Reappearance of PSC in the liver allograft suggests that the mechanisms that lead to the initial development of the disease persist after liver transplantation. This would provide a wonderful opportunity to learn about the pathogenesis of the disease. However, factors determining disease development in the post-transplantation situation have been studied only to a limited extent. Several transplant groups have attempted to identify peritransplantation variables that may predict patients who will develop recurrent PSC. The results in general have been heterogeneous. Potential risk factors associated with disease recurrence included recipient age [15], male gender [26], donor-recipient gender mismatch [17], human leukocyte antigen (HLA)-DR1*08 [21], coexistent IBD [20], intact colon before transplantation [22, 26], episodes of acute cellular rejection (ACR) [21, 24], steroid-resistant ACR [12], orthoclone (OKT3) therapy for steroid-resistant ACR [18], maintenance steroid therapy for greater than 3 months post-transplantation [20], the presence of cholangiocarcinoma before transplantation [19], and concurrent cytomegalovirus (CMV) infection in the recipient [24]. The reasons for these discrepant findings among these studies may be due to the small number of patients with recurrent disease as well as the differences in the study design, the diagnostic criteria, and the interesting and confounding variables considered in the regression model.

Although the pathogenesis of PSC remains unclear, epidemiological and laboratory studies consistently indicate that PSC is a complex autoimmune disorder resulting from the interaction between genetic and environmental factors [27] as proposed in Fig. 8.1. In the last decade, there have been major efforts to delineate the genetic architecture of this condition. Recently, genome-wide association studies (GWAS) and immunochip-based studies identified numerous risk loci for PSC that host genes involved in innate or acquired immune responses [28–34], consistent with an autoimmune component to pathogenesis. Also, GWAS have clearly demonstrated that the major component of the genetic architecture of PSC is within the HLA region. To some extent, the genetic findings from non-transplant setting may guide the discovery of interacting and coexisting environmental susceptibility in PSC patients who developed recurrent disease after liver transplantation. The prognostic relevance of the particular HLA genes that confer recurrent PSC after liver transplantation was investigated by many investigators [15, 21]. In a report from the University of Washington transplant group, the overall frequency of the HLA-DRB1*03, DQB1*02 haplotypes among their PSC recipients was higher than that among donor populations, and this confirms that this genotype is more commonly expressed in patients who have PSC [21]. However, there was no difference in the frequency of this HLA haplotype between patients with recurrent PSC and those not having recurrence, and this suggests that the recipient HLA-specific haplotype represents a genetic predisposing factor rather than an antigen for immune recognition in disease development. Interestingly, there was a higher incidence of HLA-DRB1*08, particularly in the absence of HLA-DQB1*04, in their recipients that eventually developed recurrent disease than in those that did not [21]. However, more work is required to confirm candidate genes, to evaluate the functional consequences of risk variants, and to understand how functional changes contribute to disease-specific pathologies. If the association between HLA haplotypes and risk of disease recurrence is validated in further studies, HLA typing would be useful in donor selection as well as to provide valuable prognostic information at the time of transplantation.

Of great interest is the reported higher rate of disease recurrence in 114 Japanese recipients of grafts from living-related donors, with recurrent PSC occurring in 32 % at 5 years and 52 % at 10 years after transplantation [25]. A potential explanation may be the first-degree-relatives and sibling have a prevalence of PSC about 100-fold that of nonrelatives [35]. Another possible mechanism contributing to the effect of first-degree-related donors might be linked to the effect of a shared genetic disposition in blood-related recipient and donor pairs including the HLA system. However, the incidence of recurrent PSC in recipients with grafts from related donors other than parents as well as nonrelated donors was similar to those reported for deceased donor liver transplantation [10, 12, 17–22, 26].

The pathogenesis of recurrent PSC could hypothetically be linked to autoimmunity, cross-sensitization between biliary and colonic antigens due to common epithelial epitopes, or leak of bacterial toxins from the inflamed colon with genetic predisposition [36]. The leaky theory is supported by observation of the absence of inflammation in the colon, either due to the absence of concurrent IBD or colectomy before or at the time of liver transplantation has a protective effect against disease recurrence [20, 22, 26]. This was first reported in a study by Vera et al., which demonstrated a dramatic reduction in the risk of PSC recurrence if the colon was removed before or during transplantation [26]. This finding was considerably strengthened in a study by Cholangitas et al., in which no PSC patients without ulcerative colitis or those undergoing pretransplant colectomy developed recurrent PSC [20]. The protective effect of colectomy before or during liver transplantation on the risk of developing recurrent PSC was confirmed in the largest prognostic study of recurrent PSC involved 230 consecutive adult patients who underwent liver transplantation for PSC [22]. Taken together, these findings are consistent with the hypothesis of aberrant homing of mucosal lymphocytes to the liver in the development of PSC [36] that may also be relevant in recurrent PSC. Importantly, these data should not be interpreted as an advocation for pretransplant colectomy but rather as input to understanding the mechanism of developing recurrent PSC.