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Orthotopic liver transplantation (OLT) is the only effective treatment for end-stage liver disease due to primary sclerosing cholangitis (PSC). Recurrence of PSC has recently emerged as a leading cause of allograft failure in the long term. There is limited data on risk factors for recurrence of PSC. We performed a retrospective analysis of 69 consecutive patients who underwent a first OLT for PSC over a 14-year period. Baseline characteristics and clinical and laboratory test results post-LT were recorded. Cholangiograms and liver histopathology were reviewed in a blinded manner by an experienced radiologist and hepatopathologist. Recurrent PSC was diagnosed using previously published Mayo Clinic cholangiographic or histologic criteria. Of 69 patients, 7 (10%) developed recurrent PSC at a median of 68 months (range, 24-134 months) post-LT. The following variables were associated with recurrent PSC in our cohort: presence of human leukocyte antigen (HLA)-DRB1*08 (29% versus 2%; P= 0.026; odds ratio [OR], 24.4; 95% confidence interval [CI], 1.8-318.1), acute cellular rejection (ACR) (71% versus 22%; P= 0.015; OR, 8.7; 95% CI, 1.5-49.9), and steroid-resistant ACR (29% versus 0%; P= 0.012). Despite the strong linkage disequilibrium between DRB1*08 and DQB1*04, DRB1*08-positive subjects with recurrence were negative for DQB1*04, whereas the single DRB1*08-positive subject without recurrent PSC was positive for DQB1*04. A history of ACR and presence of HLA-DRB1*08 are associated with increased risk of recurrent PSC, suggesting an immunologic mechanism for this syndrome. Further studies are required to confirm these observations and to understand the underlying mechanisms. Liver Transpl 14:245–251. 2008. © 2008 AASLD.