發(fā)布時間：2018-05-24 03:02

  本文選題：藥物肝損傷 + 中藥　； 參考：《中國人民解放軍醫(yī)學(xué)院》2017年博士論文

【摘要】：研究背景:近年來,隨著中草藥在國內(nèi)外的廣泛使用、藥品不良反應(yīng)監(jiān)測體系的愈加完善以及消費者維權(quán)意識的不斷提高,中草藥及其制劑引起的肝損傷報道呈增加趨勢,受到國內(nèi)外學(xué)者的廣泛關(guān)注。中草藥相關(guān)肝損傷(HILI)研究首要問題之一就是臨床診斷方法的建立,HILI因具有諸多復(fù)雜特性決定其診斷難度增加,課題組前期已建立基于整合證據(jù)鏈(iEC )的HILI診斷策略,但是,仍需進一步臨床評價應(yīng)用。目的:評價基于整合證據(jù)鏈(iEC ),結(jié)構(gòu)化專家觀點程序(SEOP )、RUCAM量表三者診斷效能差異;探索iEC法在回顧性與前瞻性臨床研究中適用情況;并利用代謝組學(xué)方法篩查HILI的特征生物標(biāo)志物。資料與方法:應(yīng)用iEC、SEOP、RUCAM三種診斷方法對2010年1月至2015年12月入住解放軍第302醫(yī)院HILI患者進行回顧性分析,比較三種診斷方法結(jié)果差異情況;對2015年9月至2016年6月入住解放軍302醫(yī)院HILI與DILI患者進行前瞻性研究,比較三種診斷方法結(jié)果差異情況,分析HILI及DILI的臨床特征與治療預(yù)后;對2010年1月至2015年12月入住解放軍第302醫(yī)院藥物導(dǎo)致急性肝衰竭(ALF)患者進行回顧性分析中藥與西藥導(dǎo)致ALF的臨床特征差異;采用LC-MS技術(shù)開展HILI與健康者、急性乙型病毒性肝炎(HBV)、自身免疫性肝炎(AIH)、原發(fā)性膽汁性肝硬化(PBC)的代謝組學(xué)研究,尋找可能診斷HILI的特異性生物標(biāo)志物。結(jié)果:①390例HILI患者中,iEC法臨床診斷率為42.8%,SEOP法臨床診斷率為28.7%。在HILI/DILI構(gòu)成比方面,iEC法、RUCAM法及SEOP法結(jié)果分別為10.4%、24.4%、7%。②187例HILI患者中,導(dǎo)致HILI的中藥使用目的排在前5位的基礎(chǔ)疾病有:胃炎(8.0%)、椎間盤突出(5.3%)、失眠(4.8%)、脫發(fā)(4.8%)、銀屑病(4.3%)。78例(41.7%)患者服用中藥湯劑,排在前5位的中草藥分別為:何首烏(n=21 )、延胡索(n=10)、大黃(n=9)、柴胡(n=8)、補骨脂(n=7 )。64例(34.2% )患者應(yīng)用中成藥,涉及84種中成藥。187例HILI患者中,iEC法臨床診斷率為47.6%,SEOP法臨床診斷率為29.9%; HILI/DILI構(gòu)成比方面,iEC法、RUCAM法及SEOP法結(jié)果分別為23.2%、48.7%、14.6%。有110例(58.8%)治愈,30例(16.0%)發(fā)展為慢性藥物性肝損傷,29例(15.5%)進展為肝硬化,3例(1.6%)發(fā)生死亡,15例(8.0%)失訪。對187例HILI患者進行中醫(yī)辨證分型,濕熱黃疸(44.4%)為最常見證型,其次為肝郁脾虛(33.7%)和肝腎陰虛證型(15.0% )。102例DILI患者中,iEC法臨床診斷率為65.7%,SEOP法臨床診斷率為63.7%。③96例藥物導(dǎo)致急性肝衰竭(DALF)患者中,中藥導(dǎo)致DALF年齡偏大(42±18 vs. 34±18 years,p=0.04),與西藥導(dǎo)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)。中藥導(dǎo)致急性肝衰竭患者更可能同時伴隨腎功能異常(OR3.75; 95%CI,1.330～ 10.577)。中藥與西藥導(dǎo)致ALF兩組患者在慢性化、死亡和肝移植預(yù)后方面無統(tǒng)計學(xué)差異(25 vs. 33%,40.6 vs 38.1%, 3.1 vs 7.1%, p=0.642)。96 例 DALF 中,肝細胞型患者占58例(60.4%),膽汁淤積型和混合型分別為16例(16.7%)和22例(22.9%)。④何首烏及其制劑導(dǎo)致的HILI患者平均年齡44歲,女性多見,以生發(fā)、烏發(fā)目的服用何首烏及其制劑常見。平均潛伏期為55天左右,肝損傷類型以肝細胞損傷型為主,多數(shù)患者可治愈,少部分患者可進展為慢性藥物性肝損傷及肝硬化。76例行肝臟穿刺組織病理學(xué)檢查的HILI患者中有47.4%患者外周血檢測自身抗體陽性,將76例HILI患者分為自身抗體陽性組與陰性組,兩組在年齡、過敏史、潛伏期、生化指標(biāo)等方面無顯著差異,但自身抗體陽性組進展為慢性藥物性肝損傷患者明顯高于陰性組(p0.05),同時,伴有界面炎病理學(xué)特征明顯高于陰性組(p0.01)。⑤利用代謝組學(xué)的方法研究HILI與易混肝病的差異代謝產(chǎn)物,建立決策樹模型并得到三個標(biāo)志物:Calcitetrol, Valine : Adrenaline用于區(qū)別診斷HILI與其他易混肝病。結(jié)論:基于iEC的HILI診斷策略和方法適于HILI的診斷,與回顧性研究相比,前瞻性研究中更能體現(xiàn)該方法的優(yōu)勢,代謝組學(xué)技術(shù)可供HILI預(yù)警、診斷及發(fā)病機制研究提供新思路。
[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.
【學(xué)位授予單位】：中國人民解放軍醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R575

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