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Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease caused by progressive inflammatory destruction of the intra- and extra-hepatic bile ducts. PSC occurs frequently in the setting of inflammatory bowel disease (IBD), most commonly ulcerative colitis. PSC is estimated to affect 8 to12 persons per 100,000 population and between 2% and 5% of persons with IBD. PSC is more common in men than women, and the average age of onset is 40 years. However, the disease also occurs in children in whom the clinical manifestations and course may be quite different. The etiology of PSC is unknown. Based on its HLA-associations, the high prevalence of auto-antibodies, and its occurrence in persons with IBD, PSC is believed to be an autoimmune disease. However, the typical therapies for autoimmune diseases are ineffective in PSC, and in general, therapy of this disease is unsatisfactory. Ursodeoxycholic acid (ursodiol) is commonly used, but its effects on long-term outcome have not been demonstrated. PSC leads inexorably to end-stage liver disease, and its course can be complicated by the development of cholangiocarcinoma, a highly malignant tumor. PSC now accounts for 6% of adult and 1% of pediatric liver transplants in the United States.

Thus, PSC represents an important liver disease with major morbidity and mortality for which current therapies are unsatisfactory. These factors define PSC as a disease of high priority for basic and clinical biomedical research. In the recently published trans-NIH Action Plan for Liver Disease Research (http//liverplan.niddk.nih.gov), research goals of importance for PSC included development of reliable animal models; initiation of clinical studies to evaluate natural history, etiology and therapy; development of better means of imaging for diagnosis, staging and grading of PSC; and search for non-invasive biomarkers for disease progression and for early detection of cholangiocarcinoma.

The current NIH portfolio in PSC includes studies of animal models and both pilot and full-scale clinical trials of therapies. The “High-Dose Ursodiol Trial for Primary Sclerosing Cholangitis” is an investigator-initiated trial comparing the effectiveness of a 4- to 6-year course of high doses of ursodiol (28-30 mg/kg/day) to placebo. A total of 150 adult patients will be enrolled at seven U.S. medical centers. The major endpoints of therapy are prevention of cirrhosis, hepatic decompensation, liver transplantation, and death. Secondary endpoints include improvements in quality of life and histological, cholangiographical, and biochemical features of disease. The principal investigators and study sites include:

  • Keith Lindor, Mayo Clinic, Rochester, MN

  • Denise M. Harnois, Mayo Clinic, Jacksonville, FL

  • M. Edwyn Harrison, Mayo Clinic, Scottsdale, AZ

  • Timothy McCashland, University of Nebraska, Omaha, NE

  • Velimir Luketic, Virginia Commonwealth University, Richmond, VA

  • Alex Befelar, Saint Louis University, St. Louis, MO

  • Kris Kowdley, University of Washington, Seattle, WA

To further promote excellence in research on PSC, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in collaboration with the Office of Rare Diseases and the Morgan Foundation have organized a 2-day research workshop on PSC to be held on September 19-20, 2005 at the Lister Hill Conference Center on the campus of the National Institutes of Health in Bethesda, MD. The focus of the meeting will be to summarize current understanding of the epidemiology, diagnosis and staging, pathogenesis, disease associations, management, and treatment of PSC including use of ursodiol, newer innovative therapies, surgery and liver transplantation. The meeting will also allow for discussion of areas of greatest opportunity for future research. Information on registration and the current agenda for the workshop are available at: http://www.niddk.nih.gov/fund/other/primarysclerosing.