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Identifying the molecular mechanisms responsible for acute and chronic pancreatitis in humans is one of the most difficult problems in modern science. Major obstacles include the inaccessibility of the human pancreas to observation, the unpredictability of disease onset, the non-specific nature of abdominal pain early in the course of acute pancreatitis, an inability to biopsy the pancreas safely, difficulty in distinguishing initiating events from the concomitant inflammatory response, and the obvious problems of investigating a tissue that self-destructs during the disease process. Even fundamental questions as to whether pancreatitis begins in the acinar cell or through pathology related to the pancreatic ducts continue to be debated.1 ,2 Animal models also fail to provide critical insights, partly because of the artificial methods used to induce pancreatitis.3-5
The discovery of the mutations in the cationic trypsinogen gene responsible for hereditary forms of pancreatitis in American and European kindreds6 ,7 provided tremendous insights into the mechanism of acute and chronic pancreatitis in these families. It was hypothesised that the cationic trypsinogen R117H mutation eliminates a key hydrolysis site on the chain connecting the two globular domains of trypsin that is part of a fail-safe trypsin inactivation mechanism. Rather than being autolysed, prematurely activated mutant trypsin remains active within the pancreas, activates all other digestive enzymes, leads to acinar cell autodigestion and, therefore, acute pancreatitis. The second major insight was that the chronic pancreatitis commonly seen in patients was associated with mutations in trypsinogen. This observation suggests that recurrent acute pancreatitis may lead to chronic pancreatitis.2 ,6 ,7 Families with the cationic trypsinogen R117H and N21I mutations have now been identified in Caucasians throughout the United States and Europe.
In this issue, Nishimori et al (see page 259) report the presence of the same two cationic trypsinogen gene mutations in Japanese kindreds with hereditary pancreatitis as seen in Caucasians. Additional polymorphisms in the cationic trypsinogen gene were also reported, but they either fail to result in an amino acid substitution or segregate with the panceatitis phenotype. Thus, this report expands the observation of pancreatitis causing cationic trypsinogen mutations to Asians and further defines the limits of pancreatitis causing mutations to cationic trypsinogen R117H and N21I. As hereditary pancreatitis is an autosomal dominant disorder, mutations that cause loss of function would not cause the syndrome. Furthermore, as hereditary pancreatitis is relatively rare and a number families have been investigated, it is unlikely that many additional gain-of-function mutations, such as the R117H mutation, will be identified.
The question of why the cationic trypsinogen N21I mutation predisposes individuals to pancreatitis was also tackled. Computer analysis of the N21I substitution suggests that the mutation changes the secondary structure in the region of the N21I mutation from a “turn” into a “sheet” conformation. The implications of the predicted secondary structural changes on the tertiary structure and trypsin biology may be important, but remain speculative. Other hypotheses on the role of the N21I mutation have also been offered6 and could be consistent with these predictions. However, proving the actual structural changes caused by the mutation and determination of the mechanism through which the function of trypsin is altered will require further work.
Identification of the same two mutations in the cationic trypsinogen gene in kindreds with hereditary pancreatitis of both Caucasian and Asian ancestry, combined with the finding that potent trypsin inhibitors prevent pancreatitis associated with endoscopic retrograde cholangiopancreaography in humans,8 provides us with strong evidence that cationic trypsinogen plays an important role in human acute pancreatitis. This represents a major conceptual breakthrough. Now, attention can be focused on experimental models of acute pancreatitis with premature trypsinogen activation, on mechanisms of premature trypsinogen activation and trypsin stabilisation, and on strategies to limit these processes in susceptible individuals.
Another interesting note is that the only mutations identified to date in patients with hereditary pancreatitis are in the human cationic trypsinogen gene. No pancreatitis associated mutations have been identified in anionic trypsinogen, nor in any of the other digestive enzymes. Indeed, human cationic trypsinogen is relatively unique among members of the trypsin family in its ability to autoactivate.9 Humans may differ from experimental animals in that acute pancreatitis in animals may require lysosomal hydrolases, such as cathepsin B, to activate trypsinogen.10 Thus, in experimental animals, conditions must be met that allow trypsinogen and cathepsin B to co-localise, whereas in humans trypsinogen activation may occur is a variety of locations under relatively milder conditions. However the conditions that initiate excessive trypsinogen activation and pancreatitis in hereditary and non-hereditary pancreatitis require further investigation.
A final important finding in Nishimori et al’s report was that four of the six families with hereditary pancreatitis did not have mutations in the cationic trypsinogen genes. This observation suggests that at least one additional gene mutation is associated with hereditary pancreatitis. Discovery of this new gene may provide further insights into the mechanisms of acute and chronic pancreatitis.
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