Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidified compartment.

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.

Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis.

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.

Glutathione monoethyl ester ameliorates caerulein-induced pancreatitis in the mouse.

Studies in animal models suggest that oxygen radicals may be important in the pathogenesis of acute pancreatitis. Because glutathione is an essential component of the defense against radical-mediated cellular injury, we investigated whether pancreatic glutathione content is influenced by inducing acute pancreatitis and whether augmenting the intracellular supply of glutathione would alter the course of pancreatitis. Caerulein, a decapeptide cholecystokinin analogue, induces acute necrotizing pancreatitis in mice when given in high doses (50 micrograms/kg per h) over a period of 6 h. The pancreatic glutathione content (total, GSH + GSSG) in mice treated with high-dose caerulein fell to 17% of normal within 4 h of beginning caerulein and recovered toward normal after discontinuing caerulein treatment. Mice treated with glutathione monoethyl ester (20 mmol/kg 1 h before caerulein, 10 mmol/kg 3 and 7 h after starting caerulein) were found to have blunted depletion of pancreatic glutathione, diminished histologic evidence of pancreatitis (necrosis, inflammation, and vacuolization), and lower serum amylase values compared with mice treated with caerulein alone. These findings suggest that the profound depletion of pancreatic glutathione caused by hyperstimulation of the pancreas with caerulein is critically important in the pathogenesis of acute caerulein-induced pancreatitis.

Digestive end products release pancreatic enzymes from particulate cellular pools, particularly zymogen granules.

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.

Sucralfate suspension versus titrated antacid for the prevention of acute stress-related gastrointestinal hemorrhage in critically ill patients.

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.

Isolation of cytomegalovirus-specific cytotoxic T-lymphocytes from gut-associated lymphoid tissue (GALT) of HIV type 1-infected subjects.

Cytomegalovirus (CMV) can be an important opportunistic infection in HIV-1-infected patients, particularly when the CD4+ T-cell count drops below 50 lymphocytes/mm3. CMV-associated disease, including retinitis, pneumonitis, gastroenteritis, and encephalitis, is estimated to affect up to 40% of AIDS patients. We have studied the cellular immune response to CMV in gut-associated lymphoid tissue (GALT) of HIV-1-infected patients. Two patients with chronic diarrhea of unknown etiology were examined by flexible sigmoidoscopy and upper endoscopy. Biopsy specimens were obtained from lymphoid-associated tissue sites in rectum and duodenum. Both patients were seropositive for CMV IgG, but had not been treated with ganciclovir, and neither had clinical signs of CMV disease. Mononuclear cell cultures were established from GALT and blood and assayed for the presence of CMV-specific CD8+ T cells. CD8+ T-cell phenotype and function were assessed by MHC Class I tetramer staining, using an HLA-A*0201 tetramer complex specific for peptide 495-503 (NLVPMVATV) of CMV lower matrix protein pp65, and by a standard 51Cr release assay. CMV pp65-specific cytotoxic lymphocytes (CTL) were detected in GALT and blood MNC from both patients. These results demonstrate that HIV-1-infected subjects seropositive for CMV, but without active CMV gastrointestinal disease, harbor CMV-specific CTL in intestinal lymphoid tissue. This is the first report of isolation of CMV-specific CTL in GALT and will lead to greater understanding of the pathogenesis of CMV disease in human mucosal tissue.

Experimental acute pancreatitis. In vitro magnetic resonance characteristics.

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)

Diagnosis of pancreatic carcinoma. Imaging techniques and tumor markers.

In view of the increasing number of new imaging techniques and serum tumor markers, it is not well established which combination or which order of tests may provide the most information for diagnosis of pancreatic carcinoma. This review determines the diagnostic value of the various tests and evaluates which combination of tests may provide the most information and what may be considered to be a current rational approach to the diagnosis of pancreatic carcinoma. In the present analysis endoscopic retrograde cholangiopancreatography (ERCP) provided a 92% sensitivity that exceeded the 83% and 74% sensitivities calculated for computed tomography (CT) and ultrasound, respectively. The specificity of all three imaging techniques exceeded 90%. Serum determination of CA 19-9 yielded an 83% sensitivity, which was considerably higher than sensitivities of carcinoembryonic antigen and various other tumor markers. The combination of CA 19-9 and ultrasound improved the sensitivity of each test performed alone by 10-15%. Fine-needle biopsy allows diagnosis of pancreatic carcinoma with a sensitivity of 83% and an almost perfect specificity of 99%. On the basis of these data, the combination of ultrasound and determination of CA 19-9 is recommended as the initial tests when pancreatic carcinoma is suspected. CT also must be performed if ultrasound is indeterminant or inconsistent with the clinical evaluation, as well as in patients with negative ultrasound but abnormal CA 19-9. Negative results of CT, ultrasound, and CA 19-9 will exclude pancreatic carcinoma in most patients. A positive ultrasound or CT result usually leads to fine-needle biopsy, which helps avoid most diagnostic laparotomies. ERCP must be performed in patients where ultrasound, CT, and fine-needle biopsy do not clarify the diagnosis. In the majority of patients with pancreatic carcinoma, noninvasive imaging techniques such as ultrasound and CT also allow adequate staging. In some patients, however, laparoscopy and angiography may need to be performed for strategic planning of further therapy. Although modern imaging techniques and serum tumor markers allow diagnosis of pancreatic carcinomas as small as 2-3 cm and help avoid most diagnostic laparotomies, this improvement in diagnostic capability has as yet not significantly improved the prognosis.

Effects of bile and pancreatic digestive enzymes on permeability of the pancreatic duct system in rabbits.

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.

Energy metabolism in mouse pancreas in response to different dosages of a CCK analogue.

Stimulation of the exocrine pancreas with cholecystokinin analogues leads to a variety of intraacinar processes, many coupled to energy consumption. It was hypothesized that extensive ATP depletion could play a role in the pathophysiology of acute pancreatitis, especially in the hyperstimulation (cerulein) model. Mice received seven intraperitoneal injections of cerulein at hourly intervals, at doses ranging from physiological (0.1 micrograms/kg) to pharmacological (50 micrograms/kg). A single dose of cerulein induced a 28-33% decrease in ATP, whereas a complete course of injections led to a nadir as low as 45% of the control value. The overall pattern of ATP tissue content during the observed time course was surprisingly similar in all four groups and statistically not different at any time point. Until 12 h, ATP levels in all groups remained below the control value. In contrast, serum amylase and light microscopy reflected a degree of pancreatitis in a close dose-response pattern to the administered cerulein dose. These findings suggest that ATP depletion--although probably facilitating acinar damage--does not seem to play a causal or primary role in the pathophysiology of acute pancreatitis.

Growing pancreatic acinar cells (postpancreatitis and fetal) express a ductal antigen.

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.

Effects of the seleno-organic substance Ebselen in two different models of acute pancreatitis.

This study evaluated the effects of the seleno-organic substance Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] in two models of acute hemorrhagic and acute edematous pancreatitis. Ebselen is known to catalyze glutathione peroxidase-like reactions and to inhibit lipid peroxidation. Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet to mice for 66 h. Edematous pancreatitis was induced by 7-h subcutaneous injections of 50 micrograms/kg of cerulein in mice. Ebselen was given from the beginning of the CDE diet either as a subcutaneous injection of 100 mg/kg at 6-h intervals or was mixed in with the CDE diet to yield a daily dose of 100 mg/kg of Ebselen. In further experiments, Ebselen was given at various time intervals after the beginning of the CDE diet as subcutaneous injections of 100 mg/kg at 6-h intervals. In the cerulein model, Ebselen was given 5 min prior to each cerulein injection at doses from 10-500 mg/kg. Prophylactic administration of Ebselen given orally or subcutaneously significantly improved survival from 38.5% in the control group of saline-injected CDE-fed mice to 61.9 and 65.0%, respectively. Ebselen also reduced increases in serum amylase and pancreatic weight in the diet model. Therapeutic administration of Ebselen significantly increased survival only when injections were started 20 h after the beginning of the CDE diet (64%), but not when started after 40 h (44%). Similarly, increases in serum amylase and pancreatic weight due to the CDE diet were significantly reduced by Ebselen only when injections were started after 20 h but not when started after 40 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Premature trypsinogen activation during cerulein pancreatitis in rats occurs inside pancreatic acinar cells.

Although it is widely accepted that trypsinogen activation is an initiating event in the development of acute pancreatitis, its location inside the pancreas is not known. In our studies, acute edematous pancreatitis was induced in rats by one or two intraperitoneal injections of 50 microg cerulein/kg body weight. The pancreas was removed for examination 1 or 2 h after the first and the second cerulein injection, respectively. The cleavage product of trypsinogen activation, trypsinogen activation peptide, was specifically labeled on pancreatic tissue sections by a corresponding antibody, the signal enhanced by a biotin-avidin conjugate, and the site then visualized by coupled peroxidase activity on diaminobenzidine. The sections were examined by light microscopy. Trypsinogen activation peptide, reflecting activation of the pancreatic digestive enzyme trypsinogen, was detected inside pancreatic acinar cells in this animal model of acute pancreatitis. As early as 1 h after the first injection of cerulein, protease activation was seen within the apical pole of acinar cells. Protease activation was increased 2 h after the latter of two injections of cerulein and more evenly distributed within the cells. For the first time morphologic evidence confirms that the activation originates within the acinar cell, rather than from the interstitium or the duct lumen. The location of this activation at the apical site of the acinar cell indicates its origin from subcellular compartments involving the late steps in the secretory pathway.

Gabexate mesilate (FOY) protects against ceruletide-induced acute pancreatitis in the rat.

Acute pancreatitis (AP) is believed to result from intraparenchymal activation of trypsin and other digestive enzymes within the pancreas followed by autodigestion of the gland. Gabexate mesilate (FOY), a synthetic guanidino acid ester exhibiting potent and versatile inhibitory actions on a number of proteinases (e.g., trypsin, kallikrein, C1-r, C1 esterase, plasmin, thrombin, phospholipase A2), was examined for its ability to protect the rat pancreas against development of AP induced by pharmacological doses of ceruletide (CRT). Rats were i.v. infused for 6 h with either CRT (5 micrograms/kg/h) or CRT + FOY (50 mg/kg/h). In FOY-treated rats the serum amylase and trypsinogen concentrations were reduced by 60 and 80%, respectively, compared to rats infused with CRT alone. Histologically, the extent of acinar cell vacuolization in the pancreas was significantly reduced and interstitial edema, although not assessed by quantitative morphometric techniques, appeared to be qualitatively lessened in the FOY-treated rats. The ability of FOY to inhibit significantly AP produced by supramaximal doses of CRT, coupled with its inhibitory properties on components of the coagulation and complement cascades, stress the importance of continued research on this compound as a potential therapeutic agent for treatment of AP and its systemic sequelae.

Effects of antioxidants and free radical scavengers in three different models of acute pancreatitis.

The present studies were done to evaluate the therapeutic potential of several antioxidants and free radical scavengers in three different models of acute pancreatitis. (a) Edematous pancreatitis with acinar cells necrosis was induced by seven hourly intraperitoneal injections of 50 micrograms of caerulein per kg in mice. (b) Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet in mice. (c) Hemorrhagic pancreatitis was induced by retrograde infusion of 0.6 ml of 5% sodium taurocholate into the pancreatic duct in rats. The following antioxidants and free radical scavengers were given at various doses intravenously, subcutaneously, or intraperitoneally before the onset of pancreatitis: Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], superoxide dismutase, catalase, deferoxamine (Desferal), dimethyl sulfoxide, or allopurinol. The severity of pancreatitis was assessed at various times after its onset by determination of serum amylase and pancreatic weight (edema), by grading of histological alterations, and by determination of survival (survival determined in models of hemorrhagic pancreatitis). In general, free radical scavengers and antioxidants ameliorated edema and inflammation to a greater degree than necrosis and the increase in serum amylase. Superoxide dismutase (as did Ebselen in previous studies) exerted beneficial effects on survival in diet-induced pancreatitis in the absence of marked effects on pancreatic necrosis, suggesting that these beneficial effects are due to amelioration of extrapancreatic complications that often contribute to mortality in acute pancreatitis. None of the antioxidants had major beneficial effects in taurocholate-induced hemorrhagic pancreatitis. Thus, formation of free radicals may be important for progression and outcome in diet-induced and, to a lesser degree, in caerulein-induced pancreatitis but not at all in taurocholate-induced pancreatitis. Different models of pancreatitis may, therefore, involve different degrees and mechanisms of free radical formation. Despite the amelioration of edema and the beneficial effects on mortality seen for some antioxidants in some of the models, antioxidants and free radical scavengers appear to have only a limited potential for treatment of acute pancreatitis.

Pancreatic abscess: impact of computerized tomography on early diagnosis and surgery.

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.

Endoscopy training in a three-year curriculum.

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.

Receptor strategies in 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.

Idiopathic acute pancreatitis.

In most patients presenting with acute pancreatitis, the cause can be established on the basis of initial history, physical examination, laboratory studies, and abdominal sonography. Patients with unexplained pancreatitis at that point are often considered to have idiopathic disease. However, a cause and, often, effective treatment to prevent recurrent pancreatitis are possible in many of these patients if an aggressive diagnostic approach is taken to discover undiagnosed hyperlipidemia, occult gallstones, abnormalities of the bile and pancreatic ducts, sphincter of Oddi dysfunction, pancreatic cancer and other tumors, and cystic fibrosis (in children and young adults).