Herbal Medicine-Associated Liver Injury (HILI) is a common cause of drug-induced liver injury (DILI) and adverse reactions of Chinese herbal medicine. Among them, there are various forms of herbal medicines, including marketed Chinese medicine preparations, Chinese medicine decoction pieces for clinical use, Chinese medicine formula granules, Chinese medicine extracts, folk herbal medicines, ethnic medicines and health products containing Chinese medicine. The causes and clinical manifestations of HILI are complex and diverse, involving the quality, processing, and application of Chinese herbal medicines, as well as physical constitution and underlying diseases. Although the treatment principles of HILI are basically the same as those of DILI, there are many challenges to the risk management and prevention of HILI. Based on the progress of clinical research in recent years and the author's relevant observation experience, this article reviews the risk management, preventive measures and clinical treatment of HILI, in order to provide a reference for promoting the safe use of Chinese herbal medicine.
1. HILI risk management and prevention
Detecting the risk signals of liver injury and timely and reasonable preventive treatment are the keys to preventing the occurrence of HILI events. In addition to Chinese patent medicine products, there are still a large number of decoction pieces, ointments, in-hospital preparations, Chinese medicine ingredient preparations, Chinese medicine tea substitutes, etc. In general, cases of severe DILI may be reported very rarely in pre-market clinical trials, but if the safety data of clinical trials can be properly analyzed, it is possible to evaluate the relevant evidence or signals that non-serious DILI case findings may lead to severe DILI, and the pre-research data that have a suggestive effect on the risk of DILI are mainly derived from the non-clinical data of drugs, pre-clinical study data, post-marketing data, and drug information with the same mechanism of action. For other Chinese herbal medicine products that are not proprietary Chinese medicines, the whole process from quality control to clinical application is also required for risk control and prevention. The planting and processing process of Chinese herbal medicines are important risk factors for the occurrence of HILI, and the same variety of Chinese medicine from different origins can cause differences in composition (how to multiflorum multiflori), improper processing process of traditional Chinese medicine decoction pieces, pesticide residues in the planting process of medicinal materials, heavy metals and chemical fertilizers in soil and water sources, pollution and other factors will increase the possibility of liver toxicity. For clinical application, it is necessary to pay more attention to safety education, reasonable compatibility and medication, regular monitoring, prevention and treatment.
1.1 Safety education and awareness-raising
Due to the misconception that herbal medicines and related products are "natural and non-toxic", most people often lack vigilance about the risk of liver damage caused by Chinese herbal medicines, and the resulting liver damage also constitutes one of the main causes of DILI in Asian countries. Therefore, it is necessary to strengthen public health education on the safe use of Chinese herbal medicines, and avoid the public from collecting, purchasing and taking Chinese herbal medicines on their own, especially Chinese herbal medicines that are not homologous to food and medicine. It is necessary to objectively understand the hepatotoxicity and adverse reactions of Chinese herbal medicines and dietary supplements: (1) Chinese herbal medicines, including health products and dietary supplements, are hepatotoxic; (2) Toxic traditional Chinese medicines can also be attenuated or non-toxic if they are effectively controlled; (3) Non-toxic traditional Chinese medicine may also lead to ineffective treatment or risk of liver toxicity if used irrationally. If a long course of treatment or a combination of drugs is required, the public is encouraged to take the initiative to consult a medical professional, and the doctor should also take the initiative to ask or encourage the patient to inform the patient of the exposure history of the relevant Chinese herbal products.
1.2 Rational use of drugs to avoid occurrence
The irrational use of Chinese herbal medicines, Chinese herbal decoction pieces, Chinese herbal extracts, Chinese herbal formula granules, Chinese patent medicines and other products also leads to an increase in the risk of HILI: (1) The combination of formulas is unreasonable or there are contraindications to compatibility. (2) Prescription mismatch, off-indication, overdose, repeated medication, over-treatment, etc., especially the repeated use of Chinese patent medicine and Chinese herbal medicine decoction pieces, and between Chinese patent medicine and Chinese patent medicine, can lead to an increase in the dose of a single drug, thereby increasing the risk of HILI. Most of the proprietary Chinese medicines and decoctions are compound formulas, and their ingredients are extremely complex and the drug interactions between different components are often unclear, which is also one of the important reasons for the adverse reactions of Chinese herbal medicines, including the risk of HILI. (3) Chinese herbal medicine products are often used in combination with chemical drugs and biological products, and the interactions between these traditional Chinese medicines and chemical drugs and between traditional Chinese medicine and health food are very complex, which may cause systemic pharmacokinetic changes by changing the absorption, distribution, metabolism and excretion of medicinal ingredients, resulting in adverse reactions including liver and kidney toxicity. Therefore, it is important preventive measures to avoid the hepatotoxicity associated with Chinese herbal medicines by determining the rationality of the compatibility of traditional Chinese medicine formulas, avoiding the contraindications of traditional Chinese medicine such as "eighteen antis" and "nineteen fears" of traditional Chinese medicines, avoiding the irrational use of Chinese herbal medicines such as over-indication (including the wrong prescription syndrome), over-dosage and over-treatment course, minimizing unnecessary combination drugs (especially avoiding the combination and repeated use of different traditional Chinese medicine products), and scientifically evaluating the benefits/risks of the single or combined application of traditional Chinese medicine products. In addition, when taking drugs with potential liver injury risks, it is necessary to fully investigate the effects of factors such as immunity, genetics, underlying diseases, and special populations (such as advanced age, children, and pregnant women) on HILI; Websites such as the United States Food and Drug Administration (FDA), LiverTox, and HepaTox document a wealth of resources for drug hepatotoxicity information, and provide online access to information documents such as drug labels and drug inserts and monitoring recommendations, which can be helpful in guiding clinicians in identifying and making judgments.
1.3 Regular monitoring and early detection
Whether in the clinical trial stage or in the whole process of using traditional Chinese medicine products after marketing, regular monitoring of laboratory biochemical indicators is conducive to the early detection of HILI. It is recommended that all patients who use traditional Chinese medicine preparations containing known hepatotoxic components (such as Tripterygium wilfordii) alone or in combination should include liver biochemical tests such as ALT, AST, ALP, GGT, TBil, PTA, and/or INR before treatment, and evaluate the overall benefit/risk. For patients who have been taking traditional Chinese medicine for a long time, serum liver function tests are required at least every 3 months; Once there are risk signals related to drug-induced liver injury of TCM (i.e., clinical manifestations such as fatigue, gastrointestinal symptoms, and skin itching), liver function should be checked immediately and closely observed. According to the severity of liver injury, determine the monitoring indicators and monitoring frequency (weekly, semi-monthly, monthly, etc.) to continuously observe the changes in liver biochemical indicators, if there is no change in the monitoring indicators or the symptoms disappear after stopping the drug, the monitoring frequency can be reduced as appropriate, and it is recommended to follow up until all abnormal indicators return to normal or reach the baseline level for half a year. For high-risk individuals with underlying liver disease or combined medication, more rigorous laboratory index monitoring should be carried out, and it is recommended to monitor liver function 1~2 times a month during the medication period, and once every 3 months after the liver function returns to normal. Annual hepatic elastography monitoring is also necessary for patients taking hepatotoxic drugs such as methotrexate, alone or in combination, that can cause asymptomatic fibrosis. In addition, all practicing physicians are encouraged to report suspected HILI cases to the National Adverse Drug Reaction Surveillance Database in a timely manner; At present, there is an urgent need to develop a standardized reporting procedure for traditional Chinese medicine-related DILI, so as to optimize and standardize the reporting procedure for traditional Chinese medicine-related DILI.
1.4 Prophylactic medication to prevent liver damage
At present, the DILI guidelines promulgated at home and abroad do not recommend the prophylactic application of anti-inflammatory hepatoprotective drugs to reduce the occurrence of DILI, but the Guidelines for the Diagnosis and Treatment of Anti-tuberculosis Drug-induced Liver Injury (2019 Edition) formulated by the Chinese Medical Association recommend prophylactic hepatoprotective therapy for patients with high-risk factors. Under the guidance of syndrome differentiation and treatment and the principle of "gentlemen, ministers and envoys", traditional Chinese medicine has a long tradition and advanced experience in the prevention and treatment of HILI. Zhang Zhongjing's "Treatise on Typhoid Fever and Miscellaneous Diseases" contains 112 prescriptions, of which 70 prescriptions are compatible with licorice, in order to "reconcile all medicines", suggesting that traditional Chinese medicine can prevent the occurrence of adverse reactions such as HILI through compatibility. Under the guidance of modern medical theories and methods, the processing and compatibility of traditional Chinese medicine to reduce toxicity and increase (preservation) of medicinal properties have been continuously improved and innovated: Shenghe Polygonum multiflorum is compatible with Poria cocos, Evodia officinalis is compatible with licorice, jujube, white peony, Schisandra chinensis, Coptis chinensis, psoralen is compatible with Schisandra chinensis, Rehmannia rehmannia root, Astragalus membranaceus, Salvia miltiorrhizae, etc., Huangyaozi is compatible with Schisandra chinensis, Angelica sinensis, licorice, Scutellaria baicalensis, Phellodendron phellodendron and Half-branched lotus, Tripterygium wilfordii is compatible with licorice, white peony, desmodium, mung bean, Rehmannia rehmannia, crocinin, Paeoniflorin and other glycosides, Epimedium is compatible with ligustrum, The compatibility of neem with white peony, Xanthus with astragalus, tripterygium wilfordii polyglycoside tablets with white peony total glycyrrhizin tablets, compound glycyrrhizin tablets, etc., optimization of the processing process of Polygonum multiflori, and improvement of the dosage form of decoction to pill change, etc., can effectively reduce the liver damage and other adverse reactions of hepatotoxic traditional Chinese medicine. A recent meta-analysis of 18 studies involving 4 270 patients showed that the prophylactic use of proprietary Chinese medicine Liver Protection Tablets reduced the anti-tuberculosis drug DILI. The above measures reflect the unique characteristics and advantages of traditional Chinese medicine in reducing and preventing the occurrence of HILI.
2. Clinical evaluation and treatment of HILI
When HILI occurs, the degree of liver injury should be assessed and treated according to the different conditions. Some patients still have normal or long-term abnormal serum liver function after discontinuation of suspected traditional Chinese medicine, and it is necessary to consider grading and categorical treatment according to the severity of the disease and clinical classification. The overall treatment goals of HILI are consistent with DILI: (1) to promote early recovery from liver injury; (2) prevent the severity or chronicity of liver injury, avoid the occurrence of endpoint events such as acute liver failure or chronic HILI or even liver cirrhosis, and reduce the risk of related death; and (3) reduce the impact of HILI events on the treatment of primary diseases.
2.1 Diagnose the degree of liver injury in a graded manner, and decide whether to discontinue the drug based on the risk-benefit assessment
Whether it is in the process of clinical trials of traditional Chinese medicine or the use of traditional Chinese medicine products after marketing, when HILI occurs, it is necessary to decide whether to discontinue the suspected drug on the basis of fully considering and evaluating the causal relationship of HILI, the detailed information of the drug, the clinical experience accumulated in the past, the patient's underlying diseases and the severity of liver injury, and the risk-benefit ratio. Various countries and regions around the world have formulated corresponding DILI clinical diagnosis and treatment guidelines and specifications, and most of the standards for discontinuation of drugs with suspected liver injury refer to the drug clinical trial withdrawal principles formulated by the FDA, and the discontinuation and treatment of HILI are also applicable. For patients with normal liver function at baseline, the drug should be discontinued if one of the following four conditions occurs: (1) serum ALT or AST >8×ULN; (2) ALT or AST>5×ULN persisting for more than 2 weeks; (3) ALT or AST>3×ULN, and TBil>2×ULN (or INR>1.5); (4) ALT or AST >3×ULN accompanied by fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia (>5%); For patients with abnormal liver function tests at baseline, a comprehensive evaluation should be carried out according to the characteristics of the disease and the above criteria, and reasonable discontinuation criteria should be formulated. In addition, when there is no alternative treatment for the patient, the potential benefits of the drug outweigh the risks, and the expected risks are controllable, the patient can be cautiously re-administered under close monitoring after the patient has been informed of the potential risks of re-medication in detail and informed consent has been obtained; For self-limited HILI with transient elevation of serum liver function, the drug can be continued under close monitoring; However, for patients who still develop liver damage after re-use, the drug should be permanently discontinued. In the "Guidelines for the Clinical Diagnosis and Treatment of Liver Injury Associated with Chinese Herbal Medicine" issued by mainland China in 2016, in addition to stopping the suspected drugs, it also mentions the treatment of reduced medication, but it needs to be comprehensively considered in combination with the patient's condition.
2.2 Determine the type of liver injury and formulate treatment measures based on the severity
Combined with the current evidence-based medical evidence, the drugs commonly involved in the treatment of DILI include hepatocyte protective agents that can scavenge oxygen free radicals, anti-inflammatory, antioxidant, and increase the stability of hepatocyte membranes, anti-cholestatic drugs that regulate bile acid metabolism and promote bile excretion, as well as immunosuppressants, anticoagulants, specific therapeutic drugs, etc., which are also applicable to the treatment of HILI, and the names and mechanisms of the main drugs involved are summarized in Table 1. At present, there is no sufficient evidence to show that the combination of two or more of the above drugs has better efficacy, and the Guidelines for the Diagnosis and Treatment of Drug-induced Liver Injury in China (2023 Edition) do not recommend the combination of two or more hepatocytoprotective agents, but for mixed HILI, the treatment of one hepatocytoprotective agent combined with one anti-cholestasis drug is feasible; Evidence-based medical evidence for the prophylactic treatment of HILI is insufficient and is not recommended.
In addition, according to the severity of HILI, different grades should be treated accordingly: grade 0 without liver damage, the patient can tolerate the exposure to Chinese herbal medicines and their preparations, and no drug treatment is required. Grade 1~2 mild to moderate liver injury can be treated with corresponding hepatocytoprotective agents and/or anti-cholestasis drugs according to the recovery of liver function after discontinuation of the drug. Grade 3~4 severe liver injury or liver failure should be treated with hepatocytoprotective agents combined with anti-cholestasis drugs on the basis of drug discontinuation. If hepatic encephalopathy occurs at the same time, aspartic acid, ornithine can be given, plasma or platelet transfusion is required with severe coagulation dysfunction, and symptomatic treatment such as diuresis can be given with ascites; If severe hypersensitivity reactions with obvious autoimmune signs are present, appropriate doses and courses of glucocorticoids should be given after fully weighing the benefits of treatment and possible adverse effects; In case of acute liver failure or other organ failure related to HILI, artificial liver therapy (plasma exchange, dual plasma molecular adsorption system, etc.) or liver transplantation should be performed in a timely manner. Grade 5 fatal liver injury warrants consideration for emergency liver transplantation.
2.3 Cautious consideration of TCM compound treatment for HILI, avoid re-excitation, and be vigilant against chronicity
There is still a lack of sufficient evidence-based medical evidence on whether HILI can be treated with traditional Chinese medicine combinations. Due to the complexity of the composition of traditional Chinese medicine and the incomplete understanding of the toxic components, the traditional Chinese medicine compound used in the treatment of HILI cannot be ruled out whether it contains the same or similar toxic components, so in order to avoid the occurrence of HILI re-challenge, it is necessary to use the traditional Chinese medicine compound with caution in the treatment of HILI. Traditional Chinese medicine is generally used for a long time, and there may be a history of long-term drug use when HILI occurs, and even if the suspected Chinese medicine is discontinued, there may be a chronic clinical phenotype such as drug toxicity accumulation or drug-induced cholestatic liver injury. In addition, traditional Chinese medicine ingredients can induce autoimmune reactions in the form of haptens, causing drug-induced autoimmune hepatitis, which is also prone to chronicity. Therefore, even if the suspected TCM product has been discontinued, it is necessary to pay attention to long-term follow-up, and for the manifestations of chronic inflammation, fibrosis or portal hypertension, anti-inflammatory, hepatoprotective and anti-liver fibrosis treatments should be actively targeted.
引证本文 Citation
SUN Xin, LUO Qiong, YANG Tao, et al. Management and treatment of liver injury associated with Chinese herbal medicine[J]. Journal of Clinical Hepatobiliary Diseases, 2024, 40(8): 1538-1542