Cases Of Herb-induced Liver Injury Research Articles

A Hidden Cause of Hypertransaminasemia: Liver Toxicity Caused by Chelidonium Majus L.: Report of Two Cases of Herb-Induced Liver Injury and Literature Review.

In instances where individuals manifest elevated transaminase levels without a clearly discernible cause, a comprehensive patient history proves invaluable in unveiling latent triggers. In this report, we present 2 cases of herb-induced liver injury (HILI) characterized by severe hypertransaminasemia attributed to the consumption of Chelidonium majus L. (also known as greater celandine [GC]), an agent considered an alternative therapeutic remedy. Exploring the occurrence and range of clinical manifestations in HILI linked to Chelidonium majus L., while also investigating the potential triggers and predisposing factors for hepatotoxic reactions post Chelidonium majus L. usage, remains challenging due to the absence of definitive laboratory tests to identify the causative agent. Two case reports were detailed, and a systematic literature review using PubMed was conducted including published literature till March 2023. Moreover, a manual search of reference lists of pertinent articles was performed to identify any additional relevant missed publications. In the first case, a 64-year-old woman presented with jaundice, revealing a 1-month history of using GC capsules to manage gallstones. Diagnostic assessment identified HILI, gallstones, and choledocolithiasis, with transaminase levels exceeding 1000 IU/L. After discontinuing GC and receiving intravenous therapy with amino acids and phospholipids, the patient's condition significantly improved. Subsequently, she underwent endoscopic common bile duct stone removal and cholecystectomy. In the second case, a 66-year-old woman presented with elevated liver function test results discovered incidentally during musculoskeletal pain evaluation. Upon further questioning, the patient disclosed regular consumption of GC tea for "health promotion." Following intravenous therapy using amino acids and phospholipids, her transaminase levels returned to normal. The literature review identified 38 cases of HILI associated with GC preparations, primarily in adult women aged 27-77 years, with a predominant reporting location in Germany. Various forms of GC were used, with treatment durations ranging from 1 week to a year. Discontinuation of GC generally led to recovery in these cases. Chelidonium majus L., a potent herb often used in alternative medicine, has significant hepatotoxic potential, requiring physicians to be vigilant in cases of unexplained liver injury.

Idiosyncratic Drug-Induced Liver Injury (DILI) and Herb-Induced Liver Injury (HILI): Diagnostic Algorithm Based on the Quantitative Roussel Uclaf Causality Assessment Method (RUCAM).

Causality assessment in liver injury induced by drugs and herbs remains a debated issue, requiring innovation and thorough understanding based on detailed information. Artificial intelligence (AI) principles recommend the use of algorithms for solving complex processes and are included in the diagnostic algorithm of Roussel Uclaf Causality Assessment Method (RUCAM) to help assess causality in suspected cases of idiosyncratic drug-induced liver injury (DILI) and herb-induced liver injury (HILI). From 1993 until the middle of 2020, a total of 95,865 DILI and HILI cases were assessed by RUCAM, outperforming by case numbers any other causality assessment method. The success of RUCAM can be traced back to its quantitative features with specific data elements that are individually scored leading to a final causality grading. RUCAM is objective, user friendly, transparent, and liver injury specific, with an updated version that should be used in future DILI and HILI cases. Support of RUCAM was also provided by scientists from China, not affiliated to any network, in the results of a scientometric evaluation of the global knowledge base of DILI. They highlighted the original RUCAM of 1993 and their authors as a publication quoted the greatest number of times and ranked first in the category of the top 10 references related to DILI. In conclusion, for stakeholders involved in DILI and HILI, RUCAM seems to be an effective diagnostic algorithm in line with AI principles.

Safety of co-administration of herbal and conventional medicines on liver and kidney function in stroke patients: A single-center retrospective study

BackgroundAlthough herbal medicines (HMs) are widely used worldwide, information concerning their interactions with conventional medicines (CMs) is sparse. In particular, stroke affects a high proportion of elderly people with impaired hepatic and renal function. Stroke is often accompanied by various complications and is commonly treated via the co-administration of HMs and CMs in Asia. PurposeWe aimed to investigate the effects of co-administration of HMs and CMs on liver and kidney function in patients with stroke. We estimated the prevalence of drug-induced liver injury (DILI) or herb-induced liver injury (HILI) and drug-induced acute kidney injury (DIAKI) or herb-induced acute kidney injury (HIAKI) in patients co-administered HMs and CMs. Study designThis was a retrospective study that reviewed the electronic medical records of 401 patients with stroke in a single hospital. MethodsThe prevalence of DILI or HILI and types of liver injury was examined according to abnormal increases in liver tests. The probable causality between drug or herb administration and liver injury was assessed using the Roussel Uclaf Causality Assessment Method. In addition, the prevalence of DIAKI or HIAKI was estimated using the Kidney Disease Improving Global Outcomes acute kidney injury stage criteria and related medical records. ResultsOut of a total of 401 patients, only four (1.0%) developed liver injury. Two cases of DILI (0.5%) and two cases of HILI (0.5%) were reported. Moxifloxacin and ebastine were the CMs that caused hepatotoxicity. Chungpyesagan-tang and Yeoldahanso-tang were the HMs that caused liver toxicity. Even in cases showing severe liver damage, alkaline phosphatase levels remained less than five times the normal value, and liver function test values recovered within 14 days. There were no cases of DIAKI or HIAKI in this cohort. ConclusionThese results suggest that if appropriately prescribed by experts, the co-administration of CMs and HMs is safe and does not adversely affect liver and kidney function in patients with stroke. To support these results, further large-scale multicenter prospective studies and toxicological studies based on the interaction between HMs and CMs are warranted.

Worldwide Use of RUCAM for Causality Assessment in 81,856 Idiosyncratic DILI and 14,029 HILI Cases Published 1993-Mid 2020: A Comprehensive Analysis.

Background: A large number of idiosyncratic drug induced liver injury (iDILI) and herb induced liver injury(HILI) cases of variable quality has been published but some are a matter of concern if the cases were not evaluated for causality using a robust causality assessment method (CAM) such as RUCAM (Roussel Uclaf Causality Assessment Method) as diagnostiinjuryc algorithm. The purpose of this analysis was to evaluate the worldwide use of RUCAM in iDILI and HILI cases. Methods: The PubMed database (1993–30 June 2020) was searched for articles by using the following key terms: Roussel Uclaf Causality Assessment Method; RUCAM; Idiosyncratic drug induced liver injury; iDILI; Herb induced liver injury; HILI. Results: Considering reports published worldwide since 1993, our analysis showed the use of RUCAM for causality assessment in 95,885 cases of liver injury including 81,856 cases of idiosyncratic DILI and 14,029 cases of HILI. Among the top countries providing RUCAM based DILI cases were, in decreasing order, China, the US, Germany, Korea, and Italy, with China, Korea, Germany, India, and the US as the top countries for HILI. Conclusions: Since 1993 RUCAM is certainly the most widely used method to assess causality in IDILI and HILI. This should encourage practitioner, experts, and regulatory agencies to use it in order to reinforce their diagnosis and to take sound decisions.

Herb induced liver injury after using herbal medicine: A systemic review and case-control study.

In Taiwan, traditional herbal medication was included in Taiwan's National Health Insurance (NHI) system since 1996 and in 9 out of 10 hospitals have developed their own departments of traditional medicine. This study aims to address the herb-induced liver injury (HILI) after using herbal medicine on the relationship between age, gender, epidemiology, laboratory data, pathogenesis, mobility, and mortality.We searched the PubMed database with “hepatitis after herbal medicine” and “in human” till 2018 April and returned 163 articles in a systemic review manner. Two cases reports describing in-vitro liver injury were excluded. Reviews and articles without the detailed report, laboratory data and history were excluded from this study. In the end, there were 53 articles enrolled in this study. These enrolled literatures are from France (n = 13), Germany (n = 12), Switzerland (n = 5) United States of America (n = 4), Korea (n = 4), Hong Kong (n = 4), Greece (n = 3), China (n = 2), Canada (n = 1), Italy (n = 1), Thailand (n = 1), Finland (n = 1), Taiwan (n = 1), and Japan (n = 1). The data were analyzed with a commercial statistical software Stata/SE 12.0 program Stata Corporation, College Station, TX, USA. Statistical χ2 tests were performed and the significance was set at a P value of less than .05 (2-tailed).The ages are ranged from 15 to 78 years with the mean ± SD (standard deviation) of 48.3 ± 16.2 years old. The majority of cases are female (n = 37). In elderly, man is more commonly seen than female in HILI (37.5% vs 10.5%, P = .02). Female is vulnerable to cholestatic type of HILI than male (21.1% vs 0.0%, P = .04). Of all the cases in HILI, using pure substance are more commonly seen than mixed substance (P = .02). In gender, male patients have higher alanine aminotransferase (GPT) (IU/L) level in HILI than female ones (1560 ± 819 vs 1047 ± 706, P = .03).In HILI, the female is more commonly seen than male, but less than male in the elderly. The pure substance more often happens to HILI than mixture substance. Female is predominant in the cholestatic type of HILI. The major prevalence of HILI is in Europe rather than Asia. HILI cases in Europe is 2.75-fold than in Asia. This could be due to fewer reports of the herb induced liver injury in Asia compared to Europe. Prevention of HILI is the best policy, because it needs to take 78 ± 59 days to recover.

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.

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.

Hepatotoxicity of monoterpenes and sesquiterpenes.

Public interest in natural therapies has increased significantly over past decades. Herbs and herbal products are extensively consumed worldwide and they are generally considered as safe. However, this may not always be true as many cases of herb-induced liver injury are reported every year. The liver is a frequent target tissue of toxicity from all classes of toxicants as liver structure and function predispose it to high sensitivity to xenobiotics. The present review is focused on the hepatotoxic properties of monoterpenes and sesquiterpenes, plant secondary metabolites that represent the major components of essential oils wildly used in folk medicines, pharmaceutical industry and cosmetics. Most of these terpenes easily enter the human body by oral absorption, penetration through the skin, or inhalation leading to measurable blood concentrations. Several studies showed that some monoterpenes (e.g., pulegone, menthofuran, camphor, and limonene) and sesquiterpenes (e.g., zederone, germacrone) exhibited liver toxicity, which is mainly based on reactive metabolites formation, increased concentration of reactive oxygen species and impaired antioxidant defense. There is a high probability that many other terpenes, without sufficiently known metabolism and effects in human liver, could also exert hepatotoxicity. Especially terpenes, that are important components of essential oils with proved hepatotoxicity, should deserve more attention. Intensive research in terpenes metabolism and toxicity represent the only way to reduce the risk of liver injury induced by essential oils and other terpenes-containing products.

Insights into the molecular mechanisms of Polygonum multiflorum Thunb-induced liver injury: a computational systems toxicology approach.

An increasing number of cases of herb-induced liver injury (HILI) have been reported, presenting new clinical challenges. In this study, taking Polygonum multiflorum Thunb (PmT) as an example, we proposed a computational systems toxicology approach to explore the molecular mechanisms of HILI. First, the chemical components of PmT were extracted from 3 main TCM databases as well as the literature related to natural products. Then, the known targets were collected through data integration, and the potential compound-target interactions (CTIs) were predicted using our substructure-drug-target network-based inference (SDTNBI) method. After screening for hepatotoxicity-related genes by assessing the symptoms of HILI, a compound-target interaction network was constructed. A scoring function, namely, Ascore, was developed to estimate the toxicity of chemicals in the liver. We conducted network analysis to determine the possible mechanisms of the biphasic effects using the analysis tools, including BiNGO, pathway enrichment, organ distribution analysis and predictions of interactions with CYP450 enzymes. Among the chemical components of PmT, 54 components with good intestinal absorption were used for analysis, and 2939 CTIs were obtained. After analyzing the mRNA expression data in the BioGPS database, 1599 CTIs and 125 targets related to liver diseases were identified. In the top 15 compounds, seven with Ascore values >3000 (emodin, quercetin, apigenin, resveratrol, gallic acid, kaempferol and luteolin) were obviously associated with hepatotoxicity. The results from the pathway enrichment analysis suggest that multiple interactions between apoptosis and metabolism may underlie PmT-induced liver injury. Many of the pathways have been verified in specific compounds, such as glutathione metabolism, cytochrome P450 metabolism, and the p53 pathway, among others. Hepatitis symptoms, the perturbation of nine bile acids and yellow or tawny urine also had corresponding pathways, justifying our method. In conclusion, this computational systems toxicology method reveals possible toxic components and could be very helpful for understanding the mechanisms of HILI. In this way, the method might also facilitate the identification of novel hepatotoxic herbs.

Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.

Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved.

Herbal hepatotoxicity: Analysis of cases with initially reported positive re-exposure tests

Positive re-exposure tests are diagnostic hallmarks for hepatotoxicity. To test validity of positive re-exposures in herb induced liver injury. We searched Medline database for cases of herb induced liver injury with positive re-exposures and analysed 34 cases for positive re-exposure test criteria of baseline alanine aminotransferase< 5N before re-exposure, and re-exposure alanine aminotransferase ≥ 2× baseline alanine aminotransferase. Re-exposure test was negative, if baseline alanine aminotransferase< 5N combined with re-exposure alanine aminotransferase< 2× baseline alanine aminotransferase, or if baseline alanine aminotransferase≥ 5N regardless of the re-exposure alanine aminotransferase including no available re-exposure alanine aminotransferase result. In 21/34 cases (61.8%), criteria for a positive re-exposure were fulfilled, with negative tests in 6/34 cases (17.6%) or uninterpretable ones in 7/34 cases (20.6%). Confirmed positive re-exposure tests established potential of herb induced liver injury for Aloe, Chaparral, Chinese herbal mixtures, Chinese Jin Bu Huan, Chinese Syo Saiko To, Germander, Greater Celandine, Green tea, Kava, Mistletoe, Polygonum multiflorum, and Senna, with up to 4 case reports per herb. Among 34 cases of herb-induced liver injury with initially reported positive re-exposure tests, 61.8% of the cases actually fulfilled established test criteria and provided firm diagnoses of herb induced liver injury by various herbs.

Drug- and Herb-Induced Liver Injury in Clinical and Translational Hepatology: Causality Assessment Methods, Quo Vadis?

Drug-induced liver injury (DILI) and herb-induced liver injury (HILI) are typical diseases of clinical and translational hepatology. Their diagnosis is complex and requires an experienced clinician to translate basic science into clinical judgment and identify a valid causality algorithm. To prospectively assess causality starting on the day DILI or HILI is suspected, the best approach for physicians is to use the Council for International Organizations of Medical Sciences (CIOMS) scale in its original or preferably its updated version. The CIOMS scale is validated, liver-specific, structured, and quantitative, providing final causality grades based on scores of specific items for individual patients. These items include latency period, decline in liver values after treatment cessation, risk factors, co-medication, alternative diagnoses, hepatotoxicity track record of the suspected product, and unintentional re-exposure. Provided causality is established as probable or highly probable, data of the CIOMS scale with all individual items, a short clinical report, and complete raw data should be transmitted to the regulatory agencies, manufacturers, expert panels, and possibly to the scientific community for further refinement of the causality evaluation in a setting of retrospective expert opinion. Good-quality case data combined with thorough CIOMS-based assessment as a standardized approach should avert subsequent necessity for other complex causality assessment methods that may have inter-rater problems because of poor-quality data. In the future, the CIOMS scale will continue to be the preferred tool to assess causality of DILI and HILI cases and should be used consistently, both prospectively by physicians, and retrospectively for subsequent expert opinion if needed. For comparability and international harmonization, all parties assessing causality in DILI and HILI cases should attempt this standardized approach using the updated CIOMS scale.

Suspected Herbal Hepatotoxicity

The aim of this current opinion report is to discuss relevant issues of regulatory causality assessment methods related to initially suspected herb-induced liver injury (HILI). Herbal hepatotoxicity represents a major clinical, regulatory and public challenge since its diagnosis may be difficult to be established, requiring a sophisticated approach that includes a liver-specific and validated causality assessment method. In cases of primarily suspected HILI, however, problems emerged when the US Pharmacopeia (USP) published results with causality assessments of liver disease cases. In these studies, herbal drugs and herbal dietary supplements were considered as causative products based on causality attribution by a shortened version of the Naranjo scale. However, the Naranjo scale is not liver specific and not validated for liver toxicity, and these shortcomings also apply to its shortened and thereby modified version. Consequently, these results were questioned and considered invalid, requiring re-evaluation with a liver-specific causality assessment method validated for hepatotoxicity, such as the scale of the Council for International Organizations of Medical Sciences (CIOMS) or its validated update. In essence, the USP and other regulatory agencies should apply validated liver-specific causality assessment methods rather than liver unspecific and not validated assessment methods in suspected HILI cases.