Recurrence of primary sclerosing cholangitis after liver transplantation – A model for pathogenesis?
Authors: Tobias J. Weismüller, Jochen Wedemeyer, Stefan Kubicka, Christian P. Strassburg, Michael P. Manns
Journal: Journal of Hepatology (2008)

We appreciate the important comment from Cholongitas et al. regarding our recently published article [[1]Weismuller T.J. Wedemeyer J. Kubicka S. Strassburg 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] which discusses the pathogenesis of primary sclerosing cholangitis (PSC). The comment points out that the identification of risk factors for the recurrence of PSC after liver transplantation (OLT) may help to understand pathogenetic mechanisms of this enigmatic disease.However, the issue of recurrent PSC (rPSC) following OLT has always been controversial, because there are a number of possible pathogenetic mechanisms resulting in a phenotype of sclerosing cholangitis in the liver allograft that resemble PSC [[2]Graziadei I.W. Recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2002; 8: 575-581Crossref PubMed Scopus (122) Google Scholar]. These include chronic ductopenic rejection as well as biliary complications such as anastomotic or non-anastomotic strictures. The latter can be caused by hepatic artery thrombosis or stenosis, but are also frequently seen without an obvious impaired arterial perfusion, and have therefore been designated ischemic-type biliary lesions (ITBL) [[3]Verdonk R.C. Buis C.I. Porte R.J. Haagsma E.B. Biliary complications after liver transplantation: a review.Scand J Gastroenterol Suppl. 2006; : 89-101Crossref PubMed Scopus (155) Google Scholar]. Several retrospective studies have found a greater frequency of biliary strictures in patients who were transplanted for PSC in comparison to patients receiving a liver transplantation for other end-stage liver diseases [[2]Graziadei I.W. Recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2002; 8: 575-581Crossref PubMed Scopus (122) Google Scholar]. It can be assumed that these additional bile duct changes in the allograft following OLT for PSC are due to the recurrence of the disease. Thus, in cases of a typical cholangiographic or histological picture following OLT for PSC, rPSC should be diagnosed only after the exclusion of accepted causes of sclerosing cholangitis (which include hepatic artery thrombosis/stenosis, ABO incompatibility, and chronic ductopenic rejection). While anastomotic strictures alone are clearly related to the transplantation procedure itself, the differentiation between ITBL and rPSC remains difficult. The widely accepted criteria for PSC recurrence published by the Mayo group [[2]Graziadei I.W. Recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2002; 8: 575-581Crossref PubMed Scopus (122) Google Scholar] assume that – unless otherwise explainable – biliary strictures in the cholangiogram, or a fibrous cholangitis detected in a liver biopsy specimen after more than 90 days following OLT for PSC are deemed to represent rPSC. However, this 90 day rule is questionable since a considerable number of ITBL are diagnosed more than 3 months after OLT; according to one study [[4]Campbell W.L. Sheng R. Zajko A.B. Abu-Elmagd K. Demetris A.J. Intrahepatic biliary strictures after liver transplantation.Radiology. 1994; 191: 735-740Crossref PubMed Scopus (86) Google Scholar] 40% of intrahepatic strictures were seen more than 6 months after OLT.In the accurate study of Cholongitas et al. [[5]Cholongitas E. Shusang V. Papatheodoridis G.V. 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 (145) Google Scholar] strict inclusion and exclusion criteria for rPSC as definded by the Mayo Clinic were used, based on detailed clinical data, protocol liver biopsies and radiological findings, in order to identify patients with rPSC. With this best possible approach to identify patients with rPSC they found recurrence of PSC only in patients with active ulcerative colitis (UC) after OLT. These findings are consistent with the fascinating hypothesis of an enterohepatic circulation of lymphocytes generated in the gut as a concept for the pathogenesis of PSC. However these results are based on only 53 patients and – as the authors mentioned – previous studies including one meta-analysis [[6]Gautam M. Cheruvattath R. Balan V. Recurrence of autoimmune liver disease after liver transplantation: a systematic review.Liver Transpl. 2006; 12: 1813-1824Crossref PubMed Scopus (226) Google Scholar] did not find a significant influence of UC on rPSC. In terms of methodology the study of Cholongitas et al. [[5]Cholongitas E. Shusang V. Papatheodoridis G.V. 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 (145) Google Scholar] certainly represents one of the best approaches to identifying risk factors for rPSC. Prospective studies of the same quality level are needed to verify these results.In summary, in view of the difficulties to distinguish rPSC from other biliary changes after OLT, especially ITBL, the results of studies on the recurrence of PSC should generally be considered with a degree of caution. In the situation of rPSC we are dealing with the allograft as an immunological and genetically foreign target in an immunocompromised organism. It would therefore appear to remain questionable whether findings regarding the recurrence of PSC after OLT are directly transferable to our current understanding of the pathogenesis of PSC in the pre-transplant patient. We appreciate the important comment from Cholongitas et al. regarding our recently published article [[1]Weismuller T.J. Wedemeyer J. Kubicka S. Strassburg 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] which discusses the pathogenesis of primary sclerosing cholangitis (PSC). The comment points out that the identification of risk factors for the recurrence of PSC after liver transplantation (OLT) may help to understand pathogenetic mechanisms of this enigmatic disease. However, the issue of recurrent PSC (rPSC) following OLT has always been controversial, because there are a number of possible pathogenetic mechanisms resulting in a phenotype of sclerosing cholangitis in the liver allograft that resemble PSC [[2]Graziadei I.W. Recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2002; 8: 575-581Crossref PubMed Scopus (122) Google Scholar]. These include chronic ductopenic rejection as well as biliary complications such as anastomotic or non-anastomotic strictures. The latter can be caused by hepatic artery thrombosis or stenosis, but are also frequently seen without an obvious impaired arterial perfusion, and have therefore been designated ischemic-type biliary lesions (ITBL) [[3]Verdonk R.C. Buis C.I. Porte R.J. Haagsma E.B. Biliary complications after liver transplantation: a review.Scand J Gastroenterol Suppl. 2006; : 89-101Crossref PubMed Scopus (155) Google Scholar]. Several retrospective studies have found a greater frequency of biliary strictures in patients who were transplanted for PSC in comparison to patients receiving a liver transplantation for other end-stage liver diseases [[2]Graziadei I.W. Recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2002; 8: 575-581Crossref PubMed Scopus (122) Google Scholar]. It can be assumed that these additional bile duct changes in the allograft following OLT for PSC are due to the recurrence of the disease. Thus, in cases of a typical cholangiographic or histological picture following OLT for PSC, rPSC should be diagnosed only after the exclusion of accepted causes of sclerosing cholangitis (which include hepatic artery thrombosis/stenosis, ABO incompatibility, and chronic ductopenic rejection). While anastomotic strictures alone are clearly related to the transplantation procedure itself, the differentiation between ITBL and rPSC remains difficult. The widely accepted criteria for PSC recurrence published by the Mayo group [[2]Graziadei I.W. Recurrence of primary sclerosing cholangitis after liver transplantation.Liver Transpl. 2002; 8: 575-581Crossref PubMed Scopus (122) Google Scholar] assume that – unless otherwise explainable – biliary strictures in the cholangiogram, or a fibrous cholangitis detected in a liver biopsy specimen after more than 90 days following OLT for PSC are deemed to represent rPSC. However, this 90 day rule is questionable since a considerable number of ITBL are diagnosed more than 3 months after OLT; according to one study [[4]Campbell W.L. Sheng R. Zajko A.B. Abu-Elmagd K. Demetris A.J. Intrahepatic biliary strictures after liver transplantation.Radiology. 1994; 191: 735-740Crossref PubMed Scopus (86) Google Scholar] 40% of intrahepatic strictures were seen more than 6 months after OLT. In the accurate study of Cholongitas et al. [[5]Cholongitas E. Shusang V. Papatheodoridis G.V. 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 (145) Google Scholar] strict inclusion and exclusion criteria for rPSC as definded by the Mayo Clinic were used, based on detailed clinical data, protocol liver biopsies and radiological findings, in order to identify patients with rPSC. With this best possible approach to identify patients with rPSC they found recurrence of PSC only in patients with active ulcerative colitis (UC) after OLT. These findings are consistent with the fascinating hypothesis of an enterohepatic circulation of lymphocytes generated in the gut as a concept for the pathogenesis of PSC. However these results are based on only 53 patients and – as the authors mentioned – previous studies including one meta-analysis [[6]Gautam M. Cheruvattath R. Balan V. Recurrence of autoimmune liver disease after liver transplantation: a systematic review.Liver Transpl. 2006; 12: 1813-1824Crossref PubMed Scopus (226) Google Scholar] did not find a significant influence of UC on rPSC. In terms of methodology the study of Cholongitas et al. [[5]Cholongitas E. Shusang V. Papatheodoridis G.V. 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 (145) Google Scholar] certainly represents one of the best approaches to identifying risk factors for rPSC. Prospective studies of the same quality level are needed to verify these results. In summary, in view of the difficulties to distinguish rPSC from other biliary changes after OLT, especially ITBL, the results of studies on the recurrence of PSC should generally be considered with a degree of caution. In the situation of rPSC we are dealing with the allograft as an immunological and genetically foreign target in an immunocompromised organism. It would therefore appear to remain questionable whether findings regarding the recurrence of PSC after OLT are directly transferable to our current understanding of the pathogenesis of PSC in the pre-transplant patient.