Evolving concepts in the pathophysiology of acute pancreatitis

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ACINAR CELL INJURY Premature activation of digestive enzymes is one of the earliest detectable events believed to play a central role in the pathogenesis of acinar cell injury.1 Active enzymes and markers of enzyme activation have been found in the ascites, serum, and pancreatic tissue of both humans and experimental animals with acute pancreatitis. Protease inhibitors attenuate acute pancreatitis in experimental animals and endoscopic retrograde cholangiopancreatography–induced pancreatitis in humans. Moreover, patients with hereditary pancreatitis have a gene that encodes a mutant form of trypsinogen that is resistant to the normal intracellular mechanisms of inactivation. Events that continue to elude pancreatologists result in a failure of the orderly segregation of newly synthesized zymogen granules within acinar cells. As a consequence, the lysosomal hydrolase cathepsin B co-localizes with zymogen granules and activates trypsinogen, which in turn activates other enzymes, leading to acinar cell injury. An alternative hypothesis suggests that interstitial, rather than intracellular, activation of proteases (perhaps by macrophages) may be the initiating event of acute pancreatitis. But how these events relate to the clinical setting and how a stone impacted in the bile duct results in acinar cell injury are not clear. The hypothesis that bile and pancreatic duct distention initiate the cascade of acinar cell injury by altering the neurohormonal milieu of the pancreas needs to be evaluated critically.