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IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expansions of IgG4 + plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8 + and CD4 + SLAMF7 + T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the pathogenesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Primary sclerosing cholangitis (PSC) is a chronic progressive pathological process, related to inflammatory bowel disease and subsequent bacterial translocation. Liver transplantation (LT) is the only curative therapy, but outcomes are compromised by recurrence of PSC (rPSC). The aim of the study was to investigate a potential link between intestinal bacteremia, fucosyltransferase-2 (FUT2), and rPSC after LT., Methods: LT recipients with PSC (n = 81) or without PSC (n = 271) were analyzed for clinical outcomes and positive bacterial blood cultures. A link between bacteremia and the genetic variant of the FUT2 gene was investigated., Results: The incidence of inflammatory bowel disease was significantly higher in PSC recipients but not associated with rPSC. Bacteremia occurred in 31% of PSC recipients. The incidence of rPSC was 37% and was significantly more common in patients with intestinal bacteremia versus no bacteremia (82% versus 30%; P = 0.003). The nonsecretor polymorphism of the FUT2 gene was identified as a genetic risk factor for both intestinal bacteremia and rPSC. Combined FUT2 genotype and intestinal bacteremia in recipients resulted in the highest risk for rPSC (hazard ratio, 15.3; P < 0.001)., Conclusions: Thus, in this article, we showed that bacterial translocation is associated with rPSC after LT and related to the FUT2 nonsecretor status., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Primary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life expectancy and impaired quality of life is ill-described. The aim of this study was to assess long-term disease burden in a large population-based registry with regard to survival, clinical course, quality adjusted life years (QALYs), medical consumption and work productivity loss., Methods: All PSC patients living in a geographically defined area covering ~50% of the Netherlands were included, together with patients from the three liver transplant centres. Survival was estimated by competing risk analysis. Proportional shortfall of QALYs during disease course was measured relative to a matched reference cohort using validated questionnaires. Work productivity loss and medical consumption were evaluated over time., Results: A total of 1208 patients were included with a median follow-up of 11.2 year. Median liver transplant-free survival was 21.0 years. Proportional shortfall of QALYs increased to 48% >25 years after diagnosis. Patients had on average 12.4 hospital contact days among which 3.17 admission days per year, annual medical costs were €12 169 and mean work productivity loss was 25%., Conclusions: Our data quantify for the first time disease burden in terms of QALYs lost, clinical events, medical consumption, costs as well as work productivity loss, and show that all these are substantial and increase over time., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background & Aims: Patients with primary sclerosing cholangitis (PSC) may suffer from complaints such as pruritus, right upper abdominal quadrant pain (RUQ-A) and fatigue. However, the severity of these complaints, daily and/or seasonal patterns and other factors of influence in PSC are largely unknown. The aim of this study is to assess daily symptoms and patterns thereof in PSC patients in their natural setting., Methods: A mobile application was designed according to the experience sampling method. Push notifications with a response time of max 4 h were sent during tiers of 3 months. Questions comprised VAS scales on degree of pruritus, fatigue, RUQ-A, time of the day these symptoms were worst, as well as time of intake of medication. Linear mixed modelling was used to identify patient- and external factors associated with pruritus, fatigue and RUQ-A pain., Results: A total of 6713 questionnaires were completed by 137 patients. Fatigue was the most prevalent symptom among PSC patients being reported in a striking 71% of measurements, followed by pruritus (38%). Both increased during the day and were associated with longer disease duration. A highly significant correlation between pruritus and day temperature was observed (ρ = -0.14, p = .000), and itch was generally worse during winter (p = .000). Patient preference for the tool was high., Conclusion: Pruritus and fatigue are prevalent symptoms in the daily life of PSC patients and show a distinct diurnal pattern. This may have implications for efficient dosing of anti-pruritic agents. The level of pruritus is highly correlated with day temperature, which may have several implications., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5-expression in BECs may contribute to PSC pathogenesis., Methods: TGR5-expression and -localization were analyzed in PSC livers and liver tissue, isolated bile ducts and BECs from Abcb4 -/- , Abcb4 -/- /Tgr5 Tg and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4 -/- mice. The effects of IL8/IL8 homologues on TGR5 mRNA and protein levels were studied. BEC gene expression was analyzed by single-cell transcriptomics (scRNA-seq) from distinct mouse models., Results: TGR5 mRNA expression and immunofluorescence staining intensity were reduced in BECs of PSC and Abcb4 -/- livers, in Abcb4 -/- extrahepatic bile ducts, but not in intrahepatic macrophages. No changes in TGR5 BEC fluorescence intensity were detected in liver tissue of other liver diseases, including primary biliary cholangitis. Incubation of BECs with IL8/IL8 homologues, but not with other cytokines, reduced TGR5 mRNA and protein levels. BECs from Abcb4 -/- mice had lower levels of phosphorylated Erk and higher expression levels of Icam1, Vcam1 and Tgfβ2. Overexpression of Tgr5 abolished the activated inflammatory phenotype characteristic of Abcb4 -/- BECs. NorUDCA-feeding restored TGR5-expression levels in BECs in Abcb4 -/- livers., Conclusions: Reduced TGR5 levels in BECs from patients with PSC and Abcb4 -/- mice promote development of a reactive BEC phenotype, aggravate biliary injury and thus contribute to the pathogenesis of sclerosing cholangitis. Restoration of biliary TGR5-expression levels represents a previously unknown mechanism of action of norUDCA., Lay Summary: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease-associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. Bile acid (BA) toxicity may contribute to the development and disease progression of PSC. TGR5 is a membrane-bound receptor for BAs, which is found on bile ducts and protects bile ducts from BA toxicity. In this study, we show that TGR5 levels were reduced in bile ducts from PSC livers and in bile ducts from a genetic mouse model of PSC. Our investigations indicate that lower levels of TGR5 in bile ducts may contribute to PSC development and progression. Furthermore, treatment with norUDCA, a drug currently being tested in a phase III trial for PSC, restored TGR5 levels in biliary epithelial cells., Competing Interests: Conflict of interest MR, LS, CK, KF, JS, KD, JH, EL, JV, SFG, GH, SJF, IE, DN, CDF, MGB, GG, SV, JPM, MV, KS, TL, KK, DH, TL, MH have nothing to disclose.VK has served as speaker for Falk Foundation, Albireo and Abbvie. JRH has served on the advisory board for Novartis and Orkla Health. JRH has received research support from Biogen unrelated to the current work. THK has received consulting/speaker reimbursement from Gilead and Intercept unrelated to the current work. CS has served as speaker for Falk Foundation. MT has served as speaker for Falk Foundation, Gilead, Intercept and MSD; he has advised for Albireo, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Intercept, Jannsen, MSD, Novartis, Phenex, Regulus and Shire. MT further received travel grants from Abbvie, Falk, Gilead and Intercept and research grants from Albireo, Cymabay, Falk, Gilead, Intercept, MSD and Takeda. MT is also co-inventor of patents on the medical use of NorUDCA filed by the Medical Universities of Graz and Vienna (WO2006119803, WO20099013334). PF received norUDCA, an unrestricted research grant, travel grants and advisory board fees from Dr. Falk Pharma GmbH. PF is listed as co-inventor of patents for the medical use of norUDCA filed by the Medical University of Graz (WO2006119803, WO20099013334). UB received grants for investigator-initiated studies by Dr Falk GmbH, Freiburg, and Intercept, San Diego., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease, characterized by multiple strictures and dilatations of the intra- and extrahepatic bile ducts, leading to progressive liver fibrosis, in 10-15% cholangiocarcinoma, and ultimately end-stage liver disease. The pathogenesis is poorly understood, but (epi-)genetic factors, mechanisms of innate and adaptive immunity, toxic effects of hydrophobic bile acids, and possibly intestinal dysbiosis appear to be involved. The strong link with inflammatory bowel disease (IBD) is associated with a markedly enhanced risk of colorectal cancer which next to cholangiocarcinoma represents the most serious diagnostic challenge in long-term PSC management. Despite extensive research, no medical treatment has been proven so far to prolong the time to liver transplantation (LTx), which remains the effective treatment in late-stage disease. Recurrence of PSC after LTx is observed in up to 20% of patients. Here, we briefly summarize actual views on PSC pathogenesis and provide an algorithmic approach to diagnostic procedures and recommendations for the management of PSC and its complications. We describe promising treatment options subject to current clinical trials.

Background and Aims: Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary cholangitis (PBC). Pharmacologic strategies show limited efficacy and can provoke serious side effects. We hypothesized that bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist, relieves cholestasis-associated itch by alleviating hepatobiliary injury. The aim of this investigator-initiated FITCH trial (Fibrates for cholestatic ITCH) was to assess effects of bezafibrate on pruritus in patients with PSC, PBC, and SSC., Methods: Patients with moderate to severe pruritus (≥5 of 10 on visual analog scale [VAS]) due to PSC, PBC, or SSC were recruited for this double-blind, randomized, placebo-controlled trial between 2016 and 2019. Patients received once-daily bezafibrate (400 mg) or placebo for 21 days. The primary end point was ≥50% reduction of pruritus (VAS; intention-to-treat)., Results: Of 74 randomized patients, 70 completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to ≥50% reduction of severe or moderate pruritus (P = .003). For secondary end points, bezafibrate reduced morning (P = .01 vs placebo) and evening (P = .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P = .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (-35%, P = .03 vs placebo) correlating with improved pruritus (VAS, P = .01) suggesting reduced biliary damage. Serum bile acids and autotaxin activity remained unchanged. Serum creatinine levels tended to mildly increase (3% bezafibrate, 5% placebo, P = .14)., Conclusions: Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC., Trial Registration: Netherlands Trial Register, ID: NTR5436 (August 3, 2015), ClinicalTrials.gov ID: NCT02701166 (March 2, 2016)., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Measuring symptoms and disease burden in patients with primary sclerosing cholangitis (PSC) is increasingly important for daily practice and clinical trials. The Simple Cholestatic Complaints Score (SCCS) is a four-item questionnaire, that measures cholestatic symptoms (pruritus, fatigue, RUQ abdominal pain and fever) in PSC patients. The aim of this study was to evaluate reliability and validity of SCCS in a Dutch population., Methods: The study population consisted of 212 patients from the Dutch prospective PSC registry. Data were collected via digital surveys. Reliability was evaluated by internal consistency and reproducibility. Construct-, criterion- and discriminant validity were determined. The ability to detect clinical change with SCCS was evaluated in patients who underwent endoscopic intervention. Simple Cholestatic Complaints Score collected by email and by a mobile application were compared., Results: A total of 153 patients completed the questionnaire. Internal consistency was moderate and increased to 0.71 after removal of the fever item. Test-re-test reproducibility was high (intraclass correlation coefficient = 0.96). Criterion validity was good (all > 0.82). Construct validity was in line with a priori hypothesized correlations in 80%. SCCS was able to differentiate between clinically different groups. There was no difference between inflammatory bowel disease (IBD) and non-IBD patients. Simple Cholestatic Complaints Score was responsive to change after endoscopic intervention in successfully treated patients. Simple Cholestatic Complaints Score measurement by digital questionnaire and a mobile application was comparable., Conclusion: The SCCS is a valid instrument to measure cholestatic symptoms in PSC patients. Because of its quick and easy to use properties it is suitable for frequent monitoring of symptoms in clinical trials and daily practice., (© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.)

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.

Background & Aims: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC., Methods: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat., Results: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/ml (95% CI -10.7 to -1.7; p = 0.008) and -9.4 ng/ml (-14.0 to -4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups., Conclusions: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels., Lay Summary: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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.)

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.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

IgG4-associated cholangitis (IAC) is the hepatobiliary manifestation of immunoglobulin G4-related disease, which is an immune-mediated fibroinflammatory systemic disorder characterised by often elevated IgG4 serum levels and typical histopathological findings in affected tissues. IAC is frequently (>90%) accompanied by autoimmune pancreatitis type 1 (AIP), which is the pancreatic manifestation of immunoglobulin G4-related disease. In 80-85% of the cases patients with IAC are male, above 50 years of age and present with jaundice and weight loss. A remarkable percentage of patients with IAC has a history of long-term exposure to solvents, oil products and other organic agents representing so-called "blue-collar workers". Clinical features and imaging (i. e. strictures or mass-forming lesions in the biliary tract) may mimic other biliary diseases, such as primary or secondary sclerosing cholangitis and cholangiocarinoma. The HISORt criteria are used for diagnosing IAC and comprise histologic and imaging findings, serum IgG4, organ manifestation pattern and response to immunosuppressive therapy. Serum IgG4 levels are of diagnostic value when it is above 4 times the upper limit of normal. Determination of the blood IgG4/IgG mRNA ratio using quantitative polymerase chain reaction (qPCR) is an accurate diagnostic tool currently under clinical validation. The majority of patients show an excellent response to corticosteroid therapy. Symptom recurrence, however, is common making long-term treatment with low-dose prednisolone and/or azathioprine frequently necessary.

Background: Distinguishing perihilar cholangiocarcinoma (PHC) from benign forms of sclerosing cholangitis affecting the hilar bile ducts is challenging, since histological confirmation of PHC is difficult to obtain and accurate non-invasive diagnostic tests are not available. IgG4-associated cholangitis (IAC), an imitator of PHC, may present with clinical and radiographical signs of PHC. IAC can be accurately diagnosed with a novel qPCR test. The aim of this study was to investigate the incidence and long-term activity of IAC in patients resected for PHC in a single tertiary center over a period of 30 years., Methods: All patients with benign disease who underwent surgery for presumed PHC in our institute between 1984 and 2015 were identified. Benign liver and bile duct specimens were re-evaluated by a pathologist and scored according to international consensus pathology criteria for IgG4-related disease (IgG4-RD). Patients with benign disease still alive were followed-up and a clinical diagnosis of IAC was made using a combination of the HISORt group C (response to steroids) criteria and elevated serum IgG4 levels and/or the novel IgG4/IgG RNA ratio. Also, recurrent symptomatic disease at any time after surgery requiring immunosuppression was assessed., Results: Out of 323 patients who underwent surgery for presumed PHC, 50 patients (15%) had benign disease. In 42% (n = 21/50) of these patients a histological (n = 17) or clinical (n = 4) diagnosis of IAC was established. The remaining patients were diagnosed with unclassified sclerosing inflammation, cystadenoma, or sclerosing hemangioma. Nine out of 12 IAC patients who were followed-up showed episodes of recurrent disease requiring immunosuppressive treatment., Conclusions: Liver and bile duct resections for PHC during three decades disclosed in 15% benign biliary disorders mimicking PHC of which 42% were definitely diagnosed as IAC. IgG4-RD remains active in the majority of patients with IAC years after surgery. Novel diagnostic tests for IAC might reduce misdiagnosis, unnecessary surgery, and life-threatening complications.

The etiopathogenesis of primary sclerosing cholangitis is unknown. Genetic variants of fucosyltransferase 2 (FUT2) have been identified in genome-wide association studies as risk factors for primary sclerosing cholangitis. We investigated the role of Fut2 in murine liver pathophysiology by studying Fut2 -/- mice. Fut2 -/- mice were viable and fertile, had lower body weight than wild-type (wt) littermates and gray fur. Half of the Fut2 -/- mice showed serum bile salt levels 40 times higher than wt (Fut2 -/- high ), whereas the remainder were normocholanemic (Fut2 -/- low ). Fut2 -/- mice showed normal serum liver tests, bile flow, biliary bile salt secretion, fecal bile salt loss, and expression of major hepatocellular bile salt transporters and cytochrome P450 7a1, the key regulator of bile salt synthesis, indicating that elevated serum bile salts in Fut2 -/- high mice were not explained by cholestasis. Fut2 -/- high mice, but not Fut2 -/- low mice, were sensitive to hydrophobic bile salt feeding (0.3% glycochenodeoxycholate); they rapidly lost weight and showed elevation of serum liver tests (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase) and areas of liver parenchymal necrosis. Histomorphological evaluation revealed the presence of paraportal shunting vessels, increased numbers of portal vascular structures, wall thickening of some portal arteries, and periductal fibrosis in Fut2 -/- high mice more than Fut2 -/- low mice and not wt mice. Unconjugated bilirubin and ammonia were or tended to be elevated in Fut2 -/- high mice only. Portosystemic shunting was demonstrated by portal angiography, which disclosed virtually complete portosystemic shunting in Fut2 -/- high mice, discrete portosystemic shunting in Fut2 -/- low mice, and no shunting in wt littermates., Conclusion: Liver pathology in Fut2 -/- mice is dominated by consequences of portosystemic shunting resulting in microcirculatory disturbances, mild (secondary) periductal fibrosis, and sensitivity toward human bile salt toxicity. (Hepatology 2017;66:542-554)., (© 2017 by the American Association for the Study of Liver Diseases.)

Purpose of Review: IgG4-related disease (IgG4-RD) is an immune-mediated disease of unknown cause. It predominantly affects the biliary tract [IgG4-associated cholangitis (IAC)] and pancreas [autoimmune pancreatitis (AIP)] of mostly elderly men. Accurate diagnostic tests are lacking. Patients benefit from predniso(lo)ne treatment. However, disease relapse is often seen. This review will address pathophysiological aspects and advances in diagnostic and therapeutic strategies., Recent Findings: The role of IgG1 and IgG4 in the pathophysiology of IgG4-RD was studied in mice which showed more intense organ damage of pancreas and salivary glands when IgG1 rather than IgG4 of patients with IgG4-RD was injected. Coadministration of IgG1+IgG4 led to dampening of IgG1-mediated injury supporting the view that IgG4 exerts immune-dampening effects. IgG4+ B-cell receptor clones identified by next-generation sequencing and the IgG4/IgG RNA ratio in human blood assessed by quantitative PCR were able to accurately distinguish IAC/AIP from primary sclerosing cholangitis or pancreatobiliary malignancies. Long-term treatment with low-dose prednisolone was safe and reduced the number of flare-ups in patients with AIP., Summary: Early diagnosis by a novel accurate and easy-to-use qPCR test may prevent life-threatening complications, unnecessary interventions and fatal course because of misdiagnosis. Prednisolone treatment remains the standard of care in patients with IgG4-RD.

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., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Pruritus (itch) is a frequent, burdensome and difficult-to-treat symptom in patients with cholestasis. Fibrates are currently under investigation for the treatment of primary biliary cholangitis in patients with a suboptimal response to ursodeoxycholic acid. Moreover, there is empirical evidence for a possible antipruritic effect. We aim to prove this in a randomized controlled trial, including patients with cholestatic liver diseases other than primary biliary cholangitis that are accompanied by pruritus., Methods: A multicenter investigator-initiated, double-blind, randomized placebo-controlled trial to evaluate the effect of bezafibrate on cholestatic pruritus in 84 adult patients with primary biliary cholangitis or primary/secondary sclerosing cholangitis. Primary outcome is the proportion of patients with a reduction of itch intensity of 50% or more (measured on a Visual Analog Scale) after 21 days of treatment with bezafibrate 400 mg qid or placebo. Secondary outcomes include the effect of bezafibrate on a five-dimensional itch score, liver disease-specific quality of life, serum liver tests and autotaxin activity. Safety will be evaluated through serum parameters for kidney function and rhabdomyolysis as well as precise recording of (serious) adverse events. We provide a schematic overview of the study protocol and describe the methods used to recruit and randomize patients, collect and handle data and perform statistical analyses., Discussion: Given its favorable safety profile and anticholestatic properties, bezafibrate may become the new first-line treatment option for treating cholestatic pruritus., Trial Registration: Netherlands Trial Register, ID: NCT02701166 . Registered on 2 March 2016; Netherlands Trial Register, ID: NTR5436 . Registered on 3 August 2015.

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)., (© 2016 by the American Association for the Study of Liver Diseases.)

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r G ) between PSC and ulcerative colitis (UC) (r G = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r G = 0.04) (P = 2.55 × 10 -15 ). UC and CD were genetically more similar to each other (r G = 0.56) than either was to PSC (P < 1.0 × 10 -15 ). Our study represents a substantial advance in understanding of the genetics of PSC.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most frequent chronic cholestatic liver diseases and serve as model diseases to discuss the management of cholestasis in 2017 in the lecture that is summarized in this report. PBC and PSC are characterized by inflammation and fibrosis of small intrahepatic (PBC) or larger intra- and/or extrahepatic (PSC) bile ducts. Bile duct damage leads to cholestasis and can progress to liver fibrosis and even cirrhosis. Various genetic, environmental and endogenous factors may contribute to the development of chronic cholestatic liver diseases, but the exact pathogenesis of PBC and PSC has not been clarified. Ursodeoxycholic acid (UDCA) is the standard treatment of PBC and is used also for other cholestatic conditions including PSC, and it exerts anticholestatic effects at adequate doses. Novel anticholestatic therapeutic options for patients not adequately responding to UDCA are under development or have, like obeticholic acid, already been proven to have efficacy when combined with UDCA in the treatment of PBC. The future role of immunomodulating/immunosuppressive drug regimens must be critically reviewed., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Bile salts likely contribute to liver injury in patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Fibroblast growth factor 19 (FGF19) is a bile salt-induced enterokine with hepatoprotective potential as it suppresses de novo bile salt synthesis. Here, we evaluated the bile salt receptor FXR/FGF19 gut-liver axis in PSC and PBC patients., Methods: Fasted patients with PSC (n = 12) and PBC (n = 10), and healthy controls (HC; n = 10) were orally challenged with the natural FXR agonist chenodeoxycholic acid (CDCA 15 mg/kg). Blood was sampled hourly until 8 h afterwards. Serum FGF19 and bile salt excursions were determined. Serum levels of 7α-hydroxy-4-cholesten-3-one (C4), reflecting bile salt synthesis, were measured as a biomarker of FGF19 response., Results: Baseline serum FGF19 levels were comparable between groups, while fasted bile salt levels in PSC patients were elevated. Upon CDCA challenge, HC and PBC patients showed a serum FGF19 peak after 4 h followed by a decline. PSC patients showed a prolonged and elevated serum FGF19 response up to 8 h, combined with a sustained serum elevation of CDCA and other bile salts. In general, C4 levels declined following FGF19 elevation. In PSC patients with less favorable prognosis, baseline C4 levels were drastically suppressed and did not further decline., Conclusion: Following an oral CDCA challenge, PSC patients showed an impaired clearance of CDCA and a prolonged serum FGF19 response. FXR agonist therapy in PSC could cause prolonged exposure to elevated levels of FGF19, and we propose careful monitoring for detrimental side effects in patient studies., Competing Interests: Serge Zweers, Elisabeth de Vries, Martin Lenicek, Dagmar Tolenaars, Rudi de Waart, Kiran Koelfat, Albert Groen, Steven Olde Damink, Ulrich Beuers, Cyriel Ponsioen, Peter Jansen, Frank Schaap declare that they have no conflict of interest. This study was supported by grants from the Dutch Digestive Diseases Foundation (WO#08-69), Dutch Society for Gastroenterology (Gastrostart 2012-10), Norwegian PSC Consortium (to Peter Jansen and Frank Schaap) and the German Crohn’s and Ulcerative Colitis Association (to Ulrich Beuers). Informed consent in studies with human subjects All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study.

Background & Aims: To better understand the pathogenesis of primary sclerosing cholangitis, anti- and pro-inflammatory factors were studied in bile., Methods: Ductal bile of PSC patients (n = 36) and controls (n = 20) was collected by endoscopic retrograde cholangiography. Gallbladder bile was collected at liver transplantation. Bile samples were analysed for cytokines, FGF19 and biliary lipids. Hepatobiliary tissues of PSC and non-PSC patients (n = 8-11 per patient group) were collected at transplantation and were analysed for IL8 and FGF19 mRNA expression and IL8 localization. The effect of IL8 on proliferation of primary human cholangiocytes and expression of pro-fibrotic genes was studied., Results: In PSC patients, median IL8 in ductal bile was 6.6 ng/ml vs. 0.24 ng/ml in controls. Median IL8 in gallbladder bile was 7.6 ng/ml in PSC vs. 2.2 and 0.3 ng/ml in two control groups. IL8 mRNA in PSC gallbladder was increased and bile ducts stained positive for IL8. In vitro, IL8 induced proliferation of primary human cholangiocytes and increased the expression of pro-fibrotic genes., Conclusion: Elevation of IL8 in bile of PSC patients, collected at different stages of disease, indicates an ongoing inflammatory stimulus that drives IL8 production. This challenges the idea that advanced PSC is a burned-out disease, and calls for reconsideration of anti-inflammatory therapy in PSC., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Pruritus is a common symptom of cholestatic liver disorders. The present study aimed at evaluating autotaxin (ATX), a lysophospholipase recently identified as potential cause for cholestatic pruritus, in pediatric cholestatic diseases presenting with or without itching., Methods: A cohort of 45 children consisting of 14 patients experiencing itching (Alagille syndrome [n = 10], complete extrahepatic biliary atresia [n = 2], neonatal sclerosing cholangitis (n = 1), progressive familial intrahepatic cholestasis type 2 [n = 1]), 9 patients with bile acid synthesis defects (3β-hydroxy-C27-steroid-oxidoreductase [n = 7] and Δ-3-oxosteroid-5β-reductase deficiency [n = 2]), and 22 healthy children were studied. Serum ATX activity and total serum bile salt were determined enzymatically, ATX protein content was semiquantified by Western blotting. Using real-time polymerase chain reaction, ATX mRNA expression was studied in HepG2 cells treated with farnesoid-X-receptor agonists or vehicle., Results: Serum ATX activity was increased in pruritic children with Alagille and other cholestatic syndromes (mean ± standard deviation: 16.1 ± 4.3 nmol · mL · min) compared with children with nonpruritic cholestatic diseases with bile acid synthesis defects (10.4 ± 4.7 nmol · mL · min; P < 0.01) and healthy controls (7.6 ± 2.3 nmol · mL · min; P < 0.001). ATX protein levels closely correlated with serum ATX activity. Serum ATX activity and total serum bile salt showed a linear correlation with itch intensity (r = 0.66, P < 0.001 and r = 0.80, P < 0.001, respectively). No correlation was observed between ATX activity and bilirubin. ATX mRNA expression in HepG2 cells was not induced by farnesoid-X-receptor ligands., Conclusions: Serum ATX activity correlated with itch intensity in children with cholestatic diseases. Bile salts did not increase ATX expression in vitro. ATX inhibitors may be useful antipruritic agents in pediatric cholestatic disorders.

Background & Aims: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease of unknown cause, but strongly associated with inflammatory bowel disease (IBD). Potential risk factors triggering PSC have never been studied on a population level. The aim of this study was to evaluate smoking, appendectomy, family history and geographical distribution in a population-based cohort of PSC patients, as compared to IBD control patients and healthy controls (HC)., Methods: For this case-control study 343 PSC patients, 370 IBD controls and 232 HC's living in a geographically defined area in the Netherlands filled-out a questionnaire concerning smoking, appendectomy and family history of IBD and autoimmune liver diseases., Results: Smoking was associated with a lower risk of developing PSC in PSC-ulcerative colitis (UC) patients (adjusted OR 0.21; 95% CI 0.12-0.34; P < 0.001). Comparable results were found for PSC-Crohn's disease (CD) patients (16% former smokers) compared to CD patients (55% former smokers) (adjusted OR 0.17; 95% CI 0.08-0.39; P < 0.001). Frequency of appendectomy did not differ between PSC and HC, but PSC-UC patients had undergone appendectomy more often than UC patients (13% vs. 6%) (adjusted OR 2.51; 95%CI 1.04-6.07; P = 0.041). We found no association between family history of IBD or autoimmune liver disease and risk of PSC. Degree of urbanization was not associated with PSC incidence., Conclusion: In this large population-based case-control study we confirm that smoking is associated with a lower risk of developing PSC, independent of its protective effect for developing UC. Appendectomy is not associated with the risk of developing PSC., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. At present, there is no appropriate histologic scoring system available for PSC, evaluating both degree of necroinflammatory activity (grade) and fibrosis (stage). The aim of this study was to assess if three scoring systems, commonly used in different liver diseases could be applied for grading and/or staging of PSC., Methods: Sixty-four PSC patients from a Dutch cohort, who underwent diagnostic liver biopsy, were included. Staging was scored using Ishak, Nakanuma, and Ludwig systems. Grading was scored using Ishak and Nakanuma systems. Three measures of outcome were defined; transplant-free survival, time to liver transplantation (LTx) and occurrence of cirrhosis related symptoms (CRS). Association of grade and stage with outcome was estimated using Kaplan-Meier log-rank test, and Cox regression analysis. Correlation with biochemistry was assessed by Spearman's rank test., Results: There were strong associations between disease stage measured by Ishak, Nakanuma, and Ludwig staging systems with both outcome measuring transplant-free survival (Hazard ratio (HR) 2.56; 95% CI 1.11-5.89, HR 6.53; 95% CI 2.01-21.22, HR 1.94; 95% CI 1.00-3.79, respectively), and time to LTx (HR 4.18; 95%CI 1.51-11.56, HR 7.05; 95% CI 1.77-28.11, HR 3.13; 95%CI 1.42-6.87, respectively). Ishak and Nakanuma grading systems were not associated with CRS. Weak correlations between histopathology and liver biochemistry were shown., Conclusion: Applying the Nakanuma, Ishak, and Ludwig histopathological staging systems is feasible and clinically relevant given their association with transplant-free survival and time to LTx. This suggests that these staging systems could be likely candidates for surrogate endpoints and stratification purposes in clinical trials in PSC., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Fucosyltransferase 2 (FUT2) mediates the inclusion of fucose in sugar moieties of glycoproteins and glycolipids. ABO blood group antigens and host-microbe interactions are influenced by FUT2 activity. About 20 % of the population has a "non-secretor" status caused by inactivating variants of FUT2 on both alleles. The non-sense mutation G428A and the missense mutation A385T are responsible for the vast majority of the non-secretor status in Caucasians, Africans, and Asians, respectively. Non-secretor individuals do not secrete fucose-positive antigens and lack fucosylation in epithelia. They also appear to be protected against a number of infectious diseases, such as Norovirus and Rotavirus infections. In recent years, genome-wide association studies (GWAS) identified inactivating variants at the FUT2 locus to be associated with primary sclerosing cholangitis (PSC), Crohn's disease (CD), and biochemical markers of biliary damage. These associations are intriguing given the important roles of fucosylated glycans in host-microbe interactions and membrane stability. Non-secretors have a reduced fecal content of Bifidobacteria. The intestinal bacterial composition of CD patients resembles the one of non-secretors, with an increase in Firmicutes and decreases in Proteobacteria and Actinobacteria. Non-secretor individuals lack fucosylated glycans at the surface of biliary epithelium and display a different bacterial composition of bile compared to secretors. Notably, an intact biliary epithelial glycocalix is relevant for a stable 'biliary HCO3 (-) umbrella' to protect against toxic effects of hydrophobic bile salt monomers. Here, the biology of FUT2 will be discussed as well as hypotheses to explain the role of FUT2 in the pathophysiology of PSC and Crohn's disease.

Purpose of Review: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin. There is no medical treatment of proven benefit on survival; once patients have progressed to end-stage liver disease, the only treatment option is liver transplantation., Recent Findings: Over the last years, some progress has been made in identifying biomarkers of PSC disease progression. Categories that can be distinguished include clinical and biochemical biomarkers, histology, imaging, prognostic modelling and genetics. With this review, we summarize biomarkers for progression of PSC from these six categories, which have been studied to date., Summary: Biomarkers for the progression of PSC disease course can be used for several purposes. First of all, they can be implemented as surrogate endpoints for clinical trials. Second, biomarkers of disease progression form the basis of prognostic modelling, which is needed for proper patient counselling and management. Lastly, these biomarkers may yield a better understanding of PSC pathogenesis.

Pruritus is a preeminent symptom in patients with chronic cholestatic liver disorders such as primary biliary cirrhosis and primary sclerosing cholangitis. More than two-thirds of these patients experience itching during the course of their disease. This symptom is also frequently observed in patients with other causes of cholestasis such as cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy, but may accompany almost any other liver disease. The pathogenesis of pruritus of cholestasis remains largely elusive. Increased concentrations of bile salts, histamine, serotonin, progesterone metabolites and endogenous opioids have been controversially discussed as potential pruritogens. However, for these molecules, neither a correlation with itch intensity nor a causative link could be established. The G protein-coupled receptor for bile salts, TGR5, has been shown to be expressed in dorsal root ganglia and give rise to itch in rodents, albeit upon stimuli with suprapathological concentrations of bile salts. The potent neuronal activator lysophosphatidic acid (LPA) and its forming enzyme, autotaxin (ATX), could be identified in the serum of patients with cholestatic pruritus. ATX activity correlated with itch severity and effectiveness of several anti-pruritic therapeutic interventions in cholestatic patients. Thus, the ATX-LPA-axis may represent a key element in the pathogenesis of this agonizing symptom. Treatment options for pruritus of cholestasis remain limited to a few evidence-based and several experimental medical and interventional therapies. The current guideline-based recommendations include the anion exchange resins colestyramine, the pregnane X receptor-agonist and enzyme inducer rifampicin, the μ-opioid antagonist naltrexone, and the selective serotonin reuptake inhibitors sertraline. Still, a considerable part of patients is unresponsive to these drugs and requires experimental approaches including phototherapy, plasmapheresis, albumin dialysis or nasobiliary drainage. This review outlines the current knowledge on pathogenesis of cholestatic pruritus and summarizes evidence-based and experimental therapeutic interventions for cholestatic patients with itch., (© 2015 S. Karger AG, Basel.)

Primary sclerosing cholangitis (PSC) is a chronic cholangiopathy characterized by biliary fibrosis, development of cholestasis and end stage liver disease, high risk of malignancy, and frequent need for liver transplantation. The poor understanding of its pathogenesis is also reflected in the lack of effective medical treatment. Well-characterized animal models are utterly needed to develop novel pathogenetic concepts and study new treatment strategies. Currently there is no consensus on how to evaluate and characterize potential PSC models, which makes direct comparison of experimental results and effective exchange of study material between research groups difficult. The International Primary Sclerosing Cholangitis Study Group (IPSCSG) has therefore summarized these key issues in a position paper proposing standard requirements for the study of animal models of PSC., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: The recent addition of immunoglobulin (Ig)G4-associated cholangitis (IAC), also called IgG4-related sclerosing cholangitis (IRSC), to the spectrum of chronic cholangiopathies has created the clinical need for reliable methods to discriminate between IAC and the more common cholestatic entities, primary (PSC) and secondary sclerosing cholangitis. The current American Association for the Study of Liver Diseases practice guidelines for PSC advise on the measurement of specific Ig (sIg)G4 in PSC patients, but interpretation of elevated sIgG4 levels remains unclear. We aimed to provide an algorithm to distinguish IAC from PSC using sIgG analyses. We measured total IgG and IgG subclasses in serum samples of IAC (n = 73) and PSC (n = 310) patients, as well as in serum samples of disease controls (primary biliary cirrhosis; n = 22). sIgG4 levels were elevated above the upper limit of normal (ULN = >1.4 g/L) in 45 PSC patients (15%; 95% confidence interval [CI]: 11-19). The highest specificity and positive predictive value (PPV; 100%) for IAC were reached when applying the 4 × ULN (sIgG4 > 5.6 g/L) cutoff with a sensitivity of 42% (95% CI: 31-55). However, in patients with a sIgG4 between 1 × and 2 × ULN (n = 38/45), the PPV of sIgG4 for IAC was only 28%. In this subgroup, the sIgG4/sIgG1 ratio cutoff of 0.24 yielded a sensitivity of 80% (95% CI: 51-95), a specificity of 74% (95% CI: 57-86), a PPV of 55% (95% CI: 33-75), and a negative predictive value of 90% (95% CI: 73-97)., Conclusion: Elevated sIgG4 (>1.4 g/L) occurred in 15% of patients with PSC. In patients with a sIgG4 >1.4 and <2.8 g/L, incorporating the IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved PPV and specificity. We propose a new diagnostic algorithm based on IgG4/IgG1 ratio that may be used in clinical practice to distinguish PSC from IAC., (© 2014 by the American Association for the Study of Liver Diseases.)

Unlabelled: 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., (© 2013 by the American Association for the Study of Liver Diseases.)

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiology, characterized by chronic inflammation of the biliary tree with subsequent fibrosis and cirrhosis of the liver. Patients with PSC are at increased risk for the development of cholangiocarcinoma (CCA), a highly malignant epithelial tumor arising from the intrahepatic and extrahepatic bile ducts. Currently, orthotopic liver transplantation is the only curative treatment. The lack of efficient diagnostic methods for early detection and the limited therapeutic options for CCA are major problems and are associated with poor survival. The pathogenesis of PSC-associated CCA is complex and poorly understood. It seems that pro-inflammatory cytokines play an important role in genetic and epigenetic changes that contribute to the carcinogenic process. The mapping of genetic alterations may elucidate molecular targets that may be applied as biomarkers to facilitate early diagnosis of malignant degeneration to improve patient outcome. In the last decade, the introduction of several novel molecular techniques available for genome-wide screening has advanced our knowledge on many of the genetic abnormalities that are prevalent in CCA and PSC-associated CCA. This review summarizes genetic and epigenetic abnormalities, which have important potential for clinical application.

Background: Primary sclerosing cholangitis (PSC) is strongly associated with inflammatory bowel disease (IBD). The aim of this study was to assess the IBD phenotype associated with PSC in a large well-phenotyped population-based PSC cohort using endoscopic and histopathologic criteria., Methods: PSC cases were identified and ascertained, fulfilling well-established criteria, in 39 hospitals in a geographically defined region of The Netherlands. IBD location was recorded according to the Montreal Classification. As this classification does not consider segmental inflammation, backwash ileitis, or rectal sparing, an additional subgroup analysis was performed in 80 cases and 80 age- and sex-matched IBD controls, reviewing all endoscopy and pathology reports filed between 2000 and 2010., Results: In all, 380 (66%) of a total of 579 PSC patients had coexistent IBD, mainly ulcerative colitis (UC) (75%). Overall, 207 (83%) of the PSC-UC patients had a pancolitis, 32 (13%) a left-sided colitis, and 9 (4%) a proctitis only. Seventy (95%) PSC-Crohn's disease (CD) patients had an (ileo)colitis and four (5%) ileitis only. In the subgroup analysis 53 (66%) PSC-UC patients were identified, 24 (30%) PSC-CD patients, and three (4%) PSC-IBD-U patients. Fifty (94%) PSC-UC patients had a pancolitis, compared with 32 (62%) matched UC patients (P < 0.001). Left-sided colitis was seen in 16 (31%) UC controls and in one PSC-UC patient (P < 0.001). Backwash ileitis and rectal sparing were rare findings (<10%) in the cohorts under study., Conclusions: IBD in PSC patients represents a distinct phenotype in that pancolitis is observed in 94% of PSC-UC and colitis in 96% of PSC-CD patients. Backwash ileitis and rectal sparing were rare findings in the PSC-UC patients., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)

Emerging pathophysiologic insights are leading to novel approaches to treating fibrosing cholangiopathies. The current treatment, using ursodeoxycholic acid (UDCA), may slow the progression of some chronic cholangiopathies but cannot heal them. Apart from immunosuppressive interventions aimed at minimizing immune-mediated damage, the use of specific modifiers of hepatobiliary secretory and cytoprotective mechanisms may eventually give rise to a new class of disease-modifying anti-cholangiofibrotic drugs.

Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS)., Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing., Results: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined)=2.1 × 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb)=1.9 × 10(-6), rs281377; p(comb)=2.1 × 10(-6) and rs601338; p(comb)=2.7 × 10(-6)) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients., Conclusions: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: To critically review most recent experimental evidence for the protective action of biliary HCO(3)(-) secretion against bile acid-induced bile duct damage and development of fibrosing cholangiopathy in humans and experimental animals., Recent Findings: Studies in human cholangiocytes in vitro indicate that a biliary HCO(3)(-) umbrella protects against bile acid-induced cholangiocyte damage and apoptosis in humans. The Cl(-)/HCO(3)(-) exchanger, AE2, and an intact biliary glycocalyx appear crucial for its stability. Related studies with experimental animal models in vivo have to be interpreted with caution as humans and mice differ not only with regard to bile salt pool, but also their expression patterns of transport proteins and signalling molecules., Summary: Adequate biliary HCO(3)(-) secretion may protect against bile salt-induced cholangiopathies. Future therapeutic strategies in biliary diseases will aim at stabilizing the biliary HCO(3)(-) umbrella.

Objective: Studies on the epidemiology of primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) show variable outcome. We aimed at systematically reviewing the incidence and prevalence rates, as well as geographical distribution and temporal trends of PSC and PBC., Data Sources: A systematic search of literature was performed in Medline and EMBASE (search last conducted January 10th, 2011)., Study Selection: Population-based epidemiological studies reporting incidence and/or prevalence rates for PSC or PBC in a defined geographical area of at least 100,000 adult inhabitants were considered relevant., Data Extraction: Study area, study period, number of patients, number of inhabitants, incidence per 100,000 inhabitants per year, prevalence per 100,000 inhabitants, method of case-finding, method of case-ascertainment, male/female ratio and in case of PSC, occurrence of inflammatory bowel diseases (IBD) were extracted from retrieved articles., Results: The literature search yielded 2286 abstracts of which 31 articles fulfilled all inclusion criteria. Studies varied in size from 10 to 770 patients in catchment areas from 100,312 to 19,230,000 inhabitants. The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 inhabitants/year and 0-16.2 per 100,000 inhabitants, respectively. PBC incidence rates range from 0.33 to 5.8 per 100,000 inhabitants/year and prevalence rates range from 1.91 to 40.2 per 100,000 inhabitants; prevalence rates are increasing in time., Conclusions: Incidence and prevalence rates of both PSC and PBC vary widely and seem to be increasing. True population-based studies are scarce and therefore large population-based studies combining meticulous case-finding and case-ascertainment strategies are necessary., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: There is a paucity of data on fertility or pregnancy in patients with primary sclerosing cholangitis (PSC)., Objective: To assess fertility in PSC by comparing the number of children in a large cohort of PSC patients to healthy controls and to investigate the outcome of pregnancy, as well as the influence of pregnancy on the disease course., Design: Case series., Setting: Germany., Participants: 229 PSC patients and 569 healthy controls were evaluated for the number of children. 17 patients with PSC and at least one pregnancy, or who received a diagnosis of PSC within 6 months after delivery, were included in the more detailed analysis., Main Outcome Measures: Number of children per patient and control; disease activity during pregnancy and after delivery including maternal complications; long-term development of live births, fetal loss rate and the influence of medication on fetal and maternal outcome., Results: Fertility did not seem to be reduced in PSC since the number of children did not differ between PSC patients and healthy controls. 25 pregnancies in 17 female PSC patients (median age at conception 31 years) were investigated in detail. An increase in liver enzymes was documented during five pregnancies (20%) and eight times (32%) post-partum. There were no serious maternal complications. All 21 live births presented with a normal perinatal and postnatal development over a median observation time of 50 months. Two pregnancies were delivered pre-term and four fetal losses occurred early in pregnancy (<12 wk). Continuation of treatment with ursodeoxycholic acid (15/21) or azathioprine (2/21) had no negative effects on pregnancy outcome., Conclusions: Fertility does not seem to be reduced in patients with PSC, who are able to deliver healthy children without an apparent increase in risk for mother or child.

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10⁻¹⁶ and P = 4.1 × 10⁻⁸, respectively).

This review focuses on the hypothesis that biliary HCO(3)(-) secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to prevent the uncontrolled membrane permeation of protonated glycine-conjugated bile acids. Functional impairment of this biliary HCO(3)(-) umbrella or its regulation may lead to enhanced vulnerability of cholangiocytes and periportal hepatocytes toward the attack of apolar hydrophobic bile acids. An intact interplay of hepatocellular and cholangiocellular adenosine triphosphate (ATP) secretion, ATP/P2Y- and bile salt/TGR5-mediated Cl(-)/ HCO(3)(-) exchange and HCO(3)(-) secretion, and alkaline phosphatase-mediated ATP breakdown may guarantee a stable biliary HCO(3)(-) umbrella under physiological conditions. Genetic and acquired functional defects leading to destabilization of the biliary HCO(3)(-) umbrella may contribute to development and progression of various forms of fibrosing/sclerosing cholangitis.

Background: TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants., Methodology/principal Findings: Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010) and UC (odds ratio = 1.19, 95% confidence interval 1.11-1.27, p = 8.5 x 10(-7)), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes., Conclusions/significance: Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases.

Background & Aims: We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers., Methods: A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls)., Results: The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6-6.5; P = 2.6 x 10(-26); and rs2844559: OR, 4.7; 95% CI, 3.5-6.4; P = 4.2 x 10(-26) in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06-1.50; and rs3197999: OR, 1.22; 95% CI, 1.02-1.47, respectively), with circumstantial evidence supporting the G-protein-coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes., Conclusions: Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown cause, with genetic predisposition in combination with environmental factors possibly playing a role. The diagnosis is made on the basis of a liver enzyme profile indicating cholestasis and characteristic bile duct abnormalities in cholangiography or the liver biopsy after excluding other causes. Approximately 80% of patients have concurrent inflammatory bowel disease (IBD), specifically ulcerative colitis in most patients. PSC predisposes to hepatobiliary malignancies such as cholangiocarcinoma, gallbladder carcinoma and hepatocellular carcinoma, as well as to colorectal carcinoma in patients with concurrent IBD.- UDCA and endoscopic bile duct dilatation relieve symptoms and improve the liver enzyme profile. Orthotopic liver transplantation is the only potentially curative therapy available.

A complex interplay of liver, bile ducts, and the gut critically determines functioning of these organs in health and disease. Biochemical and physiological aspects of their interaction and the role of inflammatory cells, cytokines, bile acids, visceral hormones, neuropeptides and other messengers in the pathogenesis of model immune-mediated hepatobiliary disorders are discussed in the actual issue of Clinical Reviews in Allergy and Immunology. Potential molecular targets for future therapeutic approaches are also addressed.

Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease of the liver and bile ducts that is associated with inflammatory bowel disease, generally leads to end-stage liver disease, and is complicated by malignancies of the biliary tree and the large intestine. The pathogenesis of PSC remains enigmatic, making the development of targeted therapeutic strategies difficult. Immunosuppressive and antifibrotic therapeutic agents were ineffective or accompanied by major side effects. Ursodeoxycholic acid (UDCA) has consistently been shown to improve serum liver tests and might lower the risk of colon carcinoma and cholangiocarcinoma by yet unknown mechanisms. Whether "high dose" UDCA improves the long-term prognosis in PSC as suggested by small pilot trials remains to be demonstrated. The present overview discusses potential therapeutic options aside of targeted immunological therapies and UDCA. The C23 bile acid norUDCA has been shown to markedly improve biochemical and histological features in a mouse model of sclerosing cholangitis without any toxic effects. Studies in humans are eagerly being awaited. Nuclear receptors like the farnesoid-X receptor (FXR), pregnane-X receptor (PXR), vitamin D receptor (VDR), and peroxisome-proliferator-activator receptors (PPARs) have been shown to induce expression of diverse carriers and biotransformation enzymes of the intestinal and hepatic detoxification machinery and/or to modulate fibrogenesis. Pros and cons of respective receptor agonists for the future treatment of PSC are discussed in detail. In our view, the novel bile acid norUDCA and agonists of PPARs, VDR, and PXR appear particularly attractive for further studies in PSC.

The three major immune disorders of the liver are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Variant forms of these diseases are generally called overlap syndromes, although there has been no standardised definition. Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC. The AIH-PBC overlap syndrome is the most common form, affecting almost 10% of adults with AIH or PBC. Single cases of AIH and autoimmune cholangitis (AMA-negative PBC) overlap syndrome have also been reported. The AIH-PSC overlap syndrome is predominantly found in children, adolescents and young adults with AIH or PSC. Interestingly, transitions from one autoimmune to another have also been reported in a minority of patients, especially transitions from PBC to AIH-PBC overlap syndrome. Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment. Therapy for overlap syndromes is empiric, since controlled trials are not available in these rare disorders. Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes. In end-stage disease, liver transplantation is the treatment of choice.