Dec. 10, 2001 CHAPEL HILL – Working together, medical school faculty at the University of North Carolina at Chapel Hill and Duke University have discovered a previously unrecognized cause of pancreatitis, a common ailment often correctly attributed to alcohol or drug abuse but also of mysterious -- or “idiopathic” -- origin. The newly discovered culprit has nothing to do with substance use or anatomic abnormalities, the researchers say. Instead, it involves mutations in the gene that causes the highly debilitating disease known as cystic fibrosis or, in the words of some of its younger victims, “65 roses.”
“We found that the risk of pancreatitis increased about 40-fold in people having two mutations in the gene responsible for cystic fibrosis and increased 20-fold in people having a mutation known as N34S in the pancreatic secretory trypson inhibitor, or PSTI, gene,” said Dr. Peadar G. Noone, assistant professor of medicine at UNC. “When they had mutations in both of these genes, the risk jumped 900-fold.”
A report on the team’s findings appears in the December issue of Gastroenterology, a medical journal. Other authors are Drs. Zhaoqing Zhou, former research associate; Lawrence M. Silverman, professor of pathology and laboratory medicine; and Michael R. Knowles, professor of medicine, all at UNC, and Drs. Paul S. Jowell and Jonathan A. Cohn, associate professor and professor, respectively, of medicine at Duke. Silverman also directs UNC’s Molecular Genetics Laboratory.
“This work proves what we suspected from a preliminary study we did in 1997, published in the New England Journal of Medicine, that involved three patients with double mutations,” Noone said. “It shows you can have pancreatitis from these mutations without having any of the severe lung disease people normally associate with cystic fibrosis.”
Patients with classic cystic fibrosis cannot regulate the salt and water content of cells lining the airways in their lungs. As a result, they produce overly thick and sticky mucous that traps disease-causing bacteria and other organisms in their lungs and leads to chronic infections and shorter lives.
Such patients can also suffer from pancreatitis -- an inflamed pancreas causing pain, poor insulin production and frequent complications, Noone said.
That fact led the researchers to suspect that some people with pancreatitis of unknown origin and without the pronounced pulmonary symptoms characteristic of CF might carry one or more mutations in the CF gene.
For the new study, they tested tissue from 39 patients with chronic pancreas inflammation and found genetic mutations in 24 of them, including nine with cystic fibrosis gene mutations on both chromosomes and nine with N34S mutations in the PSTI gene, he said.
Thus it appears that carriers -- those with only one chromosome affected -- of the CF gene mutations are not predisposed to pancreatitis. Otherwise, because between one in 20 to 25 U.S. whites are carriers, the number of patients with it would be staggering -- close to 10 million people in this country alone.
“These findings are a message to doctors who specialize in this disease -- gastroenterologists primarily, but also generalist physicians who might see people with idiopathic pancreatitis -- that they should really consider looking for mutations in genes encoding for CF in patients with other symptoms,” Noone said. “Often physicians or relatives of people with pancreatitis of unknown origin suspect they are abusing alcohol or drugs when really they are not. It’s always useful to be able to tell patients what’s causing their disease.”
Knowles agreed that the findings were important for several reasons.
“One, testing can now begin for genetic contributions to chronic pancreatitis,” he said. “Two, we can now understand better the mechanisms involved in the development of this clinical problem. Both will speed development of novel approaches to preventing or treating chronic pancreatitis.”
From a broader perspective, Knowles said, the work is an excellent example of the evolving recognition that clinical disease can result from unexpected genetic risk factors or predispositions.
“In this case, the presence of certain mutations in the CF gene, when combined with other genetic or environmental influences, provokes chronic pancreatitis in some individuals rather than cystic fibrosis,” the physician said.
Silverman said the work serves as a model for other situations in which the same gene may be involved with apparently different disorders, depending on genetic or environmental interactions.
“We now know of at least two disorders, other than cystic fibrosis that are caused by mutations in the CF gene,” the scientist said. “In addition to this example of chronic nonalcoholic pancreatitis, mutations in the CF gene are also associated with a form of male infertility.”
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