Extensive population‐based studies are much needed to accurately establish epidemiology and disease course in patients with primary sclerosing cholangitis (PSC). We aimed to obtain population‐based prevalence and incidence figures, insight in disease course with regard to survival, liver transplantation (LT), and occurrence of malignancies, as well as risk factors thereof. Four independent hospital databases were searched in 44 hospitals in a large geographically defined area of the Netherlands, comprising 50% of the population. In addition, all PSC patients in the three Dutch liver transplant centers and all inflammatory bowel disease (IBD) patients in the adherence area of a large district hospital were identified. All medical records were reviewed on‐site, verifying diagnosis. Five hundred and ninety PSC patients were identified, resulting in an incidence of 0.5 and a point prevalence of 6.0 per 100,000. Median follow up was 92 months. Estimated median survival from diagnosis until LT or PSC‐related death in the entire cohort was 21.3 years, as opposed to 13.2 years in the combined transplant centers cohort (n = 422; P < 0.0001). Colorectal carcinoma (CRC) risk was 10‐fold increased, as compared to ulcerative colitis controls, and developed at a much younger age (39 years; range, 26‐64), compared to IBD controls (59 years; range, 34‐73; P = 0.019). Colonoscopic surveillance was associated with significantly better outcome. Conclusion: This study exemplifies that, for relatively rare diseases, it is paramount to collect observational data from large, population‐based cohorts, because incidence and prevalence rates of PSC are markedly lower and survival much longer than previously reported. The selection of a bias‐free, population‐based cohort showed a significantly longer survival, compared to the tertiary referral cohort. CRC can develop at an early age, warranting surveillance from time of PSC diagnosis. (Hepatology 2013; 58:2045–2055)

Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end‐stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. Conclusion: At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials. (Hepatology 2016;63:1357–1367)

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.

Background: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease, strongly associated with a particular phenotype of inflammatory bowel disease (IBD) with right-sided colonic involvement. In IBD, several studies demonstrated significant aberrancies in the intestinal microbiota in comparison with healthy controls. We aimed to explore the link between IBD and PSC by studying the intestinal mucosal adherent microbiota in PSC- versus ulcerative colitis (UC)- patients and non-inflammatory controls. Methods: We included 12 PSC-, 11 UC- patients and nine non-inflammatory controls. The microbiota composition was determined in ileocecal biopsies per patient using 16S rRNA based analyses by means of the Human Intestinal Tract Chip. Results: Profiling of the mucosal adherent microbiota of PSC patients, UC patients and non-inflammatory controls revealed that these groups did not cluster separately based on microbiota composition. At the genus-like level, the relative abundance of Uncultured Clostridiales II was significantly, almost a two-fold lower in PSC (0.26%±0.10) compared to UC (0.41%±0.29) and controls (0.49%±0.25) (p= 0.02). Diveristy and richness in the microbiota composition differed across the groups and was significantly lower in PSC patients compared to non-inflammatory controls, p=0.04 and p=0.02.No significant differences were found in evenness. Conclusions: Reduced amounts of Uncultured Clostridiales II in PSC biopsies in comparison with UC- and healthy controls can be considered as a signature for a compromised gut as we have recently observed that this group of not yet cultured Firmicutes correlates significantly with health.

Background and Study Aims: Around 10 % of patients with primary sclerosing cholangitis (PSC) develop cholangiocarcinoma, which is cholangiographically often indistinguishable from a benign dominant stricture. The aim of the present study was to assess the value of brush cytology in discriminating between benign and malignant dominant strictures in primary sclerosing cholangitis. Patients and Methods: The results of all brush cytology specimens from dominant strictures from patients with established primary sclerosing cholangitis, taken at endoscopic retrograde cholangiopancreatography between 1987 and 1996, were compared with the histological diagnosis or clinical status of the patients at least 2 years later. Results: A total of 47 brush cytology samples, taken between 1987 and 1996, from 43 PSC patients could be in-cluded. Between 1993 and 1996, p53 immunocytochemical examination was done in 27 brush cytology specimens and K-ras mutation analysis in 25 patients. The sensitivity, specificity, positive predictive value, and negative predictive value of brush cytology for detection of malignancy were 60 %, 89 %, 59 %, and 89 %, respectively. These figures were not improved by adding the results of p53 and K-ras analysis. Logistic regression analysis did not reveal any additional benefit of p53 or K-ras analysis either. Prior stenting did not adversely affect specificity. Conclusions: The sensitivity and positive predictive value of brush cytology for dominant strictures in PSC are rather poor. The specificity and negative predictive value are reasonably good. There was no additional value from p53 immunocytochemistry and K-ras mutation analysis. Prior stenting did not affect the results.