Trypsinogen and Its Activation in Acute Pancreatitis

Abstract: Pancreatic enzymes, neutrophils, free radicals and cytokines are involved in the pathophysiology of AP. Clarification of their interaction and time-course will improve our understanding of AP and provide a better basis for treatment. 20% will develop severe AP and benefit from improved treatment why an accurate test for prediction of severity is needed. Aims: To investigate the interactions between those factors and the accuracy of markers of proenzyme leakage (anionic and cationic trypsinogen=ATg and CTg) and free trypsin activity (carboxypeptidase B activation peptide =CAPAP) as predictors of severity. Free radical action may lead to intracellular enzyme activation. Diminished activation of Tg was found one-three days after pancreas transplantation in pigs, when allopurinol treatment was given. Thus, early intracellular events are of importance for later extracellular activation of Tg which, may be due to autoactivation or be secondary to inflammation. We found no proof of inflammation or neutrophil activation preceding the activation of Tg in ERCP- induced AP, indicating primary Tg-activation in AP. ATg but not CTg levels in urine correlated to severity in human AP but the specificity was too low for clinical use as a severity predictor. We developed a TAP-assay (Tg activation peptide) and could show an instable immunoreactivity in serum, and that the immunoreactivity in urine consists of a degradation product of TAP. CAPAP is not degraded after sampling. CAPAP is superior to ATg as a severity predictor, according to our study where pre-set cut-off levels were used. In conclusion: 1) Tg activation is a central event in the pathophysiology of AP, 2) free radicals is of importance for this, probably extracellular activation, 3) inflammation could not be shown to precede Tg activation, 4) TAP is degraded in the circulation and is recovered as a pentapeptide in urine in AP, and 5) CAPAP is an accurate predictor of severity in human AP.