Recurrent primary sclerosing cholangitis: Clinical diagnosis and long-term management issues

Several studies have demonstrated an increased frequency of biliary strictures in patients transplanted for primary sclerosing cholangitis (PSC).1, 2 Because of the likelihood of an autoimmune origin of PSC, it is not surprising that PSC can recur after liver transplantation. The difficulty of diagnosing recurrent PSC in the allograft is compounded several fold due to a variety of factors seen exclusively after transplantation which may result in biliary strictures (Table 1).

Abbreviations

PSC, primary sclerosing cholangitis; CMV, cytomegalovirus; HLA, human leukocyte antigen.

Recurrent PSC can be diagnosed when the following criteria are met: 1) a diagnosis of PSC prior to transplantation; 2) cholangiography showing nonanastomotic strictures typical of PSC including intra- or extrahepatic ductal irregularity and/or beading; 3) a liver biopsy showing fibroobliterative lesions or fibrous cholangitis; and 4) other diagnoses as noted in Table 1 have been ruled out.

In a landmark study, Harrison et al.2 compared biopsy specimens from 22 patients transplanted for PSC, 185 control patients transplanted for reasons other than PSC, and a matched group of 22 patients without PSC with Roux-en-Y biliary anastomoses. Of the PSC patients, 32% had histologic evidence of biliary obstruction compared to 10% of non-PSC controls, and 14% of Roux-en-Y controls. Fibroobliterative lesions were seen in 14% of PSC patients but in none of the control subjects. Follow-up ranged from 13 to 100 months. Unfortunately, cholangiographic findings, documentation of hepatic artery patency, ABO blood group data, and cold ischemia times were not included.

Sheng et al.3 evaluated the cholangiographic findings in 100 patients transplanted for PSC and 543 controls transplanted without PSC. Intrahepatic biliary strictures were seen in 27% of the PSC group and 13% of the non-PSC patients (P = 0.0005). Extrahepatic, nonanastomotic strictures were identified in 6% of allografts in PSC patients compared to 2% of non-PSC allograft recipients (P = 0.008). The incidence of anastomotic strictures was similar (18% vs. 15%; P = = 0.381). In this study, cold ischemia times and hepatic artery patency were similar in both groups but ABO blood group compatibility and histology were not evaluated.

In a subsequent study by Sheng et al.,1 32 patients transplanted for PSC were compared to a matched population of 32 controls without PSC. Matching was based on the presence of a Roux-en-Y choledochojejunostomy and time elapsed between transplantation and discovery of nonanastomotic strictures. There was no difference in the incidence of hepatic artery occlusion or the use of Euro-Collins solution. Other causes of biliary stricturing (see Table 1) were not addressed. Findings included the presence of mural irregularities in 47% of PSC patients and 13% of controls. Biliary diverticula were seen in 19% of recipients with PSC and 3% of controls. Interestingly, most of the strictures in the PSC group were seen early after transplantation.

Graziadei et al.4 compared radiographic and/or histologic findings in 120 patients transplanted with PSC to 415 non-PSC controls. Patients with hepatic artery occlusion, chronic rejection, ABO blood group incompatibility, and anastomotic strictures were excluded. Intrahepatic strictures were seen in 18% of the PSC patients compared to 1% of the non-PSC recipients. Contrary to the conclusions of Sheng et al.,1 strictures were seen later in the PSC patients than in the controls. At 5-years patient and graft survival were not different between the 2 groups. In 2 patients with normal cholangiograms, histologic changes consistent with PSC were seen, raising the possibility of small duct recurrent PSC.

In the same study, Graziadei et al.4 assessed the potential risk factors for recurrent PSC by comparing the 24 patients with recurrent PSC to the 96 patients without recurrence. There were no statistical differences in the following characteristics between the 2 groups: age at time of transplantation, age at diagnosis of PSC, gender, previous biliary surgery, presence of chronic ulcerative colitis, cold ischemia time, preservation solution (Euro-Collins or University of Wisconsin solutions), mean acute cellular rejection episodes, cytomegalovirus infection, and lymphocytotoxic cross-match. In fact, there were no factors identified that predicted recurrent PSC.

Khettry et al.5 evaluated clinicopathologic features in patients with recurrent PSC compared to nonrecurrent patients with 2-14 yr of follow-up. The presence of inflammatory bowel disease, total ischemia time >11 hours, human leukocyte antigen class I and II matching, similar donor/recipient B8, DR3, and DR2 status, and recipient/donor gender mismatch were not predictive of recurrence. Only gender mismatch was statistically predictive of recurrent PSC. Among 13 peer-reviewed publications between 1995 and 2005, 8 did not demonstrate any clinical variables associated with an increased risk of PSC. The remaining studies showed cytomegalovirus infection,6 intact colon and male gender,7 OKT3 treatment,8 gender mismatch,5 and corticosteroid-resistant rejection9 to be risk factors for recurrent PSC.

The most frequent and devastating recipient complication of living donor liver transplantation is biliary stricturing. This is likely a result of small caliber biliary and hepatic artery anastomoses. Biliary complications (cholangitis, disruption, leak, or stricture) were seen in 35% of patients receiving a right lobe live donor graft at an experienced transplant center.10 At this time there are no reports of recurrent PSC in living donor liver transplant recipients.

Cholangiocarcinoma is found in approximately 10% of patients with PSC evaluated for liver transplantation. Many of these are found incidentally in the explanted liver. The presence of cholangiocarcinoma is considered an absolute contraindication to transplantation at most centers due to the high risk of recurrence in the allograft. In 2003, Heneghan et al.11 reported the first case of de novo cholangiocarcinoma in a patient with recurrent PSC 10 years after primary transplantation and 8 years after retransplantation for complications of a bile leak. The authors advocate early investigation of abnormal liver enzymes and jaundice with brushing of the biliary tree when dominant strictures are found. The patient in this case report underwent retransplantation for cholangiocarcinoma, clearly a controversial decision.

The management of patients with recurrent PSC is poorly defined for several reasons. First, the diagnosis of recurrent PSC is not uniform and the range of recurrence is estimated to be between 10 and 20%. Second, this small number of patients would require a multicenter trial to reach any meaningful conclusions. This would be a difficult study to initiate given the variable diagnostic criteria and the differing immunosuppressive strategies. Last, and perhaps most importantly, there are no proven preventive therapies for PSC in the nontransplant setting that can be used as models for investigation after transplantation. Symptomatic treatment of pruritus and interventional cholangiographic treatment of biliary strictures should be accomplished, as they present pretransplantation.