Herb-induced Liver Injury Research Articles

Chinese Herbal Medicine Hepatotoxicity: The Evaluation and Recognization Based on Large-scale Evidence Database.

Background: Due to the special nature of Chinese Herbal medicine and the complexity of its clinical use, it is difficult to identify and evaluate its toxicity and resulting herb induced liver injury (HILI).Methods: First, the database would provide full profile of HILI from the basic ingredients to clinical out-comes by the most advanced algorithms of artificial intelligence, and it is also possible that we can predict possibilities of HILI after patients taking Chinese herbs by individual patient evaluation and prediction. Second, the database would solve the chaos and lack of the relevant data faced by the current basic re-search and clinical practice of Chinese Herbal Medicine. Third, we can also screen the susceptible patients from the database and thus prevent the accidents of HILI from the very beginning.Results: The Roussel Uclaf Causality Assessment Method (RUCAM) is the most accepted method to evalu-ate DILI, but at present before using the RUCAM evaluation method, data resource collection and analysis are yet to be perfected. Based on existing research on drug-metabolizing enzymes mediating reactive me-tabolites (RMs), the aim of this study is to explore the possibilities and methods of building multidimen-sional hierarchical database composing of RMs evidence library, Chinese herbal evidence library, and indi-vidualized reports evidence library of herb induced liver injury HILI.Conclusion: The potential benefits lie in its ability to organize, use vast amounts of evidence and use big data mining techniques at the center for Chinese herbal medicine liver toxicity research, which is the most difficult key point of scientific research to be investigated in the next few years.

A conjugated-polymer-based ratiometric nanoprobe for evaluating in-vivo hepatotoxicity induced by herbal medicine via MSOT imaging

Herbal medicines are widely used around the world, while some of them are associated with adverse effects like herb-induced liver injury due to oxidative/nitrosative stress resulted from hepatically-generated ROS/RNS. It is of significance to accurately evaluate herbal-medicine-induced hepatotoxicity, since it would help provide effective monitoring method of the safety of herbal remedies. Herein we designed a ratiometric nanoprobe for in vivo imaging hepatic injury induced by herbal medicine (polygonum multiflorum, PM) via specifically responding to NO generated in liver by PM, and with MSOT imaging the precise location of liver injury can be identified. The liposomal nanoprobe consists of a responsive dye (IX-2NH2) which could specifically respond to NO and the diketopyrrolopyrrole-based conjugated polymer (DPP-TT) as the internal reference. Thus we can realize ratiometric optoacoustic detection of herbal-medicine-induced liver injury with 3D information in mouse model in a noninvasive way.

Battle Over Herb-Induced Liver Injury: Low Prevalence Confirmed through Secondary Evaluation and Research Team's Clarifying Rebuttal to Unwarranted Public Claims.

Battle Over Herb-Induced Liver Injury: Low Prevalence Confirmed through Secondary Evaluation and Research Team's Clarifying Rebuttal to Unwarranted Public Claims.

Drug-Induced Liver Injury: Highlights of the Recent Literature.

Drug-induced liver injury (DILI), herbal-induced liver injury, and herbal and dietary supplement (HDS)-induced liver injury are an important aspect of drug safety. Knowledge regarding responsible drugs, mechanisms, risk factors, and the diagnostic tools to detect liver injury have continued to grow in the past year. This review highlights what we considered the most significant publications from among more than 1800 articles relating to liver injury from medications, herbal products, and dietary supplements in 2017 and 2018. The US Drug-Induced Liver Injury Network (DILIN) prospective study highlighted several areas of ongoing study, including the potential utility of human leukocyte antigens and microRNAs as DILI risk factors and new data on racial differences, the role of alcohol consumption, factors associated with prognosis, and updates on the clinical signatures of autoimmune DILI, thiopurines, and HDS agents. Novel data were also generated from the Spanish and Latin American DILI registries as well as from Chinese and Korean case series. A few new agents causing DILI were added to the growing list in the past 2years, including sodium-glucose co-transporter-2 inhibitors, as were new aspects of chemotherapy-associated liver injury. A number of cases reported previously described hepatotoxins confirmed via the Roussel Uclaf Causality Assessment Method (RUCAM; e.g., norethisterone, methylprednisolone, glatiramer acetate) and/or the DILIN method (e.g., celecoxib, dimethyl fumarate). Additionally, much work centered on elucidating the pathophysiology of DILI, including the importance of bile salt export pumps and immune-mediated mechanisms. Finally, it must be noted that, while hundreds of new studies described DILI in 2017-2018, the quality of such reports must always be addressed. Björnsson reminds us to remain very critical of the data when addressing the future utility of a study, which is why it is so important to adhere to a standardized method such as RUCAM when determining DILI causality. While drug-induced hepatotoxicity remains a diagnosis of exclusion, the diverse array of publications that appeared in 2017 and 2018 provided important advances in our understanding of DILI, paving the way for our improved ability to make a more definitive diagnosis and risk assessment.

The Development of a Database for Herbal and Dietary Supplement Induced Liver Toxicity.

The growing use of herbal dietary supplements (HDS) in the United States provides compelling evidence for risk of herbal-induced liver injury (HILI). Information on HDS products was retrieved from MedlinePlus of the U.S. National Library of Medicine and the herbal monograph of the European Medicines Agency. The hepatotoxic potential of HDS was ascertained by considering published case reports. Other relevant data were collected from governmental documents, public databases, web sources, and the literature. We collected information for 296 unique HDS products. Evidence of hepatotoxicity was reported for 67, that is 1 in 5, of these HDS products. The database revealed an apparent gender preponderance with women representing 61% of HILI cases. Culprit hepatotoxic HDS were mostly used for weight control, followed by pain and inflammation, mental stress, and mood disorders. Commonly discussed mechanistic events associated with HILI are reactive metabolites and oxidative stress, mitochondrial injury, as well as inhibition of transporters. HDS–drug interactions, causing both synergistic and antagonizing effects of drugs, were also reported for certain HDS. The database contains information for nearly 300 commonly used HDS products to provide a single-entry point for better comprehension of their impact on public health.

Predictors of poor outcomes in 488 patients with herb-induced liver injury.

Herb-induced liver injury (HILI) can lead to chronic liver injury, liver transplantation, or even death. This study aimed to identify the predictors of poor HILI outcomes, especially chronic HILI. Clinical data of 488 patients with HILI were retrospectively analyzed from a Chinese center between January 2010 and January 2014. Logistic regression and C-statistic were used to identify risk factors and prognostic models for HILI outcomes. In all patients, 69 (14.1%) developed chronic HILI, and 20 (4.1%) died due to liver injury or underwent liver transplantation. To predict the fatal HILI prognosis, the model for end-stage liver disease (MELD) with a C-statistic of 0.981 (95%CI 0.968-0.995) was better than Hy's law (C-statistic 0.569; 95%CI 0.449-0.689). The latency, course of peak alanine aminotransferase decreasing >50% after discontinuation of herb application, peak triglyceride value, and platelet count at liver injury onset were identified as independent risk factors for chronicity with the adjusted odds ratios of 1.268 (95% confidence interval [CI] 1.034-1.554), 2.303 (95%CI 1.588-3.340), 0.580 (95%CI 0.343-0.978), and 0.183 (95%CI 0.091-0.368), respectively. A prognostic model for chronic HILI based on these four factors yielded the best prediction with a C-statistic of 0.812 (95%CI 0.755-0.868), compared with MELD (C-statistic 0.506; 95%CI 0.431-0.581) and Hy's law (C-statistic 0.418; 95%CI 0.343-0.492). Model for end-stage liver disease can be used to predict the fatal prognosis of HILI. A long latency, slow recovery, and low triglyceride value and platelet counts are important determinants for chronic HILI.

Liver-specific metabolomics characterizes the hepatotoxicity of Dioscorea bulbifera rhizome in rats by integration of GC-MS and 1H-NMR

Ethnopharmacological relevanceDioscorea bulbifera rhizome (DBR), one type of herbal medicine, is extensively used in both Indian and Chinese system of traditional medicine. It has been effective in treating various diseases, such as sore throat, struma, and tumors. However, more and more clinical investigations have suggested that DBR can cause liver injury. Aim of the studyIn the present study, we aimed to characterize the corresponding molecular changes of liver dysfunction and reveal overall metabolic and physiological mechanisms of the subchronic toxic effect of DBR. Materials and methodsA liver-specific metabolomics approach integrating GC-MS and 1H-NMR was developed to assess the hepatotoxicity in rats after DBR exposure for 12 weeks. Multivariate statistical analysis and pattern recognition were employed to examine different metabolic profiles of liver in DBR-challenged rats. ResultsA total of 61 metabolites were screened as significantly altered metabolites, which were distributed in 43 metabolic pathways. The correlation network analysis indicated that the hub metabolites of hepatotoxicity could be mainly linked to amino acid, lipid, purine, pyrimidine, bile acid, gut microflora, and energy metabolisms. Notably, purine, pyrimidine, and gut microflora metabolisms might be novel pathways participating in metabolic abnormalities in rats with DBR-triggered hepatic damage. ConclusionsOur results primarily showed that the liver-specific metabolic information provided by the different analytical platforms was essential for identifying more biomarkers and metabolic pathways, and our findings provided novel insights into understand the mechanistic complexity of herb-induced liver injury.

Risk factors analysis and security application discussion of Polygonum multiflorum based on retrospective study

In recent years，hepatotoxicity problem of Polygonum multiflorum has caused high attention. Domestic scholars also explored the causes of liver damage caused by it. For example, the establishment of guideline for diagnosis and treatment of herb-induced liver injury, and the theory about relationship between hepatocyte toxicity and chemical composition, solvents, processing, use and pathological basis of patients and so on. To try to combine theory with practice，author analyzed risk factors about the case reports of P. multiflorum causing liver damage, and made some suggestions on P. multiflorum about individualized application, drug selection and requirements for taking. This for providing reference for the safe use of P. multiflorum.

Integrated Metabolomics and Proteomics Approach To Identify Metabolic Abnormalities in Rats with Dioscorea bulbifera Rhizome-Induced Hepatotoxicity

Previous studies haveshown that Dioscorea bulbifera rhizome (DBR) can induce hepatotoxicity in clinical practice. However, its underlying mechanisms remain largely unexplored. In the present study, we investigated the global effect of DBR exposure on the proteomic and metabolomic profiles in rats over a 12-week administration using an integrated proteomics and metabolomics approach. The abundance of 1366 proteins and 58 metabolites in the liver of rats after subchronic exposure to DBR was dose-dependently altered. The results indicated that DBR mainly damaged hepatic cells through the aberrant regulation of multiple systems mainly including purine metabolism, pyrimidine metabolism, taurine and hypotaurine metabolism, and bile acid metabolism. Notably, the deregulated proteins including Pnp, Dpyd, Upp1, and Tymp and the differential metabolites including uridine, uracil, cytidine, thymine, adenine, adenosine, adenosine 3'-monophosphate, and deoxycytidine were well correlated to purine and pyrimidine metabolism, which might be novel pathways involved in metabolic abnormalities in rats with DBR-induced liver damage. Collectively, these findings not only contributed to understanding the mechanisms underlying the hepatotoxicity of DBR, but also illustrated the power of integrated proteomics and metabolomics approaches to improve the identification of metabolic pathways and biomarkers indicative of herb-induced liver injury.

Herb-Induced Liver Injury With Cholestasis and Renal Injury Secondary to Short-Term Use of Kratom (Mitragyna speciosa)

Herb-Induced Liver Injury With Cholestasis and Renal Injury Secondary to Short-Term Use of Kratom (Mitragyna speciosa)

Acute liver injury following Garcinia cambogia weight-loss supplementation: case series and literature review.

Herbal weight-loss supplements are sold as self-medication products, and are often used under the misconception that their natural origin guarantees their safety. Food supplements are not required to provide any benefit/risk profile evaluation before marketing; however, possible risks associated with use of herbal extracts in food supplements are becoming more and more documented in the literature. Some herbs are listed as the leading cause of herb-induced liver injury, with a severe or potentially lethal clinical course, and unpredictable herb-drug interactions. Garcinia cambogia (GC) extract and GC-containing products are some of the most popular dietary supplements currently marketed for weight loss. Here, we present four cases of acute liver failure in women taking GC extract for weight loss, and a literature review of clinical evidences about hepatic toxicity in patients taking dietary supplements containing GC extract.

Liver enzyme abnormalities of inpatients with rheumatic diseases: A 10-year retrospective study in a Korean medicine hospital.

Herbal medicines have been used as a treatment option for rheumatic disease (RD), but they often produce liver enzyme abnormality. This study examines the incidence of herb-induced liver injury (HILI) and the relationship between risk factors and liver enzyme abnormality (LEA) in inpatients with RD. HILI was analyzed using the Roussel Uclaf causality assessment method liver injury criteria and causality assessment. Multivariable analysis was performed to assess the relationship between patient characteristics and LEA in RD. The features of LEA were also examined in each RD. Among 352 patients included in this study, 105 patients showed LEA on admission, of which 6 had fulfilled the Roussel Uclaf causality assessment method criteria. The incidence risks of LEA and HILI were 12.55% and 0.58%, respectively. Multivariable analysis showed that LEA on admission and occasional use of alcohol could be risk factors for LEA on follow-up. In an additional analysis with each RD, all rheumatoid arthritis patients with LEA were taking nonsteroidal anti-inflammatory drugs, steroids, and disease-modifying antirheumatic drugs, and 4 out of 5 gout patients with LEA were taking steroids. The use of herbal medicine in RD is relatively safe. However, regular monitoring of liver enzyme tests and examination of alcohol consumption are required.

Herb-Induced Liver Injury: A Global Concern.

Chinese medicine and herb medicine though used to treat liver diseases are an important cause of liver injury. Many phytochemicals have the potential to injure the liver, some in a dose-related fashion and more often in an idiosyncratic fashion, meaning occurrence is uncommon to rare in the population using these treatments. As is the case with pharmaceuticals, the phytochemicals are usually tolerated despite either no or mild transient subclinical injury but rarely in some susceptible patients cause moderate to severe liver injury which is likely mediated by the adaptive immune system.

Herb-Induced Liver Injuries in Developing Nations: An Update.

The last few decades have seen a rise in the use of herbal supplements, natural products, and traditional medicines. However, there are growing concerns related to the safety and toxicities of these medicines. These herbal medicines are associated with complications such as liver damage with a high incidence of mortalities and morbidities. Clinical manifestations range from asymptomatic cases with abnormal liver functions tests to sudden and severe liver failure necessitating liver transplantation. This work aimed to review the etiology, risk factors, diagnosis, clinical manifestations and selected clinical case reports of herbal hepatotoxicity in developing nations. PubMed and Google Scholar searches were undertaken to identify relevant literature. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches. Little data exists on clinical cases of herb-induced liver injury in some developing countries such as Nigeria, as most incidences are either not reported to health care providers or reports from hospitals go unpublished. Studies in Nigeria have highlighted a possible correlation between use of herbs and liver disease. In Uganda, and association between the use of traditional herbal medicine with liver fibrosis in HIV-infected and non-HIV patients was demonstrated. Reports from China have revealed incidences of acute liver failure as a result of herbal medicine use. The actual incidence and prevalence of HILI in developing nations remain largely unknown due to both poor pharmacovigilance programs and non-application of emerging technologies. Improving education and public awareness of the potential risks of herbals and herbal products is desirable to ensure that suspected adverse effects are formally reported. There is need for stricter regulations and pre-clinical studies necessary for efficacy and safety.

Metabolomics Used in Herb-Induced Liver Injury

Metabolomics Used in Herb-Induced Liver Injury

Traditional Chinese Medicine and Herb-induced Liver Injury: Comparison with Drug-induced Liver Injury.

Cases of suspected herb-induced liver injury (HILI) caused by herbal Traditional Chinese Medicines (TCMs) and of drug-induced liver injury (DILI) are commonly published in the scientific literature worldwide. As opposed to the multiplicity of botanical chemicals in herbal TCM products, which are often mixtures of several herbs, conventional Western drugs contain only a single synthetic chemical. It is therefore of interest to study how HILI by TCM and DILI compare with each other, and to what extent results from each liver injury type can be transferred to the other. China is among the few countries with a large population using synthetic Western drugs as well as herbal TCM. Therefore, China is well suited to studies of liver injury comparing drugs with TCM herbs. Despite some concordance, recent analyses of liver injury cases with verified causality, using the Roussel Uclaf Causality Assessment Method, revealed major differences in HILI caused by TCMs as compared to DILI with respect to the following features: HILI cases are less frequently observed as compared to DILI, have a smaller proportion of females and less unintentional rechallenge events, and present a higher rate of hepatocellular injury features. Since many results were obtained among Chinese residents who had access to and had used Western drugs and TCM herbs, such ethnic homogeneity supports the contention that the observed differences of HILI and DILI in the assessed population are well founded.

"OxyElite Pro" Induced Fulminant Hepatotoxicity

Around 35% of adults or more are overweight according to a report by Global Health Observatory (GHO). In the absence of proven medical therapeutics, the use of dietary supplements to effect weight loss has increased and under much less scrutiny by regulatory agencies like the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). For many, these approaches represent apparent alternatives to failed attempts at weight loss with the use of more conventional approaches [1]. Hepatotoxicity from supplements is a growing problem while the internet facilitates obtaining these agents across national regulatory boundaries. OxyElite Pro capsules are sold as a dietary supplement for weight loss and ‘’super thermogenic’’ agent (Figure1A & B). According to the manufacture, the proposed mechanism of action is ‘fat burning via the contained ingredients which are: Rauwolfia Canescens, Thyroxine (T4) and Triiodothyronine (T3), Bauhinia Purpurea Trypsin Inhibitor (BPLTI), Bacopa monnieri, Geranium which contains a powerful constituent known as 1,3-Dimethylamylamine (DMAA), Cirsium Oligophyllum, and Caffeine’. A more recent formula of OxyElite Pro released in late 2012 contained a new ingredient, Aegeline. We describe a case of acute liver failure in an otherwise young healthy female after taking the newer OxyElite Pro formula to lose weight. Keywords: OxyElite Pro, Hepatotoxicity, acute liver failure, fulminant, herbal induced liver injury

Guidelines for the Diagnosis and Management of Herb-Induced Liver Injury.

Herb-induced liver injury (HILI) is a type of adverse drug reactions related to using Chinese medicine (CM) or herbal medicine (HM), and is now a growing segment of drug-induced liver injury (DILI) worldwide. Owing to the complicated compositions and miscellaneous risk factors associated with the clinical usage of CM or HM, it is more challenging to diagnose and manage HILI than DILI. In the present guideline issued by the China Association of Chinese Medicine (CACM), the authors present an evidence chain-based workflow with 9 structured judgment criteria for diagnosing HILI. The 3 diagnostic ending points-suspected diagnosis, clinical diagnosis, and confirmed diagnosis-could be reached according to the length of the evidence chain acquired in the structured diagnostic workflow. Either identifying the species of CM or HM or excluding adulterations and toxin contaminants was strongly recommended to improve the level of evidence for a clinical diagnosis of HILI. In addition, the authors report that the improper use of CM, which violates the general law of CM theory, is one of the most important factors that contributes to HILI and should be avoided. By contrast, based on syndrome differentiation, some CM can also be used to treat HILI if used in accordance with the general law of CM theory. Therefore, 9 recommendations are put forward in this guideline.

Drug-Induced Liver Injury: Why is the Roussel Uclaf Causality Assessment Method (RUCAM) Still Used 25Years After Its Launch?

Launched in 1993 and partially based on the results of an international consensus meeting organized under the auspices of the Council of International Organizations of Medical Sciences (CIOMS), the Roussel Uclaf Causality Assessment Method (RUCAM) is the most used causality assessment tool worldwide for the diagnosis of drug-induced liver injury (DILI) and herb-induced liver injury (HILI) in a large number of epidemiological studies, case reports, and case series. The 25-year experience of RUCAM use confirmed that the success was due to its objective, standardized, and liver-injury-specific approach structured with defined key elements derived from a series of DILI cases with positive rechallenge. Using this series, the validation procedure avoided arbitrary definitions and confirmed scores to key items. The algorithm provides a quantitative causality grading of highly probable, probable, possible, unlikely, or excluded relationship between the liver injury and the suspected product(s). Despite challenges, prospective use of RUCAM fosters case data completeness and transparent causality adjudication in real time, as opposed to subjective opinion resulting from several rounds by experts lacking defined key elements and scores. In 2016, RUCAM was updated with specification of alcohol use and Hepatitis E Virus (HEV) biomarkers and simplified item handling to further reduce inter-observer variability. RUCAM-based probable and highly probable DILI and HILI cases are essential for the detection of new hepatotoxins, confirmation of new biomarkers, description of clinical features and risk factors, and determination of incidence in pharmacoepidemiological studies. This article is intended to encourage systematic use of sophisticated causality assessment methods such as RUCAM to improve DILI and HILI case evaluation and to increase confidence in published cases.

Guidelines for clinical diagnosis and treatment of herb-induced liver injury

In recent years, the issues related to herb-induced liver injury (HILI) have received much concern. Its clinical diagnosis is much difficult than that of Western medicine-induced liver injury due to its complicated drug combination and multiple constituents. Moreover, it is also correlated with physiques, inheritance and basic diseases. China Association of Chinese Medicine has released the first standards for HILI diagnosis and treatment technology in 2016, namely Guidelines for clinical diagnosis of herb-induced liver injury (hereinafter referred to as the Guidelines). The diagnostic processes with different diagnostic results were explained in this paper to help clinicians, particularly liver specialists, in diagnosing liver diseases by applying the operation of the Guidelines.