More than a century ago, a German pathologist noted at autopsies of patients who had succumbed to acute pancreatitis that their intrapancreatic digestive enzymes had been activated.1 His fateful observation engendered the surprisingly long-lived belief that pancreatitis is an autodigestive phenomenon resulting from the inappropriate activation of digestive enzymes within the pancreas itself. The past three decades have seen the development of several animal models of pancreatitis and remarkably, early intracellular trypsinogen activation has been observed consistently during the course of pancreatitis in all of them.2–5 Subsequently, pancreatitis research began to focus on the mechanisms of premature intracellular trypsinogen activation. We and others have shown that premature trypsinogen activation takes place in membrane-bound compartments resembling autophagic vesicles within which zymogen and lysosomal contents are colocalised.6–9 In these colocalisation vacuoles, the lysosomal protease cathepsin B activates trypsinogen.10–13 The occurrence of these colocalisation vacuoles has been confirmed both in models of experimental pancreatitis and pathological specimens of human pancreatitis.14 15 It is thought that that the now-activated trypsin continues the process by activating other digestive enzymes, presumably in the same manner as it normally would in the duodenum. According to this paradigm the process culminates in prematurely active digestive enzymes ‘digesting’ the acinar cell and leading to acute pancreatitis.

So elegant and credible is this trypsin-central paradigm of pancreatitis that the reader often accepts it even before looking at the scientific evidence. It is to be noted that premature trypsinogen activation has only been observed during acute pancreatitis, and that no definitive proof exits for a causal role of trypsinogen activation in the pathogenesis of pancreatitis. Inhibition of trypsinogen activation by inhibiting the activity of cathepsin B11 12 or by deleting the cathepsin B gene13 has shown that pancreatic injury decreases during acute pancreatitis, suggesting …