No Incidence of Liver Cancer Was Observed in A Retrospective Study of Patients with Aristolochic Acid Nephropathy.

OBJECTIVE: To assess the risk of aristolochic acid (AA)-associated cancer in patients with AA nephropathy (AAN). METHODS: A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December 2014. Long-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of cancer. The primary endpoint was the incidence of liver cancer, and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to 2014. RESULTS: A total of 337 patients diagnosed with AAN were included in this study. From the initiation of taking AA to the termination of follow-up, 39 patients were diagnosed with cancer. No cases of liver cancer were observed throughout the entire follow-up period, with urinary cancer being the predominant type (34/39, 87.17%). Logistic regression analysis showed that age, follow-up period, and diabetes were potential risk factors, however, the dosage of the drug was not significantly associated with urinary cancer. CONCLUSIONS: No cases of liver cancer were observed at the end of follow-up. However, a high prevalence of urinary cancer was observed in AAN patients. Establishing a direct causality between AA and HCC is challenging.

[Interpretation on Consensus on drug-induced liver injury by CIOMS Working Group:liver injury attributed to herbal and dietary supplements].

With the increase in the medical level, the improvement of adverse drug reaction(ADR) monitoring systems, and the enhancement of public awareness of safe medication, drug safety incidents have been frequently reported. Drug-induced liver injury(DILI), especially liver injury attributed to herbal and dietary supplements(HDS), has globally attracted high attention, bringing great threats and severe challenges to the people for drug safety management such as clinical medication and medical supervision. Consensus on drug-induced liver injury had been published by the Council for International Organizations of Medical Sciences(CIOMS) in 2020. In this consensus, liver injury attributed to HDS was included in a special chapter for the first time. The hot topics, including the definition of HDS-induced liver injury, epidemiological history, potential risk factors, collection of related risk signals, causality assessment, risk prevention, control and management were discussed from a global perspective. Based on the previous works, some experts from China were invited by CIOMS to undertake the compilation of this chapter. Meanwhile, a new causality assessment in DILI based on the integrated evidence chain(iEC) method was widely recognized by experts in China and abroad, and was recommended by this consensus. This paper briefly introduced the main contents, background, and characteristics of the Consensus on drug-induced liver injury. Significantly, a brief interpretation was illustrated to analyze the special highlights of Chapter 8, "Liver injury attributed to HDS", so as to provide practical references for the medical staff and the researchers who worked on either Chinese or Western medicine in China.

[New outlook on safety of traditional Chinese medicine: concept and practice].

Profound changes have taken place in human disease spectrum, constitution spectrum, and drug use behavior, and the safety of traditional Chinese medicine(TCM) faces new trends and problems. In particular, serious adverse reactions/events such as liver injury and kidney injury caused by non-toxic TCM have been frequently reported, overturning people's understanding of TCM safety, and even shaking the public's confidence in the development of TCM. In the new era of globalization, correctly understanding the situation and problems of TCM safety and addressing the dilemmas in safety evaluation and risk prevention of TCM are the key missions to be undertaken by TCM practitioners. This paper suggests that the situation and problems of TCM safety should be viewed objectively and dialectically, and the use standard of TCM should be advanced with the times. Furthermore, this paper puts forward the new conception and methodology of TCM safety(including one innovative understanding, two types of evaluation modes, tri-elements injury hypothesis; four-quadrant risk decision processes, and five-grade safety evidence body) for the first time, hoping to provide new theories, new strategies, new methods and successful examples for solving the safety problems of TCM.

A clinical experience-based Chinese herbal formula improves ethanol-induced drunken behavior and hepatic steatohepatitis in mice models.

BACKGROUND: Bao-Gan-Xing-Jiu-Wan (BGXJW) is a clinical experience-based Chinese herbal formula. Its efficacy, pharmacological safety, targeted function, process quality, and other aspects have met the evaluation standards and the latest requirements of preparations. It could prevent and alleviate the symptoms of drunkenness and alcoholic liver injury clinically. The present work aims to elucidate whether BGXJW could protect against drunkenness and alcoholic liver disease in mice and explore the associated mechanism. MATERIAL AND METHODS: We used acute-on-chronic (NIAAA) mice model to induce alcoholic steatosis, and alcohol binge-drinking model to reappear the drunk condition. BGXJW at indicated doses were administered by oral gavage respectively to analyze its effects on alcoholic liver injury and the associated molecular mechanisms. RESULTS: BGXJW had no cardiac, hepatic, renal, or intestinal toxicity in mice. Alcoholic liver injury and steatosis in the NIAAA mode were effectively prevented by BGXJW treatment. BGXJW increased the expression of alcohol metabolizing enzymes ADH, CYP2E1, and ALDH2 to enhance alcohol metabolism, inhibited steatosis through regulating lipid metabolism, counteracted alcohol-induced upregulation of lipid synthesis related proteins SREBP1, FASN, and SCD1, meanwhile it enhanced fatty acids ß-oxidation related proteins PPAR-α and CPT1A. Alcohol taken enhanced pro-inflammatory TNF-α, IL-6 and down-regulated the anti-inflammatory IL-10 expression in the liver, which were also reversed by BGXJW administration. Moreover, BGXJW significantly decreased the blood ethanol concentration and alleviated drunkenness in the alcohol binge-drinking mice model. CONCLUSIONS: BGXJW could effectively relieve drunkenness and prevent alcoholic liver disease by regulating lipid metabolism, inflammatory response, and alcohol metabolism.

Best Practice in the chemical characterisation of extracts used in pharmacological and toxicological research-The ConPhyMP-Guidelines.

Background: Research on medicinal plants and extracts derived from them differs from studies performed with single compounds. Extracts obtained from plants, algae, fungi, lichens or animals pose some unique challenges: they are multicomponent mixtures of active, partially active and inactive substances, and the activity is often not exerted on a single target. Their composition varies depending on the method of preparation and the plant materials used. This complexity and variability impact the reproducibility and interpretation of pharmacological, toxicological and clinical research. Objectives: This project develops best practice guidelines to ensure reproducibility and accurate interpretations of studies using medicinal plant extracts. The focus is on herbal extracts used in pharmacological, toxicological, and clinical/intervention research. Specifically, the consensus-based statement focuses on defining requirements for: 1) Describing the plant material/herbal substances, herbal extracts and herbal medicinal products used in these studies, and 2) Conducting and reporting the phytochemical analysis of the plant extracts used in these studies in a reproducible and transparent way. The process and methods: We developed the guidelines through the following process: 1) The distinction between the three main types of extracts (extract types A, B, and C), initially conceptualised by the lead author (MH), led the development of the project as such; 2) A survey among researchers of medicinal plants to gather global perspectives, opportunities, and overarching challenges faced in characterising medicinal plant extracts under different laboratory infrastructures. The survey responses were central to developing the guidelines and were reviewed by the core group; 3) A core group of 9 experts met monthly to develop the guidelines through a Delphi process; and. 4) The final draft guidelines, endorsed by the core group, were also distributed for feedback and approval to an extended advisory group of 20 experts, including many journal editors. Outcome: The primary outcome is the "Consensus statement on the Phytochemical Characterisation of Medicinal Plant extracts" (ConPhyMP) which defines the best practice for reporting the starting plant materials and the chemical methods recommended for defining the chemical compositions of the plant extracts used in such studies. The checklist is intended to be an orientation for authors in medicinal plant research as well as peer reviewers and editors assessing such research for publication.

Entecavir plus Biejia-Ruangan compound reduces the risk of hepatocellular carcinoma in Chinese patients with chronic hepatitis B.

BACKGROUND & AIMS: Chronic hepatitis B (CHB) and liver fibrosis are associated with a high risk of hepatocellular carcinoma (HCC) development. We assessed whether entecavir (ETV) plus Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine, can further reduce the risk of HCC in treatment-naïve Chinese patients with CHB and an Ishak fibrosis score of ≥3 points derived from our parent double-blind randomized placebo-controlled trial. METHODS: After a 72-week comparison between ETV+BRC and ETV+placebo treatment, participants were eligible to enter an open-label treatment phase and were followed up every 6 months. The primary [secondary] endpoints were the incidence of HCC [liver-related deaths, non-HCC events, and non-liver-related deaths]. Modified intention-to-treat (mITT), intention-to-treat (ITT), and per-protocol (PP) populations were defined for the time-to-event analysis. RESULTS: A total of 1,000 patients were recruited; the median age was 42.0 years; 69.9% were male and 58.3% were HBeAg positive. In the mITT population, the 7-year cumulative incidence of HCC [liver-related deaths] was 4.7% [0.2%] for ETV+BRC, which was significantly lower than 9.3% [2.2%] for ETV monotherapy (p = 0.008 [p = 0.030]). Notably, ETV+BRC treatment yielded a lower incidence of HCC in those who did not achieve regression of fibrosis at week 72 than ETV monotherapy (p = 0.018). There were no differences in the other 2 secondary endpoints or safety profiles between the groups. Multivariable Cox proportional regression analysis, including the treatment allocation as a parameter, also demonstrated that ETV+BRC treatment was associated with a reduced incidence of HCC. The ITT and PP analyses showed consistent results. CONCLUSIONS: ETV plus BRC combination treatment could further reduce the risk of HCC and liver-related deaths in patients with CHB and advanced fibrosis or cirrhosis, which may have important clinical implications for HCC prevention. LAY SUMMARY: Patients with chronic hepatitis B virus infection are at an increased risk of developing liver cancer (specifically hepatocellular carcinoma [HCC]). While there are effective antiviral treatments that can suppress the virus in chronically infected patients, the risk of HCC remains. Herein, we show that adding a traditional Chinese medicine called Biejia-Ruangan compound to an antiviral reduced the risk of HCC in patients with chronic hepatitis B.

[Cognition innovation of toxicity of Chinese medicine and safe and precise medication].

Traditional Chinese medicine(TCM) has made outstanding contributions to disease prevention and treatment, survival, and reproduction of the Chinese nation. Currently, the inheritance and innovative development of TCM have become a national strategy. However, in recent years, adverse reactions/events of Chinese medicine frequently occurred. In particular, in terms of the safety problem of newly discovered "toxic" Chinese medicine, it is often difficult to answer the question scientifically and develop effective solutions. When facing international public opinions and public questioning, they are often "passively criticized". To solve the difficult problem about the safety of Chinese medicine, we urgently need to make breakthroughs in the cognition of toxicity of Chinese medicine and prevention and control of risks. This research team has been committed to the research on the safety of Chinese medicine for the long term. In particular, in terms of safety evaluation and risk prevention and control of newly discovered "toxic" Chinese medicine, they have made a series of original discoveries. On the basis of the discoveries, they innovated the cognition theory and methods of the toxicity of Chinese medicine, opened up a new field of research on the idiosyncratic toxicity and indirect toxicity of Chinese medicine, and proposed and established the disease-syndrome-based toxicology(DSBT), the model and method of safety evaluation of Chinese medicine related to diseases and syndromes. In light of the theory and methods of DSBT which have been applied to the objective eva-luation and analysis of the mechanism of the hepatotoxicity of Chinese medicine such as Polygoni Multiflori Radix, the mechanism hypothesis of "toxicity due to three causes" of idiosyncratic hepatotoxicity of Chinese medicine was proposed and confirmed. The findings revealed that the substances that induced idiosyncratic or indirect toxicity in Chinese medicine often did not possess definite direct toxi-city. Therefore, this research team proposed the concept of toxicity-related substances(TRS) in Chinese medicine. Based on the mo-dern scientific cognition of toxicity of Chinese medicine, the team proposed the strategy and method of Chinese medicine compatibility to reduce the toxicity based on the component-effect-target interaction to underpin the demonstration of the scientific connotation of toxicity and side effects of "toxic" Chinese medicine and establishment of scientific and effective risk prevention and control strategies. In light of the innovative development of toxicity cognition of Chinese medicine, this study is expected to provide important theoretical guidance and methodological support for scientific evaluation and precise prevention and control of the safety risk of "toxic" Chinese medicine.

Hepatic Organoid-Based High-Content Imaging Boosts Evaluation of Stereoisomerism-Dependent Hepatotoxicity of Stilbenes in Herbal Medicines.

The complexity of chemical components of herbal medicines often causes great barriers to toxicity research. In our previous study, we have found the critical divergent hepatotoxic potential of a pair of stilbene isomers in a famous traditional Chinese herb, Polygonum multiflorum (Heshouwu in Chinese). However, the high-throughput in vitro evaluation for such stereoisomerism-dependent hepatotoxicity is a critical challenge. In this study, we used a hepatic organoids-based in vitro hepatotoxic evaluation system in conjunction with using high content imaging to differentiate in vivo organ hepatotoxicity of the 2,3,5,4'-tetrahydroxy-trans-stilbene-2-O-ß-glucoside (trans-SG) and its cis-isomer (cis-SG). By using such an organoid platform, we successfully differentiated the two stereoisomers' hepatotoxic potentials, which were in accordance with their differences in rodents and humans. The lesion mechanism of the toxic isomer (cis-SG) was further found as the mitochondrial injury by high-content imaging, and its hepatotoxicity could be dose-dependently inhibited by the mitochondrial protective agent. These results demonstrated the utility of the organoids-based high-content imaging approach in evaluating and predicting organ toxicity of natural products in a low-cost and high-throughput way. It also suggested the rationale to use long-term cultured organoids as an alternative toxicology platform to identify early and cautiously the hepatotoxic new drug candidates in the preclinical phase.

Clinical correlation between serum cytokines and the susceptibility to Polygonum multiflorum-induced liver injury and an experimental study.

Polygonum multiflorum (PM), a popular functional food, and a herbal and dietary supplement, is widely used as a tonic in China and East Asia. In recent years, it has attracted great concern for its ability to cause idiosyncratic drug-induced liver injury (IDILI). However, identifying individuals susceptible to IDILI remains challenging. This is a prospective study. For 6 patients whose serum alanine aminotransferase (ALT) levels after consuming PM were abnormally elevated (susceptible group), 15 patients with normal levels of liver injury markers were matched (tolerant group) based on similar baseline characteristics. ProcartaPlex immunoassays were adopted to quantitatively detect 33 serum cytokines in the two groups of patients before consuming PM, to characterize the cytokine profile and screen differential cytokines. Subsequently, the susceptibility of a potential biomarker to regulate PM-induced liver injury was validated in animal models. There were significant differences in the cytokine profiles between the susceptible and tolerant groups, wherein the susceptible patients showed immune perturbation characterized by high expression of multiple inflammatory cytokines, especially the proinflammatory cytokine TNF-α (P = 0.006). Among them, the cytokine TNF-α had the strongest correlation with ALT, where the correlation coefficient was greater than 0.6, and the area under the receiver operating characteristic curve was more than 0.8. Animal experiments revealed that both PM water extract and its susceptibility component of liver injury, cis-stilbene glucoside, could cause liver injury in the mice pre-stimulated using TNF-α. Conversely, administration of the same dose of drugs on control mice did not show any hepatotoxicity. In conclusion, immune perturbation mainly mediated by TNF-α may regulate the susceptibility to PM-induced liver injury. This provides a new perspective for the study of susceptibility to IDILI.

[On indirect actions of Chinese medicines and innovation of indirect-acting Chinese medicines].

The output of high level innovative Chinese medicines(CM) is very rare for a few years, which is in sharp contrast to the reality that antibody drugs, small molecular targeted therapy, antibody-drug conjugate and other innovative drugs have heavy investment and high yield. Acceleration for the research and development of innovative CM drugs obviously relies on breakthrough of the modes of thinking and methodology. Deeply influenced by the thinking of allopathic medicine in Western science system, the mainstream of current basic researches on CM is to find the components and their molecular mechanisms that can directly inhibit or antagonize the target in disease focal. However, it is difficult to explain the mechanism of the reported " active" components in many CMs, since their steady-state concentrations in disease focal are usually significantly lower than the effective concentrations of those components. Therefore, based on the original methodology of CM-systemism and harmonizing medicine, this paper proposed that the mechanism of action of CMs may not be limited to the direct antagonistic effect on the target in disease focal. Instead, it may involve indirect action through the intermediate substances across different organs or systems with a long-distance action pattern.A fundamentally break may be achieved when exploring the mechanism of action of CM active components from the perspective of indirect action. It may also change the thinking of allopathic medicine in the researches of CM and start a new innovative road for the development of indirect-acting CMs.

Herb-Induced Liver Injury Related to Reynoutria multiflora (Thunb.) Moldenke: Risk Factors, Molecular and Mechanistic Specifics.

Herbal medicine is widely used in Asia as well as the west. Hepatotoxicity is one of the most severe side effects of herbal medicine which is an increasing concern around the world. Reynoutria multiflora (Thunb.) Moldenke (Polygonum multiflorum Thunb., PM) is the most common herb that can cause herb-induced liver injury (HILI). The recent scientific and technological advancements in clinical and basic research are paving the way for a better understanding of the molecular aspects of PM-related HILI (PM-HILI). This review provides an updated overview of the clinical characteristics, predisposing factors, hepatotoxic components, and molecular mechanisms of PM-HILI. It can also aid in a better understanding of HILI and help in further research on the same.

Landscape of Hepatobiliary Adverse Drug Reactions Related to Preparations Containing Psoraleae Fructus and Its Application in Pharmacovigilance.

OBJECTIVE: To analyze clinical feature and information of medication to explore the risk signals of preparations containing Psoraleae Fructus (BGZP) related with hepatobiliary adverse drug reactions (ADR), in order to reinforce pharmacovigilance. METHODS: A retrospective study was conducted based on hepatobiliary ADR related with BGZP from the China Adverse Drug Reaction Monitoring System in years from January 2012 to December 2016. Serious and general ADRs were analyzed and assessed. RESULTS: There were 355 cases of hepatobiliary ADR related to BGZP. Both the amount of cases and the proportion of serious ADR showed an increasing growth by years (P<0.05). It was found that 10.43% of 355 cases may be involved with irrational drug use, including overdose, repeated medication, and combination of multiple drugs. There were 190 cases which used BGZP (non-combination), and they were mainly for common in diseases caused by abnormal immune activation (accounting for 40.53% of the total cases). Especially at the age group with the most cases with age of 41-50 years, the cases associated with immunological diseases of female were obviously more than that of male (P<0.05). The latency of hepatobiliary ADR related to BGZP ranged from 1 to 386 days, and the median latency was 27.5 days, along with the range of cumulative dose (0.45-520.02 g) as well as the daily dose (0.09-2.64 g/d) after the conversion. CONCLUSIONS: Cases of hepatobiliary ADR related to BGZP showed significant individual differences, and there was no correlation between drug usage duration and dosage and the occurrence of hepatobiliary ADR. It may be similar with idiosyncratic drug-induced liver injury, and recommended that BGZP should be used with more caution under monitoring liver function, especially in female patients with immunological diseases.

[Anti-inflammatory target prediction of Gentianae Radix et Rhizoma based on network pharmacology and construction of a bioassay method for its quality control].

Based on the heat-clearing and detoxifying effects of Gentianae Radix et Rhizoma, the network pharmacology is mainly used to predict the potential targets of Gentianae Radix et Rhizoma for anti-inflammatory activity and to perform the experimental verification. A method for detecting the biological potency of Gentianae Radix et Rhizoma based on verifiable targets has been established to provide a reference for improving the quality evaluation and control standards of Gentianae Radix et Rhizoma. High performance liquid chromatography can be used to construct chemical fingerprints of different batches of Gentianae Radix et Rhizoma. Constructing a component-target-disease network of Gentianae Radix et Rhizoma for its anti-inflammatory activity was applied to screen potential anti-inflammatory components and related targets of Gentianae Radix et Rhizoma, and to verify the target of Gentianae Radix et Rhizoma by using biological evaluation methods. Detecting the biological potency of different batches of Gentianae Radix et Rhizoma extracts was used to inhibit COX-2 enzyme activity based the verifiable target cyclooxygenase-2(COX-2). The results showed that different batches of Gentianae Radix et Rhizoma accorded with the pharmacopoeia testing regulations, and the chemical fingerprints have a high similarity(similarity>0.93), suggesting that there is no significant difference in the characteristics of the chemical components. Based on network pharmacology predictions, 18 candidate targets were found to have potential direct interactions with the ingredients in Gentianae Radix et Rhizoma. Among them, the most important target is COX-2. Based on the experimental verification of recombinant human COX-2 protease activity inhibition, Gentianae Radix et Rhizoma can inhibit the COX-2 enzyme activity in a dose-dependent manner. It can function with a low concentration(0.75 mg·mL~(-1)), which preliminarily confirmed the accuracy of network pharmacology prediction. The biological potency detection method of Gentianae Radix et Rhizoma based on COX-2 inhibitory activity was optimized and established. The qualitative response parallel line method was used to calculate the biological potency of anti-inflammatory activity, which ranged from 23.04 to 46.60 U·mg~(-1). For network pharmacology prediction, it can screen and clarify the possible targets of traditional Chinese medicine rapidly, which can guide the establishment of a biological evaluation method for the quality of medicinal materials with related activities. Compared with chemical fingerprints, the biological potency testing can better detect quality fluctuations of traditional Chinese medicine.

Study on the Bioassay of Anti-Inflammatory Effects of Fuke Qianjin Capsule Based on COX-2 Inhibiting Activity.

Fuke Qianjin Capsule (FKQJ) is a common TCM compound formula in the treatment of gynecological inflammation-related diseases. This study intends to explore and establish a bioassay method to further improve its quality control. The bioassay method for the determination of anti-inflammatory biopotency was established based on its inhibitory activity on recombinant human cyclooxygenase-2 (COX-2), an active target of FKQJ in the treatment of female pelvic inflammatory disease. We firstly established chemical fingerprint of 20 batches of FKQJ by ultra-high-performance liquid chromatography to identify the components and analyze the chemical similarities. The similarity within different batches of FKQJ was relatively high. The values of similarity of the 19 batches were between 0.973 and 0.995, while one batch's similarity value was 0.813. Celecoxib, a selective inhibitor of COX-2, was chosen as the positive control drug in COX-2 activity assay to establish an anti-inflammatory biopotency detection method based on parallel line test of qualitative response. The methodological investigation showed that the method possessed good repeatability and precision. Secondly, the anti-inflammatory biopotency of 20 batches of FKQJ for inhibiting COX-2 was determined. The results showed that the biopotency of different batches of FKQJ ranged from 676 U/µg to 1310 U/µg, with average value of 918 U/µg and RSD of 16.7%. Based on multiple linear regression analysis, we found that three contents were highly correlated with the anti-inflammatory biopotency, while chlorogenic acid was validated of the strongest anti-inflammatory activity in vitro. Compared with chemical detection, bioassay can better reflect the quality fluctuation of different batches of products and correlate the known pharmacodynamic targets. The supplement of the bioassay method based on chemical evaluation is helpful to improve the quality control ability of Chinese patent medicine and ensure its clinical efficacy is stable and controllable.

Screening of hepatotoxic compounds in Psoralea corylifolia L., a traditional Chinese herbal and dietary supplement, using high-resolution mass spectrometry and high-content imaging.

Owing to the complexity of the composition of herbal and dietary supplements, it is a challenging problem to efficiently screen and identify active or toxic compounds. Psoralea corylifolia L. (PCL) was selected as the subbject to establish a methodology for rapid screening and identification of hepatotoxic compounds. High-content imaging, ultra-performance liquid chromatography and high-resolution mass spectrometry were used in this study to detect the hepatotoxicity and identify unknown compounds in PCL samples. Then, putative toxic compounds which are highly related to hepatotoxicity were screened by spectrum-toxicity correlation analysis, and the toxicity intensity verified by high-content imaging. The maximum nontoxic dose of processed samples with good detoxification effect reduced more than 9 times compared with unprocessed raw medicinal materials. Spectrum-toxicity correlation analysis showed that bavachinin A, bavachin, isobavachalcone and neobavaisoflavone had high correlation with the hepatotoxicity of PCL, and psoralen and isopsoralen had low correlation with hepatotoxicity. This study verified the hepatotoxicity of these six putative compound monomers, proving the results of spectrum-toxicity correlation analysis. Based on the correlation analysis of high-resolution mass spectrometry of detection compounds and high-content imaging of hepatocyte toxicity data, the potential toxic compound of herbal and dietary supplement products can be quickly and accurately screened.

Metabolomics Profiling and Diagnosis Biomarkers Searching for Drug-Induced Liver Injury Implicated to Polygonum multiflorum: A Cross-Sectional Cohort Study.

Aim: The diagnosis of drug-induced liver injury (DILI) remains a challenge and the cases of Polygonum multiflorum Thunb. (PM) induced DILI (PM-DILI) have received much attention This study aimed to identify a simple and high-efficiency approach to PM-DILI diagnosis via metabolomics analysis. Methods: Plasma metabolites in 13 PM-DILI patients were profiled by liquid chromatography along with high-resolution mass spectrometry. Meanwhile, the metabolic characteristics of the PM-DILI were compared with that of autoimmune hepatitis (AIH), hepatitis B (HBV), and healthy volunteers. Results: Twenty-four metabolites were identified to present significantly different levels in PM-DILI patients compared with HBV and AIH groups. These metabolites were enriched into glucose, amino acids, and sphingolipids metabolisms. Among these essential metabolites, the ratios of P-cresol sulfate vs. phenylalanine and inosine vs. bilirubin were further selected using a stepwise decision tree to construct a classification model in order to differentiate PM-DILI from HBV and AIH. The model was highly effective with sensitivity of 92.3% and specificity of 88.9%. Conclusions: This study presents an integrated view of the metabolic features of PM-DILI induced by herbal medicine, and the four-metabolite decision tree technique imparts a potent tool in clinical diagnosis.

[Epidemiological analysis of liver injury related to bone diseases].

A total of 1 392 reports on liver injury associated adverse drug reaction(LI-ADR) related to bone diseases were retrospectively analyzed based on national ADR monitoring system [18.75% of the patients used traditional Chinese medicine(TCM) alone and 68.68% used Western medicine alone]. This kind of cases accounted for 2.5% of all drug-related liver injury adverse reactions, ranking top ten of all drug categories. The number of reported cases and the proportion of serious cases showed an increasing trend from 2012 to 2016. The average age of the patients was(54.2±15.8) years old, and there was little difference in overall gender(male-female 1.04∶1). However, the number of female patients with rheumatoid arthritis was significantly higher than that of male patients(male-female 1∶2.6), while the number of male patients with gout was significantly higher than that of female patients(male-female 7.16∶1). The overall prognosis was good, with the recovery and improvement rate of 85.27%. The time from medication to liver injury varied due to different medicines. The median time to liver injury was 27 days in TCM alone group, later than 11 days in Western me-dicine alone group(P<0.05). Drugs for bone diseases have been one of the important categories for clinical drug-induced liver injury, and the number of reported cases on liver injury caused by drugs for bone diseases is increasing, so we should pay close attention to the safe and rational use of them. The LI-ADRs of male and female were different due to their different diseases, and the latency of adverse reactions in TCM group was generally longer than that in Western medicine group. In clinical medication, liver function should be monitored according to different diseases and characteristics of drugs to prevent the risk of liver injury.