本文選題：肝硬化 + 組織學(xué)分級�。� 參考：《南方醫(yī)科大學(xué)》2015年碩士論文

【摘要】：研究背景與目的：在國內(nèi),肝硬化在組織學(xué)上是纖維化的終末階段(S4),臨床上又依據(jù)是否有肝功能減退、門靜脈高壓癥狀及各種并發(fā)癥,將肝硬化分為代償期肝硬化與失代償期肝硬化。隨著對肝硬化研究的深入以及抗纖維化治療的發(fā)展,人們發(fā)現(xiàn)肝硬化患者的疾病嚴(yán)重程度存在較大的差別,從毫無癥狀,到出現(xiàn)腹水、食管胃底靜脈曲張或破裂出血、肝性腦病甚至死亡。但在組織學(xué)上肝硬化僅籠統(tǒng)地歸為一個級別,我們亟須對肝硬化進(jìn)行進(jìn)一步分級,以指導(dǎo)對患者病情的評估與臨床干預(yù)的選擇。近年來國外學(xué)者在肝纖維化METAVIR分級系統(tǒng)的基礎(chǔ)上制定了Laennec肝纖維化分級系統(tǒng),并證實了該分級系統(tǒng)能夠較好地預(yù)測肝硬化患者的預(yù)后。FibroScan是基于超聲技術(shù)基礎(chǔ)上的快速診斷肝纖維化嚴(yán)重程度的方法,不必對患者進(jìn)行肝臟穿刺活檢即可快速評估纖維化嚴(yán)重程度,且具有一定的準(zhǔn)確度,因此近些年對此項技術(shù)進(jìn)行了大量研究與推廣應(yīng)用,并證明了此項技術(shù)對于診斷中重度纖維化具有較高臨床應(yīng)用價值。那么我們是否可以應(yīng)用FibroScan技術(shù)對肝硬化的嚴(yán)重程度進(jìn)行進(jìn)一步的評估,所測得的FibroScan值與肝硬化的Laennec分級之間是否具有相關(guān)性,此類文獻(xiàn)在國內(nèi)報道較少。本研究旨在對肝硬化組織學(xué)分級與臨床肝臟功能積分(Child-Pugh評分、MELD評分)及肝臟FibroScan值的相關(guān)性進(jìn)行初步探討。肝硬化門靜脈高壓癥是由肝硬化引起的門靜脈血流受阻、血液瘀滯,進(jìn)而導(dǎo)致門靜脈系統(tǒng)壓力升高的一類疾病的統(tǒng)稱。臨床表現(xiàn)主要有脾大、脾功能亢進(jìn)、食管胃底靜脈曲張、腹水等。目前臨床上有各種各樣的方法來評估門靜脈壓力,包括有創(chuàng)測定法(門靜脈導(dǎo)管術(shù)法、B超引導(dǎo)下門靜脈穿刺法、術(shù)中直接測定等)和無創(chuàng)測定法(通過多普勒超聲、CT、MRI、放射性核素等測定血流動力學(xué)指標(biāo)來評估門靜脈壓力)。雖然公認(rèn)的判斷PHT的“金標(biāo)準(zhǔn)”為肝靜脈壓力梯度(hepatic vein pressure gradient, HVPG),但對于需要手術(shù)治療的患者,術(shù)中直接測定門靜脈壓力因操作簡單、準(zhǔn)確,且可動態(tài)觀察壓力的變化與手術(shù)治療的效果,具有不可替代的地位。用上述各種方法測定的門靜脈壓力可以用來指導(dǎo)臨床干預(yù)和手術(shù)方式的選擇,并對患者的預(yù)后進(jìn)行初步評估。但患者門靜脈壓力與各種臨床指標(biāo)之間是否存在相關(guān)性,相關(guān)程度如何,國內(nèi)文獻(xiàn)報道較少。本文通過對開腹手術(shù)中直接測定的門靜脈壓力與患者臨床資料進(jìn)行回顧性分析,以期對二者的相關(guān)性進(jìn)行初步探討。方法：1、收集2012年1月至2014年1月在南方醫(yī)科大學(xué)南方醫(yī)院住院并經(jīng)肝臟穿刺活檢證實為肝硬化的病例,排除肝癌、心腦血管疾病、急性感染、腎病等其他疾病后共60例,收集的臨床資料包括白蛋白(ALB)、凝血酶原時間(PT)、凝血酶原時間國際標(biāo)準(zhǔn)化比值(PT-INR)、總膽紅素(TBIL)、肌酐(Cr)以及患者肝性腦病及腹水的嚴(yán)重程度等。所有病例臨床資料的收集均在肝臟穿刺前一天完成。運(yùn)用Laennec分級系統(tǒng)對病理切片進(jìn)行組織學(xué)分級,分析肝硬化不同分級間FibroScan測定值是否存在差異、FibroScan測定值用來判斷肝硬化嚴(yán)重程度的效果如何以及肝臟功能評分與肝硬化程度的相關(guān)性。2、收集2012年1月至2014年6月在南方醫(yī)科大學(xué)南方醫(yī)院肝膽外科住院并診斷為肝硬化門靜脈高壓癥患者的臨床資料,所有患者均行開腹手術(shù)且術(shù)中直接測定門靜脈自由壓(free portal pressure, FPP),并排除肝癌、心腦血管疾病、急性感染、腎病等其他疾病后共50例。記錄患者術(shù)中測得的門靜脈自由壓(FPP),依據(jù)門靜脈壓力的高低,以30 cmH20為分界點(diǎn),將患者分為Ⅰ、Ⅱ兩組,比較兩組間的臨床指標(biāo)是否有差異,并對FPP與臨床指標(biāo)進(jìn)行相關(guān)性分析與多元回歸分析。3、統(tǒng)計學(xué)處理：計量資料滿足正態(tài)分布時以均數(shù)±標(biāo)準(zhǔn)差(x±s)表示,否則用中位數(shù)(極小值～極大值)表示,對成組設(shè)計的兩個樣本均數(shù)的比較采用獨(dú)立樣本t檢驗,對成組設(shè)計的多個樣本均數(shù)的比較采用單因素方差分析,計數(shù)資料采用X2檢驗；雙變量正態(tài)分布資料相關(guān)分析采用Pearson相關(guān)分析,非雙變量正態(tài)分布資料采用Spearman相關(guān)分析；繪制受試者工作特征(receiver operating characteristic, ROC)曲線,以敏感度與特異度之和的最大值所對應(yīng)的肝臟彈性值(liver stiffness measurement, LSM)作為最佳界值。各臨床指標(biāo)對門靜脈壓力的影響作用采用逐步多元回歸分析。P0.05代表有統(tǒng)計學(xué)意義。所有統(tǒng)計學(xué)資料采用SPSS21.0統(tǒng)計學(xué)軟件處理。結(jié)果：1.組織學(xué)分組為肝硬化輕度組27例(45%)、中度組21例(35%)、重度組12例(20%)。肝硬化輕、中、重度組的肝臟FibroScan測定值分別為14.90±5.54、25.23±10.11、33.99±13.55 (Kpa),三組間的差異具有顯著性(P0.05)；組內(nèi)比較后發(fā)現(xiàn)輕度組與中度組(P=0.001)、輕度組與重度組(P＝0.001)均值的差異具有統(tǒng)計學(xué)意義,中度組與重度組均值的差異無統(tǒng)計學(xué)意義(P=0.181)。肝臟FibroScan測定值用于判斷中重度肝硬化和重度肝硬化的ROC曲線下面積分別為0.908、0.865。選肝臟彈性值LSM=16.05Kpa為界點(diǎn)時,診斷中重度肝硬化的靈敏度為97%,陰性預(yù)測值(NPV)為95%,陰性擬然比(NLR)為0.04,特異度為70%,陽性預(yù)測值(PPV)為80%,陽性擬然比(PLR)為3.28,正確率為85%。選LSM=21.10Kpa為診斷界點(diǎn)時,診斷重度肝硬化的靈敏度為92%,陰性預(yù)測值(NPV)為97%,陰性擬然比(NLR)為0.12,特異度為71%,陽性預(yù)測值(PPV)為44%,陽性擬然比(PLR)為3.14,正確率為75%。肝硬化輕、中、重度組的Child-Pugh評分分別為5.61±1.14、6.05±1.21、5.74±0.93,三組間的差異無顯著性(P0.05)；肝硬化輕、中、重度組的MELD評分分別為5.90±4.22、7.14±5.33、7.03±5.13,三組間的差異無顯著性(P0.05)。2.門靜脈壓力不同分組間有顯著差異的指標(biāo)有淋巴細(xì)胞百分?jǐn)?shù)(L)、中性粒細(xì)胞百分?jǐn)?shù)(N)、總膽紅素(TBIL)、直接膽紅素(DBIL)、凝血酶原活動度(PTA)、脾臟長、脾臟寬、CHILD評分,共9項指標(biāo)；隨著FPP增大, N、TBIL、DBIL、脾臟長、脾臟寬、CHILD評分逐漸增大,L、PTA逐漸減小。FPP與L、谷丙轉(zhuǎn)氨酶(ALT)、谷草轉(zhuǎn)氨酶(AST)、球蛋白(GLB)、A/G、DBIL、PTA、血漿纖維蛋白原測定(FIB)、脾臟長、脾臟寬、門靜脈內(nèi)徑、CHILD評分及腹水量存在顯著相關(guān)關(guān)系,其中與L、A/G、PTA、FIB存在負(fù)相關(guān)關(guān)系,與其余指標(biāo)存在正相關(guān)關(guān)系,但與這些指標(biāo)的相關(guān)關(guān)系并不密切(相關(guān)系數(shù)小于0.5)。以門靜脈自由壓(FPP)為因變量,以各項臨床指標(biāo)為自變量,采用逐步回歸的方法進(jìn)行多元線性回歸分析,最終進(jìn)入回歸方程的自變量為腹水量、門靜脈內(nèi)徑、GLB、L,說明腹水量、門靜脈內(nèi)徑、GLB、L與FPP存在線性關(guān)系,建立的回歸方程為FPP=0.366×門靜脈內(nèi)徑+0.425×腹水量+0.375×球蛋白—0.300×淋巴細(xì)胞百分?jǐn)?shù)。此模型的復(fù)相關(guān)系數(shù)R=0.698,決定系數(shù)R2=0.487,調(diào)整的R2=0.435,說明這四個變量可以解釋因變量FPP 43.5%的變化。另外,根據(jù)各個變量標(biāo)準(zhǔn)化回歸系數(shù)的大小可以看出,四個變量對FPP影響的大小依次為腹水量、球蛋白、門靜脈內(nèi)徑和淋巴細(xì)胞百分?jǐn)?shù)。結(jié)論：1.肝硬化輕、中、重度組的肝臟FibroScan測定值之間存在顯著差異,肝臟FibroScan測定值用于判斷中重度肝硬化和重度肝硬化的ROC曲線下面積分別為0.908、0.865,從而說明FibroScan在診斷肝硬化嚴(yán)重程度方面有一定的應(yīng)用價值；肝硬化程度與肝臟功能評分無顯著相關(guān)性。2.肝硬化門靜脈高壓癥患者I、II兩組之間有多個臨床指標(biāo)存在顯著性差異,門靜脈壓力與L、ALT, AST, GLB、A/G, DBIL、PTA、FIB、脾臟長、脾臟寬、門靜脈內(nèi)徑、CHILD評分及腹水量存在顯著相關(guān)關(guān)系,并可以通過基于腹水量、球蛋白、門靜脈內(nèi)徑和淋巴細(xì)胞百分?jǐn)?shù)的多元線性回歸模型對門靜脈壓力進(jìn)行初步評估。
[Abstract]:Research background and purpose: in China, liver cirrhosis is histologically the final stage of fibrosis (S4). The liver cirrhosis is divided into compensatory cirrhosis and decompensated cirrhosis depending on whether the liver function is hypofunction, the symptoms of portal hypertension and all kinds of complications. With the deep study of cirrhosis and the development of anti fibrosis treatment There is a large difference in the severity of the disease in patients with liver cirrhosis, from asymptomatic, to ascites, esophageal varices or ruptured bleeding, and hepatic encephalopathy and even death. However, in histologically, the liver cirrhosis is only in a general level, and we are urgently required to further classify cirrhosis of the liver to guide the patient's condition. In recent years, foreign scholars have developed a Laennec classification system for liver fibrosis based on the METAVIR classification system of liver fibrosis, and confirmed that the classification system can predict the prognosis of liver cirrhosis patients better than that of.FibroScan, which is based on the rapid diagnosis of the severity of liver fibrosis based on ultrasound technology. The method, without liver biopsy, can quickly evaluate the severity of fibrosis and has a certain degree of accuracy. Therefore, this technique has been extensively studied and applied in recent years. It has been proved that this technique has a high clinical application value for the diagnosis of medium and severe fibrosis. Then whether we can apply FibroS or not The severity of liver cirrhosis was further assessed by can technique. The correlation between the measured FibroScan values and the Laennec classification of liver cirrhosis was found in the domestic report. The purpose of this study was to evaluate the histological grading of liver cirrhosis with the clinical liver function score (Child-Pugh score, MELD score) and the FibroScan value of the liver. The clinical manifestation of portal hypertension caused by cirrhosis is a general name for a class of diseases, such as splenomegaly, hypersplenism, varicose esophagogastric vein, and ascites. Evaluation of portal pressure, including invasive measurement (portal venous catheterization, B-ultrasound guided portal vein puncture, intraoperative direct measurement, etc.) and noninvasive measurement (using Doppler ultrasound, CT, MRI, radionuclides, and other hemodynamic indicators to assess portal pressure). Although it is recognized that the "gold standard" of PHT is the hepatic vein pressure The gradient (hepatic vein pressure gradient, HVPG), but for patients who need surgery, the direct measurement of portal pressure in the operation is simple, accurate, and can dynamically observe the changes of pressure and the effect of the operation. The portal pressure measured by these methods can be used to guide the clinical intervention. The selection of surgical methods and the prognosis of patients were evaluated preliminarily. However, there was a correlation between the portal pressure of the patients and the various clinical indicators, and the related degree was less reported in the domestic literature. Methods: 1. 1. A total of 60 cases of liver cirrhosis, including liver cancer, cardio cerebral vascular disease, acute infection and kidney disease, were collected from January 2012 to January 2014 at the Southern Hospital of Southern Medical University and were confirmed by liver biopsy. The clinical data included albumin (ALB), prothrombin, and prothrombin. Time (PT), prothrombin time international normalized ratio (PT-INR), total bilirubin (TBIL), creatinine (Cr), and the severity of hepatic encephalopathy and ascites. All cases were collected on the day before the liver puncture. The pathological sections were classified by the Laennec grading system, and the different grades of liver cirrhosis were analyzed. Whether there is a difference in the value of FibroScan determination, how the value of FibroScan is used to determine the severity of liver cirrhosis and the correlation between the liver function score and the degree of liver cirrhosis,.2, which was hospitalized in the Department of hepatobiliary surgery, Southern Hospital of Southern Medical University from January 2012 to June 2014, and was diagnosed as the clinical management of patients with cirrhosis of the portal hypertension. Materials, all patients were operated on open abdominal surgery (free portal pressure, FPP), and 50 cases of liver cancer, cardio cerebral vascular disease, acute infection, kidney disease and other diseases were excluded. The free pressure of portal vein (FPP) was recorded during the operation, and the level of portal vein pressure was 30 cmH20 as demarcation point. Divided into group I, group II and two groups, compare the difference between the clinical indexes between the two groups, and analyze the correlation between the FPP and the clinical indexes and the multivariate regression analysis.3. Statistical processing: when the measurement data satisfies the normal distribution, the mean number + standard deviation (x + s) is expressed, otherwise, the median (minimum value) is expressed, and the two samples are designed for the group. The comparison of the average number was compared with the independent sample t test. The single factor variance analysis was used for the comparison of the number of samples in the group design, and the count data was tested by X2 test. The correlation analysis of the bivariate normal distribution data was analyzed by Pearson correlation analysis, and the non bivariate normal distribution data were analyzed by Spearman correlation analysis, and the work characteristics of the subjects were drawn (rece Iver operating characteristic, ROC) curve, as the best value of the liver elasticity (liver stiffness measurement, LSM) corresponding to the maximum value of the sensitivity and the sum of the specificity. The effect of each clinical index on the portal pressure by stepwise multivariate regression analysis is statistically significant. All statistical data are collected. SPSS21.0 statistical software was used. Results: 1. histology groups were divided into 27 cases of liver cirrhosis (45%), 21 cases in moderate group (35%) and 12 cases in severe group (20%). The liver FibroScan values of liver cirrhosis were 14.90 + 5.54,25.23 + 10.11,33.99 + 13.55 (Kpa), respectively, and the difference between the three groups was significant (P0.05). The difference between the mild group and the moderate group (P=0.001), the mean value of the mild group and the severe group (P = 0.001) was statistically significant. The difference between the moderate and severe group was not statistically significant (P=0.181). The area of the liver FibroScan determination under the ROC curve of the moderate and severe cirrhosis and severe cirrhosis was 0.908,0.865. selection of the liver elasticity value respectively. When LSM=16.05Kpa was the boundary point, the sensitivity of the diagnosis of moderate and severe cirrhosis was 97%, the negative predictive value (NPV) was 95%, the negative pseudo natural ratio (NLR) was 0.04, the specificity was 70%, the positive predictive value (PPV) was 80%, the positive pseudo ratio (PLR) was 3.28, and the correct rate was 85%. selected LSM=21.10Kpa as the diagnostic point, the sensitivity of the diagnosis of severe cirrhosis was 92%, negative predictive value. (NPV) 97%, the negative pseudo natural ratio (NLR) was 0.12, the specificity was 71%, the positive predictive value (PPV) was 44%, the positive pseudo ratio (PLR) was 3.14, the correct rate was 75%. liver cirrhosis, the Child-Pugh score in the moderate and severe group was 5.61 + 1.14,6.05 + 1.21,5.74 + 0.93 respectively, and there was no significant difference between the three groups (P0.05); the MELD scores of the liver cirrhosis light, moderate and severe groups were respectively The difference between the three groups was 5.90 + 4.22,7.14 + 5.33,7.03 + 5.13. There was no significant difference between the three groups: the percentage of lymphocyte (L), the percentage of neutrophils (N), the total bilirubin (TBIL), the direct bilirubin (DBIL), the prothrombin activity (PTA), the spleen length, the spleen width, the CHILD score, and the 9 indexes. As FPP increased, N, TBIL, DBIL, spleen were long, spleen was wide, CHILD score increased gradually, L, PTA gradually reduced.FPP and L, glutamic pyruvic transaminase (ALT), gluten aminotransferase (AST), fibrinogen (GLB), spleen length, spleen width, portal vein diameter, score and ascites There is a negative correlation between A/G, PTA and FIB, and there is a positive correlation with the other indicators, but the correlation is not close to these indexes (the correlation coefficient is less than 0.5). With the free pressure of the portal vein (FPP) as the dependent variable, the multiple linear regression analysis is carried out by the stepwise regression method, and the regression equation is finally entered into the regression equation. The independent variable is the quantity of ascites, the diameter of the portal vein, GLB, L, indicating the linear relationship between the amount of ascites, the internal diameter of the portal vein, the GLB, the L and FPP. The regression equation is the +0.425 x ascites of the portal vein, +0.375 * globulin - 0.300 * lymphocyte percentage. The complex correlation coefficient R=0.698, the determining coefficient R2=0.487, R2=0.435 of the adjustment. These four variables can explain the change of the dependent variable FPP 43.5%. In addition, according to the size of the normalized regression coefficient of each variable, the size of the four variables affecting the FPP is ascites, globulin, portal vein and lymphocyte percentage. Conclusion: 1. the liver FibroScan values in the liver of the 1. liver are light, medium and severe. There were significant differences. The area of the liver FibroScan determination value used to determine the area under the ROC curve of moderate to severe cirrhosis and severe cirrhosis was 0.908,0.865, indicating that FibroScan had a certain value in the diagnosis of liver cirrhosis, and there was no significant correlation between the degree of liver cirrhosis and the evaluation of liver function,.2., the portal hypertension of cirrhosis. There were significant differences in multiple clinical indicators between the I and II two groups. Portal vein pressure was correlated with L, ALT, AST, GLB, A/G, DBIL, PTA, FIB, spleen length, spleen width, portal vein diameter, CHILD score and ascites, and could be multilinear through the amount of ascites, globulin, portal vein and lymphocyte percentage. The regression model was used to evaluate the pressure of the portal vein.

【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R657.34

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