Bile Diversion Research Articles

Results of surgical treatment for recurrent postoperative gastroesophageal reflux

The rate of recurrence of reflux esophagitis after classic antireflux surgery (fundoplication) is 10-15%. This rate is different in patients with esophagitis with and without Barrett's esophagus. We evaluated the clinical and laboratory findings in 104 patients with postoperative recurrent reflux esophagitis, determining the results of repeat antireflux surgery or an acid suppression-bile diversion procedure. Repeat fundoplication was performed in 26 patients, and truncal vagotomy, antrectomy, and Roux-en-Y gastrojejunostomy in 78 patients. Esophagectomy as a third operation was performed in seven patients. After repeat antireflux surgery, endoscopic evaluation demonstrated improvement of esophagitis in a small proportion of patients. Barrett's esophagus remained unchanged, and no regression of ulcer or stricture was observed. These complications improved significantly after acid suppression-bile diversion surgery. Incompetent lower esophageal sphincter (LES) was present in 55.8% after initial surgery and in 23% after reoperation. Acid reflux, initially present in 94.6% of patients, was also observed in 93.6% after fundoplication, 68.8% after redo fundoplication, and 16.6% after treatment with the acid suppression-bile diversion technique. A positive Bilitec test was present in 78% of patients before the operation and 56.6% after the repeat operation, and was negative after bile diversion surgery. Among 13 patients (50%) submitted to repeat surgery alone, esophagectomy as a third operation was necessary as a result of severe non-dilatable stricture in seven patients. Our conclusions are that repeat antireflux surgery alone failed to improve Barrett's esophagus complications and that the best results were obtained in patients submitted to acid suppression-bile diversion surgery.

The role of transhepatic bile salt flux in the control of hepatic secretion of triacylglycerol-rich lipoproteins in vivo in rodents

Bile salts (BS) have been shown to suppress the secretion of very-low-density lipoprotein-triglyceride (VLDL-TG) in rat and human hepatocytes in vitro. In the present study, we investigated whether the transhepatic BS flux affects VLDL-TG concentration and hepatic VLDL-TG secretion in vivo. In rats, the transhepatic BS flux was quantitatively manipulated by 1-week chronic bile diversion (BD), followed by intraduodenal infusion with taurocholate (TC) or saline for 6 h. In mice, the transhepatic BS flux was manipulated by a 3-week dietary supplementation with TC (0.5 wt.%) or cholestyramine (2 wt.%). In rats, BD followed by saline or TC infusion did not affect plasma triacylglycerol (TG) concentration, hepatic TG production rate or VLDL lipid composition, compared to control rats. In mice supplemented for 3 weeks with TC or cholestyramine, the transhepatic BS flux was increased by 335% and decreased by 48%, respectively, compared to controls. Among the three experimental groups of mice, an inverse relationship between transhepatic BS flux and either plasma TG concentration ( R 2=0.89) or VLDL-TG production rate ( R 2=0.87) was observed, but differences were relatively small. Present data support the concept that BS can reduce VLDL-TG concentration and inhibit hepatic TG secretion in vivo; however, this occurs only at supraphysiological transhepatic BS fluxes in mice.

Management of long-term failure after colon interposition for benign disease

Purpose: To assess causes and treatment of late failures of colon interposition. Methods: We reviewed the charts of 6 patients who underwent one or more revisions of a colonic interposition at a mean of 16 years after colon interposition (CI). Results: Symptoms of problems with the CI were dysphagia (67%), regurgitation (67%), pneumonia (40%), and chest pain (33%). Findings that accounted for failure were colonic redundancy (67%), and gastrocolonic reflux (50%). Approach was resection of redundant colon or management of reflux. Four patients underwent segmental resection of the colon preserving blood supply. Three patients had gastric resection or diversion of bile and acid for management of reflux. Treatment was successful in all patients. Conclusion: Late failure of colon interposition is secondary to conduit redundancy and severe reflux. Resection of redundant colon will correct colonic redundancy. Gastric resection or diversion of bile and acid corrects gastrocolonic reflux.

Effects of internal biliary bypass on the regulation of hepatic cholesterol 7alpha-hydroxylase activity in rats.

In order to re-evaluate the importance of the enterohepatic circulation of bile acid in the regulation of the activities of hepatic cholesterol 7alpha-hydroxylase, bile acid metabolism was examined in internal biliary bypass models of rats. A polyethylene tube was inserted into the common bile duct and another side of the tube was placed in the duodenum (DD), lower jejunum (JD), cecum (CeD), or transverse colon (CoD) as internal biliary bypass models and in the urinary bladder as an external biliary drainage (ED). After bile diversion for 7 days in each group, hepatic cholesterol 7alpha-hydroxylase activities, bile acid concentrations in bile, serum, and portal vein, biliary bile acid compositions, and intestinal absorption rates of infused labeled taurocholic acid were analyzed. Hepatic cholesterol 7alpha-hydroxylase activity was similar in the JD group compared with the DD group, however, it was significantly up-regulated in the CeD (227% of the DD group), CoD (312%), and ED groups (316%). Biliary, serum, and portal bile acid concentrations were not significantly changed in the DD, JD, and CeD groups but those were significantly lower in the CoD and ED groups compared with the DD group. The proportion of the secondary bile acids was significantly increased in the CeD group and was decreased in the CoD and ED groups. The absorption rate of taurocholic acid was almost 100%, 56%, and 23% in the JD, CeD, and the CoD group, respectively. As the cholesterol 7alpha-hydroxylase activity was not significantly changed in the JD group and the predominance of secondary bile acids did not suppress the enzyme activity in the CeD group, the luminal factor, which is absorbed in the presence of bile acids, and the bile acid metabolites are not likely the regulatory factor. The cholesterol 7alpha-hydroxylase activity seems to be primarily regulated by the intestinal absorption of bile acids and partly by the intestinal mucosal factor which is linked to the intestinal bile acid absorption.

Icteric-type hepatoma: magnetic resonance imaging and magnetic resonance cholangiographic features.

We evaluated the imaging features of magnetic resonance imaging (MRI) and magnetic resonance cholangiography (MRC) of icteric-type hepatoma and correlated these with the findings of endoscopic retrograde cholangiography (ERC), percutaneous cholangiography, and surgery. Thirteen patients with viral hepatitis complicated by cirrhosis of the liver and obstructive jaundice underwent MRC and dynamic MRI. Five patients received percutaneous transhepatic cholangiography and drainage; one of these patients also underwent resection of the left hepatic lobe. Another patient received MRC followed by thrombectomy and T-tube insertion. ERC and endoscopic nasobiliary drainage were performed in another patient for bile diversion. Primary liver tumors and dilatation of biliary system were demonstrated in all patients. No capsule formation could be found in any primary liver tumors. MRI showed the simultaneous presence of an intraluminal tumor in the portal trunk and common hepatic duct in eight patients. Three different MRC features were found: (a) an oval defect in the hilar bile duct(s) with dilated intrahepatic ducts (n = 9), (b) dilated intrahepatic ducts with missing major bile ducts (n = 2), and (c) localized stricture of the hilar bile duct(s) (n = 2). The presence of one or more of the following features in multiplanar MRI and MRC help to identify this rare, specific type of hepatocellular carcinoma: (a) the presence of an intraluminal tumor in both the portal trunk and the common hepatic duct, (b) enhancement of the intraluminal tumor in the common hepatic duct on the arterial phase, (c) type I MRC feature, and (d) hemobilia, blood clot within the gallbladder, and/or type II MRC feature.

Pharmacokinetics and tolerability of 40-0-[2-hydroxyethyl]rapamycin in de novo liver transplant recipients.

40-0-[2-Hydroxyethyl]rapamycin (RAD), a novel macrolide with potent immunosuppressive and antiproliferative activities, prevents rejection in animal allotransplantation models. This phase I trial assessed the effects of bile diversion, administration route, and time after transplant on RAD pharmacokinetics after single-dose administration in de novo liver allograft recipients. The influence of RAD on cyclosporine (CsA) pharmacokinetics and the safety of RAD were also evaluated. Twenty-six de novo liver allograft recipients were assigned to one of four treatment groups based on the presence or absence of a T tube, administration route (nasogastric or nasoduodenal), and timing of RAD administration. Patients received a single 7.5-mg RAD dose on one to three occasions in addition to CsA (Neoral) and corticosteroids. Steady-state cyclosporine profiles with and without RAD coadministration were evaluated. Results. Recipients with bile diversion demonstrated lower peak concentration (Cmax) than those without, but overall drug exposure (AUC) was not altered. Cmax and AUC were not influenced by administration route. A trend towards higher Cmax on postoperative day 3 than on postoperative day 1 was noted, although AUC was not altered. Single-dose RAD coadministration did not affect steady-state CsA pharmacokinetics. RAD was well tolerated and caused few drug-related adverse effects. RAD administration did not increase infection rates or produce clinically significant changes in laboratory parameters. Conclusions. In de novo liver transplant recipients, the overall extent of RAD absorption was not influenced by bile diversion, administration route, or time of administration. CsA pharmacokinetics were not affected by single-dose RAD coadministration. RAD capsules administered in single doses of 7.5 mg were well tolerated and safe.

Caseinomacropeptide specifically stimulates exocrine pancreatic secretion in the anesthetized rat

The effect of caseinomacropeptide (CMP) (the [106–169] fragment of κ-casein produced during digestion of milk protein), was studied in anesthetized rats using bile diversion for a pure pancreatic juice collection system. Intraduodenal administration of CMP induced a dose-related specific stimulation of pancreatic secretion which was nearly abolished by devazepide, atropine, hexamethonium, vagotomy or perivagal capsaicin pretreatment. Moreover, CMP did not inhibit in vitro trypsin activity. These results demonstrate that CMP is more likely to stimulate pancreatic secretion specifically through cholecystokinin release and activation of a vago-vagal cholinergic reflex loop than by inhibition of luminal trypsin, in anesthetized rats.

Chronic diversion of bile to the urinary bladder induces pancreatic growth in dogs

The aim of this study was to elucidate the mechanism of chronic biliary diversion and its effect on pancreatic growth. In the first part of the study, nine mongrel dogs underwent diversion of bile from the gastrointestinal tract by ligating the common bile duct and interposing a segment of jejunum between the gallbladder and the urinary bladder (cholecystojejunocystostomy [CJC]). Despite the loss of 7% of their body weight at 12 weeks after bilioenteric diversion, CJC dogs had significantly greater pancreatic wet weight than control dogs (51.2 ± 2.2 g vs. 37.1 ± 2.2 g). In the second part of the study, six other dogs underwent CJC. Twelve weeks later, bilioenteric continuity was restored by creating a cholecystojejunoduodenostomy (CJD). The dogs were given butter (3 g/kg) by mouth (prior to surgery, 12 weeks after CJC, and 4 weeks after CJD). Pancreatic excisional biopsy specimens were obtained at each operation and at autopsy. CJC induced more pancreatic RNA per milligram of weight (743 ± 52, CJC; 579 ± 44, prior to surgery, P <0.05 vs. CJC; 520 ± 26 μg/100 mg · tissue, CJD, P <0.01 vs. CJC), but not more DNA, and significantly higher basal plasma cholecystokinin levels and butter-stimulated cholecystokinin responses when compared with values prior to surgery or following CJD. We conclude that chronic biliary diversion induces pancreatic growth associated with hypersecretion of cholecystokinin in dogs.

Detection of impaired intestinal absorption of long-chain fatty acids: validation studies of a novel test in a rat model of fat malabsorption

Classic fat balance studies detect fat malabsorption but do not discriminate between the potential causes of malabsorption, such as impaired intestinal lipolysis or reduced uptake of fatty acids. We aimed to validate a novel test for the specific, sensitive detection of impaired intestinal uptake of long-chain unesterified fatty acids in an appropriate rat model of fat malabsorption. The absorption and appearance in plasma of [(13)C]palmitic acid were determined in control rats and in rats with fat malabsorption due either to chronic bile deficiency (permanent bile diversion) or to oral administration of the lipase inhibitor orlistat (200 mg/kg diet). [(13)C]Palmitic acid results were compared with the percentage absorption of ingested dietary fat determined by fat balance. Between 1 and 6 h after intraduodenal administration, plasma [(13)C]palmitate concentrations in control rats were 4-10-fold higher than in bile-deficient rats (P < 0.05) but were not significantly different between orlistat-supplemented rats and their controls. In control and bile-deficient rats, plasma [(13)C]palmitate concentrations allowed complete discrimination between normal (>92%) and reduced (<92%) fat absorption, whereas the percentage absorption of [(13)C]palmitate over 48 h appeared to be highly correlated with the percentage absorption of ingested dietary fat (r = 0.89, P < 0.001). The [(13)C]palmitic acid absorption test detects impaired intestinal absorption of long-chain fatty acids selectively and sensitively in a rat model of fat malabsorption due to bile deficiency. Our data strongly support the use of the [(13)C]palmitic acid absorption test for the diagnosis of clinical fat malabsorption syndromes.

Primary Bile Reflux Gastritis: Which Treatment is Better, Roux-en-Y or Biliary Diversion?

Primary bile reflux gastritis is an unusual and elusive problem. Postgastrectomy bile reflux has been long recognized and treated variously with Roux-en-Y gastrojejunostomy, Braun enteroenterostomy, and Henley jejunal interposition. All of these procedures have been fraught with postoperative side effects, the worst of which is stasis. A new procedure utilizing biliary diversion has been proposed to divert bile from the gastric lumen without vagotomy or gastric resection. This procedure was used for 16 patients with diagnosed bile reflux, and results were compared with those of a previous group of 21 patients who had been treated with Roux-en-Y gastrojejunostomy. The patient groups were similar in age, sex, weight, symptoms, and results of investigative studies. The earlier group all had vagotomy, antrectomy, and gastrojejunal anastomosis to a 45-cm Roux limb. The later group all had an end-to-side choledochojejunostomy to a 45-cm Roux limb, taken 45 cm from the ligament of Treitz. The patients in the bile diversion group had fewer complications and shorter hospital stays. In addition, they had few postoperative complaints, no further operations for either bile reflux or upper gastrointestinal stasis, and no long-term deaths due to gastrointestinal problems or malnutrition. Their eventual postoperative gastric emptying improved significantly when compared with the Roux-en-Y patients, suggesting that the dysmotility observed preoperatively may well have been a result of the bile injury to the stomach, rather than an underlying gastric dysmotility.

Diazepam-binding inhibitor mediates feedback regulation of pancreatic secretion and postprandial release of cholecystokinin.

Recently, we isolated a trypsin-sensitive cholecystokinin-releasing peptide (CCK-RP) from porcine and rat intestinal mucosa. The amino acid sequence of this peptide was determined to be identical to that of the diazepam-binding inhibitor (DBI). To test the role of DBI in pancreatic secretion and responses to feeding, we used pancreaticobiliary and intestinal cannula to divert bile-pancreatic juice from anesthetized rats. Within 2 hours, this treatment caused a 2-fold increase in pancreatic protein output and a >10-fold increase in plasma CCK. Luminal DBI levels increased 4-fold. At 5 hours after diversion of bile-pancreatic juice, each of these measures returned to basal levels. Intraduodenal infusion of peptone evoked a 5-fold increase in the concentration of luminal DBI. In separate studies, we demonstrated that intraduodenal administration of antiserum to a DBI peptide specifically abolished pancreatic secretion and the increase in plasma CCK levels after diversion of bile-pancreatic juice. To demonstrate that DBI mediates the postprandial rise in plasma CCK levels, we showed that intraduodenal administration of 5% peptone induced dramatic increases in pancreatic secretion and plasma CCK, effects that could be blocked by intraduodenal administration of anti-DBI antiserum. Hence, DBI, a trypsin-sensitive CCK-RP secreted from the proximal small bowel, mediates the feedback regulation of pancreatic secretion and the postprandial release of CCK.

The contribution of newly synthesized cholesterol to bile salt synthesis in rats quantified by mass isotopomer distribution analysis

A new stable isotope procedure has been developed and validated in rats, applying [1- 13C]acetate infusion to quantify the production of bile salts from de novo synthesized cholesterol making use of the mass isotopomer distribution analysis (MIDA) principle. Ions ( m/ z) 458–461, 370–373 and 285–288 were monitored by GC/MS (EI-mode) for the methyl trimethylsilylether derivatives of cholate, chenodeoxycholate and β-muricholate, respectively. Rats with intact exteriorized enterohepatic circulation and rats with chronic bile diversion were infused with [1- 13C]acetate for up to 14 h. After 10 h of infusion the enterohepatic circulation of the intact group was interrupted to deplete the existing bile salt pool (acute bile diversion). The fractions of biliary cholesterol and individual bile salts derived from newly synthesized cholesterol were determined by MIDA at t=14 h. In rats with acute bile diversion, these fractions were 20, 25, 27 and 23% for biliary cholesterol, cholate, chenodeoxycholate and β-muricholate, respectively. After bile diversion for 8 days to induce hepatic cholesterol and bile salt synthesis, these fractions increased significantly to 32, 47, 41 and 47%, respectively. Calculated enrichments of the acetyl-CoA precursor pools were similar for all bile salts and biliary cholesterol within the two rat groups. However, chronic enterohepatic interruption decreased the acetyl-CoA pool size almost two-fold. We conclude that MIDA is a validated new stable isotope technique for studying the synthetic pathway from acetyl-CoA to bile salts. This technique provides an important new tool for studying bile salt metabolism in humans using stable isotopes.

Complete down-regulation of Pgp3 expression during chronic bile diversion

Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands

The pathogenesis and treatment of pruritus and fatigue in patients with PBC.

The pathogenesis of the pruritus that complicates cholestasis in patients with primary biliary cirrhosis (PBC) is uncertain. The limited and inconsistent efficacy of conventional empiric therapies, such as anion exchange resins and rifampicin, has led to inconclusive trials of invasive experimental therapies, such as plasmapheresis, charcoal haemoperfusion and partial external diversion of bile. However, some double-blind, placebo-controlled trials that used a subjective primary efficacy end-point (the perception of pruritus) have suggested that certain drugs that affect the metabolism of many compounds, for example rifampicin, may be efficacious. The potential mechanisms by which such drugs may mediate a beneficial effect have not been determined. There is a paucity of data to indicate whether peripheral events, such as the accumulation of bile acids in interstitial fluid of the skin, initiate the neural events which mediate this form of pruritus. Recent findings suggest that central events in the brain, specifically an increase in neurotransmission/ neuromodulation mediated by endogenous opioid agonists (increased opioidergic tone), may be implicated. This hypothesis is supported by three lines of evidence. (1) Opioid receptor ligands with agonist properties (e.g. morphine) mediate pruritus. (2) Endogenous opioid-mediated neurotransmission/neuromodulation in the central nervous system (CNS) is increased in cholestasis. (3) Controlled trials have shown that opiate antagonists induce ameliorations of the behavioural consequence of the pruritus of cholestasis (scratching activity). In such trials, measurements of scratching activity independent of limb movements constituted an objective quantitative primary efficacy end-point. Potent opiate antagonists, that are bioavailable when given by mouth, such as nalmefene and naltrexone, may have a place in the long-term management of pruritus in patients with PBC. Evidence that increased serotoninergic neurotransmission also contributes to the pruritus is at present less strong than that implicating an involvement of the opioid system, and further investigation is needed to determine whether specific serotonin receptor subtype ligands have a place in the treatment of pruritus in patients with PBC. There is some evidence which suggests that increased serotoninergic neurotransmission in the CNS contributes to fatigue of central origin, but whether there is a causal relationship between altered serotoninergic neurotransmission and the profound fatigue that occurs in many patients with PBC is currently uncertain.

Bile diversion in rats leads to a decreased plasma concentration of linoleic acid which is not due to decreased net intestinal absorption of dietary linoleic acid

Decreased bile secretion into the intestine has been associated with low plasma concentrations of essential fatty acids (EFA) in humans. We studied the mechanism behind this relationship by determining the status and absorption of the major dietary EFA, linoleic acid (LA), in control and 1-week bile-diverted rats. The absorption of LA was quantified by a balance method and by measuring plasma concentrations of [ 13C]LA after its intraduodenal administration. Absolute and relative concentrations of LA in plasma were decreased in bile-diverted rats ( P<0.01 and P<0.001, respectively). Fecal excretion of LA was increased at least 20-fold in bile-diverted rats (0.72±0.11 vs. 0.03±0.00 mmol/day; P<0.0001). Due to increased chow ingestion by bile-diverted rats, net intestinal absorption of LA was similar between bile-diverted and control rats (1.96±0.14 vs. 1.91±0.07 mmol/day, respectively; P>0.05). After intraduodenal administration of [ 13C]LA, plasma concentrations were approximately 3–4-fold lower in bile-diverted rats for at least 6 h ( P<0.001). Plasma concentrations of both [ 12C]arachidonic acid and [ 13C]arachidonic acid were increased in bile-diverted rats ( P<0.05). We conclude that decreased plasma concentrations of LA in 1-week bile-diverted rats are not due to decreased net intestinal absorption of LA, but may be related to increased metabolism of LA.

Pancreatic hypersecretion in the jejunal-bypass rat.

We diverted bile and pancreatic juice from jejunal blind loops of different lengths in conscious rats to see if the pancreatic secretory response was dependent on the length of the jejunal blind loop. Short-term bile and pancreatic juice diversion from a short jejunal blind loop, representing only 8-10% of the total length of the small intestine, stimulated a significant increase in pancreatic exocrine secretion. Short-term bile and pancreatic juice diversion from jejunal blind loops of increasing length resulted in a progressive decrease in the pancreatic secretory response to diversion (i.e., there appears to be a length-dependent inhibition of the pancreatic secretory response to short-term bile and pancreatic juice diversion from the jejunum). Cholinergic receptor blockade with atropine eliminated this length-dependent inhibition of pancreatic exocrine secretion during short-term bile and pancreatic juice diversion. In contrast to what was observed with short-term bile and pancreatic juice diversion, there was a length-dependent increase in pancreatic secretion during long-term bile and pancreatic juice diversion. The jejunal-bypass rat model can facilitate the investigation of the intestinal mechanisms mediating feedback regulation of pancreatic exocrine secretion.

Differential effects of 17α-ethinylestradiol on the neutral and acidic pathways of bile salt synthesis in the rat

Effects of 17alpha-ethinylestradiol (EE) on the neutral and acidic biosynthetic pathways of bile salt (BS) synthesis were evaluated in rats with an intact enterohepatic circulation and in rats with long-term bile diversion to induce BS synthesis. For this purpose, bile salt pool composition, synthesis of individual BS in vivo, hepatic activities, and expression levels of cholesterol 7alpha-hydroxylase (CYP7A), and sterol 27-hydroxylase (CYP27), as well as of other enzymes involved in BS synthesis, were analyzed in rats treated with EE (5 mg/kg, 3 days) or its vehicle. BS pool size was decreased by 27% but total BS synthesis was not affected by EE in intact rats. Synthesis of cholate was reduced by 68% in EE-treated rats, while that of chenodeoxycholate was increased by 60%. The recently identified Delta22-isomer of beta-muricholate contributed for 5.4% and 18.3 % (P < 0.01) to the pool in control and EE-treated rats, respectively, but could not be detected in bile after exhaustion of the pool. A clear reduction of BS synthesis was found in bile-diverted rats treated with EE, yet biliary BS composition was only minimally affected. Activity of CYP7A was decreased by EE in both intact and bile-diverted rats, whereas the activity of the CYP27 was not affected. Hepatic mRNA levels of CYP7A were significantly reduced by EE in bile-diverted rats only; CYP27 mRNA levels were not affected by EE. In addition, mRNA levels of sterol 12alpha-hydroxylase and lithocholate 6beta-hydroxylase were increased by bile diversion and suppressed by EE. This study shows that 17alpha-ethinylestradiol (EE)-induced intrahepatic cholestasis in rats is associated with selective inhibition of the neutral pathway of bile salt (BS) synthesis. Simultaneous impairment of other enzymes in the BS biosynthetic pathways may contribute to overall effects of EE on BS synthesis.

Intestinal synthesis and lymphatic secretion of apolipoprotein A-IV after cessation of duodenal fat infusion: mediation by bile

We tested whether secretion of apolipoprotein (apo) A-IV depends upon intestinal triglyceride (TG) transport by comparing output kinetics of TG and apo A-IV during and after duodenal lipid infusion in lymph-fistula rats. Lipid infusion (triolein, 40 μmol/h, 8 h) produced increases in lymphatic TG and apo A-IV output. After 8 h, triolein infusate was replaced with glucose–saline; TG output returned to basal levels 4–5 h later. However, apo A-IV output continued at significantly elevated levels until 20 h after the start of the experiment. Bile diversion blocked this continued output of A-IV during the post-lipid period, and resulted in basal TG output that was 75% lower than in bile-intact rats. Return of bile or low-dose triolein infusion (5 μmol/h) into the intestine reversed these effects. There were no differences in hepatic synthesis or filtration of plasma A-IV into lymph between bile-intact and bile-diverted groups. Intestinal A-IV synthesis was elevated in both groups even during the post-lipid period. The results support the hypothesis that intestinal triglyceride transport drives apo A-IV secretion, and suggest the existence of a bile-dependent, post-translational mechanism for the control of lymphatic apo A-IV output.

Effect of duodenal components of the refluxate on development of esophageal neoplasia in rats

When duodenal content is allowed to reflux into the esophagus of nitrosamine-treated rats, esophageal cancer is induced more rapidly and at higher frequency than after carcinogen treatment alone. The purpose of the present study was to identify the components of the duodenal content that are responsible for enhancing esophageal carcinogenesis. Eight-week-old Sprague-Dawley rats underwent one of four operations as follows: diversion of bile alone, pancreatic juice alone, both bile and pancreatic juice into the esophagus, or a control operation with no induced reflux. Two weeks after surgery, rats were treated with the esophageal carcinogen 2,6-dimethylnitrosomorpholine (48 mg/kg [0.1 of LD 50] intraperitoneally weekly for 20 weeks). The rats were killed at age 30 weeks. The esophagus was removed and full-length strips were examined under a microscope; separate segments were taken for flow cytometric evaluation. The prevalence of DNA aneuploidy and histologic esophageal papillomas or squamous cancer was increased in carcinogen-treated rats with pancreatic juice reflux ( P <0.05 vs. control) and the combination of pancreatic and bile reflux ( P <0.05 vs. control) but not in rats with bile reflux alone. We conclude that pancreatic juice is the most potent component of the duodenal refluxate in the promotion of esophageal carcinogenesis in rats.

Pituitary adenylate cyclase-activating peptide stimulates rat pancreatic secretion via secretin and cholecystokinin releases

Background & Aims: Pituitary adenylate cyclase–activating polypeptide (PACAP) stimulates protein and/or amylase secretion from isolated rat pancreatic acini. The effect of PACAP on pancreatic secretion in vivo and its mechanism of action were studied. Methods: Rats were prepared with pancreatic duct cannulation, pyloric ligation, and bile diversion into duodenum, and 2.5, 5, and 10 nmol/kg PACAP-27 was administered intravenously while pancreatic juice was collected for 30 minutes. In other groups of rats, the effect of 10 nmol/kg PACAP-27 was studied under the influence of either atropine; loxiglumide, an antisecretin serum; a combination of both loxiglumide and the antiserum; or a PACAP antagonist (PACAP 6-38). Plasma secretin and cholecystokinin concentrations were measured by radioimmunoassay. Results: (1) PACAP dose-dependently increased pancreatic secretion of fluid, bicarbonate, and protein; (2) the increase in pancreatic secretion paralleled that of plasma secretin and cholecystokinin; (3) a combination of loxiglumide and antisecretin serum eliminated the PACAP-stimulated pancreatic secretion, whereas loxiglumide or antisecretin serum alone partially but significantly blocked pancreatic secretion; (4) atropine failed to influence PACAP-induced pancreatic secretion; and (5) PACAP antagonist profoundly suppressed the PACAP action. Conclusions: PACAP-27 dose-dependently stimulates pancreatic secretion of fluid, bicarbonate, and protein in rats. This effect is mediated by release of both secretin and cholecystokinin and is independent of cholinergic tone. GASTROENTEROLOGY 1998;114:1054-1060