EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Primary sclerosing cholangitis is a chronic inflammatory disease of the intrahepatic and extrahepatic bile ducts. More than half of the patients will face end-stage liver disease and require liver transplant. Here, we describe the long-term outcomes of liver transplant in patients with primary sclerosing cholangitis at our center.

Materials and Methods: For this retrospective, observational study, we investigated all patients who underwent liver transplant for primary sclerosing cholangitis between January 2005 and June 2013 at the Dokuz Eylul University Hospital. Patient data were obtained from hospital records. Our inclusion criteria were patients over 18 years old and diagnosed with primary sclerosing cholangitis.

Results: Of 11 patients included the study, 6 (54.5%) were male and 5 (45.5%) were female. Mean age was 40.6 ± 11.0 years (range, 23-60 y). All patients had cirrhosis due to primary sclerosing cholangitis. With regard to Child-Turcot-Pugh classification, 2 patients (18.2%) were classified as having Child-Turcot-Pugh A cirrhosis, 7 patients (63.6%) were classified as having B cirrhosis, and 2 patients (18.2%) were classified as having C cirrhosis. Mean Modified End-Stage Liver Disease score was 17.5 ± 6.1 (range, 7-25). Cholangiocarcinoma was not detected in explant pathologic examinations. Primary sclerosing cholangitis recurrence developed in 2 patients (18.1%). Three patients (27.2%) died during the follow-up period.

Conclusions: Liver transplant is a good therapeutic option for primary sclerosing cholangitis with satisfactory long-term outcomes. Liver transplant should be reserved for patients with end-stage liver disease and other conditions that significantly impair quality of life.

Key words : Bile duct disease, End-stage liver disease, Fibrosis, Survival

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease leading to concentric fibrosis of the intrahepatic and extrahepatic biliary ducts.¹ Although PSC affects both sexes and all age groups, more than 60% of patients are men and the median age at onset is 30 to 40 years.^2-4 More than half of the patients will face end-stage liver disease and require liver transplant (LT). Patients with PSC may require LT due to significant impairment of quality of life in noncirrhotic patients (ie, severe recurrent bacterial cholangitis, asthenia, or debilitating pruritus) or because of end-stage liver disease, suspicion of bile duct neoplasia without intrahepatic or extrahepatic malignancy according to relevant imaging techniques, or, in selected cases, hilar cholangiocarcinoma (ie, according to the Mayo protocol).^1,5 The high life-time cumulative risk of developing cholangiocarcinoma is 10% to 15% in patients with PSC. Primary sclerosing cholangitis accounts for approximately 5% of all LTs per year in the United States. In Europe, the rates are higher at 8% to 16% per year. Survival of patients with PSC after LT has increased markedly in the past few decades and is approximately 80% at 5 years.⁵ Similar graft and patient survival outcomes have been shown after both living-donor LT (LDLT) and deceased-donor LT (DDLT). The risk of recurrent PSC during the first year posttransplant is low (2%); however, 20% to 37% of patients at 3- to 10-year follow-up have shown recurrent PSC.

Materials and Methods

In this retrospective, observational study, we analyzed patients who had undergone LT for PSC between January 2005 and June 2013 at the Dokuz Eylul University Hospital. Patient data were obtained from hospital patient records. Our inclusion criteria were patients over 18 years old and diagnosis of PSC.

During the pretransplant preparation of patients with PSC, we utilized tumor markers such as CA19-9 and CA125 and abdominal magnetic resonance imaging to exclude bile duct neoplasia. Endoscopic bile duct brush cytology tests were not used in pretransplant evaluations.

Liver transplant procedures involving deceased or living donors were performed by the same surgical team, and standard techniques were used. The extrahepatic bile duct was resected in the recipient. A surgical margin was confirmed regarding cholangiocarcinoma via frozen section biopsy. Right liver grafts were used in 5 patients, and left liver grafts (segments 2, 3, 4) were used in 2 patients in LDLT. Temporary portocaval shunting and side-to-side cavocaval anastomosis were performed in recipients of DDLT, and right/middle plus left hepatic hepatocaval anastomoses were performed in recipients of LDLT. Biliodigestive anastomoses were performed in all patients. Pathologic examinations of explants were evaluated by 2 expert pathologists.

During the early posttransplant period, calcineurin inhibitors (ie, cyclosporine or tacrolimus) and mycophenolate mofetil plus prednisolone-based immunosuppression regimens were used in all patients. Mycophenolate mofetil therapy was stopped in the first year after LT. Low-dose corticosteroid therapy was continued in all patients. All patients underwent regular follow-up examinations in outpatient clinics. Both the surgical team and an experienced hepatologist maintained surveillance for disease recurrence and malignancy development. All patients had yearly magnetic resonance cholangiopancreatography examinations. Percutaneous transhepatic cholangiographies and/or liver biopsies were conducted when PSC recurrence was suspected.

Statistical analyses
All statistical analyses were performed using IBM SPSS Statistics version 18.0 (IBM, Chicago, IL, USA). All data are shown as means ± standard deviation.

Eleven patients were included the study. Patient characteristics are shown in Table 1. Of these patients, 6 (54.5%) were male and 5 (45.5%) were female. Mean age was 40.6 ± 11.0 years (range, 23-60 y). All patients had cirrhosis due to PSC. According to the Child-Turcot-Pugh classification, 2 patients (18.2%) were classified as having A cirrhosis, 7 patients (63.6%) were classified as having B cirrhosis, and 2 patients (18.2%) were classified as having C cirrhosis. Mean Modified End-Stage Liver Disease (MELD) score was 17.5 ± 6.1 (range, 7-25). Further details of patients are shown in Table 2.

We found that 4 patients (36.4%) had biopsy-proven inflammatory bowel disease (IBD) and were using ursodeoxycholic acid (UDCA) and corticosteroid medication before and after LT. None of the patients showed cholangiocarcinoma during pretransplant evaluation. Seven patients (63.6%) had LDLT, and 4 patients (36.4%) had DDLT.

Cholangiocarcinoma was not detected in extrahepatic bile duct via frozen section biopsy. In explant pathologic examinations, cholangiocarcinoma was not seen.

Tacrolimus-based immunosuppression was used in 8 patients (72.7%) and cyclosporine-based immunosuppression was used in 3 patients (26.3%). Four patients had hypertension during the posttransplant period and received antihypertensive treatment.

Mean follow-up was 101.4 ± 46.2 months (range, 18.1-157.9 mo).

Recurrence
Primary sclerosing cholangitis recurrence developed in 2 patients (18.1%). Recurrence was detected in 1 patient radiologically 142 months after LT (Figure 1), with recurrence confirmed by liver biopsy. In the other patient, PSC recurrence developed 84 months after LT. Pathologic examination revealed bile duct inflammation, mild portal inflammation, and rise of periductal fibrous tissue (Figure 2). Corticosteroids and UDCA were given to treat PSC recurrence, with both patients responding to treatment. However, 1 patient died 158 months after LT due to renal insufficiency. The second patient recovered and has shown uneventful follow-up 34 months after PSC recurrence.

Morbidity and mortality
Three patients (27.2%) died during the follow-up period. In one patient, a cholangitis-related hepaticojejunostomy stricture occurred 18 months after LT. Two duct jejunostomies had been performed during LDLT, but progressive duct jejunostomy stricture and recurrent cholangitis occurred. The patient died due to sepsis despite antibiotic therapy and bile duct drainage using percutaneous transhepatic cholangiography. The second patient died from cirrhosis, which developed due to de novo hepatitis C virus infection 30 months after LT. The third patient, who had Pott disease, chronic pancreatitis, and PSC recurrence, died 158 months after LT due to unexplained postureteral obstruction and renal insufficiency. Our patient group showed 5- and 10-year overall survival rates of 81.8% and 81.8%, respectively (Figure 3).

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown cause.⁶ There is no effective medical therapy. Liver transplant is a life-saving procedure for patients with PSC. More than 50% of patients need LT 10 to 15 years after symptom development as a result of cholangitis, secondary biliary cirrhosis, and hepatobiliary malignant disease.^7-9 The major indications for LT in PSC patients are end-stage liver disease and cirrhosis, significantly impaired quality of life (recurrent bacterial cholangitis, asthenia, intractable pruritus, and so forth), and suspicion of bile duct neoplasia or cholangiocarcinoma. In our series, the indication for LT was end-stage liver disease in all patients. Bile duct neoplasia and cholangiocarcinoma were not detected in any of our patients.

Organ allocation for PSC is similar to that for other indications in the United States and is prioritized by the MELD score, which is cause independent. Timing of LT is difficult to predict because of variations in disease course in individual patients. Several prognostic models have been developed for PSC. These models have included demographic, serologic, and radiologic variables. Unfortunately, these models are not precise in predicting outcomes for individual patients, and no consensus exists about the optimal model.¹⁰ Thus, the American Association for the Study of Liver Disease recommends against using disease-specific models for prediction of clinical outcomes in individual patients.¹¹ Additional MELD (exception) points can be requested from the regional transplant review boards for specific manifestations of PSC, such as intractable pruritus, recurrent or refractory bacterial cholangitis, and carefully selected limited-stage cholangiocarcinoma, which are granted on a case-by-case basis by determining risk of wait list mortality, wait list removal, and non-liver-related comorbidities.^11,12 In Turkey, all PSC patients are enrolled on the wait list with 16 MELD points, in accordance with the national organ allocation committee policy.¹² Seven patients (63.6%) in our series had more than 16 MELD points because of end-stage liver disease. Although the other 4 patients (36.7%) had less than 16 MELD points, they were added to the LT wait list, with DDLT performed in 3 of these 4 patients.

Primary sclerosing cholangitis is vigorously associated with IBD, predominantly in the form of ulcerative colitis, which affects up to 70% to 80% of PSC patients in Western countries.¹³ Unfortunately, the risk of colorectal cancer in patients with PSC and IBD persists after LT; therefore, continued colorectal surveillance is required every 1 to 2 years for patients with PSC and IBD who receive LT.^14-16 In our study, 4 patients (36.7%) had ulcerative colitis only.

A Roux-en-Y hepaticojejunostomy is the preferred bile duct reconstruction technique in PSC patients.⁵ However, duct-to-duct reconstruction should also be considered when feasible in patients with PSC.¹⁷ Isolated strictures at biliary-enteric anastomosis may be a technical complication, occurring in approximately 5% of patients. We chose to perform Roux-en Y hepaticojejunostomy in all patients in this series. None of the patients in this series developed biliary leakage, and only 1 patient (9.1%) developed bile duct stricture. This patient died as a result of cholangitis and sepsis.

Recurrence of PSC in the transplanted liver has been a continued topic of debate. Although patients with PSC have excellent survival, they are at risk of recurrent PSC, which is estimated to occur in 15% to 35% of LT recipients anywhere from 5 to 10 years posttransplant.^6,18 Primary sclerosing cholangitis recurrence has radiographic, endoscopic, and/or histologic findings similar to PSC before LT. However, hepatic artery stenosis/thrombosis, chronic ductopenic rejection, cytomegalovirus infections of the biliary tract, and/or transplant from a donor with an incompatible blood type or as a donation after cardiac death can mimic the features characteristics of PSC recurrence posttrasplant.⁶ Diagnostic criteria for recurrent PSC after LT were proposed by Graziadei and associates.19 For differential diagnosis, laboratory tests should be carried out.

Recurrence rate of PSC was 18.1% (2 patients) in this series. We used UDCA and corticosteroids to treat recurrent PSC, with remission achieved in both patients. Although no further complications regarding recurrent disease were shown, 1 patient died due to renal failure.

After LT for PSC, overall survival tends to be good, with 5- and 10-year survival rates of 87.4% and 83.2%.²⁰ The European Liver Transplant Registry data showed a 5-year survival rate for PSC of 83%.²¹ In our study, overall survival rates were similar to literature reports at 81.8% at 5 years and 81.8% at 10 years. Furthermore, 2 of the 3 patients who died after LT in our series died due to non-PSC-related causes. In conclusion, long-term outcomes of patients with PSC are satisfactory. We suggest LT is a good therapeutic option for patients with PSC. After LT, patients should be closely monitored with regard to recurrence. We suggest that LT in PSC patients should be reserved in cases of cirrhosis or other life-impairing conditions.

Volume: 16 Issue: 4 August 2018

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