Possible liver toxicity due to Chinese herbal medicines
Liver damage caused due to Chinese herbal medicine (CHM) occurs rarely, but it is probably the most important side effect to be considered with this therapy. It accounts for nearly half of all reports of adverse drug reactions to the CTCA (Center for Safety of Chinese Herbal Medicine, Berlin). Slight elevation of liver enzymes up to twice the normal upper limit are more likely to be an adaptation response of the liver to increased metabolic activity than damage . Higher enzyme elevations occur in just under one percent of CHM treatments and these are usually normalized with continuation of therapy or after dose reduction [2, 3]. Approximately 75% of the liver values, which had already been increased before therapy, decreased during CHM therapy or remained the same .
In very rare cases, however, severe liver reactions can occur. This is often a so-called idiosyncratic liver toxicity, which is not predictable. Certain substances, which normally do not show liver abnormalities, may cause severe reactions in certain individuals. These reactions may include liver failure, and they can happen relatively independent of the dose. Genetic polymorphism, allergic reactions, or other factors are possible causes. This type of liver damage caused by medicines generally occurs with an expected frequency of approximately 1:10,000 to 1:100,000 although sometimes it may occur more frequently .
Which substances require increased attention?
If one ignores the most toxic substances, which are either not used at all or hardly used in Europe (e.g. Tripterygii wilfordii Radix, lei gong teng or Dioscoreae bulbiferae Rhizoma huang yao zi), few are associated with liver toxicity under regular dosing. These are Polygoni multiflori Radix (he shou wu) and Dictamni Cortex (bai xian pi). With regards to polygoni multiflori Radix, there are a series of reports in the international literature about occasional severe reactions [5-11, among others], which pertain more to the unprepared substance (sheng he shou wu) than the prepared version (zhi he shou wu) . Dictamni Cortex usually does not show any signs of liver toxicity, but it has been found disproportionately often (more than circumstantial) in prescriptions which led to severe reactions, especially in England in the 90s [13, 14, among others]. As a result of this, safety controls have obviously improved, and reports of hepatotoxicity from western countries have become rarer. A few reports of liver toxicity for Ephedrae Herba (ma huang) [15-17, among others] and Psoraleae Fructus (bu gu zhi) [18, 19, among others] also exist, but they are not sufficient to determine definite causality.
Bupleuri Radix (chai hu) and Scutellariae Radix (huang qin), which are often used in combination, deserve a special consideration. To date, there have been numerous cases of hepatotoxicity from Japan involving these herbs, mostly in the formula xiao chai hu tang, which is frequently used in the treatment of liver diseases [20-22, et al.]. However, virtually no cases have been reported from mainland China, at least as to xiao chai hu tang . Similar discrepancies also exist with interstitial pneumonia, which emerge with similar formulas in Japan, but not in China . Risks from Kampo medicine cannot readily be transferred to Chinese medicine. In Kampo medicine, a different plant species is used for Bupleurum than in Chinese medicine. Also, in Japan, granules are predominantly used, and according to the Japanese Pharmacopoeia, alcoholic extraction is allowed, therefore they cannot be equated with decoctions or aqueous extractions. To the best of our knowledge, so far only two cases of liver injury involving these drugs have been published from other countries: one from Taiwan , and one from Austria with inadequate causality criteria .
A recent comprehensive study, which included 21,470 patients from the TCM hospital in Kötzting  found these two drugs to be involved in a significant number of cases of liver reactions. Most often, they both appeared together in the formulas. Although a critical analysis indeed has to make some relativisations, it does not basically alter this characteristic. Therefore, when using either Bupleuri Radix (chai hu) or Scutellariae Radix (huang qin), or both drugs together, one should be aware of a rare risk and use caution as one would do with other potentially hepatotoxic drugs. A clear causality assignment to one drug or the other is currently not possible. Another finding of the study is that liver reactions by Toosendan Fructus (chuan lian zi) appear to be possible with regular dosage, too.
According to the current state of knowledge regarding other established Chinese herbal medicines, liver reactions are only a concern in cases where they are overdosed or improperly prepared, e.g. in Meliae Cortex (ku lian pi), Artemisiae argyi Folium (ai ye), Gleditsiae Fructus (zao jiao), or Xanthii Fructus (cang er zi) . The designated dosing limits should be adhered to and they should also be adapted to the physique and energetics of the patient.
In a number of cases, toxic liver damage has occurred among Chinese prescriptions in which the initiating agent could not be identified. In some publications, other drugs or drug combinations were also made responsible [e.g. 27.28]. Sometimes these cases have nothing to do with CHM, e.g. in the case of food supplements in the U.S., which also contain a Chinese medicinal plant among other ingredients, or substances whose identity is unclear . Since herbal medicines are often subject to misidentification, contamination or even deliberate adulteration, herbal medicines or formulas which have been implicated only once in the international literature in connection with liver damage, or those which have been detected repeatedly by only one specific finished medicinal product, without identification of identity and exclusion of contamination, can not be regarded as proof of their hepatotoxicity. Unfortunately, in these publications, scientific standards are often neglected .
Measures to minimize liver damage
Liver damage can’t be completely prevented in medicine; however, to ensure that it occurs as rarely as possible, or is stopped in the early stages, the CTCA recommends taking precautionary measures.
- One measure is the control of the liver values, especially before beginning the therapy. In this case, the enzyme ALAT (GPT) and a cholestatic enzyme (GGT or AP) are sufficient. The CTCA recommends that the liver values should be checked before beginning and also at regular intervals for any therapy involving long-term treatment or high dosing. However, this can not eliminate the possibility of liver damage, because it could develop relatively quickly between the control intervals, even if previous laboratory results showed no striking findings.
- Therefore, it is important to inform patients that in the case of symptoms such as unusual fatigue or prolonged nausea, and especially in the case of dark urine with a light-colored stool or jaundice, they should contact the prescriber immediately, or if this is not possible, stop taking the Chinese medicine in the interim.
- Special care should be taken in the following cases:
► with known liver damage, increased alcohol consumption or liver disease in the medical history
► With patients over 65 years of age
► With patients taking other medication (in particular, those with a risk of liver toxicity) or other substances with which interactions might occur (e.g. grapefruit juice, St. John's wort)
What to do if liver damage occurs?
- Stop taking Chinese medicine and, if appropriate, other medication immediately
- Examine all possible alternative causes (see section "Urgent diagnostics in case of suspected liver injury caused by CHM").
- Report the case with all details to the CTCA (report form - in German only) in order to clarify a possible connection with Chinese medicine, to extend the knowledge about possibly liver-damaging substances and to increase the general safety of CHM.
- Urge patients to stop taking the medicines that are suspected to be the cause of the reaction. Many cases, most notably a death in England, could have been prevented by doing this.
- Teschke R. [Drug-induced liver damage] (German). Dt Aerztebl 2001;98:B-2220-2225
- Al-Khafaji M. Monitoring of liver enzymes in patients on Chinese medicine. J Chin Med 2000:6-10
- Melchart D, Linde K, Hager S, et al. Monitoring of liver enzymes in patients treated with traditional Chinese drugs. Complement Ther Med 1999;7:208-216
- Fontana RJ, Hayashi PH, Gu J, et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology 2014;147:96-108
- But PP, Tomlinson B and Lee KL. Hepatitis related to the Chinese medicine Shou-wu-pian manufactured from Polygonum multiflorum. Vet Hum Toxicol 1996;38:280-282
- Park GJ, Mann SP and Ngu MC. Acute hepatitis induced by Shou-Wu-Pian, a herbal product derived from Polygonum multiflorum. J Gastroenterol Hepatol 2001;16:115-117
- Battinelli L, Daniele C, Mazzanti G, et al. New case of acute hepatitis following the consumption of Shou Wu Pian, a Chinese herbal product derived from Polygonum multiflorum (letter). Ann Intern Med 2004;140:E-589-590
- Panis B, Wong DR, Hooymans PM, De Smet PA and Rosias PP. Recurrent toxic hepatitis in a Caucasian girl related to the use of Shou-Wu-Pian, a Chinese herbal preparation. J Pediatr Gastroenterol Nutr 2005;41:256-258
- Furukawa M, Kasajima S, Nakamura Y, et al. Toxic hepatitis induced by show-wu-pian, a Chinese herbal preparation. Intern Med 2010;49:1537-1540
- Dong H, Slain D, Cheng J, Ma W and Liang W. Eighteen cases of liver injury following ingestion of Polygonum multiflorum. Complement Ther Med 2014;22:70-74
- Xu J, Wang MR, He CL, Sui YH and Qiao F. [Liver injury by peroral Polygonum multiflorum: an analysis of 40 cases] (Chinese). Dongnan Guofang Yiyao 2009;11:209-210
- Wu X, Chen X, Huang Q, Fang D, Li G and Zhang G. Toxicity of raw and processed roots of Polygonum multiflorum. Fitoterapia 2012;83:469-475
- Perharic-Walton L, Murray V. Toxicity of Chinese herbal remedies (letter). Lancet 1992;340:674
- Vautier G, Spiller RC. Safety of complementary medicines should be monitored (letter). BMJ 1995;311:633
- Estes JD, Stolpman D, Olyaei A, et al. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg 2003;138:852-858
- Charalampopoulos A, Karatsourakis T and Tsiodra P. Acute hepatitis associated with the use of Ma-huang in a young adult (letter). Eur J Intern Med 2007;18:81
- Nadir A, Agrawal S, King PD and Marshall JB. Acute hepatitis associated with the use of a Chinese herbal product, ma-huang. Am J Gastroenterol 1996;91:1436-1438
- 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. Clin Toxicol (Phila) 2009;47:683-685
- Hwang SH, Park JA, Jang YS, et al. [A case of acute cholestatic hepatitis caused by the seeds of Psoralea-corylifolia] (Korean). Taehan Kan Hakhoe Chi [Korean J Hepatol] 2001;7:341-344
- Mantani N, Kogure T, Sakai S, et al. Incidence and clinical features of liver injury related to Kampo (Japanese herbal) medicine in 2,496 cases between 1979 and 1999: problems of the lymphocyte transformation test as a diagnostic method. Phytomedicine 2002;9:280-287
- Kamiyama T, Nouchi T, Kojima S, Murata N, Ikeda T and Sato C. Autoimmune hepatitis triggered by administration of an herbal medicine. Am J Gastroenterol 1997;92:703-704
- Itoh S, Marutani K, Nishijima T, Matsuo S and Itabashi M. Liver injuries induced by herbal medicine, syo-saiko-to (xiao-chai-hu-tang). Dig Dis Sci 1995;40:1845-1848
- Wu SX, Sun HF, Yang XH, et al. ["Re-evaluation upon suspected event" is an approach for post-marketing clinical study: Lessons from adverse drug events related to Bupleuri Radix preparations] (Chinese). Zhongguo Zhongyao Zazhi 2014;39:2983-2988
- Hsu LM, Huang YS, Tsay SH, Chang FY and Lee SD. Acute hepatitis induced by Chinese hepatoprotective herb, xiao-chai-hu-tang. J Chin Med Assoc 2006;69:86-88
- Melchardt T, Magnes T, Weiss L, et al. Liver toxicity during temozolomide chemotherapy caused by Chinese herbs. BMC Complement Altern Med 2014;14:115
- Bensky D, Clavey S and Stöger E. Chinese Herbal Medicine. Materia Medica. 3rd ed. Seattle, WA: Eastland Press, 2004
- Teschke R. Traditional Chinese Medicine induced liver injury. J Clin Translat Hepatol 2014;2:80-94
- Teschke R, Wolff A, Frenzel C and Schulze J. Review article: herbal hepatotoxicity - an update on traditional Chinese medicine preparations. Aliment Pharmacol Ther 2014;40:32-50
- Wiebrecht A, Kalg A. Herbal hepatotoxicity - an update on traditional Chinese medicine preparations (letter). Aliment Pharmacol Ther 2014;40:737-738
- Wiebrecht A. Ist bei einer Risikobeurteilung der Chinesischen Medizin die Einhaltung wissenschaftlicher Standards überflüssig? [In case of risk evaluation of Chinese medicine - is the adherence to scientific standards dispensible?] (German) Dt Zschr Akupunktur 2014;57:16-19
- Melchart D, Hager S, Albrecht S, Dai J, Weidenhammer W and Teschke R. Herbal Traditional Chinese Medicine and suspected liver injury: A prospective study. World J Hepatol 2017;9:1141-1157