Herbal hepatotoxicity by Greater Celandine (Chelidonium majus): causality assessment of 22 spontaneous reports

Toxic liver injury due to the herb Greater Celandine (GC) (Chelidonium majus L.) has been assumed in patients originating from various European countries and created concern. Based on regulatory and liver unspecific ad hoc causality assessments in 22 spontaneous cases of Germany, causality levels for GC were considered probable in 16 and possible in 6 cases. We now analyzed the data of these 22 cases regarding their causality levels employing the liver specific, standardized, structured and quantitative assessment method of the updated scale of CIOMS (Council for International Organizations of Medical Sciences). Causality for GC was found highly probable (n = 2), probable (n = 6), possible (n = 10), unlikely (n = 1), and excluded (n = 3). Thus, causality could be upgraded in 2 cases to a highly probable causality level, but had to be down graded to excluded, unlikely, or possible causality levels in 3, 1, or 9 cases, respectively. GC hepatotoxicity shows a hepatocellular pattern of liver injury with female gender predominance. On average, age of the patients was 56.4 years, treatment 36.4 days, and latency period until first symptoms and jaundice 29.8 and 35.6 days, respectively. This analysis therefore provides further evidence for the existence of GC hepatotoxicity as a distinct form of herb induced liver injury, but due to poor data quality the causal association between GC use and liver injury is less strong than hitherto assumed. We propose replacement of the regulatory organ unspecific by a liver specific causality assessment method in cases of herb induced liver injury as well as stricter pharmacovigilance strategies towards improvements of data quality. Toxicological studies are now warranted to elucidate the mechanism(s) of human GC hepatotoxicity that represents a European issue.     

Clinical and causality assessment in herbal hepatotoxicity

Introduction: Herbal hepatotoxicity represents a poorly understood, neglected and multifaceted disease with numerous confounding variables and missing established causality in the majority of cases. This review discusses overt shortcomings in its clinical and causality assessment and suggests improvements.

Areas covered: A selective literature search of PubMed using the terms herbal hepatotoxicity, herb-induced liver injury, drug hepatotoxicity and drug-induced liver injury was performed to identify published case reports, spontaneous case reports, case series and review articles regarding hepatotoxicity due to herbs, herbal drugs and herbal dietary supplements. Covered areas focused on confounding variables related to the documentation of the herbal product and the clinical course, hepatotoxicity and reexposure criteria, temporal association, comedication and alternative causes with special attention to preexisting diseases of the liver, bile ducts and the pancreas. Of particular interest were recent discussions of approaches designed and validated for hepatotoxicity causality, such as the scale of CIOMS (Council for International Organizations of Medical Sciences).

Expert opinion: The authors call for substantial improvements in data quality of herbal products and case characteristics and strongly recommend using the CIOMS scale to assess causality in suspected herbal hepatotoxicity.     

Idiosyncratic drug hepatotoxicity: a 2008 update

Pharmaceutical preparations, and also herbal products and dietary supplements, are emerging contributors to severe forms of liver disease. Although acetaminophen intoxication is still the reason for many cases of drug-induced liver injury (DILI) in Western countries, the bulk of hepatic reactions to drugs are idiosyncratic. Only a small fraction of individuals exposed to a drug associated with liver injury will develop hepatotoxicity. Indeed, the rarity of this serious adverse event prevents its detection in clinical trials. The pathogenesis of idiosyncratic DILI is not well known because of a lack of reliable animal models, although it probably involves the metabolism of the drug and/or activation of the immune system. Different databases have described antibiotics, NSAIDs and anticonvulsants as the main group of drugs incriminated in DILI. Clinical presentation of DILI includes predominantly a hepatocellular type of damage, yet cholestatic and mixed types are also common; the determinants of the type of damage induced by a given drug are poorly understood. Analysis of pooled data has recently underlined the influence of older age in the cholestatic/mixed expression of liver injury, as well as the independent association of female gender, older age, aspartate aminotransferase levels with hepatocellular type of damage and high bilirubin levels with the risk of fulminant liver failure/death. In the long term (providing the patient survives the initial episode), persistent damage may occur in at least 6% of patients, with the cholestatic mixed type of damage more prone to becoming chronic, while in the hepatocellular pattern the severity is greater, with further likelihood of evolution to cirrhosis. Cardiovascular and CNS drugs are the main groups leading to chronic liver damage. The diagnosis of hepatotoxicity remains a difficult task owing to the lack of reliable markers for use in general clinical practice. Diagnostic algorithms may add consistency to clinical judgment by translating a suspicion into a quantitative score. Currently, the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method instrument is considered the gold standard in causality assessment of hepatotoxicity, although there is probably room for improvement. Current efforts in collecting bona fide cases will make refinements of existing scales feasible. Efforts should also be directed towards the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be taken. The treatment of idiosyncratic DILI is largely supportive. Early suspicion and withdrawal of the offending agent is the most important therapeutic measure.     

Kava,the anxiolytic herb: back to basics to prevent liver injury?

The use of the anxiolytic herb kava has caused toxic liver injury in Western countries and economic problems in South Pacific Islands due to tthe regulatory ban on kava. This analysis shows poor quality of kava raw material as a cause for its toxicity and suggests preventative measures by going back to the traditional use of kava for the sake of the patients and the South Pacific economy.     

Kava hepatotoxicity in traditional and modern use: the presumed Pacific kava paradox hypothesis revisited

Kava, a Pacific herb consumed worldwide for medicinal, recreational and cultural purposes, has been associated with rare hepatotoxicity, and there is currently a critical need to determine this causation. The previously proposed Pacific kava paradox was based on the theory that kava hepatotoxicity was not observed following use of traditional aqueous extracts in the Pacific region, but was restricted to use of Western acetonic and ethanolic extracts. Subsequent cases analyzed by the World Health Organization and published case reports revealed that traditional aqueous extracts used in New Caledonia, Australia, the USA and Germany may also be hepatotoxic; thus, there is no longer a basis to sustain the previously proposed Pacific kava paradox. It appears that the primary cause of toxicity may reside in the time before the preparation of the various kava extracts, possibly attributed to poor quality of the raw material caused by mould hepatotoxins. Rigorous testing of kava raw material is urgently advised, in addition to Pan-Pacific kava manufacturing quality standards.     

Causality assessment in drug-induced hepatotoxicity

Drugs are currently an important cause of liver disease, ranked as the most frequent reason for acute liver failure. Despite recent advances in knowledge of the mechanisms implicated in drug-induced hepatocellular damage and cholestasis, as well as the identification of several risk factors, the diagnosis of hepatotoxicity remains a difficult task because specific tests are not available. In a step-by-step approach, the incrimination of a drug in liver symptoms requires a high degree of suspicion on the part of the physician, temporal eligibility, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage, and the ability to detect the presence of subtle data that favour a toxic aetiology. Ultimately, the use of diagnostic algorithms may add consistency to the diagnostic process either by translating the suspicion into a quantitative score or by providing a framework that emphasises the features that merit attention in cases of suspected hepatic adverse reactions.     

Rechallenge in drug-induced liver injury: the attractive hazard

Progress in the understanding of drug-induced liver injury (DILI) is clearly hampered by the lack of specific markers of the disease. In this scenario, recrudescence of the liver injury upon re-exposure to the suspicious drug is considered the more reliable evidence of DILI. On-purpose re-exposure, however, entails both practical and ethical issues because the bulk of situations in clinical practice are non-immunoallergic DILI in which a provocation test frequently would give negative results. Besides, deliberate re-exposure with a drug that is not considered vital or essential is potentially harmful and, hence, hardly justified in DILI, and rechallenge is more commonly described in an unintentional basis. The causes, characteristics and consequences of rechallenge have been specifically addressed recently. For causality assessment, a positive rechallenge test carries the strong value, and is accordingly scored by clinical algorithms. Such clinical scales, however, reward drugs that are associated with a positive rechallenge response, but might be considered biased against those where re-administration fails to elicit a response or, more commonly, for which no rechallenge is attempted.     

基于斑马鱼模型的中药致肝脏毒性评价的研究进展

中药的广泛使用,提高了肝脏毒性发生风险。斑马鱼模型在肝脏毒性研究中显现出较大潜力的同时,也面临评价标准难以统一的问题。在使用斑马鱼进行药物肝损伤检测和评价之前应先明确其在不同生长阶段的肝功能状态,利用斑马鱼胚胎和幼鱼的通体透明的特点,以胚胎的孵化率、死亡率、畸形率作出初步的发育毒性判断,以幼鱼肝脏灰度值,肝脏面积大小,卵黄囊吸收程度作为药物是否具有肝脏毒性的判断标准,利用成鱼肝脏容易分离的特点研究肝脏毒性的作用机制。检测时可根据这些指标判断斑马鱼肝脏发育阶段,为其是否发生药物肝损伤提供依据,从而进一步提高临床用药安全性。综述了不同发育时期斑马鱼评估中药肝毒性的研究方法及研究进展,以期为后续中药的肝脏毒性评价提供参考。     

Regulatory causality evaluation methods applied in kava hepatotoxicity: Are they appropriate?

Since 1998 liver injury has been assumed in some patients after the use of kava (Piper methysticum G. Forster) as an anxyolytic herbal extract, but the regulatory causality evaluation of these cases was a matter of international and scientific debate. This review critically analyzes the regulatory issues of causality assessments of patients with primarily suspected kava hepatotoxicity and suggests recommendations for minimizing regulatory risks when assessing causality in these and other related cases. The various regulatory causality approaches were based on liver unspecific assessments such as ad hoc evaluations, the WHO scale using the definitions of the WHO Collaborating Centre for International Drug Monitoring, and the Naranjo scale. Due to their liver unspecificity, however, these causality approaches are not suitable for assessing cases of primarily assumed liver related adverse reactions by drugs and herbs including kava. Major problems emerged trough the combination of regulatory inappropriate causality assessment methods with the poor data quality as presented by the regulatory agency when reassessment was done and the resulting data were heavily criticized worldwide within the scientific community. Conversely, causality of cases with primarily assumed kava hepatotoxicity is best assessed by structured, quantitative and liver specific causality algorithms such as the scale of the CIOMS (Council for International Organizations of Medical Sciences) or the main-test as its update. Future strategies should therefore focus on the implementation of structured, quantitative and liver specific causality assessment methods as regulatory standards to improve regulatory causality assessments for liver injury by drugs and herbs including kava.     

美国FDA药物肝毒性监测和管理文件简析

药物是造成肝损害的重要原因之一。目前，对药物肝毒性进行科学监测和管理是制药企业和药品监管部门面临的一项具有挑战性的任务，对新药研发、临床诊断和治疗以及药品上市后监管都有重要的意义。通过介绍美国FDA、美国药物研究与制药商协会（PbRMA）、美国肝病协会（AASLD）共同制定的关于药物肝毒性监测和管理的文件，为读者提供了关于药物肝毒性的探测、评价和管理的许多有价值的信息；通过简析这些文件，以期为我国药物肝毒性的监测和管理提供重要的借鉴作用。     

Drug-induced liver injury: a safety review

Introduction: Idiosyncratic drug-induced liver injury (DILI) remains one of the most important causes of drug attrition both in the early phases of clinical drug development and in the postmarketing scenario. This is because, in spite of emerging data on genetic susceptibility variants associated to the risk of hepatotoxicity, the precise identification of the individual who will develop DILI when exposed to a given drug remains elusive.

Areas covered: In this review, we have addressed recent progress made and initiatives taken in the field of DILI from a safety perspective through a comprehensive search of the literature.

Expert opinion: Despite the substantial progress made over this century, new approaches using big data analysis to characterize the true incidence of DILI are needed and to categorize the drugs’ hepatotoxic potential. Genetic studies have highlighted the role of the adaptive immune system yet the mechanisms leading adaptation versus progression remain to be elucidated. There is a compelling need for development and qualification of sensitive, specific, and affordable biomarkers in DILI to foster drug development, patient treatment stratification and, improvement of causality assessment methods. Gaining mechanistic insights in DILI is essential to uncover therapeutic targets and design prospective clinical trials with appropriate endpoints.     

Autoimmune-like drug-induced liver injury: a review and update for the clinician

Introduction: Autoimmune-like drug-induced liver injury (DI-AIH) is a rare but serious event with a growing body of scientific evidence and a fair degree of uncertainty.

Areas covered: This review covers the definition, pathophysiology, treatment and patient-centered outcomes of DI-AIH and presents up-to-date information on the most commonly implicated drugs.

Expert opinion: A high degree of clinical suspicion is required for the diagnosis of DI-AIH. This diagnosis should be considered in any patient with either acute or chronic elevations in liver-associated enzymes. Prevalence rates exceed 15% based on large international registry data. Autoantibodies, while common, are neither specific nor diagnostic of DI-AIH. Histology may be helpful in describing subtle differences between DI-AIH and de novo idiopathic autoimmune hepatitis (iAIH), but oftentimes the two are indistinguishable histologically. Alpha-methyldopa, fibrates, hydralazine, minocycline, nitrofurantoin, HMG-CoA reductase inhibitors (statins), iplimumab and tumor necrosis factor alpha antagonists are the most commonly associated drugs with DI-AIH. Complete recovery of liver injury is most often seen with DI-AIH, however, cases of prolonged injury may occur and may require treatment with immunosuppressive therapy. Relapse following cessation of corticosteroids for suspected DI-AIH should prompt reconsideration of the diagnosis and further exploration into possible iAIH.     

中药肝毒性及肝脏保护作用的研究方法进展

近年来,中药的肝毒性越来越被人们所了解和重视,中药的肝毒性及肝脏保护作用的研究方法已被广泛建立。与传统的动物体内药代动力学实验相比,精密肝切片法、肝细胞及亚细胞模型体外实验法得以直观地反映出药物对细胞及组织的影响。基因组学,蛋白质组学,代谢组学的方法利用质谱联用技术找出新的生物标记物,阐明肝毒性机制。这一系列的进展为广大的药学工作者对中药肝毒性及肝脏保护作用的研究提供了较大的帮助。     

肝样细胞模型在药物肝脏代谢和毒性研究中的进展

药物诱导肝损伤（DILI）是导致药物临床试验失败和撤市的主要原因。在临床试验前,通常采用人源化的肝样细胞筛选模型来评估药物的代谢和预测药物发生DILI的风险。目前,常用的肝细胞模型包括肝癌细胞系、永生化原代肝细胞、多能干细胞诱导分化肝细胞和直接转分化肝细胞。但这些细胞模型均不能全面重现体内肝细胞功能。为了使体外肝细胞模型更接近体内肝细胞的状态,肝细胞培养体系的作用开始受到重视。与传统的二维（2D）和三明治培养模型相比,三维（3D）培养模型和微灌流系统能够更好地模拟肝细胞的体内微环境,是目前与体内肝细胞的形态和功能最为相似的细胞模型。综述肝样细胞模型在药物肝脏代谢和毒性研究中的进展,旨在为药物临床前研究选择合适的肝样细胞模型提供参考。