Recurrence of primary sclerosing cholangitis: What do we learn from several transplant centers?

Liver transplantation remains the only effective therapeutic option for patients with advanced primary sclerosing cholangitis (PSC). Approximately 5% of all liver transplants that are performed each year in adults in the United States are for PSC.1 As the long-term outcome of PSC patients following liver transplantation continues to improve, reaching over 80% at 5 years,1 there appears to be an increase in the number of patients developing recurrent PSC, which has emerged as clinically and academically important.2-4 Three remarkably similar studies from the American and British communities2-4 in this issue of Liver Transplantation provide further evidence of the cumulative effect of recurrent PSC on survival outcome and reveal some potential risk factors, which might provide insight into the pathogenesis of the primary and recurrent disease. ACR, acute cellular rejection; HLA, human leukocyte antigen; IBD, inflammatory bowel disease; PSC, primary sclerosing cholangitis. Recurrence of PSC in the hepatic graft was first reported by Lerut et al.5 in 1988. Despite controversy that followed shortly after this concept was introduced; the recognition of recurrent PSC is now firmly established in the liver transplant community. Recurrent PSC occurs in 2%-40% of the transplanted grafts.6 The variation is related in part to differences in diagnostic criteria and duration of follow-up. The use and timing of the protocol applied to detect biliary strictures and/or liver histology appears to be the most important factor for the disparity in the reported incidence of recurrent PSC. Given that cholangiographic features of recurrent PSC are not correlated with biochemical indices, cholangiographic studies only for clinical indications will underestimate the extent of this problem. Protocol cholangiography with a magnetic resonance technique may allow systemic and noninvasive evaluation of recipients with possibly full documentation of disease recurrence. The main problem with establishing a diagnosis of recurrent PSC is the lack of gold-standard diagnostic criteria. In addition, the diagnosis of recurrent PSC has been complicated by the knowledge that a variety of potential insults to the hepatic graft may result in biliary injury and stricturing. In particular, non-anastomotic biliary strictures in the liver allograft can occur because of the use of an ABO-incompatible allograft, chronic rejection, biliary tract infection, hepatic artery thrombosis, preservation injury, and prolonged cold ischemic time. Recently, a set of criteria has been proposed by a group of investigators from the Mayo Clinic7 to serve as a uniform clinicopathologic standard for the diagnosis of recurrent PSC. The diagnostic criteria consist of a confirmed diagnosis of PSC before transplantation; cholangiogram showing non-anastomotic biliary strictures occurring >3 months after liver transplantation; exclusion of other conditions associated with biliary strictures; and/or liver biopsy showing fibrous cholangitis and/or fibro-obliterative lesions. Thereafter, these diagnostic criteria have been increasingly used as the standard tool for diagnosis of recurrent PSC. In the three follow-up studies published in this issue of Liver Transplantation by Alexander et al.,2 Campsen et al.,3 and Cholangitas et al.,4 overall, 36 (14%) of 252 PSC patients had evidence of recurrent PSC as defined by the Mayo Clinic criteria, for whom cholangiography was performed when clinically indicated and/or protocol liver biopsy was consistent with PSC. The cumulative incidence of developing recurrent PSC in surviving patients at 1, 5, and 10 years posttransplantation was 2%, 12%, and 20%, respectively.3 Comparison with the nonrecurrent disease group showed that the duration of survival free of death or transplantation among recipients with recurrent disease was not significantly different.3, 4 The observed patient survival at 5 and 10 years after primary transplantation was 76%-85% and 61%-76%, respectively.3, 4 One-third of the recurrent disease patients had progressive disease ultimately requiring retransplantation, and some patients died of recurrent PSC.2-4 Similar to PSC in the native liver, the natural course of recurrent PSC is variable and difficult to predict. However, the prognosis of recurrent disease seems to be better than that of symptomatic PSC patients before liver transplantation. This may in part be due to a diagnosis of recurrent PSC being often made in the early course of the disease, or possibly the effects of immunosuppression may delay or modify disease expression within the graft. The pathogenesis of PSC remains unclear, but promising inroads have been made in elucidating genetic and immunologic mechanisms.1 Several human leukocyte antigen (HLA)–associated and non-HLA–associated genes have been implicated in the development of the disease.8, 9 Currently, there is increasingly evidence that susceptibility to PSC is conferred by the concurrent presence of HLA and non-HLA susceptibility alleles that favor production of high sustained levels of proinflammatory cytokines and recirculating gut-primed memory T cells.9 In a study of HLA class II alleles involving 265 PSC patients from five European countries,10 the HLA-DRB1*03, DQA1*0501, DQB1*02 (that is, DR3, DQ2) heterozygous genotype is associated with a more rapid progression of the disease, whereas the HLA-DR3, DQ2 homozygous genotype is positively associated with a risk of developing PSC.11 This observation indicates that association of HLA with the development and progression of PSC may be caused by different mechanisms.10 Therefore, it would be of interest to perform major histocompatibility complex typing in transplant recipients with recurrent PSC. Currently, the prognostic relevance of the particular HLA genes that confer disease recurrence was investigated by the University of Washington transplant group.2 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.10 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 this HLA haplotype represents a recipient-specific genetic predisposition to PSC and does not serve as 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.2 This finding, however, should be cautiously interpreted because of the small number of patients. Reappearance of PSC in the liver allograft suggests that the mechanisms that lead to the initial development of the disease persist after transplantation. This would provide a wonderful opportunity to learn about the pathogenesis of the disease. However, factors determining disease development in the posttransplantation 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. Potential risk factors associated with disease recurrence included recipient age,12, 13 male gender,14 gender mismatch,15 coexistent inflammatory bowel disease (IBD),13 presence of intact colon after liver transplantation,14 cytomegalovirus infection,12 recurrent acute cellular rejection (ACR),12 steroid-resistant ACR,16 and OKT3 therapy for steroid-resistant ACR.17 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. The article by the University of Colorado Health Sciences Center transplant group3 published in this issue surprisingly shows that the presence of cholangiocarcinoma prior to liver transplantation was significantly predictive of recurrent PSC following transplantation. The pathway in which cholangiocarcinoma proceeds to recurrent disease remains unclear. In another series from the University of Washington,2 histologically proven ACR and steroid-resistant ACR were associated with an increased risk of the development of recurrent PSC after liver transplantation. That disease recurrence is more likely with ACR, an immune attack of the biliary epithelium, was first noted by Jeyarajah et al.12 in 1998. The association between ACR and recurrent PSC may arise because ACR may increase autoimmune epitopes that can lead to ductal damage.12 Patients who develop recurrent disease may also have a hyperresponsive immune system and hence have an increased risk of developing ACR.12 In the same study, they also noted that OKT3 monoclonal antibody therapy for refractory ACR was associated with a greater incidence of recurrent PSC.12 This observation, rather than indicating an adverse effect of OKT3, is more likely to represent an increased risk of recurrent PSC as a byproduct of ACR. In liver transplantation for PSC, corticosteroids not only are used to prevent and treat allograft rejection but also may be necessary to manage coexistent IBD.17 Furthermore, we have known that the prolonged use of corticosteroids may cause or worsen certain metabolic complications that occur after liver transplantation. Also, the effect of corticosteroids on the rate or severity of recurrent PSC is unclear. A previous published study by Kugelmas et al.17 of immunosuppression after liver transplantation showed that PSC recurrence was most often seen (but not significantly) in patients who received maintenance corticosteroids, and the time to recurrence was not associated with length of corticosteroid administration. Furthermore, a current study from the Royal Free Hospital transplant group4 in this issue showed that maintenance corticosteroids after liver transplantation were associated with an increased risk of recurrent PSC. The reason for this observation is unclear, whether it is greater immunosuppression, associated with graft rejection, or opportunistic (yet undefined) biliary infections, which may be from a leaky mucosa in IBD that leads to recurrence. On the basis of a higher likelihood of PSC recurrence and adverse metabolic consequences in patients exposed to corticosteroids chronically, early corticosteroid withdrawal should be recommended in the management of these recipients. This, however, must be weighed against the need for corticosteroids for control of graft rejection or colitis in patients with coexistent IBD. In summary, recurrent PSC is now established as an important clinical outcome after liver transplantation. Over time, this problem is likely to increase and exert more impact on patient and graft survival. Thus, further large-scale longitudinal multicenter studies will be necessary to assess the impact of recurrent PSC on long-term outcomes. The mechanism for recurrent PSC is unknown, but current data lend support to an association with rejection and corticosteroid therapy in susceptible patients. With respect to this growing problem, several critical questions can be posed as priorities for researchers in the future. What effect will novel immunosuppressive medications or rapid corticosteroid withdrawal protocols have on the incidence and severity of recurrent disease? Which patients are more likely to develop recurrence? What medication should be administered as preventive therapy for recurrence? Understanding the pathogenesis of the disease is a key to answering these questions.