Different markers of alcohol consumption, smoking and body mass index in relation to risk of pancreatic cancer. A prospective cohort study within the Malmö Preventive Project.

BACKGROUND/AIM: The association between alcohol consumption and pancreatic cancer is not clear. This study investigates different prediagnostic measurements of alcohol consumption, a laboratory marker (gamma-glutamyltransferase; gamma-GT), and a score measuring alcohol addiction (Mm-MAST), in relation to the risk of pancreatic cancer. Furthermore, the study investigated whether smoking and alcohol consumption interact with each other, or if the risk of pancreatic cancer associated with these factors is modified by obesity or weight gain. METHODS: A cohort of 33,346 subjects provided prediagnostic information on the above factors. During a mean follow-up of 22.1 years, 183 cases of pancreatic cancer occurred. Cox's analysis yielded relative risks (RR) with 95% confidence intervals (CI). RESULTS: The highest gamma-GT quartile was associated with a high risk of pancreatic cancer (RR = 2.15, 95% CI = 1.34-3.44), and this association was even stronger in subjects that reported a previous weight gain (RR = 3.61, 95% CI = 1.29-10.09). A high Mm-MAST score was also associated with pancreatic cancer (p = 0.02). Current smoking was associated with pancreatic cancer (RR = 2.34, 95% CI = 1.60-3.43), and obese smokers had an even higher risk (RR = 7.45, 95% CI = 1.65-33.64). CONCLUSION: High alcohol intake is associated with subsequent risk of pancreatic cancer and this risk may be higher following weight gain. The risk associated with smoking may be even higher in obese subjects.

Activated protein C-protein C inhibitor complex, activation peptide of carboxypeptidase B and C-reactive protein as predictors of severe acute pancreatitis.

INTRODUCTION: The concentration of carboxypeptidase B activation peptide (CAPAP) is proposed to be a predictor of severe acute pancreatitis. The activated protein C (APC)-protein C inhibitor (PCI; APC-PCI) complex in plasma could be useful in detecting the hypercoagulative condition in severe acute pancreatitis. METHOD: In this prospective study, mild (n = 50) and severe (n = 9) cases of acute pancreatitis were compared with respect to levels of CAPAP and APC-PCI, and sorted in time intervals from onset of symptoms to sampling. The peak values of the C-reactive protein (CRP) within the 1st week were also compared. RESULTS: CRP detected the severe cases with a sensitivity of 0.89 and a specificity of 0.74 (cut-off level 200 mg/l). In the interval 0-72 h, CAPAP could predict the severity of the disease in serum and urine (sensitivity 0.52/0.29, specificity 0.73/0.93, cut-off 2 nM/60 nM). The level of APC-PCI in plasma could predict the severe condition in the interval 0-24 h after the onset of symptoms (sensitivity 0.6, specificity 0.66, cut-off level 0.54 microg/l). CONCLUSION: Of the parameters explored, CRP is still the best biochemical marker to distinguish between severe and mild acute pancreatitis. CAPAP could be useful in combination with other tests, but the APC-PCI complex's diagnostic time interval is too short to be used in the clinical routine.

A prospective study of Helicobacter pylori in relation to the risk for pancreatic cancer.

BACKGROUND: The relationship between Helicobacter pylori infection and pancreatic cancer has been investigated in three previous studies with contradictory results. The aim of the present study was to investigate the association between H. pylori seropositivity and the risk for pancreatic cancer in a nested case-control study within a population based cohort. METHODS: Selected birth-year cohorts (born 1921-1949) of residents in Malmö, Sweden, were invited to a health screening investigation. A total of 33 346 subjects participated. Cases with pancreatic cancer (n = 87) were matched to controls (n = 263) using age, sex and time for baseline investigation as matching variables. H. pylori serology was analysed in stored serum samples using an enzyme-linked immunosorbent assay. Odds ratios (OR) for pancreatic cancer were calculated with 95% confidence intervals (CI) using logistic regression. RESULTS: H. pylori seropositivity was not associated with pancreatic cancer in the total cohort (adjusted OR 1.25 (0.75-2.09)). However, a statistically significant association was found in never smokers (OR 3.81 (1.06-13.63) adjusted for alcohol consumption) and a borderline statistically significant association was found in subjects with low alcohol consumption (OR 2.13 (0.97-4.69) adjusted for smoking). CONCLUSION: We conclude that no association between H. pylori infection and the risk for pancreatic cancer was found in the total cohort. However, in never smokers and in subjects with low risk alcohol consumption, a positive H. pylori serology was associated with an increased risk for pancreatic cancer. These findings should be interpreted cautiously due to the limited number of cases in these subgroups.

Long-term nicotine exposure causes increased concentrations of trypsinogens and amylase in pancreatic extracts in the rat.

UNLABELLED: To develop radioimmunoassays (RIAs) for rat trypsinogens 1 and 2 and to investigate the effect of nicotine exposure on concentration and production of pancreatic zymogens in the rat. METHODS: Male Sprague-Dawley rats were supplied with either normal or nicotine-containing (0.77 mM) water for 28 days and were then killed. Rabbit antibodies for the activation peptides of trypsinogens 1 and 2 were obtained for use in the RIAs. Concentrations of the both trypsinogens in pancreatic extracts were measured by the RIAs after activation by enterokinase. DNA and amylase were measured using commercial kits. mRNA for trypsinogens 1 and 2, procolipase, and cholecystokinin receptor was measured by in situ hybridization. RESULTS: The specificity of the RIA for the trypsinogen 1 activation peptide was satisfactory. The RIA for the trypsinogen 2 activation peptide showed a limited cross-reaction toward the synthetic trypsinogen 1 activation peptide, but the importance of this cross-reaction was moderate when investigated in samples of activated trypsinogens. Weight gain was reduced in nicotine-treated animals. Concentrations of amylase, trypsinogen 1, trypsinogen 2, and the ratio of trypsinogen 2 to 1 were all increased in pancreatic extracts of nicotine-fed animals. Total DNA and mRNA for the trypsinogens, procolipase, and cholecystokinin receptor were not affected by nicotine exposure. CONCLUSIONS: The combination of increased proenzyme concentrations and unaffected mRNA levels suggests that nicotine impairs secretion rather than production of pancreatic zymogens.

A prospective cohort study of smoking in acute pancreatitis.

BACKGROUND/AIMS: Little is known about risk factors for acute pancreatitis other than gallstones and alcohol consumption. The aim of this study was to investigate if smoking or body mass index (BMI) are associated with acute pancreatitis and to determine relative risks (RR) for acute pancreatitis related to smoking, BMI, and alcohol consumption. METHODS: From 1974 to 1992, selected birth-year cohorts of residents in Malmo, Sweden (born 1921-1949) were invited to a health-screening investigation including physical examination, blood sampling and a questionnaire. In total, 33,346 individuals participated. Cases of acute pancreatitis were identified from diagnosis registries (n = 179). Incidence rates were calculated in different risk factor categories. A Cox's analysis revealed RR. RESULTS: Current versus never smoking at baseline was associated with acute pancreatitis (RR 2.14, 95% confidence interval (CI) 1.48-3.09) after adjustment for age, sex, BMI and alcohol consumption. This association was stronger in heavy smokers (20-30 cigarettes/day) (RR 3.19, 95% CI 2.03-5.00). Smoking was associated with a RR of 3.57 (95% CI 0.98-13.0) for acute pancreatitis in subjects who reported no alcohol consumption. An increased risk for acute pancreatitis was also found for high versus low risk, self-reported alcohol consumption (RR 2.55, 95% CI 1.59-4.08) and for gamma-GT levels in the highest versus the lowest quartile (RR 2.14, 95% CI 1.32-3.49). There was also a weak correlation between BMI and acute pancreatitis. CONCLUSIONS: Smoking is associated with the incidence of acute pancreatitis in a dose-response manner. and IAP.

Corticosteroid-binding globulin: a possible early predictor of infection in acute necrotizing pancreatitis.

OBJECTIVE: Infected pancreatic necrosis is the main cause of death in patients with acute pancreatitis, and therefore its early prediction is of utmost importance. Endogenous cortisol metabolism plays a basic role both in the course of acute pancreatitis and in the process of infection. The purpose of this study was to analyze corticosteroid-binding globulin (CBG), total cortisol, calculated free cortisol and adrenocorticotropic hormone as potential early predictors in order to differentiate between infected pancreatic necrosis and sterile pancreatic necrosis in patients with acute pancreatitis. MATERIAL AND METHODS: Serum levels of CBG, total cortisol, calculated free cortisol, and plasma levels of adrenocorticotropic hormone were determined in 109 consecutive patients with acute pancreatitis. C-reactive protein was measured as the control parameter. Thirty-five patients developed necrotizing pancreatitis and 10 developed infection of the necrosis. Blood was monitored for 6 days after the onset of pain; 30 healthy individuals served as controls. RESULTS: Of all parameters only CBG showed a significant difference (p = 0.0318) in its peak levels measured in the first 48 h in patients with sterile (26.5 microg/ml, range 21.3-34.7) and infected (16.0 microg/ml, range 15.2-25.0) necrosis at a cut-off level of 16.8 microg/ml. That difference was further preserved for the first 6 days after onset of pain. CONCLUSIONS: In our group of patients, a decreased CBG level below 16.8 g/ml within the initial 48 h of acute pancreatitis was an early predictor of later infected pancreatic necrosis, with a positive predictive value of 100% and a negative predictive value of 87.5%.

Characterization of immunoreactive trypsinogen activation peptide in urine in acute pancreatitis.

CONTEXT: All work on human trypsinogen activation peptide (TAP) in acute pancreatitis has been carried out with the same assay. Despite the extensive use of this original TAP assay, there is no characterization of the TAP-like immunoreactivity measured. OBJECTIVE: The aims of this study were to develop an additional TAP assay and to attempt to characterize the TAP-like immunoreactivity found in the urine of patients with acute pancreatitis. METHODS: Antibodies against the human TAP were prepared using the whole octapeptide APFD4K, conjugated at its N-terminal end. Characterization of the immunoreactivity measured with these assays was performed using gel filtration of human pancreatic juice before and after activation of trypsinogen with enterokinase. RESULTS: After activation of the pancreatic juice, there was a large initial increase in immunoreactive TAP and a decrease 6-24 hours later. Using our antiserum, we found low levels of immunoreactive TAP in urine from patients with acute pancreatitis, although many of these samples contained high levels of immunoreactive TAP when tested with the commercially available TAP kit (Biotrin). The pentapeptide D4K, used as a standard in the Biotrin kit, showed much lower immunoreactivity than the synthetic octapeptide APFD4K in our assay. The octapeptide, however, reacted similarly to D4K in the Biotrin kit assay. CONCLUSION: n Our antibody prepared against the synthetic octapeptide APFD4K is directed against the N-terminal part of the octapeptide and does not recognize the pentapeptide D4K. Immunoreactive TAP in urine in acute pancreatitis is mainly composed of the C-terminal pentapeptide, D4K.

Cathepsin B activates human trypsinogen 1 but not proelastase 2 or procarboxypeptidase B.

BACKGROUND/AIMS: Activation of trypsinogen to trypsin is a crucial step in the development of acute pancreatitis. The cause of this activation is not known although suggested explanations include autoactivation, cathepsin B-mediated activation and activation by mast cell tryptase. The aim of this study was to investigate cathepsin B and tryptase activation of pancreatic zymogens. METHODS: Trypsinogen-1, proelastase, and procarboxypeptidase B were purified from human pancreatic juice. Human cathepsin B and betaI-tryptase are commercial products. Activation and degradation of zymogens were measured by activity towards specific substrates for trypsin and pancreatic elastase, ELISAs for procarboxypeptidase B and its activation peptide, and a radioimmunoassay for the trypsinogen activation peptide. RESULTS: Cathepsin B caused activation of trypsinogen-1 with a trypsin yield of about 30% of that produced by enterokinase. Proelastase and procarboxypeptidase B was not activated by cathepsin B. None of the zymogens were inactivated by cathepsin B. Neither monomeric nor tetrameric tryptase could activate any of the examined zymogens. CONCLUSION: Cathepsin B is a competent activator of trypsinogen-1, although not as efficient as enterokinase. If cathepsin B is to play a role in protease activation in acute pancreatitis, this most probably occurs by activation of trypsinogen.

Role of endogenous glucocorticoid metabolism in human acute pancreatitis.

OBJECTIVE: This study aimed to observe how levels of total cortisol, calculated free cortisol, corticosteroid-binding globulin, and adrenocorticotropic hormone change during the early course of human acute pancreatitis and to describe how these changes affect the development of pancreatic necrosis. DESIGN AND PATIENTS: In a total of 109 consecutive patients with acute pancreatitis (74 with edematous pancreatitis, 35 with necrotizing pancreatitis), serial daily blood monitoring of total and free cortisol, adrenocorticotropic hormone, and corticosteroid-binding globulin was done after hospital admission, up to day 6 after the onset of pain; 30 healthy individuals served as controls. MEASUREMENTS: Corticosteroid-binding globulin and total cortisol were measured by immunoassays, and free cortisol was calculated according to Coolens et al. The adrenocorticotropic hormone was measured with an enzyme-linked immunoassay. RESULTS: Initially, highly elevated levels of calculated free cortisol (median, 86.2 ng/mL; quartile ranges, 50.6-106.7 ng/mL) and total cortisol (41.2 microg/dL, 30.4-51.1 microg/dL) and depressed levels of adrenocorticotropic hormone (0.2 pg/mL, 0.1-2.0 pg/mL) and corticosteroid-binding globulin (30.6 microg/mL, 24.1-35.5 microg/mL) were observed. Further, daily measurements revealed increasing adrenocorticotropic hormone levels, whereas cortisol levels decreased. CONCLUSIONS: Although an increase in adrenocorticotropic hormone levels is suggested to increase corresponding cortisol levels, cortisol levels decreased during the development of necrotizing acute pancreatitis. This phenomenon, along with the continuously decreasing corticosteroid-binding globulin levels, brings up the hypothesis of a relative adrenal insufficiency, which favors acinar cell apoptosis and hence may trigger the development of necrosis in the initial vulnerable phase of acute pancreatitis.

Active carboxypeptidase B is present in free form in serum from patients with acute pancreatitis.

BACKGROUND: Active carboxypeptidase B (aCAP) is the main product of activation of procarboxypeptidase. The other product derived from procarboxypeptidase B (proCAP), the activation peptide carboxypeptidase B (CAPAP), has been shown to be a marker for severity in acute pancreatitis. There have been relatively few studies dealing with the role of this enzyme in acute pancreatitis. METHODS: A double-antibody ELISA for immunoreactive aCAP (ir-aCAP) was developed, and ir-aCAP was determined in the serum of patients with acute pancreatitis and characterized using gel filtration. RESULTS: Serum from healthy individuals contained minimal levels of ir-aCAP, while serum from 25 patients with acute pancreatitis contained between 0.6 and 158 nmol/l. Gel filtration of serum samples from patients with acute pancreatitis showed the presence of two peaks of ir-aCAP, one corresponding to the molecular size of the free active enzyme and one corresponding to cross-reactive proCAP. When pure aCAP was mixed with serum in vitro, all ir-aCAP was recovered as one peak of free enzyme. No immunoreactivity disappeared or changed in molecular size, as might be expected if the active enzyme was bound to an inhibitor. CONCLUSION: aCAP is present in free form in the circulation of patients with acute pancreatitis.

Trends in incidence of acute pancreatitis in a Swedish population: is there really an increase?

BACKGROUND AND AIMS: Recent reports have suggested an increasing incidence of acute pancreatitis, and changing patterns of risk factors, over the past decades. The aim of this study was to investigate trends in the incidence of acute pancreatitis, and risk factors related to the disease, in a general population over a 15-year period. METHODS: Clinical, autopsy, and forensic records for all patients with a first attack of acute pancreatitis in Malmö, Sweden, from 1985 to 1999, were validated retrospectively. Evidence for diagnosis was reconsidered and plausible cause was assessed. The incidence of gallstone disease, lung cancer, and alcohol-related conditions in the background population were retrieved from hospital diagnosis records and cancer and cause-of-death registries. RESULTS: A total of 929 first attacks of acute pancreatitis were identified. The total incidence of acute pancreatitis increased by 3.9% per year (95% confidence interval [CI], 2.1-5.8). The incidence of gallstone-related pancreatitis increased by 7.6% per year (95% CI, 4.0-11.4), and this correlated with an increase in the incidence of other gallstone-related conditions ( r = 0.68; P = 0.005). Alcohol-related pancreatitis decreased by -5.1% per year (95% CI, -7.4 to -2.8), and this correlated with a decrease in the incidence of delirium tremens ( r = 0.75; P = 0.001), mortality from cirrhosis ( r = 0.81; P < 0.001), and incidence of lung cancer ( r = 0.57; P = 0.026). CONCLUSIONS: There was a statistically significant increase in the incidence of acute pancreatitis. Gallstone-related pancreatitis increased, and alcohol-related pancreatitis decreased. Both of these trends were statistically significant and correlated with trends in the incidence of other conditions associated with either gallstone disease or alcohol abuse.

[Guidelines for management of patients with chronic pancreatitis. Report from a consensus conference]. / Riktlinjer för handläggning av patienter med kronisk pankreatit. Rapport från ett konsensusmöte.

Chronic pancreatitis has an incidence of 3-8 new cases per 100,000 inhabitants and year. Alcohol is the most common cause. It is, however, not an independent risk factor but rather a co-factor. Smoking and genetic predisposition are increasingly regarded as causative factors. The diagnosis is today based mainly on history and findings at imaging tests. Pain treatment starts with NSAID-medication with or without paracetamol. Oral pancreatic enzyme therapy for pain should be tested early in the course. Endoscopic stent insertion into the main pancreatic duct can be used in selected cases. Operation is not recommended until other less invasive methods have been tested but should ideally be performed before addiction to opiates occurs. Oral enzyme supplementation is effective in the majority of cases with malnutrition. Most patients with chronic pancreatitis and diabetes need insulin treatment. Interdisciplinary specialist treatment teams should be established and take responsibility for diagnosis, assessment and interventional procedures (e.g. endoscopy, surgery). Due to the low incidence of the disease 3-4 such teams/centres seem appropriate in our country to allow a critical patient load.

A study on the activation peptide released from procarboxypeptidase B (CAPAP) and anionic trypsinogen in patients with acute abdominal disorders of non-pancreatic origin.

BACKGROUND: The activation peptide released from procarboxypeptidase B, CAPAP, is a marker of the activation of pancreatic enzymes in acute pancreatitis while anionic trypsinogen (AT) levels in urine relate to leakage of unactivated proenzymes. Data on these markers in patients suffering from severe acute abdominal disorders of non-pancreatic origin are lacking. PURPOSE: To examine levels of CAPAP and AT in serum and urine from patients with severe acute abdominal disorders of non-pancreatic origin in order to better define the diagnostic specificity of these two markers in severe acute pancreatitis in relation to other acute intra-abdominal disorders. SUBJECTS AND METHODS: The study included 54 patients with severe acute abdominal disorders of non-pancreatic origin with an APACHE II score >3. Immunoreactive CAPAP (irCAPAP) and immunoreactive AT (irAT) were measured in serum and urine using specific immunoassays. RESULTS: In urine, irCAPAP levels were mildly increased (>2 nmol/l) in 13% of the patients with severe acute abdominal diseases of non-pancreatic origin, but on no occasion did the increase approach the cutoff levels described for severe acute pancreatitis (>100 nmol/l). However, irAT levels in serum and urine were increased (>50 micro g/l) in 54% of the cases. CONCLUSION: Contrary to what is found for irAT, patients with acute abdominal pain of non-pancreatic origin rarely have markedly increased levels of irCAPAP in serum and urine.

Early prediction of severity in acute pancreatitis. Is this possible?

One out of ten cases of acute pancreatitis develops into severe acute pancreatitis which is a life threatening disorder with a high mortality rate. The other nine cases are self limiting and need very little therapy. The specificity of good clinical judgement on admission, concerning the prognosis of the attack, is high (high specificity) but misses a lot of severe cases (low sensitivity). The prediction of severity in acute pancreatitis was first suggested by John HC Ranson in 1974. Much effort has been put into finding a simple scoring system or a good biochemical marker for selecting the severe cases of acute pancreatitis immediately on admission. Today C-reactive protein is the method of choice although this marker is not valid until 48-72 hours after the onset of pain. Inflammatory mediators upstream from CRP like interleukin-6 and other cytokines are likely to react faster and preliminary results for some of these mediators look promising. Another successful approach has been to study markers for the activation of trypsinogen such as TAP and CAPAP. This is based on studies showing that active trypsin is the initial motor of the inflammatory process in acute pancreatitis. In the near future a combined clinical and laboratory approach for early severity prediction will be the most reliable. Clinical judgement predicts 1/3 of the severe cases on admission and early markers for either inflammation or trypsinogen activation should accurately identify 50-60% of the mild cases among the rest, thus missing only 2-4% of the remaining severe cases. One problem is that there is no simple and fast method to analyze any of these parameters.

[Guidelines for management of patients with pancreatic cancer]. / Riktlinjer för handläggning av patienter med pankreascancer.

The incidence of pancreatic cancer has fallen during the last ten years in Sweden. Early signs and symptoms of the disease are still undiscovered and when diagnosis is made the disease is incurable in most patients. Transabdominal ultrasonography is the first-line imaging test followed by spiral computed tomography (CT) and magnetic resonance imaging (MRI) if required for definite diagnosis. Spiral CT is also the imaging test of choice for assessment of resectability of the tumor. Surgical removal of the tumor is the only chance of cure. Markedly improved hospital mortality after pancreaticoduodenectomy is reported and an association between hospital volume and outcome of the operation has been established. Longterm survival after attempted curative resection continues to be dismal, however. Adjuvant treatment should not be given outside clinical studies. Palliative treatment has improved thanks to progress in the field of endoscopy, interventional radiology and in management of pain and nutrition. Palliative chemotherapy should only be given selectively outside clinical studies. Radiotherapy has no proven effects on survival. Special pancreatic cancer treatment teams with catchment areas of 2-4 million inhabitants are recommended by international authorities.

Acute pancreatitis in Soweto, South Africa: relationship between trypsinogen load, trypsinogen activation, and fibrinolysis.

OBJECTIVE: It is not known why acute pancreatitis in Soweto, South Africa, pursues an aggressive course. We sought clues from circulating trypsinogen load at admission as marker of initial acinar injury, trypsinogen activation using the carboxypeptidase B activation peptide as surrogate, proteinase inhibitors, the coagulation-fibrinolysis axis, indicators of inflammation, oxidative stress markers, and antioxidant status. This article reports on the first four aspects. METHODS: The study involved 24 consecutive patients with a first attack. All of them were admitted within 24 h, and 22 were alcoholic. Urine was analyzed for anionic trypsinogen and the carboxypeptidase B activation peptide. Serum was tested for anionic and cationic trypsinogen, alpha1 proteinase inhibitor and alpha2 macroglobulin. Plasma from a subset was assayed for soluble fibrin, cross-linked fibrin degradation products (surrogates for thrombin and plasmin activity, respectively), and tissue-type plasminogen activator and inhibitor. RESULTS: Soweto controls had higher serum anionic trypsinogen (p = 0.004) and plasminogen activator:inhibitor ratio (p = 0.047) than U.K. controls. The outcome of acute pancreatitis was mild in 17 but severe in seven with three deaths, two on day 2. In mild pancreatitis, intense plasmin activity (p < 0.001) accompanied the surge in trypsinogen, especially anionic (p < 0.001), but without increased thrombin activity and in five patients without trypsinogen activation. In severe pancreatitis, further significant increments in plasmin activity and trypsinogens were accompanied by increased thrombin activity (p = 0.013) and trypsinogen activation (p = 0.046). There was no correlation between surrogates of plasmin and thrombin activity, or between either and the carboxypeptidase B activation peptide, which showed a curvilinear relationship to total serum trypsinogen. CONCLUSIONS: The aggressive nature of alcoholic acute pancreatitis in Soweto seems to reflect early profound fibrinolysis, which precedes coagulation and is initially independent of trypsin. Subclinical acinar-cell injury and a profibrinolytic diathesis in outwardly healthy Sowetans may predispose to this problem.

Enzyme leakage, trypsinogen activation, and inflammatory response in endoscopic retrograde cholangiopancreatography-induced pancreatitis.

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis (EIP) provides an opportunity to study different pathophysiologic events early in the course of acute pancreatitis. AIMS: To investigate whether the leakage of pancreatic proenzymes (anionic trypsinogen), pancreatic protease activation (carboxypeptidase B activation peptide), cytokine response (interleukin [IL]-1 receptor antagonist, IL-6, and soluble tumor necrosis factor receptor-I) and neutrophil activation (neutrophil gelatinase-associated lipocalin and polymorphonuclear elastase) differ between patients with and without EIP. A second aim was to clarify the temporal relation between these different events. METHODOLOGY: Ninety-nine nonconsecutive patients undergoing ERCP were investigated in the study. RESULTS: Fourteen of 99 patients undergoing ERCP developed mild EIP. Six hours after the investigation the concentration of anionic trypsinogen was significantly higher in patients with EIP than in patients without EIP. The day after ERCP, higher concentrations of anionic trypsinogen, carboxypeptidase B activation peptide, IL-6, and polymorphonuclear elastase were recorded in the EIP group. No significant differences in IL-1 receptor antagonist, soluble tumor necrosis factor receptor-I or neutrophil gelatinase-associated lipocalin were found between the groups in this study. CONCLUSION: Mild EIP was accompanied by early leakage of proenzymes and later activation of trypsinogen/proteases. A significant cytokine response and neutrophil activation were recorded the day after ERCP, but further studies are needed to determine the temporal relation between these different pathophysiologic events.