Search

A 26-year-old woman complained of upper abdominal pain. Computed tomography (CT) showed acute pancreatitis, a left adrenal tumor and solitary right pulmonary metastasis. She underwent left adrenalectomy; the adrenal tumor was diagnosed as adrenocortical carcinoma (ACC). When preparing to resect the pulmonary metastasis, she suffered a second acute pancreatic attack. Magnetic resonance cholangiopancreatography (MRCP) showed that the proximal main pancreatic duct (MPD) was dilated, and the distal MPD was diminished; however, no pancreatic tumor was observed on CT or MRCP. Endoscopic ultrasonography revealed a solitary pancreatic mass, which was diagnosed as pancreatic metastasis from ACC by endoscopic ultrasonography-guided fine-needle aspiration.

Background: Rapid urinary trypsinogen-2 dipstick test and levels of urinary trypsinogen-2 and trypsinogen activation peptide (TAP) concentration have been reported as prognostic markers for the diagnosis of acute pancreatitis., Aim: To reconfirm the validity of all these markers in the diagnosis of acute pancreatitis by undertaking a multi-center study in Japan., Methods: Patients with acute abdominal pain were recruited from 17 medical institutions in Japan from April 2009 to December 2012. Urinary and serum samples were collected twice, at enrollment and on the following day for measuring target markers. The diagnosis and severity assessment of acute pancreatitis were assessed based on prognostic factors and computed tomography (CT) Grade of the Japanese Ministry of Health, Labour, and Welfare criteria., Results: A total of 94 patients were enrolled during the study period. The trypsinogen-2 dipstick test was positive in 57 of 78 patients with acute pancreatitis (sensitivity, 73.1%) and in 6 of 16 patients with abdominal pain but without any evidence of acute pancreatitis (specificity, 62.5%). The area under the curve (AUC) score of urinary trypsinogen-2 according to prognostic factors was 0.704, which was highest in all parameter. The AUC scores of urinary trypsinogen-2 and TAP according to CT Grade were 0.701 and 0.692, respectively, which shows higher than other pancreatic enzymes. The levels of urinary trypsinogen-2 and TAP were significantly higher in patients with extended extra-pancreatic inflammation as evaluated by CT Grade., Conclusion: We reconfirmed urinary trypsinogen-2 dipstick test is useful as a marker for the diagnosis of acute pancreatitis. Urinary trypsinogen-2 and TAP may be considered as useful markers to determine extra-pancreatic inflammation in acute pancreatitis., Competing Interests: Conflict-of-interest statement: The qualitative and quantitative analyses of urinary trypsinogen-2 were performed free of charge by Unitika Ltd. (Osaka, Japan). Mayumi T received research funding. The other authors declare no conflict of interest.

Recent diagnostic and therapeutic progress for severe acute pancreatitis (SAP) remarkably decreased the case-mortality rate. To further decrease the mortality rate of SAP, it is important to precisely evaluate the severity at an early stage, and initiate appropriate treatment as early as possible. Research Committee of Intractable Diseases of the Pancreas in Japan developed simpler criteria combining routinely available data with clinical signs. Severity can be evaluated by laboratory examinations or by clinical signs, reducing the defect values of the severity factors. Moreover, the severity criteria considered laboratory/clinical severity scores and contrast-enhanced computed tomography (CE-CT) findings as independent risk factors. Thus, CE-CT scans are not necessarily required to evaluate the severity of acute pancreatitis. There was no fatal case in mild AP diagnosed by the CE-CT severity score, whereas case-mortality rate in those with SAP was 14.8%. Case-mortality of SAP that fulfilled both the laboratory/clinical and the CE-CT severity criteria was 30.8%. It is recommended, therefore, to perform CE-CT examination to clarify the prognosis in those patients who were diagnosed as SAP by laboratory/clinical severity criteria. Because the mortality rate of these patients with SAP is high, such patients should be transferred to advanced medical units.

The incidence of acute pancreatitis in Japan is increasing and ranges from 187 to 347 cases per million populations. Case fatality was 0.2% for mild to moderate, and 9.0% for severe acute pancreatitis in Japan in 2003. Experts in pancreatitis in Japan made this document focusing on the practical aspects in the early management of patients with acute pancreatitis. The correct diagnosis of acute pancreatitis and severity stratification should be made in all patients using the criteria for the diagnosis of acute pancreatitis and the multifactor scoring system proposed by the Research Committee of Intractable Diseases of the Pancreas as early as possible. All patients diagnosed with acute pancreatitis should be managed in the hospital. Monitoring of blood pressure, pulse and respiratory rate, body temperature, hourly urinary volume, and blood oxygen saturation level is essential in the management of such patients. Early vigorous intravenous hydration is of foremost importance to stabilize circulatory dynamics. Adequate pain relief with opiates is also important. In severe acute pancreatitis, prophylactic intravenous administration of antibiotics at an early stage is recommended. Administration of protease inhibitors should be initiated as soon as the diagnosis of acute pancreatitis is confirmed. A combination of enteral feeding with parenteral nutrition from early stage is recommended if there are no clear signs and symptoms of ileus and gastrointestinal bleeding. Patients with severe acute pancreatitis should be transferred to ICU as early as possible to perform special measures such as continuous regional arterial infusion of protease inhibitors and antibiotics, and continuous hemodiafiltration. The Japanese Government covers medical care expense for severe acute pancreatitis as one of the projects of Research on Measures for Intractable Diseases.

Objectives: Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with chronic pancreatitis in Caucasians. We developed a simple method for measuring finger sweat chloride concentration to test whether CFTR dysfunction underlies chronic pancreatitis in Japan where cystic fibrosis (CF) is rare., Methods: We studied 25 patients with chronic (21 alcoholic and 4 idiopathic) pancreatitis and 25 healthy volunteers. Sweat chloride concentrations were measured by a finger sweat chloride test. We analyzed DNA for 20 common CFTR mutations in Europeans, 9 CF-causing mutations in Japanese, and 2 polymorphic loci, a poly-T tract and (TG) repeats, at intron 8., Results: Thirteen patients (52%) had sweat chloride levels >60 mmol/L, a level consistent with CF, while only 4 (16%) healthy subjects exceeded this level. The 29 CF mutations and the 5T allele were detected in neither the patients nor controls. The (TG) 12 allele was common in both the patients (58%) and controls (48%). The (TG) 12/12 genotype was common in alcoholic pancreatitis (29%) compared with the (TG) 11/11 (10%). Patients with the (TG) 12/12 genotype had significantly higher sweat chloride concentrations than the controls., Conclusion: CFTR dysfunction as evidenced by a finger sweat chloride test is present in about half of Japanese patients with chronic pancreatitis, suggesting that this test may be useful for detecting the high-risk group. A higher proportion of the (TG) 12 allele may be a genetic background for elevated sweat chloride concentrations in Japanese patients.

The discovery of the gene for cystic fibrosis (CF), the cystic fibrosis transmembrane conductance regulator (CFTR), brought about a new era in the study of this disease. Identification of the molecular target has yielded a flood of data that add to our understanding of the pathogenesis, diagnosis and treatment of CF. The CFTR protein is a cAMP-regulated Cl(-) channel with multiple functions in epithelial cells. In the exocrine pancreas the CFTR plays a key role in the apical Cl(-), HCO(3)(-), and water transport in duct cells. The severe loss of functions, caused by mutations of the CFTR gene, leads to pathological lesions of the pancreas. Over 1200 CFTR mutations and polymorphisms have been identified and their diversity may explain the high level of heterogeneity in the CF phenotype. Mutation analyses of the CFTR gene have revealed a spectrum of CFTR-related diseases that do not fit the classical CF picture but are associated with dysfunction of CFTR, such as chronic pancreatitis., (Copyright 2002 Elsevier Science Ltd.)

Context: The role of protein components of pancreatic secretions has been controversial in pancreatic stone formation., Objective: To study the lithogenic role of pancreatic stone protein and lactoferrin in stone formation in chronic pancreatitis., Patients: Pancreatic stones were collected from 13 patients with alcoholic (n=6) and nonalcoholic (n=7) chronic calcified pancreatitis., Main Outcome Measures: Pancreatic stone extracts were analyzed for pancreatic stone protein and lactoferrin using enzyme immunoassay. The localization of pancreatic stone protein immunoreactivity in the stone was observed using immunogold staining and scanning electron microscopy., Results: Immunoreactivities for pancreatic stone protein were detected in the stones from all 13 patients with chronic calcified pancreatitis and for lactoferrin in the stones from five of the 13 patients. Pancreatic stone protein immunoreactivity distributed diffusely from the center to the periphery of the pancreatic stones., Conclusions: Involvement of pancreatic stone protein seems to be constant from the initial step of the stone formation to subsequent steps of the stone growth. However, pancreatic stone protein is only one of the precipitating proteins in pancreatic secretions such as lactoferrin, trypsinogen, etc.

Chronic pancreatitis is a continuing inflammatory disease characterized by irreversible morphological change and, typically, by pain and permanent impairment of function. The pathogenesis of pancreatitis, either acute or chronic, is still controversial. There have been no widely accepted concepts to provide a reasonable explanation linking the known etiological factors and the pathophysiological aspects of the disease. Alcohol is undoubtedly the major etiological factor in most countries, and the relative importance of alcohol as a cause of chronic pancreatitis ranges from 40% to 90% in various countries. As fewer than 10% of alcoholics develop chronic pancreatitis, other nutritional or genetic influences are likely to be involved in the pathogenesis of alcoholic pancreatitis. Accessory pancreas incidentally found in patients with chronic alcoholic pancreatitis does not always have the pathological findings seen in the main pancreas. Integrity of the pancreatic duct seems to be another important factor for chronic alcoholic pancreatitis. Gene mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen, and pancreatic secretory trypsin inhibitor have been investigated in idiopathic chronic pancreatitis. Molecular and cell biology research during the past few years has elucidated pathophysiological factors that are involved in the pathogenesis of chronic pancreatitis, but cannot demonstrate a common pathway between etiological factors and the pathogenesis or development of the disease.

Trypsinogen activation peptide (TAP) is a useful marker of severe acute pancreatitis. However, it is sometimes difficult to detect an elevation of plasma TAP in patients with acute pancreatitis because TAP is rapidly cleared from plasma. Therefore, urine TAP has been evaluated to provide an accurate prediction of the outcome of pancreatitis. In the present study, we examined the time course of plasma and urine TAP simultaneously after induction of taurocholate-induced pancreatitis in rats. Plasma TAP levels peaked at 1 hour after the induction of pancreatitis and then gradually decreased, but was still higher than prepancreatitis levels at 48 hours. Significant increases in urine TAP levels were seen at 0-6, 6-12, and 30-36 hours after induction of pancreatitis. The peak level of urine TAP output and TAP/creatinine ratio was observed at 6-12 and 30-36 hours, respectively. Urine TAP concentration showed a significant correlation with both urine TAP/creatinine ratio and TAP output in urine (p < 0.01). In conclusion, plasma TAP increased immediately after the induction of pancreatitis, but excretion of TAP into urine was delayed several hours in taurocholate-induced pancreatitis in rats. The measurement of urine TAP concentration alone sufficiently can reflect the amount of TAP liberated in the pancreas at initial stage of acute pancreatitis.

Fast magnetic resonance (MR) imaging of the rat pancreas was carried out using a snapshot method to observe three-dimensional (3D) and temporal development of the pancreatic cyst after experimental pancreatitis. Acute pancreatitis was induced by a retrograde infusion of the trypsin-taurocholate solution into the pancreatic duct in 23 rats, of which seven survived for one month. Under 2% enflurane anesthesia, (1)H images of the rat abdomen were taken by a 4.7 T magnetic resonance spectrometer under spontaneous breathing. 3D images of the pancreas and cyst were reconstructed from the axial, sagittal and coronal images taken before, 24 h, 7 days, 14 days, 21 days and 28 days after the induction of pancreatitis. The 3D images reconstructed from different slice orientations at each time point showed good agreement with each other. The calculated volumes of the cyst on 7th, 14th, 21st, and 28th day were 0.3 +/- 0.1, 0.8 +/- 0.3, 2.1 +/- 0.6, 6.5 +/- 1.3 mL, respectively. The cystic fluid volume on 28th day was 6.4 +/- 1.4 mL, which confirmed reliability of volume measurement by MR imaging. Fast MR imaging (snapshot) together with 3D reconstruction allows us to understand the detailed chronological and spatial development of pancreatic cyst after acute pancreatitis in rats.

Long-term effects of nafamostat mesylate, a protease inhibitor, and imipenem, an antibiotic, on trypsintaurocholate-induced acute pancreatitis were studied in rats. Sham-operated rats infused with a buffer solution into the pancreatic duct served as controls. Nafamostat (1 mg/kg), imipenem (10 mg/kg), or imipenem + nafamostat in saline was injected subcutaneously 0.25, 3, 24, and 48 hours after the induction of pancreatitis. In untreated rats and control rats, saline was injected at the same intervals as in the treated rats. All rats in an untreated group died within 3.5 days (median survival, 1.25 day) after the induction of pancreatitis. The 2-week survival rate was significantly (p < 0.05) improved by a combination of nafamostat and imipenem (42%), but not by nafamostat (17%), or imipenem (8%) alone. Bacterial culture at 24 hours revealed infection of necrotic pancreatic tissues and ascites by intestinal bacteria in all untreated rats but not in control rats. Bacterial counts were significantly reduced by imipenem, but not by nafamostat. In conclusion, bacterial infection occurred within 24 hours after the induction of trypsintaurocholate pancreatitis in rats. Early treatment with nafamostat + imipenem, but not nafamostat or imipenem alone, improves long-term survival.

Plasma and urine levels of trypsinogen activation peptides (TAP) reflect the severity of acute pancreatitis in experimental and clinical acute pancreatitis. In trypsin-taurocholate-induced pancreatitis in rats, the extrinsic bovine trypsin used for the induction of pancreatitis might influence on the TAP levels after induction of pancreatitis. The aim of the present study was to elucidate whether infused trypsin itself affects TAP levels in trypsin-taurocholate-induced pancreatitis. Rats were divided into three groups. In the pancreatitis group, acute pancreatitis was induced by a retrograde infusion of bovine trypsin and sodium taurocholate into the pancreatic duct. In the duct infusion group and peritoneal injection group, a mixture of bovine trypsin and trypsin inhibitor, ONO-3403, was infused into the pancreatic duct or the peritoneal cavity. Plasma and urine TAP concentration significantly increased in trypsin-taurocholate-induced pancreatitis but not in the duct infusion and peritoneal injection groups for 6 hours after the infusion of trypsin. Serum rat immunoreactive trypsin (IRT) and amylase significantly increased in the pancreatitis and duct infusion groups but not in the peritoneal injection group. Serum levels of bovine IRT in the pancreatitis group was significantly lower than those in duct infusion and peritoneal injection groups. In conclusion, an intraductal infusion of bovine trypsin itself into pancreatic duct does not influence the levels of plasma and urine TAP in trypsin-taurocholate-induced pancreatitis.

The aim of this study was to estimate the number of patients treated for chronic pancreatitis in 1994 in Japan and to explore the clinico-epidemiological features of chronic pancreatitis. Two surveys were conducted. Stratified random sampling was used to select departments in which patients with chronic pancreatitis were treated, and two different questionnaires were administered to obtain relevant information. From the first survey, the total number of patients treated for chronic pancreatitis in Japan in the year 1994 was estimated as 32,000 (95% confidence interval, 25,000-39,000). Clinico-epidemiological features, based on the 2,523 patients reported from the second survey, were subsequently clarified. The sex ratio (male/female) of the patients was 3.5. Alcoholic pancreatitis was the most common type in males (68.5%), and idiopathic pancreatitis in females (69.6%). Compared with the findings in the last survey in 1985, the proportion of patients with alcoholic pancreatitis has decreased slightly, from 58.7% to 55.5%, while that of idiopathic chronic pancreatitis has increased in both males and females. Patients diagnosed by advanced techniques such as computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP) accounted for 68.1% of the total. The number of patients with chronic pancreatitis treated in 1994 in Japan, was estimated as 32,000, with an overall prevalence rate of 45.4 per 100,000 population in males and 12.4 per 100,000 population in females.

Despite the recent development of medical imaging technology, chronic pancreatitis can only be diagnosed when the disease is fully established. This is due to the lack of specific and sensitive markers for this disease. The discovery of mutations in the cationic trypsinogen gene in patients with hereditary pancreatitis and a high incidence of mutations in the cystic fibrosis transmembrane conductance regulator gene in patients with chronic pancreatitis might be important clues to understanding the molecular mechanisms of this disease. The interaction between ethanol and ion channels might be the missing link between alcohol ingestion and chronic pancreatitis.

The catalytic activity of type II phospholipase A2 (PLA2) in blood has been reported to increase in acute pancreatitis and to reflect the severity of pancreatitis. In this study, we evaluated the effects of a new inhibitor of type II PLA2, S5920/LY315920Na, on trypsin-taurocholate-induced pancreatitis in rats. Hemorrhagic pancreatitis was induced by an infusion of a mixture of trypsin and taurocholate into the pancreatic duct. S5920/LY315920Na was administered subcutaneously at 0 h and 3 h after the induction of pancreatitis. Survival rates for 24 h in rats treated with 0.1 and 1 mg/kg of S5920/LY315920Na were significantly higher than that in untreated rats (71 and 86% vs. 14%). Serum levels of amylase and lipase in rats treated with 1 mg/kg of S5920/LY315920Na were significantly lower than those in untreated rats (amylase, 6,903 vs. 32,516 U/L; and lipase, 514 vs. 6,710 U/L) at the time of death or 24 h after the induction of pancreatitis. Plasma levels of S5920/LY315920Na were enough to inhibit catalytic activity of PLA2 in plasma for 9 h. A new inhibitor of type II PLA2, S5920/LY315920Na, inhibited catalytic activity of PLA2 and improved the survival rate in experimental hemorrhagic pancreatitis in rats.

Conclusion: Elevation of serum pancreatic stone protein-(PSP) S1 suggests activation of trypsinogen in the pancreas. This information would prompt the start of intensive treatment and may improve prognosis of acute pancreatitis (AP)., Background: PSP exists in two molecular forms, PSP-S2-5 and PSP-S1. PSP-S1 is produced by enzyme cleavage of PSP-S2-5 by trypsin. Total serum PSP rose in AP, but little is known about its molecular forms. In this study, we characterized the molecular forms of serum PSP in AP., Methods: Sera were taken from 8 patients with severe acute pancreatitis (sAP) and from 11 patients with mild acute pancreatitis (mAP). Serum PSP was characterized by high-performance liquid chromatography (HPLC) followed by the specific enzyme immunoassay (EIA)., Results: The total serum PSP in sAP was higher than in mAP, but the difference was not significant. The PSP-S1 was detected in serum in all (7/7) patients in sAP and in 72% (8/11) of patients in mAP. Serum level of PSP-S1 was significantly higher in sAP than that in mAP (p < 0.05), and the cutoff value to distinguish the two groups was 30 ng/mL. Serum PSP-S1 did not show significant correlation with total PSP, immunoreactive trypsin, or C-reactive protein.

The effects of a new benzodiazepine-derivative, cholecystokinin receptor antagonist, TS-941, on experimental acute pancreatitis were studied in rats. Hemorrhagic pancreatitis was induced by an infusion of a mixture of trypsin and taurocholate into the pancreatic duct. Edematous pancreatitis was induced by intraperitoneal injection of 40 microg/kg body weight of cerulein at 0 and 1 h after the start of the experiment. TS-941 (3 mg/kg) was injected subcutaneously immediately and 3 h after the induction of pancreatitis. In trypsin-taurocholate-induced pancreatitis, TS-941, with or without the synthetic trypsin inhibitor ONO-3403, had no beneficial effects on the survival rate, pancreatic wet weight, and serum pancreatic enzymes. In cerulein-induced pancreatitis, the treatment with TS-941 significantly reduced the increases of pancreatic wet weight and serum amylase and lipase. Plasma trypsinogen activation peptide (TAP) significantly rose 1 h after the first injection of cerulein. TS-941 inhibited the liberation of TAP in cerulein-induced pancreatitis. These results show that TS-941 is effective for prevention of cerulein-induced edematous pancreatitis. ONO-3403 has beneficial effects on trypsin-taurocholate-induced hemorrhagic pancreatitis, but the combination of TS-941 and ONO-3403 has no additive effect.

Based primarily on our experience, we review current problems on etiology, pathogenesis, classification, diagnosis, and treatment of chronic pancreatitis. Much of the confusion and difficulty associated with chronic pancreatitis originates from the relative inaccessibility of this organ. A lack of specific and sensitive markers that are suitable for the follow-up of a long natural course of chronic pancreatitis also hinders our understanding of this disease. The resolution of the present imaging tests, even by the latest technology, is not good enough to detect early changes of the pancreas. In the past 10 years, several subgroups of patients with alcoholic and idiopathic pancreatitis have been identified based on the long-term follow-up study. Pain disappeared spontaneously in many patients during the course of the disease, but its mechanism is still poorly understood. Removal of pancreatic stones and protein plugs by chemical, endoscopic, or extracorporeal shock-wave therapy has been tried with some success, but their clinical values remain to be established. Attempts have been made to understand the etiology and pathogenesis of chronic pancreatitis at molecular levels. This approach, together with a prospective follow-up of patients, will improve our understanding on chronic pancreatitis.

To evaluate the effectiveness of exocrine function tests in diagnosing chronic pancreatitis (CP), we compared the sensitivity and specificity of duodenal intubation with tubeless tests. While the secretin test (ST) was necessary to diagnose CP, especially in noncalcified CP, and tubeless tests demonstrated insufficient sensitivity to diagnose CP, the combination assay of tubeless tests was specific enough to diagnose severe exocrine dysfunction. Our studies found the sensitivity of secretin testing to diagnose definite CP to be 87%. In patients with probable CP, 60% had mild exocrine insufficiency and 40% had normal function. The false-positive rate of the ST results in nonpancreatic diseases, except diabetes mellitus, was 5%. The correlation between morphological changes in endoscopic retrograde pancreatography (ERP) and exocrine function evaluated by ST was 74%. In patients with calcified CP, 81% had parallel results between ERP and the ST, but in noncalcified CP, 47% had parallel results. In patients with severe or moderate exocrine insufficiency demonstrated by ST, abnormally low levels were observed in 63% by N-benzoyl-L-tyrosyl-p-aminobenzoic acid (BT-PABA) test, 61% by fecal chymotrypsin test (FCT), and 44% by pancreatic amylase (PA). In patients with normal exocrine function demonstrated by ST, abnormally low levels were observed in 28% by BT-PABA test, 28% by FCT, and 10% by PA. A combination assay of BT-PABA test, FCT, and PA improved the specificity for diagnosing CP but not the sensitivity.

The effect of a potent and long-acting bradykinin B2-receptor antagonist (HOE140) on acute pancreatitis induced by retrograde infusion of trypsin and taurocholate into the pancreatic duct was studied in rats. HOE140 was administered subcutaneously immediately before and 3 h after the induction of pancreatitis and the systemic blood pressure, ascites volume, serum amylase, 24-h survival rate, and pathology of the pancreas were evaluated. Plasma concentrations of bradykinin increased significantly 15 min after the induction of pancreatitis and decreased to basal levels at 90 min. HOE140 (0.1 mg/kg) alleviated hypotension developing immediately after the induction of pancreatitis and reduced the ascites volume. The 24-h survival rate in rats treated with 0.1 mg/kg HOE140 (70.3%) was significantly higher than that in controls (35.6%). Treatment with 0.01, 0.3, 1.0, and 3.0 mg/kg of HOE140, however, had no beneficial effect on the survival rate. Ascites volume, serum amylase, and pathology of the pancreas at 24 h were not improved by treatment with HOE140. These data suggest that HOE140 may improve the survival rate by maintaining hemodynamics in the early stage of experimental acute pancreatitis.

Trypsinogen activation peptide (TAP) concentration and alpha 2-macroglobulin-trypsin complex (alpha 2M-T) activity were measured in two experimental models of acute pancreatitis in rats to evaluate the significance of activation of trypsinogen in acute pancreatitis. TAP concentration and alpha 2M-T activity in serum rose significantly in trypsin-taurocholate-induced hemorrhagic acute pancreatitis, while in cerulein-induced edematous acute pancreatitis they did not rise in spite of a similar increase in immunoreactive trypsin. When rats in trypsin-taurocholate-induced pancreatitis were treated by protease inhibitor (FUT-175; nafamostat mesilate; FUT group), alpha 2M-T activity in serum was significantly lower than that in nontreated controls (mean +/- SEM, 20.8 +/- 1.43 U/L in the FUT group vs 79.1 +/- 24.5 in controls; p < 0.01). The survival rate at 24 h was significantly improved in the FUT group compared with the controls (70 vs 43%; p < 0.05). The increase in TAP concentration in the FUT group was similar to that in controls. The TAP concentration in pancreatic tissue at 24 h was significantly (p < 0.01) lower in the survival group (7.8 +/- 0.8 ng/ml) than in the lethal group (25.9 +/- 3.7 ng/ml). Activation of trypsinogen and its subsequent enzyme activity play an important role in the evolution of severe acute pancreatitis.

Lactoferrin and pancreatic stone protein (PSP) are thought to be closely related to pancreatic stone formation in chronic pancreatitis. However, the results reported so far have not been conclusive. To reevaluate the pathological importance of PSP in chronic pancreatitis, compared to lactoferrin, levels of PSP were determined by applying an immunoassay specific to PSP to pure pancreatic juice taken from a total of 52 patients. The patients consisted of 16 controls, 19 chronic pancreatitis patients (13 noncalcified and 6 calcified), and 17 probable cases of pancreatitis. The monoclonal antibody PSP antagonist used in the study recognizes both forms of the protein, PSP S1 and S2-5, with equal effectiveness. No significant reduction of PSP was observed in either calcified (mean +/- SEM, 111 +/- 30 micrograms/mg and 24 +/- 3 micrograms/mg protein) or noncalcified (305 +/- 133 and 97 +/- 47) chronic pancreatitis patients compared with controls (85 +/- 23 and 34 +/- 16). PSP levels did not decrease, at least not in the complete forms of the protein found in chronic pancreatitis. PSP antibody and assay results indicated that a reduction of PSP S2-5 alone could not be ruled out in chronic pancreatitis either.

Protein analysis of intraductal precipitates and calculi is important to elucidate the mechanism of stone formation in chronic pancreatitis. We revealed human cationic trypsin immunoreactivity in protein extracts of pancreatic stones from 11 of 13 patients with chronic calcified pancreatitis, ranging from 0 to 42.3 ng/micrograms protein. On gel filtration the immunoreactivity eluted as one peak, which is identical to that of human cationic trypsinogen. On immunostaining of pancreatic stone, using an immunogold technic and scanning electron microscopy, the immunoreactivity was observed more densely in the amorphous portion of the center of the stones than in the concentric laminar layer of the periphery. Only negligible activity was detected for elastase 1 or amylase in the stone extracts. These results suggest that the presence of trypsinogen in pancreatic stone is not due to coprecipitation or adsorption of pancreatic enzymes but that trypsinogen is more likely involved in an initial step of intraductal precipitate formation than in a subsequent step of stone formation. However, the absence of trypsinogen in the stones from two of the 13 patients also suggests that trypsinogen is not the sole protein initiating precipitate formation.

Serum alpha 2-macroglobulin-trypsin complex (alpha 2M-T) was measured to differentiate the elevation of serum pancreatic enzymes caused by severe acute pancreatitis from simple elevation after endoscopic retrograde pancreatography (ERP). A patient with severe acute pancreatitis demonstrated marked elevation of serum alpha 2M-T. In patients without severe acute pancreatitis, serum alpha 2M-T did not rise in spite of elevated serum pancreatic enzymes. In conclusion, abdominal pain with elevated serum alpha 2M-T can be an early diagnostic clue to severe acute pancreatitis after ERP.

The effect of a novel synthetic trypsin inhibitor, 4-(2-succinimidoethylthio)-phenyl 4-guanidinobenzoate methanesulfonate (E3123), on severe acute pancreatitis was studied in trypsin-taurocholate-induced acute experimental pancreatitis in rats. Rats were divided into four groups according to difference of subdivided doses of E3123 with fixing the total dose at 3 mg/kg body weight. Group A: 1.5 mg/kg of E3123 subcutaneously (SC) each at 1 h before and after induction of pancreatitis. Group B: 1 mg/kg SC each at 1 h before, 1 and 3 h after induction. Group C: 1.5 mg/kg SC each at 1 and 3 h after induction. Group D: 1.5 mg/kg SC each at 3 and 5 h after induction of pancreatitis. The survival rate at 24 h was significantly improved in group B (77% in group B, vs. 36% in paired control; p < 0.01) and in group C (70 vs. 38%; p < 0.05), but not in group A or D. Residual tryptic activity of serum alpha 2-macroglobulin trypsin complex (alpha 2M-TRY) was reduced after the injection of E3123 though immunoreactive trypsin remained unchanged in the early phase of pancreatitis. The reduction of alpha 2M-TRY reflected the inhibitory capacity of E3123 in plasma. E3123 showed favorable effects on the initial stage of severe acute pancreatitis and the effects were probably based on the inhibition of alpha 2M-TRY activity in serum.

Plasma pancreatic enzymes and hormones were longitudinally observed after producing partial obstruction of the major pancreatic duct in dogs to study an initial state of chronic pancreatitis or pancreatolithiasis. Fasting plasma immunoreactive cationic trypsin was elevated during the first six months and then decreased in a subgroup with pancreatic calculi, marked fibrosis, or duct dilatation when compared with the corresponding opposite at the end of the 12-month period. Similar but less prominent changes were found in fasting plasma immunoreactive pancreatic polypeptide (IRPP). Plasma amylase, glucose, or immunoreactive insulin or glucagon (IRG) show no significant variation. Plasma IRG and IRPP responses to intravenous insulin were reduced in the subgroups with marked pancreatic changes towards the end of the 12-month period. These results suggest that plasma pancreatic enzymes and hormones remain elevated as long as pancreatic damage is mild and then start to decline as the damage progresses in chronic pancreatitis or pancreatolithiasis.

The effect of a novel synthetic trypsin inhibitor, 4-sulfamoylphenyl 4-guanidinobenzoate methanesulfonate (ONO-3307), on severe acute pancreatitis was studied by changing its timing, frequency, and dose in trypsin-taurocholate-induced acute experimental pancreatitis in rats. Rats were divided into four groups according to difference of ONO-3307 administration: group A, 2 mg/0.5 ml of ONO-3307 s.c. 1 h before and after induction of pancreatitis; group B, 2 mg/0.5 ml s.c. 1 and 3 h after; group C, 4 mg/1 ml s.c. 1 h before; group D, 4 mg/1 ml s.c. 1 h after. The survival rate at 24 h was significantly improved in group A (75% in A vs. 17% in control; p < 0.01) and in group B (57 vs. 29%; p < 0.05), but not in group C or D. Amylase and immunoreactive trypsin in serum and ascites of the treated were significantly lower than those of controls in both groups A and B. The survival rates were improved dose dependently when ONO-3307 was administered 1 h before and after induction of pancreatitis. ONO-3307 showed favorable effects on the initial stage of severe acute pancreatitis when given in divided doses to maintain the effective serum levels.

Effects of prostaglandin E (PGE) on acute pancreatitis have been controversial. This study shows the effects of PGE1 oligomer, MR-356, on trypsin-taurocholate-induced acute pancreatitis in rats. Divided intraperitoneal doses of 0.6 mg/rat were administered, which increased 24 h survival rates when the oligomer was given both at 1 h before and after (group A) and immediately and 3 h after (group B) induction of pancreatitis. In group A MR-356 significantly improved the survival rates at 18 h (94 vs 61%, P < 0.05) and 24 h (68 vs 33%, P < 0.05) when compared with controls. MR-356 improved the survival rates dose-dependently up to 0.6 mg/rat when given by the same protocol of group A. In group B MR-356 also improved the survival rate (72 vs 39%, P < 0.05) only at 24 h, while other parameters failed to improve. The present results suggest that the PGE1 oligomer may play a beneficial role in bile-induced pancreatitis, probably through its proposed effects of stabilization of lysosomal membranes, maintenance of microcirculation and inhibition of protease in the pancreas.

Three cases of chronic alcoholic pancreatitis associated with aberrant pancreas are reported. All three patients underwent laparotomy, and an aberrant pancreas was found in the jejunum of each of the three patients. Microscopic examination of the aberrant pancreas did not show any changes suggestive of chronic pancreatitis, despite severe chronic pancreatitis in the main pancreas.

The diagnostic significance of serum immunoreactive pancreatic phospholipase A2 (PLA2) was studied in 119 patients with pancreatic disease, 200 with various non-pancreatic disease, and 203 healthy controls using radioimmunoassay (RIA) specific to human pancreatic PLA2. This newly developed RIA using monoclonal antibody was satisfactorily sensitive and reliable. Serum PLA2 was elevated in all six patients with acute pancreatitis. Frequency of abnormal serum PLA2 levels was 60% in chronic pancreatitis (n = 52) and 67% in pancreatic cancer (n = 61). Serum PLA2 levels were low in chronic pancreatitis with severe exocrine insufficiency and advanced pancreatic cancer. In chronic pancreatitis, patients with low serum PLA2 level showed lower enzyme output in secretin test than patients with normal or high serum PLA2 level. Frequency of abnormal PLA2 levels was 27% in non-pancreatic disease and, in particular, patients with renal failure showed high PLA2 levels. Sensitivity (62%) and efficiency (69%) of serum PLA2 assay in pancreatic disease were superior to those of amylase. In conclusion, serum PLA2 determination using RIA was useful for the diagnosis of acute pancreatitis by high serum PLA2 levels and the diagnosis of severe exocrine pancreatic insufficiency by low serum PLA2 levels.

To confirm that trypsin activity is a most important initiating factor in closed duodenal loop pancreatitis in rats, we observed the course of acute pancreatitis when trypsinogen activation was inhibited by intraduodenal infusion of a potent synthetic trypsin inhibitor (TI, nafamostat mesilate) but the other conditions were left unchanged. Intraduodenal and intrapancreatic trypsinogen activation was inhibited for 16 hr after the intraduodenal infusion of the inhibitor, although elevation of serum amylase and immunoreactive trypsin and pancreatic trypsinogen remained similar both in the TI and control groups. The mortality decreased from 44% (control) to 4% (TI) at 48 hr after establishing the model. Active trypsin in duodenal reflux is an initiating factor for further development of acute pancreatitis in the closed loop model, and inhibition of the initial activation of trypsinogen has a favorable effect on acute pancreatitis even if other deleterious factors remain unchanged.

To evaluate the influence of chronic alcoholism on clinical features of chronic pancreatitis in Japan, pain evolution, pancreatic insufficiency, and long-term prognosis were studied by comparing chronic alcoholic pancreatitis (N = 88) with idiopathic pancreatitis (N = 67). The 155 patients with known course of the disease over three years were followed-up further for five more years, and pain evolution was evaluated once at the start and once at the end of the follow-up period. At the time of diagnosis, severe pain (59 vs 33%, P less than 0.001), pancreatic calcification (63 vs 31%, P less than 0.001), advanced exocrine pancreatic insufficiency (72 vs 60%, NS), and overt diabetes (48 vs 17%, P less than 0.001) were more common in alcoholic than in idiopathic pancreatitis, respectively. Pain evolution was similar in both pancreatitis, and the pain decreased with time. The rate of abstinence was higher in groups with pain relief than without in alcoholic pancreatitis. Cumulative mortality rate during the five years was higher in alcoholic than idiopathic pancreatitis (26 vs 10%, P less than 0.01). These results suggest more favorable evolution of the disease can be expected by abstinence from alcohol.

Urinary and serum zinc levels were determined in 51 patients with chronic pancreatitis. Urinary zinc excretion in patients with chronic calcified pancreatitis (832 +/- 111 micrograms/day) (mean +/- SE) but not in noncalcified pancreatitis (684 +/- 65 micrograms/day) was significantly higher than in normal controls (418 +/- 46 micrograms/day). The urinary zinc excretion increased with deterioration of exocrine pancreatic function. Serum zinc levels in advanced pancreatitis (105.9 +/- 4.5 micrograms/100 ml) were significantly higher when compared to the pancreatitis with normal exocrine pancreatic function (91.6 +/- 3.0 micrograms/100 ml), but the difference was less pronounced than for urinary zinc excretion. This may be due to complicating diabetes, which usually lowers serum zinc. Serum zinc and urinary zinc excretion were low in a patient with chronic calcified pancreatitis complicated with a pulmonary abscess and hypoalbuminemia. In conclusion, urinary and serum zinc levels in chronic pancreatitis were increased as a result of exocrine pancreatic dysfunction. Association of diabetes may lower serum zinc, and associated malnutrition depresses both urinary and serum zinc levels.

Cases of pancreas divisum (PD) were reviewed in our patients and 19 Japanese and 14 English series during the past 10 yr to see any significant association of PD with certain diseases. PD was diagnosed in 20 (0.64%) among our 3121 patients with successful endoscopic pancreatograms (ERP). Of 20 PD patients, acute pancreatitis in one, chronic pancreatitis in two, ampullary cancer in one, and cholelithiasis in five were diagnosed. Incidences of PD were 2.6% (1/38) in acute pancreatitis, 0.8% (2/248) in chronic pancreatitis, 0% (0/100) in pancreatic cancer, 20% (1/5) in ampullary cancer, and 0.8% (5/615) in cholelithiasis. The incidences were similar to overall incidences of ours and other Japanese series (0.69% of 36,171 patients). Higher incidences of acute pancreatitis (12.9% of 559) and pancreatic cancer (5.5% in 448) may result from the higher overall incidence (4.6% in 16,257) in English series. The relationship between pancreatitis and PD has been controversial, but our present data suggest that PD is a coincidental finding and not a predisposing factor to pancreatitis in Japan.