Clinical Characteristics And Genetic Polymorphism Of Antituberculous Drug-induced Hepatotoxicity In Children

Objective: Through analyzing the clinical characteristics of and the gene polymorphism of genes correlated to ATDH,to delineate the risk factors and potential susceptible genes,and better prevent and identify the drug-induced liver damage in advance.Methods: From January 2015 to December 2019,821 Patients whom diagnosed as tuberculosis and received first-line anti-TB treatment in the Children’s Hospital affiliated to Chongqing Medical University were enrolled,the clinical data were collected and analyzed.Peripheral blood samples from 19 patients with ATDH and 33 controls were collected and further conducted for gene typing detection.And use logistic regression to analyze the correlation between gene polymorphism and the risk of ATDH.Results: 1.The incidence of ATDH in children was about 7.1%,while the incidence of patients younger than 1 year old was 17.1%,significantly higher than other age groups(P<0.05).The median incubation period of ATDH was 8 days range from 6-34 days,and female patients have longer incubation time than male(P<0.05).The hepatocellular injury was about71.7%,the cholestatic injury was about 1.9%,no hepatic vascular injury and the mixed injury was found.Patients with central nervous system tuberculosis had higher risk of ATDH,the proportion of the digestive system tuberculosis was higher in patients with moderate to severe ATDH than that of patients with mild ATDH.The level of total bilirubin and bile acid in patients whose R≤2 was higher than 2<R<5 and R≥5,and the R value was negatively correlated with the degree of liver damage(correlation coefficient-0.399,P<0.05).Logistic analysis shows that age less than 1 year old(OR=3.048,95%CI 1.463-6.347,P=0.003)and central nervous system tuberculosis(OR=2.947,95%CI,1.652-5.255,P<0.001)are independent risk factors for ATDH in children(P<0.05).Pyrazinamide was the main causative agent of ATDH,followed by rifampicin,isoniazid and ethambutol.2.Rs1799930 A/A of the NAT2 gene(OR=7.917,95%=1.209-51.841,P=0.031)is associated with an increased risk of ATDH in children.Haplotype analysis showed the TAG haplotype with rs1799930(A)(OR=2.813,95CI% 1.202-6.581,P=0.015)was related to an increased ATDH risk,while the TGG haplotype(OR=0.166,95CI% 0.061-0.450,P<0.001)was associated with a reduced risk.And compared to rapid acetylators and intermediate acetylators,the frequency of slow acetylators(68.4%)in the ATDH group was significantly higher than that in the control group(18.2%),with a higher risk of ATDH(OR=9.750,95%CI2.629-36.165,P=0.001).Conclusion: 1.The incubation period of ATDH in female is longer than male patients.The types of hepatotoxicity are mostly hepatocellular injury,the cholestatic injury is less,the hepatic vascular injury and the mixed injury are rare.Patients younger than 1 year old and with central nervous system tuberculosis have a higher risk of ATDH.Patients with tuberculosis of the digestive system and lower R value have more severe ATDH.2.NAT2 gene polymorphism in children is associated with the onset of ATDH.Patients with rs1799930 A/A had an increased risk of ATDH,the TAG haplotype was related to an increased ATDH risk,while the TGG haplotype was associated with a reduced risk.And patients with NAT2 slow acetylators had higher ATDH risk.