The Protective Effect Of Secretin On Intestinal Failure Associated Liver Disease

With the successful implementation of parenteral nutrition (PN) on canine by Dudrick and Wilmore in 1968, PN had been widely used in clinical practice. Numerous intestinal dysfunction or intestinal failure patients could be long-term survivals, especially in neonatal field. It has become an important treatment to save lives. However, only 3 years later, there were some reports about intestinal failure associated liver disease. Even in the 21st century, according to the reports of all intestinal failure centers, the incidence of intestinal failure associated liver disease was still maintained between 70-80% in long-term PN support patients and the mortality for 3 year of intestinal failure associated liver disease patients was about 20%. Therefore, the high incidence and mortality of intestinal failure associated liver disease was always the difficult problem in parenteral nutrition field. Also, it hindered the development of nutrition support and nutrition therapy. Recent years, some researchers discovered that the long-term survival of short bowel syndrome patients was significantly lower than that of chronic intestinal pseudo-obstruction patients who also accepted long-term PN support. Combining the clinical observation, we analyzed that the hormones from the intestine might play an important role in intestinal failure associated liver disease and we also thought that secretin might be the hormone which produced directly effect.In this study, we established stable SBS intestinal failure associated liver disease rat models and studied the difference of intestinal failure associated liver disease between SBS and non-SBS rats. Then, we supplied a physiological doses secretin to SBS rat and compared the difference of intestinal failure associated liver disease between secretin SBS rat and non-secretin SBS rat. We studied the biochemical indicators and apoptosis-related indicators of liver of all groups in order to confirm the protective effect and potential mechanisms of secretin in intestinal failure associated liver disease. In addition, we also conducted related clinical trial, supplying ursodeoxycholic acid which had similar effects to secretin to those long-term PN support patients. We observed the clinical effect of ursodeoxycholic acid and our reseach provided a new strategy to prevent and treat intestinal failure associated liver disease.PartⅠ Long-term intravenous infusion model in unrestrained rats: A new model with high efficiency and low cost[Abstract] Objective To establish a new simple long-term intravenous infusion model in unrestrained rats and compared its efficacy and related complications with conventional intravenous infusion model. Methods Using 2×2 factorial design and forty adult male Sprague-Dawley rats, weighing 200-250 g, were equally divided into four groups and all rats underwent jugular vein catheterization surgery. Polyurethane intubation and figure 8 wire were used in group Ⅰ. Polyurethane intubation and vest were used in group Ⅱ. Silicone intubation and figure 8 wire were used in group III. Silicone intubation and vest were used in group IV. Results The effective rate of group I to IV were 90%,30%,40%,10% at 14 days after operation. Group I was significantly higher than the other groups. The positive rate of catheter tip culture in group Ⅰ(10%) was significantly lower than that of group Ⅲ(60%). Daily body weight gain was also greater in group 1(2.79±0.44 g/d) than that in group Ⅲ(1.89± 0.20 g/d) and group Ⅳ(1.89±0.17 g/d). Conclusions This new model increases the patency time, reduces the incidence of catheter infection and prones to maintain growth compared with conventional methods. Therefore, it’s a new model with high efficiency and low cost.Part II The protective effect of secretin on liver injury caused by parenteral nutritionExperiment I:The changes of serum secretin levels of short bowel syndrome rat[Abstract] Objective To observe the changes of serum secretin levels of short bowel syndrome rat and verify the hypothesis that gut-derived secretin failure in short bowel syndrome model. Methods Using 22 male SD rats, we divided them into four groups randomly. SBS+Diet group (n=6), SBS+TPN (n=6), Sham+Diet group (n=6), Sham+TPN group (n=4). SBS group underwent 80% intestinal resection and anastomosis. TPN group underwent jugular vein cannulation. The serum secretin levels were measured at preoperative day, postoperative 1st day,3rd day,7th day,14th day and 28th day in order to observe the dynamic changes. Results At postoperative 1st day the secretin levels of SBS+Diet group (442.21±64.91 pg/ml) and SBS+TPN group (370.54±38.79 pg/ml) were significantly lower than that of Sham+Diet group (964.23±247.50 pg/ml) and Sham+TPN (1032.27±177.37 pg/ml). After 4 weeks compensation, the secretin levels of Sham+TPN group decrease to 718.77±89.14 pg/ml. But the secretin levels of SBS+Diet group maintained at 779.47±72.83 pg/ml.Conclusions The secretin levels of SBS model rat decreased significantly, but it could compensate gradually. It reached compensative balance at about postoperative 2 weeks. Secretin levels of long-term fasting model with PN also decreased gradually. About fasting for 1 week, secretin reached the lowest level.Experiment II:Liver injury of total parenteral nutrition to short bowel syndrome rat[Abstract] Objective To compare the biochemical indicators and liver tissue injury of SBS rat after long-term TPN support. Methods Using 12 male SD rats, we divided them into two groups randomly:SBS+TPN (n=6), Sham+TPN group (n=6). SBS group underwent 80% intestinal resection and anastomosis. TPN group underwent jugular vein cannulation. We detected blood biochemistry of all rats at preoperative day, postoperative 1st day,7th day and 14th day. Finally, before sacrifice, detect bile flow and keep liver tissue specimens of all rats. Results The biochemical indicators of both groups increased along with the prolonged TPN support. The bile flow of both groups was significantly lower than that of control rat. But the bile flow of SBS+TPN group (7.13±2.12, u ml/min) was also lower than that of Sham+TPN group (11.80 ±4.18, u ml/min). It also showed that the pathological score and TUNEL apoptosis semiquantitative of SBS+TPN group were significantly higher than those of Sham+TPN group. Conclusions The IFALD related indicators of SBS rat were significantly higher than that of sham rat. The liver apoptosis of SBS rat were significantly higher than that of sham rat. The specific mechanism needs further study.Experiment Ⅲ:The effect of secretin supplement to IFALD[Abstract] Objective To explore the effect of secretin to IFALD by supplying physiological doses of secretin to SBS rat model. Methods Using 24 male SD rats, we divided them into four groups randomly:SBS+secretin (n=6), SBS+ placebo (n=6), Sham+secretin group (n=6), Sham+placebo (n=6). SBS group underwent 80% intestinal resection and anastomosis. All rats underwent jugular vein cannulation and accepted TPN support for 14 days. Sham group underwent sham resection and anastomosis. We detected blood biochemistry of all rats at preoperative day,7th day and 14th day. Finally, before rats were sacrificed, we detected bile flow and kept liver tissue specimens. Results the ALT (95.28±18.25 U/L), AST (211.96±19.27 U/L), TB (211.96±0.30μmol/L), TBA (23.78±3.59μmol/L) of SBS+placebo group were significantly higher than those of SBS+secretin group (ALT,76.35±8.12 U/L;AST,175.35±7.53 U/L;TB,175.35±7.53μmol/L;TBA,19.59±1.54 u mol/L). In addition, the bile flow of SBS+placebo group(6.14±3.04, u ml/min) was also lower than that of SBS+secretin group (14.11±4.97μml/min). The pathological score and TUNEL apoptosis semiquantitative of SBS+secretin group were significantly lower than those of SBS+placebo group.Conclusions The secretin can significantly decrease IFALD by supplying physiological doses of secretin. This protective effect was associated with the inhibition of hepatocyte apoptosis. The specific mechanism needs further study.Part Ⅲ The prevention and treatment effect of UDCA on adult SBS patients IFALD:a prospective randomized double-blind crossover trial[Abstract] Objective To explore the prevention and treatment effect of UDCA on adult SBS patients IFALD by a prospective randomized double-blind crossover trial of UDCA. Methods From 2013 Jan to 2015 Feb, we recruited 30 adult SBS patients who were treated in our center and met the inclusion criteria. We divided them into 2 groups randomly:UDCA+Placebo (UP) group; Placebo+UDCA (PU) group. We analyzed the biochemical indicators and adverse reactions after 4 month crossover trial. The clinical trials number was NCT01974336. Results Before crossover, hepatobiliary function index of UP group was significantly improved as compared with that of PU group. After crossover, liver function index of UP group was still significantly improved as compared with that of PU group but there was no difference in biliary tract function index. Finally, after 4 month, the IFALD relevant indicators of UP group were significantly better than that of PU group.Conclusions UDCA could prevent and treat adult SBS patients IFALD effectively. Those patients who need long-term PN supporting should start UDCA treatment at the early-stage.