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Introduction: Patients with inflammatory bowel disease and primary sclerosing cholangitis may require both liver transplantation and colectomy. There are concerns about increased rates of hepatic artery thrombosis, biliary strictures, and hepatic graft loss in patients with ileal pouch-anal anastomosis compared to those with end ileostomy. We hypothesized that graft survival was not negatively affected by ileal pouch-anal anastomosis compared to end ileostomy., Materials and Methods: A tertiary center's database was searched for patients meeting the criteria of liver transplantation because of primary sclerosing cholangitis and total proctocolectomy with ileal pouch-anal anastomosis or end ileostomy because of ulcerative colitis. Primary endpoints were hepatic graft survival and post-transplant complications., Results: Fifty-five patients met the inclusion criteria between January 1990 and December 2022. Of these, 46 (84%) underwent ileal pouch-anal anastomosis, and 9 (16%) underwent end ileostomy. The average age at total proctocolectomy (41.5 vs. 49.1 years; p = 0.12) and sex distribution (female: 26.1% vs. 22.2%; p = 0.99) were comparable. The rates of re-transplantation (21.7% vs. 22.2%; p = 0.99), hepatic artery thrombosis (10.8% vs. 0; p = 0.58), acute rejection (32.6% vs. 44.4%; p = 0.7), chronic rejection (4.3% vs. 11.1%; p = 0.42), recurrence of primary sclerosing cholangitis (23.9% vs. 22.2%; p = 0.99), and biliary strictures (19.6% vs. 33.3%; p = 0.36) were similar between the ileal pouch-anal anastomosis and end ileostomy groups, respectively. None of the end ileostomy patients developed parastomal varices. The log-rank tests for graft (p = 0.97), recipient (p = 0.3), and combined graft/recipient survival (p = 0.73) were similar., Conclusion: Ileal pouch-anal anastomosis did not negatively affect graft, recipient, and combined graft/recipient survival, or the long-term complications, compared to end ileostomy., (© 2024. Springer Nature Switzerland AG.)

Living donor liver transplantation (LDLT) offers the opportunity to decrease waitlist time and mortality for patients with autoimmune liver disease (AILD), autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. We compared the survival of patients with a potential living donor (pLDLT) on the waitlist versus no potential living donor (pDDLT) on an intention-to-treat basis. Our retrospective cohort study investigated adults with AILD listed for a liver transplant in our program between 2000 and 2021. The pLDLT group comprised recipients with a potential living donor. Otherwise, they were included in the pDDLT group. Intention-to-treat survival was assessed from the time of listing. Of the 533 patients included, 244 (43.8%) had a potential living donor. Waitlist dropout was higher for the pDDLT groups among all AILDs (pDDLT 85 [29.4%] vs. pLDLT 9 [3.7%], p < 0.001). The 1-, 3-, and 5-year intention-to-treat survival rates were higher for pLDLT versus pDDLT among all AILDs (95.7% vs. 78.1%, 89.0% vs. 70.1%, and 87.1% vs. 65.5%, p < 0.001). After adjusting for covariates, pLDLT was associated with a 38% reduction in the risk of death among the AILD cohort (HR: 0.62, 95% CI: 0.42-0.93 [ p <0.05]), and 60% among the primary sclerosing cholangitis cohort (HR: 0.40, 95% CI: 0.22-0.74 [ p <0.05]). There were no differences in the 1-, 3-, and 5-year post-transplant survival between LDLT and DDLT (AILD: 95.6% vs. 92.1%, 89.9% vs. 89.4%, and 89.1% vs. 87.1%, p =0.41). This was consistent after adjusting for covariates (HR: 0.97, 95% CI: 0.56-1.68 [ p >0.9]). Our study suggests that having a potential living donor could decrease the risk of death in patients with primary sclerosing cholangitis on the waitlist. Importantly, the post-transplant outcomes in this population are similar between the LDLT and DDLT groups., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Primary sclerosing cholangitis is a cholestatic disease with a low prevalence in Italy. Indications for liver transplantation and the time of listing are not stated., Aim: We performed a national survey to investigate the listing criteria, comorbidities, and outcomes., Methods: In April 2022, we surveyed liver transplantation in primary sclerosing cholangitis nationwide for the last 15 years., Results: From 2007 to 2021, 445 patients were included on waiting lists, and 411 had undergone liver transplants. The median age at transplantation was 46 years (males 63.9%); 262 patients (59%) presented an inflammatory bowel disease. Transplants increased over the years, from 1.8 % in 2007 to 3.0 % in 2021. Cholangitis (51%) and hepatic decompensation (45%) were the main indications for listing. The disease recurred in 81 patients (20%). Patient survival after the first transplant was 94 %, 86% and 84% at one, five, and ten years. Twenty-four died in the first year (50% surgical complications, 25% infections); 33 between one to five years (36% recurrence, 21% cholangiocarcinoma recurrence) and nine after five years (56% de novo cancer, 44% recurrence)., Conclusions: Primary sclerosing cholangitis has been an increasing indication for transplantation in Italy. Cholangitis and decompensation were the main indications for listing. Recurrence and cancer were the leading causes of death., Competing Interests: Conflict of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objectives: Primary sclerosing cholangitis is an autoimmune illness affecting the intrahepatic and/or extrahepatic bile ducts that has a varying clinical history and no clear therapy. Recurrence of primary sclerosing cholangitis after transplantation can cause recurring liver failure, decreased survival, and the necessity for retransplant. Here, we explored the incidence of recurrence while also identifying the risk factors of primary sclerosing cholangitis., Materials and Methods: In this retrospective cohort study, we collected demographic and clinical data from patients with a history of primary sclerosing cholangitis after liver transplant between 2011 and 2021. With SPSS software, we compared results in 2 groups of patients (with and without recurrent sclerosing biliary cholangitis) in terms of demographic and clinical variables., Results: The study included 408 patients. Lower donor age and the occurrence of acute cellularrejection were shown to be key risk factors for recurrence of primary sclerosing cholangitis. Acute cellularrejection showed the best likelihood of predicting primary sclerosing cholangitis recurrence. As the number of acute cellular rejection episodes increased, so did the chance of primary sclerosing cholangitis. Death rate of patients with recurrence of primary sclerosing cholangitis was 40.8% (n = 20 patients) compared with 18.9% (n = 68 patients) in those without recurrence (significant at P < .001)., Conclusions: The recurrence of primary sclerosing cholangitis had a detrimental effect on survival after liver transplant. Modifiable risk variables have the potentialto affecttherapies on care and prevention of primary sclerosing cholangitis recurrence. Donor age and acute cellular rejection were risk factors for decreased survival and higher primary sclerosing cholangitis recurrence. The use of mycophenolate (Cellcept) increased recurrence, but tacrolimus reduced mortality.

Background and Aims: During the coronavirus disease 2019 (COVID-19) pandemic a significant proportion of patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 infection developed secondary sclerosing cholangitis (SSC) as a hepatobiliary complication., Methods: 17 patients were endoscopically diagnosed and treated with COVID-19 SSC from February 2020 until October 2022 at our center. We retrospectively reviewed and analyzed the data to define risk factors, establish endoscopic treatment options, and to estimate incidence and outcomes., Results: 258 patients with COVID-19 infection were admitted to our tertiary center and mechanically ventilated. 10 patients developed COVID-19 SSC in-house, and 7 patients were transferred for further endoscopic treatment. All 17 patients were mechanically ventilated, received vasoactive substances and 12 of them were treated with extracorporeal membrane oxygenation therapy. Endoscopic retrograde cholangiography (ERC) was performed in all patients to establish the diagnosis of COVID-19 SSC and evaluate endoscopic treatment options. All ERCs revealed biliary casts. 9 patients had developed severe rarefication of the intrahepatic bile ducts and 4 showed biliary strictures. As endoscopic treatment approaches, casts were removed repeatedly, and strictures were dilated. During the study period, 14 patients died (82%). 3 patients are in follow-up to reassess the need for liver transplantation., Conclusions: COVID-19 SSC was observed in 2.6 % of the patients with severe COVID-19 in our center. We show that endoscopic approaches offer the opportunity to extract casts and to treat biliary strictures. As the mortality rate of COVID-19 SSC is high, endoscopic treatment can be of great clinical relevance as a bridge to liver transplantation.

Background: The benefits of regular surveillance imaging for cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC) are unclear. Hence, we aimed to evaluate the impact of regular magnetic resonance cholangiopancreatography (MRCP) on outcomes of patients with PSC in Australia, where the practice of MRCP surveillance is variable., Methods: The relationship between MRCP surveillance and survival outcomes was assessed in a multicenter, retrospective cohort of patients with PSC from 9 tertiary liver centers in Australia. An inverse probability of treatment weighting approach was used to balance groups across potentially confounding covariates., Results: A total of 298 patients with PSC with 2117 person-years of follow-up were included. Two hundred and twenty patients (73.8%) had undergone MRCP surveillance. Regular surveillance was associated with a 71% reduced risk of death on multivariate weighted Cox analysis (HR: 0.29, 95% CI: 0.14-0.59, p < 0.001) and increased likelihood of having earlier endoscopic retrograde cholangiopancreatography from the date of PSC diagnosis in patients with a dominant stricture (p < 0.001). However, survival posthepatobiliary cancer diagnosis was not significantly different between both groups (p = 0.74). Patients who had surveillance of less than 1 scan a year (n = 41) had comparable survival (HR: 0.46, 95% CI 0.16-1.35, p = 0.16) compared to patients who had surveillance at least yearly (n = 172)., Conclusions: In this multicenter cohort study that employed inverse probability of treatment weighting to minimize selection bias, regular MRCP was associated with improved overall survival in patients with PSC; however, there was no difference in survival after hepatobiliary cancer diagnosis. Further prospective studies are needed to confirm the benefits of regular MRCP and optimal imaging interval in patients with PSC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background and Aims: Recent studies point out to epidemiological changes in primary sclerosing cholangitis (PSC). Our aims were to determine in PSC patients followed in several centers in a Mediterranean geographic area: (i) changes in baseline features and (ii) effect of gender on clinical course., Methods: Retrospective multicenter study of PSC patients treated in 8 hospitals in a Mediterranean area between 2000 and 2021. Charts were reviewed compiling demographic, clinical, radiological, and histological variables., Results: Cohort of 112 PSC patients included, 42% women, 70% diagnosed after 2010. Women were increasingly diagnosed in recent cohorts. The median time from diagnosis to the combined endpoint liver transplantation (Lt) and/or death was 6.9 years. Asthenia at diagnosis (p = 0.009) was associated with lower transplant-free survival, while diagnosis before 2005 was associated with greater LT-free survival (p < 0.001). By Cox regression, LT-free survival was not influenced by age, sex, or cirrhosis at the time of diagnosis. Women were found to have less jaundice at diagnosis (2 vs 14%; p = 0.013), higher prevalence of ANA antibodies (43.9 vs 15.7%; p = 0.003), and lower GGT levels at diagnosis (GGT 123 vs 209U/L; p = 0.014) than men., Conclusion: In an area traditionally considered to have low prevalence, the prevalence of affected women surpasses expectations based on existing literature. There appear to be gender-related variations in the presentation of the condition, highlighting the need for confirmation through larger-scale studies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction and Objectives: Autoimmune liver diseases (AILDs): autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) have different survival outcomes after liver transplant (LT). Outcomes are influenced by factors including disease burden, medical comorbidities, and socioeconomic variables., Materials and Methods: Using the United Network for Organ Sharing database (UNOS), we identified 13,702 patients with AILDs listed for LT between 2002 and 2021. Outcomes of interest were waitlist removal, post-LT patient survival, and post- LT graft survival. A stepwise multivariate analysis was performed adjusting for transplant recipient gender, race, diabetes mellitus, model for end-stage liver disease (MELD) score, and additional social determinants including the presence of education, reliance on public insurance, working for income, and U.S. citizenship status., Results: Lack of college education and having public insurance increased the risk of waitlist removal (HR, 1.13; 95 % CI, 1.05-1.23, and HR, 1.09; 95 % CI, 1.00-1.18; respectively), and negatively influenced post-LT patient survival (HR, 1.16; 95 % CI, 1.06-1.26, and HR, 1.15; 95 % CI, 1.06-1.25; respectively) and graft survival (HR, 1.13; 95 % CI, 1.05-1.23, and HR, 1.15; 95 % CI, 1.06-1.25; respectively). Not working for income proved to have the greatest detrimental impact on both patient survival (HR, 1.41; 95 % CI, 1.24-1.6) and graft survival (HR, 1.21; 95 % CI, 1.09-1.35)., Conclusions: Our study highlights that lack of college education and public insurance have a detrimental impact on waitlist mortality, patient survival, and graft survival. Not working for income negatively affects post-LT survival outcomes. Not having U.S. citizenship does not affect survival outcomes in AILDs patients., Competing Interests: Conflicts of interest AB sits on the science advisory board of Intercept and is a primary investigator for trials for Zydus Therapeutics Inc., ChemomAb Ltd., CymaBay Therapeutics Inc., Mirum Pharmaceuticals Inc., Intercept Pharmaceuticals, Gilead Sciences, and CARA; he receives royalties or holds licenses from UptoDate and DynaMed; he works with the AASLD Editorial Board for Clinical Liver Disease; and he has given expert testimony for Expert Review, Inc. The other authors do not have conflicts of interest relevant to this work., (Copyright © 2023 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Imaging-based assessment of sarcopenia is a well-validated prognostic tool for patients with chronic liver disease. However, little is known about its value in patients with primary sclerosing cholangitis (PSC). This cross-sectional study aimed to investigate the predictive value of the cross-sectional imaging-based skeletal muscle index (SMI) for transplant-free survival (TFS) in patients with PSC., Methods: A total of 95 patients with PSC who underwent abdominal cross-sectional imaging between 2008 and 2022 were included in this retrospective study. SMI was measured at the third lumbar vertebra level (L3-SMI). The cut-off values to define sarcopenia were < 50 cm²/m² in male patients and < 39 cm²/m² in female patients. The primary outcome of this study was TFS, which was defined as survival without liver transplantation or death from any cause., Results: Our study indicates that L3-SMI sarcopenia impairs TFS in patients with PSC (5-year TFS: 33.9% vs. 83.3%, p = 0.001, log-rank test). L3-SMI sarcopenia was independently associated with reduced TFS via multivariate Cox regression analysis (HR = 2.749; p = 0.028). Body mass index reduction > 10% at 12 months, which is used as MELD standard exception (SE) criterion in Eurotransplant (in Germany only until September 2023), was not significantly associated with TFS in the multivariate Cox regression analysis (HR = 1.417; p = 0.330). Substitution of BMI reduction with L3-SMI in the German SE criteria improved the predictive accuracy of TFS compared to the established SE criteria (multivariable Cox regression analysis: HR = 4.007, p < 0.001 vs. HR = 1.691, p = 0.141)., Conclusion: Imaging-based diagnosis of sarcopenia via L3-SMI is associated with a low TFS in patients with PSC and may provide additional benefits as a prognostic factor in patient selection for liver transplantation., (© 2024. The Author(s).)

Background and Aims: The impact of sex on the postcirrhosis progression of primary biliary cholangitis (PBC) has not been well defined. Prior studies have suggested that men have worse outcomes but present at more advanced stages of fibrosis than women. This observation, however, has been limited by small numbers of men and even fewer patients with cirrhosis., Approach and Results: We investigated the association of sex with the development of all-cause and liver-related mortality or transplantation, decompensation, and hepatocellular carcinoma (HCC), using competing-risk time-updating Cox proportional hazards models in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. In a cohort of 532 participants (418 male) with PBC-related cirrhosis with a total follow-up of 3,231.6 person-years (PY) from diagnosis of compensated cirrhosis, male participants had a higher unadjusted rates of death or transplantation (8.5 vs. 3.8 per 100 PY; P < 0.0001), liver-related death or transplantation (5.5 vs. 2.7 per 100 PY; P < 0.0001), decompensation (5.5 vs. 4.0 per 100 PY; P = 0.002), and HCC (0.9 vs. 0.3 per 100 PY; P < 0.0001). After adjusting for confounders, male sex was associated with a higher risk of death or transplantation (adjusted hazard ratio, 1.80; 95% CI, 1.01-3.19; P = 0.046), and liver-related death or transplantation (subhazard ratio, 2.17; 95% CI, 1.15-4.08; P = 0.02). A sensitivity analysis that defined ursodeoxycholic acid response as normalization of alkaline phosphatase and total bilirubin revealed similar findings., Conclusions: In patients with PBC and well-compensated cirrhosis, male sex is associated with a higher risk of both death and liver-related death or transplantation., (© 2021 by the American Association for the Study of Liver Diseases. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

A diagnosis of primary sclerosing cholangitis (PSC) has been associated with increased risk of hepatobiliary cancers, colorectal cancer and all-cause mortality in several studies, while associations with cardiovascular disease have been inconsistent. We conducted a systematic review and meta-analysis of published cohort studies on the topic to summarize these associations. PubMed and Embase databases were searched up to January 13th, 2020. Cohort studies on PSC and risk of cancer, cardiovascular disease, or mortality were included. Summary relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated using random effects models. The summary RR (95% CI) comparing persons with PSC to persons without PSC was 584.37 (269.42-1267.51, I 2  = 89%, n = 4) for cholangiocarcinoma (CCA), 155.54 (125.34-193.02, I 2  = 0%, n = 3) for hepatobiliary cancer, 30.22 (11.99-76.17, I 2  = 0%, n = 2) for liver cancer, 16.92 (8.73-32.78, I 2  = 88%, n = 4) for gastrointestinal cancer, 7.56 (2.42-23.62, I 2  = 0%, n = 3) for pancreatic cancer, 6.10 (4.19-8.87, I 2  = 14%, n = 7) for colorectal cancer (CRC), 4.13 (2.99-5.71, I 2  = 80%, n = 5) for total cancer, 3.55 (2.94-4.28, I 2  = 46%, n = 5) for all-cause mortality, and 1.57 (0.25-9.69, I 2  = 79%, n = 2) for cardiovascular disease. Strong positive associations were observed between PSC and risk of CCA, hepatobiliary cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, CRC, total cancer, and all-cause mortality, but not for cardiovascular disease.

Background and Aims: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC., Approach and Results: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well., Conclusions: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials., (© 2020 by the American Association for the Study of Liver Diseases.)

Introduction: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterized by bile duct inflammation and fibrosis. The role of macrophages in PSC development and progression is less studied. Macrophage activation markers soluble (s)CD163 and mannose receptor (sMR) are associated with disease severity and outcome in other liver diseases, but not previously investigated in PSC. We evaluated sCD163 and sMR regarding disease severity and prognosis in patients with PSC., Methods: We investigated 2 independent PSC cohorts from Oslo (n = 138) and Helsinki (n = 159) and analyzed blood sCD163 and sMR levels. The Mayo score, Enhanced Liver Fibrosis Test, and Amsterdam-Oxford model were assessed for comparison., Results: Median (interquartile range) sCD163 was 3.32 (2.27-5.60) and 1.96 (1.47-2.70) mg/L in the Oslo and Helsinki cohorts, respectively, reflecting differences in disease severity between cohorts. Median sMR was similar in both cohorts, 0.28 (0.22-0.44) and 0.28 mg/L (0.20-0.36), respectively. In both cohorts, sCD163 and sMR levels raised with increasing disease severity (liver enzymes, Mayo score, and enhanced liver fibrosis test). Patients with high baseline levels of sCD163 had shorter transplant-free survival than patients with low baseline levels. Furthermore, sCD163 was associated with transplant-free survival in univariate cox-regression analyses. Both sCD163 and sMR performed better in the Oslo cohort of more severely diseased patients than those in the Helsinki cohort of more mildly diseased patients., Discussion: Macrophage activation markers are elevated according to disease severity suggesting an important role of macrophages in PSC. Furthermore, sCD163 was identified as a prognostic marker and predictor of transplant-free survival in PSC (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A516)., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Aim: To evaluate the association between single time-point quantitative liver and spleen volumes in patients with PSC and transplant-free survival, independent of Mayo risk score., Materials and Methods: This HIPAA-compliant retrospective study included 165 PSC patients in a hospital. Total (T), and lobar (right [R], left [L], and caudate [C]) liver volumes and spleen volume (S) were measured. Adverse outcome was identified as being on liver transplantation list, transplantation or death (outcome 1), and transplantation or death (outcome 2). Cox-regression was performed to assess the predictive value of volumetric parameters to predict transplant-free survival with and without Mayo risk score. Stratified analysis by Mayo risk score categories was performed to assess the discriminative value of volumes in the model. Prediction models were developed dependent of Mayo score, based on patients demographics, lab values and volumetric measures for both defined outcomes. Kaplan-Meier curves were depicted for different liver and spleen volumes. P value <0.05 was considered statistically significant., Results: In this cohort (age 43 ± 17 years; 59 % men) 51 % of patients had adverse outcome. Cox-regression analysis demonstrated statistically significant association between values of T, L, R, C, S, L/T, and C/T and outcome 1; and also statistically significant association between values C, S, and C/T and outcome 2. Prediction models included age, INR, total bilirubin, AST, variceal bleeding, S, and C for outcome 1 and age, INR, total bilirubin, AST, variceal bleeding, and S for outcome 2., Conclusions: Based on our observational study, quantitative liver and spleen volumes may be associated with transplant-free survival in patients with PSC and may have the potential for predicting the outcome but this should be validated by randomized clinical trial studies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Selected patients with unresectable perihilar cholangiocarcinoma (p-CCA) are now considered as candidates for liver transplant, provided they fulfill a strict perioperative treatment and staging protocol. The aim of this study was to examine the outcomes of patients after liver transplant with incidental p-CCA found in the liver explants., Methods: A cohort of 10 patients with incidental p-CCA after liver transplant in the period between 1994 and 2019 was included in this retrospective analysis. All patients with this diagnosis were scheduled for transplant because of primary sclerosing cholangitis. The primary and secondary endpoints comprised patient's death and tumor recurrence, respectively, assessed over a 5-year postoperative period., Results: Patient median age was 35 years (range, 32-42 years). Median size of the tumor was 3.0 cm (range, 2.5-4.0 cm). Five patients (50%) had metastases to local lymph nodes. Overall survival was 100%, 37.5%, and 18.8% after the first, third, and fifth postoperative year, respectively, with median survival of 21 months. Patient age (P = .827), R1 resection status (P = .144), tumor diameter (P = .432), and presence of lymph node metastases (P = .663) were not significantly associated with overall survival. Recurrence-free survival was 60.0% after the first postoperative year and 22.5% after the third and fifth postoperative years, with median recurrence-free survival of 13.6 months. No significant predictors of tumor recurrence were found., Conclusions: Incidental p-CCA in patients with primary sclerosing cholangitis undergoing liver transplant is associated with universally very high risk of postoperative tumor recurrence and short expected survival., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is an emerging disease with grim prognosis., Objective: Our aim was the analysis of prognostic factors, long-term outcome and risk of tumour development in SSC-CIP compared with primary sclerosing cholangitis (PSC) patients., Methods: Retrospective analysis between 2008 and 2018., Results: One hundred and eleven patients with SSC-CIP and 408 PSC patients were identified. Median orthotopic liver transplantation (OLT)-free survival was 16 months for SSC-CIP and 147 months for PSC ( p  < 0.001). OLT was performed in 18/111 SSC-CIP compared with 166/408 PSC patients ( p  < 0.001). Malignant tumours were detected in 17.9% of PSC patients (73/408) compared with 2.7% (3/111) in SSC-CIP ( p  < 0.001). In multivariate Cox regression analysis low levels of C-reactive protein (hazard ratio 4.687 (95% confidence interval (CI) 1.144-19.199, p  = 0.032) were significantly associated with a prolonged survival whereas higher age (hazard ratio 0.488 (95% CI 0.23-1.038), p  = 0.062) showed a trend for shorter survival in SSC-CIP. For PSC malignancies (hazard ratio 0.42 (95% CI 0.313-0.575), p  < 0.001) and higher age (hazard ratio 0.709 (95% CI 0.544-0.922), p  = 0.01) were associated with a shorter OLT-free survival., Conclusion: SSC-CIP is characterized by acute onset of liver disease and poor prognosis but with lower tumour incidence compared with PSC.

Introduction: Studies on the epidemiology of primary sclerosing cholangitis (PSC) are mainly based on tertiary referral centers; and are retrospective case series susceptible to selection bias . The aim of this study was to estimate incidence; survival and cause of mortality of PSC in Italy; using population-based data. Methods: Data collected from the National Rare Diseases Registry (RNMR) and the National Mortality Database (NMD) were integrated and analyzed. Results: We identified 502 PSC incident cases. The crude incidence rate between 2012 and 2014 was 0.10 per 100,000 individuals. Sixty percent were male; mean age at disease onset and at diagnosis were 33 and 37 years; respectively; highlighting a mean diagnostic delay of 4 years. The rate of interregional mobility was 12%. Ten-year survival was 92%. In 32% of cases the cause of death was biliary-related; 12% died of biliary or gallbladder cancer. Conclusions: For rare diseases such as PSC; population-based cohort's studies are of paramount importance. Incidence rates of PSC in Italy are markedly lower and survival much longer than the ones reported from tertiary; single-centre series. Moreover; the diagnostic delay and the patient interregional mobility highlights the need for increasing awareness on the disease and for resource reallocation among Italian regions within the National Health Service.

Background: There are only a few and mostly small population-based epidemiological studies of primary sclerosing cholangitis (PSC). Objective: We aimed to estimate prevalence and incidence rates of PSC, and survival and malignancy risk for PSC patients in a large population-based study. Methods: We retrieved 632 PSC patients from 1990 to 2015 in the Hospital District of Helsinki and Uusimaa (HUS), comprising 29% of the Finnish population. Mortality information of the PSC patients was obtained from the national Population Registry, malignancy information from the Finnish Cancer Registry and the causes of death from the Statistics Finland. Standardized incidence ratio and standardized mortality ratio (SMR) were calculated for predefined malignancy types. Results: The crude incidence of PSC in the HUS area was 1.58/100,000 person-years, and the point prevalence in 2015 was 31.7/100,000 inhabitants. The mean time from diagnosis to death was 21.9 years. The risk for any malignancy was three-fold and the risk for colorectal carcinoma was five-fold when comparing with the general population. During the first year after diagnosis of PSC, the risk for cholangiocarcinoma is 900-fold compared to the general population and after that 150-fold. SMR for all malignant neoplasms was 5.9 (95% CI 4.2-8.1). Conclusion: We found that the incidence of PSC in the HUS area in Finland is similar or higher than previously reported from other countries. The prevalence is markedly higher than reported elsewhere, probably due to the active search of the disease, suggesting that the disease is underdiagnosed.

Background: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC., Methods: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic., Results: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy., Conclusions: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

Objectives: Magnetic resonance (MR) risk scores and liver stiffness (LS) have individually been shown to predict clinical outcomes in primary sclerosing cholangitis (PSC). The aim of this study was to assess their complementary prognostic value., Methods: Patients with PSC from 3 European centers with a 3-dimensional MR cholangiography available for central reviewing and a valid LS measurement assessed by vibration-controlled transient elastography by FibroScan performed within a 6-month interval were included in a longitudinal retrospective study. The MR score (Anali) without gadolinium (Gd) was calculated according to the formula: (1 × dilatation of intrahepatic bile ducts) + (2 × dysmorphy) + (1 × portal hypertension). The primary end point was survival without liver transplantation or cirrhosis decompensation. The prognostic values of LS and Anali score without Gd were assessed using Cox proportional hazard models., Results: One hundred sixty-two patients were included. Over a total follow-up of 753 patient-years, 40 patients experienced an adverse outcome (4 liver transplantations, 6 liver-related deaths, and 30 cirrhosis decompensations). LS and Anali score without Gd were significantly correlated (ρ = 0.51, P < 0.001) and were independently associated with the occurrence of an adverse outcome. Optimal prognostic thresholds were 10.5 kPa for LS and 2 for the Anali score without Gd. Hazard ratios (95% confidence interval) were 2.07 (1.06-4.06) and 3.78 (1.67-8.59), respectively. The use in combination of these 2 thresholds allowed us to separate patients into low-, medium-, and high-risk groups for developing adverse outcomes. The 5-year cumulative rates of adverse outcome in these 3 groups were 8%, 16%, and 38% (P < 0.001), respectively., Discussion: The combined use of MRI and vibration-controlled transient elastography permits easy risk stratification of patients with PSC.

Background & Aims: Recently the Amsterdam-Oxford model (AOM) was introduced as a prognostic model to assess the risk of death and/or liver transplantation (LT) in primary sclerosing cholangitis (PSC). We aimed to validate and assess the utility of the AOM., Methods: Clinical and laboratory data were collected from the time of PSC diagnosis until the last visit or time of LT or death. The AOM was calculated at yearly intervals following PSC diagnosis. Discriminatory performance was assessed by calculation of the C-statistic and prediction accuracy by comparing the predicted survival with the observed survival in Kaplan-Meier estimates. A grid search was performed to identify the most discriminatory AOM threshold., Results: A total of 534 patients with PSC and a mean (SD) age of 39.2 (13.1) years were included. The diagnosis was large duct PSC in 466 (87%), PSC with features of autoimmune hepatitis in 52 (10%) and small-duct PSC in 16 (3%). During the median (IQR) follow-up of 7.8 (4.0-12.6) years, 167 patients underwent LT and 65 died. The median LT-free survival was 13.2 (11.8-14.7) years. The C-statistic of the AOM ranged from 0.67 at baseline to 0.75 at 5 years of follow-up. The difference between the predicted and observed survival ranged from -1.6% at 1 year to + 3.9% at 5 years of follow-up. Patients that developed AOM scores >2.0 were at significant risk of LT or death (time-dependent hazard ratio 4.09; 95% CI 2.99-5.61)., Conclusions: In this large cohort of patients with PSC, the AOM showed an adequate discriminative performance and good prediction accuracy at PSC diagnosis and during follow-up. This study further validates the AOM as a valuable risk stratification tool in PSC and extends its utility., Lay Summary: In our study we assessed whether the Amsterdam-Oxford model (AOM) is able to correctly estimate the risk of liver transplantation or death in patients with primary sclerosing cholangitis (PSC). This model uses 7 objective and readily available variables to estimate prognosis for individual patients at the time of PSC diagnosis. The AOM may aid in patient counselling and timing of diagnostic procedures or therapeutic interventions for complications of liver disease. We confirm that the model works well at PSC diagnosis, but also when the AOM is recalculated at different timepoints during follow-up, greatly improving the applicability of the model in clinical practice and for individual patients., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Sclerosing cholangitis (SC) is a severe liver disease leading to destruction of bile ducts. It is believed to run a milder course in children than in adults. To test this assumption, we evaluated time-to-complication curves in two independent paediatric-onset cohorts from the same geographical area., Methods: Short-term disease outcomes were evaluated with an online clinical registry that was filled with data on children with SC diagnosed between 2000 and 2017 and who were followed bi-annually thereafter. Long-term disease outcomes were evaluated in a paediatric-onset subcohort derived from a previously published population-based study from the Netherlands. Time-to-complication in the first cohort was defined as the time from diagnosis until portal hypertension, biliary obstructions and infections, development of malignancy, or liver transplantation, whichever came first. In the second cohort time-to-complication was defined as the time until liver transplantation or PSC-related death., Results: Median age at diagnosis in the first cohort (n = 86) was 12.3 years. In the first 5 years post-diagnosis 23% of patients developed complications. The patients in the population-based study (n = 683) were stratified into those diagnosed before the age of 18 years ('paediatric-onset' subcohort, n = 43) and those diagnosed after the age of 18 years ('adult-onset' subcohort, n = 640). Median age at diagnosis was 14.6 and 40.2 years, respectively. Median time-to-complication in the paediatric-onset and adult-onset subcohorts was not statistically different., Conclusion: Paediatric and adult-onset SC run a similar long-term disease course. Paediatricians who treat children with SC should monitor them closely to recognize early complications and control long-term sequelae., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Cholestasis often occurs after burn injuries. However, the prevalence of cholestasis and its effect on outcomes in patients with severe burn injuries are unknown. The aim of this study was to describe the course and the burden of cholestasis in a cohort of severely burned adult patients., Methods: We investigated the relationship between burn-associated cholestasis (BAC) and clinical outcomes in a retrospective cohort of patients admitted to our unit for severe burn injuries between 2012 and 2015. BAC was defined as an increased level of serum alkaline phosphatase (ALP) ≥1.5x the upper limit of normal (ULN) with an increased level of gamma-glutamyltransferase (GGT) ≥3x ULN, or as an increased level of total bilirubin ≥2x ULN., Results: A total of 214 patients were included: 111 (52%) patients developed BAC after a median (IQR) stay of 9 (5-16) days. At 90 days, the mortality rate was 20%, including 34 and 9 patients with and without BAC (p <0.001), respectively, which corresponded to a 2.5-fold higher (95% CI 1.2-5.2, p = 0.012) risk of 90-day mortality for patients with BAC. After being adjusted for severity of illness, patients with BAC, hyperbilirubinemia and without elevated ALP and GGT levels had a hazard ratio of 4.51 (95% CI 1.87-10.87) for 90-day mortality. BAC was associated with the severity of the burn injury, shock and bacteraemia. BAC was present in 38 (51%) patients at discharge, and 7 (18%) patients had secondary sclerosing cholangitis. These patients maintained elevated levels of ALP and GGT that were 5.8x (1.7-15) the ULN and 11x the ULN (4.5-22), respectively, 20 months (3.5-35) after discharge., Conclusion: BAC is prevalent among patients with severe burn injuries and is associated with worse short-term outcomes, especially when total bilirubin levels were increased without elevated ALP and GGT levels. BAC survivors are at risk of developing sclerosing cholangitis., Lay Summary: Cholestasis is common after burn injuries and is associated with burn severity, sepsis, organ failure and mortality. Patients with hyperbilirubinemia without elevated alkaline phosphatase and gamma-glutamyltransferase levels after the burn injury have a poor prognosis. Patients with burn-associated cholestasis may develop sclerosing cholangitis and secondary biliary cirrhosis., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Aim: To assess the value of quantitative spleen and liver volume changes in predicting the survival of patients with primary sclerosing cholangitis (PSC)., Materials and Methods: This institutional review board-approved single-centre study included 89 PSC patients with baseline and follow-up liver imaging studies and laboratory data between 2000 and 2018. Change in spleen, total and lobar liver volumes, and lobar-to-total liver volume ratio was compared between patients with and without adverse outcome (liver transplantation, transplant waiting list, and death). Receiver operating characteristic (ROC) and Kaplan-Meier analysis were performed to identify the volumetric threshold for prediction of outcome and show how these thresholds predict survival, respectively. A p-value of <0.05 was considered statistically significant., Results: The present cohort included 53 men (60%), with mean age of 42 years at baseline. The only volumetric parameters with significant differences in change between patients with and without adverse outcome were spleen volume (p<0.001) and left-to-total liver volume ratio (L/T; p=0.025). The probability of transplant-free survival at 36 months was 59.1% versus 11.9% for patients with spleen volume change <50 ml versus ≥50 ml, respectively (AUC=0.731); and 61.3% versus 13.8% for patients with L/T change <0.04 versus ≥0.04, respectively (AUC=0.638). The patients with changes below the cut-off in both spleen volume and L/T, had a higher probability of transplant-free survival at 36 months (76.8%), compared to those with change at or below the cut-offs in one or both of these two parameters (36.7%, 15%, respectively; p=0.001)., Conclusion: Spleen volume change and L/T change might be useful biomarkers for prediction of transplant-free survival in patients with PSC., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Primary sclerosing cholangitis is a chronic cholestatic liver disease. The pathomechanism is still not fully understood, but there is evidence that immune-mediated processes may contribute to disease progression., Methods: We studied the prognostic relevance of serum immunoglobulin G (IgG) elevated above the upper limit of normal as a marker for immune activation at initial diagnosis and its influence on transplantation-free survival in a well-defined cohort of PSC patients., Results: The final study cohort comprises of 148 PSC patients. Elevated IgG levels were found in 66 patients (44.6%). Apart from their younger age at first diagnosis, there was no significant difference between patients with or without elevated IgG levels. The presence of a concomitant inflammatory bowel disease, an autoimmune hepatitis or immunosuppressive medication was equally distributed between both groups. Patients with elevated IgG levels reached the combined endpoint (34 (59.6%) vs. 23 (40.4%); p = 0.004) significantly more often and had reduced transplantation-free survival (Log-rank: 24.0 (10.2-37.9) vs. 14.0 (8.5-19.5); p < 0.05). Cox regression analysis including age, gender, presence of IBD, presence of dominant stricture (DS), Mayo Risk Score (MRS), immunosuppression, biochemical response to UDCA and elevated IgG-levels confirmed MRS (p = 0.03), DS (p = 0.04), biochemical response (p = 0.04) and elevated IgG level (p = 0.04) as independent risk factors for reduced transplantation-free survival., Conclusion: We identified elevated serum IgG levels at first diagnosis as an independent risk factor for reduced transplant free-survival in patients with PSC.

Autotaxin has been associated with liver disease severity and transplant-free survival. This study aimed to validate autotaxin as a biomarker in two cohorts of Norwegian large-duct PSC patients, one discovery panel (n = 165) and one validation panel (n = 87). Serum activity of autotaxin was measured in diluted sera by a fluorometric enzymatic assay. Patients reaching an end-point, liver transplantation or death, (discovery panel: n = 118 [71.5%]; validation panel: n = 35 [40.2%]), showed higher autotaxin activity compared with the other patients, P < 0.001 and P = 0.004, respectively. Kaplan-Meier survival analyses showed a strong association between increasing autotaxin activity and shorter liver transplant-free survival (discovery panel: P < 0.001, validation panel: P = 0.001). There was no relationship between autotaxin activity and the presence of inflammatory bowel disease or occurrence of hepatobiliary malignancy. In a multivariable analysis, high autotaxin activity was associated with an increased risk of liver transplantation or death (hazard ratio 2.03 (95% confidence interval 1.21-3.40), P < 0.01), independent from Mayo risk score, an in-house enhanced liver fibrosis score and interleukin-8 in serum. In conclusion, increased serum autotaxin activity is associated with reduced liver transplant-free survival independent from Mayo risk score and markers of inflammation and fibrosis.

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation., (© 2018 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.)

Background/aims: Primary sclerosing cholangitis (PSC) is a chronic, progressive, fibrotic bile duct disease. Resultant complications include infection, progressive liver disease and cancer. While diagnosis relies extensively on imaging, the role of imaging in determining prognosis is unclear. The aim of this study was to systematically review existing imaging indices and features that predict PSC progression., Materials and Methods: We performed a systematic review of imaging features that predict PSC progression. PubMed, EMBASE, MEDLINE, Clinicaltrials.gov and the Cochrane Library were searched from inception to November 2018 for relevant studies. Pertinent data were extracted and assessed. Study quality was evaluated using the Newcastle-Ottawa scale (NOS)., Results: The search returned 2504 results. Nine studies were included in the final review. Four studies evaluated the prognostic value of imaging features and five evaluated prognostic algorithms. The mean NOS score was 4.44 ± 0.98 on a scale of 0 to 9. Imaging features that were of prognostic value were degree of intrahepatic duct narrowing, the presence of a dominant biliary duct stricture and percentage of narrowed intraheptic ducts. Three imaging indices (one endoscopic retrograde cholangiopancreatography (ERCP)-based and two magnetic resonance-based) had been derived. The ERCP index was validated in a second cohort and subsequently updated to improve its predictive ability. The magnetic resonance cholangiopancreatography (MRCP) index was validated in two studies and was found to be predicative of transplant-free survival. A modified MRCP index (MRCP-risk score) was evaluated in a prospective multicenter study and was found to be predicative of PSC-related disease progression., Conclusion: In conclusion, ERCP and MRCP-based indices have short-term prognostic value in PSC. However, more studies are required to validate their predictability of disease-related progression, such as liver decompensation, ascending cholangitis, cholangiocarcinoma and liver transplantation., Competing Interests: None

Autoimmune diseases are a broad range of diseases in which the immune system produces an inappropriate response to self-antigens. This results in inflammation, damage, or dysfunction of tissues and/or organs. Many autoimmune diseases are more common in women and differences between female and male immune and autoimmune responses have been well documented. In general, most of the autoimmune diseases seem to affect more females, although there are exceptions. Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are considered to be autoimmune liver diseases (AILD). They all are rare diseases and they result in significant morbidity and mortality. The female predominance in PBC and AIH are among the strongest among autoimmune diseases. However, the mechanisms responsible for the sex differences in autoimmune liver diseases are largely unknown. In this review, we discuss the recent findings on the influence of sex-dependent mechanisms, which may contribute to differences in presentation, clinical characteristics, disease course, and complications observed between female and male patients with autoimmune liver disease.

Background & Aims: One important hypothesis in primary sclerosing cholangitis pathophysiology suggests that bacterial products from an inflamed leaky gut lead to biliary inflammation. We aimed to investigate whether circulating markers of bacterial translocation were associated with survival in a Norwegian primary sclerosing cholangitis cohort., Methods: Serum levels of zonulin, intestinal fatty acid binding protein, soluble CD14, lipopolysaccharide and lipopolysaccharide-binding protein were measured in 166 primary sclerosing cholangitis patients and 100 healthy controls., Results: Lipopolysaccharide-binding protein and soluble CD14 were elevated in primary sclerosing cholangitis compared with healthy controls (median 13 662 vs 12 339 ng/mL, P = 0.010 and 1657 vs 1196 ng/mL, P < 0.001, respectively). High soluble CD14 and lipopolysaccharide-binding protein (values >optimal cut-off using receiver operating characteristics) were associated with reduced liver transplantation-free survival (P < 0.001 and P = 0.005, respectively). The concentration of soluble CD14 was higher in patients with hepatobiliary cancer compared to other primary sclerosing cholangitis patients and healthy controls. Zonulin was lower in primary sclerosing cholangitis than controls, but when excluding primary sclerosing cholangitis patients with increased prothrombin time zonulin concentrations were similar in primary sclerosing cholangitis and healthy controls. Concomitant inflammatory bowel disease did not influence the results, while inflammatory bowel disease patients without primary sclerosing cholangitis (n = 40) had lower concentration of soluble CD14. In multivariable Cox regression, high soluble CD14 and high lipopolysaccharide-binding protein were associated with transplantation-free survival, independent from Mayo risk score (HR: 2.26 [95% CI: 1.15-4.43], P = 0.018 and HR: 2.00 [95% CI: 1.17-3.43], P = 0.011, respectively)., Conclusions: Primary sclerosing cholangitis patients show increased levels of circulating markers of bacterial translocation. High levels are associated with poor prognosis measured by transplantation-free survival, indicating that ongoing gut leakage could have clinical impact in primary sclerosing cholangitis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. The aim of this study was to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables., Design: The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected. We derived the prognostic index from a multivariable Cox regression model in which predictors were selected and parameters were estimated using the least absolute shrinkage and selection operator. The composite end point of PSC-related death and liver transplantation was used. To quantify the models' predictive value, we calculated the C-statistic as discrimination index and established its calibration accuracy by comparing predicted curves with Kaplan-Meier estimates., Results: The final model included the variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up., Conclusion: The Amsterdam-Oxford model for PSC showed adequate performance in estimating PSC-related death and/or liver transplant in a predominantly population-based setting. The transplant-free survival probability can be recalculated when updated biochemical values are available., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: This study investigated the impact of Model of end-stage liver disease (MELD)-score introduction (MELDi) on waitlist mortality and post-liver transplant (LT) survival in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC)., Methods: LT candidates with PSC or PBC listed between January 1983 and March 2016 were included and followed until December 2016. After MELDi in 2004, PBC patients were listed according to labMELD, PSC patients according to the highest MELD during active cholangitis (chMELD)., Results: In total, 100 PBC and 76 PSC patients were included. Waitlist mortality in PBC was significantly higher than in PSC (16% vs. 5.3%, p = 0.031), whereas PSC patients were significantly more often withdrawn from the waitlist due to improved condition (3.0% vs. 13.2%, p = 0.017). Competing risks analysis identified MELDi (HR = 4.12) and PBC (HR = 2.95) as significant predictors of waitlist mortality. Yet, overall 10 y-patient survival increased after MELDi by 18.8% leading to a 1 y-, 5 y-, and 10 y-patient survival of 98.2%, 70.6% and 70.6% in PBC, and 83.3%, 83.3%, and 80.6% in PSC, respectively., Conclusions: PSC patients showed significantly lower waitlist mortality irrespective of MELDi, whereas in PBC waitlist mortality further increased after MELDi. Utility of MELD and chMELD did not impair post LT outcome., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Although risk factors for the long-term mortality of liver transplantation are well described, there is a lack of detailed study regarding these factors for adult living donor liver transplantation (LDLT)., Methods: We retrospectively analyzed 528 adult LDLT recipients in our hospital. The risk factors were analyzed for overall deaths more than 5 years post-LDLT., Results: Over the 20-year follow-up, 137 patients died. Patient survival at 1, 3, 5, and 10 years post-LDLT was 87.8%, 81.8%, 79.4%, and 72.8%, respectively. The independent risk factors for more than 5 years post-LDLT overall death were hepatocellular carcinoma recurrence (hazard ratio [HR], 38.9; P < 0.001), lymphoid de novo malignancy (HR, 47.2; P = 0.001), primary sclerosing cholangitis as primary diagnosis (HR, 11.5; P < 0.001), chronic rejection (HR, 6.93; P = 0.006), acute rejection (HR, 2.96; P = 0.017), and bile duct stenosis (HR, 2.30; P = 0.045)., Conclusions: Not only malignancies and rejection but also bile duct stenosis and primary sclerosing cholangitis had significant impacts on late period post-LDLT mortality.

Non-invasive predictors for the development of cirrhosis-related conditions are needed for patients with primary biliary cholangitis (PBC). We investigated the association between cytokeratin-18 fragments (M30 and M65) and liver histology, treatment response and the development of cirrhosis-related conditions in patients with PBC. We retrospectively reviewed the clinical data of 111 individuals with biopsy-proven PBC. Serum M30 and M65 levels were measured using stored sera. M30 were significantly decreased after treatment, but there was no significant change in the M65 levels. M65 was significantly higher in non-responders according to the Paris-I and Paris-II definitions. In the multivariate analysis, high levels of M65 were significantly associated with advanced Scheuer stage (odds ratio 5.86; 95% confidence interval 0.55-22.2; P = 0.009) and with the development of cirrhosis-related conditions (hazard ratio 3.94; 95% confidence interval: 1.06-14.5, P = 0.039). Among PBC patients without cirrhosis, those with high serum M65 levels at baseline were at higher risk of developing cirrhosis-related conditions (log-rank test; P = 0.001). High levels of serum M65 may be a non-invasive and early predictor of the development of cirrhosis-related conditions in PBC patients. Our findings may help initiate therapies earlier for those at risk for cirrhosis.

Objective: Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications., Design: We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes., Results: We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10 -9 ). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3 , we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells., Conclusion: We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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.

Background: Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Biomarkers of disease activity or prognostic models predicting outcome at an individual level are currently not established., Aim: To evaluate the prognostic utility of four biomarkers of basement membrane and interstitial extracellular matrix remodeling in patients with primary sclerosing cholangitis., Methods: Serum samples were available from 138 large-duct primary sclerosing cholangitis patients (of which 102 [74%] with IBD) recruited 2008-2012 and 52 ulcerative colitis patients (controls). The median follow-up time was 2.2 (range 0-4.3) years. Specific biomarkers of type III and V collagen formation (PRO-C3 and PRO-C5, respectively) and type III and IV collagen degradation (C3M and C4M, respectively) were assessed. The Enhanced Liver Fibrosis test, including procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinase-1 and hyaluronic acid was assessed for comparison., Results: All markers were elevated in primary sclerosing cholangitis compared to ulcerative colitis patients (P < 0.001). PRO-C3 showed the largest difference between the two groups with a threefold increase in primary sclerosing cholangitis compared to ulcerative colitis patients. Patients with high baseline serum levels of all markers, except C3M, had shorter survival compared to patients with low baseline serum levels (P < 0.001). Combining PRO-C3 and PRO-C5 the odds ratio for predicting transplant-free survival was 47 compared to the Enhanced Liver Fibrosis test's odds ratio of 11., Conclusions: Extracellular matrix remodeling is elevated in primary sclerosing cholangitis patients compared to ulcerative colitis patients. Furthermore, the interstitial matrix marker PRO-C3 was identified as a potent prognostic marker and an independent predictor of transplant-free survival in primary sclerosing cholangitis., (© 2018 John Wiley & Sons Ltd.)

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&#95;transplant&#95;2002. In conclusion we present a new tool that accurately estimates individual post liver transplantation survival.

Background and Aims: Inflammatory bowel disease (IBD) may be complicated by primary sclerosing cholangitis (PSC). We aimed to assess the characteristics of Danish PSC-IBD patients and to compare their prognosis with IBD patients without PSC., Methods: A retrospective nationwide population-based cohort of 257 PSC-IBD patients was assessed through Danish national registries and manual scrutiny of patient files., Results: For all PSC-IBD patients diagnosed after 1976 (n = 222) and 8231 IBD controls (ie, without PSC), the cumulative probability of resective surgery, liver transplantation, cancer, and survival from 1977 through 2011 was estimated and compared by log-rank test and Cox regression. PSC-IBD patients primarily had ulcerative colitis (UC) (72%), were diagnosed in young adulthood (median age at IBD diagnosis, 23 years), and 9% were smokers. Among PSC-UC patients 78% had pancolitis at diagnosis. Among patients with PSC and Crohn's disease (CD) 91% had colonic involvement. The PSC-IBD patients had a significantly higher probability of receiving resective surgery (HR; 2.13, 95% CI: 1.50-3.03); of developing colorectal cancer (CRC) (HR; 21.4, 95% CI: 9.6-47.6), of cholangiocarcinoma (HR; 190, 95% CI: 54.8-660), and of dying (HR; 4.39, 95% CI: 3.22-6.00) as compared to non-PSC-IBD controls. The 25-year cumulative risk of liver transplantation was high (53%)., Conclusions: This unselected population-based study shows that PSC-IBD patients not only have an extensive phenotype of IBD, they are also treated more intensively than other patients with IBD. However, the prognosis remains poor and without any apparent improvement over calendar time., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Autoimmune liver diseases (ALDs) consist of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), IgG4-associated cholangitis and overlap syndromes. Patients with these diseases may gradually progress to end-stage liver diseases and need liver transplantation. The present study aimed to explore the prognosis of patients with ALDs after liver transplantation., Methods: The clinical data of 80 patients with ALD (24 cases of AIH, 35 of PBC, 15 of PSC and 6 of AIH-PBC overlap syndromes) who underwent liver transplantation in Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2004 to September 2016 were collected retrospectively. The causes of death were analyzed and the postoperative cumulative survival rate was estimated by the Kaplan-Meier method. Recurrence and other complications were also analyzed., Results: Of the 80 patients, 18 were males and 62 were females. The average age was 50.5 years and the average Model for End-stage Liver Disease (MELD) score was 14.1. After a median follow-up of 19.8 months, 8 patients died. The 1-, 3- and 5-year cumulative survival rates were all 89.0%. Three cases of recurrent ALDs were diagnosed (3.8%) but they were not totally consistent with primary diseases. Biliary tract complication occurred in 10 patients (12.5%). The new onset of tumor was observed in 1 patient (1.3%). De novo HBV/CMV/EBV infection was found in 3, 8 and 3 patients, respectively., Conclusion: Liver transplantation is an effective and safe treatment for end-stage ALD., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Despite the close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), the association between colectomy and the prognosis of PSC remains controversial., Aim: To explore whether colectomy prior to PSC-diagnosis is associated with transplant-free survival., Methods: A nationwide cohort study in Sweden including all patients aged 18 to 69 years in whom both PSC and IBD was diagnosed between 1987 and 2014 was undertaken. Each patient was followed from date of both PSC and IBD diagnoses until liver transplantation or death, or 31 December 2014. Patients with colon in situ, and colectomy prior to PSC-diagnosis were compared. Survival analyses were performed using the Kaplan-Meier method and multivariable Cox regression models., Results: Of the 2594 PSC-IBD patients, 205 patients were treated with colectomy before PSC-diagnosis. During follow-up, liver transplantations were performed in 327 patients and 509 died. The risk of liver transplantation or death was lower in patients treated with colectomy prior to PSC-diagnosis (HR 0.71, 95% CI 0.53-0.95) than in patients with colon in situ. Male gender, longer time between IBD and PSC-diagnosis and older age were all associated with an increased risk of liver transplantation or death. Colectomy after PSC-diagnosis was however not associated with an increased risk of liver transplantation or death during long-term follow-up., Conclusions: In PSC-IBD patients, colectomy prior to PSC-diagnosis is associated with a decreased risk of liver transplantation or death., (© 2017 John Wiley & Sons Ltd.)

Background: There is increasing evidence for a heterogeneity of phenotypes in primary sclerosing cholangitis (PSC), but differences across the age spectrum in adults with PSC have not been well characterized., Aims: To characterize phenotypic variations and liver transplantation outcomes by age group in adults with PSC., Methods: The United Network for Organ Sharing database was used to identify waitlist registrations for primary liver transplantation in adults with PSC. Patients were split into three age groups: 18-39 (young), 40-59 (middle-aged), and ≥60 (older). Their clinical characteristics and outcomes on the waitlist and post-transplant were compared., Results: Overall, 8272 adults with PSC were listed for liver transplantation during the study period, of which 28.9% were young, 52.0% were middle-aged, and 19.1% were older. The young age group had the greatest male predominance (70.0 vs. 66.2 vs. 65.1%, p = 0.001), the highest proportion of black individuals (20.0 vs. 11.0 vs. 5.5%, p < 0.001), and the most patients listed with concomitant autoimmune hepatitis (2.2 vs. 1.0 vs. 0.8%, p < 0.001). Older patients experienced the greatest waitlist and post-transplant mortality. Graft survival was greatest in the middle-aged group. Young patients were most likely to experience acute rejection (31 vs. 22.8 vs. 18.0%, p < 0.001) and have graft failure due to chronic rejection or PSC recurrence (47.8 vs. 42.3 vs. 17.9%, p < 0.001)., Conclusions: Age-related differences exist among adults with PSC and are associated with outcomes pre- and post-transplant. Young patients may have a more robust immune-related phenotype that is associated with poorer graft survival. Future studies are needed to further investigate these findings.

Introduction: Hepatic morphology changes are well described in Primary Sclerosing Cholangitis and characterised by a combination of atrophy and hypertrophy changes. This study investigates the relationship between progression of these changes over time and clinical outcome in patients with PSC., Methods: Fifty-three patients with PSC (mean age 44, 28 males and 25 females) who underwent serial MRI liver studies at least one year apart were identified. The first and the last MRI studies were selected for the retrospective analysis. Three radiologists reviewed and compared both studies for changes in hepatic morphology, specifically atrophy and/or hypertrophy. The imaging findings were correlated with adverse clinical outcomes defined as death or liver transplantation and with serum bilirubin., Results: There was a mean interval of 60 months between MRI examinations and a mean clinical follow-up period thereafter of 22 months. Thirty-three (62.3%) patients had stable hepatic morphology, whilst 20 (37.7%) patients showed hepatic morphology changes (atrophy: 13 patients, 24%; hypertrophy: 16 patients, 30%). Eleven patients (21%) died or underwent liver transplantation. There was a significant correlation between interval hepatic atrophy and adverse clinical outcomes (P = 0.001). Significant correlations were found between increasing serum bilirubin level and interval hepatic atrophy, hepatic hypertrophy and combined changes (P = 0.025, P = 0.022, P = 0.027, respectively)., Conclusion: Hepatic morphology changes over time in patients with PSC are heterogeneous with some patients developing atrophy and/or hypertrophy whilst other patients remain stable. In this retrospective study, progressive hepatic atrophy showed significant association with adverse clinical outcome defined by either death or liver transplantation., (© 2017 The Royal Australian and New Zealand College of Radiologists.)

Background & Aims: Biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC) have not been firmly established. Enhanced liver fibrosis (ELF) test was previously reported to predict outcome in PSC. We aimed to validate the prognostic utility of ELF test in an independent, multi-centre, retrospective PSC study population., Methods: We collected serum samples from PSC patients from seven countries. We estimated rates of transplant-free survival by the Kaplan-Meier method, used Cox proportional hazards regression to explore the association between ELF test and clinical outcome and determined prognostic performance of ELF test by computing the area under the receiver operating characteristic (AUC-ROC) curve., Results: The final analysis included 534 PSC patients (61% males). Features of autoimmune hepatitis or concomitant inflammatory bowel disease affected 44 (8%) and 379 (71%) patients respectively. ELF test levels were higher in patients reaching the combined endpoint liver transplantation or death (median 10.9 [Interquartile range (IQR): 9.8-12.1]; n=24 deaths, 79 liver transplantations) compared to those censored (8.8 [IQR: 8.0-9.8]); P<.001. ELF test expressed as mild, moderate and severe fibrosis was significantly associated with the risk of reaching the endpoint (P<.001). ELF test independently predicted clinical outcome (Hazard ratio 1.31; 95% confidence interval [1.05-1.65]; P=.018), and enabled good discrimination between PSC patients with and without endpoint (AUC-ROC: 0.79)., Conclusion: Our retrospective data validates the predictive utility of ELF test for clinical outcomes in PSC. The clinical utility of biomarkers for fibrosis in patients with PSC should be assessed in prospective patient cohorts., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Secondary sclerosing cholangitis in critically ill patients is a rapidly progressing disease leading to biliary fibrosis and cirrhosis. We describe the course of sclerosing cholangitis in critically ill patients after cardiac surgery and compare this with matched patients., Methods: A retrospective search for "secondary sclerosing cholangitis" and "liver and/or hepatic failure" in all adult patients (aged 18-93 years) who underwent cardiac surgery from April 2007 to March 2016 identified 192 of 8625 patients. Of those, 12 were diagnosed with sclerosing cholangitis in critically ill patients (incidence, 0.14%). A 3:1 matching was performed. Laboratory values, pharmacologic requirements, ventilation times, mechanical circulatory support, and endoscopic retrograde cholangiopancreatography studies were extracted from the hospital database., Results: A total of 9 men and 3 women were affected (age 71 years; range, 59.8-75.5 years). Critically ill patients with sclerosing cholangitis required vasoconstrictors and inotropes longer than control patients (norepinephrine 356.5 hours [264.5-621] vs 68 hours [15-132.5], P = .003; enoximone 177 hours [124.3-249.5] vs 48.5 hours [12-81 hours], P < .001, respectively). Critically ill patients with sclerosing cholangitis had longer intubation time (628.5 hours [377.3-883] vs 25 hours [9.8-117.5]; P < .001) and more surgical revisions (3 [2.5-6] vs 1 [0-2], P = .003) than the matching group. Bilirubin (23.3 mg/dL [14.4-32.9] vs 1 mg/dL [0.6-2.7]; P < .001), gamma-glutamyltransferase (1082.3 U/L [259.5-2265.7] vs 53.8 U/L [35.1-146]; P < .001), and alkaline phosphatase (751.5 U/L [372-1722.3] vs 80.5 U/L [53.3-122]; P < .001) were higher in critically ill patients with sclerosing cholangitis. One critically ill patient with sclerosing cholangitis underwent successful liver transplantation. A total of 11 patients sclerosing cholangitis died (92%) versus 12 patients (33%, P < .001) in the control group., Conclusions: Sclerosing cholangitis in critically ill patients is a fatal complication in patients undergoing cardiac surgery who have a complicated postoperative course with prolonged vasoconstrictor, inotropic, and respiratory therapy, or who require frequent surgical revisions. Liver transplantation remains the only curative option but is often precluded by the age and critical state of patients undergoing cardiac surgery., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Aim: To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis (PSC) patients., Methods: Sera of 67 PSC patients [median age (range): 32 (5-79) years, concomitant IBD: 67% and cirrhosis: 20%] were assayed for the presence of antibodies against to F-actin (AAA IgA/IgG) and gliadin (AGA IgA/IgG)] and for serum level of intestinal fatty acid-binding protein (I-FABP) by ELISA. Markers of lipopolysaccharide (LPS) exposure [LPS binding protein (LBP)] and various anti-microbial antibodies [anti-OMP Plus IgA and endotoxin core IgA antibody (EndoCAb)] were also determined. Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up [median: 99 (14-106) mo]. One hundred and fifty-three healthy subjects (HCONT) and 172 ulcerative colitis (UC) patients were the controls., Results: A total of 28.4%, 28.0%, 9% and 20.9% of PSC patients were positive for AAA IgA, AAA IgG, AGA IgA and AGA IgG, respectively. Frequencies of AAA IgA and AAA IgG ( P < 0.001, for both) and AGA IgG ( P = 0.01, for both) but not AGA IgA were significantly higher compared to both of the HCONT and the UC groups. In survival analysis, AAA IgA-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis [HR = 5.15 (1.27-20.86), P = 0.022 or for the Mayo risk score (HR = 4.24 (0.99-18.21), P = 0.052]. AAA IgA-positivity was significantly associated with higher frequency of anti-microbial antibodies ( P < 0.001 for EndoCab IgA and P = 0.012 for anti-OMP Plus IgA) and higher level of the enterocyte damage marker (median I-FABP AAA IgA pos vs neg : 365 vs 166 pg/mL, P = 0.011), but not with serum LBP level., Conclusion: Presence of IgA type AAA identified PSC patients with progressive disease. Moreover, it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage further highlighting the importance of the gut-liver interaction in PSC., Competing Interests: Conflict-of-interest statement: Gary L Norman and Zakera Shums are employees of Inova Diagnostics.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.