Acute pancreatitis begins when the pancreas activates its own digestive enzymes inside the acinar cells instead of in the duodenum.
The exocrine part of the pancreas is formed mainly by two groups of cells: acinar cells, which make inactive enzymes called zymogens that are released outside the cell and become active outside the pancreas, and duct cells. The enzymes of the pancreatic juice are kept in this inactive form — more than 90% of the pro-enzymes of the acinar cells are proteases such as trypsinogen, and the juice also carries amylase, lipase and nucleases. The main site of activation, or conversion, of trypsinogen is the duodenum, by cell-membrane-bound enzymes called enterokinase.
A small amount of trypsinogen is activated inside the acinar cells even in normal conditions, and protective mechanisms keep it from doing harm. These molecular safeguards — SPINK1, meso-trypsin, enzyme Y, trypsin itself, α1-antitrypsin and α2-macroglobulin — either prevent the activation of trypsinogen or inhibit the trypsin already activated inside the cell. A second safeguard is needed once trypsinogen reaches the lysosomes, and that safeguard is compartmentalisation: the zymogens of the acinar cell, including trypsinogen, are stored inside the zymogen granules, which are kept completely separate from the lysosomes. The lysosomes contain enzymes such as cathepsin B, which is able to activate trypsinogen inside the acinar cell.
The initial step in the pathogenesis of acute pancreatitis is the conversion of trypsinogen to trypsin within the acinar cells in an amount large enough to overwhelm these normal physiological mechanisms — an overwhelming activation of trypsin. The activated trypsin in this state then activates other zymogens: elastase, phospholipase A2, carboxypeptidase and further trypsin. One hypothesis, not completely clear at present, is that in patients with acute pancreatitis the trypsinogen inside the zymogen granules and the lysosome become co-localised at the same time, which leads to activation of trypsinogen by cathepsin B inside the acinar cell.
The other important change in the course of the disease is damage to the inter-cellular barriers of the acinar and ductal cells, which lets the activated enzymes leak into the interstitial space and finally into the systemic circulation. The very first site of cellular damage and inflammatory response is the pancreas itself, so the inflammation of the pancreas worsens all of the pathophysiological mechanisms above.
Release of pancreatic enzymes into the systemic circulation damages the endothelial cells, and that damage increases the expression of endothelial adhesion molecules such as VCAM-1, the initial step in the formation of the systemic inflammatory response in these patients. This activation of endothelial cells leads to vasoconstriction, hypoperfusion and progressive organ ischaemia.
Some patients with acute pancreatitis develop SIRS — the systemic inflammatory response syndrome — which is hypothesised to be caused by the release of pancreatic enzymes and cytokines into the portal circulation from the damaged pancreas. This activates the hepatic Kupffer cells, inducing inflammation and the production of large amounts of inflammatory mediators such as CRP and IL-6, which initiate the systemic inflammatory response that can propagate to other organs. The organs involved more commonly after the liver are:
- Lung — ARDS can develop, caused by circulatory activated phospholipase A, a lecithinase that is able to destroy the alveolar surfactant.
- Renal failure — hypotension and hypovolemia caused by the vasoactive amines made during SIRS can lead to renal failure.
- Hypocalcemia — caused by hypoalbuminemia mediated by the liver injury.
Pancreatic infections such as infected necrosis of the pancreas or infected pseudocyst formation can occur in the course of acute pancreatitis by haematogenous or lymphatic routes. The hypothesis behind the pathophysiological mechanism of pancreatic infection in acute pancreatitis is that during SIRS the colon becomes ischemic, which disrupts the epithelial barrier that prevents bacteria from entering the circulation from the colon. Once that physical barrier of the intestine is disrupted, a localised infection in the pancreas or a systemic infection can follow.
Several causes can lead to an overwhelming activation of trypsinogen and thus to acute pancreatitis, but the mechanism can be seen most clearly in gallstone-induced acute pancreatitis. The theory behind gallstone-induced pancreatitis is that blockade of the distal bile duct by the gallstone increases the pressure in the pancreatic duct, which damages the ductal and acinar cells and predisposes them to inflammation and damage with subsequent activation of trypsinogen.