异烟肼/利福平致肝损伤的生物标志物研究进展

异烟肼(INH)和利福平(RFP)是临床抗结核一线药物,也是我国急性药物性肝损伤(DILI)的重要病因。INH和RFP单独使用均会引起DILI,二者联用会使肝损伤的发生率及严重程度显著增加。目前临床上对INH、RFP致肝损伤的检测指标主要有血清转氨酶、总胆红素等,存在灵敏度和特异性不高、早期预测性差等缺点。近年来多项研究试图通过多种方法发现更为理想的生物标志物,提高对INH、RFP致DILI检测与诊断的特异性与灵敏性。本文从代谢组学、蛋白质组学、转录组学、基因组学等方面就INH、RFP致DILI的新型潜在生物标志物予以综述。     

吗替麦考酚酯分散片致药物性肝损伤1例分析

目的分析吗替麦考酚酯分散片致药物性肝损伤的不良反应特点。方法总结上海仁济医院2019年12月收治的1例服用吗替麦考酚酯后出现肝酶升高不良反应的病例。结果患者进行性视力下降2月余,诊断视神经脊髓炎谱系疾病,服用吗替麦考酚酯分散片(0.25 g/d)后5天中出现肝酶逐渐升高,最高时谷丙转氨酶(ALT)350 U/L、谷草转氨酶(AST)161 U/L,乳酸脱氢酶(LDH)126 U/L,碱性磷酸酶(ALP)63 U/L,γ-L-谷氨酰转肽酶(γ-GT)25 U/L。停用吗替麦考酚酯后,给予保肝治疗。5天后复查,肝功能正常。结论吗替麦考酚酯分散片可致药物性肝损伤的不良反应,应加强其用药监测。     

补骨脂致药物性肝损伤一例

补骨脂为豆科植物补骨脂Psoralea corylifolia的干燥成熟果实,是一味常见的补虚药,按照炮制方法可分为生补骨脂和盐补骨脂。生补骨脂长于温补脾肾而止泻,外用治白瘢风;盐补骨脂温肾助阳、纳气、止泻之功较强,多用于阳痿遗精、遗尿、尿频等[1]。补骨脂的保健作用值得认可,但在应用过程中的用药安全问题值得关注。现将我院发现的1例补骨脂致药物性肝损伤报道如下。     

Diagnostic and predictive performance and standardized threshold of traditional biomarkers for drug‐induced liver injury in rats

Traditional biomarkers such as alanine and aspartate aminotransferase (ALT, AST) and total bilirubin (TBIL) have been widely used for detecting drug‐induced liver injury (DILI). Although the Food and Drug Administration (FDA) proposed standardized thresholds for human as Hy's law, those for animals have not been determined, and predictability of these biomarkers for future onset of hepatic lesions remains unclear. In this study, we investigated these diagnostic and predictive performance of 10 traditional biomarkers for liver injury by receiver‐operating characteristic (ROC) curve, using a free‐access database where 142 hepatotoxic or non‐hepatotoxic compounds were administrated to male rats (n = 5253). Standardization of each biomarker value was achieved by calculating the ratio to control mean value, and the thresholds were determined under the condition of permitting 5% false positive. Of these 10 biomarkers, AST showed the best diagnostic performance. Furthermore, ALT and TBIL also showed high performance under the situation of hepatocellular necrosis and bile duct injury, respectively. Additionally, the availability of the diagnostic thresholds in difference testing facility was confirmed by the application of these thresholds to in‐house prepared dataset. Meanwhile, incorrect diagnosis by the thresholds was also observed. Regarding prediction, all 10 biomarkers showed insufficient performance for future onset of hepatic lesions. In conclusion, the standardized diagnostic thresholds enable consistent evaluation of traditional biomarkers among different facilities, whereas it was suggested that novel biomarker is required for more accurate diagnosis and prediction of DILI. Copyright © 2014 John Wiley & Sons, Ltd.     

华法林致药物性肝损伤报告分析

目的 分析浙江省华法林在临床使用中导致的药物性肝损伤(DILI)的特点,为临床合理用药提供参考.方法 针对2010年1月1日至2019年8月31日期间国家药品不良反应监测系统浙江省平台收集到的华法林相关不良反应报告进行统计,分析怀疑使用华法林导致的肝胆系统损伤的不良反应报告.结果 27例华法林导致DILI病例,女性患者...     

西地那非致肝内胆汁淤积的病例分析

目的探讨西地那非导致肝损伤的临床表现及处理措施。方法通过对1例男性患者应用西地那非致肝内胆汁淤积的案例报道,并结合相关文献报道进行分析。结果和结论西地那非引起的肝损害少见,但仍需警惕。肝损伤的类型可表现为转氨酶升高,或重度胆汁淤积。使用西地那非时应定期监测肝功能。     

Lipopolysaccharide exposure augments isoniazide‐induced liver injury

Isoniazide (INH) is a classic antituberculosis drug associated with clinical idiosyncratic drug‐induced liver injury. It has been hypothesized that the interaction between a drug and modest inflammation results in a decreased threshold for drug toxicity. In this study, we tested the hypothesis that INH causes liver injury in rats when coadministered with lipopolysaccharide (LPS). Neither INH nor LPS alone caused liver injury. The coadministration of INH and LPS was associated with increases in serum and histopathological markers of liver injury. Tumour necrosis factor‐α expression was significantly increased in the coadministered group. The downregulation of the bile acid transporter, bile salt export pump, and multidrug resistance protein 2 at both mRNA and protein levels was observed. Furthermore, the level of Farnesoid X receptor, which regulates the bile salt export pump and multidrug resistance protein 2, were clearly decreased. These results indicate that the coadministration of nontoxic doses of LPS and INH causes liver injury; the disruption of biliary excretion is considered the primary inflammation‐related characteristic of INH‐induced hepatotoxicity. Copyright © 2014 John Wiley & Sons, Ltd.     

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.     

Proteomic profiling in incubation medium of mouse,rat and human precision‐cut liver slices for biomarker detection regarding acute drug‐induced liver injury

Drug‐induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision‐cut liver slices (PCLS) exposed to liver injury‐inducing drugs for biomarker identification, using matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry. PCLS were incubated with acetaminophen (APAP), 3‐acetamidophenol, diclofenac and lipopolysaccharide for 24–48 h. PCLS medium from all species treated with APAP demonstrated similar changes in protein profiles, as previously found in mouse urine after APAP‐induced liver injury, including the same key proteins: superoxide dismutase 1, carbonic anhydrase 3 and calmodulin. Further analysis showed that the concentration of hepcidin, a hepatic iron‐regulating hormone peptide, was reduced in PCLS medium after APAP treatment, resembling the decreased mouse plasma concentrations of hepcidin observed after APAP treatment. Interestingly, comparable results were obtained after 3‐acetamidophenol incubation in rat and human, but not mouse PCLS. Incubation with diclofenac, but not with lipopolysaccharide, resulted in the same toxicity parameters as observed for APAP, albeit to a lesser extent. In conclusion, proteomics can be applied to identify potential translational biomarkers using the PCLS system. Copyright © 2013 John Wiley & Sons, Ltd.     

Anakinra‐Induced Acute Liver Failure in an Adolescent Patient with Still's Disease

The interleukin‐1 (IL‐1) family consists of 11 cytokines that play key regulatory roles in many immune and inflammatory processes. Anakinra (Kineret, Amgen, Inc.) is an IL‐1 receptor antagonist (IL‐1ra). Increased levels of IL‐1 are found in several disease states suggesting that anakinra may be beneficial in disorders associated with elevated IL‐1 levels. Anakinra has been effectively used in the treatment of systemic juvenile idiopathic arthritis and adult‐onset Still's disease (AOSD). Despite its therapeutic benefits, anakinra also has potential side effects, including hepatotoxicity. We present a case of AOSD in an adolescent male that was treated with anakinra. During treatment, the patient developed acute liver failure that resolved upon withdrawal of anakinra. Although anakinra‐induced liver injury has been reported in adults, including one case of subacute liver failure, we believe our case is the first to show severe acute liver failure in an adolescent treated with anakinra. This case provides significant insight into a potentially serious complication associated with anakinra. It is important to further delineate these complications as the treatment indications for this drug expand.     

Kupffer cell‐mediated exacerbation of methimazole‐induced acute liver injury in rats

Methimazole (MTZ), an anti‐thyroid drug, is known to cause liver injury in humans. It has been demonstrated that MTZ‐induced liver injury in Balb/c mice is accompanied by T helper (Th) 2 cytokine‐mediated immune responses; however, there is little evidence for immune responses associated with MTZ‐induced liver injury in rats. To investigate species differences in MTZ‐induced liver injury, we administered MTZ with a glutathione biosynthesis inhibitor, L‐buthionine‐S,R‐sulfoximine (BSO), to F344 rats and subsequently observed an increase in plasma alanine aminotransferase (ALT) and high‐mobility group box 1 (HMGB1), which are associated with hepatic lesions. The hepatic mRNA expression of innate immune‐related genes significantly increased in BSO‐ and MTZ‐treated rats, but the change in Th2‐related genes was not much greater than the change observed in the previous mouse study. Moreover, an increase in Kupffer cells and an induction of the phosphorylation of extracellular signal‐regulated kinase (ERK)/c‐Jun N‐terminal kinase (JNK) proteins were accompanied by an increase in Toll‐like receptor 4 (TLR4) expression, indicating that Kupffer cell activation occurs through HMGB1‐TLR4 signaling. To elucidate the mechanism of liver injury in rats, gadolinium chloride, which inactivates the function of Kupffer cells, was administered before BSO and MTZ administration. The gadolinium chloride treatment significantly suppressed the increased ALT, which was accompanied by decreased hepatic mRNA expression related to innate immune responses and ERK/JNK phosphorylation. In conclusion, Kupffer cell‐mediated immune responses are crucial factors for the exacerbation of MTZ‐induced liver injury in rats, indicating apparent species differences in the immune‐mediated exacerbation of liver injury between mice and rats. Copyright © 2015 John Wiley & Sons, Ltd.