Colectomy and the risk of recurrent primary sclerosing cholangitis following liver transplantation

Sclerosing cholangitis recurs in approximately 10% to 25% of patients within 5 years of transplant. Recurrent primary sclerosing cholangitis (rPSC) may cause graft loss and necessitate re-transplantation. Primary sclerosing cholangitis (PSC) patients without inflammatory bowel disease (IBD) have a lower risk of recurrent PSC. There is no medical therapy known to reduce the risk of recurrent PSC. It has been suggested that pre-transplant colectomy may reduce the risk of recurrence. It has also been suggested that end ileostomy, rather than ileal pouch anal anastomosis (IPAA) may reduce the risk of recurrence.

PSC is an enigma. It is a chronic progressive cholestatic liver disease that may ultimately result in end-stage liver disease. Approximately 80% of cases are associated with IBD but only about 2% of patients with IBD have PSC (1). The epidemiology mirrors that of IBD with the highest prevalence reported in Europe, North America, and Oceania (2). There is no effective medical therapy. Patients with advanced disease may require liver transplantation and it now accounts for about 15% of liver transplants in many American and European centres. PSC is believed to be an auto-immune disease and it is associated with a number of other auto-immune diseases (3). However immunosuppressive therapy appears to have little or no effect. Sadly, we don’t know how to prevent or slow the progression of recurrent disease in a new liver following transplantation.

Following liver transplantation sclerosing cholangitis recurs in approximately 10–20% of patients within 5 years. This can lead to graft loss, re-transplantation, and reduced patient survival (4). Active IBD appears to be an important risk factor and patients without IBD have a reduced risk of rPSC (5). In 2002, Vera et al. reported that colectomy prior to or during transplant surgery reduced the risk of recurrence (6). This would make sense if active colitis was a driver of inflammation in the liver graft. A number of other studies followed, and two meta-analyses concluded that pre-transplant colectomy significantly reduced the risk of rPSC (7,8). Hazard ratios for recurrence in patients with pre-transplant colectomies were significantly lower at 0.65 (95% CI: 0.42–0.99) and 0.59 (95% CI: 0.37–0.96) (7,8). More recent studies have been less clear. A number are summarised in Table 1 (9-15). In these later studies, there is no obvious, consistent advantage in the pre-transplant colectomy group. Perhaps some of the differences between earlier and later studies may relate to cohort effects. All the results cited are from observational, cohort studies and there is no controlled data. Management of IBD has changed significantly over time and colectomy for medically refractory disease is much less common now, than previously (16).

The results reported by Matar et al. in the current issue suggest further complexity (17). Matar et al. report a retrospective multicentre study from 9 centres participating in the United States IBD Surgery Collaborative (17). The study looked at outcomes in patients transplanted for PSC who had a colectomy either before (52%) or after transplant (48%). It was a long-term outcomes study in 127 patients with the earliest colectomy in 1970 and the earliest liver transplant in 1988. There was no control group without colectomy so this study cannot address the question of whether pre-transplant colectomy alters the risk of recurrent PSC. The cumulative incidence of rPSC at 1, 5,10 and 20 years was 0%, 9%, 25.5%, and 74.2% respectively. The rates at 5 and 10 years are comparable with other studies. It is a highly selected group of patients, all of whom had colectomies. Nevertheless, the very high recurrence rate of 74.2% at 20 years suggests that the prevalence of rPSC continues to increase over time. In this study, patients who required colectomy post-liver transplant had a higher rate of PSC recurrence. A strength of this study was that the indications for colectomy were reported. The authors found that patients having colectomy for refractory colitis had a higher incidence of rPSC and biliary complications compared to those performed for oncologic reasons (colonic dysplasia or malignancy). In multivariate analysis, the only significant association for rPSC was having a colectomy for medically refractory colitis (P=0.03). Patients who had colectomies for refractory colitis following liver transplant fared particularly badly. The studies summarised in Table 1 also appear to show a higher rate of rPSC in patients requiring colectomy following transplant. While the indications for colectomy were not reported it is likely that many were for refractory colitis. Both the results of Matar et al. and the studies in Table 1 support the concept that colonic inflammation is important in the pathogenesis of rPSC (17).

What about colectomy for IBD in the non-transplant setting? Does it influence the development PSC? Data from Swedish registries suggests that having a colectomy for IBD prior to the diagnosis of PSC does not prevent the subsequent development of PSC (18). However, the same authors report that having a colectomy in this situation is associated with a decreased risk of subsequent liver transplantation or death (19). The method used for diagnosing PSC may be important in interpreting these studies. In a Norwegian study using magnetic resonance cholangiopancreatography (MRCP) in 322 patients with IBD, 7.5% were found to have PSC-like lesions (20). Only 2.2% were previously diagnosed with PSC. Thus, many of the patients in the Swedish study having a colectomy without a diagnosis of PSC may already have had sub-clinical PSC. These results are interesting and could suggest that colectomy may slow the progression of PSC in a non-transplant population. However, this would need to be confirmed by other high-quality studies.

The Matar paper also addresses the issue of intestinal reconstruction following colectomy. We know that pouchitis is more common in patients with PSC, both with and without liver transplantation. Maspero reported pouchitis rates of 45.5% in PSC patients and 67% in PSC patients with a liver transplant, compared to a historical rate of 16% in all comers (21). In a meta-analysis that included 7 studies and 291 patients, pouchitis was more common when performed prior to liver transplant rather than following it (83% vs. 59%) (22). It has been suggested that there is increased liver graft loss from hepatic artery thrombosis and biliary strictures in transplanted PSC patients with IPAA (23). It has also been suggested that colectomy and end ileostomy are associated with increased transplant-free survival in patients with PSC (24). In the present study, IPAA was performed in 57.5% and end ileostomy in 37.8% of patients. The authors reported that IPAA outcomes and complications were comparable to those observed in non-PSC patients. At least one episode of pouchitis occurred in 53.5% of patients. Matar et al. found there was a trend towards increased PSC recurrence in those undergoing IPAA compared to end ileostomy, although this did not reach statistical significance (P=0.07) (17). Another study which included 46 patients with IPAA and 9 with end ileostomy found no significant difference in graft survival, but the number with end ileostomy was small (25).

In summary, recurrent PSC following liver transplant is a significant problem and we don’t know how to prevent it. IBD is clearly important as recurrence is more common in patients with IBD and more common in those who require colectomy for refractory colitis post-transplant. It is probable, but not proven, that colectomy pre-transplant may reduce the risk of recurrence. While this is interesting from a pathophysiology point of view, it is of little practical value. It is highly unlikely that colectomy would be performed purely to prevent PSC recurrence. The issue of IPAA versus end ileostomy intestinal reconstruction is of greater practical significance. Although not proven, end ileostomy appears to have the potential to reduce the risk of recurrent PSC. However, a randomized, controlled trial would be required to determine the relative risk and assess whether this outweighs the other advantages of IPAA. As demonstrated by Matar et al., the numbers in any unit are likely to be small (17). A long-term, multi-centre, and likely multi-national, trial would be required to provide a definitive answer. This would clearly be a difficult organisational task but perhaps we owe it to our patients to provide a definitive answer to this question.

Acknowledgments

None.

Footnote

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