Idiosyncratic drug-induced liver injury: an overview

Drug-induced liver injury (DILI) encompasses a spectrum of clinical disease ranging from mild biochemical abnormalities to acute liver failure. The majority of adverse liver reactions are idiosyncratic, occurring in most instances 5 – 90 days after the causative medication was last taken. The diagnosis of DILI is clinical, based on history, probability of the suspect medication as a cause of liver injury and exclusion of other hepatic disease. DILI can be hepatocellular (predominant rise in alanine transaminase), cholestatic (predominant rise in alkaline phosphatase) or mixed liver injury. An elevated bilirubin level more than twice the upper limit of normal in patients with hepatocellular liver injury implies severe DILI, with a mortality of ～ 10% and with an incidence rate of 0.7 – 1.3 per 100,000. Although acute liver failure is rare, 13 – 17% of all acute liver failure cases are attributed to idiosyncratic drug reactions. Response to drug withdrawal may be delayed up to 1 year with cholestatic liver injury with occasional subsequent progressive cholestasis known as the vanishing bile duct syndrome. Overall, chronic disease may occur in up to 6% even if the offending drug is withdrawn. Antibiotics and NSAIDs are the most common cause of DILI. Statins rarely cause significant liver injury whereas antiretroviral therapy is associated with hepatotoxicity in 10% of treated patients. Multiple mechanisms of DILI have been implicated, including TNF-α-activated apoptosis, inhibition of mitochondrial function and neoantigen formation. Risk factors for DILI include age, sex and genetic polymorphisms of drug-metabolising enzymes such as cytochrome P450. In patients with human immunodeficiency virus, the presence of chronic viral hepatitis increases the risk of antiretroviral therapy hepatotoxicity. Over the next decade, the combination of accurate case ascertainment of DILI via clinical networks and the application of genomics and proteomics will hopefully lead to accurate prediction of risk of DILI, so that pharmacotherapy can be optimised with avoidance of adverse hepatic events.     

Herbal hepatotoxicity: a critical review

This review deals with herbal hepatotoxicity, identical to herb induced liver injury (HILI), and critically summarizes the pitfalls associated with the evaluation of assumed HILI cases. Analysis of the relevant publications reveals that several dozens of different herbs and herbal products have been implicated to cause toxic liver disease, but major quality issues limit the validity of causality attribution. In most of these reports, discussions around quality specifications regarding herbal products, case data presentations and causality assessment methods prevail. Though the production of herbal drugs is under regulatory surveillance and quality aspects are normally not a matter of concern, low quality of the less regulated herbal supplements may be a critical issue considering product batch variability, impurities, adulterants and herb misidentifications. Regarding case data presentation, essential diagnostic information is often lacking, as is the use of valid and liver specific causality assessment methods that also consider alternative diseases. At present, causality is best assessed by using the Council for International Organizations of Medical Sciences scale ( CIOMS) in its original or updated form, which should primarily be applied prospectively by the treating physician when evaluating a patient rather than retrospectively by regulatory agencies. To cope with these problems, a common quality approach by manufacturers, physicians and regulatory agencies should strive for the best quality. We propose steps for improvements with impact on future cases of liver injury by herbs, herbal drugs and herbal supplements.     

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.     

Highlights of drug - and herb- induced liver injury in the literature from 2016: how best to translate new information into clinical practice?

Introduction: Over 1500 papers on drug-induced liver injury (DILI) and herb-induced liver injury (HILI) were published in 2016, many of which have the potential to impact clinical practice.

Areas covered: Clinical studies and case series that lent themselves to new concepts in diagnosing, and treating DILI were selected for inclusion. Epidemiology of DILI in large prospective registries was highlighted. Causality assessment of drug hepatotoxicity remains challenging, as seen with cases of OxyELITE Pro (OEP). In 2016 updates to the Roussel Uclaf Causality Assessment Method (RUCAM) were published to aid in the accuracy of diagnosing DILI/HILI. New reports of established hepatotoxins were again discussed in 2016, including genetic risk factors for DILI with respect to antituberculous agents.

Expert opinion: 2016 marked a turning point in how much credence should be placed in the current causality assessment for DILI/HILI cases. Many recognized hepatotoxins are backed by a relatively few number of literature reports. Danan and Teschke make a strong case that an updated RUCAM should remain the gold standard for diagnosing DILI/HILI going forward, although the role of expert opinion is often still needed in cases where RUCAM falls short. The field of chemoinformatics continues to evolve while we await a truly predictive and diagnostic DILI biomarker.     

临床药师运用Roussel Uclaf因果关系评价法诊治赖氨匹林致幼儿严重肝损害1例

目的:探讨临床药师在药物性肝损害因果分析及治疗中的作用。方法:临床药师参与1例赖氨匹林注射液致严重药物性肝损害的治疗过程,运用Roussel Uclaf因果关系评价法对肝损害与赖氨匹林的因果关系进行评估,根据相关文献与临床医师共同制定个体化给药方案。结果:临床药师参与治疗后,患儿肝功能生化指标明显下降,病情得到控制。结论:临床药师为患者提供个体化药学服务,有利于促进临床用药安全、合理。     

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.     

Overdose pattern and outcome in paracetamol-induced acute severe hepatotoxicity

AIMS

Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported.

METHODS

Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit.

RESULTS

Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P < 0.001). The King''s College poor prognostic criteria had reduced sensitivity in unintentional overdoses (77.8%, 95% confidence intervals (CI) 62.9, 88.8) compared with intentional overdoses (89.9%, 95% CI 83.4, 94.5). Unintentional overdose was independently predictive of death or liver transplantation on multivariate analysis (odds ratio 1.91 (95% CI 1.07, 3.43), P= 0.032).

CONCLUSIONS

Unintentional paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses.     

Using high-content screening technology for studying drug-induced hepatotoxicity in preclinical studies

Introduction: The need for alternatives to animal experimentation and traditional testing methods has been widely discussed in recent years. This has led scientists and regulatory authorities to investigate alternative methods for toxicity testing. High-content screening (HCS) has emerged as a powerful tool in predictive toxicology since it permits molecular, cellular and tissue-based toxicity assessments. HCS allows automated image acquisition and analysis, and provides information on multiple properties of individual cells loaded simultaneously with fluorescent dyes, which is used for drug safety evaluations.

Areas covered: Herein, the authors review the principles of HCS technology and some of the most widely used HCS assays for studying drug-induced hepatotoxicity in preclinical studies in general and in the pharmaceutical industry in particular.

Expert opinion: The widespread acceptation of HCS by pharmaceutical companies and academic researchers highlights the potential usefulness of this technology as a prioritization tool in drug development. The improvement of different key points such as fluorescent probes or bioinformatics tools will consolidate HCS in drug discovery.     

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。     

164例住院患者药物性肝损害临床分析

目的 分析药物性肝损害（DILI）的致病药物和临床特点,为临床合理用药提供参考。方法 收集本院2013-01~12住院患者中发生药物性肝损害的病例,对患者的基础疾病、用药史、肝损害分型及预后进行回顾性分析。结果 共筛选到符合DILI诊断标准的患者164例,导致药物性肝损害的前五类药物分别是化疗药（51.98%）、中药（8.42%）、抗结核药（8.42%）、抗菌药（7.43%）和心血管系统用药（5.45%）;肝损害类型以肝细胞型为主,占71.34%,其次为胆汁淤积型（15.24%）和混合型（13.41%）;经过保肝治疗,19.51%的患者治愈,64.63%的患者好转,9.15%的患者无效,1.22%的患者死亡。结论 本院导致肝损害的药物以化疗药为主,多数为肝细胞型,经治疗后预后较好。     

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。     

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity

AIMS

Paracetamol (acetaminophen) poisoning remains the major cause of severe acute hepatotoxicity in the UK. In this large single centre cohort study we examined the clinical impact of staggered overdoses and delayed presentation following paracetamol overdose.

RESULTS

Between 1992 and 2008, 663 patients were admitted with paracetamol-induced severe liver injury, of whom 161 (24.3%) had taken a staggered overdose. Staggered overdose patients were significantly older and more likely to abuse alcohol than single time point overdose patients. Relief of pain (58.2%) was the commonest rationale for repeated supratherapeutic ingestion. Despite lower total ingested paracetamol doses and lower admission serum alanine aminotransferase concentrations, staggered overdose patients were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, P = 0.025), although this overdose pattern did not independently predict death. The King''s College poor prognostic criteria had reduced sensitivity (77.6, 95% CI 70.8, 81.5) for this pattern of overdose. Of the 396/450 (88.0%) single time point overdoses in whom accurate timings could be obtained, 178 (44.9%) presented to medical services >24 h following overdose. Delayed presentation beyond 24 h post overdose was independently associated with death/liver transplantation (OR 2.25, 95% CI 1.23, 4.12, P = 0.009).

CONCLUSIONS

Both delayed presentation and staggered overdose pattern are associated with adverse outcomes following paracetamol overdose. These patients are at increased risk of developing multi-organ failure and should be considered for early transfer to specialist liver centres.     

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.     

The hepatotoxicity of Polygonum multiflorum: The emerging role of the immune-mediated liver injury

Herbal and dietary supplements(HDS)-induced liver injury has been a great concern all over the world.Polygonum multiflorum Thunb.,a well-known Chinese herbal medicine,is recently drawn increasing attention because of its hepatotoxicity.According to the clinical and experimental studies,P.multiflorum-induced liver injury(PM-DILI)is considered to be immune-mediated idiosyncratic liver injury,but the role of immune response and the underlying mechanisms are not completely elucidated.Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury(DILI).However,most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury.The aim of this review is to assess current epidemiological,clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P.multiflorum.The potential effects of factors associated with immune tolerance,including immune checkpoint molecules and regulatory immune cells on the individual’s susceptibility to PM-DILI are also discussed.We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.     

新型冠状病毒肺炎患者肝损的原因分析

自2019年12月以来,新型冠状病毒(SARS-CoV-2)感染的肺炎(COVID-19)已对公共卫生造成重大威胁[1]。值得关注的是,除呼吸系统外,大量的COVID-19患者还表现出各种程度的肝损伤临床特征[2-3]。本文将初步探讨COVID-19患者肝损伤的原因。1基于文献分析COVID-19患者肝损伤原因Chen等[4]在99名COVID-19患者中,发现有43例患者出现了不同程度的肝功能损伤。     

The inhibition of hepatic bile acids transporters Ntcp and Bsep is involved in the pathogenesis of isoniazid/rifampicin-induced hepatotoxicity

Abstract

Co-treatment of isoniazid (INH) and rifampicin (RFP) is well known for clinically apparent liver injury. However, the mechanism of INH/RFP-induced liver injury is controversial. Emerging evidence shows links between inhibition of bile acids transporters and drug-induced liver injury (DILI). The present study investigates whether sodium taurocholate cotransporting polypeptide (NTCP/Ntcp; SLC10A1) and bile salt export pump (BSEP/Bsep; ABCB11) are involved in the anti-tuberculosis medicines induced liver injury. ICR female mice were intragastrically treated with INH (50 or 100?mg/kg), RFP (100 or 200?mg/kg), or the combination of INH/RFP (50?+?100?mg/kg or 100?+?200?mg/kg) for 14 consecutive days. Liver histopathological examination, serum biochemical and liver malondialdehyde tests were evaluated. Apparent histopathological alterations and hepatic oxidative stress showed in INH (100?mg/kg), RFP (200?mg/kg) and their combination group. The hepatoxic effect was also indicated by increased serum biomarkers, such as aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), direct bilirubin (DBil), total bilirubin (TBil) and total bile acids (TBA). Both doses of INH/RFP administration significantly down-regulated the expression of Ntcp and Bsep in liver. Furthermore, the combination of INH and RFP displayed stronger effect on the expression of Ntcp compared with the corresponding dose of INH or RFP alone. In conclusion, down-regulated expression of hepatic Ntcp and Bsep might play an important role in the development of INH and RFP induced liver injury.     

抗菌药物致肝损伤的研究进展

近年来,药物引起的肝损伤报道逐年增加。其中,抗菌药物是引起药物性肝损伤的最常见药物之一。抗菌药物临床应用非常广泛,如果应用不当会增加肝损伤的发生率和严重程度。本文按照抗菌药物的分类,从研究现状、流行病学、发病机制、病例报道等方面,综述了近期各类抗菌药物所致肝损伤的研究进展,旨在为抗菌药物的合理应用提供参考。     

间接型药物性肝损伤:新类型与新挑战

间接型药物性肝损伤是由药物的治疗作用所引起的肝损伤,而不是因为药物固有的肝毒性或免疫原性所导致的一类新型药物性肝损伤(DILI)。目前临床常见的间接型DILI主要有3种临床表型,即免疫检测点抑制剂相关肝损伤、药物引起肝炎病毒再激活和药物影响肝细胞代谢所致的脂肪肝或原有脂肪肝加重。由于间接型DILI是一类新型DILI,临床对其认识不足,诊治经验缺乏。尤其是随着免疫检测点抑制剂在临床快速推广应用,间接型DILI迅速增加,给临床诊断和治疗带来更大的挑战。因此,对间接型DILI常见类型的临床特点、发病机制及诊断治疗等研究进展等进行综述,具有重要的临床意义。