Cholestasis from primary sclerosing cholangitis (PSC) frequently causes pruritus. However, the prevalence of pruritus and its management have not been well studied. Investigating the Cholestatic Pruritus of Primary Sclerosing Cholangitis (ItCh-PSC) includes a retrospective medical record review to determine the prevalence, severity, and treatment patterns of pruritus.

Data was collected at 5 academic medical centers in the United States. Medical records were searched for the terms "itch" and "pruritus" and data abstracted related to itch severity, number of encounters, and treatment.

Among 724 patients with PSC, 359 (50%) of patients had a documented history of pruritus, including 40%, 39%, and 21% with mild, moderate, or severe itch. Itch was less common in those with small ducts compared to large duct PSC (p=0.02) and more frequent in those of Hispanic versus non-Hispanic ethnicity (p=0.001). Compared to patients with mild itch, patients with moderate or severe itch were younger, and had more elevated liver biochemistries, more encounters with itch, and more frequently prescribed 2 or more anti-pruritic medications. Bile acid-binding resins were prescribed in 36%, hydroxyzine in 23%, rifampin in 11%, and fenofibrate in 4% of patients with any itch. The prevalence and severity of pruritus were not affected by cirrhosis, hepatic decompensation, or inflammatory bowel disease.

Itch is common in patients with PSC and is often associated with multiple prescriptions of antipruritic agents. Effective treatments for pruritus in patients with PSC remain an unmet need.

Background: The Mayo Risk Score (MRS) predicts short-term mortality in primary sclerosing cholangitis (PSC) using the age, bilirubin, albumin, aspartate aminotransferase (AST), and variceal bleeding history. While the MRS has been validated in end-stage PSC, its ability to predict liver transplantation (LT) and outcomes in newly diagnosed patients without advanced disease remains unclear. This study evaluated the effectiveness of the MRS in predicting LT and mortality in this patient population. Methods: We analyzed data from 109 adults with PSC enrolled in a prospective registry (2018-2024) with ≥4 years of follow-up. Logistic regression identified the predictors of LT or death, and the model performance was assessed using the area under the receiver operating characteristic curve (AUROC). Multicollinearity was evaluated using the variance inflation factor (VIF). Results: Among the 109 patients (mean age 45 ± 15 years, 51% female), 85% remained alive without LT, 12% underwent LT, and 3% died over a median follow-up of 4.63 years. The MRS was significantly associated with LT or death (OR 3.08, p < 0.001) and demonstrated excellent predictive performance (AUROC 0.99, p < 0.001). The model achieved 95.45% sensitivity, 98.85% specificity, and a correct classification rate of 98.17%, supporting its clinical utility. Conclusion: The MRS is a robust tool for risk stratification in PSC, predicting LT and mortality. These findings highlight its broader applicability beyond end-stage PSC and underscore its potential for guiding clinical management and early intervention strategies.

Despite more than 50 years of research and parallel improvements in hepatology and oncology, there is still today neither a treatment to prevent disease progression in primary sclerosing cholangitis (PSC), nor reliable early diagnostic tools for the associated hepatobiliary cancers. Importantly, the limited understanding of the underlying biological mechanisms in PSC and its natural history not only affects the identification of new drug targets but implies a lack of surrogate markers that hampers the design of clinical trials and the evaluation of drug efficacy. The lack of easy access to large representative well-characterised prospective resources is an important contributing factor to the current situation.

We here present the SUPRIM cohort, a national multicentre prospective longitudinal study of unselected PSC patients capturing the representative diversity of PSC phenotypes. We describe the 10-year effort of inclusion and follow-up, an intermediate analysis report including original results, and the associated research resource. All included patients gave written informed consent (recruitment: November 2011-April 2016).

Out of 512 included patients, 452 patients completed the five-year follow-up without endpoint outcomes. Liver transplantation was performed in 54 patients (10%) and hepatobiliary malignancy was diagnosed in 15 patients (3%). We draw a comprehensive landscape of the multidimensional clinical and biological heterogeneity of PSC illustrating the diversity of PSC phenotypes. Performances of available predictive scores are compared and perspectives on the continuation of the SUPRIM cohort are provided.

We envision the SUPRIM cohort as an open-access collaborative resource to accelerate the generation of new knowledge and independent validations of promising ones with the aim to uncover reliable diagnostics, prognostic tools, surrogate markers, and new treatment targets by 2040.

This work was supported by the Swedish Cancer Society, Stockholm County Council, and the Cancer Research Funds of Radiumhemmet.

Early identification of incident chronic kidney disease (CKD) in individuals with diabetes may help improve patients' clinical outcomes. This study aimed to develop a prediction equation for incident CKD among people with type 2 diabetes (T2D).

A time-varying Cox model was applied to data from the ACCORD trial to predict the risk of incident CKD. A list of candidate variables was chosen based on literature reviews and experts' consultations, including demographic characteristics, vitals, laboratory results, medical history, drug use and health care utilization. Model performance was evaluated. Decomposition analysis was conducted, and external validation was performed.

In total, 6006 patients with diabetes free of CKD were included, with a median follow-up of 3 years and 2257 events. The risk model included age at T2D diagnosed, smoking status, body mass index, high-density lipoprotein, very-low-density lipoprotein, alanine aminotransferase, estimated glomerular filtration rate, urine albumin-creatinine ratio, hypoglycaemia, retinopathy, congestive heart failure, coronary heart disease history, antihyperlipidaemic drug use, antihypertensive drug use and hospitalization. The urine albumin-creatinine ratio, estimated glomerular filtration rate and congestive heart failure were the top three factors that contributed most to the incident CKD prediction. The model showed acceptable discrimination [C-statistic: 0.772 (95% CI 0.767-0.805)] and calibration [Brier Score: 0.0504 (95% CI 0.0477-0.0531)] in the Harmony Outcomes Trial.

Incident CKD prediction among individuals with T2D was developed and validated for use in decision support of CKD prevention.

Early identification and prediction of incident heart failure (HF) is important because of severe morbidity and mortality. This study aimed to predict onset of HF among patients with diabetes.

A time-varying Cox model was derived from ACCORD clinical trial to predict the risk of incident HF, defined by hospitalization for HF (HHF). External validation was performed on patient-level data from the Harmony Outcome trial and Chronic Renal Insufficiency Cohort (CRIC) study. The model was transformed into an integer-based scoring algorithm for 10-year risk evaluation. A stepwise algorithm identified and selected predictors from demographic characteristics, physical examination, laboratory results, medical history, medication and health care utilization, to develop a risk prediction model. The main outcome was incident HF, defined by HHF. The C statistic and Brier score were used to assess model performance.

In total, 9649 patients with diabetes free of HF were used, with median follow-up of 4 years and 299 incident hospitalization of HF events. The model identified several predictors for the 10-year HF incidence risk score 'DM-CURE': socio-Demographic [education, age at type 2 diabetes (T2DM) diagnosis], Metabolic (glycated haemoglobin, systolic blood pressure, body mass index, high-density lipoproteins), diabetes-related Complications (myocardial infarction, revascularization, cardiovascular medications, neuropathy, hypertension duration, albuminuria, urine albumin-to-creatinine ratio, End Stage Kidney Disease), and health care Utilization (all-cause hospitalization, emergency room visits) for Risk Evaluation. Among them, the strongest impact factors for future HF were age at T2DM diagnosis, health care utilization and cardiovascular disease-related variables. The model showed good discrimination (C statistic: 0.838, 95% CI: 0.821-0.855) and calibration (Brier score: 0.006, 95% CI: 0.006-0.007) in the ACCORD data and good performance in the validation data (Harmony: C statistic: 0.881, 95% CI: 0.863-0.899; CRIC: C statistic: 0.813, 95% CI: 0.794-0.833). The 10-year risk of incident HF increased in a graded fashion, from ≤1% in quintile 1 (score ≤14), 1%-5% in quintile 2 (score 15-23), 5%-10% in quintile 3 (score 24-27), 10%-20% in quintile 4 (score 28-33) and ≥20% in quintile 5 (score >33).

The DM-CURE model and score were useful for population risk stratification of incident HHF among patients with T2DM and can be easily applied in clinical practice.

Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.

We characterized recent outcomes in US pediatric acute liver failure (PALF) subjects listed for liver transplantation (LT) using the Scientific Registry of Transplant Recipients (SRTR) database.

Pediatric subjects listed for LT from 2002 to 2015 were assigned to the "PALF" group based on status 1/1A listing, INR >2, no hepatic artery thrombosis, and no primary graft nonfunction (N = 397). Subjects were assigned to the "non-PALF" group if listed with any status other than 1/1A (N = 4509).

The PALF group had more infants <3 months of age and males at listing for LT compared to the non-PALF group. Two-thirds of PALF subjects had an indeterminate etiology. LT waitlist survival was significantly worse in the PALF group compared to the non-PALF group. Likelihood of removal from the LT waitlist for being "too sick" was higher, while that of removal for "spontaneous recovery" was lower in PALF subjects. Post-LT short-term (30 days) and long-term (60 months) outcomes were also significantly worse in PALF versus non-PALF subjects. PALF subjects who underwent living-donor-liver-transplant (LDLT) had similar LT waitlist times and post-LT survival compared to those undergoing deceased-donor-liver-transplant (DDLT). Over the study period, we observed a decreased number of liver transplants, and increase in LT waitlist- and short-term post-LT-survival in PALF subjects.

LT waitlist and post-LT outcomes are worse in PALF subjects compared to non-PALF subjects. PALF subjects who undergo LDLT have similar waitlist times and post-LT outcomes compared to those undergoing DDLT.

The elucidation of differences between adult and pediatric-onset primary sclerosing cholangitis (PSC) may inform clinical decision making, and whether results of adult PSC clinical trials can be extrapolated to pediatric subjects.

A single-center retrospective analysis of PSC subjects diagnosed during the epoch 2000-13 was conducted. Demographic, clinical, and laboratory data were compared between PSC subjects diagnosed between 0-18 (pediatric) and 19+ (adult) years of age. An adverse outcome was defined as PSC-related death, liver transplant, or malignancy. Survival without any of these was defined as event-free survival.

Analyses of 28 pediatric-diagnosed and 59 adult-diagnosed subjects revealed that incidence of early portal hypertension (PHT; P = 0.2), laboratory parameters of liver disease severity, and fibrosis grade at diagnosis were comparable between adult and pediatric PSC subjects. Adult-diagnosed PSC subjects had higher incidences of adverse outcomes compared to pediatric-diagnosed PSC subjects (P = 0.02). The age group 0-18 years (n = 30) had significantly better event-free survival compared to the age group more than 40 years (n = 25; P = 0.03). The prevalence of PHT in adult PSC subjects was 2.6 that of pediatric PSC subjects. PHT adversely affected outcomes in both adult (P < 0.001) and pediatric (P = 0.01) subjects. Adult PSC subjects were more likely to develop biliary complications (BCs; P = 0.001), ascites (P = 0.004), and variceal bleed (P = 0.03). Adult PSC subjects were more likely to have extra-hepatic co-morbidities (P < 0.001). Adult subjects had a longer follow-up duration compared to pediatric subjects (P = 0.06).

Despite having a comparable clinical, laboratory, and histologic biomarkers of liver disease severity at the time of diagnosis, adult PSC subjects had a worse outcome compared to pediatric PSC subjects. Possible reasons for this finding include higher incidence of PHT, BCs, extra-hepatic co-morbidities, and longer duration of follow-up.

ANALI-scores are two prognostic magnetic resonance imaging (MRI)-based scores developed for patients with primary sclerosing cholangitis (PSC). Our study aims to assess the interreader agreement between expert radiologists of the two ANALI-scores and of the radiological parameters they utilize, and to test the prognostic performance of the scores in our population.

Three radiologists evaluated MRIs of 98 PSC-patients from a prospectively collected cohort with median follow-up of 6.7 years. Each parameter of ANALI-scores was assessed, and the scores were calculated. Interreader agreement was assessed with intraclass correlation coefficient (ICC). After consensus reading was reached, the prognostic value of ANALI-scores was assessed with Cox regression, and outcome-free survival rates were evaluated with Kaplan-Meier estimates.

The ANALI-score without gadolinium had poor to moderate (ICC = 0.56, 95 %CI: 0.42-0.68) and with gadolinium poor (ICC = 0.30, 95 %CI: 0.16-0.44) agreement. Liver deformity (ICC = 0.28, 95 %CI: 0.13-0.44) and parenchymal enhancement heterogeneity (ICC = 0.24, 95 %CI: 0.12-0.38) had poor agreement. Portal hypertension had poor to moderate (ICC = 0.48, 95 %CI: 0.36-0.59) and dilatation of the intrahepatic ducts had moderate (ICC = 0.64, 95 %CI: 0.54-0.73) agreement. Hazard ratios for liver-related death, transplantation or cirrhosis decompensation of the ANALI-scores with and without gadolinium were 3.53 (95 %CI: 1.40-8.93) and 2.25 (95 %CI: 1.56-3.24), respectively. Outcome-free survival was better for patients with low ANALI-scores.

The ANALI-scores show poor to moderate agreement, which challenges their usefulness in clinical practice. They are associated with clinical outcomes, confirming the value of imaging in prognosis of PSC, but need further multicenter evaluation.

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.

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.

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.

Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of inflammatory bowel disease (IBD). Magnetic resonance cholangiography (MRC) has become the primary diagnostic modality for PSC. However, data on radiological progression over time of large-duct PSC-IBD are limited.

We performed a nested case-control study to estimate the frequency of PSC in adult patients with IBD from a Middle Eastern population to assess the risk factors associated with major disease progression (formation of dominant strictures or cholangiocarcinoma) over time.

Data of IBD patients who were registered in the Saudi IBD Information System at tertiary care center were analyzed. Among 960 patients [477 ulcerative colitis (UC); 483 Crohn's disease (CD)], 40 PSC-IBD patients with at least two MRC performed in a one-year interval were matched with 141 IBD patients without PSC. The frequency of PSC was 4.1%. UC patients (6.2%) compared to CD (2%), 65% had extensive colitis. The incidence rate of PSC among our cohort was increased from 2.62 to 10 per 1000 patient-years between 2005 and 2019. MRC features stabilized in (46.7%); worsened in (36.9%) and 15.4% of patients developed CCA. Alkaline phosphatase (ALP) levels of PSC patients who had major changes or CCA increased significantly after 44 months of follow-up (p = 0.01). The propensity score adjusted showed that hospitalization rate among PSC patients was higher than their non-PSC counterparts (OR 8.24; 95% CI 3.16-21.47; p < 0.01).

ALP rise and hospitalization history as clinical outcome were the only factors associated with PSC-IBD major progression on MRCP.

With an enormous amount of research concerning kidney cancer being conducted, various treatments have been applied to its cure. However, high recurrence and metastasis rates continue to pose a threat to the survival of patients with kidney renal clear cell carcinoma (KIRC).

Data from The Cancer Genome Atlas were downloaded, and a series of analyses were performed, including differential analysis, Cox analysis, weighted gene coexpression network analysis, least absolute shrinkage and selection operator analysis, multivariate Cox analysis, survival analysis, and receiver operating characteristic curve and functional enrichment analysis.

A total of 5,777 differentially expressed genes were identified from the differential analysis. The Cox analysis showed 1,853 significant genes (P < 0.01). Weighted gene coexpression network analysis revealed that 226 genes in the module were related to clinical parameters, including Tumor-Node-Metastasis (TNM) staging. Least absolute shrinkage and selection operator and multivariate Cox analyses suggested that four genes (CDKL2, LRFN1, STAT2, and SOWAHB) had a potential function in predicting the survival time of patients with KIRC. Survival analysis uncovered that a high risk of these four genes was associated with an unfavorable prognosis. Receiver operating characteristic curve analysis further confirmed the accuracy of the risk score model. The analysis of clinicopathological parameters of the four identified genes revealed that they were associated with the progression of KIRC.

The gene expression model consisting of CDKL2, LRFN1, STAT2, and SOWAHB is a promising tool for predicting the prognosis of patients with KIRC. The results of this study may provide insights into the diagnosis and treatment of KIRC.

New British Society of Gastroenterology/UK-PSC guidelines have recently discussed the current state-of-the-art on primary sclerosing cholangitis and outlined key elements for the management of this disease. The current lack of effective pharmacological treatments to prevent progression of liver fibrosis to cirrhosis limits our ability to modify the natural history of the disease. However, a personalised approach and structured follow-up could allow earlier diagnosis and management of complications and favour access to liver transplantation, which remains the only available treatment. Our commentary overviews the updates and summarises the key recommendations of the recent guidelines for the management of primary sclerosing cholangitis.

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.

Clinical prediction models (CPMs) predict the risk of health outcomes for individual patients. The majority of existing CPMs only harness cross-sectional patient information. Incorporating repeated measurements, such as those stored in electronic health records, into CPMs may provide an opportunity to enhance their performance. However, the number and complexity of methodological approaches available could make it difficult for researchers to explore this opportunity. Our objective was to review the literature and summarise existing approaches for harnessing repeated measurements of predictor variables in CPMs, primarily to make this field more accessible for applied researchers.

MEDLINE, Embase and Web of Science were searched for articles reporting the development of a multivariable CPM for individual-level prediction of future binary or time-to-event outcomes and modelling repeated measurements of at least one predictor. Information was extracted on the following: the methodology used, its specific aim, reported advantages and limitations, and software available to apply the method.

The search revealed 217 relevant articles. Seven methodological frameworks were identified: time-dependent covariate modelling, generalised estimating equations, landmark analysis, two-stage modelling, joint-modelling, trajectory classification and machine learning. Each of these frameworks satisfies at least one of three aims: to better represent the predictor-outcome relationship over time, to infer a covariate value at a pre-specified time and to account for the effect of covariate change.

The applicability of identified methods depends on the motivation for including longitudinal information and the method's compatibility with the clinical context and available patient data, for both model development and risk estimation in practice.

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.

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.

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.

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.

Primary sclerosing cholangitis [PSC] is usually associated with inflammatory bowel disease [IBD]. An increased risk of malignancies, mainly colorectal cancer [CRC] and cholangiocarcinoma [CCA], has been reported in PSC-IBD patients. Our aim was to determine the clinical characteristics and management of PSC in IBD patients, and the factors associated with malignancies.

PSC-IBD patients were identified from the Spanish ENEIDA registry of GETECCU. Additional data were collected using the AEG-REDCap electronic data capture tool.

In total, 277 PSC-IBD patients were included, with an incidence rate of 61 PSC cases per 100 000 IBD patient-years, 69.7% men, 67.5% ulcerative colitis and mean age at PSC diagnosis of 40 ± 16 years. Most patients [85.2%] were treated with ursodeoxycholic acid. Liver transplantation was required in 35 patients [12.6%] after 79 months (interquartile range [IQR] 50-139). It was more common in intra- and extrahepatic PSC compared with small-duct PSC (16.3% vs 3.3%; odds ratio [OR] 5.7: 95% confidence interval [CI] = 1.7-19.3). The incidence rate of CRC since PSC diagnosis was 3.3 cases per 1000 patient-years [95% CI = 1.9-5.6]. Having symptoms of PSC at PSC diagnosis was the only factor related to an increased risk of CRC after IBD diagnosis [hazard ratio= 3.3: 95% CI = 1.1-9.9]. CCA was detected in seven patients [2.5%] with intra- and extrahepatic PSC, with median age of 42 years [IQR 39-53], and presented a lower life expectancy compared with patients without CCA and patients with or without CRC.

PSC-IBD patients with symptoms of PSC at PSC diagnosis have an increased risk of CRC. CCA was only diagnosed in patients with intra- and extrahepatic PSC and was associated with poor survival.

These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.

Primary sclerosing cholangitis is a rare, complex autoimmune disease in relatively young patients. There is currently no treatment for the disease, resulting in high rates of advanced liver disease leading to death or liver transplantation. However, advances have been made in our understanding of the pathophysiological mechanisms of the disease, particularly from breakthroughs in the underlying genetics. Moreover, large international collaborations have generated important clinical data that have given greater detail on the different disease phenotypes and natural history, generating new risk prediction models. As a result, drug development may be designed to target specific disease mechanisms at known points of the disease natural history. Therefore, more drugs are entering phase II and III development, giving hope that soon patient-specific treatments may be available to treat this difficult disease.

Primary sclerosing cholangitis (PSC) is a fibrostenosing disease of the bile ducts associated with inflammatory bowel disease (IBD), for which the only treatment is liver transplantation. PSC progression has been defined in cohorts from referral centers or single-nation population databases. However, observations made from these cohorts have limited applicability owing to referral bias and demographic confounders. We analyzed data from the worldwide PSC Partners Patient Registry, an international online database established in 2014 to obtain information from individuals with PSC or their caretakers and compare symptoms, disease progression, and treatments of PSC in the United States and other countries.

We analyzed demographic and clinical characteristics, symptoms, and clinical outcomes of patients with PSC using the PSC Partners Patient Registry. Participants completed an online standardized questionnaire and electronic case report, providing information on age, age at symptom onset, age at PSC diagnosis, methods of diagnosis, concurrent diagnoses, family history, and medication use.

Of 873 registrants, 811 (92.9%) had completed questionnaires and 528 (65.1%) had their PSC diagnosis confirmed; we found no significant demographic or clinical differences between patients with vs without a confirmed diagnosis. In contrast to other studies, we found a higher proportion of individuals with PSC to be female (52.5%). However, the mean age at PSC diagnosis (32.4 ± 14.7 y) and the proportion of individuals with PSC and IBD (67.1%) were similar to those from prior reports. Most cases in the database were from the United States (74.9%). More than half of the participants reported having pruritus, abdominal pain, fatigue, or sleep disturbances; rates were not significantly different among participants within vs outside the United States. There was no significant difference in treatment with ursodeoxycholic acid between participants within vs outside the United States (50.0% and 57.8%; P = .07). The median time of transplant-free survival was 21 years; transplant-free survival was associated with female sex and Crohn's disease.

Our findings from an analysis of data from the PSC Partners Patient Registry confirm those from previous studies, although we found a higher proportion of individuals with PSC to be female. In addition to allowing efficient collection of patient-reported outcomes, the patient-driven registry allows for inclusion of previously under-represented cases of PSC.

To correlate total and lobar liver and spleen volume with disease severity in primary sclerosing cholangitis (PSC) as determined by Mayo risk score.

This HIPAA-compliant single center retrospective study included 147 PSC patients with available imaging studies (MRCP/CT) and laboratory data between January 2003 and January 2018. Total and lobar (right, left and caudate) liver volume and spleen volume were measured. ANOVA test was performed to assess the differences in volumes between low, intermediate and high-risk groups (Mayo risk score <0, >0 and <2, >2, respectively). Correlations between volumes and Mayo risk score were calculated. ROC analysis was performed to assess the accuracy of the variable with the strongest correlation to PSC severity to predict Mayo risk score. P value <0.05 was considered statistically significant.

The mean age of this cohort was 45 ± 17 years; 58% were men. Absolute volumes of left lobe, caudate and spleen and volume ratios of left lobe and caudate to total liver volume of the high-risk group were significantly higher compared to those of low and intermediate risk groups (p < 0.05). Left lobe to total liver volume ratio had the highest correlation to Mayo risk score (Pearson correlation coefficient 0.61, p < 0.05) and on ROC analysis it had 84.4% accuracy in detecting high-risk PSC.

In this single institution large cohort study, the left lobe to total liver volume ratio was the best quantifiable volumetric biomarker to correlate with severity of PSC as identified by Mayo risk score.

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.

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.

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.

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.

Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterised by intrahepatic or extrahepatic stricturing, or both, with bile duct fibrosis. Inflammation and fibrosis of bile ducts and the liver are followed by impaired bile formation or flow and progressive liver dysfunction. Patients might be asymptomatic at presentation or might have pruritus, fatigue, right upper quadrant pain, recurrent cholangitis, or sequelae of portal hypertension. The key diagnostic elements are cholestatic liver biochemistry and bile duct stricturing on cholangiography. Genetic and environmental factors are important in the cause of the disease, with the intestinal microbiome increasingly thought to play a pathogenetic role. Approximately 70% of patients have concurrent inflammatory bowel disease and patients require colonoscopic screening and surveillance. Primary sclerosing cholangitis is associated with increased malignancy risk and surveillance strategies for early cholangiocarcinoma detection are limited. No single drug has been proven to improve transplant-free survival. Liver transplantation is effective for advanced disease but at least 25% of patients develop recurrent disease in the graft.

Primary sclerosing cholangitis (PSC) is a rare disorder characterised by multi-focal bile duct strictures and progressive liver disease. Inflammatory bowel disease is usually present and there is a high risk of cholangiocarcinoma and colorectal cancer. Most patients ultimately require liver transplantation, after which disease recurrence may occur. With limited therapeutic options and a lack of proven surveillance strategies, patients currently have significant unmet needs. In the present seminar, we provide a comprehensive review of the status of the field. We emphasise developments related to patient stratification and disease behaviour, and provide an overview of management options from a practical, patient-centered perspective. We survey advances made in the understanding of PSC pathogenesis and summarise the ongoing efforts to develop an effective therapy based on these insights.

Autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis represent the three major autoimmune liver diseases (AILDs). Their management is highly specialized, requires a multidisciplinary approach and often relies on expensive, orphan drugs. Unfortunately, their treatment is often unsatisfactory, and the care pathway heterogeneous across different centers. Disease-specific clinical outcome indicators (COIs) able to evaluate the whole cycle of care are needed to assist both clinicians and administrators in improving quality and value of care. Aim of our study was to generate a set of COIs for the three AILDs. We then prospectively validated these indicators based on a series of consecutive patients recruited at three tertiary clinical centers in Lombardy, Italy.

In phase I using a Delphi method and a RAND 9-point appropriateness scale a set of COIs was generated. In phase II the indicators were applied in a real-life dataset.

Two-hundred fourteen patients were enrolled and followed-up for a median time of 54months and the above COIs were recorded using a web-based electronic medical record program. The COIs were easy to collect in the clinical practice environment and their values compared well with the available natural history studies.

We have generated a comprehensive set of COIs which sequentially capture different clinical outcome of the three AILDs explored. These indicators represent a critical tool to implement a value-based approach to patients with these conditions, to monitor, compare and improve quality through benchmarking of clinical performance and to assess the significance of novel drugs and technologies. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC.

We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates.

Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002).

In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.

Primary sclerosing cholangitis (PSC) is 1 of the leading causes of liver transplantation (LTX) in Scandinavia, and an increasing number of PSC patients have been transplanted in Norway during the last 2 decades. This trend is partly attributable to the recently established practice in Norway of offering LTX to PSC patients with cholangiocellular dysplasia. Based on the controversy associated with this practice, we herein aimed to report the main features and outcomes of our LTX program in PSC.

The primary indication for LTX (quality of life/end-stage liver disease or suspected neoplasia) was retrospectively determined for 222 patients undergoing LTX for PSC or other autoimmune liver diseases (primary biliary cirrhosis/autoimmune hepatitis) with at least 5 years of follow-up.

In PSC patients impaired quality of life (43.5%) and end-stage liver disease (38.4%) were the most frequent indications for LTX, whereas suspected neoplasia accounted for 18.1%. The proportion of PSC patients with manifest encephalopathy, variceal bleeding, or ascites declined over time. In patients with suspected neoplasia as the primary indication for LTX (n = 25), neoplasia was confirmed in the explanted liver in 20 patients (80%). Five-year survival rates for PSC patients transplanted between 2001 and 2009 were 91.9% for patients receiving LTX due to impaired quality of life or end-stage liver disease and 83.3% for suspected neoplasia.

The PSC patients are increasingly listed for LTX at an earlier stage of their liver disease. In patients with suspected neoplasia before LTX, 5-year survival was acceptable, despite confirmation of neoplasia in 80% of the liver explants.

There is a need to determine biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC). We evaluated the prognostic utility of the enhanced liver fibrosis (ELF) score in Norwegian PSC patients. Serum samples were available from 305 well-characterized large-duct PSC patients, 96 ulcerative colitis patients, and 100 healthy controls. The PSC patients constituted a derivation panel (recruited 1992-2006 [n = 167]; median age 41 years, 74% male) and a validation panel (recruited 2008-2012 [n = 138]; median age 40 years, 78% male). We used commercial kits to analyze serum levels of hyaluronic acid, tissue inhibitor of metalloproteinases-1, and propeptide of type III procollagen and calculated ELF scores by the previously published algorithm. Results were also validated by analysis of ELF tests using the ADVIA Centaur XP system and its commercially available reagents. We found that PSC patients stratified by ELF score tertiles exhibited significantly different transplant-free survival in both panels (P < 0.001), with higher scores associated with shorter survival, which was confirmed in the validation panel stratified by ELF test tertiles (P = 0.003). The ELF test distinguished between mild and severe disease defined by clinical outcome (transplantation or death) with an area under the curve of 0.81 (95% confidence interval [CI] 0.73-0.87) and optimal cutoff of 10.6 (sensitivity 70.2%, specificity 79.1%). In multivariate Cox regression analysis in both panels, ELF score (hazard ratio = 1.9, 95% CI 1.4-2.5, and 1.5, 95% CI 1.1-2.1, respectively) was associated with transplant-free survival independently of the Mayo risk score (hazard ratio = 1.3, 95% CI 1.1-1.6, and 1.6, 95% CI 1.2-2.1, respectively). The ELF test correlated with ultrasound elastography in separate assessments.

The ELF score is a potent prognostic marker in PSC, independent of the Mayo risk score.