Genetic, immunological and clinical risk factors for biliary strictures following liver transplantation

Background: Biliary strictures after liver transplantation (LT) are a major cause of morbidity and reduced graft survival. Aims: The purpose of this study was to investigate genetic, immunological and clinical risk factors for the occurrence of post-LT ischaemic type biliary lesions (ITBLs) and biliary anastomotic strictures (AS). Methods: Clinical and laboratory data, chemokine receptor (CCR) genotypes, chemotactic cytokines and anti-major-histocompatibility complex antibodies in serum were investigated in 162 LT patients. Results: In the univariate analysis, older donor and recipient age, partial LT, high peak aspartate aminotransaminase (AST) levels and CC chemokine receptor 5 delta32 loss-of-function mutation (CCR5 Delta 32) were associated with ITBL, whereas LT for acute liver failure (ALF), ABO-compatible non-identical LT, presence of donor-specific anti-human leucocyte antigen (HLA) class II antibodies and fractalkine receptor (CX3CR1)-249II allele were associated with AS. In the multivariate analysis, CCR5 Delta 32 was an independent risk factor for ITBL, whereas LT for ALF, ABO-compatible non-identical LT, and CX3CR1-249II allele remained predictive for AS. Serum levels of interferon-gamma and interleukin (IL)-6 as well as IL-10 were significantly increased in patients with biliary strictures. Conclusion: Specific chemokine receptor polymorphisms of the recipient are associated with development of post-LT biliary strictures. Altered cytokine profile may contribute to enhanced fibrotic tissue remodelling and biliary stricture formation. Screening of anti-HLA antibodies might be useful for early identification of at-risk patients who could benefit from closer surveillance and tailored immunosuppressive regimen. Our findings may have relevance for prediction and management of post-LT biliary strictures.