Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive immune-mediated liver disease, for which no medical therapy has been shown to slow disease progression. However, the horizon for new therapies is encouraging, with several innovative clinical trials in progress. Despite these advancements, there is considerable heterogeneity in the outcomes studied, with lack of consensus as to what outcomes to measure, when to measure and how to measure. Furthermore, there has been a paradigm shift in PSC treatment targets over recent years, moving from biochemistry-based endpoints to histological assessment of liver fibrosis, imaging-based biomarkers and patient-reported outcome measures. The abundance of new interventional trials and evolving endpoints pose opportunities for all stakeholders involved in evaluating novel therapies. To this effect, there is a need to harmonise measures used in clinical trials through the development of a core outcome set (COS). METHODS AND ANALYSIS: Synthesis of a PSC-specific COS will be conducted in four stages. Initially, a systematic literature review will be performed to identify outcomes previously used in PSC trials, followed by semistructured qualitative interviews conducted with key stakeholders. The latter may include patients, clinicians, researchers, pharmaceutical industry representatives and healthcare payers and regulatory agencies, to identify additional outcomes of importance. Using the outcomes generated from the literature review and stakeholder interviews, an international two-round Delphi survey will be conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting will be convened to ratify the COS and disseminate findings for application in future PSC trials. ETHICS AND DISSEMINATION: Ethical approval has been granted by the East Midlands-Leicester Central Research Ethics Committee (Ref: 24/EM/0126) for this study. The COS from this study will be widely disseminated including publication in peer-reviewed journals, international conferences, promotion through patient-support groups and made available on the Core Outcomes Measurement in Effectiveness Trials (COMET) database. TRIAL REGISTRATION NUMBER: 1239.

Critical shortfalls in the management of PBC: Results of a UK-wide, population-based evaluation of care delivery.

Background & Aims: Guidelines for the management of primary biliary cholangitis (PBC) were published by the British Society of Gastroenterology in 2018. In this study, we assessed adherence to these guidelines in the UK National Health Service (NHS). Methods: All NHS acute trusts were invited to contribute data between 1 January 2021 and 31 March 2022, assessing clinical care delivered to patients with PBC in the UK. Results: We obtained data for 8,968 patients with PBC and identified substantial gaps in care across all guideline domains. Ursodeoxycholic acid (UDCA) was used as first-line treatment in 88% of patients (n = 7,864) but was under-dosed in one-third (n = 1,964). Twenty percent of patients who were UDCA-untreated (202/998) and 50% of patients with inadequate UDCA response (1,074/2,102) received second-line treatment. More than one-third of patients were not assessed for fatigue (43%; n = 3,885) or pruritus (38%; n = 3,415) in the previous 2 years. Fifty percent of all patients with evidence of hepatic decompensation were discussed with a liver transplant centre (222/443). Appropriate use of second-line treatment and referral for liver transplantation was significantly better in specialist PBC treatment centres compared with non-specialist centres (p <0.001). Conclusions: Poor adherence to guidelines exists across all domains of PBC care in the NHS. Although specialist PBC treatment centres had greater adherence to guidelines, no single centre met all quality standards. Nationwide improvement in the delivery of PBC-related healthcare is required. Impact and implications: This population-based evaluation of primary biliary cholangitis, spanning four nations of the UK, highlights critical shortfalls in care delivery when measured across all guideline domains. These include the use of liver biopsy in diagnosis; referral practice for second-line treatment and/or liver transplant assessment; and the evaluation of symptoms, extrahepatic manifestations, and complications of cirrhosis. The authors therefore propose implementation of a dedicated primary biliary cholangitis care bundle that aims to minimise heterogeneity in clinical practice and maximise adherence to key guideline standards.

Genetic alterations during the neoplastic cascade towards cholangiocarcinoma in primary sclerosing cholangitis.

Carcinogenesis of primary sclerosing cholangitis (PSC)-associated cholangiocarcinoma (CCA) is largely unexplored. Improved understanding of the molecular events involved may guide development of novel avenues for rational clinical management. We aimed to assess the genetic alterations during progression of the neoplastic cascade from biliary dysplasia towards CCA in PSC. Forty-four resection specimens or biopsies of PSC patients with biliary dysplasia (n = 2) and/or CCA (n = 42) were included. DNA was extracted from sections of formalin-fixed paraffin-embedded tissue blocks with dysplasia (n = 23), CCA (n = 69), and nonneoplastic tissue (n = 28). A custom-made next-generation sequencing (NGS) panel of 28 genes was used for mutation and copy number variation (CNV) detection. In addition, CNVs of CDKN2A, EGFR, MCL1, and MYC were examined by fluorescence in situ hybridization. Alterations in 16 low-grade dysplasia samples included loss of FGFR1 (19%), CDKN2A (13%), and SMAD4 (6%), amplification of FGFR3 (6%), EGFR (6%), and ERBB2 (6%), and mutations in SMAD4 (13%). High-grade dysplasia (n = 7) is characterized by MYC amplification (43%), and mutations in ERBB2 (71%) and TP53 (86%). TP53 mutations are the most common aberrations in PSC-CCA (30%), whereas mutations in KRAS (16%), GNAS (14%), and PIK3CA (9%) are also common. In conclusion, PSC-CCA exhibits a variety of genetic alterations during progression of the neoplastic cascade, with mainly CNVs being present early, whereas mutations in ERBB2, TP53, and KRAS appear later in the development of CCA. These findings are promising for the development of NGS-guided diagnostic strategies in PSC-CCA. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Epidemiology, Natural History, and Outcomes of Primary Sclerosing Cholangitis: A Systematic Review of Population-based Studies.

BACKGROUND & AIMS: The aim of this study was to quantify the global epidemiology of primary sclerosing cholangitis (PSC), alongside the incidence of liver transplantation, cancer, and death, through robust systematic review of population-based data. METHODS: We searched MEDLINE and EMBASE up to and including June 30, 2020 to identify population-based studies reporting the incidence and/or prevalence of PSC. Studies that did not report original data, or of exclusively pediatric-onset disease (diagnosis age <16 years) or exclusively PSC-associated with inflammatory bowel disease were excluded. RESULTS: Of 4922 published studies, 17 fulfilled inclusion criteria; 16 documenting incidence and 14 prevalence. The highest reported incidence of PSC was reported in Northern Europe (Finland, 1.58 and Norway, 1.3 per-100,000 population, respectively) and North America (Minnesota, 1.47); with the lowest being observed across the Mediterranean Basin (Italy, 0.1). Prevalence ranged from 31.7 in Finland and 23.99 in Minnesota, to 1.33 in Singapore and 0.0 in Alaska. Of studies reporting temporal occurrence, an increase in disease incidence was observed across North America and Northern Europe (4 studies), alongside an increase in prevalence over time (4 studies). The incidence and risks for clinical outcomes were presented by 9 of the included studies. Median transplant-free survival ranged from 9.7 (United States) to 20.6 years (Netherlands), with standardized mortality ratios of 2.5 and 4.2 compared with the control population. The standardized incidence of cholangiocarcinoma ranged from 235 (Finland) to 398 (Netherlands). CONCLUSIONS: Estimates of PSC incidence and prevalence vary, with most studies conducted in North America and Western Europe; the latter showing a steady increase in disease occurrence over time. Further research is needed to understand changes in disease epidemiology, including etiological drivers, the implications of rising case burden on health care policy, and better appreciation of PSC in the developing world.

Effects of Primary Sclerosing Cholangitis on Risks of Cancer and Death in People With Inflammatory Bowel Disease, Based on Sex, Race, and Age.

BACKGROUND & AIMS: There are insufficient population-level data on the effects of primary sclerosing cholangitis (PSC) in patients with inflammatory bowel disease (IBD). METHODS: We identified incident cases of IBD, with PSC (PSC-IBD) and without, from April 2006 to April 2016 and collected data on outcomes through April 2019. We linked data from national health care registries maintained for all adults in England on hospital attendances, imaging and endoscopic evaluations, surgical procedures, cancer, and deaths. Our primary aim was to quantify the effects of developing PSC in patients with all subtypes of IBD and evaluate its effects on hepatopancreatobiliary disease, IBD-related outcomes, and all-cause mortality, according to sex, race, and age. RESULTS: Over 10 years, we identified 284,560 incident cases of IBD nationwide; of these, 2588 patients developed PSC. In all, we captured 31,587 colectomies, 5608 colorectal cancers (CRCs) 6608 cholecystectomies, and 41,055 patient deaths. Development of PSC was associated with increased risk of death and CRC (hazard ratios [HRs], 3.20 and 2.43, respectively; P < .001) and a lower median age at CRC diagnosis (59 y vs 69 y without PSC; P < .001). Compared to patients with IBD alone, patients with PSC-IBD had a 4-fold higher risk of CRC if they received a diagnosis of IBD at an age younger than 40 years; there was no difference between groups for patients diagnosed with IBD at an age older than 60 years. Development of PSC also increased risks of cholangiocarcinoma (HR, 28.46), hepatocellular carcinoma (HR, 21.00), pancreatic cancer (HR, 5.26), and gallbladder cancer (HR, 9.19) (P < .001 for all). Risk of hepatopancreatobiliary cancer-related death was lower among patients with PSC-IBD who received annual imaging evaluations before their cancer diagnosis, compared to those who did not undergo imaging (HR, 0.43; P = .037). The greatest difference in mortality between the PSC-IBD alone group vs the IBD alone group was for patients younger than 40 years (incidence rate ratio >7), in contrast to those who received a diagnosis of IBD when older than 60 years (incidence rate ratio, <1.5). Among patients with PSC-IBD we observed 173 first liver transplants. Liver transplantation and PSC-related events accounted for approximately 75% of clinical events when patients received a diagnosis of PSC at an age younger than 40 years vs 31% of patients who received a diagnosis when older than 60 years (P < .001). African Caribbean heritage was associated with increased risks of liver transplantation or PSC-related death compared with white race (HR, 2.05; P < .001), whereas female sex was associated with reduced risk (HR, 0.74; P = .025). CONCLUSIONS: In a 10-year, nationwide study, we confirmed that patients with PSC-IBD have increased risks of CRC, hepatopancreatobiliary cancers, and death compared to patients with IBD alone. In the PSC-IBD group, diagnosis of IBD at age younger than 40 years was associated with greater risks of CRC and all-cause mortality compared with diagnosis of IBD at older ages. Patients who receive a diagnosis of PSC at an age younger than 40 years, men, and patients of African Caribbean heritage have an increased incidence of PSC-related events.

The Complementary Value of Magnetic Resonance Imaging and Vibration-Controlled Transient Elastography for Risk Stratification in Primary Sclerosing Cholangitis.

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.

Fibrosis stage is an independent predictor of outcome in primary biliary cholangitis despite biochemical treatment response.

BACKGROUND: Fibrosis stage predicts prognosis in patients with chronic liver disease independent of aetiology, although its precise role in risk stratification in patients with primary biliary cholangitis (PBC) remains undefined. AIM: To assess the utility of baseline fibrosis stage in predicting long-term outcomes in the context of biochemical risk stratification METHODS: In a large and globally representative cohort of patients with PBC, liver biopsies performed from 1980 to 2014 were evaluated. The predictive ability of histologic fibrosis stage in addition to treatment response at 1 year (Toronto/Paris-II criteria), as well as non-invasive markers of fibrosis (AST/ALT ratio [AAR], AST to platelet ratio index [APRI], FIB-4), for transplant-free survival was assessed with Cox proportional-hazards models. RESULTS: There were 1828 patients with baseline liver biopsy. Advanced histologic fibrosis (stage 3/4) was an independent predictor of survival in addition to non-invasive measures of fibrosis with the hazard ratios ranging from 1.59 to 2.73 (P < .001). Patients with advanced histologic fibrosis stage had worse survival despite biochemical treatment response, with a 10-year survival of 76.0%-86.6% compared to 94.5%-95.1% depending on the treatment response criteria used. Poor correlations were observed between non-invasive measures of fibrosis and histologic fibrosis stage. CONCLUSION: Assessment of fibrosis stage grants prognostic value beyond biochemical treatment response at 1 year. This highlights the need to incorporate fibrosis stage in individual risk stratification in patients with PBC, partly to identify those that may derive benefit from novel therapies.

Systematic review with meta-analysis: risk factors for recurrent primary sclerosing cholangitis after liver transplantation.

BACKGROUND: After liver transplantation primary sclerosing cholangitis (PSC), the condition returns in the transplanted liver in a subset of patients (recurrent primary sclerosing cholangitis, rPSC). AIM: To define risk factors for rPSC. METHODS: We searched Pubmed, Embase, Web of Science, and Cochrane library for articles published until March 2018. Studies addressing risk factors for developing rPSC were eligible for inclusion. A random effects meta-analysis was conducted using hazard ratios (HR) as effect measure. Study quality was evaluated with the Newcastle Ottawa scale. Statistical analysis was performed using Cochrane Review Manager. RESULTS: The electronic database search yielded 449 results. Twenty-one retrospective cohort studies met the inclusion criteria for the review; 14 were included in the meta-analysis. The final cohort included 2159 patients (age range 31-49 years, 68.8% male), of whom 17.7% developed rPSC. Colectomy before liver transplantation, HR 0.65 (95% CI: 0.42-0.99), cholangiocarcinoma before liver transplantation, HR 2.42 (95% CI: 1.20-4.86), inflammatory bowel disease, HR 1.73 (95% CI: 1.17-2.54), donor age, HR 1.24 (95% CI 1.0-1.45) per ten years, MELD score, HR 1.05 (95% CI: 1.02-1.08) per point and acute cellular rejection, HR of 1.94 (95% CI: 1.32-2.83) were associated with the risk of rPSC. CONCLUSIONS: Multiple risk factors for rPSC were identified. Colectomy before liver transplantation reduced the risk of rPSC.

Patterns of disease progression and incidence of complications in primary biliary cholangitis (PBC).

Clinical outcome for patients with primary biliary cholangitis (PBC) is dictated by development of cirrhosis, portal hypertension and its associated complications; including for some, a predisposition toward hepatocellular carcinoma. However rates of clinical progression vary, and accurately identifying disease course is of critical importance to patients, clinicians, as well as industry, who are committed to developing new effective and life-prolonging therapy as well as treating symptoms that appear disproportionate to underlying disease severity. Patients seek reassurance and guidance as to their own prognosis, and clinicians wish to confidently recognise those at highest risk of poor outcomes as equally as they strive to reassure individuals with a more favourable disease trajectory. International registries have facilitated a much greater knowledge of disease incidence and heterogeneity of presenting phenotypes. In so doing they highlight the opportunity to provide a more individualized estimate of the clinical course that patients experience, and have led to a renewed approach to risk stratification; both in terms of 'hard outcomes' and also disease-associated complications in PBC specifically.

Alcohol Consumption in Patients with Non-alcoholic Fatty Liver Disease: Convenient vs. Inconvenient Truths.

Understanding the role of modest alcohol consumption in patients with non-alcohol induced fatty liver disease (NAFLD) remains a significant challenge, with no clear guidance on counselling regarding alcohol use. Conventionally, the strong association of alcohol excess and development of complications related to chronic liver disease, including hepatocellular carcinoma, has led practitioners to advocate complete abstinence to those with NAFLD. New evidence published in this issue of the Red Journal challenges the historic paradigm by showing that modest, non-binge wine consumption (<70 g/week) associates with significantly lower risk of advanced hepatic fibrosis on biopsy compared with complete abstinence across a well-characterised single centre cohort of nearly 200 patients with NAFLD.

The Paddington International Virtual Chromoendoscopy Score in ulcerative colitis exhibits very good inter-rater agreement after computerized module training: a multicenter study across academic and community practice (with video).

BACKGROUND AND AIMS: Electronic virtual chromoendoscopy (EVC) can demonstrate ongoing disease activity in ulcerative colitis (UC), even when Mayo subscores suggest healing. However, applicability of EVC technology outside the expert setting has yet to be determined. METHODS: Fifteen participants across 5 centers reviewed a computerized training module outlining high-definition and EVC (iScan) colonoscopy modes. Interobserver agreement was then tested (Mayo score, Ulcerative Colitis Endoscopic Index of Severity [UCEIS], and the Paddington International Virtual Chromoendoscopy Score [PICaSSO] for UC), using a colonoscopy video library (30 cases reviewed pretraining and 30 post-training). Knowledge sustainability was retested in a second round (42 cases; 9/15 participants), 6 months after training provision. RESULTS: Pretraining intraclass correlation coefficients (ICC) were good for the Mayo endoscopic subscore (ICC, .775), UCEIS scoring erosions/ulcers (ICC, .770), and UCEIS overall (ICC, .786) and for mucosal (ICC, .754) and vascular components of PICaSSO (ICC, .622). For the vascular components of UCEIS, agreement was only moderate (ICC, .429) and did not enhance post-training (ICC, .417); conversely, use of PICaSSO improved post-training (mucosal ICC, .848; vascular, .746). Histologic correlation using the New York Mt. Sinai System was strong for both PICaSSO components (Spearman's ρ for mucosal: .925; vascular, .873; P < .001 for both). Moreover, accuracy in specifically discriminating quiescent from mild histologic strata was strongest for PICaSSO (area under the receiver operating characteristic curve [AUROC] for mucosal, .781; vascular, .715) compared with Mayo (AUROC, .708) and UCEIS (AUROC for UCEIS overall, .705; vascular, .562; bleeding, .645; erosions/ulcers, .696). Inter-rater reliability for PICaSSO was sustained by round 2 participants (round 1 and 2 ICC for mucosal, .873 and .869, respectively; vascular, .715 and .783, respectively), together with histologic correlation (ρ mucosal, .934; vascular, .938; P < .001 for both). CONCLUSIONS: PICaSSO demonstrates good interobserver agreement across all levels of experience, providing excellent correlation with histology. Given the ability to discriminate subtle endoscopic features, PICaSSO may be applied to refine stratified treatment paradigms for UC patients.

Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner.

OBJECTIVE: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of IBD. This clinical association is linked pathologically to the recruitment of mucosal T cells to the liver, via vascular adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to examine the expression, function and enzymatic activation of the ectoenzyme VAP-1 in patients with PSC. DESIGN: We examined VAP-1 expression in patients with PSC, correlated levels with clinical characteristics and determined the functional consequences of enzyme activation by specific enzyme substrates on hepatic endothelium. RESULTS: The intrahepatic enzyme activity of VAP-1 was elevated in PSC versus immune-mediated disease controls and non-diseased liver (p<0.001). The adhesion of gut-tropic α4ß7+lymphocytes to hepatic endothelial cells in vitro under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). Of a number of natural VAP-1 substrates tested, cysteamine-which can be secreted by inflamed colonic epithelium and gut bacteria-was the most efficient (yielded the highest enzymatic rate) and efficacious in its ability to induce expression of functional mucosal addressin cell adhesion molecule-1 on hepatic endothelium. In a prospectively evaluated patient cohort with PSC, elevated serum soluble (s)VAP-1 levels predicted poorer transplant-free survival for patients, independently (HR: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis. CONCLUSIONS: VAP-1 expression is increased in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and elevated levels of its circulating form predict clinical outcome in patients.

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Validation of the prognostic value of histologic scoring systems in primary sclerosing cholangitis: An international cohort study.

Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC-related death and liver transplantation), 2 (liver transplantation), and 3 (liver-related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow-up was 142 months. During follow-up, 31 patients died (20 PSC-related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver-related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49-6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17-3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10-2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10-1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19-5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09-3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22-3.77). Interobserver agreement was moderate for Nakanuma stage (κ = 0.56) and substantial for Nakanuma component fibrosis (κ = 0.67), Ishak stage (κ = 0.64), and Ludwig stage (κ = 0.62). CONCLUSION: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system-incorporating features of chronic biliary disease-again showed the strongest predictive value. (Hepatology 2017;65:907-919).

The Immunogenetics of Autoimmune Cholestasis.

The immune-mediated hepatobiliary diseases, primary biliary cirrhosis and primary sclerosing cholangitis are relatively rare, albeit and account for a significant amount of liver transplant activity and liver-related mortality globally. Precise disease mechanisms are yet to be described although a contributory role of genetic predisposition is firmly established. In addition to links with the major histocompatibility complex, a number of associations outside this region harbor additional loci which underscore the fundamental role of breaks in immune tolerance and mucosal immunogenicity in the pathogenesis of autoimmune biliary disease. We provide an overview of these key discoveries before discussing putative avenues of therapeutic exploitation based on existing findings.

Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (PBC); however, predictive tools remain ill-defined. Our objective was to identify candidate risk factors for HCC development in patients with PBC. DESIGN: Risk factor analysis was performed in over 15 centres from North America and Europe spanning >40 years observation period using Cox proportional hazards assumptions, logistic regression, and Kaplan-Meier estimates. RESULTS: Of 4565 patients with PBC 123 developed HCC, yielding an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p<0.0001), and on univariate analysis factors at PBC diagnosis associated with future HCC development were male sex (unadjusted HR 2.91, p<0.0001), elevated serum aspartate transaminase (HR 1.24, p<0.0001), advanced disease (HR 2.72, p=0.022), thrombocytopenia (HR 1.65, p<0.0001), and hepatic decompensation (HR 9.89, p<0.0001). As such, non-treatment with ursodeoxycholic acid itself was not associated with cancer development; however, 12-month stratification by biochemical non-response (Paris-I criteria) associated significantly with future risk of HCC (HR 4.52, p<0.0001; IR 6.6 vs 1.4, p<0.0001). Non-response predicted future risk in patients with early stage disease (IR 4.7 vs 1.2, p=0.005), advanced disease (HR 2.79, p=0.02; IR 11.2 vs 4.4, p=0.033), and when restricting the analysis to only male patients (HR 4.44, p<0.001; IR 18.2 vs 5.4, p<0.001). On multivariable analysis biochemical non-response remained the most significant factor predictive of future HCC risk (adjusted HR 3.44, p<0.0001). CONCLUSIONS: This uniquely powered, internationally representative cohort robustly demonstrates that 12-month biochemical non-response is associated with increased future risk of developing HCC in PBC. Such risk stratification is relevant to patient care and development of new therapies.