治疗肝胆管结石两种胆道重建术的临床及实验对比研究
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摘要
肝胆管结石是一种良性而无自愈倾向的难治性疾病，以其并发症发生率高、术后复发率高和再次手术率高等特点而成为胆道外科亟待解决的课题之一。手术是治疗肝胆管结石的首要措施，手术中切除病变肝脏以及切开狭窄胆管并整形后，缺损的肝胆管前壁通常行胆肠吻合达到通畅引流的目的。由于废弃了Oddi括约肌的生理作用，传统的胆肠吻合术尚存在许多难以克服的缺点，如易发肠胆返流、功能大多正常的胆囊无法保留以及胃肠道生理功能紊乱等。因此，保留Oddi括约肌的手术方式受到广泛关注。94年底田伏洲教授设计了皮下通道型胆囊肝胆管成形术（STHG）应用于胆囊、Oddi括约肌功能基本正常的肝胆管结石患者。STHG是在功能完好的胆囊与肝胆管间建立一吻合通道以解除胆管狭窄，并将胆囊底部缝至腹壁下预留通道。该术式可使得胆囊、胆管及Oddi括约肌的功能保持在相对正常的协调状态，从而既实现了治疗目的，又维护了胆道及胃肠道的正常解剖结构和生理功能，避免了传统胆肠吻合术废弃Oddi括约肌等带来的诸多弊端。业已证明，手术后胆囊的收缩、排空功能基本正常。尽管如此，目前尚需获得深入的临床及基础研究资料，如术后胆管结石复发和胆管炎发生情况如何、胆囊浓缩功能是否存在、胆汁成分有何改变以及胆管吻合口愈合情况等。为此，本课题随访观察了STHG术后结石复发和胆管炎发生的情况，并与传统胆肠吻合术进行对比；探讨了在胆道不全梗阻的基础上建立两种胆道重建术［即：犬左肝管胆囊吻合术（HC）和左肝管空肠吻合术（HJ）］动物模型的可行性；进一步对比研究了犬HC和HJ术后不同时期一系列与胆管结石发生相关的因素。通过本课题的的研究以期为临床肝胆管结石手术方式的选择提理论和实验依据。本研究的主要结果和结论如下：
1. 对本中心1994年12月至1999年11月5年间开展的STHG和皮下盲襻型胆管空肠吻合术（SLCJ）患者平均4年2月的随访发现，STHG组术后胆管炎的发生率和胆管结石的复发率明显低于SLCJ组，差异有统计学意义。提示STHG组术后远期疗效优于SLCJ组。
2. 在犬左肝管不全梗阻基础上成功建立了左肝管胆囊吻合术（HC）和左肝管空肠吻合术（HJ）的动物模型，该模型与临床胆肠通道重建术有较好
的相似性，能够用于两种胆道重建术的实验研究。
3. HC组手术时间、术中出血量以及术后1月下降体重均低于HJ组，差异有统计学意义；HC和HJ后1月时，肝功能各项指标均恢复正常。提示HC较HJ术中损伤小，术后恢复好；但HC和HJ两种术式均能较好的解除胆道梗阻以恢复肝脏功能。
4. HC和HJ术后吻合口上方胆汁成分浓度对比：HC术后总胆汁酸（TAB）明显高于HJ术后，有统计学意义，而Ca2＋和游离胆红素（UCB）两组间差异不显著，术后5月时，HC组胆汁Ca2＋·UCB／TAB值明显低于HJ组；自由基相关指标过氧化脂质（LPO）HC组明显低于HJ组，而过氧化物歧化酶（SOD）正好相反，差异均有统计学意义；术后5月时，粘蛋白HC组低于HJ组，细菌培养阳性比例HC组为0／5，而HJ组为4／4，差异均有统计学意义。上述结果提示：HC术后左肝管胆汁成分改变较HJ更有利于防止结石发生。
5. 胆管壁组织HE染色结果对比：形成左肝管不全梗阻7周后，梗阻部位胆管壁组织有较多炎性细胞浸润和腺体增生，部分纤维细胞增生，组织有轻度水肿。HC组胆管壁有纤维组织增生，纤维组织排列稍紊乱，少量炎细胞浸润，粘膜腺体增生，随时间的延长，以上改变有减轻趋势；而HJ组胆管壁组织明显，纤维排列紊乱，有炎细胞浸润，腺体增生明显，随时间的延长，纤维组织和腺体增生逐渐加重。提示HC术较HJ术更有利于胆管部分病理改变的恢复。
6. 两种胆道术后胆管愈合情况的对比：免疫组化检测吻合口胆管壁(-SMA表达显示：HC和HJ术后(-SMA表达均增强，阳性细胞率均较术前明显增加。术后5月时，HC组胆管壁组织的(-SMA免疫组化染色阳性细胞率低于同期HJ组，差异有统计学意义。HC术后1月组与5月组进行对比，发现(-SMA免疫组化染色阳性细胞率有下降趋势，且达统计学差异；而HJ术后1月组与5月组进行对比无显著性差异。RT-PCR检测吻合口胆管壁组织collagen-ⅠmRNA表达的对比结果与(-SMA相同。结果提示：HC术后发生吻合口瘢痕的程度可能较HJ更轻。
Background and Aim
Hepatolithiasis is not only a common disease, but also a benign disease without trend of spontaneous cure. Because of the high incidence rate of complication, the high recurrence rate of hepatolithiasis, as well as the high rate of reoperation, how to cure the patients with hepatolithiasis become an arduous task in the field of biliary tract surgery. Professor Fuzhou Tian devised and performed a new operation: subcutaneous tunnel and hepatocholangioplasty using gallbladder(STHG). The strictured bile ducts in the hilus were opened after removal of stones or resection of the damaged liver segments. The gallbladder, instead of usually used jejunum, was anastomosed to the widely opened bile duct in the hilus to form a widened way from intrahepatic to extrahepatic ducts. The fundus of gallbladder was mobilized and pulled to abdominal wall to form a subcutaneous tunnel which could be used for re-entry to biliary tree at any time. The disadvantages of traditional choledochojejunostomy were avoided by the new operation. More than ninety patients with hepatolithiasis had undergone the new operation from Dec. 1994 to Nov.2000. The curative effect was satisfactory. It has been proved that the mobile function of the gallbladder was normal following the STHG, however, further clinical and experimental studies should be carried out, such as the incidence rate of cholangitis, the recurrence rate of hepatolithiasis, the changes of bile component, healing process of the Hepaticocholedocho-stoma following STHG. Those problems were discussed in this study, so that the experimental basis for the clinical therapy for hepatolithiasis could be offered.
Methods
1. To observe the incidence rate of cholangitis and the recurrence rate of hepatolithiasis, the patients with hepatolithiasis cured by STGH or subcutaneous blindloop and cholangio-jejunostomy (SLCJ) from 1994 to 2000
were followed up.
2. 29 dogs were divided randomly into two groups: control group(5 dogs) and model(stenosis of left hepatic duct) group(24 dogs). The 24 dogs in model group were divided randomly into four groups: 1 month after hepaticocholedochostomy (HC) group(5 dogs), 5 month after HC group(6 dogs), 1 month after hepaticojejunostomy(HJ) group (5 dogs) and 5 month after HJ group (4 dogs). At the end of the experiment, the bile was withdrown from the bile duct and the bile duct tissue was removed. The bile components such as Ca++, unconjugated bilirubin(UCB), mucin, superoxide dismutase (SOD), lateral preoptic(LPO) were mensurated. Histopathological changes in the bile duct were observed with HE staining. The expression of α-smooth muscle actin（(-SMA） in bile duct tissue was observed with immunohistochemical SP staining. The expression of collagen-ⅠmRNA in bile duct tissue was observed with semi-quantified RT-PCR.
Main Results
1. During the 5 years, 134 patients were followed up for an average of 4 years and 2 months. For STHG and SLCJ group, the postoperative incidence rate of cholangitis was 6.1%(3/49) and 21.2%(18/85) respectively; the recurrence rate of hepatolithiasis was 4.1%(2/49) and 17.6%(15/85) respectively. The postoperative incidence rate of cholangitis and the recurrence rate of hepatolithiasis were both lower significantly in STHG group compared with SLCJ group. The factors associated with formation of hepatolithiasis in the two groups, such as age, gender, the ratio of patients with lobectomy of liver, the type of hepatolithiasis, stenosis of bile duct, jaundice happened before the surgery and dystrophia, had no significant difference between STHG and SLCJ group.
2. Hepaticocholedochostomy used shorter time and lost less blood than hepaticojejunostomy. The dogs with hepaticocholedochostomy lost less weight than the dogs with hepaticojejunostomy. For HC and HJ groups, the mortality rate was 1/12 and 3/12; the infectious rate of incision was 3/12 and 5/12 respectively.
3. Serum levels of total bilirubin and transaminase increased significantly on the 7th week after stenosis of left hepatic duct compared
1. 对本中心1994年12月至1999年11月5年间开展的STHG和皮下盲襻型胆管空肠吻合术（SLCJ）患者平均4年2月的随访发现，STHG组术后胆管炎的发生率和胆管结石的复发率明显低于SLCJ组，差异有统计学意义。提示STHG组术后远期疗效优于SLCJ组。
2. 在犬左肝管不全梗阻基础上成功建立了左肝管胆囊吻合术（HC）和左肝管空肠吻合术（HJ）的动物模型，该模型与临床胆肠通道重建术有较好
的相似性，能够用于两种胆道重建术的实验研究。
3. HC组手术时间、术中出血量以及术后1月下降体重均低于HJ组，差异有统计学意义；HC和HJ后1月时，肝功能各项指标均恢复正常。提示HC较HJ术中损伤小，术后恢复好；但HC和HJ两种术式均能较好的解除胆道梗阻以恢复肝脏功能。
4. HC和HJ术后吻合口上方胆汁成分浓度对比：HC术后总胆汁酸（TAB）明显高于HJ术后，有统计学意义，而Ca2＋和游离胆红素（UCB）两组间差异不显著，术后5月时，HC组胆汁Ca2＋·UCB／TAB值明显低于HJ组；自由基相关指标过氧化脂质（LPO）HC组明显低于HJ组，而过氧化物歧化酶（SOD）正好相反，差异均有统计学意义；术后5月时，粘蛋白HC组低于HJ组，细菌培养阳性比例HC组为0／5，而HJ组为4／4，差异均有统计学意义。上述结果提示：HC术后左肝管胆汁成分改变较HJ更有利于防止结石发生。
5. 胆管壁组织HE染色结果对比：形成左肝管不全梗阻7周后，梗阻部位胆管壁组织有较多炎性细胞浸润和腺体增生，部分纤维细胞增生，组织有轻度水肿。HC组胆管壁有纤维组织增生，纤维组织排列稍紊乱，少量炎细胞浸润，粘膜腺体增生，随时间的延长，以上改变有减轻趋势；而HJ组胆管壁组织明显，纤维排列紊乱，有炎细胞浸润，腺体增生明显，随时间的延长，纤维组织和腺体增生逐渐加重。提示HC术较HJ术更有利于胆管部分病理改变的恢复。
6. 两种胆道术后胆管愈合情况的对比：免疫组化检测吻合口胆管壁(-SMA表达显示：HC和HJ术后(-SMA表达均增强，阳性细胞率均较术前明显增加。术后5月时，HC组胆管壁组织的(-SMA免疫组化染色阳性细胞率低于同期HJ组，差异有统计学意义。HC术后1月组与5月组进行对比，发现(-SMA免疫组化染色阳性细胞率有下降趋势，且达统计学差异；而HJ术后1月组与5月组进行对比无显著性差异。RT-PCR检测吻合口胆管壁组织collagen-ⅠmRNA表达的对比结果与(-SMA相同。结果提示：HC术后发生吻合口瘢痕的程度可能较HJ更轻。
Background and Aim
Hepatolithiasis is not only a common disease, but also a benign disease without trend of spontaneous cure. Because of the high incidence rate of complication, the high recurrence rate of hepatolithiasis, as well as the high rate of reoperation, how to cure the patients with hepatolithiasis become an arduous task in the field of biliary tract surgery. Professor Fuzhou Tian devised and performed a new operation: subcutaneous tunnel and hepatocholangioplasty using gallbladder(STHG). The strictured bile ducts in the hilus were opened after removal of stones or resection of the damaged liver segments. The gallbladder, instead of usually used jejunum, was anastomosed to the widely opened bile duct in the hilus to form a widened way from intrahepatic to extrahepatic ducts. The fundus of gallbladder was mobilized and pulled to abdominal wall to form a subcutaneous tunnel which could be used for re-entry to biliary tree at any time. The disadvantages of traditional choledochojejunostomy were avoided by the new operation. More than ninety patients with hepatolithiasis had undergone the new operation from Dec. 1994 to Nov.2000. The curative effect was satisfactory. It has been proved that the mobile function of the gallbladder was normal following the STHG, however, further clinical and experimental studies should be carried out, such as the incidence rate of cholangitis, the recurrence rate of hepatolithiasis, the changes of bile component, healing process of the Hepaticocholedocho-stoma following STHG. Those problems were discussed in this study, so that the experimental basis for the clinical therapy for hepatolithiasis could be offered.
Methods
1. To observe the incidence rate of cholangitis and the recurrence rate of hepatolithiasis, the patients with hepatolithiasis cured by STGH or subcutaneous blindloop and cholangio-jejunostomy (SLCJ) from 1994 to 2000
were followed up.
2. 29 dogs were divided randomly into two groups: control group(5 dogs) and model(stenosis of left hepatic duct) group(24 dogs). The 24 dogs in model group were divided randomly into four groups: 1 month after hepaticocholedochostomy (HC) group(5 dogs), 5 month after HC group(6 dogs), 1 month after hepaticojejunostomy(HJ) group (5 dogs) and 5 month after HJ group (4 dogs). At the end of the experiment, the bile was withdrown from the bile duct and the bile duct tissue was removed. The bile components such as Ca++, unconjugated bilirubin(UCB), mucin, superoxide dismutase (SOD), lateral preoptic(LPO) were mensurated. Histopathological changes in the bile duct were observed with HE staining. The expression of α-smooth muscle actin（(-SMA） in bile duct tissue was observed with immunohistochemical SP staining. The expression of collagen-ⅠmRNA in bile duct tissue was observed with semi-quantified RT-PCR.
Main Results
1. During the 5 years, 134 patients were followed up for an average of 4 years and 2 months. For STHG and SLCJ group, the postoperative incidence rate of cholangitis was 6.1%(3/49) and 21.2%(18/85) respectively; the recurrence rate of hepatolithiasis was 4.1%(2/49) and 17.6%(15/85) respectively. The postoperative incidence rate of cholangitis and the recurrence rate of hepatolithiasis were both lower significantly in STHG group compared with SLCJ group. The factors associated with formation of hepatolithiasis in the two groups, such as age, gender, the ratio of patients with lobectomy of liver, the type of hepatolithiasis, stenosis of bile duct, jaundice happened before the surgery and dystrophia, had no significant difference between STHG and SLCJ group.
2. Hepaticocholedochostomy used shorter time and lost less blood than hepaticojejunostomy. The dogs with hepaticocholedochostomy lost less weight than the dogs with hepaticojejunostomy. For HC and HJ groups, the mortality rate was 1/12 and 3/12; the infectious rate of incision was 3/12 and 5/12 respectively.
3. Serum levels of total bilirubin and transaminase increased significantly on the 7th week after stenosis of left hepatic duct compared
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全国临床检验操作规程, 叶应妩, 王毓三主编. 东南大学出版社, 1991,第一版:234
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全国临床检验操作规程, 叶应妩, 王毓三主编. 东南大学出版社, 1991,第一版:150
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现代药理实验方法下册. 张均田主编, 北京医科大学中国协和医科大学联合出版社, 1996, 第一版:1226
全国临床检验操作规程, 叶应妩, 王毓三主编. 东南大学出版社, 1991,第一版:392
王伯云, 李玉松, 黄高升, 张远强主编. 常用的特殊染色方法, 病理学技术, 人民卫生出版社, 2000, 第一版:142
Yamazzko K, Abe S, Takawa H, et al. Tumor Angiogenesis inhumanlung adenocarcinoma. Cancer, 1994, 74:2245
Levy R, Schlaeffer F, Keynan A, et al. Increased neutrophil function induced by bile duct ligation in a rat model. Hepatology, 1993, 17:908
Stephan Kr?henbühl, Ulrich Marti, Ian Grant, et al. Characterization of mechanisms causing hypoalbuminemia in rats with long-term bile duct ligation.Journal of Hepatology, 1995, 23:79
李巧云, 刘伟健, 候朝明等. 十味蒂达胶囊对动物胆汁分泌及胆石溶解作用的研究. 世界华人消化杂志, 2000, 8:37
Erpecum KJ, Portincasa P, Stolk MF, et al. Effects of bile salt and phospholipid hydrophobicity on lithogenicity of human gallbladder bile. Eur J Clin Invest, 1994, 24:744
Alfredo GC, Massimo CP, Giovanni DT, et al. The human gallbladder increases cholesterol solubility in bile by differential lipid absorption:a study using a new in vitro model of isolated intra-arterially perfused gallbladder.Hpatolog, 1998, 28:314
张继红, 杨可桢, 韩本立. 胆囊结石形成的动力学机制, 中华普通外科杂志, 2001, 16:424
史树毅, 谭毓铨, 关文曾, 等. 自由基在胆色素结石形成中的作用. 吉林医学, 2000, 21:135
61
Elek G, Reckenbouer A. The free radical sibnal of pigment gallstones. Klin Wochenschr, 1982, 60:33
62
刘湘陶. 从分子水平对胆色素结石形成过程的在认识. 北京医科大学学报, 1989, 21:243
63
方学军, 迟彦邦, 李靖. 胆道梗阻再通后犬肝MDA及SOD含量的变化.广东医学, 1997, 18:692
64
Haley-Russel D, Calabuig R, Moddy FG. Anatomy of the bibliooduodenal junction of the opossum.Anat Rec, 1992, 232:579
65
Calabuig R, Ulrich Baker MG, Moody FG, et al. The propulsive behavior of the opossum sphincter of Oddi. Am J Physiol, 1991, 258:138
66
黄辉, 唐胜建, 鲍卫汉. α-平滑肌肌动蛋白在瘢痕成纤维细胞中的表达.中国修复重建外科杂志, 2001, 15:743
67
耿智敏, 向国安, 韩庆, 等. 肌成纤维细胞在胆道愈合过程中的表达及意义.中华实验外科杂志, 2001, 18:205
68
耿智敏, 向国安, 韩庆, 等. 犬胆肠吻合愈合过程的超微结构观察. 西安医科大学学报, 2000, 21:551
69
耿智敏, 高寰, 刘效恭, 等. 犬肝外胆管愈合过程的实验观察. 中华实验外科杂志, 1996, 13:197
70
Krotzsch-Gomez FE, Furuzawa-Carballeda J, Reyes-Marquez R, et al. Cytokine expression is down regulated by collagen -polyvinylpyrrolidone in hypertrophicscars. J Invest Dermatol, 1998, 111:828