Liver Transplantation For Primary Sclerosing Cholangitis Research Articles

P787 Use of upadacitinib to treat IBD in post-liver transplant

Abstract Background Approximately 2% of patients with inflammatory bowel disease (IBD) have concurrent primary sclerosing cholangitis (PSC). Liver transplantation (LT) is sometimes required due to progressive PSC. However, the management of active IBD post-LT is challenged due to concomitant anti-rejection immunotherapies. Janus kinase inhibition has been previously described to have anti-rejection properties in patients who have had renal transplants. Here, we describe our experience with upadacitinib (UPA), a selective Janus kinase-1 inhibitor, for post-LT active IBD combined with anti-rejection immunosuppression therapy. Methods This is a retrospective, single-center observational study in a tertiary IBD center. We identified patients with LT treated with UPA for their IBD. Patient related outcomes including transplanted liver status and clinical efficacy and safety of UPA for IBD activity were reviewed. Results We identified four patients (3 with Crohn’s disease, 1 with ulcerative colitis) treated with UPA after LT due to PSC, with the UPA indication for the treatment of IBD (n=3) and organ rejection (n=1). Median follow-up was 3 months (interquartile range (IQR) 1.5-7.1), median age at starting UPA was 41.5 years (IQR 40-44), and median interval from the transplant was 3.2 years (IQR 2.3-5.6). Two patients with Crohn’s disease clinically responded to UPA, one weaned off prednisone 30mg/day and remained in clinical remission after reducing UPA from 30 mg/day to 15 mg/day. Two patients developed elevated AST/ALT of up to 107/57 U/L and 83/228 U/L; one required discontinuation of UPA at one month with subsequent AST/ALT normalization; the other remained on UPA with 1.5 month follow-up so far. One UC patient was treated with UPA combined with vedolizumab in an attempt to discontinue prednisone for their immunosuppression for organ rejection, however, they were unable to wean off prednisone due to recurrent ALT and Alk Phos elevations. One patient acquired a mild case of COVID-19 which resolved without change in therapy. No life-threatening adverse events were observed. Conclusion We describe 4 patients with IBD who had LT for PSC and who were treated with UPA with successful management of active IBD in 2 cases but lack of efficacy in one case and liver enzyme elevations limiting UPA use in a second. These findings support further exploration of this novel mechanism for treatment of IBD in the post-LT setting.

Cyclosporine vs. tacrolimus after liver transplantation for primary sclerosing cholangitis – a propensity score-matched intention-to-treat analysis

There is controversy regarding the optimal calcineurin inhibitor type after liver transplant(ation) (LT) for primary sclerosing cholangitis (PSC). We compared tacrolimus with cyclosporine in a propensity score-matched intention-to-treat analysis based on registries representing nearly all LTs in Europe and the US. From the European Liver Transplant Registry (ELTR) and Scientific Registry of Transplant Recipients (SRTR), we included adult patients with PSC undergoing a primary LT between 2000-2020. Patients initially treated with cyclosporine were propensity score-matched 1:3 with those initially treated with tacrolimus. The primary outcomes were patient and graft survival rates. The propensity score-matched sample comprised 399 cyclosporine-treated and 1,197 tacrolimus-treated patients with PSC. During a median follow-up of 7.4 years (IQR 2.3-12.8, 12,579.2 person-years), there were 480 deaths and 231 re-LTs. The initial tacrolimus treatment was superior to cyclosporine in terms of patient and graft survival, with 10-year patient survival estimates of 72.8% for tacrolimus and 65.2% for cyclosporine (p <0.001) and 10-year graft survival estimates of 62.4% and 53.8% (p <0.001), respectively. These findings were consistent in the subgroups according to age, sex, registry (ELTR vs. SRTR), time period of LT, MELD score, and diabetes status. The acute rejection rates were similar between groups. In the multivariable Cox regression analysis, tacrolimus (hazard ratio 0.72, p <0.001) and mycophenolate use (hazard ratio 0.82, p= 0.03) were associated with a reduced risk of graft loss or death, whereas steroid use was not significant. Tacrolimus is associated with better patient and graft survival rates than cyclosporine and should be the standard calcineurin inhibitor used after LT for patients with PSC. The optimal calcineurin inhibitor to use after liver transplantation in patients with primary sclerosing cholangitis has yet to be firmly established. Since randomized trials with long follow-up are unlikely to be performed, multicontinental long-term registry data are essential in informing clinical practices. Our study supports the practice of using tacrolimus instead of cyclosporine in the initial immunosuppressive regimen after liver transplantation for patients with primary sclerosing cholangitis. The retrospective registry-based design is a limitation.

Natural history and prognosis of pediatric PSC with updates on management.

Natural history and prognosis of pediatric PSC with updates on management.

Concurrent inflammatory bowel disease and primary sclerosing cholangitis: a review of pre- and post-transplant outcomes and treatment options.

Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic liver disease which is associated with Inflammatory Bowel Disease (IBD) in 70% of cases. It seems PSC/IBD is a distinct phenotype that is different from PSC, and IBD alone. Hence, we review the epidemiology, pathogenesis, natural course and management of PSC/IBD before and after LT for PSC. Extensive colitis, rectal sparing, backwash ileitis, and mild symptoms are the characteristics of IBD coexisting with PSC. Moreover, PSC patients with concurrent IBD have higher risk of cholangiocarcinoma, and colorectal neoplasia predominantly in right colon and at younger age. Therefore, it is essential to monitor these individuals continuously. It is interesting to note that the course of IBD (ulcerative colitis) after liver transplantation (LT) for PSC varies greatly, and some patients may develop worsening colitis after LT despite immunosuppressive regimens. As well, management of these patients was discussed in this review.

Primary sclerosing cholangitis-A long night's journey into day.

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Donor age (≥45years) and reduced immunosuppression are associated with the recurrent primary sclerosing cholangitis after liver transplantation - a multicenter retrospective study.

The present study investigated the possible risk factors, including relationship/HLA matching between donor and recipient, and immunosuppressive therapies on the recurrence of primary sclerosing cholangitis (PSC) after liver transplantation (LT). Subjects were 197 recipients of LT for PSC, among whom 180 surviving more than 1year after LT were further analyzed for risk factors of recurrence. The 5- and 10-year patient- and graft survival rates were 83% and 68%, and 71% and 62%, respectively. The overall PSC recurrence rate was 25% with a 5- and 10-year graft survival rate of 34% and 18%, which was significantly lower than the survival rate of those without recurrence (P<0.001). Univariate analysis identified the following as risk factors for recurrence: donor age (P<0.001), cyclosporine use (P=0.012), mono or no immunosuppressive agent (P<0.001), postoperative biliary complication (P<0.001), and active intestinal bowel disease after LT (P<0.001). Among these factors, donor age ≥45years [hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.21-2.69; P=0.003] and mono or no immunosuppressive agent 1-year after LT (HR, 2.38; 95% CI, 1.23-3.45; P=0.011) were identified as independent risk factors in the final multivariate Cox regression model. The results were similar in sub-analysis for ABO-identical/compatible adult living donor LT cases.

Impact of Preexisting Inflammatory Bowel Disease on the Outcome of Liver Transplantation for Primary Sclerosing Cholangitis.

Approximately 80% of patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD), and its effect on the outcomes of liver transplantation (LT) for PSC is unclear. We retrospectively collected data from adults who underwent LT for PSC from 1989 to January 2018 in 4 French LT centers. We compared the rates of patient and graft survivals and of complications after LT. Among 87 patients, 52 (60%) had preexisting IBD. Excluding those who died within the first 3months, the 10-year patient survival and graft survival rates were 92.6% (95% confidence interval [CI], 84.3%-100%) and 77.1% (53.8%-85.3%), respectively, in the PSC with IBD (PSC-IBD) group and 97.1% (91.4%-100%; P=0.44) and 83.2% (69.6%-96.9%; P=0.43) in the isolated PSC group, respectively. Exposure to azathioprine after LT was significantly associated with mortality (odds ratio [OR], 15.55; 1.31-184.0; P=0.03), whereas exposure to mycophenolate mofetil was associated with improved survival (OR, 0.17; 95% CI, 0.04-0.82; P=0.03), possibly an era effect. The rate of recurrent PSC was 21% in the PSC-IBD group and 11% in the isolated PSC group (P=0.24). Severe infections occurred in 125 per 1000 person-years in both groups. Exposure to mycophenolate mofetil was associated with a lower risk of infection (OR, 0.26; 95% CI, 0.08-0.85; P=0.03). The presence of IBD was associated with cytomegalovirus (CMV) infection (OR, 3.24; 95% CI, 1.05-9.98; P=0.04). IBD prior to LT for PSC may not affect patient or transplant survival but may increase the risk of CMV infection.

LIVER TRANSPLANTATION FOR PRIMARY SCLEROSING CHOLANGITIS

Introduction: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin. Liver transplantation (LT) is require in more than half of this patients. In this study, we analyzed our results in the patients with LT owing to PSC. Materials and Methods: A total of 649 LT were performed in our center between December 1988 and December 2019. The results were retrospectively analyzed from 12 patients, who underwent LT for PSC. Demographic features, presence of any concomitant inflammatory bowel disease (IBD), time to LT, and outcome data were recorded. Results: There were 12 patients (8 men and 4 women). Ten of the patients were adult and 2 of them were pediatric patient. Mean age of these patients was 27 ± 12 (range, 5 to 40 years). Seven of the transplantations were living donor liver transplantation. Mean follow-up period was 123±49 months. Bile duct reconstruction was performed with hepaticojejunostomy in 7 patients and duct to duct in 5 patients. Biliary leakage was detected in 4 patients postoperatively and they were treated with interventional radiological techniques successfully. Biliary stenosis developed in 4 patients in the late period and 3 of them were treated with interventional radiological methods. In 1 patient surgical treatment was applied. In 1 patient PSC recurred 11 years after LT and retransplantation was performed. Two patients passed away during the follow up period due to sepsis. Conclusions: LT in PSC resulted in favorable outcomes regarding postoperative morbidity and mortality compared with other etiologies.

Activity of Inflammatory Bowel Disease After Liver Transplantation for Primary Sclerosing Cholangitis Predicts Poorer Clinical Outcomes.

The impact of inflammatory bowel disease (IBD) activity on long-term outcomes after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is unknown. We examined the impact of post-LT IBD activity on clinically significant outcomes. One hundred twelve patients undergoing LT for PSC from 2 centers were studied for a median of 7 years. Patients were divided into 3 groups according to their IBD activity after LT: no IBD, mild IBD, and moderate to severe IBD. Patients were classified as having moderate to severe IBD if they met at least 1 of 3 criteria: (i) Mayo 2 or 3 colitis or Simple Endoscopic Score-Crohn's Disease ≥7 on endoscopy; (ii) acute flare of IBD necessitating steroid rescue therapy; or (iii) post-LT colectomy for medically refractory IBD. Moderate to severe IBD at any time post-transplant was associated with a higher risk of Clostridium difficile infection (27% vs 8% mild IBD vs 8% no IBD; P = 0.02), colorectal cancer/high-grade dysplasia (21% vs 3% both groups; P = 0.004), post-LT colectomy (33% vs 3% vs 0%) and rPSC (64% vs 18% vs 20%; P < 0.001). Multivariate analysis revealed that moderate to severe IBD increased the risk of both rPSC (relative risk [RR], 8.80; 95% confidence interval [CI], 2.81-27.59; P < 0.001) and colorectal cancer/high-grade dysplasia (RR, 10.45; 95% CI, 3.55-22.74; P < 0.001). Moderate to severe IBD at any time post-LT is associated with a higher risk of rPSC and colorectal neoplasia compared with mild IBD and no IBD. Patients with no IBD and mild IBD have similar post-LT outcomes. Future prospective studies are needed to determine if more intensive treatment of moderate to severe IBD improves long-term outcomes in patients undergoing LT for PSC.

Metal, magnet or transplant: options in primary sclerosing cholangitis with stricture.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tree of unknown etiology leading to stricturing and dilation. There is currently no effective medical therapy for PSC and liver transplantation (LT) remains the ultimate treatment for severe disease defined as repeated episodes of cholangitis, decompensated biliary cirrhosis or in exceptional cases, cholangiocarcinoma (CCA). Patients often present with a "dominant" stricture and the therapeutic endoscopist plays an important role in management to improve biliary patency using a variety of techniques that involve sampling, balloon dilation and temporary stenting. Newer modalities such as self-expanding metal stents or magnetic compression anastomosis that have been used in other diseases may have a role to play in PSC but should remain investigational. Liver transplantation for PSC is curative in most cases but the optimal timing remains unclear. The lifetime risk of CCA is 10-15% in PSC patients and LT is often not possible at the time of diagnosis. Multiple studies have tried to identify risk factors and to diagnose CCA at an early stage when surgical resection may be possible or LT can be performed. However, deceased donor organs for LT remain in short supply throughout the world so even identifying PSC patients with CCA at an early stage may not be beneficial unless a live donor organ is available.

A novel learning algorithm to predict individual survival after liver transplantation for primary sclerosing cholangitis.

Deciding who should receive a liver transplant (LT) depends on both urgency and utility. Most survival scores are validated through discriminative tests, which compare predicted outcomes between patients. Assessing post-transplant survival utility is not discriminate, but should be “calibrated” to be effective. There are currently no such calibrated models. We developed and validated a novel calibrated model to predict individual survival after LT for Primary Sclerosing Cholangitis (PSC). We applied a software tool, PSSP, to adult patients in the Scientific Registry of Transplant Recipients (n = 2769) who received a LT for PSC between 2002 and 2013; this produced a model for predicting individual survival distributions for novel patients. We also developed an appropriate evaluation measure, D-calibration, to validate this model. The learned PSSP model showed an excellent D-calibration (p = 1.0), and passed the single-time calibration test (Hosmer-Lemeshow p-value of over 0.05) at 0.25, 1, 5 and 10 years. In contrast, the model based on traditional Cox regression showed worse calibration on long-term survival and failed at 10 years (Hosmer-Lemeshow p value = 0.027). The calculator and visualizer are available at: http://pssp.srv.ualberta.ca/calculator/liver_transplant_2002. In conclusion we present a new tool that accurately estimates individual post liver transplantation survival.

Natural History of Established and De Novo Inflammatory Bowel Disease After Liver Transplantation for Primary Sclerosing Cholangitis.

BackgroundThe course of inflammatory bowel disease (IBD) after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is poorly understood. We describe the natural history of established IBD after LT (including risk of disease progression, colectomy, and neoplasia) and de novo IBD.MethodsIn a retrospective cohort, we identified all patients with PSC who underwent LT for advanced PSC at Mayo Clinic, Rochester, Minnesota. Risk factors were identified using multivariate Cox proportional hazard analysis.ResultsThree hundred seventy-three patients were identified (mean age, 47.5 ± 11.7 years; 64.9% male). Over a median (range) of 10 (5.5–17.1) years, 151 patients with PSC-IBD with an intact colon at the time of LT were studied. Post-LT, despite transplant-related immunosuppression, 56/151 (37.1%) required escalation of therapy, whereas 87 had a stable course (57.6%) and 8 patients (5.3%) improved. The 1-, 5-, and 10-year risks of progression of IBD were 4.0%, 18.5%, and 25.5%, respectively. On multivariate analysis, tacrolimus-based immunosuppression post-LT were associated with unfavorable course, and azathioprine use after LT was associated with improved course post-LT. Of 84 patients with no evidence of IBD at the time of LT, 22 (26.2%) developed de novo IBD post-LT. The 1-, 5-, and 10-year cumulative incidences of de novo IBD were 5.5%, 20.0%, and 25.4%, respectively. On univariate analysis, mycophenolate mofetil use after LT was associated with increased risk of de novo IBD, but azathioprine use after LT seemed to be protective.ConclusionsThe 10-year cumulative probability of IBD flare requiring escalation of therapy after LT for PSC was 25.5%, despite immunosuppression for LT. The 10-year cumulative risk of de novo IBD after LT for PSC was 25.4%. Transplant-related immunosuppression may modify the risk of de novo IBD, with an increased risk with mycophenolate and a decreased risk with azathioprine.

Long-term Prognosis and Recurrence of Primary Sclerosing Cholangitis After Liver Transplantation: A Single-Center Experience.

Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease, with liver transplantation being the sole life-saving treatment for end-stage PSC-related liver disease. However, recurrence of PSC after liver transplantation is a common complication, with the risk factors for recurrence being controversial. We conducted a retrospective chart review of 45 patients who had undergone liver transplantation for PSC at our institute. The risk factors for PSC recurrence and graft failure after liver transplantation were analyzed. The graft survival rates were 55.4% at 5 years and 32.8% at 10 years after liver transplantation for PSC. PSC recurrence was diagnosed in 16 (40%) of 40 patients, at a median 30 months (range, 9-70 months) after liver transplantation. The cumulative incidence rate of PSC recurrence was 24.5% at 3 years, 39.3% at 5 years, and 45.8% at 6 years. Among the 16 patients diagnosed with PSC recurrence, the graft survival rate was 56.3% at 5 years, and 21.9% at 10 years after the recurrence. Active inflammatory bowel disease after liver transplantation was identified as an independent risk factor for PSC recurrence. Age younger than 30 years at the time of PSC diagnosis and bacteremia were factors significantly associated with graft failure after liver transplantation on multivariate analysis. PSC frequently recurred and progressed to graft failure after liver transplantation for PSC. Maintaining an inactive status of inflammatory bowel disease might offer protection against PSC recurrence.

Safety and Efficacy of Biologic Agents for the Management of Inflammatory Bowel Disease After Liver Transplantation.

Primary sclerosing cholangitis (PSC) frequently progresses to end-stage liver disease and cirrhosis, requiring liver transplantation. Approximately 70% of patients with PSC have concomitant inflammatory bowel disease (IBD) during their clinical course. After liver transplantation for PSC, corticosteroids and other high-intensity immunosuppressants are initiated to keep IBD in remission. Patients with IBD that is refractory to these agents may need to be managed with biologic therapies. Biologic agents, however, may further increase the risks for malignancy and infection due to their immunosuppressive effects. Thus, to gain a better understanding of the risks and benefits of these agents in this high-risk patient population, we performed a literature search of the PubMed database (2002-2017) to identify studies assessing the efficacy and safety of various biologic agents for the management of IBD in liver transplant recipients. No randomized controlled studies or retrospective comparative studies were identified; however, 15 case reports and case series were identified that met our inclusion criteria. From these case reports, we identified 67 patients who developed de novo or recurrent IBD after liver transplantation and received anti-tumor necrosis factor-α or anti-integrin therapy. Of the 13 published cases reporting clinical response or remission of IBD activity in liver transplant recipients (59 patients), clinical response or remission of IBD was reported in 38 (64.4%) of those patients. Adverse complications reported included cholangitis, oral candidiasis, Clostridium difficile colitis, bacterial pneumonia, cryptosporidiosis, Epstein-Barr virus-positive posttransplantation lymphoproliferative disease, and hepatotoxicity. Given the limited literature (case reports and case series) highlighted in this review, biologic agents such as tumor necrosis factor-α inhibitors and integrin inhibitors commonly used for moderate to severe IBD may be appropriate after liver transplantation; however, consideration of risk versus benefit should always occur in a patient-specific manner.

Survival Outcomes of Liver Transplant Patients With Primary Sclerosing Cholangitis and Inflammatory Bowel Disease

Introduction: The effect of inflammatory bowel disease (IBD) on outcomes after liver transplantation (LT) for primary sclerosing cholangitis (PSC) has been inconclusive. It has been reported that patients with IBD who undergo LT for PSC may be at increased risk for adverse outcomes including re-LT. We evaluated the survival outcomes of patients who underwent LT for PSC with and without IBD. Methods: We retrospectively analyzed 2208 patients who underwent deceased donor LT at a large transplant center between January 2000 and December 2012. Adult PSC patients were included, while those with multiorgan transplantation or prior LTs were excluded. Kaplan-Meier survival analysis was performed. Results: 131 PSC patients underwent LT for PSC. Mean recipient age 49±14 years, 65% males, 74% Caucasians. Mean biologic MELD score at transplant 19 (range 6-40). Mean donor age 49±23. 89% had roux-en Y duct anastomosis. 11% (14) had cholangiocarcinoma and 2% (3) had HCC. 77 patients with PSC had IBD. 71% were male. Mean recipient age 50±14 years, mean MELD score 19.7±7. 88% (68) had ulcerative colitis (UC) and 10% (8) had Crohn's disease. 10% (8) had cholangiocarcinoma (CCA). The estimated PSC patient survival probabilities with and without IBD were 77% vs. 75% at 5-years. The estimated graft survival probabilities with and without IBD were 68% vs. 75% at 5-years. Kaplan-Meier patient and graft survival distributions were not statistically different among LT recipients for PSC with IBD compared to those without IBD (log-rank p=0.61 and p=0.11, respectively) (Figure 1).FigureConclusion: Liver transplant recipient and graft survival among PSC patients who have IBD are not significantly different from PSC patients who do not have IBD. IBD of PSC may not have a negative impact on survival as previously thought. PSC patients who are being evaluated for liver transplantation should have equal consideration and follow up following LT regardless of the IBD status.

Risk Factors and Outcomes of De Novo Cancers (Excluding Nonmelanoma Skin Cancer) After Liver Transplantation for Primary Sclerosing Cholangitis.

Patients with primary sclerosing cholangitis (PSC) may be at higher risk of malignancy after liver transplantation (LT) compared to other LT recipients. We aimed to determine the cumulative incidence of/risk factors for long-term cancer-related mortality in patients with PSC after LT. All adult patients underwent LT for PSC without cholangiocarcinoma from 1984 to 2012, with follow-up through June 2015. We estimated cumulative incidence, risk factors, and mortality from de novo malignancies after LT. Two hundred ninety-three patients were identified (mean [SD] age, 47 [12] years; 63.3% males; 2.4% smoking at LT). Over a median of 11.5 years (range, 6.4-18.6 years), 64 patients (21.8%) developed 73 nonskin cancers, including 46 solid-organ cancers (renal, 11; colorectal, 11; prostate, 7; breast, 5; pancreas, 5; ovarian/endometrial/vulvar cancers, 3; and de novo cholangiocarcinoma, 4). Twenty-two patients developed hematologic malignancies (posttransplant lymphoproliferative diseases, 18; Hodgkin disease, 2; and myelodysplastic syndrome, 2). Five patients developed melanoma. The 1-, 5-, 10-, and 20-year cumulative incidences of cancer were 2.1%, 8.6%, 18.7%, and 27%, respectively. Mortality of patients with PSC who developed cancer was higher than that of patients with PSC without cancer (hazard ratio, 2.2; P < 0.01). On multivariate analysis, recipient's age and elevated pre-LT international normalized ratio were associated with increased risk of de novo (nonskin) malignancy. The 10-year cumulative risk of cancer after LT for advanced-stage PSC was 18.7%, with posttransplant lymphoproliferative diseases, colorectal cancer, and renal cell cancer being the most common. Post-LT de novo nonskin cancer decreased overall posttransplant survival. Only recipient's age and elevated international normalized ratio at LT were associated with increased nonskin cancer risk.

Clinical outcomes of donation after circulatory death liver transplantation in primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a progressive fibro-inflammatory cholangiopathy for which liver transplantation is the only life-extending intervention. These patients may benefit from accepting liver donation after circulatory death (DCD), however their subsequent outcome is unknown. The aim of this study was to determine the clinical impact of using DCD liver grafts in patients specifically undergoing transplantation for PSC. Clinical outcomes were prospectively evaluated in PSC patients undergoing transplantation from 2006 to 2016 stratified by donor type (DCD, n=35 vs. donation after brainstem death [DBD], n=108). In liver transplantation for PSC; operating time, days requiring critical care support, total ventilator days, incidence of acute kidney injury, need for renal replacement therapy (RRT) or total days requiring RRT were not significantly different between DCD vs. DBD recipients. Although the incidence of ischaemic-type biliary lesions was greater in the DCD group (incidence rate [IR]: 4.4 vs. 0 cases/100-patient-years; p<0.001) there was no increased risk of post-transplant biliary strictures overall (hazard ratio [HR]: 1.20, 0.58-2.46; p=0.624), or in sub-analysis specific to anastomotic strictures or recurrent PSC, between donor types. Graft loss and mortality rates were not significantly different following transplantation with DCD vs. DBD livers (IR: 3.6 vs. 3.1 cases/100-patient-years, p=0.34; and 3.9 vs. 4.7, p=0.6; respectively). DCD liver transplantation in PSC did not impart a heightened risk of graft loss (HR: 1.69, 0.58-4.95, p=0.341) or patient mortality (0.75, 0.25-2.21, p=0.598). Transplantation with DCD (vs. DBD) livers in PSC patients does not impact graft loss or patient survival. In an era of organ shortage, DCD grafts represent a viable therapeutic option for liver transplantation in PSC patients. Lay summary: This study examines the impact of liver transplantation in primary sclerosing cholangitis (PSC) with organs donated after circulatory death (DCD), compared to donation after brainstem death (DBD). We show that in appropriately selected patients, the outcomes for DCD transplantation mirror those using DBD livers, with no significant differences in complication rate, patient survival or transplanted liver survival. In an era of organ shortage and increasing wait-list times, DCD livers represent a potential treatment option for transplantation in PSC.

Rate, Risk Factors, and Outcomes of Pouchitis After Liver Transplantation for Primary Sclerosing Cholangitis

Introduction: The presence of primary sclerosing cholangitis (PSC) is associated with an increased risk of chronic pouchitis following total proctocolectomy with ileal pouch-anal anastomosis (IPAA). It is unclear how liver transplantation (LT) for PSC modifies this risk. Aims: To determine the cumulative incidence of and risk factors for chronic pouchitis in patients (pts) with PSC undergoing LT. Methods: We identified all pts who underwent LT for advanced stage PSC for non-cholangiocarcinoma indications at our center from 1984-2012, with follow-up through December, 2015. Information on chronic pouchitis was extracted. The 1-, 5- and 10- cumulative risks of chronic pouchitis were estimated using Kaplan-Meier curves. Demographic and transplant--related features associated with risk of developing chronic pouchitis were assessed using multivariate Cox proportional hazard analysis. Results: Three hundred seventy-three pts underwent LT for PSC, of which 80 were performed for cholangiocarcinoma, and 177 had no colectomy before or after LT. One hundred and sixteen PSC pts who underwent colectomy (72 pre-LT and 44 post-LT) for refractory disease or advanced neoplasia (mean age, 45.6±11.5 yrs; 58.6% males, 2.6% smoking at time of LT, 92.2% with IBD before LT) formed our study cohort. Of 72 patients who underwent colectomy pre-LT (34 IPPA, 32 ileostomy, 6 ileoanal pull through), 44 (61.1%) developed pouchitis before or after LT; four of them were antibiotics-dependent. Of 44 pts who underwent colectomy post-LT (25 IPAA, 19 ileostomy) and were followed a median (interquartile range) of 3.0 yrs (1.5-7.2), 16 IPAA pts (64%) developed at least one episode of pouchitis after LT; three of them had antibiotics-refractory pouchitis. The 1-, 5- and 10-yr cumulative incidence of pouchitis was 20%, 60% and 60% respectively. On univariate analysis, high neutrophils counts at time of LT (hazard ratio [HR], 1.32; 95% CI, 1.004-1.734, P=0.046) increased pouchitis risk. Conclusion: The 10-year risk of pouchitis after LT for advanced stage PSC was about 60%. High neutrophil counts at time of LT increased the risk of pouchitis.

First-Degree Living-Related Donor Liver Transplantation in Autoimmune Liver Diseases.

Liver transplantation (LT) is the treatment of choice for end-stage autoimmune liver diseases. However, the underlying disease may recur in the graft in some 20% of cases. The aim of this study is to determine whether LT using living donor grafts from first-degree relatives results in higher rates of recurrence than grafts from more distant/unrelated donors. Two hundred sixty-three patients, who underwent a first LT in the Toronto liver transplant program between January 2000 and March 2015 for autoimmune liver diseases, and had at least 6 months of post-LT follow-up, were included in this study. Of these, 72 (27%) received a graft from a first-degree living-related donor, 56 (21%) from a distant/unrelated living donor, and 135 (51%) from a deceased donor for primary sclerosing cholangitis (PSC) (n = 138, 52%), primary biliary cholangitis (PBC) (n = 69, 26%), autoimmune hepatitis (AIH) (n = 44, 17%), and overlap syndromes (n = 12, 5%). Recurrence occurred in 52 (20%) patients. Recurrence rates for each autoimmune liver disease were not significantly different after first-degree living-related, living-unrelated, or deceased-donor LT. Similarly, time to recurrence, recurrence-related graft failure, graft survival, and patient survival were not significantly different between groups. In conclusion, first-degree living-related donor LT for PSC, PBC, or AIH is not associated with an increased risk of disease recurrence.

Controversies in the management of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) remains a rare but significant disease, which affects mainly young males in association with inflammatory bowel disease. There have been few advances in the understanding of the pathogenesis of the condition and no therapeutics with proven mortality benefit aside from liver transplantation. There remain areas of controversy in the management of PSC which include the differentiation from other cholangiopathies, in particular immunoglobulin G4 related sclerosing cholangitis, the management of dominant biliary strictures, and the role of ursodeoxycholic acid. In addition, the timing of liver transplantation in PSC remains difficult to predict with standard liver severity scores. In this review, we address these controversies and highlight the latest evidence base in the management of PSC.