Editor’s Note: The liver, as the “chemical factory” of the human body, is responsible for the synthesis and metabolism of various crucial substances, while also serving as the “detoxification center” for harmful waste and toxins. However, the liver faces numerous challenges, including external factors such as viruses, bacteria, alcohol, drugs, and internal factors like self-consumption, immune imbalance, acute and chronic liver diseases, which can disrupt the liver’s tissue structure and functioning. Traditional Chinese Medicine (TCM) has rich applications in safeguarding the liver. Still, issues related to liver damage caused by Chinese herbal medicine have sparked debates about whether TCM is a “toxin” or a “guardian” for the liver. In a recent report at the 10th “Huaxia Shanghai Liver Disease Forum and Advances in Diagnosis and Treatment of Liver Failure and Its Complications Forum,” Dr. Xiaohe Xiao from the Fifth Medical Center of the PLA General Hospital discussed the overall situation of the safety of Chinese herbal medicine and explored practical solutions.
- Combining the distinctive advantages of our hospital’s treatment, we have independently developed a series of innovative Chinese herbal medicines.
Addressing different types of liver diseases, the Fifth Medical Center of the PLA General Hospital (formerly the 302nd Hospital) has developed a series of innovative Chinese herbal medicines (Figure 1). Among them, Liuwei Wuling Pills, Chidan Tuihuang Granules, and Compound Biejia Ruanjian Tablets have unique mechanisms of action and significant therapeutic effects. Liuwei Wuling Pills, a national-level new drug, are mainly used to treat liver damage caused by various factors, with a high rate of liver function recovery. Chidan Tuihuang Granules are the world’s first new drug specifically designed to treat obstructive jaundice liver diseases and liver failure, with a high overall effective rate. Compound Biejia Ruanjian Tablets are the first national-level new drug in China for anti-liver fibrosis and early-stage liver cirrhosis, capable of reversing liver fibrosis and reducing the incidence of liver cancer.
Figure 1. Series of Innovative Chinese Herbal Medicines Developed by Our Hospital(From Speaker’s Presentation)
As the use of traditional Chinese medicine (TCM) has become widespread globally, safety incidents related to TCM have gradually increased. Especially in recent years, some traditionally considered “non-toxic” Chinese herbal medicines have been reported to cause severe adverse reactions, attracting high attention domestically and internationally, and sparking significant controversy. Events such as the 2017 publication in the United States on the “Association between Aristolochic Acid and Liver Cancer,” the Hepatology journal’s report on “Chinese herbs and dietary supplements as the second leading cause of drug-induced liver injury in the United States,” and the Gastroenterology journal’s publication on “Chinese herbs and health foods as the leading cause of drug-induced liver injury in China” have ignited public discussions. We should objectively and rationally address issues related to the safety of Chinese herbal medicine, avoiding exaggeration or disregard and not shying away from the topic.
- Cracking the Safety Puzzle of Chinese Medicine, with Herbal Liver Damage as the Representative Challenge
- Innovating the Understanding of Herbal Toxicity, Proposing a New Safety Perspective for Chinese Medicine
The term “toxicity” in traditional Chinese medicine primarily refers to the inherent or direct toxicity of the drug itself. In the context of limited technological advancements in ancient times, ancient medical practitioners had insufficient knowledge of the delayed, concealed, occasional, specific, and indirect toxicities associated with Chinese herbal medicine. With the development of modern science and technology, there has been a significant shift in the understanding of drug toxicity. Apart from the drug itself, other factors such as the body and the environment also play a crucial role in the occurrence of drug toxicities.
Taking hepatotoxicity as an example, international classifications of drug toxicity include intrinsic toxicity, idiosyncratic toxicity, and indirect toxicity. Chinese herbal medicine, characterized by multiple components, targets, and effects, may exhibit different types of toxicities (Figure 2). Therefore, in addition to intrinsic, idiosyncratic, and indirect toxicities, Chinese herbal medicine may also demonstrate mixed toxicities, simultaneously possessing various types. Hence, we propose a classification of Chinese herbal medicine toxicity into four types: intrinsic, idiosyncratic, indirect, and mixed.
Figure 2. New Classification Model for Chinese Herbal Medicine Toxicity (From Speaker’s Presentation)
In summary, the overall safety situation of Chinese herbal medicine is stable and controllable, showing an upward trend. However, numerous challenges and issues exist. We should objectively and rationally analyze safety concerns related to Chinese herbal medicine, neither underestimating nor exaggerating the situation. The continuous increase in adverse reaction reports related to Chinese herbal medicine does not necessarily indicate a deteriorating safety situation. As awareness of the safety issues deepens, detection methods improve, drug regulatory systems enhance, and societal media attention to Chinese herbal medicine safety increases, safety problems are more likely to be discovered, disclosed, and addressed than in any previous period, reflecting an improvement in China’s drug safety monitoring capabilities.
- Establishing Objective Identification Methods and Standard Systems for Herbal-Originated Damage
Drug-induced liver injury (DILI) has a high misdiagnosis rate, posing an international challenge for objective diagnosis. Currently, there is a lack of specific detection indicators for drug-induced liver injury internationally, and diagnosis typically relies on exclusion. Given the exceptionally complex composition of Chinese herbal medicine and the widespread use of combined traditional Chinese and Western medicine treatments in clinical practice, distinguishing between liver damage caused by the patient’s condition and that caused by drugs, especially Chinese herbal medicine, is challenging. Misdiagnoses, particularly regarding drug-induced liver injury from Chinese herbal medicine, are common.
- Pioneering Objective Identification Method for Drug-Induced Liver Injury: Integrated Evidence Chain Method (iEC)
In response to this challenge, we have recently developed and established an objective diagnostic method for drug-induced liver injury called the “Integrated Evidence Chain Method” (iEC). Building upon international guidelines for diagnosing drug-induced liver injury, integrates techniques and indicators from pharmacognostic traceability identification, quality and safety standards, drug metabolism products, specific biomarkers, and other detection technologies to form a relatively complete evidence chain. Based on the completeness and reliability of the evidence chain, we have formulated a five-level evaluation standard for objective diagnosis of drug-induced liver injury, including Chinese herbal medicine. The levels are “Exclusion – Suspicious – Possible – Likely – Definite.” This enhances the scientific rigor and accuracy of the diagnosis of drug-induced liver injury, particularly from herbal medicine, reducing misdiagnosis rates and avoiding the one-sidedness of habitual thinking of “non-Western medicine, that is, Chinese herbal medicine”.
Integration of Evidence Chain Method
We have applied the Integration of Evidence Chain Method to clarify over a hundred cases of controversies related to liver damage caused by Chinese herbal medicine. This has provided technical demonstrations and consultations for national regulatory authorities, medical institutions, companies, and patients. By using this method, we have, for the first time, confirmed that Polygonum multiflorum (He Shou Wu) may lead to specific liver damage.
- Leading the Formulation of “Society/National/International” Guidelines for Herbal-Related Liver Damage
We have led the development of the “Clinical Diagnosis and Treatment Guidelines for Herbal-Related Liver Damage” by the Chinese Association of Traditional Chinese Medicine. This guideline aims to provide guidance for clinical medical institutions and healthcare professionals. Additionally, we were entrusted by the National Medical Products Administration to lead the formulation of the “Clinical Evaluation Technical Guidance Principles for Herbal-Originated Liver Damage.” This guidance is primarily directed towards departments involved in drug research and development, evaluation, regulation, and production. The formulation of these guidelines has allowed China to gain dominance in the international discourse on setting safety standards for traditional medicine and has contributed to a Chinese solution. With the widespread application and promotion of guidelines for the evaluation and prevention of herbal-related liver damage domestically and internationally, public attitudes towards the toxic side effects of herbal medicine have gradually become more rational, eliminating the fear associated with the term “toxic.” In May 2023, the China Association of Chinese and Western Medicine, the Chinese Association of Traditional Chinese Medicine, and the Chinese Medical Association jointly released the “Clinical Diagnosis and Treatment Guidelines for Herbal-Related Kidney Damage in Integrated Traditional Chinese and Western Medicine,” and Dr. Xiaohe Xiao, as the sole pharmaceutical expert, participated in the writing.
- Utilizing National ADR Monitoring Big Data to Understand China’s DILI “Roots”
In 2022, the first investigation report on adverse reactions related to drug-induced liver injury (DILI) in mainland China was officially released. The analysis indicated that Chinese herbal medicine is not the primary cause of drug-induced liver damage in our country. China’s drug-induced liver damage mainly exhibits two low and three high characteristics: a low proportion of Chinese herbal medicine (absolute value is 4.5%, adjusted to 20% after volume correction); a low benefit-risk ratio for individual varieties; a high variety and high dispersion, with the majority of cases being unforeseen (87%), and a higher proportion of severe and chronic cases. Furthermore, the research data has altered the international understanding of the age composition of the drug-induced liver damage population.
Age and sex distribution of DILI in China after population-adjusted
Top 10 Suspected Hepatotoxic Chemical Drugs in Different Age Groups
- Creating Theoretical and Methodological Analysis of Pharmacological Pathology for Drug-Induced Liver Injury
The team inherits and innovates traditional Chinese medicine thinking, proposing the Drug- Syndrome-Pathology-Toxicology (DSBT) evaluation model. This model studies the differences and patterns of the body’s response to the toxic effects of drugs in normal and different pathological states, comprehensively examining drug safety, and formulating safety risk prevention and control strategies. Using this method, it clarifies the dose-time-toxicity-efficacy relationship of drugs with inherent toxicity in different pathological states and formulates the drug’s safe therapeutic window. It identifies susceptible populations for drug-specific toxic effects or related pathologies or concurrent/compatibility drugs.
Through pharmacological pathology research, it was confirmed that Polygonum multiflorum was unreasonably applied, leading to toxicity. Clinical metabolomics research and pharmacogenomics research also identified metabolic markers and susceptibility genes (HLA-B35:01) for individuals prone to liver damage from Polygonum multiflorum (He Shou Wu). Carriers of HLA-B35:01 had a risk of liver damage more than 8 times higher when taking Polygonum multiflorum (He Shou Wu) (Figure 3). This discovery has been independently and repeatedly validated by multiple third parties and received international acclaim. These research findings not only help elucidate the mechanism of liver damage caused by Polygonum multiflorum but also provide new methods and ideas for the safety assessment of Chinese herbal medicine.
Figure 3. Susceptible Genes for Polygonum multiflorum-Induced Liver Injury (From Presenter’s Slides)
In recent years, research has revealed that Polygonum multiflorum-specific liver injury is synergistically caused by the body’s immune stress state, immune-promoting substances (trans-2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside), and liver injury-susceptible substances (cis-2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside, emodin-8-O-β-D-glucoside, etc.). Based on this, the hypothesis of the “Three Factors Toxic” mechanism of immune-specific liver injury caused by traditional Chinese medicine was proposed for the first time (also known as the “Wood-Oil-Spark” hypothesis): when the body’s immune system is in an excessively activated state (Wood), immune-promoting substances in traditional Chinese medicine (Oil) can further intensify the body’s immune response, increasing the liver’s sensitivity to substances that are prone to liver damage (Spark), leading to damage to liver parenchymal cells and overexpression of inflammatory factors, thereby inducing immune-specific liver injury. The “Three Factors Toxic” mechanism hypothesis has changed the one-sided thinking of the “toxicity of herbal medicine components only” in long-term research on the safety of traditional Chinese medicine and has been verified in a series of Chinese medicine formulations containing Polygonum multiflorum, Psoralea corylifolia, Epimedium, etc.
- Creating a Technical System for Predicting and Controlling the Risk of Herbal Liver Injury
The “Three Factors Toxic” provides new strategies and methods for evaluating and studying specific and indirect toxicity. Based on this, guided by the “systematic identification of targets for treatment” theoretical method, a system for preventing and controlling the risk of herbal source damage from a “people-medicine-use” perspective has been established in three aspects: identifying susceptible populations, personalized precise medication, and quality control of traditional Chinese medicine (Figure 4). This includes creating a method for identifying individuals susceptible to traditional Chinese medicine-specific liver injury based on disease-syndrome-biomarker, establishing a multi-dimensional quality control system for traditional Chinese medicine, and developing precise compatibility control methods based on the interaction of effects, components, and targets.
Figure 4. “People-Use-Drug” Prevention and Control Strategy
Based on the three-dimensional prevention and control strategy, the team led the formulation of the “Safety Medication Guide for Polygonum multiflorum” by the Chinese Association of Traditional Chinese Medicine. The relevant recommendations were adopted by the national regulatory authorities, preventing more than 600 related traditional Chinese medicine products containing Polygonum multiflorum from being wrongly “blacklisted.” The number of adverse reactions related to Polygonum multiflorum-induced liver injury dropped by more than 90% from its peak, while the production and sales of Polygonum multiflorum and related products remained unaffected. The effective resolution of the Polygonum multiflorum-induced liver injury issue is hailed as a representative success story of scientific supervision for the safety of traditional Chinese medicine. The achievements in preventing and controlling Polygonum multiflorum-induced liver injury have been incorporated into several international authoritative guidelines or consensus.
In addition, the team developed the first shared and co-created drug vigilance platform, “SafeMedWise,” and initiated the establishment of the first international cooperation alliance for research on the safe use of traditional medicines, assisting multiple departments including the National Medical Products Administration in scientifically resolving a series of significant safety events related to traditional Chinese medicine.
Conclusion
In summary, precision medication can make traditional Chinese medicine a guardian of the human “chemical factory.” By creating a critical technical system for the risk assessment and control chain of traditional Chinese medicine safety, the team effectively addressed the safety challenges of traditional Chinese medicine, represented by herbal-induced liver injury. This has propelled the risk management of traditional Chinese medicine safety from passive response to active prevention and control.
