As early as 1952, Comfort and Steinberg9 reported a hereditary predisposition to chronic or recurrent pancreatitis that is independent of additional environmental factors in a number of families. Hereditary pancreatitis (HP) is an autosomal dominant disorder with a clinical manifestation that is indistinguishable from other etiological varieties of pancreatitis. In affected patients, HP begins with recurrent attacks of acute pancreatitis that usually start in childhood, but the age of onset of the disease can vary considerably and can sometimes be delayed until late in adulthood. The severity of acute attacks ranges from mild to complicated cases with progression to pancreatic necrosis and organ failure. Recurrent attacks of acute pancreatitis frequently progress to chronic disease at an early age and are associated with significant lifetime risk for the development of pancreatic cancer.
Although HP is not a common disease and to date only several hundred families have been identified worldwide, the studies addressing the onset of HP have permitted some recent breakthroughs in understanding the pathophysiology of acute and chronic pancreatitis in general.
The exocrine pancreas synthesizes and secretes large amounts of digestive proteases and a number of protective mechanisms are operative to prevent a self-destruction of the pancreas by premature protease activation. The induction of acute pancreatitis is believed to follow — independent of the different etiologic factors, such as gallstones, toxins, hyperlipidemia, hypercalcemia, inheritance, and others — a uniform mechanism that primarily affects the acinar cell and involves the activation of trypsinogen and other intracellular digestive enzymes. The initial triggering event in pancreatitis must therefore include a disruption of the protective mechanisms that prevent the primary activation of digestive enzymes (see Chapter 11). The intracellular zymogen activation represents an early event in the disease process and has to be looked at separately from other pathogenic events that include the generation of oxygen free radicals, the release of cytokines, the infiltration of pancreatic tissue by inflammatory cells, and in some cases the progression to necrotizing pancreatitis. Acute pancreatitis is associated with a proteolytic autodigestion of the pancreas and because trypsin is a known activator of other proteolytic enzymes in the gut, dysregulation of pancreatic trypsin activity has long been regarded as a key event in the onset of pancreatitis.
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