Objective

1. Risk of liver injury associated with Chinese herbal products containing Radix bupleuri in hepatitis B virus infection Chang-Hsing Lee,1,2 Jung-Der Wang,1,3,4 Pau-Chung Chen1 • This study was conducted to determine the association between the use of CHPs containing Radix bupleuri and the risk of hospitalizations related to liver injury among HBV infected patients in Taiwan. 1Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health2Department of Occupational Medicine, Ton Yen General Hospital, Hisn-Chu County, Taiwan3Department of Internal Medicine, and 4Department of Environmental and Occupational Medicine, National Taiwan University Hospital, Taipei, Taiwan Results Background • After conforming to the inclusive and exclusive criteria, there were 1,080 cases with at least one 30-day referent window during the study period. • Among them, 13.4% were 60 year of age or older, with a mean age of 40.2 ± 14.6 years. In the case-control design, the adjusted odds ratio during the 30-day period was 1.90 (confidence interval (CI): 1.30 to 2.77) between all products with Radix bupleuri and admissions with liver injury. • The risks from Xiao-Chai-Hu-Tang and Long-Dan-Xie-Gan-Tang were significantly high, and the tests for trends in dose-response reaction were significant. • The risk of adding each 19 gm of Radix bupleuri was 2.19 (CI: 1.66 to 2.89); the results using the case-crossover design remained similar. • Chinese herbal products (CHPs) containing Radix bupleuri are often prescribed for chronic hepatitis, especially in the areas with a high prevalence of hepatitis B virus (HBV). • No epidemiologic studies about CHP containing Radix bupleuri -induced liver injury were conducted in populations with HBV Objective Discussions Material and Methods • Main finding: our study found that the use of two CHPs containing Radix bupleuri, Xiao-Chai-Hu-Tang and Long-Dan-Xie-Gan-Tang, increased the risk of hospitalization for liver injury among the subjects with HBV. • The risk may have been related to the cumulative dose of Radix bupleuri. Results might be underestimated when we limited the analysis to hospitalized cases. • We conducted further sensitivity analyses to examine other potential confounders, which revealed no notable changes in the results. • The other popular products prescribed frequently in HBV infection had no significantly higher risk of liver injury, and confounding by indication was probably minimal. • Although a clinical trial of applying Xiao-Chai-Hu-Tang in patients with HBV for three months showed a significant improvement and had no side effect,5 our results did not support the above claim. • Design: 1.case-control design (1-4 age, sex, admission date matching) 2.Case-crossover design (1-4 matching windows) 3.case-time-control design (Figure 1) • Exposures: CHPs containing Radix bupleuri • Setting: casegroup:hospitalized subjects with liver injury; control group: without admission with liver injury among the population with diagnoses related to HBV coded as 070.2, 070.3 and V02.61 by ICD-9 code in Taiwan’s National Health Insurance database from 1997 to 2004 • Case inclusion and exclusion: incident hospitalized subjects with the major diagnosis of acute and sub-acute necrosis of the liver (ICD-9 570), toxic hepatitis (ICD-9 573.3), other specified disorders of liver (573.8) and unspecified disorder of liver (573.9) ; excluded viral, other causes of hepatobiliary diseases, <19years • Exposure windows: 30-day exposure windows; 90 days between recent or reference exposure windows in crossover designs • Statistics: conditional logistic regression model to adjust for the frequency of other hepatoxic drugs or Charlsonco-morbidity index Conclusion • Our study provided the safety information of using CHPs containing Radix bupleuriin populations with HBV. • Further mechanistic research on the hepatotoxicity of Radix bupleuri is warranted. Table 1 Characteristics, co-morbidities and time-dependent hepatoxic drugs of study subjects admitted with diagnosis of acute liver injury, 1997-2004 Table 2. Number of exposed subjects with viral hepatitis B in the 30-day periods and adjusted odds ratios between hospitalizations with liver injury and Chinese herbal products with Radix bupleuri by case-control and case-crossover designs, 1997-2004. Conclusions OMIH Corresponding author’s e-mail: pchen@ntu.edu.tw; First author’s e-mail: d95841004@ntu.edu.tw