基于整合证据链的中草药相关肝损伤诊断方法的应用评价

发布时间：2018-05-24 03:02

本文选题：药物肝损伤 + 中药　；参考：《中国人民解放军医学院》2017年博士论文

【摘要】：研究背景:近年来,随着中草药在国内外的广泛使用、药品不良反应监测体系的愈加完善以及消费者维权意识的不断提高,中草药及其制剂引起的肝损伤报道呈增加趋势,受到国内外学者的广泛关注。中草药相关肝损伤(HILI)研究首要问题之一就是临床诊断方法的建立,HILI因具有诸多复杂特性决定其诊断难度增加,课题组前期已建立基于整合证据链(iEC )的HILI诊断策略,但是,仍需进一步临床评价应用。目的:评价基于整合证据链(iEC ),结构化专家观点程序(SEOP )、RUCAM量表三者诊断效能差异;探索iEC法在回顾性与前瞻性临床研究中适用情况;并利用代谢组学方法筛查HILI的特征生物标志物。资料与方法:应用iEC、SEOP、RUCAM三种诊断方法对2010年1月至2015年12月入住解放军第302医院HILI患者进行回顾性分析,比较三种诊断方法结果差异情况;对2015年9月至2016年6月入住解放军302医院HILI与DILI患者进行前瞻性研究,比较三种诊断方法结果差异情况,分析HILI及DILI的临床特征与治疗预后;对2010年1月至2015年12月入住解放军第302医院药物导致急性肝衰竭(ALF)患者进行回顾性分析中药与西药导致ALF的临床特征差异;采用LC-MS技术开展HILI与健康者、急性乙型病毒性肝炎(HBV)、自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)的代谢组学研究,寻找可能诊断HILI的特异性生物标志物。结果:①390例HILI患者中,iEC法临床诊断率为42.8%,SEOP法临床诊断率为28.7%。在HILI/DILI构成比方面,iEC法、RUCAM法及SEOP法结果分别为10.4%、24.4%、7%。②187例HILI患者中,导致HILI的中药使用目的排在前5位的基础疾病有:胃炎(8.0%)、椎间盘突出(5.3%)、失眠(4.8%)、脱发(4.8%)、银屑病(4.3%)。78例(41.7%)患者服用中药汤剂,排在前5位的中草药分别为:何首乌(n=21 )、延胡索(n=10)、大黄(n=9)、柴胡(n=8)、补骨脂(n=7 )。64例(34.2% )患者应用中成药,涉及84种中成药。187例HILI患者中,iEC法临床诊断率为47.6%,SEOP法临床诊断率为29.9%; HILI/DILI构成比方面,iEC法、RUCAM法及SEOP法结果分别为23.2%、48.7%、14.6%。有110例(58.8%)治愈,30例(16.0%)发展为慢性药物性肝损伤,29例(15.5%)进展为肝硬化,3例(1.6%)发生死亡,15例(8.0%)失访。对187例HILI患者进行中医辨证分型,湿热黄疸(44.4%)为最常见证型,其次为肝郁脾虚(33.7%)和肝肾阴虚证型(15.0% )。102例DILI患者中,iEC法临床诊断率为65.7%,SEOP法临床诊断率为63.7%。③96例药物导致急性肝衰竭(DALF)患者中,中药导致DALF年龄偏大(42±18 vs. 34±18 years,p=0.04),与西药导致的急性肝衰竭患者相比,具有更高的肌酐、尿素氮值(155.2±108.8 vs. 97.5±130. 4 umol/L, p=0.047; 9.11±7.67 vs. 4.26±5.03 mmol/L, p=0.002)。中药导致急性肝衰竭患者更可能同时伴随肾功能异常(OR3.75; 95%CI,1.330～ 10.577)。中药与西药导致ALF两组患者在慢性化、死亡和肝移植预后方面无统计学差异(25 vs. 33%,40.6 vs 38.1%, 3.1 vs 7.1%, p=0.642)。96 例 DALF 中,肝细胞型患者占58例(60.4%),胆汁淤积型和混合型分别为16例(16.7%)和22例(22.9%)。④何首乌及其制剂导致的HILI患者平均年龄44岁,女性多见,以生发、乌发目的服用何首乌及其制剂常见。平均潜伏期为55天左右,肝损伤类型以肝细胞损伤型为主,多数患者可治愈,少部分患者可进展为慢性药物性肝损伤及肝硬化。76例行肝脏穿刺组织病理学检查的HILI患者中有47.4%患者外周血检测自身抗体阳性,将76例HILI患者分为自身抗体阳性组与阴性组,两组在年龄、过敏史、潜伏期、生化指标等方面无显著差异,但自身抗体阳性组进展为慢性药物性肝损伤患者明显高于阴性组(p0.05),同时,伴有界面炎病理学特征明显高于阴性组(p0.01)。⑤利用代谢组学的方法研究HILI与易混肝病的差异代谢产物,建立决策树模型并得到三个标志物:Calcitetrol, Valine : Adrenaline用于区别诊断HILI与其他易混肝病。结论:基于iEC的HILI诊断策略和方法适于HILI的诊断,与回顾性研究相比,前瞻性研究中更能体现该方法的优势,代谢组学技术可供HILI预警、诊断及发病机制研究提供新思路。
[Abstract]:Background: in recent years, with the extensive use of Chinese and foreign herbal medicine at home and abroad, the improvement of the monitoring system for adverse drug reactions and the increasing awareness of consumers' rights to rights, the report of liver injury caused by Chinese herbal medicine and its preparation is increasing, and it is widely concerned by scholars at home and abroad. The study of liver injury related to Chinese herbal medicine (HILI) is the first question. One of the problems is the establishment of clinical diagnostic methods. HILI has established a HILI diagnostic strategy based on integrated evidence chain (iEC) because of its complex characteristics. However, further clinical evaluation is still needed. Objective: To evaluate the application of integrated evidence chain (iEC), structured expert opinion program (SEOP), RUCAM quantity Table three differences in diagnostic effectiveness; explore the application of iEC in retrospective and prospective clinical studies; and screen the characteristic biomarkers of HILI by metabonomics. Data and methods: a retrospective analysis of the use of the three diagnostic methods of iEC, SEOP, and RUCAM to the HILI patients in the PLA 302nd hospital from January 2010 to December 2015 The difference between the results of the three diagnostic methods and the prospective study on the HILI and DILI patients in No.302 Hospital from September 2015 to June 2016 were prospectively studied, and the difference between the results of the three diagnostic methods was compared, the clinical features of HILI and DILI and the prognosis of the treatment were analyzed, and the drug caused by the 302nd Hospital of PLA from January 2010 to December 2015 resulted in the acute liver disease. The patients with exhaustion (ALF) had a retrospective analysis of the differences in the clinical characteristics of ALF caused by traditional Chinese medicine and Western medicine; the metabolomics of HILI and healthy persons, acute hepatitis B (HBV), autoimmune hepatitis (AIH), and primary biliary cirrhosis (PBC) was studied by LC-MS, and the specific biomarkers for the diagnosis of HILI were found. Results: (1) 3 Of the 90 cases of HILI, the clinical diagnostic rate of iEC was 42.8%, and the clinical diagnostic rate of SEOP was 28.7%. in the HILI/DILI constitution ratio. The results of iEC, RUCAM and SEOP were respectively 10.4%, 24.4%, and 187 of the 187 HILI patients, leading to the basic diseases of HILI Chinese medicine used in the top 5: gastritis (8%), disc herniation (5.3%), and insomnia (4.8%). Alopecia (4.8%), psoriasis (4.3%).78 (41.7%) patients (41.7%) took the decoction of traditional Chinese medicine, the first 5 Chinese herbs were: n=21, n=10, n=9, n=8, n=7.64 cases (34.2%), including 84 Chinese patent medicines in HILI patients, the clinical diagnosis rate of iEC method was 47.6%, SEOP method clinical diagnosis The rate of HILI/DILI was 29.9%; the results of iEC, RUCAM and SEOP were respectively 23.2%, 48.7%, and 14.6%. were cured in 110 cases (58.8%), 30 (16%) developed chronic drug-induced liver injury, 29 (15.5%) progressed to cirrhosis, 3 cases (1.6%) died, 15 cases (8%) were lost. For the most common syndrome types, followed by liver depression and spleen deficiency (33.7%) and liver kidney yin deficiency syndrome (15%).102 patients with DILI, the clinical diagnostic rate of iEC was 65.7%, and the clinical diagnostic rate of SEOP was 63.7%. (DALF) in the patients with 63.7%. (DALF), and the traditional Chinese medicine resulted in the large DALF age (42 + 18 vs. 34 + 18 years, p=0.04), and the acute liver caused by western medicine. The patients with exhaustion had higher creatinine, urea nitrogen value (155.2 + 108.8 vs. 97.5 + 130.4 umol/L, p=0.047; 9.11 + 7.67 vs. 4.26 + 5.03 mmol/L, p=0.002). Chinese medicine caused acute liver failure more likely to accompany renal dysfunction (OR3.75; 95%CI, 1.330 to 10.577). Chinese medicine and Western medicine led to the chronicity, death of group ALF two. Death There was no statistical difference in the prognosis of death and liver transplantation (25 vs. 33%, 40.6 vs 38.1%, 3.1 vs 7.1%, p=0.642) in.96 case DALF, hepatocyte type in 58 cases (60.4%), cholestasis and mixed type in 16 (16.7%) and 22 (22.9%) respectively. (4) the average age of HILI patients caused by Polygonum multiflorum and its preparation was 44 years old, female more common, hair, and hair. Objective the use of Polygonum multiflorum and its preparation is common. The average incubation period is about 55 days. The type of liver injury is mainly liver cell damage type, most patients can be cured. A few patients can advance to 47.4% of the patients with chronic drug-induced liver injury and liver cirrhosis.76 routine histopathological examination of liver puncture, and 47.4% patients can detect autoantibodies in peripheral blood. Positive, 76 cases of HILI patients were divided into autoantibody positive group and negative group. The two groups had no significant difference in age, allergy history, latent period and biochemical index, but the progression of autoantibody positive group was significantly higher than that of negative group (P0.05) in chronic drug induced liver injury (P0.05), meanwhile, the pathological features of interface inflammation were significantly higher than that of negative group (P0.01). The metabolic products of HILI and mixed liver disease were studied by metabonomics, and a decision tree model was established and three markers: Calcitetrol, Valine: Adrenaline were used to distinguish between HILI and other mixed liver diseases. Conclusion: iEC based HILI diagnosis strategies and methods are suitable for the diagnosis of HILI, compared with retrospective study, prospective research Metabonomics can provide new ideas for early warning, diagnosis and pathogenesis of HILI.
【学位授予单位】：中国人民解放军医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R575

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