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.     

Association of genetic variants with anti-tuberculosis drug induced hepatotoxicity: A high resolution melting analysis

BackgroundTuberculosis (TB) treatment remains a challenge owing to the high incidence of drug induced hepatotoxicity (DIH). Apart from environmental factors, single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs), nuclear receptors (NRs) and transporter proteins (TPs) contribute to DIH. In the present study, we report known and novel SNPs in a total of seven genes of DMEs, NRs and TPs with high resolution melting (HRM) technique.MethodsDNA samples of 185 TB patients of Western Indian population, of which 50 showed DIH, were analyzed. Grouping of the temperature-shifted difference plots obtained from the DNA melt curves enables identification of known and novel SNPs. Representative samples of each group were sequenced.ResultsWe report 18 novel SNPs, of which 3 are in 5′-UTR, 14 in exonic and 1 in intronic region. Of the SNPs in exons, 7 non-synonymous, 3 synonymous and 4 deletion mutations were observed. Among the known SNPs, CYP2E1 wild-type, NAT2¹5 mutant and NAT2¹6 heterozygous genotypes were associated with DIH (p < 0.05). Among the novel SNPs, group 2 of SLCO1B1 showed a significant association (p < 0.05).ConclusionsWhile several SNPs showed borderline p values between 0.05 and 0.15, the confidence in association can be improved further by using larger data sets.     

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。