The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.
OBJECTIVE
Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury.


METHODS
In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays.


RESULTS
2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes.


CONCLUSIONS
In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury.
Department of Epidemiology and Biostatistics, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China.
Yang
Y
Xiang
The Red Cross of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China.
Long
L
Ma
Center for Tuberculosis Control and Prevention, Xinjiang Uygur Autonomous Region Center for Disease Control and Prevention, Urumqi, Xinjiang, China.
Weidong
W
Wu
Xinjiang Ili Kazak Autonomous Prefecture Centers for Disease Control and Prevention, Ili, Xinjiang, China.
Wei
W
Liu
Xinjiang Aksu District Center for Disease Control and Prevention, Aksu, Xinjiang, China.
Yongguang
Y
Li
Library of Xinjiang Medical University, Urumqi, Xinjiang, China.
Xia
X
Zhu
Graduation School of Xinjiang Medical University, Urumqi, Xinjiang, China.
Qian
Q
Wang
Department of Epidemiology and Biostatistics, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China.
Jinfeng
J
Ma
Department of Epidemiology and Biostatistics, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China.
Mingqin
M
Cao
Department of Epidemiology and Biostatistics, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China.
Qian
Q
Wang
Department of Epidemiology and Biostatistics, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China.
Xuemei
X
Yao
Department of Epidemiology and Biostatistics, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China.
Lei
L
Yang
Department of Epidemiology and Biostatistics, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China.
Atikaimu
A
Wubuli
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Corinne
C
Merle
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Paul
P
Milligan
Department of Epidemiology and Biostatistics, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China.
Ying
Y
Mao
Department of Epidemiology and Biostatistics, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China.
Jiayi
J
Gu
Care Division, the Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Xiumei
X
Xin
D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D002681:China / Q000453:epidemiology; D003430:Cross-Sectional Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D004359:Drug Therapy, Combination / Q000009:adverse effects; D004977:Ethambutol / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D015994:Incidence; D007538:Isoniazid / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011718:Pyrazinamide / Q000009:adverse effects / Q000627:therapeutic use; D012293:Rifampin / Q000009:adverse effects / Q000627:therapeutic use; D017678:Sex Distribution; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*; D055815:Young Adult
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; D019392:Cytochrome P-450 CYP2E1; D004977:Ethambutol; D005982:Glutathione Transferase; D007538:Isoniazid; D011718:Pyrazinamide; D012293:Rifampin; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1