Acute pancreatitis pathophysiology

The pathophysiology of acute pancreatitis involves acute inflammation and edema of the pancreas. The process is mediated by the abnormal activation of trypsinogen to trypsin inside the pancreas, and the involvement of other mediators such as cathepsin, lysosomal enzymes, and caspases. Intrapancreatic activation of amylase and lipase is what causes necrosis of pancreatic cells.

• The two types of pancreatitis are mild pancreatitis and severe pancreatitis, which are separated based on whether their predominant response to cell injury is inflammation or necrosis, respectively.
• In mild pancreatitis there is inflammation and edema of the pancreas.
• In severe pancreatitis, there are additional features of necrosis and secondary injury to extrapancreatic organs.
• Both types share a common mechanism of abnormal inhibition of secretion of zymogens and inappropriate activation of pancreatic zymogens inside the pancreas, most notably trypsinogen. Normally, trypsinogen is activated to trypsin in the duodenum where it assists in the digestion of proteins.
• During an acute pancreatitis episode there is co-localization of lysosomal enzymes, specifically cathepsin with trypsinogen.
• Cathepsin activates trypsinogen to trypsin leading to further activation of other molecules of trypsinogen and immediate pancreatic cell death according to either the necrosis or apoptosis mechanism (or a mix between the two).
• The balance between these two processes is mediated by caspases which regulate apoptosis and have important anti-necrosis functions during pancreatitis: preventing trypsinogen activation, preventing ATP depletion through inhibiting poly ADP-ribose polymerase, and by inhibiting the inhibitors of apoptosis (IAPs). If, however, the caspases are depleted due to either chronic ethanol exposure or through a severe insult then necrosis can predominate.

• The aforementioned inflammatory process which primarily manifests as oversecretion of zymogens and activation of trypsinogen in the pancreas is often a result of transient obstruction of the pancreatic ducts.
• This obstruction is the triggering insult which is the underlying mechanism for the most common cause of acute pancreatitis – migrating gallstones or sludge.
• Other causes of transient obstruction include:
  • Dysfunctional sphincter of Oddi
  • Pancreas divisium, though the association of these disorders with acute pancreatitis has come into question in the absence of underlying genetic disease.^[1][2]

• Alcohol is proposed to have a direct, toxic effect on the pancreas.
• It is metabolized by the pancreas and may result in oxidative stress and induce the release of pancreatic enzymes. This excessive release may result in auto-digestion of the gland.
• Additionally, alcohol may result in activation of pancreatic stellate cells which are primarily responsible for fibrosis of the gland and weakening of the intracellular membranes, which results in anatomical changes in the pancreas, further predisposing to pathological auto-digestion.^[3][2]

• Triglyceride rich lipoproteins are primarily comprised of chylomicrons and VLDLs. These molecules are large and in abundance in conditions of hypertriglyceridemia.
• These molecules have been postulated to occlude pancreatic capillaries and result in subsequent acinar pancreatic structural changes.
• Additionally, this triggers the release of pancreatic lipases to catabolize the lipid rich molecules.
• It results in increased local oxidative stress which further contributes to the inflammatory response in the pancreas, resulting in the symptomatology of acute pancreatitis. ^[4][5][6][2]

• The mechanism by which post-ERCP pancreatitis (PEP) occurs is not fully understood.
• However, it is proposed that mechanical, chemical, allergic, and thermally induced trauma to the pancreatic orifice and duct are the underlying causes.
• Instrumental manipulation of the pancreatic orifices, as well as chemical and allergic damage due to contrast injection contribute to the pathogenesis.^[7][8]
• Additionally, cauterization of the superficial and intraluminal pancreatic structures may result in thermal damage.^[9]
• These iatrogenic traumatic and toxic influences may, again, stimulate the fibrogenic pancreatic stellate cells to initiate a cascade of events responsible for activation of zymogens and autodigestion of the pancreas.^[10][11][2]

• The acute pancreatitis (acute hemorrhagic pancreatic necrosis) is characterized by:
  • Acute inflammation and necrosis of pancreas parenchyma
  • Focal enzymatic necrosis of pancreatic fat
  • Vessel necrosis
  • Hemorrhage

• These are produced by intrapancreatic activation of pancreatic enzymes.
  • Lipase activation produces the necrosis of fat tissue in pancreatic interstitium and peripancreatic spaces.

• Necrotic fat cells appear as:
  • Shadows
  • Contours of cells
  • Lacking the nucleus with pink, finely granular cytoplasm
• Calcium precipitates (hematoxylinophilic).
• Digestion of vascular walls results in thrombosis and hemorrhage.
• Inflammatory infiltrate is rich in neutrophils.

Several genes have been proposed to play a role in the pathogenesis of acute pancreatitis. While the exact role of every implicated genetic mutation is not fully understood, the following genes have been associated with the development of acute pancreatitis:^[12][2]

• CFTR
• PRSS-1
• SPINK-1
• Chymotrypsin C
• Claudin-2
• Calcium sensing receptors

The most common conditions associated with acute pancreatitis include:^[2]

• Alcoholism^[13]
• Smoking^[14]
• Obsesity^[15]

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