance liquid chromatography was used to measure the serum concentration of INH and acetylisoniazid (AcINH). NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism methods. Data were analyzed using SPSS software (version 22.0) with independent two-sample t test, Chi square test, or Fisher's exact test. P<0.05 was considered statistically significant. A total of 40 patients showed hepatotoxicity. The risk of anti-tuberculosis drug-induced hepatotoxicity was significantly higher in patients who are slow acetylator (SA) phenotype than in rapid or intermediate acetylator (P<0.001). NAT2*4/*4 genotypes were not found in patients with hepatotoxicity. The frequency of NAT2*5 and NAT2*6 haplotypes and serum INH concentration was significantly higher in patients with hepatotoxicity than in those without (P=0.003, P<0.001, and P<0.001, respectively). NAT2*4 haplotype was correlated with protection against hepatotoxicity. A combination of SA and CYP2E1 C1/C1 genotype was significantly associated with hepatotoxicity (P<0.001). Hepatotoxicity in Iranian patients with tuberculosis was confirmed due to the presence of NAT2 SA polymorphism. Determining NAT2 and CYP2E1 genotypes and/or INH concentration can be a valuable tool to identify patients susceptible to hepatotoxicity.

Relationship between common telomere length-related genetic variations, telomere length, and risk of antituberculosis drug-induced hepatotoxicity in Chinese Han population: As assessed for causality using the updated Roussel Uclaf Causality Assessment Method.

Antituberculosis drug-induced hepatotoxicity (ATDH) is a significant threat to tuberculosis control, and two recent studies indicated that leukocyte telomere length (LTL) might be a potential biomarker for ATDH. This study aimed to investigate the relationship between common telomere length-related genetic variations, LTL, and risk of ATDH in Eastern Chinese antituberculosis treatment patients. A 1:4 matched case-control study was conducted among 79 ATDH cases assessed for causality using the updated RUCAM and 316 controls. LTL was determined by quantitative real-time PCR, and nine SNPs involved in telomere biology reported by previous GWAS were assessed. Conditional logistic regression model was used to estimate the association between genotypes and risk of ATDH with odds ratios (ORs) and 95% confidence intervals (CIs). The average RUCAM score of cases was 7.1. The average LTL in cases was significantly shorter than that in controls (median = 1.239 vs. 1.481, P = 0.032). Differences in the distribution of LTL were statistically significant among three genotypes of SNP rs2736098 (CC vs. CT vs. TT, median = 1.544 vs. 1.356 vs. 1.337, P = 0.026) and rs2853677 (AA vs. AG vs. GG, median = 1.511 vs. 1.544 vs. 1.159, P = 0.005) in TERT. SNP rs7675998 in NAF1 was statistically associated with the risk of ATDH under the dominant model (adjusted OR = 1.725, 95% CI: 1.021-2.913, P = 0.042). This is the first study to investigate the relationship of LTL, common telomere length-related variations, and risk of ATDH. SNP rs2736098 and rs2853677 in TERT were significantly associated with LTL, and SNP rs7675998 in NAF1 may be associated with ATDH in Chinese population.

The Effectiveness of Silymarin in the Prevention of Anti-tuberculosis Drug-induced Hepatotoxicity: A Randomized Controlled Clinical Trial.

Several animal studies have shown the protective effect of silymarin (the extract of Silybum marianum seeds) against anti-tuberculosis drug-induced hepatotoxicity (ATDH). However, the knowledge of ATDH of silymarin in humans is scarce. In this study, we aimed to clinically evaluate it. During this randomized controlled clinical trial, 36 new cases of tuberculosis (TB) were enrolled to receive either silymarin 150 mg twice daily for two weeks along with a standard anti-TB therapeutic regimen (experimental group; n = 16) or standard anti-TB therapeutic regimen alone (control group; n = 21). Liver function tests (serum AST, ALT, ALP, and total bilirubin) at the end of weeks 1 and 2 as well as the rate of ATDH during the study were determined and compared between the groups. No significant differences between the experimental and control groups were observed at the end of the first week regarding liver function tests; However, at the end of the second week, the mean serum levels of AST (P = 0.03) and ALP (P = 0.04) were significantly lower in the experimental group. ALT (P = 0.016) and ALP (P = 0.027) levels in the experimental group significantly decreased during the study, while the changes in the control group were not significant. Two patients in the control group (9.5%) developed ATDH, while no one in the experimental group manifested this adverse effect. Our study suggests that silymarin use has the potential for the reduction of anti-TB drug-induced hepatotoxicity.

Study of antitubercular drugs on liver function tests in newly diagnosed tuberculosis

Background: Particularly in areas where both tuberculosis and liver illness are prominent, it is necessary to determine the factors that put patients at risk for developing anti-tuberculosis drug-induced hepatotoxicity (anti-TB-DIH). In this study, both the prevalence of anti-TB-DIH and the factors that contribute to its development were studied. As a consequence of this, the purpose of the present study was to explore the abnormal liver function test in patients who were being treated for tuberculosis. Aims and Objectives: (i) To investigate hepatotoxicity in antitubercular patients. (ii) To protect the liver from chemotherapy drug side effects through early detection. (iii) To understand drug-induced hepatotoxicity risk factors. Materials and Methods: This is a prospective study of one hundred patients who were treated at the Department of Pulmonary Medicine and the Department of Pharmacology at the Rajiv Gandhi Institute of Medical Sciences in Kadapa between January 2022 and January 2023. Results: Patients varying in age from 15 to 30 years comprised 21 (21%) of the study, 31–50 years comprised 31% of the study, 51–70 years comprised 38% of the study, and 71–80 years comprised 10% of the study, with 68 (68%) males and 32 (32%) females. When compared to the levels that were present before therapy, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) exhibited a substantial increase after 2 months of treatment. A comparison of the patient’s levels of AST, ALT, ALP, and gammaglutamyl transpeptidase (GGT) before treatment and after treatment for 6 months demonstrated a considerable rise in all of these enzymes’ activities. Conclusion: Because it was established that the majority of patients suffer hepatotoxicity within the first 14 days of beginning antituberculosis therapy (ATT) medication, it is imperative that the liver function of patients be monitored in the initial days in which treatment with ATT is being initiated.

GSTT1/GSTM1 Genotype and Anti-Tuberculosis Drug-Induced Hepatotoxicity in Peruvian Patients.

In Peru, 24,581 people were diagnosed with tuberculosis (TB) in 2020. Although TB treatments are effective, 3.4–13% are associated with significant adverse drug reactions (ADRs), with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid (INH) is the main drug responsible for the appearance of DILI. In the liver, INH is metabolized by the enzymes N-acetyltransferase-2 (NAT2), cytochrome P450 2E1 (CYP2E1), and glutathione S-transferase (GST) with two isoforms, GSTT1 and GSTM1. Based on previous studies, we hypothesized that interactions between the GSTT1 and GSTM1 null genotypes induce DILI in TB patients. In this cross-sectional study of 377 participants who completed their anti-TB treatment, we genotyped by revealing the presence or absence of 215- and 480-bp bands of GSTM1 and GSTT1, respectively. We found that the prevalence of the GSTM1 genotype was 52.79% and 47.21% for presence and null, respectively, and for GSTT1 it was 69.76% and 30.24% for presence and null, respectively. Neither genotype was prevalent in the patients who developed DILI (n = 16). We did not confirm our hypothesis; however, we found that the combination of GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype had a significant risk for the development of ADR (OR 11; p = 0.017; 95% CI: (0.54–186.35)). We propose that the presence of the GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype in the Peruvian population could be considered a risk factor for the development of ADR due to therapeutic drug intake.

NAT2 and CYP2E1 polymorphisms and antituberculosis drug-induced hepatotoxicity in Peruvian patients.

BackgroundIn Peru, 32,970 people were diagnosed with tuberculosis (TB) in 2019. Although TB treatment is effective, 3.4%–13% is associated with significant adverse drug reactions (ADR), considering drug‐induced liver injury (DILI) as the most prevalent. Among the first‐line anti‐TB drugs, isoniazid (INH) is primarily responsible for the occurrence of DILI. INH is metabolized in the liver by the enzymes N‐acetyltransferase‐2 (NAT2) and Cytochrome P450 2E1 (CYP2E1). Based on the previous studies, we hypothesized that the interactions between slow CYP2E1 genotype and NAT2 slow acetylators will induce DILI in TB patients.MethodsIn this cross‐sectional study, all 377 participants completed their anti‐TB treatment, and we genotyped SNPs: rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2 and rs3813867 and rs2031920 for CYP2E1.ResultsWe found that rapid, intermediate, and slow NAT2 acetylator were 15%, 38%, and 47%, respectively, in the general population. Intermediate NAT2 acetylator is the least prevalent among patients with adverse reactions (p = 0.024). We did not confirm our hypothesis, however, we found that the combination of intermediate NAT2 acetylators and CYP2E1 c1/c1 genotype significantly protected (OR = 0.16; p = 0.049) against the development of DILI in our population.ConclusionWe propose that the presence of NAT2 intermediate and CYP2E1 c1/c1 genotype could help in therapeutic drug monitoring, and optimize its therapeutic benefits while minimizing its risk for side effects or toxicity.

NAT2 polymorphism and clinical factors that increase antituberculosis drug-induced hepatotoxicity.

Aim: Hepatotoxicity is a known adverse effect of antituberculosis drugs. The NAT2 gene polymorphism has been associated with an increased risk of antituberculosis drug-induced hepatotoxicity (ATDIH). Materials & methods: This study investigates the association of NAT2 polymorphism and clinical risk factors that may contribute to the development of ATDIH. The authors sequenced the NAT2 region of 33 tuberculosis patients who developed ATDIH and 100 tuberculosis patients who did not develop ATDIH during tuberculosis treatment. NAT2 haplotypes were inferred and NAT2 acetylator status was predicted from the combination of the inferred haplotypes. Multiple logistic regression was performed to identify possible factors that are associated with ATDIH. Results: The TT genotype of NAT2*13A and the AA genotype of NAT2*6B were found to be substantially linked with the risk of ATDIH, with odds ratios of 3.09 (95% CI: 1.37-6.95) and 3.07 (95% CI: 1.23-7.69), respectively. NAT2 slow acetylators are 3.39-times more likely to develop ATDIH. Factors that were associated with ATDIH include underlying diabetes mellitus (adjusted odds ratio[AOR]: 2.96; 95% CI: 1.05-8.37), pre-treatment serum bilirubin (AOR: 1.09; 95% CI: 1.02-1.16) and NAT2 slow acetylator (AOR: 3.77; 95% CI: 1.51-9.44). Conclusion: Underlying diabetes mellitus, having a higher baseline bilirubin and being a slow acetylator are identified as the risk factors associated with ATDIH among patients in Malaysia.

Association of ABCG2 polymorphisms with susceptibility to anti-tuberculosis drug-induced hepatotoxicity in the Chinese population

The accumulation of endogenous hepatotoxin protoporphyrin IX (PPIX) in the liver was proposed to be a novel mechanism of anti-tuberculosis drug-induced hepatotoxicity (ATDH). ATP-binding cassette transporter G2 (ABCG2) plays an important role in modulating PPIX concentrations. This study aimed to explore the role of ABCG2 genetic polymorphisms in the risk of ATDH in Chinese patients. A 1:4 matched case–control study was performed among 202 ATDH cases and 808 controls. Conditional logistic regression model was used to estimate the association between genotypes and the risk of ATDH by odds ratios (ORs) with 95% confidence intervals (CIs). Male patients with CC genotype of rs2622605 had an increased risk of ATDH (adjusted OR = 1.615, 95% CI: 1.119–2.332, p = 0.011). The peak value of alkaline phosphatase (ALP) was significantly higher in male patients with CC genotype of rs2622605 than in those with TT + TC genotype during antituberculosis treatment (102.0 U/L vs. 98.0 U/L, p = 0.029). This is the first attempt to evaluate the association between ABCG2 genetic variants and the risk of ATDH. Based on the 1:4 matched case–control study, the polymorphism at rs2622605 in the ABCG2 gene may be associated with the susceptibility to ATDH in Chinese male patients.

Relevance of gene polymorphisms of NAT2 and NR1I2 to anti-tuberculosis drug-induced hepatotoxicity

The recommended treatment regimen for tuberculosis is a combination of agents with antitubercular activity, during which hepatotoxicity is one of the most common side effects. In addition to the N-acetyltransferase 2 (NAT2) genotype, rs3814055 in nuclear receptor subfamily 1, group I, member 2 (NR1I2) has been demonstrated to be associated with anti-tuberculosis drug-induced hepatotoxicity (ATDH), but previous results have been inconsistent. A retrospective nested hospital-based case–control study was performed to investigate the association between genetic polymorphisms and the risk of ATDH. Fifteen genetic variants (13 SNPs and two null genotypes) in cytochrome P450 2E1, NR1I2, UDP-glucuronosyltransferase 1A1, NAT2, superoxide dismutase 1, superoxide dismutase 2, and glutathione S-transferases (GSTT1, GSTM1, GSTP1) were genotyped. Odds ratios with 95% confidence intervals were calculated with drug doses, body mass index comorbidity of diabetes mellitus, and baseline alanine transaminase value as covariates. Conditional logistic regression demonstrated that the NAT2 slow acetylation genotype and the T allele of rs3814055 in NR1I2 may contribute to susceptibility to ATDH. Stratified association analysis demonstrated that in NAT2 non-slow acetylators, the T allele of rs3814055 was a risk factor for ATDH, whereas the T allele did not increase the susceptibility to ATDH in slow acetylators.

Heme oxygenase-1 and hemopexin gene polymorphisms and the risk of anti-tuberculosis drug-induced hepatotoxicity in China.

Objective: To assess whether the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH) might be influenced by heme oxygenase-1 (HMOX1) and hemopexin (HPX) gene polymorphisms. Methods: A dynamic anti-tuberculosis treatment cohort was constructed, and the 1:4 matched nested case-control study was analysed. Eight single-nucleotide polymorphisms (SNPs) of the two genes were selected for genotypingand Bonferroni correction was performed to correct for multiple comparison. Results: Overall, 7.8% of patients developed ATDH. SNP rs1807714 in the HMOX1 gene had decreased effects on the risk of moderate and severe hepatotoxicity under the dominant and additive models, and hepatocellular injury under the additive model. SNP rs2682099 in the HPX gene had increased effects on the risk of moderate and severe hepatotoxicity under the recessive model. However, these associations disappeared after Bonferroni correction. Conclusion:HMOX1 and HPX gene polymorphisms might not be associated with susceptibility to ATDH in the Chinese population.

Metabolomics and microbiomes for discovering biomarkers of antituberculosis drugs-induced hepatotoxicity

Anti-tuberculosis (TB) drug-induced hepatotoxicity (ATDH) was related to metabolic and microbial dysregulation, but only limited data was available about the metabolomes and microbiomes in ATDH. We aimed at detecting the metabolic and microbial signatures of ATDH. Urine samples were obtained from ATDH (n = 33) and non-ATDH control (n = 41) and analyzed by untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Metabolites were analyzed by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and pathway analysis. Eight ATDH and eight non-ATDH control were evaluated by sequencing of 16S rRNA genes, and the Clusters of Orthologous Groups of proteins (COG) database were used for function prediction. Linear discriminant analysis (LDA) effect size (LEfSe) was applied to detect the differential microbiotas between the two groups. The differential microbiotas were further validated by correlation analysis with differential metabolites. OPLS-DA analysis suggested 11 metabolites that differed ATDH from non-ATDH control. Pathway analysis demonstrated that metabolism of arginine and proline, metabolism of d-arginine and d-ornithine, glutathione glycine metabolism, galactose metabolism, niacin and nicotinamide metabolism, and glycine, serine and threonine metabolism were related to ATDH. LEfSe suggested significant differences in microbiotas between the two groups. The o_ Bacteroidales, f_Prevotellaceae, and g_Prevotella were significantly increased in ATDH. In contrast, the f_Chitinophagaceae, c_Gammaproteobacteria, and p_Proteobacteria were significantly increased in non-ATDH group. The biological functions of the sequenced microbiota in this study were related to amino acid transport and metabolism and defense mechanisms. Finally, we detected strong association between urine metabolites and specific urine bacteria (|r| > 0.8). d-glucoheptose showed a strong relationship to Symbiobacterium. Creatine (r = −0.901; P < 0.001) and diglycerol were strongly associated with Alishewanella. Metabolomics and microbiomes indicate ATDH characterized by metabolic and microbial profiles may differ from non-ATDH control.

Homozygotes NAT2*5B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs.

BACKGROUND Distinct N-acetyltransferase 2 (NAT2) slow acetylators genotypes have been associated with a higher risk to develop anti-tuberculosis drug-induced hepatotoxicity (DIH). However, studies have not pointed the relevance of different acetylation phenotypes presented by homozygotes and compound heterozygotes slow acetylators on a clinical basis.OBJECTIVES This study aimed to investigate the association between NAT2 genotypes and the risk of developing DIH in Brazilian patients undergoing tuberculosis treatment, focusing on the discrimination of homozygotes and compound heterozygotes slow acetylators.METHODS/FINDINGS The frequency of NAT2 genotypes was analysed by DNA sequencing in 162 patients undergoing tuberculosis therapy. The mutation analyses revealed 15 variants, plus two new NAT2 mutations, that computational simulations predicted to cause structural perturbations in the protein. The multivariate statistical analysis revealed that carriers of NAT2*5/*5 slow acetylator genotype presented a higher risk of developing anti-tuberculosis DIH, on a clinical basis, when compared to the compound heterozygotes presenting NAT2*5 and any other slow acetylator haplotype [aOR 4.97, 95% confidence interval (CI) 1.47-16.82, p = 0.01].CONCLUSION These findings suggest that patients with TB diagnosis who present the NAT2*5B/*5B genotype should be properly identified and more carefully monitored until treatment outcome in order to prevent the occurrence of anti-tuberculosis DIH.

The efficacy of Jujube syrup on the prevention of drug-induced hepatotoxicity in pulmonary tuberculosis patients: A pilot randomized double-blind placebo-controlled clinical trial.

Liver injury is the most common complication of anti‐tuberculosis drugs that can cause significant problems. The study aimed to determine the effectiveness of Jujube syrup on the prevention of antituberculosis drug‐induced hepatotoxicity (DIH). This pilot randomized double‐blind study was conducted based on a placebo‐controlled design in patients with tuberculosis (TB). The patients were divided into two groups based on the block random allocation method and received 10 cc of jujube or placebo syrup per day. The liver enzyme levels were assessed as primary outcomes, and the severity of cough, anorexia, and nausea along with the quality of life (QOL) was assessed as secondary outcomes. Finally, eight and nine patients in the jujube and placebo groups completed the study, respectively. In the second week of the study, 27.3% of the patients in the placebo group developed hepatotoxicity. Moreover, there was no liver toxicity in the jujube group. This difference between the two groups was statistically significant (p = .037). Furthermore, the severity of cough in patients in the jujube group decreased significantly during weeks 2 and 4. The QOL significantly improved in the jujube group, compared to the placebo group. This study suggested that Jujube syrup could prevent anti‐TB DIH. It can also improve the severity of cough and the QOL in pulmonary TB patients.

Profile of SGPT Levels in Multidrug Resistant Tuberculosis Patients (MDR-TB)

Multidrug Resistant Tuberculosis (MDR-TB) has recently become a health threat in Indonesia. The clinical management of MDR TB is more complicated than that of ordinary TB. Hepatotoxicity or commonly known as Anti-Tuberculosis Drug-induced Hepatotoxicity (ATDH) is a serious effect of OAT that often occurs. The basic parameter for diagnosing or following up the presence of impaired liver function is the SGPT examination. The purpose of this study was to describe the level of SGPT in MDR-TB patients at the Kendal District Health Center. This study is an observational (non-experimental) study with descriptive research criteria with a cross sectional approach which was conducted on 7 MDR-TB patients at Kendal I Health Center, Kaliwungu Health Center, and South Kaliwungu Health Center with total sampling technique. The results of the study: obtained SGPT levels in 7 patients with MDR-TB there were 7 research respondents (100%) had normal SGPT levels with the lowest level of 2.17 U/L and the highest level of 37.75 U/L and the average level of SGPT ie 18.01 U/L. TB mostly attacks the age group of 56-65 years (57%). Males (57%) were the patients with the most TB cases. The most OAT consumption time was in the continuation phase (100%). Diabetes is a disease that often accompanies TB patients. The conclusion of this study is that from 7 research subjects, MDR-TB patients had SGPT levels that were in the normal range.

Genetic and Functional Evaluation of the Role of FOXO1 in Antituberculosis Drug-Induced Hepatotoxicity.

Background The accumulation of the hepatotoxic substance protoporphyrin IX (PPIX) induced by aminolevulinate synthase 1 (ALAS1) activation is one of the important mechanisms of antituberculosis drug-induced hepatotoxicity (ATDH). Forkhead box protein O1 (FOXO1) may activate ALAS1 transcription. However, little is known about their roles in ATDH; we performed a study to determine the association between polymorphisms in the two genes and ATDH susceptibility. Then, we verified this possible association by cellular functional experiments. Materials and Methods Tag single-nucleotide polymorphisms (TagSNPs) in the two genes were genotyped in 746 tuberculosis patients. The frequencies of the alleles, genotypes, genetic models, and haplotype distribution of the variants were compared between the case and control groups. L-02 cells and HepG2 cells were incubated with the indicated concentration of isoniazid (INH) and rifampicin (RIF) for the desired times, and then the expression levels of ALAS1 and FOXO1 mRNAs and proteins were detected. HepG2 cells were transiently transfected with FOXO1 siRNA to observe the effect of changes in the FOXO1 expression on the cell survival rate and ALAS1 expression. Results The C allele at rs2755237 and the T allele at rs4435111 in the FOXO1 gene were associated with a decreased risk of ATDH. The expression of ALAS1 in both L-02 cells and HepG2 cells was increased by the coadministration of INH/RIF (600/200 μM) for 24 h. Although FOXO1 expression was reduced slightly by the same treatment, its content in the nucleus was significantly increased. However, the cell survival rate and ALAS1 expression level were not significantly altered by the downregulation of FOXO1 in HepG2 cells. Conclusions Variants of the rs4435111 and rs2755237 loci in the FOXO1 gene were associated with susceptibility to ATDH. Coadministration of INH/RIF promoted the transfer of FOXO1 from the cytoplasm to the nucleus, but the functional significance of its nuclear translocation requires further verification.

NAT2 Gene rs1041983 is Associated with Anti-Tuberculosis Drug Induced Hepatotoxicity Among Pediatric Tuberculosis in Bandung, Indonesia.

BackgroundAs pediatric tuberculosis (TB) globally is still reported challenging in diagnosis, to date, a lot of efforts have been established to eliminate the disease including proper treatment regimen using anti-TB drugs. However, antituberculosis drug-induced hepatotoxicity (ADIH) is known to interfere the success of the prescribed therapy. ADIH was found to be correlated with polymorphisms of NAT2 gene, that is responsible to transcript the NAT2 enzyme, a metabolizer of isoniazid (INH). The most common NAT2 gene polymorphisms in Asian population associated with ADIH are rs1041983, rs1799929, rs1799930 and rs1799931. The study aimed to investigate the 4 single nucleotide polymorphisms (SNPs) in pediatric TB that experienced ADIH.MethodsWe conducted a case–control study comparing 31 each of pediatric TB experience with and without ADIH. All pediatric TB was selected from 451 pediatric TB Registry of Respirology Division, Department of Child Health Faculty of Medicine Universitas Padjadjaran/Dr Hasan Sadikin Hospital during January 2016 to July 2018. Genomic DNA PCR and sequencing to identify polymorphisms of rs1041983, rs1799929, rs1799930 and rs1799931 were performed in both groups. Data analysis was performed using the Epi info Ver. 7 software.ResultsThirty-one pediatric TB experiences with and without ADIH were enrolled in this study. SNP rs1041983 significantly affected the occurrence of ADIH (OR 2.39, CI 95% (1.15–4.96), p=0.019). The rs1799929, rs1799930 and rs1799931 did not significantly affect the occurrence of ADIH (p=0.133, p=0.150 and p=0.659, respectively).ConclusionPolymorphism SNP rs1041983 had association with the occurrence of ADIH.

A validation study of the UGT1A4 rs2011404 variant and the risk of anti-tuberculosis drug-induced hepatotoxicity in an Eastern Chinese Han population.

Anti-tuberculosis (anti-TB) drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. A recent study found that the rs2011404 variant of uridine 5'-diphospho-glucuronosyl-transferase 1A4 (UGT1A4) is a marker of susceptibility to ATDH. The present study aimed to validate this relationship in an Eastern Chinese Han anti-TB treatment population. A 1:4matched case-control study was conducted among anti-TB treatment patients in four regions of Jiangsu. ATDH was diagnosed based on the criteria from the Chinese Society of Hepatology and the updated Roussel Uclaf Causality Assessment Method. A conditional logistic regression model was used to estimate the association between rs2011404genotypes and the risk of ATDH using odds ratios (ORs) with 95% confidence intervals (95% CIs) and smoking, drinking, hepatoprotectant use and liver diseases as covariates. A total of 202 ATDH cases and 808 controls were matched according to age, sex and treatment history. After correcting for potential confounding factors, conditional logistic regression analysis indicated no significant differences in genotypes between the two groups (CC vs. TC: OR=0.933, 95% CI: 0.457-1.905, p=0.849). Subgroup analysis suggested that patients carrying the CC genotype at rs2011404 in UGT1A4 were at a reduced risk of moderate or severe liver injury (OR=0.293, 95% CI: 0.093-0.921, p=0.036). Based on a 1:4 individual matched case-control study, possessing the CC genotype at rs2011404 of the UGT1A4gene reduces the risk of moderate or severe liver injury in Eastern Chinese Han patients receiving anti-TB treatment. Further research is warranted to explain the role of the UGT1A4gene and its contribution to individual differences in susceptibility to ATDH.

Determinants of Drug-Induced Hepatotoxicity Among Patients with Human Immunodeficiency Virus Taking a High Dose of Rifapentine Plus Isoniazid Drugs at the All Africa Leprosy Tuberculosis Rehabilitation and Training Center in Addis Ababa, Ethiopia.

PurposeThe drugs for the treatment of latent Tuberculosis are potentially hepatotoxic and can lead to drug-induced hepatotoxicity. The current study aimed at identifying the determinants of anti-tuberculosis drug-induced hepatotoxicity among patients living with Human Immunodeficiency Virus taking Isoniazid and rifapentine at All Africa Leprosy Tuberculosis Rehabilitation and Training Center in Addis Ababa, Ethiopia.MethodsAn unmatched case–control study was conducted from March, 21, to April 21, 2020, at All Africa Leprosy Tuberculosis Rehabilitation and Training Center. A total of 65 cases and 130 controls were interviewed. Data were collected using a data extraction tool from clinical reporting forms, follow-up charts, and patients’ logbooks. Binary and multiple logistic regressions were conducted to check the association between independent and dependent variables. Adjusted odds ratios and the corresponding 95% confidence intervals were estimated to assess the strength of association. P-values <0.05 were used to declare statistical significance.ResultsThe prevalence of anti-TB drug-induced hepatotoxicity was 8%. Body mass index <18.5 Kg/m2 (AOR = 5.8 [95% CI: 2.2–8.9]), low CD4 count (AOR = 4.9 [95% CI: 1.6–15.8]), and the presence of comorbid illnesses (AOR = 3.9 [95% CI: 1.7–8.9]) were identified as independent predictors of drugs-induced hepatotoxicity among Human Immunodeficiency Virus positive patients taking Isoniazid and rifapentine.ConclusionThe prevalence of anti-TB drug-induced hepatotoxicity was higher compared to standard references. BMI<18 kg/m2, low CD4 count, and comorbid illness were positively associated with anti-tuberculosis drug-induced hepatotoxicity among patients with HIV.