Acute pancreatitis appears to be caused by autodigestion of the pancreas by inappropriately activated pancreatic enzymes. As discussed earlier, once activated trypsin is capable of converting other zymogen forms of pancreatic enzymes to their active forms. Premature activation of trypsin within the substance of the pancreas can unleash these proenzymes (e.g., phospholipases and elastases), leading to tissue injury and inflammation. Trypsin also converts prekallikrein to its activated form, thus sparking the kinin system, and, by activation of factor XII (Hageman factor), also sets in motion the clotting and complement systems (Chapter 4). Three pathways can incite the initial enzyme activation that may lead to acute pancreatitis (
Fig.
17.1
Pancreatic duct obstruction. Impaction of a gallstone or biliary sludge, or extrinsic compression of the ductal system by a mass blocks ductal flow, increases intraductal pressure, and allows accumulation of an enzyme-rich interstitial fluid. Since lipase is secreted in an active form, local fat necrosis may result. Injured tissues, periacinar myofibroblasts, and leukocytes then release pro-inflammatory cytokines that promote local inflammation and interstitial edema through a leaky microvasculature. Edema further compromises local blood flow, causing vascular insufficiency and ischemic injury to acinar cells.
Primary acinar cell injury. This pathogenic mechanism comes into play in acute pancreatitis caused by ischemia, viral infections (e.g., mumps), drugs, and direct trauma to the pancreas.
Defective intracellular transport of proenzymes within acinar cells. In normal acinar cells, digestive enzymes intended for zymogen granules (and eventually extracellular release) and hydrolytic enzymes destined for lysosomes are transported in discrete pathways after synthesis in the endoplasmic reticulum. However, at least in some animal models of metabolic injury, pancreatic proenzymes and lysosomal hydrolases become packaged together. This results in proenzyme activation, lysosomal rupture (action of phospholipases), and local release of activated enzymes. The role of this mechanism in human acute pancreatitis is not clear.
Alcohol consumption may cause pancreatitis by several mechanisms. Alcohol transiently increases pancreatic exocrine secretion and contraction of the sphincter of Oddi (the muscle regulating the flow of pancreatic juice through papilla of Vater). Alcohol also has direct toxic effects on acinar cells, including induction of oxidative stress in acinar cells, which leads to membrane damage (discussed later). Finally, chronic alcohol ingestion results in the secretion of protein-rich pancreatic fluid, which leads to the deposition of inspissated protein plugs and obstruction of small pancreatic ducts.
lar leakage causing edema, (2) necrosis of fat by lipases, (3) an acute inflammatory reaction, (4) proteolytic destruction of pancreatic parenchyma, and (5) destruction of blood vessels leading to interstitial hemorrhage.
http://ebooksmedicine.net
CAUSES: DUCT OBSTRUCTION ACINAR CELL INJURY DEFECTIVE INTRACELLULAR TRANSPORT
MECHANISMS:
LESIONS:
Release of intracellular proenzymes and lysosomal hydrolases
Activation of enzymes (intracellular or extracellular) (proteases) (lipase, phospholipase)
Delivery of proenzymes to lysosomal compartment
Intracellular activation of enzymes
Fig.17.1 Proposedpathogenesisofacutepancreatitis.
Inmildforms,thereisinterstitialedemaandfocalareasoffat necrosisinthepancreasandperipancreaticfat(