Acetaminophen toxicity up-regulates MRP2 expression in the liver of cats: an old story with new vision

This study was conducted to clarify the role of efflux transporter MRP₂ in acetaminophen-induced hepatotoxicity in cats. Sixteen mixed bred male cats and four liver samples from mixed breed male dogs were used. The cats were assigned into four groups (n?=?4), received saline and 2, 10 and 50?mg/kg doses of acetaminophen orally for 14 days. Unlike the intact dogs, the MRP₂ was not detectable in control cats. MRP₂ at mRNA level was expressed in the liver of cats, which received the medium and high doses. Data suggest that the MRP₂ expression may involve in the acetaminophen-induced hepatotoxicity in cats.     

MiR-122 and other microRNAs as potential circulating biomarkers of drug-induced liver injury

Introduction: Drug-induced liver injury (DILI) is a severe adverse drug reaction which is of major concern to patients, clinicians and the pharmaceutical industry. Accurate and rapid detection of DILI is important for patient stratification and treatment in the clinic and benefits preclinical drug design and risk assessment. MicroRNAs (miRNAs) offer a potential new and improved class of circulating biomarkers of DILI over the current gold standard biomarkers.

Areas covered: This review highlights the shortcomings of the currently used panel of biomarkers and how miRNAs, primarily miR-122, show an improved level of specificity and sensitivity in the prediction of DILI. Furthermore, the use of miRNAs as potential markers of progression of DILI and specific zonated damage within the liver is discussed.

Expert commentary: MiRNAs offer more sensitive and specific markers over the current biomarkers for DILI. Combinations of different miRNAs may be able to relay the location of DILI and the progression of disease. More studies using different hepatotoxins apart from acetaminophen will ultimately strengthen the case for the clinical introduction of miRNAs as biomarkers of DILI.     

Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system

Aim

We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS).

Methods

We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications.

Results

DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively).

Conclusions

The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury.     

阻塞性睡眠暂停低通气综合征氧化应激与肝损害的关系

探讨氧化应激对于阻塞性睡眠暂停低通气综合征（OSAHS）患者发生慢性肝脏损害的影响。选取2011年5月至2013年5月因打鼾及睡眠障碍就诊于呼吸科门诊的30例患者,均进行多道睡眠图(PSG),确诊为阻塞性睡眠呼吸暂停低通气综合征。监测30例OSAHS患者和15例健康对照者血清谷丙转氨酶（ALT）、血清天冬氨酸氨基转移酶（AST）、丙二醛（MDA）水平,并监测患者体质量指数、呼吸暂停低通气指数(AHI)、血氧饱和度＜90%的时间(sIT90)、平均血氧饱和度(MSaO2)、最低血氧饱和度(LSaO2)等睡眠指标。OSAHS患者根据AHI分为中度14例、重度16例。OSAHS患者与健康对照组比较血清ALT、AST、MDA水平明显升高 (P＜005)。OSAHS患者血清ALT、AST水平与MSaO2呈负相关,与MDA呈正相关(相关系数分别为-0137、0115,P＜005),OSAHS患者的血清MDA水平与sIT90呈正相关（相关系数为0135）。16例重度OSAHS患者经CPAP治疗2个月后血清ALT、AST、MDA明显降低(P＜005)。间歇缺氧导致氧化性应激产物如MDA增加,MDA水平与睡眠呼吸暂停低通气综合征患者肝损害存在正相关,CPAP治疗后改善间断缺氧状态,进而改善肝损害。     

Monitoring and management of antituberculosis drug induced hepatotoxicity

BACKGROUND: Hepatotoxicity to antituberculosis therapy (ATT) poses a major challenge. This often results in inadequate therapy. The risk of fulminant hepatic failure and mortality is high once icteric hepatitis develops. There is no consensus on monitoring protocols and for the reintroduction of ATT. METHODS: All patients (from the Department of Internal Medicine and Gastroenterology, Jagjivanram Hospital and the Department of Gastroenterology, Bombay Hospital, Mumbai, India) with a diagnosis of tuberculosis, who were to receive ATT during the study period, were included in the present study for prospective periodic laboratory monitoring for the development of hepatotoxicity. Those patients who developed hepatotoxicity formed Group A (n = 21), whereas those who did not develop hepatotoxicity were included in Group C (n = 179). For the purpose of comparison with Group A, all the patients who presented directly with ATT induced hepatotoxicity during the study period were categorized as Group B (n = 24). Group A and B were further studied after normalization of liver functions for sequential reintroduction with therapeutic doses at a weekly interval. RESULTS: In Group A, 66.6% (14 patients) of the patients were diagnosed in the asymptomatic period. Seven patients had symptomatic hepatitis, but none had icteric illness. There were no mortalities in Group A. In contrast, all the patients in Group B had symptomatic hepatitis (75% icteric hepatitis). There was a mortality rate of 16.6% (four patients). Of the 41 patients from Groups A and B who survived, reintroduction was successful in 38/39 (97.4%). In the remaining two patients who were in Group B, reintroduction was not attempted because of decompensated liver disease. CONCLUSIONS: Periodic laboratory monitoring is important in detecting hepatotoxicity at an early stage, thereby preventing mortality. Sequential reintroduction is often successful.     

静脉应用胺碘酮致急性肝损害六例临床分析

目的分析静脉应用胺碘酮致急性肝损害的临床特点及转归。方法对我院2001年1月至2005年1月静脉应用胺碘酮后致急性肝损害6例患者应用的适应证、剂量、肝损害出现的时间及转归进行分析。结果6例患者出现急性肝损害前静脉应用胺碘酮剂量为290—3000（1322．5±973．8）mg。6例患者用药后（40±29）h肝酶开始升高，天门冬氨酸氨基转移酶（AST）峰值为199—9885（2992±3453）U／L，丙氨酸氨基转移酶（ALT）峰值为247—6750（2583±2402）U／L。停药护肝降酶治疗后（28±17）d肝酶降至正常。结论静脉应用胺碘酮可以导致急性肝损害，应及时监测肝脏功能。     

Collagen type XVIII alpha 1 chain (COL18A1) variants affect the risk of anti‐tuberculosis drug‐induced hepatotoxicity: A prospective study

BackgroundThe role of collagen type XVIII alpha 1 chain (COL18A1) in anti‐tuberculosis drug‐induced hepatotoxicity (ATDH) has not been reported. This study aimed to explore the association between of COL18A1 variants and ATDH susceptibility.MethodsA total of 746 patients were enrolled in our study from December 2016 to April 2018, and all subjects in the study signed an informed consent form. The custom‐by‐design 2x48‐Plex SNPscanTM kit was used to genotype all selected 11 SNPs. Categorical variables were compared by chi‐square (χ²) or Fisher''s exact test, while continuous variables were compared by Mann‐Whitney''s U test. Plink was utilized to analyze allelic and genotypic frequencies, and genetic models. Multivariate logistic regression analyses were used to adjust potential factors. The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were also calculated.ResultsAmong patients with successfully genotyping, there were 114 cases and 612 controls. The mutant A allele of rs12483377 conferred the decreased risk of ATDH (OR = 0.13, 95%CI: 0.02–0.98, P = 0.020), and this significance still existed after adjusting age and gender (P = 0.024). The mutant homozygote AA genotype of rs12483377 was associated with decreased total protein levels (P = 0.018).ConclusionOur study first revealed that the A allele of COL18A1 rs12483377 was associated with the decreased risk of ATDH in the Western Chinese Han population, providing new perspective for the molecular prediction, precise diagnosis, and individual treatment of ATDH.     

腺苷受体及其介导的 cAMP-PKA 信号通路在对乙酰氨基酚致药物性肝损伤中的作用

目的：探讨腺苷受体及其介导的环磷酸腺苷-蛋白激酶 A (cAMP-PKA)信号通路在对乙酰氨基酚致药物性肝损伤中的作用。方法将20只雄性昆明种小鼠随机分为空白对照组和模型组。模型组给予对乙酰氨基酚500 mg/ kg,空白对照组给予等量的生理盐水,两组均为单次灌胃给药。24 h 后处死小鼠,检测谷丙转氨酶( ALT)、谷草转氨酶(AST)、碱性磷酸酶(ALP)、总胆汁酸(TBA),HE 染色观察肝脏病理变化;原位肝灌注法分离小鼠肝细胞;Real-Time qPCR 法、 Western blot 法分别检测肝细胞腺苷 A1受体(A1R)、A2A 受体( A2AR)、A2B 受体( A2BR)和 A3受体(A3R)水平;ELISA 法检测各组细胞 cAMP 含量;Western blot 法检测各组细胞 PKA、磷酸化-环磷酸腺苷反应元件结合蛋白(p-CREB)的表达水平。结果与空白对照组比较,模型组 AST、ALT、ALP、TBA 表达明显增加(P <0．01)且肝组织损伤明显;与空白对照组比较,模型组腺苷 A1R、A2AR的表达明显升高(P <0．01),cAMP 含量、PKA、p-CREB 蛋白的表达水平也相应增加(P <0．05)。结论对乙酰氨基酚致药物性肝脏损伤可能与 cAMP-PKA 信号通路有关。