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The Genetics Of Inflammatory Bowel Disease

Posted Aug 24 2008 1:49pm
ANNOUNCER: Every eight weeks, Lisa Gurevitz makes a long trip to the University of Chicago Hospitals for an infusion of the medicine Remicade.

LISA GUREVITZ: I have Crohn's disease. My father has ulcerative colitis. My mom was just diagnosed with Crohn's disease. I had a brother who had Crohn's disease. Most of the females on my mom's side of the family at point or another had some type of inflammatory bowel disorder.

DR. DAVID RUBIN: Well, what we currently understand is that the strongest risk factor for an individual to have inflammatory bowel disease is either to be the child of two parents with inflammatory bowel disease. And then, secondly, to be a sibling of somebody who has inflammatory bowel disease.

ANNOUNCER: Lisa's father, Robert Jacobs, had his first flare-up of ulcerative colitis as a young man.

BOB JACOBS: My first bout, Lisa was just born. It was in 1971. I was very sick for about two years.

ANNOUNCER: Bob then went symptom free until the year 2000. When the colitis flared again, it was severe.

BOB JACOBS: It was bad enough that I had to have surgery. I got sick in January of 2000 to the degree that I was unable to work. I was home for eight months.

ANNOUNCER: The latest diagnosis of Inflammatory Bowel Disease in the family came as one of those surprises in life that, in hindsight, should not have been.

MARY LOU JACOBS: I actually was diagnosed with Crohn's disease just recently. I've had for many years some sort of stomach problems, stomach pain, diarrhea on and off, an ulcer.

ANNOUNCER: Mary Lou Jacobs, like Bob, now, too, is doing well. In her case, medication is keeping her disease under control. The real IBD tragedy in the family was what happened to the Jacobs' son, Brian. His story starts with a doctor who, the Jacobs say, was quick to dismiss a diagnosis of Crohn's disease.

MARY LOU JACOBS: Brian was 18. And he was anemic and had had diarrhea for quite a while. And the pediatrician kept saying, "He's anorexic." It was his first year of college. He's not adjusting. And I kept saying, "No, you've got the wrong person."

The first thing I said, "Do you think he has Crohn's disease?"

He said, "Oh, no, absolutely not."

ANNOUNCER: Over the next few years, Brian's symptoms got worse. In the Summer of 1992, when Brian was 24, he underwent surgery.

BOB JACOBS: Things just went downhill from the sixth day post-op. He was taking massive doses of immunosuppressive drugs. They compromised his immune system. And he literally came apart surgically at the site of the anastomosis. Peritonitis set in and then it was all downhill from that point. He never left the hospital. He died on December 12th.

ANNOUNCER: Families like the Jacobs's provided evidence of a genetic link in IBD from the time Crohn's disease was first identified.

DAVID RUBIN, MD: When the disease called Crohn's disease was first described by Burrill Crohn and Oppenheimer and others in 1932, they were already seeing that some families had more than one person in the family with a similar set of symptoms and problems.

ANNOUNCER: Evidence for a genetic link in IBD comes also from two other observations. Prevalence varies according to ethnic background. And risk increases when an identical twin has disease.

Judy Cho, a research scientist at the University of Chicago, led a team that made a milestone discovery in the hunt for a genetic link to IBD.

In the summer of 2000, the team found that many patients with Crohn's disease have mutations in a gene called NOD-2.

DR. JUDY CHO: And so if you have one copy of those risk alleles or mutations, it increases your risk of developing Crohn's disease, about two to four fold over the general population. If you carry two copies of the NOD-2 mutations, your chance of developing Crohn's disease increases 20-40 fold.

ANNOUNCER: In the Jacobs family, the first diagnosis of IBD among the two children came when Lisa was ten.

MARY LOU JACOBS: Lisa never let anything stand in her way when she wanted to do something and ice skating was her #1 thing.

LISA GUREVITZ: I was very sick. I think I was in and out of the hospital a few times that spring, and I had my solo for the first time in the ice show, and I was in five or six numbers, and I had a lot of quick changes with costumes, so right during my solo I was skating, and I tripped and I basically fell in front of, you know, at that time it was everybody in the world that I knew.

MARY LOU JACOBS: Just kind of felt flat on her face, got up, finished it, and we had her in the hospital the next day.

LISA GUREVITZ: If I wasn't as sick as I was, I probably would have been able to concentrate more.

MARYLOU JACOBS: For a while we were holding her together with chicken soup to get her through that because she absolutely would not go into the hospital before the ice show.

ANNOUNCER: Judy Cho's research helps explain just what may go wrong in the intestines of Crohn's patients like Lisa.

JUDY CHO, MD: What is unique about the intestine over any other organ or tissue system in the body is that it's exposed to very high concentrations of bacteria within the intestinal lumen. That constant interplay-how to balance the right about of inflammation, the exposure to these high concentrations of bacteria, how to limit that inflammation-is what we think is the key to understanding Crohn's disease and ulcerative colitis.

DAVID RUBIN, MD: The NOD-2 protein in healthy individuals likely responds to the environment and turns on a controlled inflammatory reaction and then it is turned off in a number of other ways. In people with abnormal NOD-2 proteins, they have inflammation that may be turned on when it shouldn't be or, once it's turned on, it doesn't know how to turn itself off.

ANNOUNCER: The genetics of Crohn's disease is very much on Lisa Gurevitz's mind. She got married in the Fall of 2002, and she and her husband are planning a family.

LISA GUREVITZ: I've always known, or had a feeling since I was a little girl and first diagnosed with the Crohn's that it would be a strong possibility that one or more of my children would have the Crohn's, especially after my brother developing it, as well.

ANNOUNCER: What value would being tested for the abnormal NOD-2 gene have for a person like Lisa? What about for a child of hers?

JUDY CHO, MD: Because carrying a NOD-2 mutation does not assure that you're going to get disease and that conversely, not every patient with Crohn's disease has NOD-2, we don't think that the genetic testing, testing an individual whether they have the mutations or not, is going to be useful in predicting disease onset.

ANNOUNCER: Doctors say there may be some value, however, in testing for NOD-2 in patients, like Lisa, who are already diagnosed. The testing may help determine what subtype of disease a patient may have, and treatment decisions might be adjusted, accordingly.

DAVID RUBIN, MD: Patients with NOD-2 abnormalities are more likely to have disease that's confined to the last part of the small intestine, called the terminal ileum. And the behavior of that disease tends to be more of a stricturing or scarring type of disease, rather than inflammatory or fistulizing disease. In addition, patients with NOD-2 abnormalities are more likely to have a younger age of onset of the disease.

ANNOUNCER: There's also the possibility that knowledge about genetic factors in IBD may lead to prevention or a cure. But those goals remain far off, and depend on a great deal more research.

JUDY CHO, MD: We don't really understand at this point in time what the prevention of Crohn's disease may entail. But if through genetics and through the identification of additional genes we can identify a subset of individuals at high risk, we can then start thinking about prevention, which is really what families and patients care about. And so if we could identify disease at its earliest stages, if we can start identifying the earliest triggers that go wrong to cause disease, then we can start thinking about the big words: like prevention and cure.

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