Abstract
Traditional Chinese medicine (TCM) herbs are commonly regarded to be safe with minimal toxicities in Chinese communities. Cancer patients who are receiving Western oncology therapy often concurrently take TCM herbs for anticancer and symptom relief purposes. We performed a literature review for current evidence on TCM herb–induced liver injury from an oncological perspective. A literature search on PubMed was performed to identify publications regarding TCM herbs and concoctions with hepatoprotective or hepatotoxic properties. Lists of commonly used herbs and their causality levels were compiled. In view of the wide range of evidence available, cases assessed by the well-established RUCAM (Roussel Uclaf Causality Assessment Method) algorithm were categorized as the highest level of evidence. More than one case of TCM herb–induced liver injury was confirmed by RUCAM in the following herbs and concoctions: Lu Cha (
Keywords
Introduction
Multiple studies have shown that there is widespread use of traditional Chinese medicine (TCM) among Chinese patients as an adjuvant to Western medicine in cancer treatment.1-5 Another study revealed that the self-care of Chinese cancer patients has been heavily influenced by the TCM philosophy. 6 In addition to taking herbal medicines prescribed by Chinese medicine practitioners, it is also common for the general public to use proprietary Chinese medicine on their own or add herbs to meals and soups. A study found that over half of the Hong Kong cancer patients surveyed used at least one form of TCM. Furthermore, 60% of these patients who were receiving chemotherapy concurrently used TCM. 7 According to a Taiwanese survey, 69% of respondents thought that TCM is mild and has no ill effects at all. 8 TCM herbs and concoctions, like any drug, also have side effects and toxicities.
Many oncologists do not encourage the concurrent use of TCM due to the potential of having adverse interactions between Chinese and Western drugs that may lead to hepatotoxicity. There have been numerous reports of liver injury caused by TCM herbs and concoctions. However, the establishment of causality varies in these reports. A typical example of TCM-induced liver toxicity is He Shou Wu, which is a popular herb for preventing hair loss and aging. A study found that only 30.6% of literature case reports demonstrate a high probability of He Shou Wu–induced liver injury causality. 9 The causality between TCMs and drug-induced liver injury was ascertained by various methods, such as by patient recall, clinical suspicion, exclusion, and algorithms. It is important to note the complexity and difficulty in establishing causality for TCM herbs. One difficulty is due to polypharmacy as TCM is rarely used as a single herb, and TCM may sometimes be used concomitantly with Western drugs. Another difficulty is contamination by heavy metals. 10 Evidence available in case reports, case series, and reviews may not be complete. If these confounders are not excluded, misdiagnosis and overreporting may occur.
Hence, there is a need to categorize the cases in the existing literature into different evidence levels of causality. Focus should be given to hepatotoxic TCM for which clear evidence has been demonstrated by standardized causality assessment algorithms. RUCAM (Roussel Uclaf Causality Assessment Method), or its previous synonym CIOMS (Council for International Organizations of Medical Sciences), is the most commonly used causality instrument for drug-induced liver toxicity. 11 RUCAM is used to assess causality quantitatively, by applying numerical weighting to key features such as chronology and risk factors, and it generates an overall score to indicate the probability of causality. The RUCAM scale ranges as follows: 0, excluded; 1 to 2, unlikely; 3 to 5, possible; 6 to 8, probable; and ≥9, highly probable. 12
Furthermore, not all TCM herbs and concoctions cause hepatotoxicity. In fact, some of them have hepatoprotective effects against drug-induced liver injury, such as chemotherapy-induced hepatotoxicity.
In this article, we present a review of the current literature to identify potentially hepatotoxic or hepatoprotective TCM that cancer patients may concurrently use with Western systemic therapies, and stratify them using causality levels to offer easier interpretation.
Methodology
Data Sources and Searches
We carried out a systematic search of the PubMed database on March 11, 2019, to identify publications of laboratory findings, case reports, case series, and review articles of TCM-induced hepatotoxicity. By using Medical Subject Headings, English articles that were associated with the terms “Chemical and Drug-Induced Liver Injury” and “Medicine, Chinese Traditional” were selectively included. Our search yielded 64 results.
Exclusion of Publications
Publications were excluded by the following criteria. Publications were excluded if
They were unrelated to TCM-induced hepatotoxicity or hepatoprotection, or
Access to the full article could not be obtained, or
No specific TCM herbs or concoctions were named, or
No significant results were directly shown with specific TCM herbs or concoctions.
As a result, 14 publications were excluded from this review.
Data Analysis
Data Extraction
Fifty publications were analyzed. Individual herbs and herbal concoctions were identified. The scientific names of each herb and its corresponding Chinese name were determined. As a single TCM herb could have different scientific names (eg,
Duplication of Data
The references of these 50 publications were carefully inspected. There were case reports, case series, and reviews referring to the same event of hepatotoxicity caused by a certain TCM herb or concoction. In particular, 3 systematic reviews were published by the same author in 3 consecutive years, and each systematic review cited cases from the previous review. Duplicated data were discarded in this review.
Exclusion of TCM Herbs or Concoctions
If the publication failed to provide any of the aforementioned data (eg, number of cases), the reference lists of the primary and review articles were scanned. If the primary source could not be accessed, the data of the individual herb or concoction were also excluded.
Levels of Causality
Hepatotoxic herbs or concoctions
In view of the wide range of clinical causality ascertainment methods in the literature, as well as the fact that laboratory findings do not directly infer clinical significance, a stratified level of causality was devised in order to provide a clearer and more clinically oriented picture.
Entries of hepatotoxic herbs or herbal concoctions found from the publications were categorized into 1 of the 4 following levels according to the following description:
Hepatoprotective herbs or concoctions
After excluding uncommonly used hepatoprotective herbs and herbal concoctions, only nonclinical ones remained; hence, they were not graded by causality levels.
Results
Lists of herbs and concoctions that were hepatotoxic or hepatoprotective, their respective causality levels, and number of cases are compiled in Tables 1 to 5.9,13-46
TCM Herbs That Were Assessed by RUCAM to Demonstrate Clear Causality of Hepatotoxicity.
Abbreviations: TCM, traditional Chinese medicine; RUCAM, Roussel Uclaf Causality Assessment Method.
TCM Concoctions That Were Assessed by RUCAM to Demonstrate Clear Causality of Hepatotoxicity.
Abbreviations: TCM, traditional Chinese medicine; RUCAM, Roussel Uclaf Causality Assessment Method.
Single Herbs With Hepatotoxic Risks.
Herb Concoctions With Hepatotoxic Risks.
TCM Herbs Found to Have Hepatotoxic Properties in the Laboratory Setting.
Abbreviation: TCM, traditional Chinese medicine.
We found 20, 17, 34, and 27 individual herbs that were graded level 4, 3, 2, and 1 for their causality toward liver injury, respectively. For herbal concoctions, we found 6, 10, 7, and 2 concoctions that were graded level 4, 3, 2, and 1, respectively. There were in total 21 herbs or concoctions that were hepatoprotective in laboratory settings. Using RUCAM, clear causality (level 4) was established in 194 cases of TCM-induced liver toxicity.
Discussion
TCM for Symptom Relief and Body Enhancement
He Shou Wu (何首烏,
In TCM, Chuan Lian Zi (川楝子,
Ren Shen (人參,
San Qi (三七,
Chai Hu (柴胡,
Another herb that showed conflicting results was Yin Chen Hao (茵陳蒿,
Wu Wei Zi (五味子,
Bai Shao (白芍,
TCM With Anticancer Properties
Bai Xian Pi (白鮮皮,
An interesting finding was
Huang Yao Zi (黃藥子,
Our review found 1 case of Huang Qin (黃芩
Topoisomerase inhibitors, like irinotecan and topotecan, are a type of chemotherapeutic agents that were derived from camptothecin from the bark of
Causality Assessment
As demonstrated in the tables above, there are varying levels of evidence in the current literature. However, the clinical and histopathological features of herb-induced liver toxicity may mimic any liver injury histopathological model, 63 and expert judgement could be limited by subjectivity. Hence, a widely accepted and standardized algorithm is needed to confirm causality. RUCAM is a quantitative scale that has been used worldwide,17,64-66 allowing results to be comparable across countries. When compared with other general causality assessment algorithms like the Naranjo scale, it is more liver-specific and more relevant. 12 Among liver-oriented methods, RUCAM was found to be superior. Clinical Diagnostic Scale showed poorer discriminative power, whereas the Digestive Disease Week-Japan scale included an in vitro drug lymphocyte stimulation test evaluation criterion, which was not widely accessible. 67 RUCAM also addresses other alternative causes of liver injury like concomitant drug use. Therefore, RUCAM is by far the most preferred algorithm used in the field.
Future Implications
First of all, we should note the presence of different types of evidence in the literature. Without following established causality algorithms, problems like comedication and poor data quality may affect the establishment of causality; hence, it is unjustifiable to ascertain the causal relationship immediately. Furthermore, contaminants during production and processing may lead to liver injury. Hence, clear-cut causality is often difficult to achieve. Our review presented the stratification of causality of the current literature. RUCAM is an important tool that should be applied to all future cases to determine causality accurately. Further studies are needed to confirm the causality of herb-induced liver injury with RUCAM in order to clarify the hepatotoxicity of herbs that are suspected in the literature. The use of RUCAM should be encouraged among physicians to aid diagnosis, and RUCAM should be employed before publication of cases and inclusion in databases.
In Chinese communities, there is a common misconception that TCM is free of side effects and toxicities. Our review highlights the importance to evaluate the potential hepatotoxicity of TCM. We suggest that there is a fundamental need for raising the awareness of this issue among Chinese communities. Cancer patients should consult TCM practitioners before using TCM, instead of taking TCM without professional advice.
Also, TCM can have hepatoprotective effects. However, proving the hepatoprotective effects of a herb clinically can be challenging, and the therapeutic benefit of TCM is often questioned. TCM herbs are rarely used alone, as each patient receives a personally tailored concoction. Hence, the effectiveness of TCM is difficult to be proven in the Western-dominated setting based on a medical system that treats the same disease with the same drug on different patients.
In practice, oncologists are often uncertain of the efficacy and safety of TCM and therefore urge patients not to take any TCM during systemic treatment. TCM has been practiced for over 2000 years, and its ideologies and effectiveness have been deeply rooted and accepted in Chinese communities. A survey done in Hong Kong found that over two thirds of all interviewed Chinese cancer patients believed that integrated TCM and Western medicine was effective in treating cancer. 7 Hence, Chinese cancer patients are keen to use TCM. The total rejection by some oncologists may prompt patients to hide the truth. The aforementioned survey found that among patients who were concurrently receiving Western medicine treatment and TCM, nearly two thirds of them did not inform their physicians. This is not only harmful to the doctor-patient relationship but also unhelpful in monitoring and treating the patient.
Recent research has shown that certain TCM when used in combination with Western medicine can be beneficial. It was found that some TCM could act as effective chemosensitizers and radiosensitizers, and could be helpful in palliative care. 68 We have learnt from history that some modern anticancer drugs were derived from plants. The Pacific Yew, the Madagascar Periwinkle, and the Chinese happy tree have yielded valuable chemicals for chemotherapy. If TCM was excluded from treating cancer patients, the advancement of cancer therapy may be hindered. More research is needed to clarify the hepatotoxicity and hepatoprotectiveness of different TCM herbs and concoctions. This is crucial to aid TCM practitioners and Western medicine doctors in making clinical decisions, as well as paving the way for TCM and Western medicine integration in treating cancer.
Conclusion
This literature review compiled a list of hepatotoxic and hepatoprotective TCM herbs and concoctions, and highlighted some that are highly likely to be used by cancer patients as they either have anticancer properties or symptom relief purposes. They were then stratified according to their levels of causality, to provide a clearer and more clinically relevant picture of the current evidence. More stringent research with the use of RUCAM is needed to confirm the causality of herb-induced liver injury before publication and inclusion in databases. Cancer patients should note the potential hepatotoxic effects of TCM herbs and should not assume the absence of side effects of TCM herbs. More collaboration between TCM and Western medicine should be encouraged to establish effective and safe screening of drug-herb interaction.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
