How Radix bupleurum (Chai Hu) has evaded discovery of its split personality as both liver protectant and liver risk for thousands of years remains a mystery. Now that scientific analysis has exposed its true nature, investigators are looking into other herbs’ hepatotoxic properties as well. Traditional Chinese Veterinary Medical herb texts and handbooks brim with acclaim for bupleurum as a hepatoprotectant, anti-pyretic and anti-inflammatory agent.1,2,3 Veterinary herbalists recommend it for patients with acute and chronic hepatitis and even hepatic lymphoma.4,5,6 TCVM practitioners maintain that bupleurum will “disperse Liver Qi stagnation” and “soothe the Liver Qi.”7 Who would suspect that bupleurum-containing formulae with names such as “Free and Easy Wanderer” and something to the effect of “Liver Livin’ It Up” might require an index of suspicion not sufficiently conveyed by their innocent appellations? Bupleurum’s role in inducing hepatitis rather than remedying it is drawing closer attention, whether it is couched in a popular formula, such as Xiao Chai Hu Tang (a.k.a. Minor Bupleurum), or tested as a sole saponin in rodent models.8 Xiao Chai Hu Tang “is the most common traditional drug in Asian countries for patients with chronic hepatitis and liver cirrhosis.”9 That humans have been injured and/or killed by the plant drug comes as a rude awakening. TCVM manuals do caution practitioners about Xiao Chai Hu Tang, saying, “This formula is contraindicated in patients with Excess above and Deficiency below, Liver Yang Rising, Liver Fire or oral bleeding due to Yin Deficiency.” How do these translate into modern medical terminology? Can’t the veterinary herbal professorial staff provide factual data? When adequate warnings fail to appear,10 veterinarians would be wise to seek hard facts about an herb before dispensing it to clients. Claiming one sold a TCVM product to harmonize the relationship between the liver and spleen might be insufficient to medicolegally justify giving it to a dog or cat with cholangiohepatitis, chronic pancreatitis and vomiting.11 Many products veterinary practitioners sell to clients contain undisclosed and unverified amounts of each ingredient. This complicates investigations into potential cause of liver injury. Many labels lack warnings, so clients may fail to report their use to an emergency doctor examining a jaundiced cat or dog. As a group of Hong Kong toxicologists said, “Herbal products should be used cautiously and enhanced pharmacovigilance is necessary.”12 Part of the reason the harmful effects of bupleurum are now coming to light may stem from the growing study of Kampo medicine, a traditional Japanese herbal system that takes a more scientific approach than Traditional Chinese Medicine does. Both systems utilize similar plant combinations, but Kampo’s emphasis on evidence from clinical and laboratory studies brings to light adverse effects of Asian herbs.13-14 For example, “[I]t has been well demonstrated that several potential side effects such as allergic reactions, cramps, diarrhoea [sic], fever, gastrointestinal disturbances, headaches, haematuria [sic] … nausea, photosensitization and vomiting may be experienced when administering Kampo medicine or herbal medicines. In addition, it has been reported that Kampo medicine or herbal medicine may have antagonistic or synergistic interactions with Western drugs or with some foods. ...”15 The reporting of adverse events from Asian herbs led to the withdrawal of Xiao Chai Hu Tang in Japan, where it is known as Shosaikoto. The product had once been an “immensely popular liver treatment,” according to TIMEAsia, and was widely regarded by liver specialists as an effective means of preventing hepatitis C from transitioning into liver cancer.16 Years ago, however, after dangers surfaced, “The Ministry of Health, Labour and Welfare of Japan has cautioned against using Kampo medicines containing Bupleurum root and Glycyrrhiza, especially Shosaikoto, in clinical use. The usage of Shosaikoto in hepatitis, cirrhosis or liver cancer patients was prohibited.”17 This ruling by Japan’s Health Ministry came after a wave of deaths in the 1990s that implicated Shosaikoto as the cause, especially in patients receiving interferon for liver disease. How can veterinarians avert similar disasters? Two factors stand out in particular: dose and long-term toxicity. While pharmacokinetic and pharmacodynamic studies for cats and dogs do not exist for bupleurum, two reports on studies in rodents raise questions about possible outcomes from high-dose and long-term bupleurum. Both papers, published in late 2010, evaluated hepatotoxicity as a result of various doses. One found that liver injury corresponded in a dose-dependent fashion with the amount of extract gavaged and the concentration of a bupleurum component called “saikosaponin.” The research team at the Shandong Research Academy of Traditional Chinese Medicine in China concluded that saikosaponin may be the main toxic agent responsible for inducing liver damage, evidenced by cellular injury and necrosis.18 Huang, et.al., then monitored when the ALT and AST in rats’ serum started to rise and at what dose. They found that, beginning at one week of receiving doses ranging from 50 to 125 g/kg of total bupleurum saponin crude extracts, rats experienced liver injury such as edema, fatty degeneration in liver cells and necrosis. After two weeks, some rats succumbed. How do levels of intake, such as those given to rats, compare to amounts provided clinically to cats and dogs? How long can a mammal receive bupleurum before the liver begins to break down? How does bupleurum affect the liver’s capacity to metabolize other xenobiotics, such as chemotherapy and corticosteroids? Should patients already afflicted with hepatitis receive bupleurum; i.e., will it help or hurt? Uncertainties linger. Research in veterinary patients is sparse. Nevertheless, concerns about hepatotoxicity in other herbs such as Pinellia ternate,19 Fructus psoraleae and more20 are growing. A Japanese gastroenterologist/hepatologist commented, “Among various modalities of alternative medicine, Chinese herbal medicine is most prevalent worldwide. … As the amount of herbal medicines consumed increased, more reports appeared concerning untoward effects including liver injuries putatively caused by herbal medicines. These include acute hepatitis, chronic hepatitis, cholestatic hepatitis and bile duct injuries. Wild germander (Teucrium chamaedrys), syo-saiko-to (TJ-9, Xiao-Chai-Hu-Tang), cascara sagrada, and dai-saiko-to (TJ-8, Da-Chai-Hu-Tang) are reported to cause various drug-induced liver injuries.”21 It is wise to be wary; clinicians should monitor liver function regularly and maintain constant pharmacovigilance.22 Dr. Narda Robinson, DVM, DO, Dipl. ABMA, FAAMA, oversees complementary veterinary education at Colorado State University. FOOTNOTES 1. Xie H, Preast V (eds.). Xie’s Chinese Veterinary Herbology. Ames, IA: Wiley-Blackwell, 2010. 2. Beebe S, Salewski M, Monda L, et al. Clinical Handbook of Chinese Veterinary Herbal Medicine. Placitas, NM: Herbal Medicine Press, 2006. 3. Xie H. Chinese Veterinary Herbal Handbook, 2nd edition. Reddick, FL: Chi Institute of Chinese Medicine, 2008. 4. Scanlan N. Getting started with Chinese herbs. Veterinary Practice News, June 2010. Accessed on 05-16-10 at http://www.veterinarypracticenews.com/vet-dept/small-animal-dept/getting-started-with-chinese-herbs.aspx . 5. Xie H, Preast V. Xie’s Chinese Veterinary Herbology. Ames, IA: Wiley-Blackwell, 2010. P. 424. 6. Marsden, S. Chinese herbal treatment of cancer in small animals. Small animal and exotics. Proceedings of the North American Veterinary Conference, Orlando, Florida, USA, 16-20 January 2010; Gainesville: The North American Veterinary Conference, 2010, 45-52 (Conference paper) AN: 20103181461 7. Xie H, Preast V. Xie’s Chinese Veterinary Herbology. Ames, IA: Wiley-Blackwell, 2010. P. 350, 372. 8. Hsu L-M, Huang Y-S, Tsay S-H, et al. Acute hepatitis induced by Chinese hepatoprotective herb, Xiao-Chai-Hu-Tang. J Chin Med Assoc. 2006;69(2):86-88. 9. Hsu L-M, Huang Y-S, Tsay S-H, et al. Acute hepatitis induced by Chinese hepatoprotective herb, Xiao-Chai-Hu-Tang. J Chin Med Assoc. 2006;69(2):86-88. 10. Xie H. Chinese Veterinary Herbal Handbook, 2nd edition. Reddick, FL: Chi Institute of Chinese Medicine, 2008, p. 169. 11. Beebe S, Salewski M, Monda L, et al. Clinical Handbook of Chinese Veterinary Herbal Medicine. Placitas, NM: Herbal Medicine Press, 2006. P. 73. 12. Cheung WI, Tse ML, Ngan T, et al. Liver injury associated with the use of Fructus Psoraleae (Bol-gol-zhee or Bu-gu-zhi) and its related proprietary medicine. Clinical Toxicology. 2009l;47:683-685. 13. Yu F, Takahashi T, Moriya J, et al. Traditional Chinese Medicine and Kampo: a review from the distant past for the future. The Journal of International Medical Research. 2006;34:231-239. 14. Ikegami F, Sumino M, Fujii Y, et al. Pharmacology and toxicology of Bupleurum root-containing Kampo medicines in clinical use. Human & Experimental Toxicology. 2006;25:481-494. 15. Ikegami F, Sumino M, Fujii Y, et al. Pharmacology and toxicology of Bupleurum root-containing Kampo medicines in clinical use. Human & Experimental Toxicology. 2006;25:481-494. 16. Walsh B. Deadly Herbs. In Japan, a popular liver cure proves to be a killer. In “The Science of Herbal Asian Medicine”. Accessed on 05-16-11 at http://www.time.com/time/asia/features/asian_medicine/killer.html . 17. Ikegami F, Sumino M, Fujii Y, et al. Pharmacology and toxicology of Bupleurum root-containing Kampo medicines in clinical use. Human & Experimental Toxicology. 2006;25:481-494. 18. Sun R and Huang W. “Dose-toxicity” relationship study on rat’s chronic hepatotoxicity of refined products by saikosaponin by alcohol elution. Zhongguo Zhong Yao Za Zhi. 2010;35(17):2338-2341. [Article in Chinese] 19. Aiba T, Takahashi T, Suzuki K, et al. Liver injury induced by a Japanese herbal medicine, sairei-to (TJ-114, Bupleurum and Hoelen combination, Chai-Ling-Tang) R1. Journal of Gastroenterology and Hepatology. 2007;22:762-763. 20. Cheung WI, Tse ML, Ngan T, et al. Liver injury associated with the use of Fructus Psoraleae (Bol-gol-zhee or Bu-gu-zhi) and its related proprietary medicine. Clinical Toxicology. 2009l;47:683-685. 21. Aiba T, Takahashi T, Suzuki K, et al. Liver injury induced by a Japanese herbal medicine, sairei-to (TJ-114, Bupleurum and Hoelen combination, Chai-Ling-Tang) R1. Journal of Gastroenterology and Hepatology. 2007;22:762-763. 22. Lee C-H, Wang J-D, Chen P-C. Risk of liver injury associated with Chinese herbal products containing Radix bupleuri in 639,779 patients with hepatitis B virus infection. PLoS ONE. 2011;6(1):e16064. <HOME>
