Pathophysiology

Acute pancreatitis may occur when factors involved in maintaining cellular homeostasis are out of balance. The initiating event may be anything that injures the acinar cell and impairs the secretion of zymogen granules, such as alcohol use, gallstones and certain drugs. In addition, acute pancreatitis can develop when ductal cell injury leads to delayed or absent enzymatic secretion.

Once a cellular injury pattern has been initiated, cellular membrane trafficking becomes chaotic, with the following deleterious effects:

1) lysosomal and zymogen granule compartments fuse, enabling activation of trypsinogen to trypsin;

2) intracellular trypsin triggers the entire zymogen activation cascade;

3) secretory vesicles are extruded across the basolateral membrane into the interstitium, where molecular fragments act as chemoattractants for inflammatory cells.

Activated neutrophils then exacerbate the problem by leasign superoxide or proteolytic enzymes (cathepsins B, D, and G; collagenase; and elastase).

Finally, macrophages release cytokines that further mediate local (and, in severe cases, systemic) inflammatory responses. The early mediators defined to date are tumor necrosis factor-alpha, interleukin-6, and interleukin-8.

These mediators of inflammation cause an increase of pancreatic vascular permeability, leading to haemorrhage, oedema, and eventually pancreatic necrosis. As the mediators are excreted into the circulation, systemic complications can arise, such as bacteremia due to gut flora translocation, acute respiratory distress syndrome, pleural effusions, gastrointestinal haemorrhage and renal failure.

In mild pancreatitis the inflammatory response is well controlled. There may be oedema, usually confined to the pancreas, but tissue necrosis is uncommon. In severe pancreatitis the response is uncontrolled, leading to more widespread tissue injury and the many systemic manifestations of the disease. An inflammatory exudate rich in proteolytic enzymes, kinins, and vasoactive substances escapes from the pancreas into the lesser sac, retroperitoneum and peritoneal cavity. It can then be absorbed into the systemic circulation leading to shock, respiratory failure and renal failure.

The aetiology of shock in the early phase of acute pancreatitis is multifactorial. Sequestration of fluid in the interstitium, or the third space (intestinal tract), results in intravascular fluid depletion. However, restoration of euvolaemic status, as indicated by central venous pressure and pulmonary capillary wedge pressure measurements may not restore normal blood pressure and haemodynamic. Kinins, serotonin and vasoactive amines have been implicated as mediators of diminished peripheral vascular resistance and increased vascular permeability. Patients have high concentration of these substances in the peritoneal fluid during acute pancreatitis. Removal of this fluid by peritoneal lavage reverses the haemodynamic alterations.

A failure of system vascular resistance increases appropriately in the face of hypovolaemia and inability of the myocardium to compensate appropriately for this loss of peripheral resistance by increasing cardiac output. This is attributed to a myocardial depressant factor.

Circulated lipases and phospholipases destroy surfactant. Development of atelectasis and pneumonia is possible. Plevritis may occur as a result of pleura injuries by enzymes.

The mechanisms underlying the development of renal failure are: hypotension and hypovolaemia, reductions in glomerular filtration, toxic injuries of renal cells.