Herbal medicine containing aristolochic acid and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection

Abstract

It was suspected that aristolochic acid-induced mutations may be associated with hepatitis B virus (HBV), playing an important role in liver carcinogenesis. The purpose of this study was to investigate the association between the use of Chinese herbs containing aristolochic acid and the risk of hepatocellular carcinoma (HCC) among HBV-infected patients. We conducted a retrospective, population-based, cohort study on patients older than 18 years who had a diagnosis of HBV infection between January 1, 1997 and December 31, 2010 and had visited traditional Chinese medicine clinics before one year before the diagnosis of HCC or the censor dates. A total of 802,642 HBV-infected patients were identified by using the National Health Insurance Research Database in Taiwan. The use of Chinese herbal products containing aristolochic acid was identified between 1997 and 2003. Each patient was individually tracked from 1997 to 2013 to identify incident cases of HCC since 1999. There were 33,982 HCCs during the follow-up period of 11,643,790 person-years and the overall incidence rate was 291.8 HCCs per 100,000 person-years. The adjusted hazard ratios (HRs) were 1.13 (95% confidence interval [CI], 1.11-1.16), 1.21 (95% CI, 1.13-1.29), 1.37 (95% CI, 1.24-1.50) and 1.61 (95% CI, 1.40-1.84) for estimated aristolochic acid of 1-250, 251-500, 501-1,000 and more than 1,000 mg, respectively, relative to no aristolochic acid exposure. Our study found a significant dose-response relationship between the consumption of aristolochic acid and HCC in patients with HBV infection, suggesting that aristolochic acid which may be associated with HBV plays an important role in the pathogenesis of HCC.

Chinese nonmedicinal herbal diet and risk of nasopharyngeal carcinoma: A population‐based case‐control study

“…9,12,13,42 Another possibility might be true differences in the nature and usage of traditional herbal medicines across different regions as well as differences in the types of plants and populations across studies. Some medicinal plants contain phorbol esters, which can activate EBV 11 ; aristolochic acid, a compound found in herbs such as Aristolochia fangchi and Aristolochia debilis, may be associated with an increased risk for certain malignancies other than NPC, [45][46][47] These herbal medicines are traditionally used for treating certain diseases and were not commonly used in herbal soups or teas in our study area.…”

Mutational Processes in Hepatocellular Carcinoma: The Story of Aristolochic Acid

“…This suggests a conjunction between HBV and aristolochic acid that fosters tumor development as previously shown for aflatoxin B1. 54 More recently, Ng et al identified the aristolochic acid mutational signature in 78% of HCC in Taiwan, making it the primary cause of liver cancer in this country. 55 In The Cancer Genome Atlas (TCGA) data, 9 patients from Japan and United States harbored a typical signature of AA among the 364 patients analyzed and we also reported AA signature in our analysis of pan genomic data of HCC.…”

<p>New Users of Herbal Medicine Containing Aristolochic Acids and the Risk of Dementia in the Elderly: A Nationwide, Population-Based Study in Taiwan</p>

“…We also calculated the estimated cumulative dosage of aristolochic acid for each subject using an estimated average dosage of aristolochic acid per 1 g. For Guan Mu Tong, Guang Fang Ji, Ma Dou Ling, Qing Mu Xiang, Tian Xian Teng, and Xi Xin, this was 2.59, 2.04, 0.63, 0.009, 0.026, and 0.042 mg, respectively, with the reference from one previous study on HMCAA. 41 We also analyzed the cumulative dosage as 1-250, 251-500, 501-1000, >1000 mg of HMCAA and the risk of dementia.…”

“…We also included the common indications of the usage of HMCAA as hepatitis, UTI, dysuria, urolithiasis, vaginitis, scrotum swelling, inguinal hernia, dysmenorrhea, oral ulcer, upper respiratory tract infection (URI), bronchitis, pneumonia, cough, allergy, eczema, headache, arthralgia, pain, neuralgia, heart failure, edema, CVA (Table S1). 41…”