The Cantankerous Pancreas

Boston University scientists have discovered two new genetic mutations associated with chronic pancreatitis, a painful inflammatory disease of the digestive tract that afflicts about 100,000 Americans.

The disease, which can lead to severe digestive problems, chronic abdominal pain, and diabetes, occurs when digestive juices secreted by the pancreas, notably an enzyme called trypsin, become active before reaching their intended destination — the nearby small intestine — and instead begin eating away at the pancreas itself.

“Trypsin is the bad guy in pancreatitis,” says Miklos Sahin-Toth, an associate professor in the School of Dental Medicine’s department of molecular and cell biology, who has been studying the disease for nearly a decade. Over the past year, he and SDM postdoctoral researcher Richard Szmola tracked down two genetic mutations that hinder the body’s production of a separate enzyme known as chymotrypsin C (CTRC) — which, in a healthy body, regulates trypsin and keeps it from going active in the wrong places. Their findings, which could improve screening and early treatment of the disease, appeared earlier this week in Nature Genetics online.

Sahin-Toth and Szmola collaborated with German gastroenterologists at hospitals in Leipzig and Berlin to scour the genetic profiles of about 1,320 pancreatitis patients and 3,320 healthy individuals. They focused on the gene sequence that codes for CTRC and looked for variants that occurred more frequently in people with pancreatitis than in the healthy control subjects.

“We needed to keep searching until the differences became significant,” explains Sahin-Toth. Two mutations made the cut, occurring in 3.3 percent of people with chronic pancreatitis, but in only 0.7 percent of healthy individuals. The researchers then replicated their results in patients whose pancreatitis resulted from alcohol abuse. The same variants also showed up disproportionately in a third study population: patients from India with so-called tropical pancreatitis, prevalent in tropical climates.

Once the genetic associations were validated, Sahin-Toth and Szmola used cultured human kidney cells to confirm that the variants actually decreased the production and activity of CTRC. Their findings are the first genetic links to pancreatitis to be uncovered since 2000, and Sahin-Toth hopes the discovery will “revitalize” the search for the disease’s genetic risk factors. Szmola says their findings won’t immediately lead to new treatments, since they need to perform animal experiments to verify that CTRC is a protective enzyme — but armed with this additional genetic information, doctors could more easily persuade patients whose DNA puts them at greater risk for pancreatitis to watch what they eat and not to drink, as about 70 percent of chronic pancreatitis cases can be traced back to alcohol abuse, according to the National Institutes of Health.

“Such discoveries provide for more refined screening to identify those at greater risk of developing the disease,” says Szmola, “and that brings the hope of intervention at an earlier stage.”

Chris Berdik can be reached at cberdik@bu.edu.