Pathogenesis of acute pancreatitis

●Although a number of conditions can precipitate acute pancreatitis, only a small fraction of patients with these predisposing conditions develops acute pancreatitis. For example, the incidence of acute pancreatitis is only 3 to 7 percent in patients with gallstones and 10 percent in alcoholics. 

●It is unclear why alcohol-induced pancreatitis occurs only after many years of alcohol abuse and not after a single binge in individuals not habituated to alcohol use. However, several mechanisms have been proposed:

•Sensitization of acinar cells to cholecystokinin (CCK)-induced premature activation of zymogens

•Potentiation of the effect of CCK on the activation of transcription factors, nuclear factor kB, and activating protein-1

•Generation of toxic metabolites such as acetaldehyde and fatty acid ethyl esters

•Sensitization of the pancreas to the toxic effects of coxsackie virus B3

•Activation of pancreatic stellate cells by acetaldehyde and oxidative stress and subsequent increased production of collagen and other matrix proteins

●Two factors have been suggested as the possible initiating event in gallstone pancreatitis: reflux of bile into the pancreatic duct due to transient obstruction of the ampulla during passage of gallstones, or obstruction at the ampulla secondary to stone(s) or edema resulting from the passage of a stone.

●In hypertriglyceridemia, free fatty acids are released from serum triglycerides in toxic concentrations by the action of pancreatic lipase within pancreatic capillaries.

●Premature activation of pancreatic zymogens within the pancreas has also been proposed as the pathogenetic mechanism for the acute attacks of pancreatitis seen in patients with hereditary pancreatitis.

●How CFTR mutations might produce acute pancreatitis is unclear. A possible explanation is that the mutations are associated with production of a more concentrated and acidic pancreatic juice leading to ductal obstruction or altered acinar cell function.

●It is becoming increasingly apparent that the central requirement for induction of acute pancreatitis is the intraacinar activation proteolytic enzymes, which ultimately leads to an autodigestive injury to the gland.

●Activated pancreatic enzymes, microcirculatory impairment, and the release of inflammatory mediators lead to rapid worsening of pancreatic damage and necrosis. However, approximately 80 percent of patients with pancreatitis develop only interstitial pancreatitis rather than necrotizing pancreatitis; the factors involved in limiting the pancreatic damage are not well understood.

●Some patients with severe pancreatic damage develop systemic inflammatory response syndrome (SIRS) probably mediated by activated pancreatic enzymes and cytokines released into the circulation from the inflamed pancreas. A compensated antiinflammatory response syndrome (CARS) balances SIRS and leads to recovery. An imbalance between SIRS and CARS results in severe organ failure with high morbidity and mortality. The causes for such imbalance are not clearly understood.

●During the course of acute pancreatitis, the gut barrier is compromised, leading to translocation of bacteria, which can result in local and systemic infection. The consequences of bacterial translocation from the gut in acute pancreatitis can be lethal. Local bacterial infection of pancreatic and peripancreatic tissues occurs in approximately 30 percent of patients with severe acute pancreatitis, potentially resulting in multiorgan failure and its sequelae. 

●Evidence questions the role of premature activation of trypsinogen as the main event in the pathogenesis of acute pancreatitis and this may only cause acinar injury but not the inflammatory response in pancreatic and extra-pancreatic areas. The more pronounced pancreatic and extra-pancreatic (systemic) inflammatory response is driven by NFkB activation. Endoplasmic reticulum and oxidative stress together with the induction of a defective autophagic pathway are other important factors described in the pathogenesis along with the role of TLR4 (Toll-Like Receptor family).