Faculty Bibliography

Pancreatic disease has been infrequently reported in patients with acquired immunodeficiency syndrome. Over the last 3 years at our hospital, two patients with the acquired immunodeficiency syndrome and acute pancreatic or biliary disease, demonstrated at autopsy to be secondary to cytomegalovirus infection of the pancreas, have been evaluated. However, pancreatic disease was not recognized antemortem in our two patients because of their underlying diseases and the atypical presentation. Cytomegalovirus infection of the pancreas may cause acute symptomatic disease in patients with acquired immunodeficiency syndrome.

Monoclonal antibodies specific for luminal plasma membranes of acinar and duct cells of the exocrine pancreas were used to investigate changes in antigen expression during regeneration of the pancreas after acute pancreatitis and during fetal pancreatic development in mice. During regeneration after acute pancreatitis induced by supramaximal injections of cerulein or by a choline-deficient, ethionine-supplemented diet, morphologically identifiable acinar cells expressed the ductal antigen on their luminal surface, but at a lower level than this antigen is expressed on duct cells. As the pancreas regenerated, the ductal antigen was lost from acinar cells and was found only on duct cells. Characteristic tubular complexes formed in both pancreatitis models and were positive for the acinar antigen, demonstrating their acinar origin. In fetal pancreas, acinar cells between prenatal days 3 through 1, when zymogen granules were already abundant, expressed the duct-cell antigen on their luminal surface. By birth duct antigen was mostly present on ducts with only occasional label on acinar cells. The presence of a ductal antigen on acinar cells is associated with acinar-cell growth during regeneration and during fetal development and may reflect a less differentiated state.

This study evaluated the effects of long-term cholecystokinin (CCK) stimulation and blockade on pancreatic and intestinal growth, function, and morphology. CCK release was induced by feeding of the protease inhibitor camostate and CCK blockade by feeding of the CCK antagonist CR 1409. Four groups of NMRI-mice received the following diets for 9 months (each group consisting of 36 mice): (1) chow (control); (2) chow + 100 mg/kg/day camostate; (3) chow + 50 mg/kg/day CR 1409; (4) chow + 100 mg/kg/day camostate + 50 mg/kg/day CR 1409. Long-term feeding of camostate greatly increased pancreatic weight by induction of marked hypertrophy (increase in protein content) and moderate hyperplasia (increase in DNA content). Camostate feeding also increased secretory capacity of the exocrine pancreas. Despite camostate-induced growth neither hyperplastic nor neoplastic nodules developed. The CCK-antagonist CR 1409 markedly inhibited the effects of camostate which are therefore mainly mediated by CCK. Neither long-term CCK stimulation nor CCK blockade altered morphology or composition of duodenal mucosa. Feeding of CR 1409 alone (i.e., without camostate) slightly but significantly decreased pancreatic content of protein and secretory capacity of enzymes when compared to the chow-fed control; pancreatic weight and DNA content remained unchanged after long-term administration of CR 1409. Thus, long-term, continuous and effective blockade of the CCK-receptor only slightly inhibited pancreatic growth and secretory capacity. CCK is, therefore, not an essential growth factor for the pancreas, although increases of endogenous CCK stimulate pancreatic growth and secretory capacity.

The present experiments evaluate in vivo effects of recently described cholecystokinin (CCK) receptor antagonists on rat pancreatic secretion. Pancreaticobiliary secretion was studied after bile duct cannulation in anesthetized rats. After two basal 10-min fractions were selected, secretion was stimulated by intravenous caerulein (0.1-30.0 micrograms/kg) or secretin, and collected for seven further 10-min fractions. Peptide antagonists (CR 1409, CR 1392, and CR 1505) and nonpeptide antagonists (asperlicin and L364,718) were given intravenously 10 min before agonists. Increasing doses of antagonists gradually reduced secretion of protein and enzymes stimulated by submaximal and maximal doses of caerulein. The antagonists did not alter nonstimulated or secretin-stimulated secretion, indicating their specificity for the CCK receptor. Except for proglumide and asperlicin, all antagonists were able to abolish caerulein-stimulated pancreatic secretion, as evaluated by the mean integrated 1-h response to a near-maximal dose of caerulein. The caerulein dose-response curve was gradually shifted to the right by increasing doses of CR 1409, indicating competitive-like kinetics. Inhibition of secretion due to supramaximal doses of caerulein, however, could be reversed by doses of CR 1409 smaller than expected from extrapolating truely competitive kinetics from an in vitro situation to the in vivo situation. The rank order of potency of the compounds to antagonize caerulein-stimulated secretion in vivo agreed with their relative potencies to antagonize caerulein-stimulated amylase secretion from pancreatic acini in vitro as well as with their affinity to bind to peripheral CCK receptors in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study we evaluated the effects of hydration, oxygenation, peritoneal lavage, and the protease inhibitor gabexate mesilate in acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented diet. Different groups of mice were kept at various concentrations of O2 (21%, 35%, and 45% O2), or were treated by either s.c. injections or i.p. injections of electrolyte solution at various doses (0, 4, 6, or 8 ml/day). Further groups were treated either with i.p. lavage, lavage with 1.5 mg/ml of gabexate, or i.p. injections of 100 mg/kg of gabexate without lavage. The potential benefits of the various regimens were assessed by measuring survival, various biochemical and histologic features, and alterations in hematocrit, pH, and blood gases. Increasing O2 concentrations reversed hypoxemia and acidosis, but had no effect on biochemical or morphologic alterations and did not improve survival. However, hydration by s.c. fluid markedly improved survival and normalized the hematocrit without having major effects on biochemical or morphologic alterations. Intraperitoneal fluid did not improve survival. Gabexate injections without lavage had a slight effect on survival and serum amylase concentration and very little effect on histology. Lavage without gabexate had a greater effect on survival, serum amylase, and histology. Addition of gabexate to the lavage fluid increased the beneficial effect of lavage. Increases in amylase and activated trypsin in ascites were markedly reduced by lavage and even more so by lavage with addition of gabexate. We conclude that sufficient hydration appears to be an important factor in supportive care for severe acute pancreatitis, whereas oxygenation without sufficient hydration has no major benefit. Peritoneal lavage with gabexate showed the greatest benefit of the various regimens for acute severe pancreatitis and is worthy of clinical trials.

The appearance of vacuoles inside acinar cells characterizes an early stage of development in different models of acute pancreatitis and, possibly, also in human disease. The vacuoles have been shown to contain both digestive and lysosomal enzymes. This abnormal admixture may have important implications for the pathogenesis of pancreatitis because the lysosomal enzyme cathepsin B can activate trypsinogen and may, by this way, trigger pancreatic autodigestion. For the activation process of trypsinogen by cathepsin B, however, an acidic pH is required. This study, therefore, looked for evidence of vacuole acidification in two different models of acute pancreatitis. Edematous pancreatitis was induced in rats by hyperstimulation with cerulein and hemorrhagic pancreatitis was induced in mice by feeding a choline-deficient, ethionine-supplemented diet. Pancreatic acinar cells were isolated at different times after induction of pancreatitis and incubated with 50 microM of acridine orange to identify acidic intracellular compartments. As shown in previous work, zymogen granules are the main acidic compartment of normal acinar cells; they remained acidic throughout the course of pancreatitis in both models. Vacuoles became increasingly more frequent in both models as pancreatitis progressed. Throughout development of pancreatitis, vacuoles accumulated acridine orange indicating an acidic interior. Addition of a protonophore (10 microM monensin or 5 microM carbonyl cyanide m-chlorophenylhydrazone [CCCP] or a weak base (5 mM NH4Cl) completely and rapidly abolished acridine orange fluorescence inside both zymogen granules and vacuoles providing further evidence for an acidic interior. The acidification of vacuoles seen in two different models of pancreatitis may be an important requirement for activation of trypsinogen by cathepsin B and thus for the development of acute pancreatitis.

Seventy-four medical and surgical patients having a minimum of two risk factors for stress-related gastric mucosal bleeding were prospectively selected randomly to receive prophylaxis by antacid titration (to maintain a gastric pH of more than 4) or with sucralfate suspension (1 g/10 ml every four hours). Gastric aspirates were monitored every two hours for pH and overt and occult bleeding. Despite a significantly greater severity of illness in the sucralfate group (p less than 0.01), no significant difference in overt or occult bleeding between the groups could be demonstrated. Low-grade occult blood loss occurred frequently in both groups, but only one of the 74 patients (four risk factors, sucralfate group) had significant stress-related bleeding as defined by preset criteria and documented by endoscopy. The effectiveness of sucralfate appeared unrelated to acid neutralization in keeping with its classification as a cytoprotective agent. There were eight antacid-related side effects (four severe diarrhea, four hypermagnesemia), and none related to sucralfate. Sucralfate suspension was safe and effective and had fewer side effects than antacid titration for the prophylaxis of stress-related bleeding in critically ill patients.

The effect of pancreatitis on magnetic resonance T1 and T2 relaxation times was evaluated in two different models of acute pancreatitis in the rat. Acute edematous pancreatitis was induced by repetitive intraperitoneal injections of the cholecystokinin-analogue caerulein; acute hemorrhage pancreatitis was induced by retrograde infusion of the bile salt sodium taurocholate into the pancreatic duct. T1 and T2 relaxation times were obtained in vitro from fresh pancreatic specimens at 37 degrees C with a 0.25 resistive spectrometer. In both edematous and hemorrhagic pancreatitis, significant prolongation of T1 and T2 was noted as early as 1.5 hours after the initiation of pancreatitis when compared with normal rat pancreas. Maximal prolongation occurred at 7 hours in the caerulein model with T1 of 966 +/- 46 msec (mean +/- SEM) (normal + 278 +/- 12 msec) and T2 of 75.9 +/- 2.9 msec (normal = 32.8 +/- 3.3 msec), and after 6 hours in the bile salt model with T1 of 798 +/- 40 msec and T2 of 92.5 +/- 3.3 msec. After the time point of maximal prolongation, T1 and T2 gradually decreased toward the normal values. The prolongation of T1 and T2 paralleled each other throughout the time course of pancreatitis in both models. The prolongation of both relaxation times correlated closely with pancreatic weight, water content, and amylase concentration in serum and ascites. The present determination of T1 and T2 relaxation times by in vitro spectrometry suggests that magnetic resonance imaging has the potential for detecting early pathologic changes in acute pancreatitis and thus may be helpful for an early clinical diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

The value of a recently reported grading system of early abdominal computed tomography (CT) for predicting development of pancreatic abscess in patients with acute pancreatitis was reassessed. When the previously described CT grading system was used in another patient population, it did not demonstrate the same degree of prognostic value of baseline CT. In this series pancreatic abscess occurred in only eight of 29 patients (28%) with grade E CT scans (with grade E representing the most severe involvement), compared with 60% in the previous series. Of 44 patients with either grade D or E baseline CT scans, abscesses developed in only 30%, with a minimum clinical follow-up of 3 months. A second grading system, which used a semiquantitative analysis of the degree of peripancreatic inflammation (a "CT severity score"), also did not strongly correlate with the future risk of abscess, The authors conclude that early abdominal CT should be performed selectively in patients with acute pancreatitis and reserved for patients who are either diagnostic dilemmas or who fail to respond to supportive treatment and have clinically suspected surgical complications such as pancreatic abscess.

In a continuation of a trial for which preliminary results were reported in the Journal two years ago, a total of 64 patients with Child Class C cirrhosis and variceal hemorrhage requiring six or more units of blood were randomly assigned to receive either a portacaval shunt (32 patients) or endoscopic sclerotherapy (32 patients). The duration of initial hospitalization and the total amount of blood transfused during hospitalization were significantly less in the patients receiving sclerotherapy (P less than 0.001). There was no difference in short-term survival (50 percent of the sclerotherapy group were discharged alive, as compared with 44 percent of the shunt-surgery group). Both groups were followed for a mean of 530 days after randomization. Rebleeding from varices, the duration of rehospitalization for hemorrhage, and transfusions received after discharge were all significantly greater in the sclerotherapy group (P less than 0.001). Forty percent of the sclerotherapy-treated patients discharged alive (7 of 16 patients) ultimately required surgical treatment for bleeding varices, despite a mean of 6.1 treatment sessions. Health care costs and long-term survival did not differ significantly between the groups (P greater than 0.05). We conclude that although endoscopic sclerotherapy is as good as surgical shunting for the acute management of variceal hemorrhage in poor-risk patients with massive bleeding, sclerotherapy-treated patients in whom varices are not obliterated and bleeding continues should be considered for elective shunt surgery.