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Tests to Predict Severity in Acute Pancreatitis

Norton J. Greenberger, MD, MACP
Ocotber 16, 2000

Trypsinogen activation peptide (TAP), which is released during activation of trypsinogen to trypsin, has shown promising predictive values because of its status as a single marker specifically related to the onset of acute pancreatitis. In a prospective multicenter study published in Lancet, the predictive value of a TAP assay was compared with C-reactive protein and other clinical scoring systems as a test of severity in acute pancreatitis (1).

Methods: Determination of TAP, as measured by immunoassay, was compared with C-reactive protein, the Ransom Scoring System, Glasgow Scoring System and the Apache II Scoring System in 137 patients with mild pancreatitis, 35 patients with severe pancreatitis and 74 controls.

Main Findings:
  • At 24 hours the mean urinary TAP was 37 nmol/L for patients with severe pancreatitis compared to a value of 15 nmol/L in mild pancreatitis.
  • Values for C-reactive protein were 24 mg/L in severe patients and 25 mg/L in patients with mild pancreatitis. The sensitivity, specificity, positive predictive value, and negative predictive value for the TAP urinary assay was 58%, 73%, 39% and 86% respectively at 24 hours.


Conclusions: The authors conclude that urinary TAP provides an accurate prediction of severity 24 hours after onset of symptoms in patients with acute pancreatitis. Further, they suggest that this single marker of severity deserves routine clinical application

Commentary
Considerable attention has been focused on the important role of inflammatory mediators in the pathophysiology of the systemic complications of acute pancreatitis. Several mediators have shown demonstrable activity in the course of acute pancreatitis and these include: 1) C-reactive protein; 2) neutrophil elastase; 3) cytokinins IL-6 and IL-8; 4) platelet activating factor (PAF) and trypsinogen activation peptide (TAP). Acute pancreatitis represents an autodigestion of the pancreas by its own proteases. How and where these digestive processes are activated has remained a topic of much controversy and speculation. However, it seems clear that activation of zymogens within the pancreatic acinar cells plays an important role in the development of acute pancreatitis.

In experimentally induced pancreatitis in rats, TAP immunoreactivity appeared in a vesicular supranuclear compartment distinct from zymogen granules and increased in time after hyperstimulation with caerulein (2). In a similar study the pancreatic content of TAP increased continuously, and although predominately localized in the zymogen fraction early, it then expanded to other intracellular compartments (3). In experimentally induced acute pancreatitis in the rat, levels of TAP in the peritoneal exudate measured 3 and 6 hours after induction correlated well with the amount of late histopathological injury (4).

In an earlier study dealing with urinary trypsinogen activation peptide in patients with acute pancreatitis, Tenner et al determined urinary TAP obtained within the first 40 hours after onset of symptoms in patients with acute pancreatitis (5). This was a multicenter trial involving several institutions. Urine samples were collected for TAP concentration determination in 199 patients. Measurements were made at 6-12 hours, 24 hours and 40 hours after admission to the hospital. 99 patients had mild disease, 40 had severe disease and 50 served as controls. The main finding was that the median urinary TAP in 139 patients was significantly greater than in 50 controls on admission 4-6, 6-12 and 24 hours after admission. Importantly, urinary TAP levels for patients with severe disease (N=29) was significantly higher than for 40 patients with mild disease 39.6 verses 3.6 ng/ml. All patients with severe pancreatitis had admission urinary TAP levels greater than 10 ng/ml. In this particular study, the sensitivity for TAP in predicting severe pancreatitis was 100% and specificity 85%.

To put the study of Neoptolemos et al in perspective, it is instructive to examine the measurement of TAP compared with plasma C-reactive protein, Apache II scoring systems, the Glasgow score and the Ransom score. This summary is shown in the table. It can be seen that the sensitivity, specificity, positive predictive value and negative predictive value as well as the accuracy of the urinary TAP test were not that different from plasma CRP or the Apache II score. When the urinary TAP values greater that 35 nmol/L were combined with plasma C-reactive protein greater than 150 mg/L the results were marginally better in terms of specificity and overall accuracy. Forty-eight hours after admission, the accuracy of the five tests is comparable. However, it can be argued that 48 hours is a relatively late point to be identifying the patient with severe disease. As pointed out in an instructive editorial by Windsor, "these results do not support the claim that urinary TAP excretion has advantages over all of the other available prognostic systems. However, urinary TAP is a single marker that can be measured easily and early and because it is probably as good as other prognostic markers its wider use is justified." I agree with this conclusion and I look forward to other studies using this peptide.

Table: Scoring System
    Sensitivity (%) Specificity (%) Positive Predictive Value (%) Negative Predictive Value (%) Accuracy (%)
24 hours after admission            
Urinary TAP > 35 nmol/L   68 74 44 89 73
Plasma CRP > 150 mg/L   47 82 42 84 74
APACHE II > 8   63 73 38 88 71
Urinary TAP > 35 nmol/L & plasma CRP > 150 mg/L   40 91 57 83 79
             
48 hours after admission            
Urinary TAP > 35 mnol/L   83 72 44 94 74
Plasma CRP > 152   80 61 37 94 66
APACHE II > 8   56 64 30 85 63
Glasgow Score >/=3   75 75 44 93 76
Ransom Score >/=3   89 64 38 96 69
             
*Modified from Neoptolemos, J.P., Lancet, 355:1955-1960, 2000


References

  1. Neoptolemos, J.P., Kemppainen, E. A., Mayer, J. M. et al: Early prediction of severity in acute pancreatitis by urinary trypsinogen activation peptide. A multicenter study. Lancet, 355:1955-60, 2000.
  2. Otani, T., Chepilko, S.M., Grendell, J.H. et al: Codistribution of TAP and the granule membrane protein GRAMP-92 in rat caerulein-induced pancreatitis. Am. J. Physiol., 275:G999-G1009, 1998.
  3. Mithofer, K, Fernandez-del-Castillo, C., Rattner, D., et al: Subcellular kinetics of early trypsinogen activation in acute rodent pancreatitis. Am. J. Physiol., 274:G71-79, 1998.
  4. Schmidt, J., Ryschich, E., Sinn, H.P., et al: Trypsinogen activation peptides (TAP) in peritoneal fluid as predictors of late histopathologic injury in necrotizing pancreatitis of the rat. Dig. Dis. Sci., 44:823-829, 1999.
  5. Tenner, S., Fernandes-del-Castillo, C., Warshaw, A., et al: Urinary trypsinogen activation peptide predicts severity in patients with acute pancreatitis. Int. J. Pancreatol., 21:105-110, 1997.
  6. Windsor, J.A.: Search for prognostic markers for acute pancreatitis. Lancet, 355:1924-1925, 2000.

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