| ObjectiveClinically, portal hypertension (PHT) is primarily characterized by portal vein flowing excrescent variety with ascites, splenomegaly and splenic hyper-function, esophagogastric varices , hematemesis and dark stool. Nearly 1/3 patients die of hematemesis. Treatment of esophagogastric varices and hematemesis in PHT is a challenging medical lesson in clinic. Though domestic and international scholars have been thinking of liver transplantion to cure PHT as an u-nique radical cure measure, because of the our countrys realistic circumstances, transplantion did not show its advantage in survival rate and life quality compared with devascularization and shunt operation . Ideal treatment for esophagogastric varices and hematemesis in PHT should either lower portal pressure or maintain portal vein flow toward liver to improve liver function. Extensive esophagogastric devascularization is an extensively adopted validity operation for treating esophagogastric varices and hematemesis. With the progress of portal hypertension , portrosystemic shunt often causes varices , reduction of provided flow toward liver, encephalopathy or liver function failure. Bile acids are a product of cholesterol in the liver. Variety of its regulation is a main function of liver. Changes of serum bile acides can reflect liver function more accruatly than any other indexes of hepatic function. Changes of humor medium materials are closely associated with mechanisms of portal hypertention. Among them , nitrogen monoxide (NO) and oxygen - derived free radidicals ( OFR) play a very important role in PHT and secondary injury of liver. In this study, we first investigated variety of portrosystemic shunt , bile acids and humor medium materials in portalhypertension befor and after extensive esophagogastric devascularization. Experiment is falling into four sections: 1 Evaluation of portrosystemic shunt and portal circulation by per - rectal portal scintigraphy with technetium - 99 m pertechne-tate after extensive esophagogastric devascularization. 2 Study of changes of individual serum bile acids after extensive esophagogastric devascularization. 3 Effect of nitric oxide and oxygen - derived free radidicals system after extensive esophagogastric devascularization.Experiment Materials and MethodsI Evaluation of portrosystemic shunt and portal circulation by per - rectal portal scintigraphy with technetium - 99m pertechnetate after extensive esophagogastric devascularization1 Grouping1. 1 portal hypertension group:The subjects were 12 cases admission patients of cirrhosis with portal hypertension between January 2001 and June 2002, male 6 and female 6, age40 ~ 63years, average age was 50. 6 years. They all had esophagogastric varices, splenomegaly and splenic hyperfunction. liver function Child A class 6 cases, Child B class 4 cases. Child C 2 cases.Portal hypertension all had been caused by cirrhosis. Postoperational pathology proved that 11 cases were virus cirrhosis and 1 cases was alcoholic cirrhosis.1. 2 Normal control group:6 cases( volunteer) , male 3, female 3, age45 ~ 62years, average age was 53.2 years.2 Observation index and method:2. 1 cardia - liver time - activity curvese( A - T) measurement;All subjects were fasted after supper of the day before the test with rectum emptied by clusis before test. They take orally KCLO4 - 400 mg in half an hour before examination in order to close the gastric mucosa. A polyethyene tube was inserted 20 cm into the rectum, reaching its upper part where 5 mL99mTcO4 a (20 mCi) was given through the tube, followed by 20 ml of air. SPECT startedto sum images at the same time. The areas of the liver and heart were considered region of interest. Then, time - activity curves for the areas of the liver and heart were obtained every 4s. 75 images were collected at the end of 5 - minute examination. For all subjects , the summed images could readily be classified as patterns of patients.2.2 SI( shunt index) calculation;The SI is the percentage of portal system blood diffusing into systemic circulation. Measurement of SI is namely the calculation of portal pressure, used for judgment of degree and prognosis of PHT. The SI is objective indicator for weighting in portrosystemic shunt. Model of SI calculation mathematics according to document. Equation(I) was used to calculate the SI for subjects with pattern I curves and Equation(II) pattern II,as follows:2. 3 Portal pressure;Free portal pressure of cirrhosis with PHT was measured through greater omentum vein during operation.II Effect of individual serum bile acids changes after extensive esopha-gogastric devascularization1 Grouping:1. 1 portal hypertension group:There were 27 subjects including male 19 cases, female 8 cases, age 36 ~ 65 years , average age was 53. 8 years, cirrhosis patients with PHT were 25 cases , alcohol cirrhosis patients were 2 cases, 27 cases had esophagogastric vari-ces. According to the Child - Pugh standard: A class was 10 cases, B class was 17 cases.1. 2 Normal control 20 cases:Normal control all had no hepatitis and liver disease with normal indicators of liver function,age 38 ~60years,average age was 54. 5 years.2 Observation index and method: Measurement of 10 individal bile acids in serum:It was measured by high - performance liquid chromatography technique. In the morning,venous blood was drained when the fasting patients were not given any treatment at 2nd day after admission andlst, 3rd day ,8th day after operation , and were centrifugated. Blood plasma was held in - 20 X, conservancy.Ill Effect of extensive esophagogastric devascularization on nitric oxide and oxygen - derived free radicals in portal hypertension1 Grouping:portal hypertension group:there were 19 patients with PHT in the study, 7 were male, and 12 were female , with average age of 51. 8 ( ranged from 41 to 65 ). All were suffered from PHT resulted from posthepatitic cirrhosis and splenomegaly. 18 of them suffered from esophagogastric venous varices. Among 19 patients with PHT, liver function was of Child s A in 9 cases, and Child ￡ B in 10 cases. All cirrhotic patients were diagnosed by pathology.Normal control :15 patients served as normal controls, 10 of them were affected by breast fibroma , and the others by great saphenous vein varices. The liver functions of all the 15 controls were normal,age 44 ~63 years, average age was 52. 6 years.2 Observation index and method:2.1 The measurment of concentrations of NO:It was measured by nitrate reductase, Venous blood was got from fast patients without any treatment in two days after admission and at the third postoperative day. Serum of centrifugalization was preserved under - 20Tl.2. 2 The measurement of activities of NOS;It was measured by colorimetry. Serum of centrifugalization was held as the method of NO.2. 3 The measurment of iNOSmRNA and cNOSmRNA:In the morning,4ml of venous blood was drained when the fasting patients were not given any treatment at 2nd day after admission and 3rd day ,8th day after operation, were anti - coagulated and were disposaled by separating medium of lymphocyte in order to extract leucocyte. Blood plasma was held in - 70 X. conservancy. iNOSmRNA and cNOSmRNA were measured by RT - PCR.2.4 The measurment of SOD:It was measured by xanthine oxidase. Serum of centrifugalization was held as the method of NO.2.5 The measurment of MDA:It was measured by sulfur barbituric acid ( TBA). Serum of centrifugaliza-tion was held as the method of NO.IV Statistical analysis-.According to Excel2000, all data were shown as mean value ± standard deviation, and analyzed by t test in. P value < 0.05 was thought as significant.ResultsI Evaluation of portrosystemic shunt and portal circulation by per - rectal portal scintigraphy with technetium - 99 m pertechnetate after extensive esopha-gogastric devascularization1 Cardia - liver time -activity curvese( A - T) : cardia - liver time - activity curvese( A - T) was significantly lower in PHT than in control. In Pattern I, the liver and potal vein were clearly seen, but the heart was not seen. Pattern II showed the opposite;the heart was clearly seen while the portal vein and liver were not. there were mainly Pattern II inPHT. After extensive esophagogastric devascularization , liver times were significantly earlier than heart times ( P < 0. 01).2 SI: The SI was significantly higher in PHT (72.56% ) than in control (17. 56). The SI was significantly lower after operation in PHT(52. 65) than before operation.3 Free portal hypertension: Free portal hypertension was 42. 32 ± 5. 35 cmH20,was 35. 1 ±5. 28 cmH20 and 34.15 ±5.92 cmH20 before and after operation respectively.II Effects of individual serum bile acids changes after extensive esophagogastric devascularization1 Ten bile acids individuals ( conjugated, non - conjugated) were higher in PHTthan that incontrols. GCA, GCDCA, LCA increased more than 90%.2 Ten bile acids individuals was lower on the 1 st day after devascularization than befor devascularization, GCA, CA, GCDCA, TDCA - CDCA, DCA reached under 70%.3 The conjugated bile acids began to increase at the 3rd day. Among them ,CA, DCA fast increasrd again and reached the level of PHT.4 Ten bile acids individuals still increased at the 8 th day after operation , but were still lower than controls (P <0.01).Ill Effect of extensive esophagogastric devascularization on nitric oxide and oxygen - derived free radicals in portal hypertension1 Concentration of NO and activity of NOS: Preoperatively, the serum level of NO and the activity of NOS in Child' s A and B group were significantly higher than those in control group(P <0. 01) ,and were also significantly higher in Child' s B group than in Child' s group A( P <0. 01). On the 3rd day after operation , NO level and NOS activity in Child' s A and Child' s B group were significantly lower than those before operation ( P < 0. 05,0. 01) , but significantly higher than those in control group(P <0.05,0.01). After operation, the CRs of NO,NOS in Child's A group were greater than those in Child's B group.2 The expression of iNOSmRNA and eNOSmRNA: The express of iN-OSmRNA, eNOSmRNA were significant higher in PHT than in controls and they began to decrease after extensive esophagogastric devascularization. But they were still higher than that of the controls.3 Concentration of MDA and activity of SOD: The preoperative activity of SOD in patients with PTH was significantly lower than that in controls ( p < 0. 01), but the level of MDA was significantly higher than that in controls (p <0. 01). The differences of SOD and MDA between Child s A and B group were significant p <0. 01,0. 05). The level of MDA in Child's A and B group on the 3rd postoperative day was significantly lower than that before operation(P <0. 05 ) , but still higher than that in the control group ( P < 0. 01). The activity of SOD in Child' s A and Child' s B group was significantly higher than that before operation(P <0. 01,0.05) ,but still lower than that in control group(P <0.01, 0.05). Postoperatively, the change degrees of SOD and MDA in Child's A group were greater than those in Childs B group.DiscussionI Evaluation of portrosystemic shunt and portal circulation by per - rectalportal scintigraphy with technetium - 99m pertechnetate after extensive esopha-gogastric devascularizationPer - rectal portal scintigraphy with technetium - 99m pertechnetate is a fairly noninvasive method for analysis of imsgines made of portosystemic shunts , and with its use , In Pattern I, the liver and potal vein were clearly seen, and the heart was not . Pattern II showed the opposite;the heart was clearly seen, and the portal vein and liver were notThis study showed that there was Pattern I in controls and there were mainly Pattern II in PHT and portal blood was against liver in PHT. After extensive esophagogastric devascularization, liver times were significantly earlier than heart tims. Portal biood was toward liver.. In addition,SI was significantly lower after operation (52. 56% ) than before operation(72. 56). That C groups before operation became B groups after operation showed that extensive esophagogastric devascularization could improve liver function and prognosis of patients with PHT.II Effect of individual serum bile acids changes after extensive esophagogastric devascularizationThe changes of metabolism of biles acids can serve as an indicator of the abnormality of liver function. So, investigation of serum bile acids can give some important information of liver function. Serum bile acids are of very low level normally,which increases with liver damage,bile fluid reflux and portosystemic shunts. The study showed that sernm total bile acids was 5 times than normal and increased significant higher in patients with varices than controls.The study showed that free bile acids and conjugated bile acids were significant higher in PHT than in controls, in particularly, among them conjugated bile acids obviously increased. GCA,GCDCA,TCA,TCDCA were obviously increase, this showed conjugated bile acids and free bile acids could increase by portosystemic shunt. Ten bile acids decreased significantly before operation to after operation. Among them,harmful conjugated bile acids decreased very obviously, this showed extensive esophagogastric devascularization could hamper abnormal reflu of portosystemic flow, affect enterohepatic circulation and decrease the levels of bile acids to flow into body system. In addition, liver blood supply could increaseafter extensive esophagogastric devascularization, improve liver function and enhance liver cells function of uptake and cleaning for bile acids.HI Effect of extensive esophagogastric devascularization on nitric oxide and oxygen - derived free radicals in portal hypertensionNO could produced by various cells and had a lot of function. As we have found, the content of NO and the activity of NOS in patients with liver cirrhosis and PHT were significantly higher than those in controls. Moreover, the poorer the liver function was, the more obvious the change was. The reasons might be as follows: 0The portosystemic shunt and decreasr of reticuloendothelial system function in PHT could cause endotoxemia. Endotoxin stimulated and produced cytokine to induce iNOS. (D The increase of hormones and peptides in blood of PHT could stimulate vascular endotheliocytes and increased the expression of cNOS. (D The increase of portal vein flow - rate and decrease of blood viscosity resulted in the increase of shearing stress so that cNOS in endothelial cells were stimulated and produced a large of NO. (J) The lack of endogenetic inhibitor of NOS , hypoxia and other factors could stimulate and increase the expression of cNOS,too.A large amount of NO could have effect as follows: (J) NO induced hyperki-netic circulation state in PHT. (g)The higher concentration of NO could damage hepatocytes, and playe an important role in the pathophysiology in cirrhosis with PHT.It has been shown in this study that the expression of iNOSmRNA and cNOSmRNA, the levels of NO and the activities of NOS were significantly lower at the postoperative day than those before operation ,but they were significantly higher than those in controls. The reasons might be as follows: (I) Postoperative-ly, portal - systemic shunt volume decreased apparently, which decreased the endotoxin level produced by bacteria in systemic circulation and iNOS expression . Therefore, synthesis of NO decreased. ? Postoperatively, blood supply to liver was improved, which strengthened the detoxication of hepatocytes and decreased the initiators such as endotoxin which induces NOS expression. @ Devascularization relieved the hyperkinetic circulatory state in portal system and decreased serum levels of NOS and NO in peripheral vessels. (|) Postoperatively,routine support therapy could improve liver function, while antibiotic administration inactivated entero - endotoxin, which decreased NO. (D It had been proved that NOS expressed highly in the vascular walls of splenic artery and vein in patients with PHT. Therefore, after splenectomy, NOS expression dcreased, and reduced production of NO. We might know about - mentioned that devascular-ization was not treat essence of PHT,and only improved the situation of disease and recovered partly liver function. So the various different indicator in PHT after operation were lower than that befor operation, but were still higher than controls.In this study , the level of SOD in patients with PHT was significantly lower than that in controls, but the level of MDA was significantly higher than that in controls. The more deteriorated the liver function was, the more obvious the changes of these parameters were. OFR not only directly damaged hepatocytes, but also caused a series of pathophysiological changes such as the disorder of immunity ,hepatic microcirculation, toxemia, calcium imbalance and so on. A lot of OFR caused not only lipid peroxidation, but also intracellular calcium overload and hyperkinetic circulation in PHT. Above - mentioned hepatocyte damage could aggrevate hepatocyte degeneration and fibrosis , markedly increased portal venous resistance, hampered the blood flow from visceral organs to liver, and aggravated liver hypoxia and ischemia. At last vicious circle formed . Our results also showed that after extensive esophagogastric devascularization, the level of SOD was obviously higher than that before operation, but it was lower than that in controls. Postoperatively, the level of MDA was markedly lower than that before operation, but it was higher than that in controls. The changes of SOD and MDA were associated with the liver function. The more severe liver function damage was, the less the changes of these parameters were. After extensive esophagogastric devascularization, the reasonable causes of the changes of MDA and SOD were as follows: On the one hand, extensive esophagogastric devascularization played a role in stopping endotoxin into blood through hampering portosystemic shunt, on the other hand , it enhanced liver detoxication ability and decreased OFR production by increasing perfusion of liver flow. However, extensive esophagogastric devascularization did not eradicate the cause of PHT,so SOD and MDA could not recover normal level after opration.Conclusions1 Per - rectal portal scintigraphy with technetium - 99m pertechnetate after extensive esophagogastric devascularization can enhance portal flow toward liver, and increase flow perfusion of liver and be helpful to recovering of liver function.2 Serum bile acids could have very important significance in the study of hepatic disease. Individual serum bile acids were significantly higher in PHT than in controls. All were decreased after extensive esophagogastric devascularization. Among them, harmful conjugated bile acids decreased very obviously, extensive esophagogastric devascularization can partly reverse their changes.Extensive esophagogastric devascularization can improve NO - NOS and OFR system. It can inhibit the activities of NOS either molecule or gene. Postop-eratively, The indicator of NO, NOS iNOSmRNA, cNOSmRNA, SOD MDA in Child s A group were greater than those in Child & B group.Per - rectal portal scintigraphy with technetium - 99m pertechnetate, serum bile acids individuals, NO - NOS and OFR system may become a use sign of judgment of liver function, evaluation of disease situation and prognosis befor and after extensive esophagogastric devascularization.
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