胰液胆管逆流对胆囊的影响
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摘要
胰胆管汇合异常(PBM)因汇合部无Oddi括约肌(SO)而导致胰液和胆汁相互逆流,由于通常情况下胰管压力>胆管压力,因而主要引起胰液胆管逆流(PBR)。活化的胰酶,次级胆汁酸以及致突变物质可导致胆道黏膜增生、化生、异型及多种基因突变,最终发展成胆囊癌或胆管癌。研究显示部分正常胰胆管汇合亦存在PBR,称为功能性胰胆管汇合异常,包括胰胆管高位汇合(HCPBD)和潜在性PBR。HCPBD几乎均存在明显的PBR,胆囊癌发生率高。近年来日本报道潜在性PBR亦与胆囊癌发生有关。功能性汇合异常的发生机制,与SO功能的关系,内镜下乳头括约肌切开(EST)对其影响等尚不清楚。
目前PBR的治疗以手术为主：PBM采用胆囊切除,并切除扩张的胆管,预防胆道癌发生；日本对HCPBD亦行预防性胆囊切除术。关于潜在性PBR的治疗原则尚未确立。PBR治疗尚无有效的药物。中医对该领域的研究尚属空白,如何发挥传统医学的优势,运用中医学理论解释PBR的病因病机,寻找行之有效的治疗药物,是摆在中西医结合专业医生面前亟待解决的问题。
本课题旨在研究正常胰胆管汇合PBR对胆囊黏膜病理变化的影响；SO功能对PBR的影响；探讨PBR的病因病机,通过动物PBR模型加以论治。从中、西医两方面研究PBR,为指导临床治疗提供重要的理论依据。
方法
一、临床研究
1、选择因胆囊疾病需行胆囊切除的患者为研究对象,超声(US)测胆囊壁血流、胆囊壁及内膜厚度,测胆汁淀粉酶(BA)并做细菌培养,切除的胆囊行病理学及免疫组化(COX2, Ki-67, p53)检测。根据BA值分为PBR组和对照组,比较两组间各项检测结果。
2、选择因胆道疾病需行内镜下逆行胰胆管造影(ERCP)治疗的患者为研究对象,行SO压力测定(SOM),测BA及细菌培养,研究对象分为SO压力正常组,升高组及EST组(既往行EST治疗)。
二、动物实验
1、7周龄雌性叙利亚金黄地鼠,结扎离断胰胆管共同管远端,并行胆囊十二指肠吻合,制成PBR模型。4周后将存活仓鼠随机分为2组：单纯手术组和手术+N-亚硝基双(2-氧丙基)胺(BOP)诱导组,后者每周1次皮下注射BOP,共9周；将同周龄未手术仓鼠分为2组：空白对照组和单纯BOP诱导组,后者每周1次皮下注射BOP,共9周。13周后处死,比较各组间体重、脾脏指数、肝功及胆囊病理情况。
2、制备仓鼠PBR造模,4周后随机分为4组：单纯手术组,低、中、高剂量薏苡仁油组,每日分别经口灌服1.25g/kg.2.5g/kg.5.0g/kg薏苡仁油。28周后处死,比较各组间体重、脾脏指数、肝功及胆囊病理情况。
结果
一、临床研究
1、PBR组(24例)与对照组(30例)胆囊病理变化结果比较：两组间胆囊壁及内膜的厚度、胆囊壁血流,胆汁细菌培养阳性率,胆囊黏膜炎症、增生、化生及p53表达情况差异均无统计学意义(P>0.05),而细胞异型、COX2和Ki-67表达水平差异有统计学意义(P<0.05)。
2、SO压力与PBR关系的研究结果：SO压力正常组21例,升高组47例,EST组15例。正常组和升高组细菌培养阳性率、PBR发生率及其BA值差异均无统计学意义(P>0.05)。升高组中SO压力与BA呈负相关(r=-0.43),且胆总管直径≥15mm较<15mmBA值明显升高(P<0.05).EST组与完整乳头组(正常组和升高组)比较,PBR发生率及细菌培养阳性率差异均有明显差异(P<0.05)。
二、动物实验
1、仓鼠PBR和BOP诱导癌模型胆囊病理学变化
21只仓鼠造模后存活12只：单纯手术组6只,手术+BOP组6只。空白对照组和单纯BOP组各5只。屠杀时空白对照组体重和脾脏指数明显高于其他三组(P<0.05)。各组间肝功无明显差异。
病理结果：空白对照组与单纯BOP组胆囊上皮由单层立方～柱状上皮组成,未见增生、化生、异型及胆囊癌病灶；单纯手术组和手术+BOP组上皮增生例数明显高于前两组(P<0.05)；手术+BOP组细胞异型+胆囊癌例数(6/6)明显高于空白对照组及单纯BOP组。
2、不同剂量薏苡仁油对仓鼠PBR模型胆囊的影响
40只造模后存活39只：单纯手术组9只,低、中、高剂量薏苡仁油组各10只。屠杀时各组间体重均无明显差异(P>0.05)。不同剂量薏苡仁油组脾脏指数均明显高于单纯手术组(P<0.05),且中、高剂量组明显高于低剂量组(P<0.05)。各组间肝功无明显差异。
中、高剂量组上皮增生及异型例数明显低于单纯手术组(P<0.05)。中、高剂量组增生例数较低剂量组明显减低(P<0.05),中、高剂量组间胆囊病理变化无显著差异。低剂量组异型例数虽然与单纯手术组无明显差异,但程度似乎减轻,以中度为主。各组均无胆囊癌病灶。
结论
一、潜在性PBR胆囊黏膜显示细胞异型和增殖活跃,可能是发生胆囊癌的因素。
二、SO基础压力升高与PBR无直接关联,但胆管直径的显著增加会导致BA升高,对PBR产生间接性影响。EST虽可引起PBR和胆汁细菌感染,但同时能减轻胆汁淤积,有利于逆流胰液的排出。
三、成功建立了PBR模型,为研究PBR的病因病机及探索有效的中药治疗手段奠定了实验基础。
四、阐述了PBR的病因病机为胆气郁滞,胆失疏泄,导致胰液胆汁逆流并淤积在胆囊胆管中而生痰生湿,加之机体正气虚弱,无力抗邪而致病。薏苡仁油通过抑制PBR胆囊上皮的增生和异型,对PBR相关胆囊恶变倾向具有抑制作用,并可提高仓鼠的免疫功能,副作用小,适合长期应用。对于此PBR模型,中、高剂量薏苡仁油治疗作用相似
Pancreatobiliary maljunction (PBM) is a congenital anomaly. Since the action of the sphincter of Oddi (SO) does not functionally affect the junction, continuous reciprocal reflux between pancreatic juice and bile occurs. As the hydropressure within the pancreatic duct is usually greater than that in the bile duct, pancreatobiliary reflux (PBR) often occures. The activated of pancreatic enzymes, secondary bile acids and mutagenic substances result in multiple pathological changes such as hyperplasia, metaplasia, dysplasia and gene mutations may occure, and even malignancies of gallbladder or bile duct. It reveals that PBR may also exist in nomal pancreatobiliary junction, which is termed as functional pancreatobiliary maljunction, including high confluence of pancreatobiliary ducts (HCPBD) and occult PBR. Significant PBR almost exists in all HCPBD, with high incidence of gallbladder carcinoma. Moreover, occult PBR is also related to gallbladder carcinoma, reported by Japanese experts. However, it is still unclear about mechanism of PBR in functional pancreatobiliary maljunction, its relation with SO or the effect of endoscopic sphincterotomy on it.
So far the treatment of PBR has been mainly on surgery since no effective medication is confirmed. Cholecystectomy is adopted in PBM, followed by hepaticojejunostomy with Roux-en-Y in dilated type to prevent malignancies. Prophylactic cholecystectomy for HCPBD is recommended in Japan, while there is still no therapeutic consensus on occult PBR. Traditional Chinese medicine has not involved in this field. The aim of this study is to explore the impact of PBR in normal pancreatobiliary junction on gallbladder, SO function and endoscopic sphincterotomy (EST) on PBR, to explain its etiology and pathogenesis with traditional Chinese medicine theory and verify it in PBR models.
Methods:
1. Clinical research
(1) Patients with gallbladder diseases hospitalized for cholecystectomy underwent abdominal ultrosonography to evaluate the thickness of gallbladder wall and inner layer and gallbladder wall bloodflow. Bile was sampled to detect BA and cultivate bacteria. All patients were assigned into PBR group and control group according to the BA level. Resected gallbladder specimens were examined histopathologically and immunohistochemically. Data of the two groups were compared.
(2) Consecutive patients who received SO manometry (SOM) during therapeutic ERCP for biliary tract diseases were assigned into three groups:normal SO basal pressure group, elevated SO pressure group and EST group. Data of SO basal pressure, BA and bacteria culture findings were analyzed and compared between the three groups.
2. Animal experiments
(1)Seven-week-old female Syrian golden hamsters were subjected to cholecystoduodenostomy and dissection of common duct at the distal end to create PBR model. Four weeks after operation, the surviving ones were randomly assigned into operation group and operation with N-Nitrosobis(2-oxopropyl)amine (BOP) group. Those in the latter group were subcutaneously injected BOP weekly for9successive weeks. Meanwhile, hamsters without operation were assigned into blank control group and simple BOP group. The simple BOP group was injected BOP weekly four weeks after the experiment for9weeks. All animals were killed13weeks later. The body weight, spleen index and pathological changes of gallbladder between the groups were compared.
(2) Hamster PBR models were established. Four weeks later, the surviving ones were randomly assigned into four groups:the operation group without further intervention, low dose of Coicis Semen oil group (1.25g/kg Coicis Semen oil taken orally per day), middle dose group (2.5g/kg per day) and high dose group (5.0g/kg per day) until sacrifice. All animals were killed28weeks after experiment. The body weight, spleen index and pathological changes of gallbladder between the groups were compared.
Results:
1.Clinical research
(1) Comparison of gallbladder pathological changes between the PBR group (n=24) and the control group (n=30):The thickness of gallbladder wall and inner layer, the bloodflow of gallbladder wall and the positive rate of bacteria culture were not different between the two groups (p>0.05). There was no significance both in frequency of inflammation, hyperplasia, metaplasia and in expression of p53between them (p>0.05) either, while higher presence of dysplasia and higher expression of COX2and Ki-67were seen in PBR group (p<0.05).
(2) All patients were enrolled and assigned into three groups:normal SO basal pressure group (n=21), elevated pressure group (n=47) and EST group (n=15). There was no difference in positive rate of bacteria culture, proportion of PBR patients and their BA value between the normal pressure group and the elevated pressure group. However in the latter group, negative correlation was seen between SO pressure and BA (r=-0.43). The BA value in patients with common bile duct wider than15mm was significantly higher than that in patients with common bile duct less than15mm. Furthermore, significant difference in both the proportion of elevated BA patients (P<0.05) and the positive rate of bacteria culture was seen between the intact papilla patients in the former two groups and those in EST group (P<0.05).
2. Animal experiments
(1) A total of21hamsters were operated.4weeks later,12surviving ones were randomly assigned into operation group and operation with BOP group with6in each group. Other10without operation were assigned into blank control group and simple BOP group,5in each group. When they were killed13weeks later, both body weight and spleen index were significantly higher in the blank control group than in the other three groups (P<0.05).There was no difference in liver function between the groups (P>0.05).
Pathological findings:The gallbladder epithelium in both the blank control group and simple BOP group was normal, composed of monolayer cubic or columnar cells. No occurrence of hyperplasia, metaplasia, dysplasia or tumors was seen in these two groups, while in the operation group operation with BOP group, the number of hamsters with hyperplasia was significantly more than the former two groups (P<0.05). The total number with dysplasia or cancer in operation with BOP group was significantly more than that in the blank control group or simple BOP group.
(2) The impact of different dose of Coicis Semen oil on PBR models:40hamsters were operated.4weeks later,39surviving ones were randomly assigned into operation group (n=9), low dose group (n=10), middle dose group(n=10) and high dose group(n=10). No difference in body weight was seen between the groups (P>0.05) on sacrifice. The spleen index in Coicis Semen oil groups was significantly higher than that in operation group. So with the moderate or high dose group versus the low dose one(P<0.05). The difference in liver function between the groups was not significant (P>0.05)
Pathological findings:The incidence of hyperplasia and dysplasia in both middle and high dose groups were far more less than operation group (P<0.05). The incidence of hyperplasia in middle or high dose was less than that in low dose group. However with further increase in dose, no increasing therapeutic effect was seen. Although the frequency of dysplasia in low dose group was not different from that of the operation group, its degree was seemingly less serious.
Conclusions:
1. In patients with occult PBR, dysplasia and active proliferation in gallbladder epithelium more commonly occurred which might relate to the progress to malignancy.
2. There was no direct relation between the elevated basal SO pressure and PBR, but marked increase in diameter of common bile duct can lead to a rise in BA. Moreover, although EST can bring about PBR and bile bacterial infection, it may facilitate the outflow of the refluent pancreatic juice by relieving cholestasis.
3. A PBR model was established successfully and the epithelial lesions such as hyperplasia, metaplasia and dysplasia in gallbladder were induced, laying foundations for further investigation of pathogenesis and chemoprevention of PBR.
4. We managed to explain the etiology and pathogenesis of PBR with the theory of traditional Chinese medicine, which was that phlegm-dampness condensation due to stagnation of gallbaladder Qi, as well as deficiency of vial QI. The results of our study proved that Coicis Semen oil had inhibitory effect on gallbladder malignant tendency related to PBR in animal models by decreasing hyperplasia and dysplasia, and also enhanced their immunity. With the feature of safety with little side effects, its long-term application was feasible. Moreover, middle dose and high dose had similar effect for the hamster models.
目前PBR的治疗以手术为主：PBM采用胆囊切除,并切除扩张的胆管,预防胆道癌发生；日本对HCPBD亦行预防性胆囊切除术。关于潜在性PBR的治疗原则尚未确立。PBR治疗尚无有效的药物。中医对该领域的研究尚属空白,如何发挥传统医学的优势,运用中医学理论解释PBR的病因病机,寻找行之有效的治疗药物,是摆在中西医结合专业医生面前亟待解决的问题。
本课题旨在研究正常胰胆管汇合PBR对胆囊黏膜病理变化的影响；SO功能对PBR的影响；探讨PBR的病因病机,通过动物PBR模型加以论治。从中、西医两方面研究PBR,为指导临床治疗提供重要的理论依据。
方法
一、临床研究
1、选择因胆囊疾病需行胆囊切除的患者为研究对象,超声(US)测胆囊壁血流、胆囊壁及内膜厚度,测胆汁淀粉酶(BA)并做细菌培养,切除的胆囊行病理学及免疫组化(COX2, Ki-67, p53)检测。根据BA值分为PBR组和对照组,比较两组间各项检测结果。
2、选择因胆道疾病需行内镜下逆行胰胆管造影(ERCP)治疗的患者为研究对象,行SO压力测定(SOM),测BA及细菌培养,研究对象分为SO压力正常组,升高组及EST组(既往行EST治疗)。
二、动物实验
1、7周龄雌性叙利亚金黄地鼠,结扎离断胰胆管共同管远端,并行胆囊十二指肠吻合,制成PBR模型。4周后将存活仓鼠随机分为2组：单纯手术组和手术+N-亚硝基双(2-氧丙基)胺(BOP)诱导组,后者每周1次皮下注射BOP,共9周；将同周龄未手术仓鼠分为2组：空白对照组和单纯BOP诱导组,后者每周1次皮下注射BOP,共9周。13周后处死,比较各组间体重、脾脏指数、肝功及胆囊病理情况。
2、制备仓鼠PBR造模,4周后随机分为4组：单纯手术组,低、中、高剂量薏苡仁油组,每日分别经口灌服1.25g/kg.2.5g/kg.5.0g/kg薏苡仁油。28周后处死,比较各组间体重、脾脏指数、肝功及胆囊病理情况。
结果
一、临床研究
1、PBR组(24例)与对照组(30例)胆囊病理变化结果比较：两组间胆囊壁及内膜的厚度、胆囊壁血流,胆汁细菌培养阳性率,胆囊黏膜炎症、增生、化生及p53表达情况差异均无统计学意义(P>0.05),而细胞异型、COX2和Ki-67表达水平差异有统计学意义(P<0.05)。
2、SO压力与PBR关系的研究结果：SO压力正常组21例,升高组47例,EST组15例。正常组和升高组细菌培养阳性率、PBR发生率及其BA值差异均无统计学意义(P>0.05)。升高组中SO压力与BA呈负相关(r=-0.43),且胆总管直径≥15mm较<15mmBA值明显升高(P<0.05).EST组与完整乳头组(正常组和升高组)比较,PBR发生率及细菌培养阳性率差异均有明显差异(P<0.05)。
二、动物实验
1、仓鼠PBR和BOP诱导癌模型胆囊病理学变化
21只仓鼠造模后存活12只：单纯手术组6只,手术+BOP组6只。空白对照组和单纯BOP组各5只。屠杀时空白对照组体重和脾脏指数明显高于其他三组(P<0.05)。各组间肝功无明显差异。
病理结果：空白对照组与单纯BOP组胆囊上皮由单层立方～柱状上皮组成,未见增生、化生、异型及胆囊癌病灶；单纯手术组和手术+BOP组上皮增生例数明显高于前两组(P<0.05)；手术+BOP组细胞异型+胆囊癌例数(6/6)明显高于空白对照组及单纯BOP组。
2、不同剂量薏苡仁油对仓鼠PBR模型胆囊的影响
40只造模后存活39只：单纯手术组9只,低、中、高剂量薏苡仁油组各10只。屠杀时各组间体重均无明显差异(P>0.05)。不同剂量薏苡仁油组脾脏指数均明显高于单纯手术组(P<0.05),且中、高剂量组明显高于低剂量组(P<0.05)。各组间肝功无明显差异。
中、高剂量组上皮增生及异型例数明显低于单纯手术组(P<0.05)。中、高剂量组增生例数较低剂量组明显减低(P<0.05),中、高剂量组间胆囊病理变化无显著差异。低剂量组异型例数虽然与单纯手术组无明显差异,但程度似乎减轻,以中度为主。各组均无胆囊癌病灶。
结论
一、潜在性PBR胆囊黏膜显示细胞异型和增殖活跃,可能是发生胆囊癌的因素。
二、SO基础压力升高与PBR无直接关联,但胆管直径的显著增加会导致BA升高,对PBR产生间接性影响。EST虽可引起PBR和胆汁细菌感染,但同时能减轻胆汁淤积,有利于逆流胰液的排出。
三、成功建立了PBR模型,为研究PBR的病因病机及探索有效的中药治疗手段奠定了实验基础。
四、阐述了PBR的病因病机为胆气郁滞,胆失疏泄,导致胰液胆汁逆流并淤积在胆囊胆管中而生痰生湿,加之机体正气虚弱,无力抗邪而致病。薏苡仁油通过抑制PBR胆囊上皮的增生和异型,对PBR相关胆囊恶变倾向具有抑制作用,并可提高仓鼠的免疫功能,副作用小,适合长期应用。对于此PBR模型,中、高剂量薏苡仁油治疗作用相似
Pancreatobiliary maljunction (PBM) is a congenital anomaly. Since the action of the sphincter of Oddi (SO) does not functionally affect the junction, continuous reciprocal reflux between pancreatic juice and bile occurs. As the hydropressure within the pancreatic duct is usually greater than that in the bile duct, pancreatobiliary reflux (PBR) often occures. The activated of pancreatic enzymes, secondary bile acids and mutagenic substances result in multiple pathological changes such as hyperplasia, metaplasia, dysplasia and gene mutations may occure, and even malignancies of gallbladder or bile duct. It reveals that PBR may also exist in nomal pancreatobiliary junction, which is termed as functional pancreatobiliary maljunction, including high confluence of pancreatobiliary ducts (HCPBD) and occult PBR. Significant PBR almost exists in all HCPBD, with high incidence of gallbladder carcinoma. Moreover, occult PBR is also related to gallbladder carcinoma, reported by Japanese experts. However, it is still unclear about mechanism of PBR in functional pancreatobiliary maljunction, its relation with SO or the effect of endoscopic sphincterotomy on it.
So far the treatment of PBR has been mainly on surgery since no effective medication is confirmed. Cholecystectomy is adopted in PBM, followed by hepaticojejunostomy with Roux-en-Y in dilated type to prevent malignancies. Prophylactic cholecystectomy for HCPBD is recommended in Japan, while there is still no therapeutic consensus on occult PBR. Traditional Chinese medicine has not involved in this field. The aim of this study is to explore the impact of PBR in normal pancreatobiliary junction on gallbladder, SO function and endoscopic sphincterotomy (EST) on PBR, to explain its etiology and pathogenesis with traditional Chinese medicine theory and verify it in PBR models.
Methods:
1. Clinical research
(1) Patients with gallbladder diseases hospitalized for cholecystectomy underwent abdominal ultrosonography to evaluate the thickness of gallbladder wall and inner layer and gallbladder wall bloodflow. Bile was sampled to detect BA and cultivate bacteria. All patients were assigned into PBR group and control group according to the BA level. Resected gallbladder specimens were examined histopathologically and immunohistochemically. Data of the two groups were compared.
(2) Consecutive patients who received SO manometry (SOM) during therapeutic ERCP for biliary tract diseases were assigned into three groups:normal SO basal pressure group, elevated SO pressure group and EST group. Data of SO basal pressure, BA and bacteria culture findings were analyzed and compared between the three groups.
2. Animal experiments
(1)Seven-week-old female Syrian golden hamsters were subjected to cholecystoduodenostomy and dissection of common duct at the distal end to create PBR model. Four weeks after operation, the surviving ones were randomly assigned into operation group and operation with N-Nitrosobis(2-oxopropyl)amine (BOP) group. Those in the latter group were subcutaneously injected BOP weekly for9successive weeks. Meanwhile, hamsters without operation were assigned into blank control group and simple BOP group. The simple BOP group was injected BOP weekly four weeks after the experiment for9weeks. All animals were killed13weeks later. The body weight, spleen index and pathological changes of gallbladder between the groups were compared.
(2) Hamster PBR models were established. Four weeks later, the surviving ones were randomly assigned into four groups:the operation group without further intervention, low dose of Coicis Semen oil group (1.25g/kg Coicis Semen oil taken orally per day), middle dose group (2.5g/kg per day) and high dose group (5.0g/kg per day) until sacrifice. All animals were killed28weeks after experiment. The body weight, spleen index and pathological changes of gallbladder between the groups were compared.
Results:
1.Clinical research
(1) Comparison of gallbladder pathological changes between the PBR group (n=24) and the control group (n=30):The thickness of gallbladder wall and inner layer, the bloodflow of gallbladder wall and the positive rate of bacteria culture were not different between the two groups (p>0.05). There was no significance both in frequency of inflammation, hyperplasia, metaplasia and in expression of p53between them (p>0.05) either, while higher presence of dysplasia and higher expression of COX2and Ki-67were seen in PBR group (p<0.05).
(2) All patients were enrolled and assigned into three groups:normal SO basal pressure group (n=21), elevated pressure group (n=47) and EST group (n=15). There was no difference in positive rate of bacteria culture, proportion of PBR patients and their BA value between the normal pressure group and the elevated pressure group. However in the latter group, negative correlation was seen between SO pressure and BA (r=-0.43). The BA value in patients with common bile duct wider than15mm was significantly higher than that in patients with common bile duct less than15mm. Furthermore, significant difference in both the proportion of elevated BA patients (P<0.05) and the positive rate of bacteria culture was seen between the intact papilla patients in the former two groups and those in EST group (P<0.05).
2. Animal experiments
(1) A total of21hamsters were operated.4weeks later,12surviving ones were randomly assigned into operation group and operation with BOP group with6in each group. Other10without operation were assigned into blank control group and simple BOP group,5in each group. When they were killed13weeks later, both body weight and spleen index were significantly higher in the blank control group than in the other three groups (P<0.05).There was no difference in liver function between the groups (P>0.05).
Pathological findings:The gallbladder epithelium in both the blank control group and simple BOP group was normal, composed of monolayer cubic or columnar cells. No occurrence of hyperplasia, metaplasia, dysplasia or tumors was seen in these two groups, while in the operation group operation with BOP group, the number of hamsters with hyperplasia was significantly more than the former two groups (P<0.05). The total number with dysplasia or cancer in operation with BOP group was significantly more than that in the blank control group or simple BOP group.
(2) The impact of different dose of Coicis Semen oil on PBR models:40hamsters were operated.4weeks later,39surviving ones were randomly assigned into operation group (n=9), low dose group (n=10), middle dose group(n=10) and high dose group(n=10). No difference in body weight was seen between the groups (P>0.05) on sacrifice. The spleen index in Coicis Semen oil groups was significantly higher than that in operation group. So with the moderate or high dose group versus the low dose one(P<0.05). The difference in liver function between the groups was not significant (P>0.05)
Pathological findings:The incidence of hyperplasia and dysplasia in both middle and high dose groups were far more less than operation group (P<0.05). The incidence of hyperplasia in middle or high dose was less than that in low dose group. However with further increase in dose, no increasing therapeutic effect was seen. Although the frequency of dysplasia in low dose group was not different from that of the operation group, its degree was seemingly less serious.
Conclusions:
1. In patients with occult PBR, dysplasia and active proliferation in gallbladder epithelium more commonly occurred which might relate to the progress to malignancy.
2. There was no direct relation between the elevated basal SO pressure and PBR, but marked increase in diameter of common bile duct can lead to a rise in BA. Moreover, although EST can bring about PBR and bile bacterial infection, it may facilitate the outflow of the refluent pancreatic juice by relieving cholestasis.
3. A PBR model was established successfully and the epithelial lesions such as hyperplasia, metaplasia and dysplasia in gallbladder were induced, laying foundations for further investigation of pathogenesis and chemoprevention of PBR.
4. We managed to explain the etiology and pathogenesis of PBR with the theory of traditional Chinese medicine, which was that phlegm-dampness condensation due to stagnation of gallbaladder Qi, as well as deficiency of vial QI. The results of our study proved that Coicis Semen oil had inhibitory effect on gallbladder malignant tendency related to PBR in animal models by decreasing hyperplasia and dysplasia, and also enhanced their immunity. With the feature of safety with little side effects, its long-term application was feasible. Moreover, middle dose and high dose had similar effect for the hamster models.
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