Faculty Bibliography

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)

We sought to determine whether the clinical setting in which pancreatitis occurs affects the incidence and distribution of increased values of renal clearance of amylase relative to creatinine, CAm/CCr, and whether the increased values reflect a tubular disorder that impairs renal reclamation of certain low molecular weight proteins. We measured the renal clearance of three low molecular weight proteins (amylase, beta 2-microglobulin, and lysozyme) and urinary excretion of three lysosomal enzymes that originate from the renal tubule in three groups of patients (alcoholic pancreatitis, pancreatitis without alcoholism, and alcoholism without pancreatitis). When compared to normal controls, the mean CAm/CCr was significantly elevated in alcoholic pancreatitis (p less than 0.05) but not in equally severe pancreatitis without alcoholism nor in alcoholism without pancreatitis. The clearance ratio of beta 2-microglobulin was significantly increased in each of the three patient groups; mean clearance ratio of lysozyme was not significantly increased in any of the patient groups. Excretion of each of the three lysosomal enzymes was significantly increased in each of the patient groups. We conclude that the etiology of pancreatitis affects the distribution of values for CAm/CCr, impaired tubular reclamation of amylase is the mechanism of the increase in CAm/CCr, and a factor or factors associated with both pancreatitis and with alcoholism per se appear to disorder the renal tubule and to impair tubular reclamation of some but not all low molecular weight proteins-a novel finding of considerable potential significance.

Until recently pancreatic abscess was often a lethal complication of acute pancreatitis. A major factor contributing to this high mortality has been delay in diagnosis. When combined with diagnostic needle aspiration, computed tomography (CT) has greatly enhanced the early detection of pancreatic abscesses. In the past 5 years at our institutions 23 patients with proven pancreatic abscesses were evaluated early in their clinical course by CT. In follow-up ranging from 4 months to 4 1/2 years there were only 4 deaths: a mortality rate of 17%. Many of the surviving patients had a long and protracted clinical course (mean length of hospitalization, 58 days) and reoperation for recurrent abscess or gastrointestinal complications was required in 9 patients (39%). Computed tomography proved helpful both in localizing the site of de novo or recurrent pancreatic abscess and in detecting postoperative complications. An aggressive approach to early CT scanning with diagnostic needle aspiration appears to be a factor in the improved survival of these patients.

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.

The present study evaluates the ability of two recently synthesized analogues of proglumide, both 4-benzamido-N,N-di-alkyl-glutaramic acid derivatives, to act as cholecystokinin receptor antagonists. Both new antagonists inhibited cholecystokinin-stimulated amylase release and, similarly, binding of 125I-cholecystokinin to isolated rat pancreatic acini. These effects displayed competitive kinetics; both antagonists showed no agonist activity and were specific in that only those secretagogues were inhibited that interact with the cholecystokinin receptor. Both antagonists also inhibited binding of 125I-cholecystokinin to mouse pancreatic membrane particles similarly to results with rat pancreatic acini. With the more potent of the two new antagonists, half-maximal inhibition of action and binding of cholecystokinin was observed with low concentrations of approximately 10(-7) M; compared with proglumide, the new antagonists were as much as 4,000 times more potent. Unlike proglumide, which inhibits binding of cholecystokinin to pancreas and brain tissue similarly, both antagonists inhibited binding of cholecystokinin to the pancreas at much lower concentrations compared with brain. The more potent of the inhibitors was 300 times more potent in inhibiting binding of cholecystokinin to pancreatic tissues compared with brain.

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).

In this study, we looked for acidification in pancreatic zymogen granules as recently reported for other secretory vesicles. In intact dispersed acinar cells, acidic intracellular compartments identified by fluorescence microscopy using acridine orange corresponded exactly to the distribution of zymogen granules visualized by light microscopy. Acridine orange fluorescence in zymogen granules was reversibly dissipated by protonophores (carbonyl cyanide m-chlorophenylhydrazone, monensin) and NH4Cl; and the percentages of cytoplasmic area occupied by the acidic compartments and by zymogen granules were identical under fasting conditions and decreased in parallel after in vivo cholinergic stimulation. Zymogen granules released acutely from hypotonically disrupted cells without homogenization also accumulated acridine orange. Red-orange fluorescence in released granules was also abolished by protonophores and NH4Cl; and it reappeared after washout of protonophores in the presence, but not absence of adenosine triphosphate. Dicyclohexylcarbodiimide, which inhibits all proton pumps, and N-ethylmaleimide, which inhibits the proton pump of endocytic vesicles and lysosomes, but not mitochondria, prevented this adenosine triphosphate-dependent reappearance of acridine orange fluorescence, whereas vanadate did not. In contrast to these observations with zymogen granules in situ or acutely released from disrupted cells, granules isolated by conventional multistep homogenization/centrifugation procedures did not exhibit adenosine triphosphate-dependent acidification or development of a positive membrane potential as measured by quenching of acridine orange or Oxonol V, respectively. The latter findings may indicate release of inhibitors or granule damage during isolation. Collectively, the present results provide direct evidence that zymogen granules contain an active acidification mechanism which appears similar to that of other secretory vesicles and endosomes. This acidification process may have important implications for the storage, stabilization, and secretion of intragranular proteins including proenzymes.

The effects of the cholecystokinin (CCK)-receptor antagonist proglumide, the protease inhibitor gabexate, and the hormones secretin and cholecystokinin-octapeptide (CCK-8) were studied in a model of acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. Injections of gabexate and proglumide from initiation of CDE diet (before induction of pancreatitis) increased survival from 37% (diet alone) to 85 and 75%, respectively, and also ameliorated histological alterations and increases in serum amylase concentration and pancreatic activated trypsin. Secretin had no major beneficial effect. When proglumide or gabexate were given after induction of pancreatitis, proglumide still increased survival to 75%, whereas gabexate no longer did. Injection of nontoxic doses of CCK-8 before proglumide or gabexate injections completely abolished all beneficial effects and also increased the severity of pancreatitis due to CDE diet alone. Blockade of CCK receptors and early inhibition of protease activity may be beneficial in severe acute pancreatitis. Cholecystokinin appears to play a contributory role in the development of pancreatitis.

Bleeding from esophageal varices remains a difficult clinical problem, carrying a high likelihood both of rebleeding and of mortality. The initial approach requires adequate but not overly vigorous volume replacement with blood and other fluids. Once the patient is resuscitated, upper gastrointestinal endoscopy should be performed to establish the source of bleeding. Both endoscopic variceal sclerotherapy and balloon tamponade appear to be effective in achieving temporary control of acute ongoing hemorrhage from esophageal varices. The value of intravenous vasopressin remains controversial. Rebleeding can be prevented in most patients by shunt surgery. However, surgery carries both considerable early morbidity and mortality (related mainly to the severity of the underlying liver disease) and substantial longer-term morbidity and mortality from hepatic encephalopathy and liver failure. The role of pharmacologic agents (eg, propranolol) intended to prevent variceal hemorrhage by reducing portal pressure remains to be established. At present, we recommend use of endoscopic variceal sclerotherapy for the control of active variceal bleeding, with employment of balloon tamponade and intravenous vasopressin if sclerotherapy is successful. Emergency shunt surgery should be reserved only for those patients whose bleeding cannot be controlled by these other means. For prevention of rebleeding in Child class C patients, we attempt to obliterate the varices by repeated endoscopic sclerotherapy. Patients who have two to three episodes of rebleeding despite this approach are considered for shunt surgery. For better-risk patients who do not have ascites, which is difficult to control, we are currently recommending a distal splenorenal shunt. Alternatively, repeated endoscopic variceal sclerotherapy is used for these better-risk patients (Child class A or B) in some centers, with shunt surgery reserved for patients who continue to rebleed. Which approach to preventing rebleeding in the better-risk patient is more effective, as well as the role of pharmacologic therapy with propranolol or other agents, remains to be settled by well-controlled randomized clinical trials.