Faculty Bibliography

The effects of various amino acids and phosphorylated forms of glucose on the release of digestive enzymes from particulate cellular pools, particularly zymogen granules, were evaluated in rat pancreas. Whole tissue homogenates, as well as zymogen granules isolated either by differential centrifugation in 0.3 M sucrose or by preparation in buffered sucrose and subsequent centrifugation in a Percoll gradient, were studied. The basic amino acids L-arginine and L-lysine, sites of tryptic cleavage, caused the release of trypsinogen, but not chymotrypsinogen, whereas the aromatic amino acids L-phenylalanine and L-tryptophan, sites of chymotryptic cleavage, caused release of both trypsinogen and chymotrypsinogen. Neither led to the release of the starch-splitting enzyme amylase. All effects occurred within the range of normal plasma concentrations for these amino acids in the rat. Two amino acids, L-threonine and hydroxy-L-proline, that are not sites of cleavage by trypsin or chymotrypsin, and a nonmammalian amino acid, aminoadipic acid, did not lead to release of trypsinogen, chymotrypsinogen, or amylase. Two phosphorylated forms of glucose, glucose 1-phosphate and glucose 1,6-diphosphate, caused the release of amylase, but of neither trypsinogen nor chymotrypsinogen. Contrary to previous results, D-glucose was without effect, as was glucose 6-phosphate. We propose that certain digestive end products, by direct action on zymogen granules, cause the selective release of the enzymes involved in their evolution from polymeric substrates during digestion.

Forty-three patients with recurrent bleeding from gastrointestinal vascular ectasias had endoscopic treatment with either an argon or a neodymium-YAG (yttrium-aluminum-garnet) laser. Although 22 patients had some rebleeding, only 6 patients required resection for recurrent hemorrhage not controlled by laser treatments. Overall, the number of blood transfusions per patient decreased significantly (p less than 0.0001) when calculated for 6-month periods before and after initial laser treatments (1.5 +/- 0.2 U/month compared to 0.5 +/- 0.1 U/month). Rebleeding after the initial laser treatment was significantly more likely in patients with upper gastrointestinal ectasias than in patients with colonic lesions only (p less than 0.005).

Pancreatic abscess continues to be a lethal complication of acute pancreatitis, with mortality rates of 40 percent in recent surgical series. A major factor contributing to this high mortality has been delay in diagnosis. When combined with diagnostic needle aspiration, computerized tomographic scanning has greatly enhanced the early detection of pancreatic abscesses. In a 4 year period at our institutions, 21 patients with proved pancreatic abscesses were evaluated early in their clinical course by computerized tomography. On follow-up ranging from 7 months to 3 1/2 years, there were only four deaths for a mortality rate of 19 percent. Many of the surviving patients had a long and protracted clinical course (mean length of hospitalization was 56 days) and reoperation for recurrent abscess or gastrointestinal complications was required in eight patients (38 percent). Computerized tomography proved to be of considerable value in localizing the site of de novo or recurrent pancreatic abscess and in detecting postoperative complications. An aggressive approach encompassing early computerized tomographic scanning with diagnostic needle aspiration appears to be a factor in the improved survival rate of these patients.

Previous studies have shown that proglumide acts as a cholecystokinin (CCK) receptor antagonist in isolated pancreatic acini. To establish the effect of proglumide in the intact organ, its effects on both CCK-stimulated ductal and basolateral secretion of digestive enzymes were studied in the in vitro rabbit pancreas. CCK-stimulated ductal secretion of chymotrypsinogen, amylase, and total protein, as well as basolateral secretion of amylase, was inhibited by proglumide in a dose-dependent manner. Regression lines comparing ductal chymotrypsinogen and amylase outputs also were altered significantly by proglumide in a dose-dependent manner, with amylase secretion inhibited to a lesser degree. Similarly, the relative rates of amylase secretion across the ductal versus the basolateral cell surface were altered, with basolateral secretion inhibited to a lesser degree. The effects seen with increasing concentrations of proglumide at a given concentration of CCK mirrored the effects seen with decreasing the concentration of CCK in the absence of proglumide. Proglumide did not affect ductal or basolateral secretion stimulated by a cholinergic agonist and did not affect unstimulated pancreatic secretion. Thus, proglumide appears to act as a selective antagonist of CCK-stimulated secretion in the intact organ. The results further indicate that interactions of an agonist and an antagonist at the CCK receptor can alter not only the overall amount of enzymes secreted but their relative proportions as well.

The onset, course, and regression of the biochemical and structural alterations associated with pancreatitis induced by various doses of caerulein were studied in the mouse. In addition, the protective effect of secretin was compared with that of the cholecystokinin-receptor antagonists proglumide and benzotript. Subcutaneous or intraperitoneal injections of caerulein induced increases in serum amylase concentration and pancreatic weight and histologic evidence of acute pancreatitis, all effects being dose-related. Cytoplasmic vacuoles were the earliest histologic alterations. As the pancreatitis progressed these vacuoles increased to an enormous size. Interstitial inflammation and acinar cell necrosis were prominent after 6 h, reached a maximum after 12 h, and mostly disappeared after 4 days. During the course of pancreatitis approximately 40% of the acinar cells showed signs of severe degeneration or necrosis at the most effective doses of caerulein. Electron microscopy showed both intact and degenerating granules inside the vacuoles. Signs of basolateral exocytosis of zymogen granules were not observed. During the regression of pancreatitis, focal atrophy was a remarkable histologic finding. Repetitive initiation of pancreatitis (six courses of caerulein injections over 5 wk) produced marked focal atrophy and early fibrosis. High doses of proglumide or benzotript markedly ameliorated both the biochemical and structural alterations induced by caerulein. Secretin, even at very high doses, had only minor protective effects. This study presents a model of acute necrotizing pancreatitis in which the severity of the induced pancreatitis ranges dose-dependently from mild interstitial inflammation to severe necrosis. The ultrastructural alterations described herein support the hypothesis that the trigger mechanism of acute pancreatitis appears to be a primary intracellular event rather than an interstitial event that secondarily damages the acinar cells.

Fifty-two patients with severe cirrhosis (Child Class C) and variceal hemorrhage requiring six or more units of blood were randomly assigned to either sclerotherapy or portacaval shunt. Of 38 pretreatment characteristics, only the frequency of active alcoholism differed significantly between the groups. During the initial hospitalization, the patients in the shunt group required significantly more blood (21.5 +/- 3.1 units) than did those in the sclerotherapy group (12.3 +/- 1.3 units), although the latter had significantly more rebleeding during hospitalization after the procedure (14 of 28 vs. 5 of 24 patients). There was no difference in short-term survival, with 13 patients in the sclerotherapy group discharged alive, as compared with 10 patients in the shunt group. Patients were followed for a mean of 263 days after the initial discharge (range, 8 to 1117). The sclerotherapy group required significantly more days of hospitalization for rebleeding, but we failed to demonstrate any significant difference in long-term survival between the sclerotherapy and shunt groups. Total health-care costs per patient were significantly higher for the shunt group (+23,957 +/- +3,111) than for the sclerotherapy group (+15,364 +/- +2,220). We conclude that sclerotherapy is less costly than portacaval shunt and as effective for the treatment of esophageal varices associated with severe cirrhosis.

The endocrine islet-cell hormones insulin and glucagon are secreted at high concentrations into an intrapancreatic portal circulation and have been reported to affect the secretion of digestive enzyme by the exocrine pancreas. In the present experiments, insulin and glucagon were injected into the celiac artery of anesthetized rats to evaluate their effects on the secretion of amylase and trypsinogen by the pancreas. Neither hormone when given alone significantly changed the output of either enzyme. However, when given with the pancreatic secretagogue cholecystokinin, each altered the effect of injection of cholecystokinin. In a dose-dependent fashion insulin increased trypsinogen output without affecting amylase output, whereas glucagon inhibited amylase output and left trypsinogen output unchanged. Thus, both hormones produced a more trypsinogen-dominant pancreatic juice than that observed with cholecystokinin alone, although in different ways. These findings suggest that the endocrine hormones insulin and glucagon may regulate secretion of digestive enzymes by the pancreas by modulating the response to stimuli of overall protein secretion such as cholecystokinin.

Previous cell-free studies have shown that glucose selectively elicits the release of amylase from pancreatic zymogen granules, whereas lysine promotes the selective release of trypsinogen. To investigate the expression of these effects in situ, glucose or lysine was injected into the celiac artery of anesthetized rats, either alone or together with the pancreatic secretagogue cholecystokinin, to evaluate their effects on the secretion of amylase and trypsinogen by the pancreas. When given alone neither substance significantly changed the output of either enzyme. However, when given with cholecystokinin, each altered the effect observed with injection of cholecystokinin alone. The injection of glucose resulted in a twofold increase in both peak and total amylase output without significantly increasing trypsinogen secretion, whereas lysine increased both peak and total trypsinogen output by about 50%, leaving amylase output unchanged. These findings provide in situ confirmation for the selective enzyme release produced by glucose and lysine in cell-free studies and suggest that such end products of digestion can regulate the digestive process by modifying the secretory response of the pancreas to cholecystokinin.