Trial Information

Cholestatic Drug-induced Liver Injury: Correlation With Genotypes of UGT1A1 and 1A7, and Treatment Effect of Ursodeoxycholic Acid

Cholestatic drug-induced liver injury (DILI) is the severe form of DILI with a grave
outcome. Drug-metabolizing enzymes play an important role in the metabolism of drugs. The
genetic polymorphism of drug-metabolizing enzymes may influence the activities and
expression of these enzymes and thereby affect the susceptibility and severity of DILI.
UDP-glucuronosyltransferase (UGT) is an important phase 2 detoxification enzyme, which is
related to congenital hyperbilirubinemia. Recently, the genetic polymorphism of UGT1A1 was
reported to be associated with jaundice induced by some drugs, and UGT1A7 was shown to be
related to the susceptibility of hepatocellular carcinoma and other cancers. Ursodeoxycholic
acid (UDCA ) is a hydrophilic bile acid that is increasingly used for the treatment of
various cholestatic disorders. The aims of this study are (1) to assess the association of
the genetic polymorphism of UGT1A1 and 1A7, and the susceptibility and severity of
drug-induced liver injury (DILI), with emphasis on the cholestatic DILI; (2) to evaluate the
treatment effect of UDCA in the DILI, with special reference to the cholestatic
hepatotoxicity.

Owing to the limited number of DILI patients, 3 years are needed in this study. Each year, a
total of 60 patients with DILI and 60 age- and sex-matched controls will be enrolled in this
study. Their genetic polymorphisms of UGT1A1 and UGT1A7 will be assessed using the real time
PCR, or PCR with RFLP. The DILI patients will be randomized to UDCA Treatment group and
Control group. UDCA 13-15 mg/kg/day with 3 divided doses will be administered to the
patients with Treatment group.

The frequencies of genotypes of UGT1A1 and 1A7 will be compared between DILI cases and
controls, survival cases and non-survival cases, and cholestatic and non-cholestatic cases.
Chi-square test, with or without Yates' correction, will be used to compare the categorical
parameters. A paired t test will be performed to compare the continuous parameters. Odds
ratios (OR) and confidence intervals (CI) will be calculated using a logistic regression
analysis. The multivariate logistic regression analysis will be applied to check on the OR,
adjusted with other possible risk factors. Survival rates will be estimated from survival
curves based on the Kaplan-Meier method and compared with the log-rank test between the UDCA
Treatment group and Control group.

We believe that this pharmacogenetic study may help us realize the pathogenesis of
cholestatic DILI, and the clinical trial can elucidate the therapeutic value of UDCA in the
DILI, especially in the cholestatic hepatotoxicity.