MSCT评价小型猪终末期肝病肝功能储备实验研究
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摘要
研究目的：建立小型猪终末期肝病实验模型,采用16层螺旋CT研究终末期肝病肝脏的体积、密度、门脉压力以及血流动力学的变化规律,并与肝组织病理、血液生化指标及吲哚氰绿R151CG变化对照分析,获得小型猪终末期肝病功能储备最佳的形态学和功能学评价指标,建立小型猪门脉自由压力与肝脏灌注指数相关性的回归方程式。
材料与方法：研究对象,选择同种系巴马小型猪60头,随机分为实验组40头,对照组20头,雌雄不限,3-4月龄,体重12-15kg,由广西医科大学动物实验中心提供。实验组采用复合因素法造模(65%的玉米面+35%的胆固醇+四氯化碳+苯巴比妥钠的混合饲料,10%的无水乙醇作为唯一饮料),每日一次,连续24周至形成终末期肝病为止；对照组正常喂养(65%的玉米面+35%的米糠,清水作为唯一饮料),与实验组同期喂养。两组动物分别在0、4、8、12、16、20、24周末按编号进行抽血检测肝脏、肾脏功能生化指标(包括T.BIL、Alb、Glb、A/G、ALT、AST、Cr、PT、INR),行16层螺旋CT常规及灌注扫描,吲哚氰绿排泄试验,开腹测量门静脉自由压力以及取肝组织病理活检。CT常规扫描结束后,测量肝、脾实质的密度,计算肝脾CT值比值以及测量门静脉主干及左右支的管径,同时判断有无腹水；运用仪器自身携带的Volume功能软件,测量肝脏的体积。所获得灌注数据采用仪器自身携带的功能软件(Body perfCT-syngo CT2009A)进行分析,由软件自动生成灌注参数,包括肝动脉灌注量(hepatic artery perfusion, HAP)、门脉灌注量(portal venous perfusion, PVP)、总肝灌注量(total hepatic blood flow, TLP)以及肝动脉灌注指数(hepatic artery perfusion index, HPI),其中TLP=HAP+PVP。每一例测量的指标均重复2次,取其平均值。吲哚氰绿排泄试验、门脉压力测定及活检：小猪基础麻醉后移至手术台,气管插管给氧,开腹后游离门静脉主干,插入21#静脉留置针,接压力传感器,连接Spacelab监护仪测量门静脉自由压力(free portal pressure, FPP);吲哚氰绿经注射用水溶解后按公斤体重0.5mgICG/kg的溶液经一侧耳背静脉30s内注入并开始计时,分别在注射前及注射后5、10、15分钟从另一侧耳背静脉抽取血3ml,离心后取血浆,用紫外-可见光分光光度计比色,绘制标准曲线,计算15分钟潴留率(R151CG)；然后取肝左、右叶各1cm×1cm组织,福尔马林固定后病理送检,术毕关腹继续观察喂养。对实验组采用(1)病理组织标本为肝硬化。(2)有腹水。(3)生化指标取总胆红素(T.BIL)>30.9±11.9umol/L,白蛋白(ALB)<37.96±3.96g/L,血清肌酐>80.10±16.23umol/L,凝血酶原时间(PT)>13.21±3.43s三个标准同时具备作为终末期肝病组的纳入标准。对肝脏储备功能进行Child-Pugh (CTP)分级和Modle of end-stage liver diease (MELD)评分。CTP分级取白蛋白,腹水,肝性脑病,胆红素,凝血酶原时间五项指标,按病情的严重程度分别计为A,B,C级,小于5分为A级,5-9分为B级,10-15分为C级。MELD评分采用公式MELD=3.8Ln[BIL(ml／dL)]+11.2Ln(1NR)+9.6 Ln[Cr(mg／dL)]+6.4(病因：胆汁性或乙醇性为0,其他为1),并将分值划分为<15,15～24,≥25三个等级。
采用SPSS15.0软件对所得的各种数据进行统计及分析。对实验组和对照组以及实验组各组间的肝脏体积、肝脾密度、肝脾密度比值、各项生化指标、门静脉自由压力、灌注参数、R15ICG进行统计学分析。所得结果用均数±标准差表示。两组均数的比较采用两独立样本的t检验,多组均数的比较采用单析因方差分析(One-Way ANOVA),方差不齐时应用非参数秩和检验(Kruskal-Wallis检验、),P<0.05有统计学差异；采用Logistic回归分析的方法探讨CT形态学研究指标、CT灌注参数对终末期肝病肝功能储备评级的影响；P<0.05认为差异有统计学意义。采用接受者操作特性曲线(receiver operating characteristic curve, ROC曲线)研究诊断终末期肝病的CT形态学指标、CT灌注值的最佳临界点。采用多元线性回归的Stepwise逐步回归方式建立正常至终末期肝病的灌注参数与同期门静脉压力测量值的回归方程；利用回归方程推导出肝纤维化至终末期肝病各期的门静脉压力,所得结果与实测值进行两个独立样本t检验分析；判断经公式推导出的压力值落在实测值95%可信区间的例数,评价门静脉自由压的实际测量值和MSCTP测量值所得结果之间的符合率。
结果：(1)成功制备出小型猪终末期肝病实验模型。其中对照组20头无1例死亡,0至24周末肝脏组织病理表现正常,实验组40头猪24周末共死亡16头,终末期肝病造模率为60%(24／40)；24周末获得完整实验数据正常组80例次,轻度肝纤维化82组例次,重度肝纤维化组62例次,终末期肝病组33例次。(2)正常组肝功能各项指标分别为ALT(42.00±19.16)u／l,AST(27.26±9.51)u／l,ALB(37.96±3.96)g/l,GLO(19.74±9.12)g／l,A／G(1.12±0.05),T.BIL(30.9±11.9)umol/l1, Cr (80.10±16.23)umol/L, PT(13.21±3.43s)s。实验组轻度肝纤维化至终末期肝病期肝功能各项指标ALT、AST均表现为逐渐升高(67.56±25.74,113.56±26.43,131.56±35.57)u／l,(92.51±13.69,196.18±78.2,380.18±153.7)u／l；ALB表现为逐渐下降(32.57±10.92,27.47±4.45,22.73±4.05)g/L,A／G比值倒置(0.97±0.13,0.76±0.35,0.47±0.17)；T.BIL, Cr、PT均逐渐升高,分别为(35.6±7.9,42.7±14.8,52.2±17.6)Umol/L,(85.93±14.07,96.59±21.32,101.31±23.47)Umol/L,(13.53±3.67,17.3±4.79,22.79±9.16)s。实验组ALT、AST、T.BIL、ALB、GLO、A/G、Cr、PT组间均有统计学差异(P<0.05)。(3)正常组肝脏体积为(1166.18±181.35)cm3,实验组轻度肝纤维化期肝脏体积较正常组稍增大(1172.78±191.03cm3),但组间没有统计学差异(P>0.05)；实验组轻度肝纤维化至终末期肝病期肝脏体积逐渐缩小,分别为(1172.78±191.03 cm3,1075.89±198.29cm3,850.53±141.04 cm3),组间有统计学差异(P<0.05)；(4)正常组肝实质密度为(63.43±5.34)HU,实验组从轻度肝纤维化至终末期肝病期,全肝密度呈逐渐下降的趋势,分别为(59.52±4.99,55.11±4.57,53.33±5.44)HU,组间有统计学差异(P<0.05)。脾脏密度各组间变化不大,正常组至终末期肝病组分别为(49.26±3.50,49.89±1.97,49.14±1.59,48.23±4.20)HU,组间没有统计学差异(P>0.05)。实验组的肝／脾CT值比值均小于正常组,以终末期肝病组最低(1.01±0.10),组间有统计学差异(P<0.05)。(5)实验组门静脉主干随着病变程度的加重而逐渐增大,正常至终末期肝病期分别为(1.39±0.27,1.374±0.05,1.57±0.73,1.49±0.69)cm,门静脉左右支在重度肝纤维化／早期肝硬化时期管径最大(1.22±0.11,1.27±0.11)cm,终末期肝病组则变小；Logistic回归分析显示,在门静脉系的CT测量指标中,门静脉主干的标准化回归系数最大(1.829),其次为门静脉右支(1.315),门静脉左支(1.162),(P<0.001)。(6)正常组门静脉自由压(FPP)为(4.61±0.84)mmHg。实验组轻度肝纤维化至终末期肝病期门静脉自由压(FPP)逐渐升高,分别为(7.74±1.94,12.79±4.00,17.03±3.41)：mmHg,组间有统计学差异(P<0.05)。(7)与正常对照组比较,实验组的HAP先下降后增高,正常组、轻度肝纤维化组、重度肝纤维化／早期肝硬化组、终末期肝病组的平均HAP分别为(30.53±9.78,28.50±13.81,34.94±10.19,41.08±9.76)ml/(100ml.min); PVP、TLP明显下降,分别从正常组的(109.46±22.49,140.00±29.74)ml/(100ml.min)降为终末期肝病组的(56.32±20.92,97.40±22.04)ml/(100ml.min); HPI呈升高趋势,以终末期肝病组为甚,达(43.74±13.72)%；TTP逐渐延长,从正常组到终末期肝病,大小分别为(124.33±21.49,134.48±26.76,149.76±28.88,166.55±23.57)s。统计学分析,实验组HAP先降后升,正常组与轻度肝纤维化组之间没有统计学差异(P>0.05),其余各组均有统计学差异,(P<0.05)；实验组PVP、TLP呈下降趋势,各组之间均有统计学差异(P<0.05)；实验组HPI、TTP升高,各组之间均有统计学差异(P<0.05)。(8)从正常组到终末期肝病组,吲哚氰绿R15ICG呈逐渐升高的趋势(4.41±0.21,14.84±5.51,28.97±9.4,44.03±9.19)％,组间有统计学差异P<0.001。(9)终末期肝病组Child-Pugh A级7例,B级20例,C级6例；MELD评分<15分9例,15至24分15例,≥25分9例。(10)各项CT研究指标中,以肝脏密度,门静脉主干管径以及PVP、HPI与肝功能Child-Pugh分级、MELD评分以及R15ICG的相关性最好,其中肝脏密度、PVP呈负相关,r值分别为(-0.769,-0.667,-0.782),(-0.721,-0.731,-0.747),P<0.01；门脉主干管径及HPI呈正相关,r值分别为(+0.630,+0.634,+0.662),(+0.696,+0.744,+0.738),P<0.01。(11)logistic回归分析显示,CT研究指标中以HPI与终末期肝病的标准化回归系数最大(47.83,P<0.001),其它依次为PVP,肝体积,TTP、TLP、门脉主干管径、HAP、肝密度(回归系数分别为：-38.50,-30.36,21.17,19.6,17.34,11.56,8.43,P<0.01)；PVP、肝体积为负性关系,其它指标为正性关系；脾密度、肝脾比值及门脉左右支管径则没有统计学差异P>0.05。以ROC曲线判断得到的最佳临界点HPI=43.92%作为终末期肝病的诊断阈值,其敏感性和特异性分别为0.846,0.887,准确性达0.826。(10)实验组FPP与HAP、HPI,TTP正相关,r值分别为+0.263、+0.656,+0.563,与PVP、TLP呈负相关,r值分别为-0.816,-0.633,其中FPP与PVP相关性最好。多元线性回归分析,Stepwise逐步回归将F检验统计量p<0.05的变量纳入回归方程,而F检验统计量P>0.05的变量则剔除出方程。上述5个灌注指标中,HAP和TLP、TTP被剔除,PVP和HPI两个变量则被纳入建立起最优的回归方程Y=17.175-0.173X1+0.135X2(Y：FPP,X1：PVP,X2：HPI)；利用回归方程Y=17.175-0.173X1+0.135X2计算正常至终末期肝病的门静脉压力为12.7751±4.5631mmHg,实测值为12.7867±5.4053mmHg,两者没有统计学差异t=6.729,P<0.001,进行95%可信区间检验,轻度肝纤维化诊断率84.15%,重度肝纤维化／早期肝硬化级诊断率87.09%,终末期肝病诊断率84.85%。
结论：1.改良后的四氯化碳(CCL4)、苯巴比妥、无水乙醇+高脂、低蛋白、低胆碱食物复合因素造模法可以成功建立小型猪终末期肝病实验模型。2.与正常对照组、轻度肝纤维化组及重度肝纤维化组／早期肝硬化组相比,终末期肝病组肝脏的体积、密度、门脉主干及分支管径、血流灌注参数均发生明显的变化,而且与肝功能Child-Pugh分级、MELD评分及吲哚氰绿R151CG均具有良好的相关性。3.logistic回归分析提示肝脏体积、门脉主干管径,HPI、PVP是评价小型猪终末期肝病的形态和功能学最有效指标,以HPI=43.92%作为本研究组终末期肝病的诊断阈值,其敏感性和特异性分别为0.846,0.887,准确性达0.826。4.终末期肝病MSCTP的PVP和HPI两个变量建立起最优的回归方程：Y=17.175-0.173X1+0.135X2(Y：FPP X1：PVP X2：HPI)可以推算不同级别肝硬化门静脉的自由压,从而有助于终末期肝病功能储备的评价。
Objective:To establish a model for small pig's end-stage liver disease, by 16-sectioned spiral CT was used to study the changes of the hepatic volume,density, portal vein pressure and the axiom for the liver's haemodynamics, and make a cross-check analysis by the pathology,blood biochemical indexs,and the indocyanine green R151ICG,to obtain the best morphology and functional evaluation indexs of the end-stage liver diseases. Then calculus formula for the correlation of free portal venous pressure with priming volume and diagnosed hepatic end-stage liver disease with MSCTP.
Materials and Methods:The subjects, supplied by the Animal Experiment Centre of Guangxi Medical University, were 40 Bama small pigs of the same germline, who were divided at random into a experiment group of 40 and a control group of 20, male or female, aged 4 months, weighing 15-20 kg. In the experiment, the establishment of the end-stage liver disease model and the study with 16-slices spiral CT perfusion imaging were conducted simultaneously. Composite factors were employed to establish a model (a mixed feed of 65%of corn meal+35%of Cholest+CC14+PBS, with 10%absolute alcohol as the only one potion) for the experiment group, semel in die,24 weeks successively, and the normal feeding (65%of corn meal+35%of rice bran, with clear water as the only one potion), was synchronically given to the controlled. The two groups of the animal received 16-slices spiral CT perfusion scanning, haemospasia for the biochemical indicators of hepatic function (incl.T. BIL, Alb, Glb, A/G, ALT, AST, Cr、PT、INR), laparotomy for measuring portal venous free pressure and CT-aiming aspiration biopsy.After the routine CT scaning,the density of the liver,spleen,and the liver/spleen, the caliber of the MVP and its main branch were calculus,respectively.And the volume of the liver were measured by the CT automaticly. The perfusion data received image-analysis with functional software(Body perfect-syngo CT2009A) in the machine. CT(Hu) was determined respectively in the regions of interest of the aorta, portal vein, spleen and liver to acquire relative time density curve(TDC), i.e. correspondingly the density increase value from plain-scanning the regions of interest. A round or elliptic region of interest was taken in the aorta and portal vein, and the regions of interest in the liver and spleen were drawn along the organs'borderlines. The region of interest in the liver included mainly bulk of hepatic lobes at the scanned deck, with the liver's great vessels out of the way; the ROI of the spleen, the whole at the deck, was taken, some 1cm away from the organ's borderline to avoid the volume effect. The software, with TDC produced automatically by it, calculated with the maximum slope rate method to produce automatically perfusion parameters:hepatic artery perfusion (HAP), portal venous perfusion (PVP), total hepatic blood flow (THBF) and hepatic artery perfusion index (HPI), of which THBF= HAP+PVP. Each metered index was measured repeatedly twice, with the mean value taken.The standard of the study group of end-stage liver disease were(1) Typical example of cirrhosis in pathology.(2) Abdominal dropsy.(3) Biochemical indicator including T.BIL>30.9±11.9umol/L, ALB＜37.96±3.96 g/L, Cr>80.10±16.23umol/L, PT> 13.21±3.43s.And the Child-Pugh (CTP), Modle of end-stage liver diease (MELD) were calculus.The CTP were dividing into three group A,B,and C.The MELD were dividing into three groups,which was< 15, 15～4,≥25 respectivly. All the data obtained were analyzed statistically with SPSS15.0 software, the outcome of which were demonstrated through mean±standard deviation. The comparison of the multiple-grouped mean applied One-way ANOVA, and non-parameter rank sum test (Kruskal-Wallis test) for heterogeneity of variance, with P<0.05 statistically different; the logistic regression analysis was used to study the CT morphology indicators and the CT perfusion parameters to study the influence of the mini-pig end-stage liver disease function reservation, with P<0.05 statistically different;.The receiver operating characteristic curve(ROC) was used to study the cut point of the CT parameters in diagnosis the end-stage liver disease. Regression equation for the derivation of the portal venous pressures at stages of hepatic cirrhosis, with the results and the measured values given double var Pearson linear correlation analysis; detemined the case of pressure value induced with regression equation in 95%confidence interval, assessed the concidence of results tested by FPP and MSCTP respectively. Results:(1) The model of end-stage liver disease in mini-pigs were succeed produced. No death in the control group of 20, with their liver's histopathologically normal appearing until the 20th week; 16 deaths in the experiment group of 40 at the end of 24th week; Achievement rate for those models was 73.33%(44/60).the normal group was 80 cases,the slightly hepatic fibrosis was 82 cases,the early-stage liver cirrhosis was 62 cases,and the end-stage liver disease was 33cases. (2) Normal liver functional indexs:ALT (42.00±19.16) u/l, AST (27.26±9.51) u/l, ALB (37.96±3.96) g/1, GLO (19.74±9.12), A/G (1.12±0.05), T.BIL (30.9±11.9)umol/l, Cr (80.10±16.23) umol/L, PT (13.21±3.43s) s. ALT, AST, of the pathological models rose gradually, ALB decreased gradually and A/G ratio was inversion.All index in 0 grade in the normal control group and experimental group were not significant difference (p>0.05). The interclass ALT、AST、ALB、were statistically significant (p<0.05). (3) The liver volume in control group was (1166.18±181.35) cm3, and the liver volume in experimental group decreased gradually (1166.18±181.35cm3,1172.78±191.03 cm3,1075.89±198.29 cm3,850.53±141.04 cm3),which were statistically significant (p<0.05). (4) The liver density in control group was (63.43±5.34) HU, and the liver density in experimental group decreased gradually (63.43±5.34,59.52±4.99,55.11±4.57,53.33±5.44) HU, which were statistically significant (p<0.05).no statistically significant (p> 0.05) was founded in the density of the spleen in experimental group. (5)The MVP was gradually enlarger whith the pathological changes (1.39±0.27,1.37±0.05, 1.57±0.73,1.49±0.69) cm,from control group to experimental group.Which was the maximum of the main-branch of MVP in early-stage liver cirrhosis group (1.22±0.11,1.27±0.11) cm,but in the stage of end-stage liver disaese group,it becom shrin.The logistic regression analysis show that the standard coefficient of MVP was maximum(1.829),then was the right branch of MVP(1.315),the left branch of MVP(1.162).,which were statistically significant (p<0.01).(6) FPP in normal control group was (4.61±0.84) mmHg. in the control group to end-stage liver disease group,the FPP stepped up gradually and were respectively:(4.61±0.84,7.74±1.94,12.79±4.00,17.03±3.41)mmHg, with interclass statistical significance (p<0.05).All the indexs of 0 grade was not significant difference in normal control group and experimental group.(7) HAP of experimental first decreased and rose later, The average HAP in control group,slightly liver fibrosis group,early stage-liver cirrhosis group and end-stage liver disease group were 30.53±9.78,28.50±13.81,34.94±10.19, 41.08±9.76) ml/(100ml.min) respectively. PVP、LP decreased obviosly,from control group(109.46±22.49,140.00±29.74)ml/(100ml.min)to (56.32±20.92, 97.40±22.04) ml/(100ml.min)in end-stage liver disease group. HPI increased,to the end-stage liver disease group was (43.74±13.72)%. TTP prolong gradually,which were (124.33±21.49,134.48±26.76,149.76±28.88, 166.55±23.57)s from control group to the end-stage liver disease group.It was significant of the PVP and TLP in experimental group apt to decrease and had significant difference in all the group(P<0.05) HPI in experimental group increased and significant in all the group(P<0.05).(8)The indocyanine greenR15ICG were increased from control group to end-stage liver disease group (4.41±0.21,14.84±5.51,28.97±9.4,44.03±9.19)%, with interclass statistical significance (p<0.05).(9)The experimental group Child-Pugh A was 7cases, Child-Pugh B was 20cases, Child-Pugh C was 6cases;MELD<15 was cases,15-24was 15cases,≥25 was 9 cases,respectivly (10)The best correlationship between Child-Pugh, MELD score and R15ICG of the liver density, the caliber of the MVP,PVP,HPIwere founded,which r score were (-0.769,-0.667,-0.782), (-0.721,-0.731,-0.747), (+0.630,+0.634, +0.662), (+0.696,+0.744,+0.738),P<0.01,respectivly.(11)The logistic regression analysis show that the standardize regression coefficient of the HPI with the end-stage liver disease was (47.83, P<0.001),then the PVP,the voloum of the liver,TTP,TLP, the caliber of the MVP,HAP and the density of the liver,which were(-38.50,-30.36,21.17,19.6,17.34,11.56,8.43, P<0.01) respectivly.no significant difference in the spleen density and the liver/spleen ratio.Used the cut point of ROC,the HPI=43.92%to diagnosis the end-stage liver disesae,its senstivity was0.846, specificity was 0.887, accuracy was0.826.(12) FPP in experimental group were in direct correlation with HAP, and HPI, TTP (r=+0.263,+0.656,+0.563) but inverse correlation with PVP and TLP, of which FPP was in the best correlation with PVP (r=-0.816). Multiple regression, Stepwise regression internalized F test statisticsp<0.05 into regression equation, while F test statisticsp>0.05 rejected from the equation. Of the 5 perfusion parameters stated above, HAP,TLP and TTP were rejected, and PVP and HPI, the two variables, internalized to establish the optima regression equation: regression equation for portal venous pressure and perfusion parameters Y=17.175-0.173X1+0.135X2 (Y:FPP X1:PVP X2:HPI).The portal venous pressure was calculated with FPP and PVP, HPI linear regression equation, with the outcome as 12.7751±4.5631mmHg, the measured value 12.7867±5.4053mmHg, no statistics differences can be founded between them,t=6.129, P<0.001. We measured hepatic cirrhosis at the 95%confidence interval.The results showed that the diagnosis rates of sligthly hepatic fibrosis were 84.15%, 87.09%and 84.85%at early-stage liver cirrhosis,end-stage liver disease, respectively. Conclusion:1. The model-building from composite factor food of carbon tetrachloride (CCL4), agrypnal, absolute alcohol+high lipoids, low protein and low bilineurin can establish successfully the models of small pigs' end-stage liver disease.2. The liver volume,density,the caliber of the MVP and its main branch and perfusion parameters were changed in the end-stage liver disease group,compare to the other groups,and all had a better coefficient correlation with the Child-Pugh score,MELD score, ICGR15ICG. (3) The logistic regression analysis show that the liver volume, the caliber of the MVP,HPI and PVP were best indexs to evaluate the end-stage liver disease in mini-pigs.Used the cut point of ROC,the HPI=43.92%to diagnosis the end-stage liver disesae,its senstivity was0.846, specificity was 0.887, accuracy was0.826.4. The regression equation with PVP and HPI:Y=17.175-0.173X1+0.135X2 (Y:FPP X1: PVP X2:HPI), was optimal for calculation of FPP in evaluation the reserve function of the mini-pigs'end-stage liver disease.
材料与方法：研究对象,选择同种系巴马小型猪60头,随机分为实验组40头,对照组20头,雌雄不限,3-4月龄,体重12-15kg,由广西医科大学动物实验中心提供。实验组采用复合因素法造模(65%的玉米面+35%的胆固醇+四氯化碳+苯巴比妥钠的混合饲料,10%的无水乙醇作为唯一饮料),每日一次,连续24周至形成终末期肝病为止；对照组正常喂养(65%的玉米面+35%的米糠,清水作为唯一饮料),与实验组同期喂养。两组动物分别在0、4、8、12、16、20、24周末按编号进行抽血检测肝脏、肾脏功能生化指标(包括T.BIL、Alb、Glb、A/G、ALT、AST、Cr、PT、INR),行16层螺旋CT常规及灌注扫描,吲哚氰绿排泄试验,开腹测量门静脉自由压力以及取肝组织病理活检。CT常规扫描结束后,测量肝、脾实质的密度,计算肝脾CT值比值以及测量门静脉主干及左右支的管径,同时判断有无腹水；运用仪器自身携带的Volume功能软件,测量肝脏的体积。所获得灌注数据采用仪器自身携带的功能软件(Body perfCT-syngo CT2009A)进行分析,由软件自动生成灌注参数,包括肝动脉灌注量(hepatic artery perfusion, HAP)、门脉灌注量(portal venous perfusion, PVP)、总肝灌注量(total hepatic blood flow, TLP)以及肝动脉灌注指数(hepatic artery perfusion index, HPI),其中TLP=HAP+PVP。每一例测量的指标均重复2次,取其平均值。吲哚氰绿排泄试验、门脉压力测定及活检：小猪基础麻醉后移至手术台,气管插管给氧,开腹后游离门静脉主干,插入21#静脉留置针,接压力传感器,连接Spacelab监护仪测量门静脉自由压力(free portal pressure, FPP);吲哚氰绿经注射用水溶解后按公斤体重0.5mgICG/kg的溶液经一侧耳背静脉30s内注入并开始计时,分别在注射前及注射后5、10、15分钟从另一侧耳背静脉抽取血3ml,离心后取血浆,用紫外-可见光分光光度计比色,绘制标准曲线,计算15分钟潴留率(R151CG)；然后取肝左、右叶各1cm×1cm组织,福尔马林固定后病理送检,术毕关腹继续观察喂养。对实验组采用(1)病理组织标本为肝硬化。(2)有腹水。(3)生化指标取总胆红素(T.BIL)>30.9±11.9umol/L,白蛋白(ALB)<37.96±3.96g/L,血清肌酐>80.10±16.23umol/L,凝血酶原时间(PT)>13.21±3.43s三个标准同时具备作为终末期肝病组的纳入标准。对肝脏储备功能进行Child-Pugh (CTP)分级和Modle of end-stage liver diease (MELD)评分。CTP分级取白蛋白,腹水,肝性脑病,胆红素,凝血酶原时间五项指标,按病情的严重程度分别计为A,B,C级,小于5分为A级,5-9分为B级,10-15分为C级。MELD评分采用公式MELD=3.8Ln[BIL(ml／dL)]+11.2Ln(1NR)+9.6 Ln[Cr(mg／dL)]+6.4(病因：胆汁性或乙醇性为0,其他为1),并将分值划分为<15,15～24,≥25三个等级。
采用SPSS15.0软件对所得的各种数据进行统计及分析。对实验组和对照组以及实验组各组间的肝脏体积、肝脾密度、肝脾密度比值、各项生化指标、门静脉自由压力、灌注参数、R15ICG进行统计学分析。所得结果用均数±标准差表示。两组均数的比较采用两独立样本的t检验,多组均数的比较采用单析因方差分析(One-Way ANOVA),方差不齐时应用非参数秩和检验(Kruskal-Wallis检验、),P<0.05有统计学差异；采用Logistic回归分析的方法探讨CT形态学研究指标、CT灌注参数对终末期肝病肝功能储备评级的影响；P<0.05认为差异有统计学意义。采用接受者操作特性曲线(receiver operating characteristic curve, ROC曲线)研究诊断终末期肝病的CT形态学指标、CT灌注值的最佳临界点。采用多元线性回归的Stepwise逐步回归方式建立正常至终末期肝病的灌注参数与同期门静脉压力测量值的回归方程；利用回归方程推导出肝纤维化至终末期肝病各期的门静脉压力,所得结果与实测值进行两个独立样本t检验分析；判断经公式推导出的压力值落在实测值95%可信区间的例数,评价门静脉自由压的实际测量值和MSCTP测量值所得结果之间的符合率。
结果：(1)成功制备出小型猪终末期肝病实验模型。其中对照组20头无1例死亡,0至24周末肝脏组织病理表现正常,实验组40头猪24周末共死亡16头,终末期肝病造模率为60%(24／40)；24周末获得完整实验数据正常组80例次,轻度肝纤维化82组例次,重度肝纤维化组62例次,终末期肝病组33例次。(2)正常组肝功能各项指标分别为ALT(42.00±19.16)u／l,AST(27.26±9.51)u／l,ALB(37.96±3.96)g/l,GLO(19.74±9.12)g／l,A／G(1.12±0.05),T.BIL(30.9±11.9)umol/l1, Cr (80.10±16.23)umol/L, PT(13.21±3.43s)s。实验组轻度肝纤维化至终末期肝病期肝功能各项指标ALT、AST均表现为逐渐升高(67.56±25.74,113.56±26.43,131.56±35.57)u／l,(92.51±13.69,196.18±78.2,380.18±153.7)u／l；ALB表现为逐渐下降(32.57±10.92,27.47±4.45,22.73±4.05)g/L,A／G比值倒置(0.97±0.13,0.76±0.35,0.47±0.17)；T.BIL, Cr、PT均逐渐升高,分别为(35.6±7.9,42.7±14.8,52.2±17.6)Umol/L,(85.93±14.07,96.59±21.32,101.31±23.47)Umol/L,(13.53±3.67,17.3±4.79,22.79±9.16)s。实验组ALT、AST、T.BIL、ALB、GLO、A/G、Cr、PT组间均有统计学差异(P<0.05)。(3)正常组肝脏体积为(1166.18±181.35)cm3,实验组轻度肝纤维化期肝脏体积较正常组稍增大(1172.78±191.03cm3),但组间没有统计学差异(P>0.05)；实验组轻度肝纤维化至终末期肝病期肝脏体积逐渐缩小,分别为(1172.78±191.03 cm3,1075.89±198.29cm3,850.53±141.04 cm3),组间有统计学差异(P<0.05)；(4)正常组肝实质密度为(63.43±5.34)HU,实验组从轻度肝纤维化至终末期肝病期,全肝密度呈逐渐下降的趋势,分别为(59.52±4.99,55.11±4.57,53.33±5.44)HU,组间有统计学差异(P<0.05)。脾脏密度各组间变化不大,正常组至终末期肝病组分别为(49.26±3.50,49.89±1.97,49.14±1.59,48.23±4.20)HU,组间没有统计学差异(P>0.05)。实验组的肝／脾CT值比值均小于正常组,以终末期肝病组最低(1.01±0.10),组间有统计学差异(P<0.05)。(5)实验组门静脉主干随着病变程度的加重而逐渐增大,正常至终末期肝病期分别为(1.39±0.27,1.374±0.05,1.57±0.73,1.49±0.69)cm,门静脉左右支在重度肝纤维化／早期肝硬化时期管径最大(1.22±0.11,1.27±0.11)cm,终末期肝病组则变小；Logistic回归分析显示,在门静脉系的CT测量指标中,门静脉主干的标准化回归系数最大(1.829),其次为门静脉右支(1.315),门静脉左支(1.162),(P<0.001)。(6)正常组门静脉自由压(FPP)为(4.61±0.84)mmHg。实验组轻度肝纤维化至终末期肝病期门静脉自由压(FPP)逐渐升高,分别为(7.74±1.94,12.79±4.00,17.03±3.41)：mmHg,组间有统计学差异(P<0.05)。(7)与正常对照组比较,实验组的HAP先下降后增高,正常组、轻度肝纤维化组、重度肝纤维化／早期肝硬化组、终末期肝病组的平均HAP分别为(30.53±9.78,28.50±13.81,34.94±10.19,41.08±9.76)ml/(100ml.min); PVP、TLP明显下降,分别从正常组的(109.46±22.49,140.00±29.74)ml/(100ml.min)降为终末期肝病组的(56.32±20.92,97.40±22.04)ml/(100ml.min); HPI呈升高趋势,以终末期肝病组为甚,达(43.74±13.72)%；TTP逐渐延长,从正常组到终末期肝病,大小分别为(124.33±21.49,134.48±26.76,149.76±28.88,166.55±23.57)s。统计学分析,实验组HAP先降后升,正常组与轻度肝纤维化组之间没有统计学差异(P>0.05),其余各组均有统计学差异,(P<0.05)；实验组PVP、TLP呈下降趋势,各组之间均有统计学差异(P<0.05)；实验组HPI、TTP升高,各组之间均有统计学差异(P<0.05)。(8)从正常组到终末期肝病组,吲哚氰绿R15ICG呈逐渐升高的趋势(4.41±0.21,14.84±5.51,28.97±9.4,44.03±9.19)％,组间有统计学差异P<0.001。(9)终末期肝病组Child-Pugh A级7例,B级20例,C级6例；MELD评分<15分9例,15至24分15例,≥25分9例。(10)各项CT研究指标中,以肝脏密度,门静脉主干管径以及PVP、HPI与肝功能Child-Pugh分级、MELD评分以及R15ICG的相关性最好,其中肝脏密度、PVP呈负相关,r值分别为(-0.769,-0.667,-0.782),(-0.721,-0.731,-0.747),P<0.01；门脉主干管径及HPI呈正相关,r值分别为(+0.630,+0.634,+0.662),(+0.696,+0.744,+0.738),P<0.01。(11)logistic回归分析显示,CT研究指标中以HPI与终末期肝病的标准化回归系数最大(47.83,P<0.001),其它依次为PVP,肝体积,TTP、TLP、门脉主干管径、HAP、肝密度(回归系数分别为：-38.50,-30.36,21.17,19.6,17.34,11.56,8.43,P<0.01)；PVP、肝体积为负性关系,其它指标为正性关系；脾密度、肝脾比值及门脉左右支管径则没有统计学差异P>0.05。以ROC曲线判断得到的最佳临界点HPI=43.92%作为终末期肝病的诊断阈值,其敏感性和特异性分别为0.846,0.887,准确性达0.826。(10)实验组FPP与HAP、HPI,TTP正相关,r值分别为+0.263、+0.656,+0.563,与PVP、TLP呈负相关,r值分别为-0.816,-0.633,其中FPP与PVP相关性最好。多元线性回归分析,Stepwise逐步回归将F检验统计量p<0.05的变量纳入回归方程,而F检验统计量P>0.05的变量则剔除出方程。上述5个灌注指标中,HAP和TLP、TTP被剔除,PVP和HPI两个变量则被纳入建立起最优的回归方程Y=17.175-0.173X1+0.135X2(Y：FPP,X1：PVP,X2：HPI)；利用回归方程Y=17.175-0.173X1+0.135X2计算正常至终末期肝病的门静脉压力为12.7751±4.5631mmHg,实测值为12.7867±5.4053mmHg,两者没有统计学差异t=6.729,P<0.001,进行95%可信区间检验,轻度肝纤维化诊断率84.15%,重度肝纤维化／早期肝硬化级诊断率87.09%,终末期肝病诊断率84.85%。
结论：1.改良后的四氯化碳(CCL4)、苯巴比妥、无水乙醇+高脂、低蛋白、低胆碱食物复合因素造模法可以成功建立小型猪终末期肝病实验模型。2.与正常对照组、轻度肝纤维化组及重度肝纤维化组／早期肝硬化组相比,终末期肝病组肝脏的体积、密度、门脉主干及分支管径、血流灌注参数均发生明显的变化,而且与肝功能Child-Pugh分级、MELD评分及吲哚氰绿R151CG均具有良好的相关性。3.logistic回归分析提示肝脏体积、门脉主干管径,HPI、PVP是评价小型猪终末期肝病的形态和功能学最有效指标,以HPI=43.92%作为本研究组终末期肝病的诊断阈值,其敏感性和特异性分别为0.846,0.887,准确性达0.826。4.终末期肝病MSCTP的PVP和HPI两个变量建立起最优的回归方程：Y=17.175-0.173X1+0.135X2(Y：FPP X1：PVP X2：HPI)可以推算不同级别肝硬化门静脉的自由压,从而有助于终末期肝病功能储备的评价。
Objective:To establish a model for small pig's end-stage liver disease, by 16-sectioned spiral CT was used to study the changes of the hepatic volume,density, portal vein pressure and the axiom for the liver's haemodynamics, and make a cross-check analysis by the pathology,blood biochemical indexs,and the indocyanine green R151ICG,to obtain the best morphology and functional evaluation indexs of the end-stage liver diseases. Then calculus formula for the correlation of free portal venous pressure with priming volume and diagnosed hepatic end-stage liver disease with MSCTP.
Materials and Methods:The subjects, supplied by the Animal Experiment Centre of Guangxi Medical University, were 40 Bama small pigs of the same germline, who were divided at random into a experiment group of 40 and a control group of 20, male or female, aged 4 months, weighing 15-20 kg. In the experiment, the establishment of the end-stage liver disease model and the study with 16-slices spiral CT perfusion imaging were conducted simultaneously. Composite factors were employed to establish a model (a mixed feed of 65%of corn meal+35%of Cholest+CC14+PBS, with 10%absolute alcohol as the only one potion) for the experiment group, semel in die,24 weeks successively, and the normal feeding (65%of corn meal+35%of rice bran, with clear water as the only one potion), was synchronically given to the controlled. The two groups of the animal received 16-slices spiral CT perfusion scanning, haemospasia for the biochemical indicators of hepatic function (incl.T. BIL, Alb, Glb, A/G, ALT, AST, Cr、PT、INR), laparotomy for measuring portal venous free pressure and CT-aiming aspiration biopsy.After the routine CT scaning,the density of the liver,spleen,and the liver/spleen, the caliber of the MVP and its main branch were calculus,respectively.And the volume of the liver were measured by the CT automaticly. The perfusion data received image-analysis with functional software(Body perfect-syngo CT2009A) in the machine. CT(Hu) was determined respectively in the regions of interest of the aorta, portal vein, spleen and liver to acquire relative time density curve(TDC), i.e. correspondingly the density increase value from plain-scanning the regions of interest. A round or elliptic region of interest was taken in the aorta and portal vein, and the regions of interest in the liver and spleen were drawn along the organs'borderlines. The region of interest in the liver included mainly bulk of hepatic lobes at the scanned deck, with the liver's great vessels out of the way; the ROI of the spleen, the whole at the deck, was taken, some 1cm away from the organ's borderline to avoid the volume effect. The software, with TDC produced automatically by it, calculated with the maximum slope rate method to produce automatically perfusion parameters:hepatic artery perfusion (HAP), portal venous perfusion (PVP), total hepatic blood flow (THBF) and hepatic artery perfusion index (HPI), of which THBF= HAP+PVP. Each metered index was measured repeatedly twice, with the mean value taken.The standard of the study group of end-stage liver disease were(1) Typical example of cirrhosis in pathology.(2) Abdominal dropsy.(3) Biochemical indicator including T.BIL>30.9±11.9umol/L, ALB＜37.96±3.96 g/L, Cr>80.10±16.23umol/L, PT> 13.21±3.43s.And the Child-Pugh (CTP), Modle of end-stage liver diease (MELD) were calculus.The CTP were dividing into three group A,B,and C.The MELD were dividing into three groups,which was< 15, 15～4,≥25 respectivly. All the data obtained were analyzed statistically with SPSS15.0 software, the outcome of which were demonstrated through mean±standard deviation. The comparison of the multiple-grouped mean applied One-way ANOVA, and non-parameter rank sum test (Kruskal-Wallis test) for heterogeneity of variance, with P<0.05 statistically different; the logistic regression analysis was used to study the CT morphology indicators and the CT perfusion parameters to study the influence of the mini-pig end-stage liver disease function reservation, with P<0.05 statistically different;.The receiver operating characteristic curve(ROC) was used to study the cut point of the CT parameters in diagnosis the end-stage liver disease. Regression equation for the derivation of the portal venous pressures at stages of hepatic cirrhosis, with the results and the measured values given double var Pearson linear correlation analysis; detemined the case of pressure value induced with regression equation in 95%confidence interval, assessed the concidence of results tested by FPP and MSCTP respectively. Results:(1) The model of end-stage liver disease in mini-pigs were succeed produced. No death in the control group of 20, with their liver's histopathologically normal appearing until the 20th week; 16 deaths in the experiment group of 40 at the end of 24th week; Achievement rate for those models was 73.33%(44/60).the normal group was 80 cases,the slightly hepatic fibrosis was 82 cases,the early-stage liver cirrhosis was 62 cases,and the end-stage liver disease was 33cases. (2) Normal liver functional indexs:ALT (42.00±19.16) u/l, AST (27.26±9.51) u/l, ALB (37.96±3.96) g/1, GLO (19.74±9.12), A/G (1.12±0.05), T.BIL (30.9±11.9)umol/l, Cr (80.10±16.23) umol/L, PT (13.21±3.43s) s. ALT, AST, of the pathological models rose gradually, ALB decreased gradually and A/G ratio was inversion.All index in 0 grade in the normal control group and experimental group were not significant difference (p>0.05). The interclass ALT、AST、ALB、were statistically significant (p<0.05). (3) The liver volume in control group was (1166.18±181.35) cm3, and the liver volume in experimental group decreased gradually (1166.18±181.35cm3,1172.78±191.03 cm3,1075.89±198.29 cm3,850.53±141.04 cm3),which were statistically significant (p<0.05). (4) The liver density in control group was (63.43±5.34) HU, and the liver density in experimental group decreased gradually (63.43±5.34,59.52±4.99,55.11±4.57,53.33±5.44) HU, which were statistically significant (p<0.05).no statistically significant (p> 0.05) was founded in the density of the spleen in experimental group. (5)The MVP was gradually enlarger whith the pathological changes (1.39±0.27,1.37±0.05, 1.57±0.73,1.49±0.69) cm,from control group to experimental group.Which was the maximum of the main-branch of MVP in early-stage liver cirrhosis group (1.22±0.11,1.27±0.11) cm,but in the stage of end-stage liver disaese group,it becom shrin.The logistic regression analysis show that the standard coefficient of MVP was maximum(1.829),then was the right branch of MVP(1.315),the left branch of MVP(1.162).,which were statistically significant (p<0.01).(6) FPP in normal control group was (4.61±0.84) mmHg. in the control group to end-stage liver disease group,the FPP stepped up gradually and were respectively:(4.61±0.84,7.74±1.94,12.79±4.00,17.03±3.41)mmHg, with interclass statistical significance (p<0.05).All the indexs of 0 grade was not significant difference in normal control group and experimental group.(7) HAP of experimental first decreased and rose later, The average HAP in control group,slightly liver fibrosis group,early stage-liver cirrhosis group and end-stage liver disease group were 30.53±9.78,28.50±13.81,34.94±10.19, 41.08±9.76) ml/(100ml.min) respectively. PVP、LP decreased obviosly,from control group(109.46±22.49,140.00±29.74)ml/(100ml.min)to (56.32±20.92, 97.40±22.04) ml/(100ml.min)in end-stage liver disease group. HPI increased,to the end-stage liver disease group was (43.74±13.72)%. TTP prolong gradually,which were (124.33±21.49,134.48±26.76,149.76±28.88, 166.55±23.57)s from control group to the end-stage liver disease group.It was significant of the PVP and TLP in experimental group apt to decrease and had significant difference in all the group(P<0.05) HPI in experimental group increased and significant in all the group(P<0.05).(8)The indocyanine greenR15ICG were increased from control group to end-stage liver disease group (4.41±0.21,14.84±5.51,28.97±9.4,44.03±9.19)%, with interclass statistical significance (p<0.05).(9)The experimental group Child-Pugh A was 7cases, Child-Pugh B was 20cases, Child-Pugh C was 6cases;MELD<15 was cases,15-24was 15cases,≥25 was 9 cases,respectivly (10)The best correlationship between Child-Pugh, MELD score and R15ICG of the liver density, the caliber of the MVP,PVP,HPIwere founded,which r score were (-0.769,-0.667,-0.782), (-0.721,-0.731,-0.747), (+0.630,+0.634, +0.662), (+0.696,+0.744,+0.738),P<0.01,respectivly.(11)The logistic regression analysis show that the standardize regression coefficient of the HPI with the end-stage liver disease was (47.83, P<0.001),then the PVP,the voloum of the liver,TTP,TLP, the caliber of the MVP,HAP and the density of the liver,which were(-38.50,-30.36,21.17,19.6,17.34,11.56,8.43, P<0.01) respectivly.no significant difference in the spleen density and the liver/spleen ratio.Used the cut point of ROC,the HPI=43.92%to diagnosis the end-stage liver disesae,its senstivity was0.846, specificity was 0.887, accuracy was0.826.(12) FPP in experimental group were in direct correlation with HAP, and HPI, TTP (r=+0.263,+0.656,+0.563) but inverse correlation with PVP and TLP, of which FPP was in the best correlation with PVP (r=-0.816). Multiple regression, Stepwise regression internalized F test statisticsp<0.05 into regression equation, while F test statisticsp>0.05 rejected from the equation. Of the 5 perfusion parameters stated above, HAP,TLP and TTP were rejected, and PVP and HPI, the two variables, internalized to establish the optima regression equation: regression equation for portal venous pressure and perfusion parameters Y=17.175-0.173X1+0.135X2 (Y:FPP X1:PVP X2:HPI).The portal venous pressure was calculated with FPP and PVP, HPI linear regression equation, with the outcome as 12.7751±4.5631mmHg, the measured value 12.7867±5.4053mmHg, no statistics differences can be founded between them,t=6.129, P<0.001. We measured hepatic cirrhosis at the 95%confidence interval.The results showed that the diagnosis rates of sligthly hepatic fibrosis were 84.15%, 87.09%and 84.85%at early-stage liver cirrhosis,end-stage liver disease, respectively. Conclusion:1. The model-building from composite factor food of carbon tetrachloride (CCL4), agrypnal, absolute alcohol+high lipoids, low protein and low bilineurin can establish successfully the models of small pigs' end-stage liver disease.2. The liver volume,density,the caliber of the MVP and its main branch and perfusion parameters were changed in the end-stage liver disease group,compare to the other groups,and all had a better coefficient correlation with the Child-Pugh score,MELD score, ICGR15ICG. (3) The logistic regression analysis show that the liver volume, the caliber of the MVP,HPI and PVP were best indexs to evaluate the end-stage liver disease in mini-pigs.Used the cut point of ROC,the HPI=43.92%to diagnosis the end-stage liver disesae,its senstivity was0.846, specificity was 0.887, accuracy was0.826.4. The regression equation with PVP and HPI:Y=17.175-0.173X1+0.135X2 (Y:FPP X1: PVP X2:HPI), was optimal for calculation of FPP in evaluation the reserve function of the mini-pigs'end-stage liver disease.
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