Do genetic polymorphisms of B-cell CLL/lymphoma 2 confer susceptibility to anti-tuberculous therapy-associated drug-induced liver injury?

OBJECTIVES: The aim of this study was to identify the relationship between B-cell CLL/lymphoma 2 (BCL2) polymorphisms and susceptibility to anti-tuberculous therapy-associated drug-induced liver injury (ATT-DILI). METHODS: A total of 746 tuberculosis (TB) patients were enrolled in this study. Twenty-one selected single nucleotide polymorphisms in BCL2 were analyzed by custom-by-design 2×48-Plex SNPscan kit. The allele and genotype frequencies between patients with and without ATT-DILI were compared using three different genetic models. RESULTS: A total of 727/746 participants were successfully genotyped, and 112 of them were diagnosed with ATT-DILI. The A allele of rs8085707, G allele of rs76986960, and A allele of rs949037 conferred an increased risk of ATT-DILI, with estimated odd ratios (ORs) of 2.181 (95% confidence interval (CI) 1.345-3.536, p=0.001), 1.983 (95% CI 1.060-3.709, p=0.029), and 1.390 (95% CI 1.032-1.873, p=0.03), respectively. Bonferroni correction indicated that the A allele of rs8085707 was a risk factor for ATT-DILI (Bonferroni correction: p=0.026). The additive model suggested that patients with the AA genotype of rs8085707 had a significantly higher risk of ATT-DILI compared with those with the GG genotype (Bonferroni correction: p=0.036). The influence of BCL2 polymorphisms on clinical characteristics (clinical symptoms, disease subtypes, and laboratory indicators) was also identified. CONCLUSIONS: This study is novel in suggesting an association between BCL2 polymorphisms and the risk of ATT-DILI.

Integrating physiologically based kinetic (PBK) and Monte Carlo modelling to predict inter-individual and inter-ethnic variation in bioactivation and liver toxicity of lasiocarpine.

The aim of the present study was to predict the effect of inter-individual and inter-ethnic human kinetic variation on the sensitivity towards acute liver toxicity of lasiocarpine in the Chinese and the Caucasian population, and to derive chemical specific adjustment factors (CSAFs) by integrating variation in the in vitro kinetic constants Vmax and Km, physiologically based kinetic (PBK) modelling and Monte Carlo simulation. CSAFs were derived covering the 90th and 99th percentile of the population distribution of pyrrole glutathione adduct (7-GS-DHP) formation, reflecting bioactivation. The results revealed that in the Chinese population, as compared to the Caucasian population, the predicted 7-GS-DHP formation at the geometric mean, the 90th and the 99th percentile were 2.1-, 3.3- and 4.3-fold lower respectively. The CSAFs obtained using the 99th percentile values were 8.3, 17.0 and 19.5 in the Chinese, the Caucasian population and the two populations combined, respectively, while the CSAFs were generally 3.0-fold lower at the 90th percentile. These results indicate that when considering the formation of 7-GS-DHP the Caucasian population may be more sensitive towards acute liver toxicity of lasiocarpine, and further point out that the default safety factor of 3.16 for inter-individual human kinetic differences may not be sufficiently protective. Altogether, the results obtained demonstrate that integrating PBK modelling with Monte Carlo simulations using human in vitro data is a powerful strategy to quantify inter-individual variations in kinetics, and can be used to refine the human risk assessment of pyrrolizidine alkaloids.

rs1800796 of the IL6 gene is associated with increased risk for anti-tuberculosis drug-induced hepatotoxicity in Chinese Han children.

Previous studies have revealed the important contribution of the immune response and oxidative stress to the development of anti-tuberculosis drug-induced hepatotoxicity (ATDH). To investigate whether single-nucleotide polymorphisms (SNPs) of the cytokine gene interleukin-6 (IL6) and oxidative stress genes xanthine dehydrogenase/oxidase (XO) and inducible nitric oxide synthase (NOS2) were associated with susceptibility to ATDH, we performed a case-control study including 41 ATDH cases and 116 ATDH-free controls in Chinese Han children. Significant difference in the allele distribution of rs1800796 in the IL6 gene was observed between the case and control groups, and the G allele of rs1800796 was associated with an increased risk for ATDH (odds ratio: 2.48, 95%CI: 1.40-4.40, P = 0.002). However, no significant difference was observed in the allele and genotype distributions of the other SNPs of the IL6, XO and NOS2 genes between the case and control groups after Bonferroni correction. In addition, no interaction was found between all selected SNPs. These findings indicate that genetic variants of the IL6 gene might contribute to the development of ATDH in the Chinese Han pediatric population.

Age-related common miRNA polymorphism associated with severe toxicity in lung cancer patients treated with platinum-based chemotherapy.

Platinum-based chemotherapy toxicity severely impedes successful treatment in lung cancer patients. MicroRNAs (miRs) have a significant impact on the occurrence and survival rate of lung cancer. The purpose of this study was to investigate the association between common miRNA variants and platinum-based chemotherapy toxicity in lung cancer patients. A total of eight functional single nucleotide polymorphisms (SNPs) of miRNA were genotyped in 408 lung cancer patients by MALDI-TOF mass spectrometry. All the patients were histologically confirmed as lung cancer, and were treated with platinum-based chemotherapy for at least two cycles. It was found that the polymorphism rs2042553 of miR-5197 had a significant association with overall severe toxicity in both additive (P=.031, odds ratio [OR]=1.41, 95% confidence interval [CI] 1.03-1.93) and dominant (P=.009, OR=1.80, 95% CI 1.16-2.80) models. MiR-605 rs2043556 was significantly related to severe hepatotoxicity in dominant model (P=.022, OR=2.51, 95% CI 1.12-4.14). In addition, rs2910164 of miR-146a had marginal statistical effect on severe hepatotoxicity in additive model (P=.054). The subgroup analyses showed that miR-27a rs895819 was related to gastrointestinal toxicity in age >56 years old, smoking and non-smoking patients. Taken together, our results revealed that polymorphisms of miR-5197, miR-605, miR-146a, and miR-27a contributed to the chemotherapy toxicity of lung cancer, which may serve as a predictive tool for toxicity evaluation of platinum-based chemotherapy in lung cancer patients.

[Study on polymorphisms of genes with susceptibility to drug induced liver injury in a cohort receiving anti-tuberculosis treatment].

OBJECTIVE: To investigate the association between the polymorphisms of genes involving in drug metabolism and transport as well as immunological reaction and the risk of anti-tuberculosis drug-induced liver injury(ATLI)in Chinese. METHODS: This 1∶4 matched case-control study was conducted by using the data from a cohort study of Anti-tuberculosis Drugs Induced Adverse Reactions in National Tuberculosis Prevention and Control Progtam of China. Genes involving in three phase of drug metabolism and transport as well as related immunological reaction were chosen and single nucleotide polymorphisms(SNPs)were genotyped by TaqMan allele discrimination technology. Lasso regression and multivariate conditional logistic regression analysis were used to select susceptible genes. RESULTS: A total of 33 genes with 75 SNPs were tested. The combined results of Lasso and regression logistic regression analysis showed that genetic polymorphism of SLCO1B1 rs4149014, HSPA1L rs2227956, STAT3 rs1053023 and IL-6 rs2066992 were significantly associated with the risk of ATLI(P<0.05). CONCLUSION: SLCO1B1, HSPA1L, STAT3 and IL-6 might be the susceptibility genes of drug induced liver injury in patients receiving anti-tuberculosis treatment.

Translational biomarkers of acetaminophen-induced acute liver injury.

Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.

Interleukin-4 and interleukin-10 polymorphisms and antituberculosis drug-induced hepatotoxicity in Chinese population.

WHAT IS KNOWN AND OBJECTIVE: Evidence demonstrates that the delicate balance between pro- and anti-inflammatory cytokines determines the further progress to severe injury or recovery. Therefore, understanding which cytokines are associated with the development of drug-induced hepatotoxicity (DIH) might guide the prevention and therapeutic direction. Some polymorphisms of cytokine genes have been reported to be associated with DIH involving interleukin-4 (IL-4), interleukin-10 (IL-10) and tumour necrosis factor-α (TNF-α); however, these studies are still scanty with inconsistent results. In addition, most of these associations have not been investigated in antituberculosis drug-induced hepatotoxicity (ATDH) patients with the exception of TNF-α polymorphisms. Therefore, we aimed to investigate the association between IL-4 and IL-10 gene polymorphisms with the risk of ATDH in a Chinese population. METHODS: The study was designed as a nested case-control study within a prospective cohort. Each case was matched with four controls by sex, age at baseline (±5 years), treatment history, disease severity, drug dosage and place of sample collection. Genetic polymorphisms of IL-4 and IL-10 were determined by TaqMan single nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model. RESULTS AND DISCUSSION: A total of 89 incident ATDH cases and 356 controls undergoing antituberculosis treatment were included. Six SNPs were selected for genotyping, which were rs2243289, rs2243250 and rs2070874 for IL-4, and rs1800896, rs1800871 and rs1800872 for IL-10. No significant difference was observed in genotypes frequencies of the six selected SNPs between case and control group, and the distributions of IL-4 and IL-10 haplotypes were similar in ATDH patients and controls. WHAT IS NEW AND CONCLUSION: This study is the first attempt to evaluate the associations of genetic polymorphisms of IL-4 and IL-10 genes with ATDH using a nested case-control study design. We provide preliminary evidence that there is no statistically significant association between IL-4 and IL-10 genotypes/haplotypes and the risk of ATDH in Chinese population.

Characteristics and clinical outcome of nonsteroidal anti-inflammatory drug-induced acute hepato-nephrotoxicity among Chinese patients.

AIM: To determine the clinicopathological characteristics of nonsteroidal anti-inflammatory drug (NSAID)-induced acute hepato-nephrotoxicity among Chinese patients. METHODS: We conducted a retrospective chart review of patients using the International Classification of Diseases, Ninth Revision diagnosis code for acute kidney injury (AKI) (584.5 or 584.9) and for acute liver injury (ALI) (570.0 or 573.3) from January 2004 to December 2013. Medical records were reviewed to confirm the diagnosis of AKI and ALI and to quantify NSAID administration. RESULTS: Seven of 59 patients (11.8%) were identified with acute hepato-nephrotoxicity induced by NSAIDs. Five patients (71.4%) received over the recommended NSAIDs dose. Compared with NSAIDs-associated mere AKI, the risk factors of NSAIDs-induced acute hepato-nephrotoxicity are age older than 60 years (57.1%), a high prevalence of alcohol use (71.4%) and positive hepatitis B virus (HBV) markers (85.7%). Compared with NSAIDs-associated mere ALI, the risk factors of NSAIDs-induced acute hepato-nephrotoxicity are age older than 60 years (57.1%), increased extracellular volume depletion (71.4%), and renin-angiotensin-aldosterone system (RAAS) inhibitor combined use (57.1%). Acute interstitial nephritis and acute tubulointerstitial disease were apparent in three out of six (42.9%) kidney biopsy patients, respectively. Acute hepatitis was found in four out of six (66.7%) liver biopsy patients. Overall complete recovery occurred in four patients within a mean of 118.25 ± 55.42 d. CONCLUSION: The injury typically occurred after an overdose of NSAIDs. The risk factors include age older than 60 years, alcohol use, positive HBV markers, extracellular volume depletion and RAAS inhibitor combined use.

Kava hepatotoxicity: pathogenetic aspects and prospective considerations.

Kava hepatotoxicity is a well-defined herb-induced liver injury, caused by the use of commercial anxyolytic ethanolic and acetonic kava extracts, and of traditional recreational aqueous kava extracts. The aim of this review is to elucidate possible pathogenetic factors for the development of kava-induced liver injury, considering also confounding variables. In patients with liver disease in a causal relation to kava ± comedication, confounding factors include non-adherence to therapy recommendations and comedication consisting of synthetic and herbal drugs and dietary supplements including herbal ones and herbs-kava mixtures. Various possible pathogenetic factors have to be discussed and comprise metabolic interactions with exogenous compounds at the hepatic microsomal cytochrome P450 level; genetic enzyme deficiencies; toxic constituents and metabolites derived from the kava extract including impurities and adulterations; cyclooxygenase inhibition; P-glycoprotein alterations; hepatic glutathione depletion; solvents and solubilizers of the extracts; and kava raw material of poor quality. In particular, inappropriate kava plant parts and unsuitable kava cultivars may have been used sometimes for manufacturing the kava extracts instead of the rhizome of a noble cultivar of the kava plant (Piper methysticum G. Forster). In conclusion, kava hepatotoxicity occurred independently of the extraction medium used for the kava extracts and may primarily be attributed to daily overdose, prolonged treatment and to a few kava extract batches of poor quality; by improving kava quality and adherence to therapy recommendation under avoidance of comedication, liver injury by kava should be a preventable disease, at least to a major extent.