Genetic Causes of Pancreatitis
Toan D. Nguyen, M.D.
Division of Gastroenterology, Department of Medicine
University of Washington & VA Puget Sound Health Care System
Seattle, Washington

Inflammation of the pancreas is manifested as either acute pancreatitis, which does not cause irreversible structural or functional damage to the pancreas, or chronic pancreatitis, where reversible changes are observed (e.g pancreatic calcifications, pancreatic ductal abnormalities, pancreatic insufficiency). While the common etiologies of pancreatitis have been identified (e.g. gallstones or sludge impacted at the Ampula of Vater, alcohol, hyperlipidemia, hypercalcemia), the exact mechanisms which trigger pancreatic inflammation remain to be clearly defined. Recently, two genetic causes of pancreatitis have been established: mutations of the trypsinogen gene in hereditary pancreatitis and mutaions in the gene for cystic fibrosis (CF) in CF-associated chronic pancreatitis. These discoveries are not only important clinical advances, they also contribute substantially to our understanding of the pathophysiology of pancreatitis. They will be subjected of this review.

In this report, we reviewed two genetic causes for pancreatitis. The different features of these genetic diseases are summarized in Table II.

Comparison of the mutations of trypsinogen and CFTR

Protein            Functional               Cell type            Mechanism of           Type of

Affected         consequences           affected                    defect                  pancreatitis  

Trypsinogen   Gain of function       Acinar cells         Autolysis                   Acute

PSTI              Loss of function       Acinar cells         Autolysis                   Acute

CFTR            Loss of function       Ductal cells         Duct of obstruction  Chronic

Identification of a genetic cause allows us to pinpoint a defective protein and thus elucidate the mechanism responsible for this disease. This elucidation is most important for pancreatitis where the pathogenesis is still poorly defined. Mutations of trypsinogen and of PSTI/SPINK1 indicate that premature activation of trypsin and its improper activity cause pancreatitis, a mechanism previously postulated but never conclusively established. The association between chronic pancreatitis and CFTR mutations underlines the importance of CFTR in pancreatic function and supports the role for pancreatic function in the generation of chronic pancreatitis. Reflecting the complexity of pancreatic pathophysiology, the genetic defects affect different cells of the pancreas: the pancreatic acinar cells where digestive enzymes are manufactured, store and secreted, and the pancreatic duct cells where fluid and bicarbonate are secreted. Furthermore, the defects produced by the mutations include both gain of function (trypsin) and loss of function (CFTR). Finally trypsinogen mutations account for recurrent bouts of acute pancreatitis while CFTR mutations are associated with chronic pancreatitis. Thus, while the identifications of certain genetic causes for pancreatitis advance our knowledge of this disease, they also highlight the complexity of pancreatic inflammation.
These achievements should not therefore lull us into slowing investigations into the pathogenesis and treatment pancreatitis; they should rather stimulate us to increase these efforts.

Vietnamese Medical Journal, 3: 33-38, 2003.

Toan D. Nguyen, M.D.
Division of Gastroenterology, Department of Medicine
University of Washington & VA Puget Sound Health Care System
Seattle, Washington

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