A 38-year-old man comes to the emergency department with severe abdominal pain and vomiting. The pain radiates to his back and improves by bending forward. Physical examination shows tenderness over the epigastrium and decreased bowel sounds. The patient is admitted to the hospital and treated with intravenous fluids and pain medication, but his condition fails to improve. An abdominal CT scan reveals diffuse pancreatic enlargement with areas of necrosis. The inappropriate activation of which of the following most likely initiated this patient's condition?
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Most pancreatic enzymes are synthesized by pancreatic acinar cells as inactive enzyme precursors called zymogens. Zymogen granules are secreted from the apical surface of acinar cells into the lumen. After traversing the pancreatic duct system, they drain through the ampulla of Vater into the descending part of the duodenum. The enzyme enterokinase (secreted from intestinal mucosa) cleaves trypsinogen into trypsin, its active form. Once a small quantity of trypsin is produced, it activates other zymogens, including chymotrypsin, elastase, and carboxypeptidase, through proteolytic cleavage. Trypsin can also cleave trypsinogen to produce more trypsin, accelerating pancreatic enzyme activation in the duodenum.
The pathogenesis of acute pancreatitis begins with either a toxic or an ischemic injury to the acinar cells that leads to premature activation of trypsin inside the pancreatic acini. Trypsin then activates the other proteolytic enzymes and starts a self-sustaining cycle of pancreatic inflammation and autodigestion with further release of digestive enzymes. In severe cases, this process can result in necrotizing pancreatitis, which is characterized by gross areas of parenchymal necrosis with a high propensity for secondary bacterial infection.
(Choice A) Amylase hydrolyzes starch to produce maltose (a glucose-glucose disaccharide) and trisaccharide maltotriose and limit dextrins. It does not require activation by trypsin.
(Choices B, D, and E) Chymotrypsin, phospholipase A2 (which can damage cell membranes), and elastase are secreted by the pancreas as inactive precursors (chymotrypsinogen, prophospholipase A2, and proelastase) that are subsequently activated by trypsin.
(Choice C) Lipase hydrolyzes triglycerides into fatty acids and glycerol. It does not require activation by trypsin (although its activity is increased by colipase, which is activated by trypsin). Release of lipase during acute pancreatitis causes the formation of characteristic calcium soap deposits (fat necrosis).
Educational objective:
Pancreatic zymogens are normally converted into their active form by trypsin in the duodenal lumen. Premature cleavage of trypsinogen to trypsin within the pancreas leads to uncontrolled activation of these zymogens, causing pancreatic autodigestion and acute pancreatitis.