Interview regarding recent developments of Traditional Chinese Medicine Induced Liver Injury
Using the PubMed database, a literature search was undertaken to assess the extent herbal TCM products exert rare hepatotoxicity. Analysis of reported cases revealed numerous specified herbal TCM products with potential hepatotoxicity. The use of few herbal TCM products may rarely be associated with hepatotoxicity in some susceptible individuals, necessitating a stringent pretreatment evaluation of the risk/benefit ratio, based on results of multicenter, randomized, double-blind, placebo-controlled clinical trials.
Do you feel that the use of traditional Chinese medicine is increasing in the West? Is the prevalence of traditional Chinese medicine-induced liver injury changing worldwide?
TK: Valid data on the use of traditional Chinese medicines (TCMs) in Western countries is limited. If reported, statistics concern single herbs, herbal mixtures, or herbal dietary supplements. Few refer specifically to herbal TCM. Some mix herbal TCM with non-herbal TCM. Such data do not allow valid conclusions. Similarly, prevalence rates of liver injury related to herbal TCMs cannot be calculated based on the number of publications, which increase year-by-year throughout the world.
Traditional Chinese medicine is broadly used in the world, as treatments or health products. Are there differences in formulations and quality control of traditional Chinese medicine in the East and West?
TK: Although broadly used, the efficacy of most herbal TCMs have not been established by valid clinical trials (1,2). Many trials have been published that suggest notable results, but these trials are not rigorous and their quality is insufficient (3). An exception is the herbal TCMs artemisinin (also known as qinghao su) and dihydro-qinghaosu, used for malaria treatment worldwide, for which Tu Youyou received the Nobel prize in Medicine in 2015 (3,4).
What are possible mechanisms in traditional Chinese medicine-induced liver injury? Are drug-drug interactions between traditional Chinese medicines and Western medicines known?
TK: Aside from possible adulterants or impurities in herbal TCM products, most liver injuries caused by herbal TCMs are idiosyncratic, occurring in susceptible individuals independent of the dose (5). Since such injuries in humans are not reproducible experimentally, the underlying pathogenesis remains unclear and is a matter of speculation (5,6). Human leukocyte antigen (HLA) alleles may be risk factors for idiosyncratic liver injury caused by Western drugs (7), but this has not been thoroughly investigated for herbal TCM. For TCM herbs, pathogenetic mechanisms are known only for intrinsic liver injury caused, for example, by formulas that contain unsaturated pyrrolizidine alkaloids (PAs). PAs are converted by cytochrome P450 to toxic intermediates, which damage the sinusoidal cells of the liver and lead to specific hepatic sinusoidal obstruction syndrome (HSOS). The toxicity events that cause intrinsic liver injury can be studied in animals (3,8,9).
Interactions of Western drugs with herbal TCM are to be anticipated, since both products are often intentionally used together (10). However, unintentional interactions are possible if the consumed herbal TCM product is adulterated by Western drugs to ensure efficacy (11). This is likely more of a problem in Asian countries (3,9), and less in Western countries if analyses for product quality are performed (3,12,13).
Your article was published in 2014. Can you tell us which traditional Chinese medicines most commonly cause liver injury currently? Are there trends in liver injury that clinicians should know about?
TK: Possible hepatotoxic herbal TCMs were published in one of the early issues of the Journal of Clinical and Translational Hepatology in 2014, but frequency data of liver injury cases were not available at that time (14). According to a more recent analysis of a large cohort of Chinese patients, TCM liver injury was most commonly caused by Polygonum multiflorum, followed by Psoralea corylifolia, Corydalis yanhusuo, Rheum officinale, Cassia obtusifolia, and Aconitum carmichaeli (10). For these herbs, causality was validly established using the robust RUCAM (Roussel Uclaf Causality Assessment Method), which is now available as a 2016 update (15).
Specific trends cannot be identified, but physicians in general should be aware that in any patient with suspected liver injury, an herbal TCM could be the cause. Therefore, such patients should be investigated regarding this issue, using RUCAM for causality assessment (15), which is also recommended for use in China (10,16,17).
References:
1. Manheimer E, Wieland S, Kimbrough E, Cheng K, Berman BM. Evidence from the Cochrane Collaboration for Traditional Chinese Medicine therapies. J Altern Complement Med 2009; 15: 1001–1014
2. Teschke R, Wolff A, Frenzel C, Eickhoff A Schulze J. Herbal traditional Chinese medicine and its evidence base in gastrointestinal disorders. World J Gastroenterol 2015; 21: 4466–4490
3. Teschke R, Larrey D, Melchart D, Danan G. Traditional Chinese Medicine (TCM) and herbal hepatotoxicity: RUCAM and the role of novel diagnostic biomarkers such as microRNAs. Medicines 2016, 3, 18. DOI: 10.3390/medicines3030018
4. Tu Y. The development of new antimalarial drugs: Qinghaosu and dihydro-qinghaosu. Chin Med J 1999; 112: 976–977
5. Teschke R, Eickhoff A. Herbal hepatotoxicity in traditional and modern medicine: Actual key issues and new encouraging steps. Front Pharmacol 2015; 6: 72. DOI: 10.3389/fphar.2015.00072
6. Frenzel C, Teschke R Herbal hepatotoxicity: Clinical characteristics and listing compilation. Int J Mol Sci 2016; 17, 588.DOI: 10.3390/ijms17050588
7. Sarges P, Steinberg JM, Lewis JH. Drug-induced liver injury: Highlights from a review of the 2015 literature. Drug Saf 2016; 39: 561-575. DOI: 10.1007/s40264-016-0427-8
8. Gao H, Li N, Wang JY, Zhang SC, Lin G. Definitive diagnosis of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids. J Dig Dis 2012; 13: 33-39
9. Lin G, Wang JY, Li N, Li M, Gao H, Ji Y, Zhang F, Wang H, Zhou Y, Ye Y, Xu HX, Zheng J. Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum. J Hepatol 2011; 54: 666-673
10. Zhu Y, Niu M, Chen J, Zou ZS, Ma ZJ, Liu SH, Wang RL, He TT, Song HB, Wang ZX, Pu SB, Ma X, Wang LF, Bai ZF, Zhao YL, Li YG, Wang JB, Xiao XB. Comparison between Chinese herbal medicine and Western medicine-induced liver injury of 1985 patients. J Gastroenterol Hepatol 2016; 31: 1476-1482. DOI: 10.1111/jgh.13323
11. Zhang L, Yan J, Liu X, Ye Z, Yang X, Meyboom R, Chan K, Shaw D, Duez P. Pharmacovigilance practice and risk control of Traditional Chinese Medicine drugs in China: current status and future perspective. J Ethnopharmacol 2012; 140: 519-525. DOI: 10.1016/j.jep.2012.01.058
12. Melchart D, Hager S, Dai J, Weidenhammer W. Quality control and complication screening programme of Chinese medicinal drugs at the first German hospital of Traditional Chinese Medicine - A retrospective analysis. Forsch Komplementmed 2016; 23: 21–28
13. Melchart D, Linde K, Weidenhammer W, Hager S, Shaw D, Bauer R. Liver enzyme elevations in patients treated with traditional Chinese medicine. JAMA 1999; 282: 28–29
14. Teschke R. Traditional Chinese Medicine induced liver injury. J Clin Translat Hepatol 2014; 2: 80-94. DOI: 10.14218/JCTH.2014.00003.
15. Danan G, Teschke R. RUCAM in drug and herb induced liver injury: The update. Int. J Mol Sci 2016; 17, 14. DOI: 10.3390/ijms17010014
16. Yuan D, Yang X, Guo JC. A great honor and a hugh challenge for China: You-you TU getting the Nobel Prize in Physiology or Medicine. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.) 2016, 17, 405-406.
17. Ma X, Peng JH, Hu YY. Chinese herbal medicine-induced liver injury. J Clin Translat Hepatol 2014; 2: 170-175.