Bile Replacement Research Articles

Survey on the current status of the indication and implementation protocols for bile replacement in patients with external biliary drainage with special reference to infection control.

This survey of bile replacement (BR) was conducted on patients with external biliary drainage to assess the current status of indication and implementation protocol of BR with special reference to infection control. A 12-item questionnaire regarding the performance of perioperative BR was sent to 124 institutions in Japan. BR was performed in 29 institutions, and the indication protocol was introduced in 19. BR was performed preoperatively in 11 institutions, pre- and postoperatively in 12, and postoperatively in 6. The methods used for BR administration included oral intake (n = 10), nasogastric tube (n = 1), enteral nutrition tube (n = 3), oral intake and enteral nutrition tube (n = 6), oral intake or nasogastric tube (n = 2), nasogastric tube and enteral nutrition tube (n = 2), and oral intake or nasogastric tube and enteral nutrition tube (n = 5). In 10 of 29 institutions, isolation of multidrug-resistant organisms and a high bacterial load were considered contraindications for the use of BR. Seven institutions experienced environmental contamination. Given the different implementation of BR among institutions, the appropriate indication and protocols for BR should be established for infection control.

Survey of preoperative management protocol for perihilar cholangiocarcinoma at 10 Japanese high-volume centers with a combined experience of 2,778 cases.

In Japan, strategies for preoperative management of perihilar cholangiocarcinoma (PHC) have evolved over the last decade; the operative mortality has significantly reduced to <5%. A questionnaire was sent to 10 institutions based on their case volume. Questionnaire was based on: (1) preoperative biliary drainage, (2) bile replacement, (3) role of synbiotics, (4) remnant liver volume enhancement, (5) predicted remnant liver function, (6) imaging, (7) nutrition, and(8) role of Inchinkoto. The median case volume was 226 (range105-889) cases, respectively. Eight institutions preferred endoscopic nasobiliary drainage and two preferred endoscopic biliary stenting for biliary drainage. Nine used bile replacement within 2-3days of biliary drainage. Four used synbiotics preoperatively. The median cutoff value for future remnant liver volume and serum totalbilirubin, at which portal vein embolization (PVE) is done, is <40% and <4mg/dl. The median interval between PVE and surgery was 3-4weeks. To predict remnant liver function, indocyanine green retention (n=8) and clearance rate (n=2) were mainly used. Five used Inchinkoto to improve liver function. Nine used multidetector computed tomography and direct cholangiography for surgical planning. With appropriate preoperative management of PHC, surgical morbidity and mortality can be reduced. This survey can provide recommendations to improve PHC perioperative outcomes.

Experimental study of diclofenac and its biliary metabolites on anastomotic healing.

BackgroundDiclofenac increases the risk of anastomotic leakage, but the underlying mechanism is unknown. As diclofenac is excreted largely as biliary metabolites, the aim of this study was to determine the effect of these metabolites on intestinal anastomoses.MethodsThis was a randomized controlled blinded experiment using 210 male Wistar rats to assess the effect of ‘diclofenac bile’ on the anastomotic complication score, leak rate and anastomotic strength following oral and parenteral administration of diclofenac. Bile duct and duodenal catheterization techniques were used for diversion and replacement of bile, and biliary diclofenac metabolites were determined.ResultsReplacement of control bile with diclofenac bile resulted in higher anastomotic complication scores (P = 0·006) and leakage in five of 18 animals, compared with one of 18 controls (P = 0·089). In turn, following oral diclofenac administration, replacement of diclofenac bile with control bile reduced anastomotic complications (P = 0·016). The leak rate was seven of 15 versus 13 of 17 without replacement (P = 0·127). After intramuscular administration of diclofenac, the reduction in anastomotic complications was not significant when bile was replaced with control bile (P = 0·283), but it was significant when bile was drained without replacement (P = 0·025). Diclofenac metabolites in bile peaked within 2 h after administration. Administration of diclofenac bile resulted in nearly undetectable plasma levels of diclofenac (mean(s.d.) 0·01(0·01) μg/ml) after 120 min. Following oral diclofenac, bile replacement with control bile did not affect the plasma concentration of diclofenac (0·12(0·08) μg/ml versus 0·10(0·05) μg/ml with diclofenac bile; P = 0·869).ConclusionAltered bile composition as a result of diclofenac administration increases the ileal anastomotic complication rate in rats.

Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

The role of the intestine in the maintenance of cholesterol homeostasis increasingly is recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport pathway, to which biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway, however, are poorly understood. We aimed to identify mechanisms that regulate and stimulate TICE. We performed studies with C57Bl/6J mice, as well as with mice with intestine-specific knockout of the farnesoid X receptor (FXR), mice that express an FXR transgene specifically in the intestine, and ABCG8-knockout mice. Mice were fed a control diet or a diet supplemented with the FXR agonist PX20606, with or without the cholesterol absorption inhibitor ezetimibe. Some mice with intestine-specific knockout of FXR were given daily injections of fibroblast growth factor (FGF)19. To determine fractional cholesterol absorption, mice were given intravenous injections of cholesterol D5 and oral cholesterol D7. Mice were given 13C-acetate in drinking water for measurement of cholesterol synthesis. Bile cannulations were performed and biliary cholesterol secretion rates were assessed. In a separate set of experiments, bile ducts of male Wistar rats were exteriorized, allowing replacement of endogenous bile by a model bile. In mice, we found TICE to be regulated by intestinal FXR via induction of its target gene Fgf15 (FGF19 in rats and human beings). Stimulation of this pathway caused mice to excrete up to 60% of their total cholesterol content each day. PX20606 and FGF19 each increased the ratio of muricholate:cholate in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool stimulated robust secretion of cholesterol into the intestinal lumen via the sterol-exporting heterodimer adenosine triphosphate binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, the increase in TICE induced by PX20606 was independent of changes in cholesterol absorption. Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Strategies that alter bile salt pool composition might be developed for the prevention of cardiovascular disease. Transcript profiling: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=irsrayeohfcntqx&acc=GSE74101.

Preoperative Bile Replacement Improves Immune Function for Jaundiced Patients Treated with External Biliary Drainage

BackgroundAlthough preoperative biliary drainage in jaundiced patients is controversial, external biliary drainage (EBD) is beneficial for infection control in patients with biliary cancers. When EBD is performed, additional bile replacement (BR) has the benefit of improving impaired intestinal barrier function, but the detailed mechanism remains unknown. We examined the effect of bile replacement on immune functions over the duration of BR in jaundiced patients. MethodsFifteen patients were enrolled into this prospective study. BR was started soon after the total serum bilirubin concentration reached 5.0 mg/dl and was continued for 14 days. Drained bile was given two times orally (2 × 100 ml/day). Concanavalin A (Con A)- and phytohemagglutinin (PHA)-stimulated lymphocyte proliferation and serum diamine oxidase (DAO) activity were measured before starting and during BR. Twenty patients with EBD and no BR were analyzed as a control group. ResultsSerum liver enzymes, prothrombin time–international normalized ratio (PT-INR), and responses to Con A and PHA gradually improved over the 14 days of BR, but percentages of lymphocytes and DAO levels did not. PT-INR, and Con A and PHA responses did not improve during EBD in the control group. PT-INR significantly decreased in patients with a greater fraction of their drained bile replaced. ConclusionsOur results indicate that preoperative BR using as large a quantity of bile as possible is useful for improving blood coagulability and cellular immunity in patients with EBD.

Role of Preoperative Optimization of the Liver for Resection in Patients with Hilar Cholangiocarcinoma Type III

Long-term survival after complete resection of hilar cholangiocarcinoma remains disappointing. The aim of this retrospective study was to assess the impact of liver optimization on postoperative outcome of hilar cholangiocarcinoma type III. In a retrospective, single-center analysis, outcomes in patients with hilar cholangiocarcinoma type III who underwent resection after preoperative liver optimization (preoperative transhepatic biliary drainage [PTBD], bile replacement, and/or portal vein embolization [PVE]) were compared with nonoptimized controls. Of 41 patients undergoing surgery, 38 patients undergoing curative intent procedures were identified, of whom 15 underwent preoperative optimization. After PTBD, direct bilirubin decreased from 218.0 ± 184.2 to 75.9 ± 42.7 μmol/L (P = 0.03), and there was a trend toward decreased AST and ALT levels. Overall, 3- and 5-year survival rates were 47.9 ± 9.1 and 41.9 ± 9.8%. The primary endpoint, 5-year survival after surgery, was not significantly different between groups. Preoperative jaundice was identified as an independent prognostic factor for poor outcome (hazard ratio [HR] 2.12, P = 0.02). Four patients (10.5%) without preoperative optimization died of liver failure within the first 30 days postsurgery, preceded in three cases by intra-abdominal abscesses. PTBD was associated with a lower rate of postoperative intra-abdominal abscesses; however this factor was not independently predictive of higher survival. Preoperative optimization of the liver in hilar cholangiocarcinoma Type III reduced the incidence of intra-abdominal abscesses, but its impact on postoperative survival remains unclear.

Preoperative biliary drainage for biliary tract and ampullary carcinomas

We posed six clinical questions (CQ) on preoperative biliary drainage and organized all pertinent evidence regarding these questions. CQ 1. Is preoperative biliary drainage necessary for patients with jaundice? The indications for preoperative drainage for jaundiced patients are changing greatly. Many reports state that, excluding conditions such as cholangitis and liver dysfunction, biliary drainage is not necessary before pancreatoduodenectomy or less invasive surgery. However, the morbidity and mortality of extended hepatectomy for biliary cancer is still high, and the most common cause of death is hepatic failure; therefore, preoperative biliary drainage is desirable in patients who are to undergo extended hepatectomy. CQ 2. What procedures are appropriate for preoperative biliary drainage? There are three methods of biliary drainage: percutaneous transhepatic biliary drainage (PTBD), endoscopic nasobiliary drainage (ENBD) or endoscopic retrograde biliary drainage (ERBD), and surgical drainage. ERBD is an internal drainage method, and PTBD and ENBD are external methods. However, there are no reports of comparisons of preoperative biliary drainage methods using randomized controlled trials (RCTs). Thus, at this point, a method should be used that can be safely performed with the equipment and techniques available at each facility. CQ 3. Which is better, unilateral or bilateral biliary drainage, in malignant hilar obstruction? Unilateral biliary drainage of the future remnant hepatic lobe is usually enough even when intrahepatic bile ducts are separated into multiple units due to hilar malignancy. Bilateral biliary drainage should be considered in the following cases: those in which the operative procedure is difficult to determine before biliary drainage; those in which cholangitis has developed after unilateral drainage; and those in which the decrease in serum bilirubin after unilateral drainage is very slow. CQ 4. What is the best treatment for postdrainage fever? The most likely cause of high fever in patients with biliary drainage is cholangitis due to problems with the existing drainage catheter or segmental cholangitis if an undrained segment is left. In the latter case, urgent drainage is required. CQ 5. Is bile culture necessary in patients with biliary drainage who are to undergo surgery? Monitoring of bile cultures is necessary for patients with biliary drainage to determine the appropriate use of antibiotics during the perioperative period. CQ 6. Is bile replacement useful for patients with external biliary drainage? Maintenance of the enterohepatic bile circulation is vitally important. Thus, preoperative bile replacement in patients with external biliary drainage is very likely to be effective when highly invasive surgery (e.g., extended hepatectomy for hilar cholangiocarcinoma) is planned.

The Value of Bile Replacement During External Biliary Drainage

To investigate the effect of bile replacement following percutaneous transhepatic biliary drainage, ie, external drainage, on intestinal permeability, integrity, and microflora in a clinical setting. Several authors have reported that internal biliary drainage is superior to external drainage. However, it is unclear whether bile replacement following external drainage is beneficial. Twenty-five patients with biliary cancer underwent percutaneous transhepatic biliary drainage (PTBD) as a part of presurgical management. All externally drained bile was replaced either per os or by administration through a nasoduodenal tube. The interval between PTBD and the beginning of bile replacement was 21.3 +/- 19.7 days, and the length of bile replacement was 20.7 +/- 9.6 days. The lactulose-mannitol test, measurement of serum diamine oxidase (DAO) activity, and analyses of fecal microflora and organic acids were performed before and after bile replacement. The volume of externally drained bile varied widely from patient to patient, ranging from 220 +/- 106 mL/d to 1616 +/- 394 mL/d (mean, 714 +/- 346 mL/d). Biliary concentrations of bile acids, cholesterol, and phospholipids increased significantly after bile replacement. The lactulose-mannitol (L/M) ratio decreased from 0.063 +/- 0.060 before bile replacement to 0.038 +/- 0.032 after bile replacement (P < 0.05). Serum DAO activity increased from 3.9 +/- 1.4 U/L before bile replacement to 5.1 +/- 1.6 U/L after bile replacement (P < 0.005), and the magnitude of change in serum DAO activity correlated with the length of bile replacement (r = 0.483, P < 0.05). Neither the L/M ratios nor serum DAO activities before bile replacement correlated with the interval between PTBD and the beginning of bile replacement. Fecal microflora and organic acids were unchanged. Impaired intestinal barrier function does not recover by PTBD without bile replacement. Bile replacement during external biliary drainage can restore the intestinal barrier function in patients with biliary obstruction, primarily due to repair of physical damage to the intestinal mucosa. Our results support the hypothesis that bile replacement during external drainage is beneficial.

Bile-pancreatic juice replacement not cholinergic-and cholecystokinin-receptor blockade reverses acinar cell hyperstimulation after bile-pancreatic duct ligation

Acinar cell inhibitors (eg, atropine) fail to ameliorate clinical and experimental acute pancreatitis. We hypothesized that amelioration of pancreatic acinar cell hyperstimulation after bile and pancreatic duct ligation is better with gut replacement of bile and pancreatic juice than with cholinergic- and cholecystokinin (CCK)-receptor blockade. Using acinar cell amylase activity as an index of hyperstimulation, we studied 63 rats in two sets of experiments. Bile-pancreatic juice exclusion from gut--without (set one) and with (set two) bile and pancreatic duct obstruction--was treated with atropine and CCK-receptor antagonist L-364,718, or with enteral replacement of bile-pancreatic juice. In the set one experiment, acinar cell hyperstimulation after bile-pancreatic juice exclusion was reversed by combined L-364,718 and atropine pretreatment. In set two, acinar cell hyperstimulation after bile and pancreatic duct ligation was reversed by enteral bile and pancreatic juice replacement, but not by combined L-364,718 and atropine pretreatment. According to this experimental corollary of early gallstone impaction, prevention of acinar cell hyperstimulation after duct occlusion should be aimed at the source of the response to bile-pancreatic juice exclusion, namely, the gut, rather than at the target of the response, the pancreatic acinar cell.

Bile and pancreatic juice replacement ameliorates early ligation-induced acute pancreatitis in rats

In healthy rats, combined bile and pancreatic juice diversion from gut has a synergistic rather than additive effect on stimulation of exocrine pancreatic protein secretion. We hypothesized that exclusion of combined bile and pancreatic juice from gut exacerbates bile and pancreatic-duct ligation-induced acute pancreatitis in rats to a greater extent than exclusion of either bile or pancreatic juice alone. Bile and pancreatic juice (obtained fresh from donor rats) were replaced, separately or together, via a duodenal fistula beginning immediately before 6 hours of duct ligation. Pancreatic morphologic changes were evaluated with an acute pancreatitis histology score and morphometric quantitation of acinar-cell necrosis. Plasma amylase and cholecystokinin concentrations and pancreatic subcellular distribution of cathepsin B activity were determined. Characteristics of bile and pancreatic juice obtained from donor rats were also studied. Combined bile and pancreatic juice replacement limited the increase in acute pancreatitis histology score by 77%, acinar cell necrosis by 95%, hyperamylasemia by 77%, and hypercholecystokininemia by 99%, while preventing subcellular redistribution of cathepsin B. Amelioration of pancreatic morphologic changes was significantly greater with combined bile and pancreatic juice replacement than with replacement of either bile or pancreatic juice alone. In this experimental corollary of early gallstone-induced acute pancreatitis, combined bile and pancreatic juice exclusion from gut contributes to disease pathogenesis to a greater extent than exclusion of either bile or pancreatic juice alone.

Contribution of the biliary pathway to the homeostasis of vitamin D3 and of 1,25-dihydroxyvitamin D3.

The role of the biliary pathway in the homeostasis of the vitamin D3 (D3) group of compounds is poorly understood. The purpose of the studies was to investigate the biliary excretion pattern of materials derived from the parent compound D3 and from the hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) during constant iv infusion, and to probe the influence of 1,25(OH)2D3 pretreatment on the excretion into the bile of D3-derived materials. Under anesthesia, the bile duct, duodenum (for bile replacement), and jugular veins were cannulated. The experiments were then carried out in fully awake rats with access to food and water ad libitum during a period of 6 h. Data indicate that before steady state was reached, biliary excretion of 1,25(OH)2[3H]D3 was much more important than that of [14C]D3 with bile/plasma concentration ratios above 1 in 1,25(OH)2[3H]D3-infused animals from the 15th-60th min of infusion compared to ratios between 0.12-0.40 in [14C]D3-infused rats (P less than 0.0001); this led to a cumulative excretion 6.3-fold higher after 1,25(OH)2[3H]D3 than after [14C]D3 administration, with 3.9 +/- 0.4% and 0.6 +/- 0.1% of the dose being recovered into the bile during the first hour of excretion. However, once stable plasma concentrations were reached, the rate of excretion of the two compounds became similar, with bile/plasma concentration ratios of 0.64 +/- 0.02 and 0.70 +/- 0.02 (P greater than 0.05), and plasma bile clearance of 26.4 +/- 1.0 and 25.7 +/- 1.7 microliters/min.kg for 1,25(OH)2[3H]D3 and [14C]D3, respectively (P greater than 0.05). During that period, the MCR of 1,25(OH)2D3 was estimated to be 118.3 +/- 10.5 microliters/min.kg. On the other hand, 1,25(OH)2D3 pretreatment as constant ip infusion (14 pmol/24 h for 6 days) significantly increased bile flow [1,25(OH)2D3 treated, 44.9 +/- 1.6 microliters/min.kg; untreated, 36.6 +/- 0.5 microliters/min.kg, P less than 0.01)], leading to significant increases in the plasma bile clearance of [14C]D3-derived compounds early in the course of the study (P less than 0.004) in the presence of similar bile/plasma concentration ratios in the two groups. During the steady state phase of investigation, however, bile/plasma concentration ratios became lower in 1,25(OH)2D3-than in placebo-treated animals (P less than 0.05), but due to the 1,25(OH)2D3-mediated increase in bile flow, similar plasma bile clearances were observed in both groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Percutaneous Endoscopic Stomas

Percutaneous endoscopic gastrostomy was introduced in 1980 as a method for the creation of a feeding gastrostomy without the need for laparotomy or general anesthesia. The technique originally described, the pull method, involves puncturing the apposed gastric and abdominal walls under endoscopic control. A suture is then passed from the exterior into the gastric lumen and grasped with a snare. The suture is pulled out of the mouth, affixed to the end of a gastrostomy tube, and then pulled back down into the stomach. The gastrostomy tube is thus pulled into the stomach, and its end exits the abdominal wall. Modifications of this technique have included pushing the gastrostomy tube over a guidewire (the push method) and direct puncture of the stomach under endoscopic control with an introducer and outer peel-away sheath. All of these methods have been used with good results. Complications have included infection of the abdominal wall and intraperitoneal leakage. These may be minimized by attention to detail. The indications for the method have been expanded to include gastric decompression, administration of unpalatable medications in children, and creation of a conduit for bile replacement. Careful judgment in patient selection is crucial if good results are to obtained. This technique also introduces the concept of percutaneous endoscopic fixation of a loop of bowel to the abdominal wall. This concept may be employed in other areas of the gastrointestinal tract.

Effect of bile duct obstruction on pancreatic enzyme secretion and intestinal proteolytic enzyme activity in the rat

The role of bile in regulation of intestinal proteolytic activity in rats was investigated by studying the effects of bile diversion and bile duct obstruction on pancreatic protease secretion and on recovery of protease from the intestine. Diversion of bile and pancreatic juice from the intestine caused a large increase in pancreatic enzyme secretion; replacement of bile partially suppressed this response. Bile duct obstruction resulted (3-4 days postobstruction) in a threefold increase in pancreatic juice chymotrypsin but caused a large decreases in intestinal trypsin and chymotrypsin activities and total proteolytic activity. Recovery of pancreatic juice protein (labeled with 14C) from intestinal contents was markedly decreased in bile duct obstruction, indicating a more rapid rate of degradation and absorption of pancreatic jucie protein. The evidence suggests that interruption of bile flow results in an accelerated rate of degradation of pancreatic proteolytic enzymes, and that the increase in pancreatic enzyme secretion is an adaptation to decreased intestinal proteolytic activity.

Effect of diversion and replacement of bile on pancreatic secretion.

Pancreatic bicarbonate and protein outputs have been studies under basal conditions and in response to a variety of endogenous and exogenous stimuli in conscious dogs with biliary and pancreatic fistulas and with bile diverted and then replaced into the intestine. Infusion of bile into the duodenum and jejunum but not the ileum caused a marked increase in pancreatic protein secretion, and to a lesser degree in bicarbonate output, only in tests performed under basal conditions. Pancreatic dose-response curves to intravenous secretin and caerulein, to intraduodenal hydrochloric acid and amino acids, or to feeding liver meal were not significantly altered by the diversion and subsequent replacement of bile into the duodenum. It is suggested that the release of cholecystokinin or neuroreflex stimulation of pancreas by the bile in the intestine may explain the bile stimulation of pancreatic secretion observed.

A new cannula for the study of pancreatic function.

A new cannula for the study of pancreatic function.