Genetic and molecular factors in drug-induced liver injury: a review

The diagnosis of drug-induced liver injury (DILI) is challenging and based on complex diagnostic criteria. DILI falls into two main categories i) intrinsic "dose-dependent" Type A reactions ii) "idiosyncratic" or Type B reactions (which are usually not predictable). Idiosyncratic reactions can be immunoallergic (hypersensitivity), or metabolic, although overlap between categories can occur. The aim of this review is to summarise the general view of underlying mechanisms in DILI and to highlight individual risk factors for developing hepatotoxicity. Polymorphisms of bioactivation/toxification pathways through CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III) are explored together with immunological factors that might determine DILI. The importance of establishing a multidisciplinary and multi-centric network to promote the understanding and research in hepatotoxicity is underlined. Challenges such as genetic analyses for association studies and whole genome studies, pharmacogenetic testing and future approaches to study DILI are considered. Knowledge regarding these operational mechanisms could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity.     

Metabolic activation in drug-induced liver injury

It is generally believed that metabolic bioactivation of drug molecules to form reactive metabolites, followed by their covalent binding to endogenous macromolecules, is one of the mechanisms that can lead to hepatotoxicity or idiosyncratic adverse drug reactions (IADRs). Although the role of bioactivation in drug-induced liver injury has been reasonably well established and accepted, and methodologies (e.g., structural alerts, reactive metabolite trapping, and covalent binding) continue to emerge in an attempt to detect the occurrence of bioactivation, the challenge remains to accurately predict the likelihood for idiosyncratic liver toxicity. Recent advances in risk-assessment methodologies, such as by the estimate of total body burden of covalent binding or by zone classification, taking the clinical dose into consideration, are positive steps toward improving risk assessment. The ability to better predict the potential of a drug candidate to cause IADRs will further be dependent upon a better understanding of the pathophysiological mechanisms of such reactions. Until a thorough understanding of the relationship between liver toxicity and the formation of reactive metabolites is achieved, it appears, at present, that the most practical strategy in drug discovery and development to reduce the likelihood of idiosyncratic liver toxicity via metabolic activation is to minimize or eliminate the occurrence of bioactivation and, at the same time, to maximize the pharmacological potency (to minimze the clinical dose) of the drug of interest.     

Mechanisms of drug-induced liver injury

The idiosyncratic nature and poor prognosis of drug-induced liver injury (DILI) make this type of reaction a major safety issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market. The key to predicting and preventing DILI is understanding the underlying mechanisms. DILI is initiated by direct hepatotoxic effects of a drug, or a reactive metabolite of a drug. Parenchymal cell injury induces activation of innate and/or adaptive immune cells, which, in turn, produce proinflammatory and tissue hepatotoxic mediators, and/or mount immune reactions against drug-associated antigens. Understanding the molecular and cellular elements associated with these pathways can help identify risk factors and may ultimately facilitate the development of strategies to predict and prevent DILI.     

Research advances in the association of drug-induced liver injury with polymorphisms in human leukocyte antigen

Drug-induced liver injury is an important adverse drug reaction. Due to the lack of specificity in clinical symptoms and pathological features, there are still no reliable diagnostic biomarkers, so drug-induced liver injury is a diagnosis of exclusion. The article reviews the relevant advances in the association between novel human leukocyte antigen gene polymorphisms and drug-induced liver injury in order to identify potential biomarkers and provide a new method for the prediction and diagnosis of drug-induced liver injury. Henceforth, while studying the association between them, it will also need that the large sample and prospective studies to gain supporting evidence to implement translational application, so as to improve the safety and effectiveness of medication and achieve individualized treatment.     

Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury

Three first-line antituberculosis drugs, isoniazid, rifampicin and pyrazinamide, may induce liver injury, especially isoniazid. This antituberculosis drug-induced liver injury ranges from a mild to severe form, and the associated mortality cases are not rare. The major drug-metabolizing enzyme of isoniazid is N-acetyltransferase. Other possible enzymes are CYP2E1 and glutathione S-transferase. There is evidence that polymorphisms of the genes that encode these enzymes may influence the activity of the corresponding drug-metabolizing enzymes. Recent studies demonstrated that these genetic polymorphisms may be associated with the susceptibility to antituberculosis drug-induced liver injury. The proposed risk-associated genotypes are NAT2 slow acetylator (without wild-type NAT2*4 allele), CYP2E1 *1A/*1A (homozygous wild type) and homozygous null GSTM1 genotype. Although the available data in the field are still limited and warrants further confirmation in different ethnic populations with larger sample sizes, it still cast some light on the application of these pharmacogenetic or pharmacogenomic approaches to prevent grave antituberculosis drug-induced liver injury in the near future.     

Immunological mechanisms of drug-induced liver injury

Immune-mediated drug-induced liver injury (DILI) occurs at a relatively low rate, but the outcome can often be serious and sometimes fatal. As a result, it represents a major problem in drug development and safety. The key to predicting and preventing immune-mediated DILI is to understand the underlying mechanisms. Currently, the most prevalent working model is the hapten hypothesis, which proposes that drugs, or more often their reactive metabolites, bind to endogenous proteins to form immunogenic conjugates that cause T-cell- or antibody-mediated pathological reactions. Another working model incorporates the hypothesis that most people are tolerant to immune-mediated DILI, and that these reactions only occur when the tolerance mechanism is impaired. Understanding the molecular and cellular elements in these models can help identify risk factors, and ultimately facilitate the development of prediction and prevention strategies.     

药物性肝损伤临床相关因素分析

目的探讨190例药物性肝损伤病例的病因、临床特点及预后相关因素,以指导临床诊断和治疗。方法对我院2006年1月～2010年12月190例药物性肝损伤住院病例进行回顾性研究,分析其用药、临床表现和预后转归情况。结果引起药物性肝损伤的药物品种繁多,其中抗肿瘤药占首位56例(29.4%),中药50例(26.3%);临床分型以肝细胞型为主152例(80.0%),胆汁淤积型24例(12.6%);临床表现无明显特异性,其中无任何临床表现者84例(44.2%),有明显黄疸者48例(25.3%);经治疗后治愈30例(15.8%),好转150例(78.9%),死亡0例,10例失访。结论近年来药物性肝损伤呈明显增加趋势,以抗肿瘤药及中药为主,一般预后较好。     

抗结核药物致药物性肝损害临床诊治分析

目的总结抗结核药物所致药物性肝炎的临床特点,探讨抗结核药致肝损害的诊断与及其预防和合理的治疗。方法根据临床用药史、临床症状、肝功能检查、影像学检查及药物性肝病诊断标准,对本站2004年至2006年管治的肺结核患者抗结核治疗后出现肝损害的61例患者进行回顾性分析。结果348例结核病人接受抗结核药物治疗后,有61例病人出现药物性肝病,药物性肝病发生率17．53％,348例病人中HBsAg阳性32例,其中13例出现药物性肝损害,占40．63％。结论抗结核药所致肝损害多见于具有危险因素的患者,且多发生在用药的第1～8周。在进行抗结核治疗前应常规检查肝功能、HBsAg,在治疗过程中应定期检查肝功能、对抗结核药致肝损害的早期诊断和及时合理的治疗,可以使患者肝功能恢复正常,帮助患者顺利完成抗结核治疗疗程。     

Assessment of reactive metabolites in drug-induced liver injury

The aim of the current review is to summarize present methods used for the determination of reactive metabolites, which can predict drug-induced liver injury (DILI) in drug discovery and development. DILI is one of the most frequent reasons for the withdrawal of an approved drug from the market, and it accounts for up to 50% of acute liver failure cases. This review is structured into three sections. The first section is a general overview of the relationship between drug metabolism and liver injury. The second section introduces in vitro methods for the assessment of reactive metabolites for drug discovery and development. In the third section, limitations and future directions for the development of methods for predicting DILI are described.     

Incidence of drug-induced liver injury in medical inpatients

Objectives Drug-induced liver injury (DILI) is a common concern. However, data on DILI epidemiology in inpatients are sparse.Methods To investigate the incidence of DILI, we screened all patients in the pharmacoepidemiological inpatient database according to the CIOMS (Council for International Organisation of Medical Science) criteria, which consist of the evaluation of some clinical chemistry laboratory liver parameters (CIOMS laboratory criteria) and the exclusion of any disease-related causes for the liver injury. Thus, only cases with probable or certain causality according to the World Health Organization criteria were included.Results Among a total of 6383 patients, liver parameters were determined in 4610, and 489 among them fulfilled the CIOMS laboratory criteria. However, 401 patients had to be excluded because of disease-related liver injury and, thus, the study cohort consisted of 4209 patients at risk for DILI. Among a total of 88 DILI cases, 31 had no documented normal baseline liver parameters and, thus, represented prevalent cases. The remaining 57 represented incident DILI cases. Thus, the incidence of DILI was 1.4% (95% CI 1.0, 1.7). The drug classes most frequently causing DILI were heparins, antibacterials, tuberculostatics and antineoplastic agents. Among those, antineoplastic agents and tuberculostatics showed the highest incidence. Liver injury was not mentioned among the diagnoses or in the physicians discharge letter in about 52–68% of all cases.Conclusion Approximately 1 in 100 patients develops DILI during hospitalisation in a department of medicine. Incidences of DILI were highest for antineoplastic agents and tuberculostatics. DILI is frequently missed and, therefore, DILI detection by diagnoses will result in misleadingly low incidence rates.     

药物性肝损伤的基因多态性研究进展

药物性肝损伤是常见药源性疾病之一，其临床诊治极为困难，且易发展成急性肝功能衰竭。相关药物基因组学研究已经发现包括CYP450、UGT、GST、NAT等药物代谢酶类，ABCB1、ABCC2等药物转运体以及人类白细胞抗原的基因多态性与药物性肝损伤具相关性。本文将综述药物性肝损伤的基因多态性研究进展，以期为药物性肝损伤的临床及时诊治和科学研究提供参考。     

肠道菌群介导药物性肝损伤的研究进展

药物性肝损伤是临床上最常见、最严重的不良反应之一,既增加患者的医疗负担,也给新药研发及上市带来挑战。目前,药物性肝损伤的发生机制仍不十分明确。近年来,研究发现肠道菌群与药物性肝损伤密切相关,但对肠道菌群参与药物性肝损伤的具体作用机制仍尚无统一结论。肠道菌群可能通过增加肠道通透性致使内毒素外漏、破坏肠道代谢物平衡、直接影响药物代谢及促进炎症和氧化应激等途径参与药物性肝损伤。本文将对肠道菌群参与药物性肝损伤的可能机制,及基于机制的防治措施等研究进展进行综述,以期为药物性肝损伤研究及临床安全合理用药提供科学参考。     

药物性肝损伤生物标志物研究进展

药物及其代谢产物对肝脏产生的毒性损害称为药物性肝损伤(DILI)。DILI的临床表现和病理变化较为复杂,因此,准确而可靠的生物标志物将对DILI的预防、诊断和治疗提供很大帮助。DILI的传统生物标志物有丙氨酸氨基转移酶、天冬氨酸氨基转移酶、碱性磷酸酶、γ-谷氨酰转移酶和总胆红素等。新型生物标志物有苹果酸脱氢酶、嘌呤核苷磷酸化酶、对氧磷酶-1和总胆酸等。潜在的生物标志物有活性氧、炎症标志、肝细胞渗漏酶等。肝脏再生标志物有甲胎蛋白、视黄醇结合蛋白和钙调蛋白等。多标志联合应用可能具有更好的诊断和预后价值。结合现代组学等技术的转化医学新平台无疑将提高生物标志物的研究水平。     

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 approximately 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-alpha-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.     

药物性肝损伤的流行病学研究现状

在世界范围内,药物性肝损伤(DILI)发病率逐年上升,目前已成为临床常见的肝病之一,也是新药上市后撤市的主要原因之一。因此,DILI是一个全球性临床和药学问题。本文从流行病学角度,对DILI发病情况、分布、遗传因素、相关药物、临床类型、潜伏期和预后等方面的国内外研究现状予以综述。     

元胡致严重药物性肝损伤2例

目的：分析中药元胡是否可致药物性肝损伤。方法：对临床观察到的2例元胡制剂致肝损伤的病因、肝功能指标、治疗方案、预后和转归进行分析。结果：2例患者经过对症支持治疗均有不同程度好转。临床药师认为,避免或减轻元胡造成肝损伤应做到辨证准确,用药过程中注意肝功能变化。结论：中药元胡可致严重药物性肝损伤,应引起临床高度注意。     

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.     

药物性肝损伤的生物标志物及其评价的研究进展

药物性肝损伤是伴随药物使用而出现的主要不良反应,是肝疾病的主要组成部分,目前血清天冬氨酸转氨酶、丙氨酸转氨酶、碱性磷酸酶和总胆红素等传统标志物在药物性肝损伤的预测和诊断中的地位尚无可取代,但近年发现的血清药物-蛋白加合物、嗜酸性粒细胞、乳酸脱氢酶、谷氨酰胺脱氢酶及基因组学生物标志物等多种新的生物标志物对弥补传统生物标志物检测敏感性和特异性的作用也不可忽视。本文结合药物性肝损伤评价现状对传统生物标志物和近年发现的新的肝损伤生物标志物进行概述,为更好地预测和诊断肝损伤、减轻药物性危害提供可能的帮助。