| Background and ObjectiveOut of the extrahepatic cholangiocarcinoma, 60-70% are hilar cholangiocarcinoma, and the incidence of the disease is increasing globally. Surgery is the only way for the patients to win a long-term survival. However, the disease is easy to recurrence later. The high recurrence is due to the remained carcinoma cells in the margin area. So, the strategy for radical surgery therapy of hilar cholangiocarcinoma is combined with extended hepatectomy in order to achieve negative margin. However, 90% patients with hilar cholangiocarcinoma are complicated with different levels of obstruction jaundice, among which most are complete obstruction jaundice. The damage induced by obstruction jaundice could result in liver and kidney function impairs, cruor dysfunction, gastric mucosal injury, immune suppression and liver regeneration suppression. Hepatic artery blockage and reperfusion in the process of operation could also result in the injury of liver. All these damages and injuries can lead to deadly post-operative complication---liver failure. It is clear that obstruction jaundice has become the neck of the improvement of radical hilar cholangiocarcinoma. Therefore, some treatments should be adopted pre-operatively in order to guarantee a safer and more successful radical hilar cholangiocarcinoma surgery combined with hepatectomy.Preoperative biliary drainage (PBD) could decrease the risk of liver function failure and improve total body conditions to tolerate the operation. Percutaneous transhepatic biliary drainage (PTBD) was easy to perform with a high success and an ideal result. Pre-operative PTBD was different from other obstruction jaundices. Due to the different positions of the lesion,and it had its own pathological characters. 1) For the patients with complicated liver hilar obstruction such as Bismuth III and IV, it was difficult to get an ideal biliary drainage; 2) it was difficult to get a completed drainage only by one branch, and other branches were needed; 3) the hepatic lobe that was drained might be excised; 4) hepatic drainage duct complication would increase.Today, problems related to pre-operative biliary drainage are as follows: 1) what will be the suitable cutoff of serum bilirubin for operation? 2) Whether should the drainage be performed for the hepatic lobe that will be excised? Some of authors prefered the selective external biliary drainage (SED) to total external biliary (TED) drainage just for an easier operation, a lower risk of post-operative infection and carcinoma duct metastasis, and an increase of the volume of the future remnant liver (FRL). We presumed that the SED could be more suitable for liver regeneration after hepatectomy.Since the current strategy of the surgery therapy for the hepatic hilar cholangiocarcinoma is extended hepatectomy, we set up a selective external biliary drainage (the future remnant liver are 30% of total liver) animal model induced by completed obstruction jaundice according to the anatomic characters of SD rat. We also performed about 70% liver hepatectomy with different serum bilirubin and different drainage rat models to study the different drainages in the improvement of liver function and regeneration. In this study, we wanted to solve the followed issues: 1) whether selective external biliary drainage (about 30% of total liver) will work as well as total liver drainage in decreasing serum bilirubin and improving liver function? 2) What is the mechanism of selective external biliary drainage in improving liver function? 3) How high will the post-operative serum bilirubin be to have the same animal post-operative mortality, concentration of endotoxemia in portal vein, liver function and liver regeneration as the normal serum bilirubin in the rat model? 4) Whether the selective external biliary drainage will produce the same improvement in liver function and liver regeneration as the total external liver drainage? We also hope that our study will arrive at some theories that may be beneficial to the control of jaundice pre-operation.Methods and Results1. Animal model of selective external biliary drainage induced by obstruction jaundice was set up and used in study on improvement of liver function. After ligated and placed with a drainage-duct in common bile duct, the rats were ligated twice and the hepatic duct in the junction of left and mid hepatic lobe cut. Then, all potential branch of hepatic duct in this area were ligated and cut free. In this way, an animal model of selective external biliary drainage induced by obstruction jaundice was successfully built. During this program, the model was stable and the operation was easy to perform. Ten days after the operation, bile ducts were recanalized in the rats with obstruction jaundice. During drainage, the liver function, bile flow rate, rate of right hepatic lobe weight against body weight were observed in 0,1,4,7,10,14 days after operation. The result showed that the selective external biliary drainage could improve as much liver function and decrease as much serum bilirubin as the total external biliary drainange 10 days after the drainage operation. However, compared with total external biliary drainange, the secreted bile per kilogram weigh per day and total acid bile were significant lesser in partial external hepatic drainage animal (p<0.05); while right hepatic lobe weight against body weight was significant higher in the 10th and 14th day of drainage (p<0.05).2. The molecular mechanism of selective external biliary drainage induced by obstruction jaundice. By RT-PCR and Western-blot analysis, the mRNA and protein expressions of hepatobiliary membrane transporters (HMT) such as NTCP,BSEP and MRP2 in rat liver were detected after they were treated with drainage for 0,1,4,7,10days. Results showed that expression of hepatobiliary membrane transporters in rats with obstruction jaundice induced by ligation in common bile duct could change to certain degree to suit the pathological physiologic alternation. These changes involved an increase of the expression of BSEP and a decrease of the expression of NTCP and MRP2 to get a possible protection in liver. After drainage, most HMTs could turn to normal levels gradually, but some HMTs per volume in selective external biliary drainage could be higher than total external biliary drainage. The elevation of HMTs could help to export more serum bilirubin and bile acid induced by ligation in common bile duct, and reduce as much cumulation of harmful substances and improve as much liver function as total external biliary drainage.3. The effect of selective external biliary drainage on the liver regeneration after hepatectomy. The normal SD rats and SD rats drainaged for 0day, 1day, and 10 days were received left and middle lobe (about 70% of total liver) hepatectomy. After the operation, the rat mortality, serum liver function, concentration of endotoxemia in portal vein, immunohistological analysis of PCNA index, HGF and C-MET mRNA expression in liver tissues were observed and the effects of drainage on the post-hepatectomy liver regeneration marked. Results from our studies showed that: 1. High serum bilirubin induced by obstruction jaundice could significantly suppress the post-operative liver regeneration and increase the mortality, but this suppression would be gradually overcome with the improvement of liver function due to bile recirculation, and the rat mortality could reduce by hepatectomy; 2. In a short term after drainage operation, serum bilirubin would decrease a lot whereas the liver function would improve a lot. However, the post-operative liver regeneration still be suppressed by hepatectomy. The risk for operation is still high. 3. Selective external biliary drainage would produce the same effect on the improvement of liver function, liver regeneration as the total external biliary drainage.Conclusions1 In our study, we built the selective external biliary drainage animal model for simulation of the future remnant liver external biliary drainage of the hilar cholangiocarcinoma. It is almost kept the pathological and psychical process of hepatic hilar cholangiocarcinoma. And the operation is easy to perform with a higher success rate.2. Selective external biliary drainage could improve as mush liver function as total external biliary drainage.3. In general, selective external biliary drainage could achieve the same post-operative liver regeneration as total external liver drainage.4. Selective external biliary drainage could improve liver function. It may result from an increase of the future remant volume and the molecular mechanism might be associated with elevation of per volume expression hepatobiliary membrane transporters.5. Although the serum bilirubin has decreased greatly and the liver function has improved a lot soon after drainage, the post-operative liver regeneration is still suppressed. The risks for such an operation remains high.
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