Faculty Bibliography

Studies in acutely inflamed pancreatic tissue in humans and animals suggest that premature activation of proteases within the gland plays a key role in its pathophysiology. The present study aimed to detect such protease activation in relation to protease inhibition and to changes in the concentrations of the vital cellular compounds ATP and glutathione in pancreatic tissue during caerulein-induced pancreatitis in rats. Within 1 h after supramaximal stimulation by intraperitoneal caerulein injection, pancreatic tissue activities of enzymatically active trypsin and elastase showed significant increases, accompanied by a twofold increase in trypsin inhibitory capacity. Over the same time course pancreatic ATP and glutathione concentrations dropped to 38% and 47%, respectively, after 1 h and reached a nadir of 22% and 28%, respectively, after 4-8 h. Intrapancreatic trypsin activation in this model, despite increasing trypsin inhibitory capacity, indicates concealed liberation of even more protease or enzyme-inhibitor complex instability. It is hypothesized that early acinar glutathione depletion, in part due to diminished ATP, could play a role in the premature activation of digestive enzymes by impairment of the integrity of the cytoskeleton and cell organelles or lowered defense capabilities against oxidant stress, finally leading to acute pancreatitis.

Endoscopic training has become an increasingly important part of training in gastroenterology in recent years. As plans are developed to require 3 years of training in gastroenterology for board eligibility, the outline of a 3-year curriculum is proposed that would incorporate both "basic" training and "advanced" training (where offered) in endoscopy as integral components of a flexible plan designed to suit the needs and capabilities of both trainees and programs.

BACKGROUND:Hydrocolonic ultrasonography--abdominal ultrasonography in conjunction with the retrograde instillation of water into the colon--has been advocated as an alternative to colonoscopy for detecting colorectal polyps and cancer. We conducted a prospective, blinded trial to evaluate the procedure further. METHODS:Fifty-two consecutive patients (50 men and 2 women; average age, 62 years) who were referred for colonoscopy underwent hydrocolonic ultrasonography followed by colonoscopy. The physicians performing colonoscopy were blinded to the ultrasound results. Patients who had a history of colonic polyps or tumors or who had previously undergone flexible sigmoidoscopy or colonoscopy were excluded. RESULTS:Twenty-two patients had normal results on colonoscopy, 26 had polyps, 3 had cancer and polyps, and 1 had cancer alone. Twenty patients had polyps less than 7 mm in diameter, eight had polyps 7 mm or more in diameter, and one had a polyp of unknown size. Hydrocolonic ultrasonography did not detect any cancers and detected only one polyp > or = 7 mm and one polyp < 7 mm in diameter. The overall sensitivity of ultrasonography for identifying any polyp was 6.9 percent, and for identifying a polyp > or = 7 mm, it was 12.5 percent. Ultrasonography suggested the presence of five masses and five polyps that were not confirmed by colonoscopy. Six patients had incomplete ultrasound studies because of discomfort or the inability to retain water. There were two complications: one patient had two vasovagal episodes, and another had diaphoresis. CONCLUSIONS:Hydrocolonic ultrasonography was less useful than colonoscopy for detecting colorectal polyps and cancers. The usefulness of the technique in screening for colonic polyps and tumors appears to be limited.

BACKGROUND/AIMS/OBJECTIVE:GP2 is the major membrane protein in pancreatic zymogen granules. It is linked to the membrane via a glycosyl-phosphatidylinositol linkage. After cleavage, a significant fraction of GP2 becomes soluble. The present study assessed whether GP2 is a useful serum marker for acute pancreatitis. METHODS:Using an anti-GP2 monoclonal antibody, an enzyme-linked immunosorbent assay was developed to measure the serum levels of GP2 in rats with cerulein-induced acute pancreatitis. RESULTS:The anti-GP2 antibody was specific because it did not cross-react with uromodulin, a structurally similar protein to GP2, or to protein extracts from nonpancreatic tissues. Eight hours after the induction of pancreatitis, the serum levels of amylase, lipase, and GP2 peaked. Peak GP2 levels were 4.2 times higher than those of controls. At 24 hours, GP2 was still 70% of the peak level, whereas amylase and lipase were 5.5% and 0.5%, respectively, of their peak levels. CONCLUSIONS:GP2 may serve as a potentially valuable marker for clinical acute pancreatitis.

L-Buthionine-[S,R]-Sulfoximine (BSO) decreases glutathione levels in various organs by inhibition of gamma-glutamylcysteine synthetase. We have examined the levels of total glutathione and oxidized glutathione in the pancreas of mice, as well as serum amylase and pancreatic histology, after BSO administration in two different ways. The injection of a single dose of BSO (5 mmol/kg body wt) decreased total glutathione to 10% of the control value. A similar depletion was observed after 24 h of oral administration of a 10 mM BSO solution, without changes in the levels of oxidized glutathione. BSO-induced pancreatic glutathione depletion--even if maintained for up to 14 d--did not cause morphological alterations of the pancreas or hyperamylasemia. Thus pancreatic glutathione depletion in itself does not lead to pancreatitis, although during development of experimental acute pancreatitis, glutathione depletion has been described. BSO might be used in animal models to weaken the glutathione-based acinar defense mechanisms against oxidant stress or to alter other physiologic processes in which glutathione is involved.

In order to reproduce what might occur during the initial phase in some cases of acute alcohol-induced pancreatitis, rabbits were infused with diluted ethanol and low-dose cerulein. The duct permeability was assessed by recovery of fluoresceinated dextran (molecular weight 19,500) in central venous blood following orthograde duct perfusion with this substance in the anesthetized animal. Serum ethanol, lipase, and amylase were measured; pancreatic duct morphology was examined by light microscopy and electron microscopy. ATP and glutathione were measured, as were amylase, trypsinogen/trypsin, cathepsin B, and DNA levels in differential centrifugates. As expected, acinar amylase and trypsinogen showed a significant decrease in the experimental group; cathepsin B activity was similarly diminished. Compared with the control group, the activity of serum amylase and lipase in the experimental group demonstrated a significant increase. However, no differences between saline-infused control animals and the treated group regarding pancreatic duct permeability, continuity of lumen-lining epithelium, ATP and glutathione levels, and the relative subcellular distribution of pancreatic digestive and lysosomal enzymes were observed. Thus, our findings do not support the relevance of some of the most common hypotheses on the pathophysiology of acute pancreatitis in its early stage for at least a certain subgroup of patients with acute alcohol-induced pancreatitis.

In order to reproduce what may occur during the initial phase of biliary acute pancreatitis, the rabbit pancreatic duct was perfused with preincubated mixtures of bile and different digestive enzymes at low physiologic pressure. Permeability of the pancreatic duct system, serum amylase, and histological appearance of pancreatic tissue were studied after orthograde duct perfusion in the anesthetized animal. The ductal permeability was estimated by recovery of fluoresceinated dextran (molecular weight 17,200) in central venous blood following duct perfusion with this substance. Perfusion with preincubated bile failed to increase permeability significantly (11.10 +/- 3.04 nmol/L compared to 5.80 +/- 2.71 nmol/L in the control group), whereas mixtures of bile and trypsin (27.19 +/- 5.21 nmol/L), bile and lipase (16.68 +/- 3.75 nmol/L), and bile and pancreatic juice (13.92 +/- 0.48 nmol/L) caused significant increases (p < 0.05). Similar observations were made regarding serum amylase and histology. Thus, the presence of mixtures of bile with pancreatic enzymes (following their prolonged common incubation) in the absence of elevated pressure, results in an increase in duct permeability for molecules up to the size range of pancreatic enzymes and thereby may contribute to the initiation of acute pancreatitis.

A variety of receptors on pancreatic acinar and duct cells regulate both pancreatic exocrine secretion and intracellular processes. These receptors are potential sites of action for therapeutic agents in the treatment of pancreatitis. Cholecystokinin (CCK) receptor antagonists, which may reduce the level of metabolic "stress" on acinar cells, have been shown to mitigate the severity of acute pancreatitis in a number of models. Not all studies have shown a benefit, however, and differences may exist between different structural classes of antagonists. Because increased pancreatic stimulation due to loss of feedback inhibition of CCK has been proposed to contribute to the pain of some patients with chronic pancreatitis, CCK receptor antagonists could also be of benefit in this setting. Somatostatin and its analogs diminish pancreatic secretion of water and electrolytes and have been effective in treating pancreatic fistulas and pseudocysts. These agents are also being evaluated for their ability to reduce pain in chronic pancreatitis (perhaps by reducing ductal pressure by diminishing secretory volume) and mitigating the severity of acute pancreatitis (possibly by reducing the metabolic load on acinar cells). Recently described secretin receptor antagonists may also have therapeutic value as a means of selectively inhibiting pancreatic secretion of water and electrolytes.