Pancreaticobiliary Diversion Research Articles

Cutting Your Losses: Addressing Nutritional Deficiencies in Pregnancy after Bariatric Surgery

Pregnancy after bariatric surgery in morbid obesity can reduce the risk for gestational diabetes, preeclampsia, and large for gestational age infants. However there is an increased risk for small for gestational age infants, shorter gestation, and a trend to increase in stillbirth and neonatal death. We describe a patient who had an extreme form of bariatric surgery, pancreatico-biliary diversion with duodenal switch (BPD-DS), resulting in numerous vitamin and mineral deficiencies and perinatal demise. A female patient underwent BPD-DS for morbid obesity at age 21 years, resulting in a 215-pound weight loss down to 155 pounds at height of 68 inches. Post-surgery, two pregnancies were complicated by early spontaneous abortion. In a third pregnancy, vitamin A deficiency and night blindness was detected. That pregnancy resulted in delivery of a fetus with numerous congenital anomalies, and neonatal death due to respiratory failure related to a congenital diaphragmatic hernia. The neonate had low risk DNA. At age 28 years, she presented with a 4th pregnancy at 8 weeks gestation. Multiple nutritional deficiencies were detected, including deficiencies in vitamins A, D, E, and K, iron and zinc. These were aggressively replenished. Pancreatic enzyme supplementation was added. Total parenteral nutrition was initiated 3 weeks before delivery for severe intrauterine growth retardation. At 37 weeks, a planned Cesarean section was performed with delivery of a healthy neonate. The infant is doing well 6 months post-partum. Nutritional deficiencies are well-recognized complications of bariatric surgery. BPD-DS is an extreme form of surgery. In addition to a restrictive surgical procedure, there is delayed mixing of bile and pancreatic enzymes until the final 50-100 cm of the ileum. This results in significant fat malabsorption and consequently, a greater risk of fat-soluble vitamin deficiency. Hypovitaminosis A, as in our patient, has been associated with congenital ocular abnormalities, as well as congenital diaphragmatic hernia, a lifethreatening cause of newborn respiratory failure. Our patient's case is instructive as it highlights possible consequences of not aggressively repleting nutritional deficiencies (3rd pregnancy), and contrasts the successful outcome of aggressive nutritional repletion (4th pregnancy). Monitoring and treating nutritional deficiencies during pregnancy after bariatric surgery is important, particularly for the more extreme form, BPD-DS.

The role of pancreatico-biliary secretions in intestinal adaptation after resection, and its relationship to plasma enteroglucagon.

Two groups, each containing 16 male Wistar rats, had either 75 per cent small bowel resection or jejunal transection; 8 animals from each group; had previously been subjected to pancreatico-biliary diversion. All animals were killed 12 days after the operation, plasma enteroglucagon levels were measured and crypt cell production rate (CCPR) at different sites of the remaining small intestine was measured using a metaphase arrest technique with vincristine. In each of the resected groups there was a significant increase in the CCPR and enteroglucagon levels compared with the transected groups. Furthermore it was found that the CCPR and enteroglucagon levels were higher in the resected group without the pancreatico-biliary diversion compared with the resected group with the diversion. This study, although it confirms the importance of pancreatico-biliary secretions in intestinal adaptation, could also indicate that a humoral factor may be important in the control of intestinal cell proliferation. Our findings do not exclude the possibility that enteroglucagon could be a candidate for such a role.

Endogenous cholecystokinin plays a role in down-regulation of pancreatic amylase independent of dietary carbohydrate in rats

The role of cholecystokinin (CCK) in the regulation of pancreatic amylase has not been fully clarified. We examined the effects of hyperCCKemia with chronic pancreatico–biliary diversion (PBD) and blockade of CCK A-receptor on rat pancreatic amylase activity and mRNA abundance. Also, we examined the relationship between diet and CCK in terms of regulation of pancreatic amylase. PBD was produced by transposition of the duodenal segment containing the ampulla of Vater to the upper ileum. A potent CCK A-receptor antagonist, devazepide, was injected (6 mg/kg body weight per day for 5 days) in the PBD rats fed with diets containing normal or low level of carbohydrate (695 or 345 g sucrose/kg diet). The specific activity and mRNA abundance of the pancreatic amylase were constantly lower 4, 10 and 28 days after PBD than those after the sham operation. Devazepide treatment completely restored the amylase activity lowered by PBD without any increases in amylase mRNA. Feeding a high-protein low-carbohydrate diet suppressed the pancreatic amylase activity and mRNA abundance in PBD rats to a similar degree in those treated, and those untreated, with devazepide. We conclude that endogenous CCK suppresses pancreatic amylase production, and we speculate that CCK reduced translational efficiency of amylase mRNA. The effect of CCK on amylase production is independent of regulation by dietary carbohydrate.

Effects of Intraluminal Trypsin and Bile on the Exocrine and Endocrine Pancreas After Pancreaticobiliary Diversion and Biliodigestive Shunt

Pancreaticobiliary diversion (PBD) and biliodigestive shunt (BDS) cause long-standing hypercholecystokininemia followed by pancreatic hyperplasia. These changes have been suggested to be due to the lack of intraluminal trypsin and bile, respectively, in the upper small intestine. The aim of these experiments was to study the effect of restoration of intraluminal trypsin and bile on plasma levels of cholecystokinin (CCK) and the changes found in exocrine and endocrine pancreas after PBD and BDS. Male Sprague-Dawley rats were used. PBD was done in 16 rats, eight of which had trypsin dissolved in 50 mM sodium bicarbonate (SB), and eight had SB only by gastric intubation twice daily. BDS was done in another 16 rats, eight of which had bile dissolved in SB, and eight had SB in a similar manner. Sham-operated rats had SB and served as controls. After 4 weeks, the rats were killed, and the concentrations of circulating CCK, gastrin, glucose, glucagon, and insulin were determined. The pancreas was removed, weighed, and analyzed for contents of water, protein, and DNA. In another study, PBD-operated rats got trypsin in varying dosages or trypsin and taurocholate in combination for 2 weeks before death. The concentrations of plasma CCK and glucagon were elevated after both PBD and BDS. PBD decreased the concentration of gastrin in plasma. PBD caused an increase of pancreatic weight and the contents of protein and DNA. Trypsin substitution to PBD-operated rats did not affect plasma CCK or glucagon levels, but the PBD-induced increases in weight and DNA content were counteracted by trypsin. Higher dosages of trypsin did not further influence the effects seen after PBD. Pancreatic weight and DNA content were increased after BDS. Bile administration completely abolished the increase in plasma CCK and glucagon, as well as the gain in pancreatic weight, and reduced the increase in pancreatic DNA. Substitution with bile to BDS-operated rats abolished the increase in the plasma levels of CCK and glucagon, as well as the trophic effects on the pancreas. Trypsin substitution to PBD-operated rats partly reversed the trophic effects on the pancreas but not the hormonal changes in plasma. Thus the trophic effects on the pancreas exerted by BDS seem to be dependent on the lack of bile in the upper small intestine, whereas the effects of PBD only partly are a consequence of the absence of intraluminal trypsin.

Pancreatic Growth after Pancreatico-Biliary Diversion Does Not Increase the Capacity to Secrete Amylase

Background/Aim: Cholecystokinin (CCK) stimulates secretion and evokes a hyperplastic response in the rat pancreas. The aims of this study were to measure the effect of chronic hyperCCKemia induced by pancreatico-biliary diversion (PBD) on pancreatic enzyme concentrations, on amylase secretion by dispersed acinar cells, and on the CCK-stimulated secretion of pancreatic juice in PBD-operated rats. Material and Methods: Forty-five Sprague-Dawley male rats had either PBD or sham operation 4 weeks before sacrifice or additional experiments. In the first study, 25 rats (13 PBD and 12 sham-operated rats) were either freely fed or fasted overnight before sacrifice. The pancreas was dissected out, weighed and analyzed. In the second study, the rats (6 PBD and 7 sham-operated rats) were fasted overnight before pancreatic acini were prepared. Secretion of amylase during stimulation of acini with CCK-8S and carbachol was measured. In the third study (5 sham-operated and 4 PBD rats), the rats were fasted overnight before basal and CCK-stimulated secretion was measured in vivo. Results: PBD-operated rats showed a threefold increase in pancreatic wet weight with increased contents of DNA, protein and water. The concentration of pancreatic amylase was 7–12% of that found in control animals. The concentrations of trypsin and lipase were also lowered. Stimulation of dispersed pancreatic acini with CCK-8S or carbachol resulted in secretion of amylase to a similar extent in PBD and sham-operated rats. There was no difference in the secretion of pancreatic juice in response to CCK, but although the output of amylase from PBD-operated rats increased with CCK, it remained at a low level throughout the study period. Conclusion: PBD evoked hyperplastic changes in the rat pancreas and decreased the concentrations of amylase, trypsin and lipase. However, the capacity of acinar cells to secrete amylase remained intact. The stimulated pancreatic secretion was not changed in volume, but the output of amylase was low in PBD-operated rats. The findings are consistent with the idea that the enlargement of the pancreas following PBD does not improve the secretory capacity.

Surgical aspect of enteroinsular axis after gastrointestinal surgery with reference to incretin secretion.

An alteration of the enteroinsular axis (EIA) may be an important etiologic factor in postsurgical changes in gastrointestinal (GI) function. In this review, we present recent works, both from our laboratory and others, on how changes in the EIA function may be involved in postsurgical GI complications, especially late dumping syndrome (LDS). We found no or minimal direct role for vagal signals in the control of gastric inhibitory polypeptide (GIP) and enteroglucagon secretion, which regulate EIA function. In gastrectomized patients, it is suggested that the hypersecretion of glicentin and glucagon-like peptide-1 (GLP-1) induced by a rapid arrival of nutrients to the distal gut suppresses glucagon secretion and may be a cause of LDS. In patients who underwent proctocolectomy, we observed no significant postoperative changes in EIA function, although there are some conflicting reports. It seems unlikely that ordinary pancreaticobiliary diversion would cause a significant change in EIA function after an oral glucose load. Our experimental model of ileojejunal transposition produced marked hypersecretion of incretin secreted from the distal gut, which may alter EIA function. Further elucidation of the regulatory mechanism of EIA may provide a new strategy for the medical and surgical treatment of LDS.

Chronic endogenous hypercholecystokininemia promotes pancreatic carcinogenesis in the hamster.

In order to examine the effect of cholecystokinin on spontaneous and induced pancreatic carcinogenesis in the hamster, two sets of experiments were carried out, one involving long-term hypercholecystokininemia and one involving cancer induction during hypercholecystokininemia. The effect of hypercholecystokininemia, induced by pancreaticobiliary diversion (PBD), was studied for 8 months. Neither PBD animals nor sham-operated controls developed premalignant or malignant pancreatic lesions. However, in the PBD group the mean pancreatic weight, total protein content and DNA content were increased by 30, 29 and 27% respectively. No such increases were found in PBD animals receiving a cholecystokinin-A receptor antagonist during the last 24 days of the experiment. In the cancer induction study, the effect of PBD on N-nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis was studied for 3 months. Putative premalignant pancreatic lesions were diagnosed in all PBD hamsters and in four of 15 sham-operated controls. Pancreatic ductular carcinoma in situ was only found in PBD animals. The [3H]thymidine labeling index of the pancreatic lesions was significantly higher in the PBD group than in the controls. No such increase was observed in PBD animals receiving a cholecystokinin-A receptor antagonist during the last 5 days of the experiment. It is concluded that chronic endogenous hypercholecystokininemia promotes early phase pancreatic carcinogenesis, but does not per se cause development of premalignant or malignant pancreatic lesions in the hamster.

Total Parenteral Nutrition Affects the Trophic Effect of Cholecystokinin on the Exocrine Pancreas

Background: Cholecystokinin (CCK) exerts trophic effects on the exocrine pancreas. Total parenteral nutrition (TPN) results in hypotrophy of the pancreas. The present study aimed to examine the effect of exogenous and endogenous CCK during TPN. Methods: Seventy-two Sprague-Dawley rats were orally fed or given TPN after pancreaticobiliary diversion (PBD) and were infused with CCK-8S or the CCK-receptor antagonist devazepide for 7 days. Results: Infusion of CCK and PBD caused hyperCCKemia, whereas TPN did not influence the concentration of plasma CCK. The reduced pancreatic contents during TPN could be reversed by CCK but not by PBD. The hyperplastic response to CCK in orally fed rats was abolished during TPN. Devazepide did not influence the pancreatic variables in orally fed and TPN-treated rats. Conclusion: TPN reduces the hyperplastic response of the exocrine pancreas to CCK, and CCK reverses the hypotrophy seen during TPN. The effects of CCK on the exocrine pancreas seems to need enteral nutrition for the full expression.

Stimulating effect of ileal pancreaticobiliary secretion on ileal apolipoprotein A-IV mRNA expression in fasted rats.

The effect of pancreaticobiliary secretion on the intestinal expression of the apo A-IV gene was examined in fasted rats. Pancreaticobiliary diversion, but not biliary diversion alone, into the ileum increased the ileal apo A-IV mRNA expression by 24 h post-operation. Jejunal apo A-IV mRNA was reduced by biliary exclusion. The data suggest that the biliary constituent plays an important role in the apo A-IV gene expression in the entire length of the small intestine, and that up-regulation of the apo A-IV gene requires exocrine pancreatic in addition to biliary secretion.

The changes in the rat parotid glands following total parenteral nutrition and pancreatico-biliary diversion are not mediated by cholecystokinin.

The results of the present study suggest that the pancreas and parotid glands both respond with hypoplasia during absence of food in the digestive tract and with hyperplasia following pancreatico-biliary diversion (PBD). Factors other than cholecystokinin (CCK) are, however, involved in the effects on the parotid glands, since infusion of CCK-8S and devazepide was without influence. Total parenteral nutrition (TPN) causes reduced pancreatic weight, whereas PBD evokes hyperCCKemia and enlargement of the rat pancreas. The pancreas and parotid glands have in part similar morphology and function. Therefore, we studied the possible presence of alterations also in the parotid glands during TPN, after PBD and during infusion of sulfated cholecystokinin (CCK-8S) and the CCK-A receptor antagonist devazepide, respectively. Rats either received TPN for 7 d, or were kept under otherwise identical conditions with free access to food and water. TPN markedly reduced both pancreatic and parotid wet weight and thereby also the protein and amylase contents, and pancreatic DNA content was decreased. There was a significant correlation between the pancreas and parotid glands when comparing these parameters. The concentration of plasma CCK was unaffected by TPN. PBD caused a sevenfold increase in plasma CCK and a three fold increase in the pancreatic weight compared to control rats 28 d after the operation. The protein and DNA contents in the pancreas were found to be increased. The parotid glands increased twofold in weight, but their protein and amylase contents were not affected. There was a significant correlation between the pancreas and parotid glands when comparing weight, and protein and amylase concentrations. Infusion of CCK-8S during 28 d caused a marked increase in pancreatic wet wt and protein and DNA contents. The CCK-A receptor antagonist devazepide induced a reduction in protein and DNA contents in the pancreas. The parotid glands were not affected by either treatment. No effect on the labeling index of serous and ductal cells of the parotid gland was seen at 36 h, 3, 7, and 28 d of infusion with CCK-8S or devazepide.

Imaging of patients with pancreaticobiliary diversion for obesity: post-operative anatomy and findings in small bowel obstruction.

Pancreaticobiliary diversion is a surgical procedure undertaken for obesity. It consists of a distal gastrectomy with a long Roux-en-Y reconstruction, the enteroenterostomy being placed 200 cm distal to the gastroenterostomy and 50 cm proximal to the ileocaecal valve. Three intestinal limbs are recognized: (a) the alimentary loop from the gastroenterostomy to the enteroenterostomy; (b) common loop from the enteroenterostomy to the ileocaecal valve and (c) pancreaticobiliary loop from the duodenum to the enteroenterostomy. The radiological findings in 15 pancreaticobiliary diversion patients with small bowel obstruction were reviewed (15 plain abdominal radiographs, 13 ultrasound (US), 8 CT) and compared with 20 plain abdominal radiographs, 10 US, and 10 CT studies performed for other causes in patients with pancreaticobiliary diversion and 15 CT scans from non-operated patients. After pancreaticobiliary diversion the pancreaticobiliary loop was completely air-free. In the patients operated on more than 1 year previously, alimentary and common loops were significantly larger than the pancreaticobiliary loop and small bowel loops of non-operated subjects. Obstruction of the pancreaticobiliary loop arrests only the flow of pancreaticobiliary secretions with non-specific clinical findings. Plain abdominal radiographs were not diagnostic in all but two cases with radiographically detectable dilated fluid filled loops. Air-fluid levels were never apparent. US and CT showed markedly dilatated intestinal loops and duodenum. Obstruction of the alimentary and common loops presented with symptoms, clinical signs, and radiological findings more typical for bowel obstruction in intact subjects.

Gastrin does not stimulate growth of the rat pancreas.

Gastrin is thought to stimulate growth of the pancreas via gastrin/cholecystokinin (CCK)-B-type receptors. The aim of the present study was to examine the trophic response of the pancreas to exogenous gastrin or to hypergastrinemia of endogenous origin and to hypogastrinemia with or without concomitant hyperCCKemia. Hypergastrinemia was induced in male Sprague-Dawley rats by continuous infusion of human Leu15-gastrin-17 (5 nmol/kg/h, subcutaneously), by removal of the acid-producing part of the stomach (fundectomy), or by treatment with omeprazole (400 mumol/ kg/day, orally). Hypogastrinemia was induced by antrectomy or by gastrectomy. HyperCCKemia was induced by pancreaticobiliary diversion (PBD). The rats were killed 10 days or 8 weeks after the operations or treatments. The concentrations of circulating gastrin and CCK were measured by radioimmunoassay. The pancreatic weight and DNA content were determined. Gastrin infusion, omeprazole treatment, and fundectomy greatly increased the serum gastrin concentration. The resulting levels were very similar in the three groups and probably represent the maximum attainable physiologic serum gastrin concentration. Whereas gastrin infusion or omeprazole treatment (hypergastrinemia) and antrectomy (hypogastrinemia) were without effect on the weight and DNA content of the pancreas, gastrectomy (hypogastrinemia) and fundectomy (hypergastrinemia) increased the weight and DNA content. PBD (hyperCCKemia) greatly increased the weight and DNA content of the pancreas. PBD plus fundectomy, PBD plus gastrectomy, PBD plus antrectomy, and PBD plus omeprazole increased the weight and DNA content of the pancreas, as did PBD alone. CCK is a physiologically important trophic stimulus for the rat pancreas, but gastrin is not. The increase in pancreatic weight and DNA content after fundectomy and gastrectomy cannot be explained by means of either gastrin or CCK.

The ratio between anionic and cationic trypsin in rat pancreas varies with CCK stimulation.

The effects of long-term hyperstimulation with cholecystokinin (CCK) on the pancreatic contents of anionic and cationic trypsin(ogen) and amylase were studied in the rat. Endogenous hyperCCKemia was evoked in rats by pancreaticobiliary diversion (PBD), and exogenous hyperCCKemia by continuous subcutaneous CCK infusion. In addition, the effect of continuous subcutaneous infusion of the CCK A receptor antagonist devazepide was studied. After 4 weeks blood samples were obtained for the determination of plasma CCK concentrations and the animals were sacrificed. The pancreatic glands were harvested, weighted, and extracted. The extracts were analyzed for anionic and cationic trypsin and amylase. Enzyme contents showed a large interindividual variation. The most consistent change in enzyme pattern was an increase in the ratio between anionic and cationic trypsin in animals with hyperCCKemia (PBD operated or CCK infused). Furthermore, this ratio decreased significantly in animals treated with devazepide. In conclusion, stimulation of the CCK receptor changed the ratio between anionic and cationic trypsin in the pancreatic gland, while it was reversed during blockade of the receptor.

The role of gastrin and cholecystokinin in normal and neoplastic gastrointestinal growth.

Gastrin and cholecystokinin (CCK) act as growth factors for the gastric mucosa and the pancreas, respectively. CCK is also responsible, via the CCK-A receptor, for the pancreatic hyperplasia observed following the feeding of protease inhibitors or pancreaticobiliary diversion. Hypergastrinaemia does not increase the incidence of spontaneous gastrointestinal carcinoma, but does stimulate the proliferation of gastric enterochromaffin-like cells via the gastrin/CCK-B receptor, with a consequent increase in the incidence of gastric carcinoids. Whether gastrin influences mutagen-induced gastrointestinal carcinogenesis is still controversial, but CCK clearly enhances the induction by carcinogens of acinar tumours in the pancreas. While gastrin increases xenograft growth of 50% of gastrointestinal tumours tested, effects on the proliferation of gastrointestinal tumour cell lines in vitro have been more difficult to demonstrate, perhaps because many cell lines are already maximally stimulated by autocrine gastrin. Gastrin mRNA and progastrin, but not mature amidated gastrin, have been detected in all gastrointestinal cell lines tested. Although cell proliferation is inhibited by gastrin/CCK receptor antagonists, the spectrum of antagonist affinities is not consistent with binding to either CCK-A or gastrin/CCK-B receptors. Definition of the molecular structure of the receptor involved in the autocrine loop may lead to novel therapies for gastrointestinal cancer.

Endogenous hypercholecystokininemia, but not aspirin, reduces the gallstone incidence in the hamster model.

Studies in humans and rodents indicate that gallstone development may be prevented by inhibiting gallbladder mucus hypersecretion with non-steroidal anti-inflammatory drugs or by preventing stasis of gallbladder bile with administration of cholecystokinin. The effect of oral aspirin and pancreaticobiliary diversion with endogenous hypercholecystokininemia on crystal and gallstone formation was studied in Syrian golden hamsters fed a lithogenic diet for 8 weeks. None of the control animals fed a normal diet developed gallstones or crystals in gallbladder bile. Gallstones developed in 67% of the animals fed a lithogenic diet only. The gallstone prevalence did not differ significantly in animals on a lithogenic diet and a daily aspirin dose of 6 mg/kg (gallstone prevalence, 60%) or 100 mg/kg (gallstone prevalence, 70%), whereas it was significantly lower in animals with endogenous hypercholecystokininemia on a lithogenic diet (gallstone prevalence, 29%). The prevalence of crystals in gallbladder bile did not differ significantly between any of the experimental groups. It is concluded that in hamsters on a lithogenic diet, aspirin does not prevent gallstone formation, whereas endogenous hypercholecystokininemia reduces the prevalence of stones without affecting the occurrence of crystals in gallbladder bile.

Pancreatic Exocrine Secretion in Short-Term Pancreatic Duct Obstruction Induced Acute Pancreatitis in Rats: An in vivo and in vitro Study

We investigated digestive enzyme release following a short-term pancreatic duct obstruction in rats. An in vivo experiment demonstrated that a 6-hour pancreatic duct obstruction reduced digestive enzyme release evoked both by endogenously released cholecystokinin (CCK) due to pancreaticobiliary diversion and by exogenous administration of CCK8. In vitro experiments also showed that pancreatic duct obstruction reduced the maximal CCK8-evoked amylase secretion. Amylase secretion evoked by the calcium ionophore A23187 and by phorbol myristate acetate was also markedly decreased. These data suggest that pancreatic duct obstruction probably interferes with the secretory process downstream of hormone receptor binding, intracellular Ca2+ release and protein kinase C activation.

Colonic mucosal proliferation after pancreaticobiliary diversion in the hamster

The effect of pancreaticobiliary diversion (PBD) on the colonic mucosa was studied in hamsters over 5, 10, and 24 days. Sham-operated animals served as controls. At all three time intervals, experimental animals had increased plasma cholecystokinin concentrations and decreased gastrin concentrations. Five days after PBD, there was an increase in scintigraphically measured [3H]thymidine incorporation into colonic tissue. Correspondingly, there was an increase in the [3H]thymidine DNA labeling index of goblet cells in the colonic mucosa. The total number of cells in the colonic crypt columns were significantly increased on days 5, 10 and 24. Whether this proliferative response in the colon is due to increased release of cholecystokinin, enteroglucagon, other aberrations of hormones or growth factors, or simply an increased bile load on the colonic mucosa remains to be clarified. Such further studies may reveal an alternative animal model for studies on risk factors in colonic carcinogenesis.

Pancreatic hypertrophy with acinar cell nodules after longterm fundectomy in the rat.

The effect of gastric fundectomy with hypergastrinaemia on the pancreas in rats was studied for 14 months. Rats with hypercholecystokininaemia that had had a pancreaticobiliary diversion (PBD) operation and sham operated rats served as controls. Fundectomised rats showed a significant increase in pancreatic weight and total DNA and protein content compared with sham operated rats. DNA flow cytometry showed a significantly higher ratio of tetraploid to diploid nuclei in pancreatic tissue after fundectomy than after sham operation. Mean values of all these variables were significantly lower after fundectomy than after PBD. Acidophilic atypical acinar cell foci of the pancreas were diagnosed in both fundectomised and PBD operated rats, but not in sham operated controls. The volume density and 3H-thymidine labelling index of the acidophilic atypical acinar cell foci were significantly lower after fundectomy than after PBD. Changes consistent with pancreatic adenoma were diagnosed in the PBD group only. In conclusion, fundectomy lasting about half of the life span in rats causes pancreatic hyperplasia and hypertrophy, as well as development of acidophilic atypical acinar cell foci. Although hypergastrinaemia is a prominent feature, it may not be the only factor responsible for this pancreaticotrophical effect of fundectomy.

Effects of pancreaticobiliary diversion and gastric fundectomy on azaserine-induced pancreatic carcinogenesis in the rat.

The effects of pancreaticobiliary diversion (PBD) and gastric fundectomy on the pancreas in azaserine-treated rats were studied over 14 months. Sham-operated azaserine-treated animals served as controls. A significant increase in pancreatic weight and total DNA and protein content was found in PBD-operated and fundectomized animals. DNA flow cytometry showed a significantly increased ratio of tetraploid to diploid cells in pancreatic tissue in both experimental groups. Mean values of all these variables were significantly higher after PBD than after fundectomy. Acidophilic atypical acinar cell foci of the pancreas were observed in all of the experimental and 75% of the control animals. The volume density of these foci was significantly higher in each experimental group than in the controls. The volume density, radioactive thymidine labeling index, and mitotic index of the foci were significantly higher after PBD than after fundectomy. Changes consistent with pancreatic adenoma were diagnosed in the PBD group only. It is concluded that not only PBD with endogenous hypercholecystokininemia, but also fundectomy with endogenous hypergastrinemia lasting about half of the life span in rats, induces pancreatic hypertrophy and enhances the development of precancerous pancreatic changes after azaserine treatment. In comparison with PBD, fundectomy caused less pronounced changes and no observable neoplasia.

Effect of intrinsic CCK and CCK antagonist on pancreatic growth and pancreatic enzyme secretion in pancreaticobiliary diversion rats

When pancreaticobiliary diversion (PBD) surgery was performed in rats, plasma CCK level increased, the pancreas grew mainly by proliferation, and pancreatic trypsinogen showed a remarkable increase, although amylase and lipase synthesis were somewhat decreased. The sensitivity of amylase release against CCK-8 in the pancreatic acini decreased when plasma CCK level was high. These changes in pancreatic growth and pancreatic enzyme secretion caused by PBD were completely inhibited by the CCK-receptor antagonist loxiglumide. From these results, intrinsic CCK was considered to play an important role in both pancreatic enzyme synthesis and proliferation.