Effect of microcirculatory perfusion on distribution of trypsinogen activation peptides in acute experimental pancreatitis

Extraintestinal trypsinogen activation peptides (TAP) have been shown to correlate with severity of acute pancreatitis in humans as well as in various animal models. Ischemia superimposed on experimental pancreatitis, however, increases acinar cell injury without increasing TAP in plasma. We speculated that TAP generated in the pancreas might not reach the circulation in necrotizing pancreatitis due to decreased pancreatic perfusion. To test the hypothesis that generation of TAP in plasma is related to pancreatic perfusion and that plasma TAP may therefore underestimate acinar cell injury in necrotizing disease, we correlated TAP in pancreatic tissue and body fluids with capillary pancreatic blood flow in necrotizing and edematous pancreatitis. The ratio between necrosis and TAP in tissue was similar in both models; the ratio between TAP in plasma and tissue, however, was significantly lower in necrotizing pancreatitis, indicating that a certain amount of TAP generated in the pancreas did not reach the circulation. Decreased pancreatic perfusion found in necrotizing pancreatitis was consistent with this finding. Our data suggest that TAP in tissue is most reliable to indicate severity of acute pancreatitis, whereas plasma TAP may underestimate pancreatic injury in necrotizing disease due to decreased pancreatic perfusion.     

Local and systemic zymogen activation in human acute pancreatitis

BACKGROUND: Activation of trypsinogen and phospholipase A(2) is an early event in pancreatic inflammation, but little is known about zymogen activation and the severity of human pancreatitis. METHODS: Using a new fluoroimmunoassay we measured trypsinogen activation peptide (TAP) and phospholipase A(2) activation peptide (PROP) in plasma and ascites in 25 patients with acute pancreatitis. TAP, PROP, Pro-PROP and pancreatic PLA(2)-I were measured in plasma for 14 days and in pancreatic necroses, ascitic fluid and pleural effusions. RESULTS: All 16 patients with severe acute pancreatitis (SAP) had pancreatic necrosis, 10 developed systemic complications like sepsis, pulmonary or renal failure, 6 had infected necrosis, and 4 died. All 9 patients with mild pancreatitis (MAP) survived. Plasma TAP on admission was higher in patients with SAP than in those with MAP and increased in infected necroses. It did not correlate with systemic complications. Systemic PROP was not increased in complicated courses but was significantly higher in patients with MAP than in those with SAP on admission. Pro-PROP was higher in patients with SAP than in those with MAP but was not correlated with systemic complications. Plasma pancreatic PLA(2)-I was increased but not different in patients with SAP and those with MAP. In patients with pancreatic necrosis, TAP and PROP were highest, while in those with post-acute pancreatic abscess, only PROP and Pro-PROP were high. In patients with pleural effusion, TAP was low and PROP/ Pro-PROP were high. CONCLUSION: Trypsinogen and PLA(2)-I activation are early events in acute pancreatitis and the activation peptides can be detected in plasma. In the pancreas, trypsinogen activation is accompanied by PLA(2)-I activation in patients with pancreatic necrosis. However, in our study, organ complications in SAP patients was not associated with increased plasma PROP.     

Interstitial trypsinogen release and its relevance to the transformation of mild into necrotizing pancreatitis in rats.

BACKGROUND & AIMS: Intracellular activation of trypsinogen is currently believed to initiate pancreatitis. Factors responsible for the progression of mild to necrotizing pancreatitis are poorly understood. This study evaluated the significance of interstitial protease release and activation in this process. METHODS: In rats with cerulein-induced pancreatitis, concentrations of trypsinogen and its activation peptide TAP were measured in lymph and blood, and pancreatic injury was determined. Activation of extracellular trypsinogen was induced by intravenous infusion of enterokinase, which does not enter the acinar cell. Gabexate mesilate (acinar cell permeable) or soybean trypsin inhibitor (acinar cell nonpermeable) was administered to distinguish the effects of intracellular or extracellular protease activation. RESULTS: In cerulein pancreatitis, trypsinogen levels increased prominently and were highest in lymph and portal vein blood, whereas TAP increments were modest. Combined cerulein/enterokinase infusions resulted in marked TAP increases in lymph and blood and in severe necrohemorrhagic pancreatitis. Gabexate mesilate as well as soybean trypsin inhibitor significantly decreased TAP levels in both lymph and blood and reduced pancreatic injury, with no significant differences between groups. CONCLUSIONS: In secretagogue-induced pancreatitis, large amounts of trypsinogen are present in the interstitium and drain via the portal and lymphatic circulation. Activation of this extracellular trypsinogen induces hemorrhagic necrosis in a setting of mild edematous pancreatitis. This phenomenon may be the central event in the progression to fulminant necrotizing pancreatitis.     

The effects of somatostatin on the microperfusion of the pancreas during acute necrotizing pancreatitis in rats

BACKGROUND/AIMS: Autodigestion and impairment of microcirculation of the pancreas play an important role in the pathogenesis of acute pancreatitis. Somatostatin with the reducing effect on the hepato-splanchnic blood flow decreases exocrine pancreatic secretion. Microcirculatory changes are central to the pathogenesis of acute pancreatitis. However, little is known about the effects of somatostatin on the pancreatic tissue oxygen pressure and acinar cell injury during acute pancreatitis. The aim was to evaluate somatostatin by measuring its effect on the pancreatic tissue oxygen pressure and acinar injury in acute pancreatitis. METHODOLOGY: Acute necrotizing pancreatitis was induced in rats by standardized intraductal bile acid infusion and cerulein hyperstimulation. Serum trypsinogen activation peptide was measured to verify comparable disease severity. After the induction of acute necrotizing pancreatitis, animals randomly received either ringer lactate or somatostatin. Monitoring included cardiorespiratory parameters, hematocrit, amylase, pancreatic tissue oxygen pressure, and trypsinogen activation peptide levels. At the end of the experiments the pancreas was removed for evaluation of acinar cell injury. RESULTS: The two study groups were comparable with regard to mean arterial pressure, heart rate, arterial blood gases, hematocrit, and serum amylase. The induction of pancreatitis resulted in the significant decrease of pancreatic tissue oxygen pressure in both groups. The use of somatostatin did not increase pancreatic tissue oxygen pressure. There were no significant differences in plasma trypsinogen activation peptide and serum amylase levels in the animals of two treatment groups. Only somatostatin decreased pancreatic damage significantly. CONCLUSIONS: The use of somatostatin did not improve pancreatic microcirculation or trypsinogen activation peptide level in acute necrotizing pancreatitis; however, it reduced pancreatic damage. Therefore, it has a limited value in the treatment of the acute pancreatitis.     

Mechanisms of intracellular zymogen activation.

The pancreatic acinar cell is potentially the initial site of injury that begins the series of events leading to acute pancreatitis. Pathological intrapancreatic zymogen activation occurs in experimental pancreatitis in animals and in human pancreatitis. Intracellular activation has been clearly linked to aberrant zymogen processing in one form of hereditary pancreatitis; in this genetic disease a mutation in cationic trypsinogen may eliminate the degradation of any trypsin activated in the acinar cell. Recent studies have also provided the first direct evidence that trypsinogen activation takes place early in the course of caerulein-induced pancreatitis; parallel studies have used isolated pancreatic acini and conditions that simulate those that cause pancreatitis in vivo to demonstrate that zymogens can be pathologically activated in isolated cells. A unique acinar cell pathway regulates the intracellular proteinase processing of zymogens to their active forms. Stimulating the acinar cell with supramaximal concentrations of cholecystokinin (CCK) or carbamylcholine can activate this pathway. The activation depends on a low pH compartment within the acinar cell and activation of an intracellular serine protease. A marker of trypsinogen processing, the trypsinogen activation peptide (TAP), is generated in acinar cell compartments that do not overlap with secretory granules. This compartment overlaps with a marker of recycling endosomes and lysosomes. Thus, zymogen processing within the acinar cell proceeds in a distinct subcellular compartment and is dependent on a low pH environment and activation of serine proteases.     

The Penetration of Ciprofloxacin into Human Pancreatic and Peripancreatic Necroses in Acute Necrotizing Pancreatitis

Background: Antibiotic prophylaxis in necrotizing pancreatitis has recently gained acceptance. Published studies, however, used different antibiotic regimes and some antibiotics penetrated pancreatic tissue or pancreatic necroses only poorly. The aim of this study was to assess the penetration of ciprofloxacin (CIP) into necrotic pancreatic and peripancreatic tissue. Patients and Methods: Serum, pancreatic necroses, peripancreatic fat tissue necroses and infected omental fluid levels of CIP were measured after 51 operations in 14 patients. Results: The median penetration ratio of CIP was 137.5% (range 11–196%) in infected omental bursa fluid, 59.6% (3–214%) in pancreatic necroses and 67.1% (1–250%) in peripancreatic necroses. Chemotherapeutical ratios of CIP as a marker for antimicrobial potency were high against most relevant pathogens in necrotizing pancreatitis. Conclusion: Due to its antimicrobial spectrum and the good penetration into the relevant compartments, CIP may be useful in preventing local infection in necrotizing pancreatitis. Received: August 28, 2000 · Revision accepted: August 28, 2001     

The effects of prostaglandin E1 on the microperfusion of the pancreas during acute necrotizing pancreatitis in rats

BACKGROUND/AIMS: In this study we investigated the effects of prostaglandin E1 on the microperfusion of the pancreas during acute necrotizing pancreatitis in rats. METHODOLOGY: Acute necrotizing pancreatitis was induced in rats by standardized intraductal bile acid infusion and cerulein hyperstimulation. Serum trypsinogen activation peptides were measured to verify comparable disease severity. After the induction of acute pancreatitis, animals randomly received either ringer lactate or prostaglandin E1. Monitoring included cardiorespiratory parameters, hematocrit, pancreatic oxygen tissue oxygen pressure, serum amylase and trypsinogen activation peptides. At the end of experiments pancreas was removed for evaluation of acinar cell injury. RESULTS: The two study groups were comparable with regard to mean arterial pressure, heart rate, arterial blood gases, hematocrit, and serum amylase. The induction of pancreatitis resulted in the significant decrease of pancreatic tissue oxygen pressure. In both groups the use of prostaglandin E1 did not change pancreatic tissue oxygen pressure despite of stable cardiorespiratory parameters, and serum amylase activity. Prostaglandin E1 decreased pancreatic damage and serum trypsinogen activation peptide level significantly. CONCLUSIONS: These results suggest that prostaglandin E1 had no effects on the improvement of microcirculation of pancreas, and had beneficial effects on the course of acute necrotizing pancreatitis.     

Do plasma and urine trypsinogen activation peptides (TAP) really increase in trypsin-taurocholate-induced pancreatitis?

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.     

On the protective mechanisms of nitric oxide in acute pancreatitis

Background—Ectopic proteaseactivation, microcirculatory changes, and leucocyte activation are themain events in the pathogenesis of acute pancreatitis. Nitric oxide(NO) is known to be a key mediator in the normal and inflamed pancreas.
Aims—To investigate the targets onwhich NO exerts its effect in caerulein induced pancreatitis.
Methods—Acute pancreatitis wasinduced in rats which additionally received either the NO synthasesubstrate, L-arginine; the NO donor, sodium nitroprusside;or the NO synthase inhibitor, N-nitro-L-arginine methylester (L-NAME). At six hours, pancreatic injury (oedema,leucocyte content, ectopic trypsinogen activation) was analysed andpancreatic oxygenation and perfusion were determined. A directinfluence of NO on amylase secretion and trypsinogen activation wasevaluated separately in vitro.
Results—Both NO donors reduced thegrade of inflammation. L-NAME increased the severity ofinflammation, while decreasing pancreatic tissue oxygenation. Althoughneither amylase secretion nor intracellular trypsinogen activation incaerulein stimulated pancreatic acini was influenced by either NOdonors or inhibitors, both NO donors decreased intrapancreatictrypsinogen activation peptide (TAP) and pancreatic oedema in vivo, andL-NAME increased TAP.
Conclusions—NO protects againstinjury caused by pancreatitis in the intact animal but has nodiscernible effect on isolated acini. It is likely that in pancreatitisNO acts indirectly via microcirculatory changes, including inhibitionof leucocyte activation and preservation of capillary perfusion.

Keywords:acute pancreatitis; nitric oxide; microcirculation; leucocytes; pancreatic secretion

     

Ascites fluid in severe acute pancreatitis: from pathophysiology to therapy

Several pathophysiological mechanisms are involved in the development of the inflammatory necrotizing process that takes place in the retroperitoneal area during the early phase of acute pancreatitis. They include premature intraglandular activation of pancreatic proenzymes (zymogens) and in particular trypsin, early microcirculatory impairment with subsequent ischaemia/reperfusion and overstimulation of immune effector cells. Although intra-acinar or interstitial activation of trypsinogen is most probably the trigger of acute pancreatitis, in recent years much emphasis has been put on the role of leukocytes. Based on numerous experimental and human data several pro-inflammatory mediators including cytokines, arachidonic acid derivatives, activated oxygen species and proteases are released locally by overactivated neutrophils and monocytes/macrophages among other cells. They are now believed to play a central role in the development of pancreatic necrosis and, once they gain access to the systemic circulation, in the emergence of early multisystem organ failure. However the sequential and relative contribution of each of these 3 pathophysiological mechanisms remain controversial and the precise identification of the mediators incriminated in local and remote tissue injury is still awaited. Severe acute pancreatitis still carries a mortality of 20% to 30%. With advances in intensive care management 80% of the deaths occur somewhat late in the attack due to infected pancreatic necrosis. Nevertheless early remote organ failures still remain a lifethreatening condition for most of these patients. A peritoneal exudate rich in activated lipolytic and proteolytic enzymes, vasoactive substances and several other pro-inflammatory mediators collect in over 60% of the patients with severe acute pancreatitis. On the basis of favourable animal experiments early percutaneous or surgical peritoneal lavage with or without the addition of antiproteases has been carried out in human acute pancreatitis. The rationale behind this procedure was the washout of potential toxic mediators from the peritoneal cavity before they gain access to the systemic circulation. Contrary to animal and uncontrolled human data no prospective randomized study could ever demonstrated a significant effect of peritoneal lavage neither in the prevention and control of remote organ failures or in early mortality and ultimate survival after severe acute pancreatitis in humans. Differences between experimentally-induced pancreatitis, difference in the timing of the initiation of lavage and a type II error in controlled human studies may account for the discrepancy in the outcome between these studies. Anyway, this disparity should raise the question as whether the peritoneal cavity acts simply as a reservoir or as a route of transfer of toxic mediators to the systemic circulation. Although data are scarce, conflicting and limited to animal experiments and to a few molecules, peripancreatic veins and lymphatics seem to be the major routes of transfer whereas transperitoneal absorption is trivial. Nevertheless early peritoneal aspiration of ascitic fluid in acute pancreatitis and measurement of trypsinogen activation peptides may be used as a means of severity assessment and identification of pancreatic necrosis. This implies that even if not taking part actively in the emergence of remote organ failures ascitic fluid may reflect the peripancreatic necrotizing process. So careful comparative analysis of peritoneal exudate, plasma and lymph with regards to putative mediators of local and remote injury may provide essential pathophysiological clues. At the time of trials of antimediator therapy early in the attack this kind of insight is essential.     

胰蛋白酶原激活肽的基础与临床研究进展

急性胰腺炎(AP)的始动环节为胰蛋白酶原的激活,胰蛋白酶原激活肽(TAP)作为胰蛋白酶原激活时降解的残基,与AP的发生有明确的相关性,大量的研究显示TAP有望成为良好的早期预测AP严重程度的指标。     

Trypsinogen activation peptides (TAP) concentrations in the peritoneal fluid of patients with acute pancreatitis and their relation to the presence of histologically confirmed pancreatic necrosis.

This study measured the volume and colour, as well as concentrations of trypsinogen activation peptides (TAP) in the peritoneal fluid of 22 patients with acute pancreatitis and related these findings to the presence of pancreatic necrosis. Nine patients had a severe attack with histologically confirmed pancreatic necrosis, seven a severe attack without confirmed necrosis, and six a mild attack, also without confirmed necrosis. A free fluid volume > 20 ml or free fluid colour > grade 5 on the Leeds chart, or both detected histologically confirmed pancreatic necrosis with a sensitivity of 100% and specificity of 31%. A total peritoneal fluid TAP concentration of > or = nmol detected histologically confirmed pancreatic necrosis with a sensitivity of 89% and specificity of 85%, figures comparable with contrast enhanced computed tomography. These findings suggest that the measurement of peritoneal fluid TAP concentrations can detect effectively histologically confirmed pancreatic necrosis and that such measurements may prove useful in the selection of patients for surgery.     

Cholecystokinin-8 induces edematous pancreatitis in dogs associated with short burst of trypsinogen activation

To study the early pathogenesis of acute edematous pancreatitis in dogs, we examined the relationship of pancreatic hyperstimulation with cholecystokinin-8 (10 g/kg/hr intravenously for 6 hr) to alterations in circulating pancreatic enzymes and pancreatic morphology with special reference to trypsinogen activation. Cholecystokinin-8 infusion was associated with increases in plasma amylase, lipase, trypsin-like immunoreactivity, and plasma and urine trypsinogen activation peptide. Pancreatic parenchymal swelling and interlobular and subcapsular fluid accumulations were detected ultrasonographically within 2 hr of cholecystokinin-8. Circulating trypsin-like immunoreactivity and trypsinogen activation peptide in urine reached a peak at 2 and 4 hr, respectively, then declined despite progressive increases in circulating amylase and lipase and intrapancreatic fluid. No significant changes were observed in dogs receiving a saline infusion. This study illustrates that cholecystokinin-8 induces edematous pancreatitis in dogs that is associated with a short-lived burst of trypsinogen activation.Financial support for this study was provided in part by the Wellcome Trust.     

Trypsin-based laboratory methods and carboxypeptidase activation peptide in acute pancreatitis

Acute pancreatitis is a common disease varying widely in severity. At present, there is no "gold standard" for the diagnosis of acute pancreatitis. Currently, the diagnosis of acute pancreatitis is based on measurements of serum amylase and/or lipase activity, which are considered unsatisfactory due to their low level of accuracy. Early identification of acute pancreatitis and especially detection of patients with a severe form of the disease is of utmost importance. Premature intrapancreatic activation of trypsinogen is a crucial early event in the pathophysiology of acute pancreatitis. The conversion of trypsinogen to active trypsin is mediated by the release of its activation peptide (TAP). The active trypsin is then able to activate other pancreatic zymogens (i.e. procarboxypeptidase) leading to tissue damage and eventually to autodigestion of the pancreas. To improve the laboratory diagnostics of AP, new methods have been developed to measure this primary pancreatic proteolytic insult. Here we review the current knowledge and clinical implications of trypsin based laboratory methods and carboxypeptidase activation peptide (CAPAP) in the diagnosis and severity assessment of acute pancreatitis.     

Urinary trypsinogen activation peptide (TAP) predicts severity in patients with acute pancreatitis

Summary Conclusions Urinary TAP obtained within the first 48 h of the onset of symptoms can distinguish patients with severe acute pancreatitis. Background Urinary trypsinogen activation peptide (TAP) has recently been described as an early marker of severity in acute pancreatitis. Methods In a multicenter study, urine samples were collected for TAP concentration at 6–12, 24, and 48 h after admission from 139 patients with acute pancreatitis (99 with mild disease, 40 with severe disease) and from 50 control patients. Severity of acute pancreatitis was defined by the presence of organ failure and/or pancreatic necrosis on dynamic contrast-enhanced computed tomography. Results Median urinary TAP in the 139 patients with acute pancreatitis compared to the 50 control patients was significantly higher at admission, 4.6 vs 0.8 ng/mL (p<0.001), and 6–12 h, 1.9 vs 0.55 ng/mL (p=0.04). Among patients who presented within 48h of the onset of symptoms, the median urinary TAP for severe pancreatitis (9 patients) compared to mild pancreatitis (40 patients) was significantly higher at admission, 29.6 vs. 3.6 ng/mL (p=0.001). Also, when obtained within 48h of the onset of symptoms, all patients with severe pancreatitis had an admission urinary TAP level>10 ng/mL. The sensitivity and specificity of an admission urinary TAP≥10 for severe pancreatitis was 100 and 85%, respectively. Given a cutoff of 10 ng/mL for an admission urinary TAP obtained within 48h of the onset of symptoms, the negative predictive value was 100% for mild pancreatitis.     

Usefulness of urinary trypsinogen-2 and trypsinogen activation peptide in acute pancreatitis:A multicenter study in Japan

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.     

Urinary trypsinogen activation peptide is more accurate than hematocrit in determining severity in patients with acute pancreatitis: a prospective study

OBJECTIVE: The management of patients with acute pancreatitis is complicated by the inability to distinguish mild from severe disease during the early stages. It has been previously shown that urinary trypsinogen activation peptide (TAP) and hematocrit (Hct) may serve as early predictors of severity in patients with acute pancreatitis. To establish which marker is more accurate in the determination of severity in patients with acute pancreatitis, a prospective study was performed. METHODS: A consecutive series of patients admitted with pain consistent with acute pancreatitis and an amylase of three times the upper limit of normal were included. The admission and 24-h Hct was obtained. A urine sample was obtained within 12 h of admission. Urinary TAP was determined using a modified solid phase ELISA. Severity was defined by the Atlanta Symposium, as the presence of organ failure and/or pancreatic necrosis. RESULTS: Fifty-eight consecutive patients with acute pancreatitis participated. There were 33 men and 25 women with a mean age of 60 +/- 19. Thirty-nine patients had mild disease; 19 had severe disease. Urinary TAP was elevated in 26 patients. All patients with severe pancreatitis were correctly identified as having severe disease by an elevated urinary TAP (sensitivity 100%, specificity 77%). The admission Hct was higher than 47 in only three patients, all with mild disease. Of the patients with a rise in Hct, eight had mild disease, and only one had severe disease. Using a Hct of 44 as a cutoff did not affect the accuracy. There was no association between a rise in Hct and failure of Hct to decrease in the determination of severity. CONCLUSIONS: In comparison to admission Hct, urinary TAP was more accurate in determining severity in patients with acute pancreatitis by Atlanta, APACHE II, and Ranson criteria. We conclude that urinary TAP is a more accurate predictor of severity in patients with acute pancreatitis compared with Hct. Urinary TAP should be used to determine severity in patients early in the course of acute pancreatitis.     

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.     

Update lecture: benign diseases of the exocrine pancreas

A brief overview on the physiology and regulation of digestive enzyme secretion by the exocrine pancreas is presented. Knowledge about the physiology of the exocrine pancreas should help for a better understanding of the pathophysiology of both acute and chronic pancreatitis. In the pathophysiology of acute pancreatitis, fusion of zymogen granules with lysosomes, which leads to intracellular activation of trypsinogen, is still regarded as a key step in pathophysiology. The role of activation by cathepsins and the role of autoactivation of trypsinogen are still under debate. Studies on genetic alterations in various forms of human chronic pancreatitis can be interpreted that an imbalance between protease inhibitors and active proteases plays a key role. Toxic Ca(2+) signals by excessive liberation from the endoplasmic reticulum may play another role. The mortality of necrotizing pancreatitis is still high. Early mortality is caused by a systemic inflammatory response syndrome with or without concomitant infection of necrosis; late mortality by multi-organ failure syndrome due to sepsis. Therapy of necroses should be performed as late as possible. A step-up approach using CT-guided and/or transgastric endoscopic necrosectomy seems to be superior to a primary surgical approach. A brief overview of the German S3 guidelines, not yet published, regarding diagnosis and treatment of chronic pancreatitis is presented.     

Urinary excretion of trypsinogen activation peptide (TAP) in taurocholate-induced pancreatitis in rats

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.