How Does PSC Lead to IBD?

Many patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD), which becomes more severe after liver transplantation, researchers report in the May issue of Clinical Gastroenterology and Hepatology. These patients might require special immunosuppressive regimens.

PSC is a chronic, cholestatic liver disease that eventually leads to cirrhosis and liver failure, requiring transplantation. Little is known about the pathogenesis of PSC, but 70%–80% of patients also have IBD, so immune dysregulation and loss of tolerance to gut bacteria could be involved.

PSC-associated IBD is phenotypically different from IBD in patients without liver disease, with an increased frequency of pancolitis, rectal sparing, and backwash ileitis, and a milder clinical course of colitis. Patients with PSC-associated IBD have a greater risk for colorectal neoplasia than patients with only IBD, and their risk increases even further after liver transplantation.

Kristin Kaasen Jørgensen et al. investigated whether differences in IBD activity after liver transplantation were affected by immunosuppressive regimens or other factors related to the transplantation. They used a Nordic liver transplant registry to follow 439 patients with PSC who underwent liver transplantation (353 had IBD at the time of transplantation), and compared patients’ course of IBD before and after liver transplant.

They found that IBD activity either decreased or remained unchanged in 60% of patients after liver transplantation, but worsened in 40% of patients. Patients with worsened disease had increased levels of colon inflammation, number of relapses, overall IBD activity, and risk of colectomy.

Dual immunosuppressive therapy with tacrolimus and mycophenolate mofetil (MMF) was associated with increased IBD activity after transplant, whereas the combination of cyclosporine A and azathioprine appeared to protect against IBD.

Ten of 11 patients who developed de novo IBD had received tacrolimus after liver transplantation. The authors were surprised to find this association, because tacrolimus is a well-established treatment for IBD.

In an editorial that accompanies the article, Udayakumar Navaneethan and Bret A. Lashner propose that tacrolimus could increase intestinal permeability and endotoxemia to induce an inflammatory response. Alternatively, tacrolimus might reduce T-cell apoptosis to a greater extent than cyclosporine to promote colon inflammation.

Jørgensen et al. say that it is difficult to determine whether the association with deteriorated IBD activity after liver transplantation was caused by tacrolimus, MMF, or by synergistic effects of the combination therapy.

Nonetheless, Navaneethan and Lashner conclude that patients with PSC-IBD need careful and regular follow-up evaluation and monitoring for IBD after liver transplantation—every subsequent visit should include questions about bowel symptoms. Patients also require yearly follow-up surveillance colonoscopy for colon neoplasia—even in patients with no disease activity.

Navaneethan and Lashner state that physicians should consider the use of a tacrolimus-free immunosuppressive regimens for patients with IBD at the time of liver transplantation. Further studies are needed to determine whether cyclosporine or sirolimus with MMF could be used safely without affecting graft rejection and exacerbating IBD activity.

More Information on PSC

Read the article online.
Jørgensen KK, Lindström L, Cvancarova M, et al. Immunosuppression after liver transplantation for primary sclerosing cholangitis influences activity of inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11:517–523.

Read the accompanying editorial.
Navaneethan U, Lashner BA. Effects of immunosuppression and liver transplantation on inflammatory bowel disease in patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2013;11:524-525.

About Kristine Novak, PhD, Science Editor

Dr. Kristine Novak is the science editor for Gastroenterology and Clinical Gastroenterology and Hepatology, both published by the American Gastroenterological Association. She has worked as an editor at biomedical research journals and as a science writer for more than 12 years, covering advances in gastroenterology, hepatology, cancer, immunology, biotechnology, molecular genetics, and clinical trials. She has a PhD in cell biology and an interest in all areas of medical research.
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