本文選題：肝癌 + 肝硬化　； 參考：《浙江大學(xué)》2017年碩士論文

【摘要】：目的比較分析肝硬化、肝癌和自身免疫性肝病患者的腸道優(yōu)勢菌群特點及其與臨床指標(biāo)的相關(guān)性,篩選能夠早期診斷肝癌的特異性微生態(tài)指標(biāo)。方法收集2014年1月至2017年2月間在浙江大學(xué)醫(yī)學(xué)院附屬第一醫(yī)院及杭州樹蘭醫(yī)院就診并入組的患者共117例和健康對照30例。根據(jù)臨床診斷,將病例組分為肝硬化(包括乙肝肝硬化和酒精性肝硬化)、肝癌和自身免疫性肝病(包括原發(fā)性膽汁性肝硬變與自身免疫性肝炎)三組,分析三組患者的臨床表現(xiàn)、實驗室指標(biāo)、Child-Pugh評分、MELD評分、腸道優(yōu)勢菌群的特點和差異性及其與臨床指標(biāo)的相關(guān)性;運用單因素方差分析比較病例組之間及其與健康對照組之間的腸道優(yōu)勢菌群差異性,采用Pearson相關(guān)性分析,利用Logistic回歸進(jìn)行單因素分析,篩選出肝癌的特異性腸道細(xì)菌,建立指標(biāo)模型;并將指標(biāo)模型進(jìn)行ROC曲線擬合檢驗,計算其敏感性和特異性。結(jié)果本研究中共納入117例慢性肝病患者,以中老年人群為主,平均年齡55.4±12歲,男/女=1.39:1。肝硬化及肝癌患者以男性為主,所占比例分別為79.5%與81.6%,自身免疫性肝病患者則以女性為主(94.3%)。肝癌與肝硬化患者的Child-Pugh評分及MELD評分均存在極顯著性差異(P0.001)。肝癌及肝硬化患者多以全身癥狀及消化道不適為主要臨床表現(xiàn),且50%以上患者有門脈高壓癥表現(xiàn)�？傮w上,肝硬化組并發(fā)癥發(fā)生率總體高于肝癌組。肝癌、肝硬化、自身免疫性肝病及健康對照四組組間對比結(jié)果提示普拉梭菌、腸球菌、類桿菌、雙歧桿菌、乳酸菌、柔嫩梭菌、直腸真桿菌、腸桿菌及B/E值均存在極顯著性差異(P0.01)。與健康對照組相比,三個病例組有益細(xì)菌雙歧桿菌以及B/E值均顯著降低,有害菌腸桿菌均顯著增加;肝硬化患者腸道柔嫩梭菌顯著減少。與其他三組相比,自身免疫性肝病組腸球菌含量顯著減少而類桿菌顯著增多。相對于其他三組,肝癌患者腸道中具有抗炎作用及產(chǎn)丁酸作用的普拉梭菌相對較少而直腸真桿菌較多。腸道菌群與實驗室指標(biāo)相關(guān)性分析結(jié)果顯示:肝癌組中,普拉梭菌與中性粒細(xì)胞百分比(NEUT%)及纖維蛋白原(FBG),直腸真桿菌與NEUT%、超敏C反應(yīng)蛋白(CRP)、FBG、凝血酶原時間(PT)及Child-Pugh和MELD評分,腸球菌與血小板(PLT),類桿菌與FBG,均呈負(fù)相關(guān),而直腸真桿菌與ALB呈正相關(guān),且該組中的相關(guān)性均為中度相關(guān)。肝硬化組中,普拉梭菌和直腸真桿菌均與谷丙轉(zhuǎn)氨酶(ALT)及谷草轉(zhuǎn)氨酶(AST)呈正相關(guān),而與CRP呈負(fù)相關(guān),類桿菌和柔嫩梭菌與白細(xì)胞計數(shù)(WBC)、中性粒細(xì)胞絕對值(NEUT#)、CRP,類桿菌與Child-Pugh評分,酪酸梭菌與CRP,均呈負(fù)相關(guān),而腸球菌與CRP呈正相關(guān)。利用Logistic回歸進(jìn)行單因素分析篩選出肝癌特異性微生態(tài)指標(biāo)即直腸真桿菌與普拉梭菌的對數(shù)值比值(1gEr/1gFp),其與血清甲胎蛋白(AFP)均能區(qū)分肝癌與非肝癌患者,但1gEr/1gFp能夠鑒別出AFP值在正常范圍內(nèi)的肝癌病例及AFP高于正常值的肝硬化病例(P0.01)。將AFP、1gEr/1gFp進(jìn)行二元Logistic回歸分析顯示,1gEr/1gFp(P0.05)對肝癌的診斷價值大于AFP(P≥0.05);將兩個指標(biāo)及兩者聯(lián)合對肝癌的檢測進(jìn)行ROC曲線擬合:對于肝癌與肝硬化,1gEr/1gFp與AFP聯(lián)合檢測的ROC曲線下面積最大(AUC=0.786),對肝癌的診斷效果最好,其次為 1gEr/1gFp(AUC=0.748),均優(yōu)于 AFP(AUC=0.664);且 1gEr/1gFp 的特異性較高(97.7%)。在肝癌與自身免疫性肝病兩組,兩者聯(lián)合檢測對肝癌的診斷效果最好(AUC=0.949),且其敏感性與特異性分別為81.6%和100%。對于肝癌與高AFP肝硬化以及低AFP肝癌與肝硬化,1gEr/1gFp的ROC曲線下面積均大于0.8,對肝癌的診斷具有一定的的準(zhǔn)確性,且1gEr/1gFp對于區(qū)分肝癌與高AFP肝硬化的特異性較高為93.3%,而區(qū)分低AFP肝癌與肝硬化的敏感性較好為76.5%。對于肝癌與非肝癌患者,1gEr/1gFp與AFP聯(lián)合檢測對肝癌的診斷效果最好(AUC=0.804),其次為 1gEr/1gFp(AUC=0.752),1gEr/1gFp 及聯(lián)合檢測對肝癌診斷的特異性高達(dá)98.4%。結(jié)論肝癌、肝硬化及自身免疫性肝病患者的腸道優(yōu)勢菌群結(jié)構(gòu)發(fā)生了顯著的變化,有益細(xì)菌雙歧桿菌顯著減少,有害菌腸桿菌顯著增加。在肝硬化發(fā)展到肝癌的過程中,腸道菌群可能發(fā)生了一些特異性的改變。肝癌患者腸道中同樣具有抗炎作用及產(chǎn)丁酸作用的普拉梭菌相對較低,而直腸真桿菌相對較高。肝癌及肝硬化患者腸道菌群與炎癥指標(biāo)、肝功能及凝血功能相關(guān)性較高。腸道微生態(tài)指標(biāo)1gEr/1gFp對肝癌診斷的價值大于血清AFP指標(biāo);1gEr/1gFp能夠很好地區(qū)分出AFP值在正常范圍內(nèi)的肝癌患者以及AFP高于正常值的肝硬化患者;總體上,1gEr/1gFp及聯(lián)合檢測對肝癌診斷的特異性優(yōu)于AFP,且1gEr/1gFp與AFP聯(lián)合檢測對肝癌的診斷效果最好。
[Abstract]:Objective to compare and analyze the characteristics of intestinal predominant flora in patients with liver cirrhosis, liver cancer and autoimmune liver disease, and to select the specific microecological indicators for early diagnosis of liver cancer. Methods the methods were collected from January 2014 to February 2017 at the first hospital of Zhejiang University and Hangzhou Shu Lan hospital. A total of 117 patients and 30 healthy controls were divided into three groups: liver cirrhosis (including hepatitis B cirrhosis and alcoholic cirrhosis), liver cancer and autoimmune liver disease (including primary biliary cirrhosis and autoimmune hepatitis), and analyzed the clinical manifestation, laboratory index, Child-Pugh score, MEL of the patients in the three groups. D score, the characteristics and differences of intestinal dominant flora and the correlation with clinical indexes, and using single factor variance analysis to compare the difference of intestinal dominant bacteria groups between the cases and the healthy control groups, using the Pearson correlation analysis, and using the Logistic regression to carry out single factor analysis to screen out the specific intestinal microflora of the liver cancer. The index model was established, and the index model was tested by ROC curve fitting to calculate its sensitivity and specificity. Results 117 cases of chronic liver disease were included in the study. The average age was 55.4 + 12 years old. The male / female =1.39:1. liver cirrhosis and liver cancer patients were mainly male, and the proportion of them was 79.5% and 81.6%, respectively. Patients with immune liver disease were predominantly female (94.3%). There were significant differences in Child-Pugh scores and MELD scores in patients with liver cancer and cirrhosis (P0.001). The main clinical manifestations of liver cancer and liver cirrhosis were systemic symptoms and digestive discomfort, and more than 50% of the patients had portal hypertension. The overall rate of birth was higher than that of the liver cancer group. The results of four groups of liver cancer, liver cirrhosis, autoimmune liver disease and health control group showed that there were significant differences in the value of prasulosis, Enterococcus, bacillus, Bifidobacterium, lactic acid bacteria, Clostridium tenoteriae, rectal true bacilli, Enterobacteriaceae and B/E (P0.01). Compared with the healthy control group, the three case groups were more beneficial than those in the healthy control group. The value of Bifidobacterium and B/E decreased significantly, and the Enterobacter Clostridium in the intestinal tract of the patients with liver cirrhosis significantly decreased. Compared with the other three groups, the content of Enterococcus in the autoimmune liver disease group was significantly reduced and the bacilli increased significantly. Compared with the other three groups, the intestinal cancer patients have the anti inflammatory effect and the production of butyric acid. The results of correlation analysis between intestinal flora and laboratory indicators showed that the percentage of prasperic and neutrophils (NEUT%) and fibrinogen (FBG), protobacter and NEUT%, hypersensitive C reactive protein (CRP), FBG, prothrombin time (PT), Child-Pugh and MELD scores in the liver cancer group were found in the liver cancer group. Enterococcus and platelets (PLT), bacilli and FBG were negatively correlated, while true rectal bacillus was positively correlated with ALB, and the correlation in this group was moderately related. In the liver cirrhosis group, pralopilia and true rectal Bacillus were positively correlated with alanine aminotransferase (ALT) and cereal transaminase (AST), but negatively related to CRP, Bacillus subtilis and Clostridium tenotuum and white Cell count (WBC), absolute neutrophils (NEUT#), CRP, bacilli and Child-Pugh scores, Clostridium butyricum and CRP were negatively correlated, and Enterococcus was positively correlated with CRP. The specific microecological index of liver cancer, namely, the specific ratio of Enterococcus enteriformis and praticelline (1gEr/1gFp), was screened by Logistic regression. Serum alpha fetoprotein (AFP) can distinguish between liver cancer and non liver cancer patients, but 1gEr/1gFp can identify AFP value in normal range of liver cancer cases and AFP higher than normal value of liver cirrhosis (P0.01). AFP, 1gEr/1gFp two yuan Logistic regression analysis showed that 1gEr/1gFp (P0.05) for the diagnosis of liver cancer is greater than AFP (P > 0.05); two will be ROC curve fitting for the detection of liver cancer by combination of indexes and both: for liver cancer and liver cirrhosis, the area of ROC curve under the combination of 1gEr/1gFp and AFP was the largest (AUC=0.786), which was best for the diagnosis of liver cancer, followed by 1gEr/1gFp (AUC=0.748), which was superior to AFP (AUC=0.664), and the specificity of 1gEr/1gFp was higher (97.7%). In liver cancer and itself In the two groups of immune liver diseases, the combined detection of liver cancer was the best (AUC=0.949), and its sensitivity and specificity were 81.6% and 100%. for liver cancer and high AFP liver cirrhosis and low AFP liver cancer and liver cirrhosis. The area of ROC curve under 1gEr/1gFp was more than 0.8, and the diagnosis of liver cancer was accurate and 1gEr/1gFp for the diagnosis of liver cancer. The specificity of distinguishing liver cancer from high AFP liver cirrhosis is 93.3%, and the sensitivity of differentiating the low AFP liver cancer and liver cirrhosis is better than that of 76.5%. for the patients with liver cancer and non liver cancer. The combination of 1gEr/1gFp and AFP for the diagnosis of liver cancer is best (AUC=0.804), followed by 1gEr/1gFp (AUC= 0.752), 1gEr/1gFp and the specificity of the combined detection of the diagnosis of liver cancer. The intestinal flora structure of the patients with liver cancer, liver cirrhosis and autoimmune liver disease was significantly changed, the beneficial bacterial Bifidobacterium decreased significantly and the Enterobacteriaceae increased significantly. During the development of liver cirrhosis to liver cancer, the intestinal microflora may have some specific changes. The intestinal tract of the liver cancer patients was 98.4%.. The bacteria of pralopulac is relatively low in anti-inflammatory and butyric acid production, while the true rectal bacillus is relatively high. The intestinal microflora of the patients with liver cancer and liver cirrhosis has a higher correlation with the inflammatory markers, liver function and blood coagulation function. The value of the intestinal microecological index 1gEr/1gFp is greater than the serum AFP index; 1gEr/1gFp can be a good area. The AFP value in the normal range of liver cancer patients and the patients with AFP higher than the normal value of liver cirrhosis; in general, the specificity of 1gEr/1gFp and combined detection on the diagnosis of liver cancer is superior to AFP, and the combined detection of 1gEr/1gFp and AFP is the best for the diagnosis of liver cancer.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R575;R735.7

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