Antti Hietaranta

Early prediction of severity in acute pancreatitis by urinary trypsinogen activation peptide: a multicentre study.

BACKGROUNDnThere is a pressing clinical requirement for an early simple test of severity in acute pancreatitis. We investigated the use of an assay of trypsinogen activation peptide (TAP).nnnMETHODSnWe undertook a multicentre study in 246 patients (172 with acute pancreatitis [35 with severe disease], 74 controls). We assessed the predictive value of urinary TAP concentrations measured by a validated competitive immunoassay. We compared the results with those for plasma C-reactive protein and three clinicobiochemical scoring systems. TAP and C-reactive protein concentrations were analysed at set times after symptom onset and compared with the clinicobiochemical systems scores at key times during hospital stay.nnnFINDINGSnAt 24 h after symptom onset, the median urinary TAP concentration was 37 nmol/L (IQR 17-110) for severe and 15 nmol/L (5-35) for mild disease (p<0.001). The respective values for plasma C-reactive protein were 24 mg/L (3-34) and 25 mg/L (6-75; p=0.208). The sensitivity, specificity, positive predictive, and negative predictive values of the test to show severe acute pancreatitis compared with mild acute pancreatitis at 24 h were: for TAP (>35 nmol/L), 58%, 73%, 39%, and 86%, respectively, and for C-reactive protein (>150 mg/L), 0%, 90%, 0%, and 75%. 48 h after admission the values for the clinicobiochemical scoring systems were: APACHE II (> or =8), 56%, 64%, 30%, and 85%; Ranson score (> or =3), 89%, 64%, 38%, and 96%; and Glasgow score (> or =3), 77%, 75%, 44%, and 93%. At 48 h, the values for C-reactive protein were 86%, 61%, 37%, and 94% and for TAP were 83%, 72%, 44%, and 94%. Combined testing of C-reactive protein and TAP was not superior to TAP alone for accuracy.nnnINTERPRETATIONnUrinary TAP provided accurate severity prediction 24 h after onset of symptoms. This single marker of severity in acute pancreatitis deserves routine clinical application.

Time Course Profile of Serum Trypsinogen-2 and Trypsin-2-a1-Antitrypsin in Patients with Acute Pancreatitis

Background: Trypsinogen-2 and the trypsin-2a1 antitrypsin complex are recently introduced new laboratory markers for acute pancreatitis. They show high sensitivity and specificity for acute pancreatitis on admission, but little is known on their time course profiles. Methods: The serum concentrations of trypsinogen-2 and trypsin-2a1-antitrypsin were monitored in 92 patients with verified acute pancreatitis. The follow-up period was 42 days in patients with severe acute pancreatitis ( N = 73) and 9 days in mild disease ( N = 19).Results:On admission the mean serum concentration of trypsinogen-2 was 2880 mg/l in severe and 920 mg/l in mild acute pancreatitis. These values were 32and 10-fold the upper reference limit, respectively. Trypsin-2a1-antitrypsin concentrations were 1250 mg/l (100-fold the upper reference limit) and 635mg/l (52-fold), respectively. The differences were statistically significant ( P = 0.026–0.001). The concentrations of trypsinogen-2 and trypsin-2a1-antitrypsin decreased gradually during the follow-up period, but they remained elevated for the entire study period in patients with severe and mild disease. Conclusions: The time course profile of trypsinogen-2 and trypsin-2a1-antitrypsin is favorable for diagnosing acute pancreatitis. The elevation starts within hours after the onset of the disease and it is very steep. Both markers remain elevated longer than amylase and the magnitude of the elevation correlates with the severity of the disease. This is further evidence to support the use of trypsinogen-2 and trypsin-2a1-antitrypsin for the evaluation of patients suspected of having acute pancreatitis.BACKGROUNDnTrypsinogen-2 and the trypsin-2-alpha1-antitrypsin complex are recently introduced new laboratory markers for acute pancreatitis. They show high sensitivity and specificity for acute pancreatitis on admission, but little is known on their time course profiles.nnnMETHODSnThe serum concentrations of trypsinogen-2 and trypsin-2-alpha1-antitrypsin were monitored in 92 patients with verified acute pancreatitis. The follow-up period was 42 days in patients with severe acute pancreatitis (N = 73) and 9 days in mild disease (N = 19).nnnRESULTSnOn admission the mean serum concentration of trypsinogen-2 was 2880 microg/l in severe and 920 microg/l in mild acute pancreatitis. These values were 32- and 10-fold the upper reference limit, respectively. Trypsin-2-alpha1-antitrypsin concentrations were 1250 microg/l (100-fold the upper reference limit) and 635 microg/l (52-fold), respectively. The differences were statistically significant (P = 0.026-0.001). The concentrations of trypsinogen-2 and trypsin-2-alpha1-antitrypsin decreased gradually during the follow-up period, but they remained elevated for the entire study period in patients with severe and mild disease.nnnCONCLUSIONSnThe time course profile of trypsinogen-2 and trypsin-2-alpha1-antitrypsin is favorable for diagnosing acute pancreatitis. The elevation starts within hours after the onset of the disease and it is very steep. Both markers remain elevated longer than amylase and the magnitude of the elevation correlates with the severity of the disease. This is further evidence to support the use of trypsinogen-2 and trypsin-2-alpha1-antitrypsin for the evaluation of patients suspected of having acute pancreatitis.

Sequential Changes in Pancreatic Markers in Acute Pancreatitis

Background: Trypsinogen activation within acinar cells plays a crucial role in the pathogenesis of acute pancreatitis (AP). Our aim was to characterize temporal changes of trypsinogen-1, trypsinogen-2, complexes of trypsin-1- ! 1 -antitrypsin (T1-AAT) and trypsin-2- ! 1 -antitrypsin (T2-AAT), trypsinogen activation peptide (TAP) and pancreatic secretory trypsin inhibitor (PSTI) in patients with AP. Methods: The study comprised 64 consecutive patients with AP (19 with severe disease) and 32 controls. The concentrations of trypsinogen-1 and -2, PSTI, T1-AAT and T2-AAT were determined by time-resolved immunofluorometric assays (IFMA), and TAP was measured using a competitive enzyme immunoassay from serum and urine. Results: The concentrations of trypsinogen-1 and -2 in serum reflected similar patterns, but excretion of trypsinogen-1 into urine was markedly lower than that of trypsinogen-2, the concentration of which correlated strongly with disease severity. The concentrations of T1-AAT were no higher in severe AP than in mild AP, while T2-AAT concentrations were significantly higher in severe than in mild disease. PSTI increased over the course of several days, showing strong correlation with disease severity. The concentrations of plasma and urinary TAP decreased rapidly to undetectable levels. During the early phase of AP, TAP correlated with the disease severity in plasma and urine but there was no difference between controls and patients with mild AP. Conclusion: More pronounced changes in trypsinogen-2 and its complex with AAT than in those of trypsinogen-1 were demonstrated, suggesting that trypsinogen-2 might play a more important role in the pathogenesis of AP than earlier believed. Urinary PSTI showed features warranting further investigations as a marker of disease severity.BACKGROUNDnTrypsinogen activation within acinar cells plays a crucial role in the pathogenesis of acute pancreatitis (AP). Our aim was to characterize temporal changes of trypsinogen-1, trypsinogen-2, complexes of trypsin-1-alpha1-antitrypsin (T1-AAT) and trypsin-2-alpha1-antitrypsin (T2-AAT), trypsinogen activation peptide (TAP) and pancreatic secretory trypsin inhibitor (PSTI) in patients with AP.nnnMETHODSnThe study comprised 64 consecutive patients with AP (19 with severe disease) and 32 controls. The concentrations of trypsinogen-1 and -2, PSTI, T1-AAT and T2-AAT were determined by time-resolved immunofluorometric assays (IFMA), and TAP was measured using a competitive enzyme immunoassay from serum and urine.nnnRESULTSnThe concentrations of trypsinogen-1 and -2 in serum reflected similar patterns, but excretion of trypsinogen-1 into urine was markedly lower than that of trypsinogen-2, the concentration of which correlated strongly with disease severity. The concentrations of T1-AAT were no higher in severe AP than in mild AP, while T2-AAT concentrations were significantly higher in severe than in mild disease. PSTI increased over the course of several days, showing strong correlation with disease severity. The concentrations of plasma and urinary TAP decreased rapidly to undetectable levels. During the early phase of AP, TAP correlated with the disease severity in plasma and urine but there was no difference between controls and patients with mild AP.nnnCONCLUSIONnMore pronounced changes in trypsinogen-2 and its complex with AAT than in those of trypsinogen-1 were demonstrated, suggesting that trypsinogen-2 might play a more important role in the pathogenesis of AP than earlier believed. Urinary PSTI showed features warranting further investigations as a marker of disease severity.

Severe acute pancreatitis is related to increased early urinary levels of the activation peptide of pancreatic phospholipase A2

Background/Aim: In acute pancreatitis, it is believed that generalized activation of pancreatic zymogens leads to autodigestion of the pancreas and if excessive to systemic organ injury. Under physiological circumstances, secretory phospholipase A2 type I (sPLA2-I) is activated by trypsinogen, but the extent of this activation in acute pancreatitis is unclear. The aim of this study was to assess time course and level of activation of sPLA2-I and trypsinogen in acute pancreatitis, relative to severity. Methods: 246 patients were enrolled into a prospective European multicenter study. 137 patients had mild and 35 had severe acute pancreatitis, and there were 74 control patients. Urinary samples were taken on admission and at 6-hour intervals for 48 h, then every 12 h up to 72 h, and finally daily for at least 5 days for measurement of the activation peptide of sPLA2-I (pro-phosphatase A2; PROP) and trypsinogen activation peptide. Results: The median maximum PROP values were significantly elevated 48 h after symptom onset in patients with severe acute pancreatitis [1.52 (95% CI 0.8–2.9) nmol/l] as compared with patients with mild acute pancreatitis [0.72 (0.55–1) nmol/l, p = 0.002] and controls [0.49 (0.22–1.2) nmol/l, p = 0.001], but not before or after this time point. The best cutoff point for urinary PROP to predict overall severity was >1 nmol/l ≤48 h after symptom onset (negative predictive value = 88%), but the PROP levels failed to predict the development of multi-organ dysfunction. Conclusions: Activation of sPLA2-I is associated with the early pathogenesis of acute pancreatitis, but not in the development of distant organ damage. This observation raises questions as to the theory of generalized zymogen activation being a principle mechanism involved in the pathogenesis of distant organ damage in acute pancreatitis.

Bactericidal/permeability-increasing protein and group I and II phospholipase A2 during the induction phase of human acute pancreatitis

Activated endogenous mediators of inflammation have important roles in the pathogenesis and complications of acute pancreatitis (AP). These mediators include bactericidal/ permeability-increasing protein (BPI) and phospholipase A2 (PLA2). The time course of their activation during human AP is not known. The aim of this study was to evaluate the kinetics of BPI, group I (pancreatic) and group II (synovial type) PLA2 during human AP with temporally defined onset, as being induced by endoscopic retrograde cholangiopancreatography (ERCP). Serum samples of 273 consecutive patients undergoing ERCP were collected before and at 3, 6, and 24 h after ERCP. Twenty-four (8.7%) patients developed ERCP-induced pancreatitis. Seven of them were graded to have a severe disease. Forty randomly selected patients undergoing ERCP without evidence of pancreatitis served as controls. The serum concentrations of BPI and groups I and II PLA2 were measured by specific immunoassays. The mean concentration of BPI increased from 14 to 26 microg/L at 24 h after ERCP in patients with AP. In the control group, BPI values remained unchanged, and the difference was statistically significant (p<0.001). The increase of BPI was seen in 22 of 28 patients with AP at 3 h after the onset of the disease. BPI values were higher in severe post-ERCP pancreatitis than in mild disease (p = 0.07; NS). The serum concentrations of group II PLA2 before ERCP were consistently higher in the control patients than in the patients with pancreatitis, 65.8 and 14.2 microg/L, respectively. High baseline values in the control group were associated with preexisting infectious diseases. Thereafter, the mean concentration decreased in the control group to 44 microg/L and increased in the pancreatitis group up to 27.5 microg/L. The difference was statistically significant (p = 0.007). Increased group II PLA2 values were seen in 10 of 17 patients with mild AP and in five of seven patients with severe disease. There were no significant differences in group I or II PLA2 values in patients with mild or severe AP. The serum concentration of group I PLA2 increased in the patients with post-ERCP pancreatitis from 5.4 to 37.5 microg/L at 24 h. The difference was statistically significant, (p< 0.001) as compared with controls. In conclusion, in acute pancreatitis, the increase of BPI in serum starts at 3 h after the onset of the disease, and the concentration seems to correlate with the severity of the disease. Increased group II PLA2 concentrations also were seen in patients with mild AP. The kinetics of group I PLA2 resembles that of other pancreatic enzymes.