Pathogenesis of primary sclerosing cholangitis
Authors: Evangelos Cholongitas, Vibhakorn Shusang, David Patch, Andrew K. Burroughs
Journal: Journal of Hepatology (2008)

We read with great interest the excellent review by Weismuller et al. [[1]Weismuller T.J. Wedemeyer J. Kubicka S. Srassburg C.P. Manns M.P. The challenges in primary sclerosing cholangitis – aetiopathogenesis, autoimmunity, management and malignancy.J Hepatol. 2008; 48: S38-S57Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar], recently published in the Journal, regarding the pathogenesis and management of primary sclerosing cholangitis (PSC). Although PSC has been considered an autoimmune disease, because autoantibodies are detected frequently, there is neither consistent nor favorable response to immunosuppressive therapy. However, as the authors emphasized [[1]Weismuller T.J. Wedemeyer J. Kubicka S. Srassburg C.P. Manns M.P. The challenges in primary sclerosing cholangitis – aetiopathogenesis, autoimmunity, management and malignancy.J Hepatol. 2008; 48: S38-S57Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar], some experimental studies have supported the hypothesis of an enterohepatic circulation of long-lived lymphocytes, which are generated in the gut and translocated to the liver [[2]Grant A.J. Lalor P.F. Salmi M. Jalkanen S. Adams D.H. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease.Lancet. 2002; 359: 150-157Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar]. This could explain the high frequency of inflammatory bowel disease (IBD) in PSC patients and why PSC may develop many years after colectomy. We would like to draw attention to the results of our recently published study [[3]Cholongitas E. Shusang V. Papatheodoridis G. Marelli L. Manousou P. Rolando N. et al.Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2008; 14: 138-143Crossref PubMed Scopus (147) Google Scholar], which add to and support this hypothesis(1). In this study [[3]Cholongitas E. Shusang V. Papatheodoridis G. Marelli L. Manousou P. Rolando N. et al.Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2008; 14: 138-143Crossref PubMed Scopus (147) Google Scholar], we evaluated 53 patients who underwent liver transplantation (LT) for PSC and found that after a median time of 60 months after transplantation, 7 of these patients had recurrence of PSC (rPSC) in the liver graft, based on biochemical, histological and radiological findings. Interestingly, all 7 patients had ulcerative colitis (UC) and none of them had undergone total colectomy before LT. In addition, rPSC did not develop in any of the PSC patients without UC before or after LT (n = 14), nor in those with pre-LT total colectomy (n = 6). Thus, it seems that the absence of UC after LT (due to pre-LT colectomy or not) is an important factor preventing rPSC. In the univariate analysis, the 7 patients with rPSC, compared to the 46 without rPSC, had more frequent admissions to hospital for exacerbations of UC prior to LT, and likelihood of having UC (de novo or not) after LT. In addition, the patients who developed rPSC had more active UC post-LT as reflected by the need for maintenance steroids given for beyond 3 months from LT. In fact, the latter parameter was the only variable independently associated with rPSC. Thus, the development of rPSC was associated with several factors, all related to the presence or activity of UC before or after LT. Our study [[3]Cholongitas E. Shusang V. Papatheodoridis G. Marelli L. Manousou P. Rolando N. et al.Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2008; 14: 138-143Crossref PubMed Scopus (147) Google Scholar] is the first, in which immunosuppressive therapy, activity of UC and impact of de novo UC after LT were evaluated in the same cohort. Our findings are in keeping with a previous study in which factors associated with UC were also associated with rPSC. Vera et al. [[4]Vera A. Moledina S. Gunson B. Hubscher S. Mirza D. Olliff S. et al.Risk factors for recurrence of primary sclerosing cholangitis of liver allograft.Lancet. 2002; 360: 1943-1944Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar] reported that male gender and an intact colon post-LT were the strongest predictors of rPSC, and the use of maintenance steroids had a univariate association. However, it was not stated if the absence of UC before LT and/or de novo UC post-LT were associated with rPSC, and the severity of UC was not found to be associated with rPSC [[3]Cholongitas E. Shusang V. Papatheodoridis G. Marelli L. Manousou P. Rolando N. et al.Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2008; 14: 138-143Crossref PubMed Scopus (147) Google Scholar]. However, Graziadei et al. [[5]Graziadei I.W. Wiesner R.H. Marotta P.J. Porayko M.K. Hay J.E. Charlton M.R. et al.Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.Hepatology. 1999; 30: 1121-1127Crossref PubMed Scopus (289) Google Scholar] only found a non significant association between the presence of UC and rPSC, but data concerning the severity of UC, de novo UC, or the impact of colectomy were not evaluated. Kugelmas et al. [[6]Kugelmas M. Spiegelman P. Osgood M.J. Young D.A. Trotter J.F. Steinberg T. et al.Different immunosuppressive regimens and recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2003; 9: 727-732Crossref PubMed Scopus (119) Google Scholar] only found a trend between maintenance steroids and rPSC, but they only evaluated the presence or absence of UC. In conclusion, the course of our cohort transplanted for PSC does support the hypothesis that the gut is the source of lymphocytes or their products that then set up an inflammatory process in which bile ducts are damaged leading to (recurrent) PSC. This group of transplanted patients with PSC could provide a basis for study to elucidate the pathogenesis of PSC in non transplanted patients.