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Background and Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis. We showed an elevated interferon γ response in patients with primary sclerosing cholangitis and in multidrug resistance protein 2-deficient ( Mdr2-/- ) mice developing sclerosing cholangitis. Interferon γ induced expression of the cytotoxic molecules granzyme B (GzmB) and TRAIL in hepatic lymphocytes and mediated liver fibrosis in sclerosing cholangitis., Approach and Results: In patient samples and Mdr2-/- mice, we identified lymphocyte clusters with a cytotoxic gene expression profile using single-cell RNA-seq and cellular indexing of transcriptomes and epitopes by sequencing analyses combined with multi-parameter flow cytometry. CD8 + T cells and NK cells showed increased expression of GzmB and TRAIL in sclerosing cholangitis. Depletion of CD8 + T cells ameliorated disease severity in Mdr2-/- mice. By using Mdr2-/- × Gzmb-/- and Mdr2-/- × Tnfsf10-/- mice, we investigated the significance of GzmB and TRAIL for disease progression in sclerosing cholangitis. Interestingly, the lack of GzmB resulted in reduced cholangiocyte apoptosis, liver injury, and fibrosis. In contrast, sclerosing cholangitis was aggravated in the absence of TRAIL. This correlated with elevated GzmB and interferon γ expression by CD8 + T cells and NK cells enhanced T-cell survival, and increased apoptosis and expansion of cholangiocytes., Conclusions: GzmB induces apoptosis and fibrosis in sclerosing cholangitis, whereas TRAIL regulates inflammatory and cytotoxic immune responses, subsequently leading to reduced liver injury and fibrosis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Aims: Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disorder without effective medical treatment which is characterized by inflammation and fibrotic structures around the bile ducts. Biliary epithelial cells (cholangiocytes) are the target and potential disease drivers in PSC, yet little is known if cholangiocytes from PSC patients differ from non-PSC controls. To characterize cholangiocytes at early rather than end-stage disease, cholangiocyte organoids (COs) were derived from diseased bile ducts of PSC patients and compared to organoids generated from disease controls., Methods: Cholangiocytes were obtained during endoscopic retrograde cholangiopancreatography (ERCP) brushing of diseased bile duct areas and expanded as organoids using previously established culture methods. Stable CO lines were analyzed for cell type identity, basic cholangiocyte function, and transcriptomic signature., Results: We demonstrate that cholangiocytes, derived from the damaged area within the bile ducts of PSC patients, can be expanded in culture without displaying functional or genetic disease-related features. We further show that COs from patients who later were diagnosed with dysplasia exhibit higher expression of the cancer-associated genes PGC, FXYD2, MIR4435-2HG, and HES1., Conclusions: Our results demonstrate that PSC organoids are largely similar to control organoids after culture and highlight the significance of COs as a tool for regenerative medicine approaches as well as their potential for discovering new potential biomarkers for diagnosing cholangiocarcinoma., (© 2024. The Author(s).)

Since the concept of IgG4-related disease (IgG4-RD) was proposed, that diagnosis has been considered in idiopathic fibroinflammatory diseases in various organs, particularly in cases with multi-organ involvement. We have recently encountered three cases of fibrosing disease of uncertain etiology with shared microscopic appearances. Case 1 (56-year-old man) had an irregular mass at the base of mesentery. Case 2 (29-year-old woman) presented with obstructive jaundice due to an ill-defined mass at the hepatic hilum and two lung nodules. Case 3 (53-year-old man) had multiple solid nodules in the mediastinum, peritoneum, retroperitoneum, and mesentery; he also had diffuse irregular narrowing of the intra- and extra-hepatic bile ducts in keeping with sclerosing cholangitis. Serum IgG4 concentrations were not elevated. Biopsies from the nodular lesions showed extensive hyalinizing fibrosis with an only focal lymphoplasmacytic infiltrate. Thick collagenous bundles are arranged in an irregular or partly whorl pattern. Typical storiform fibrosis or obliterative phlebitis was not observed. The number of IgG4-positive plasma cells was <10 cells/high-power field; the ratio of IgG4/IgG-positive plasma cells was <30%. After the histological diagnosis of sclerosing mesenteritis, pulmonary hyalinizing granuloma, and mediastinal fibrosis was made, they were treated with a trial of steroids, but none showed a significant response. In conclusion, a hyalinizing fibrotic condition can occur at various anatomical sites. They have shared microscopic findings, and are steroid-resistant. Although the clinical presentation may mimic IgG4-RD, the two conditions are likely distinct. We would propose a diagnostic term of 'idiopathic hyalinizing fibrosclerosis' for this under-recognized, rare, systemic condition., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although the increased risk of colorectal neoplasia in patients with both primary sclerosing cholangitis (PSC) and ulcerative colitis (UC; termed PSC-UC) is well documented, the mechanism through which concomitant PSC increases the risk of colorectal neoplasia remains unclear. Given that the risk of colorectal neoplasia in UC is positively correlated with increased histologic inflammation, this study sought to investigate whether increased histologic inflammation could be used to stratify the risk of dysplasia development in patients with PSC-UC. Twenty patients with PSC-UC and dysplasia were compared with 30 control patients with PSC-UC who had no history of neoplasia. For each patient, all surveillance biopsies were scored using a 4-point scoring system: (1) no epithelial neutrophils = 0, (2) cryptitis only = 1, (3) cryptitis plus crypt abscess in <50% of crypts = 2, and (4) crypt abscess in ≥50% of crypts, erosion, neutrophilic exudate, and/or ulceration = 3. A score was designated for each biopsy, and both mean and maximum inflammation scores were calculated from all biopsies taken during each colonoscopy. The inflammation burden score was calculated for each surveillance interval by multiplying the average maximum score between each pair of surveillance episodes by the length of the surveillance interval in years. The average scores derived from all colonoscopies for each patient were used to determine the patient's overall mean, maximum, and inflammation burden scores. In both the dysplasia and control groups, the 3 summative inflammation scores were calculated independently for the entire colon, right colon, and left colon. The dysplasia group consisted of 14 (70%) men and 6 (30%) women, with a mean age of 27 years at UC diagnosis and a long history of pancolitis (mean duration: 17 y). A total of 49 dysplastic lesions were detected in the dysplasia group, and 8 (40%) of the 20 patients had multifocal dysplasia. The majority of dysplastic lesions belonged to nonconventional subtypes (n = 28; 57%) and were located in the right colon (n = 37; 76%). Irrespective of the colon segment, there was no significant difference in the 3 summative inflammation scores between the dysplasia and control groups ( P > 0.05). However, in each group, the 3 summative inflammation scores were significantly higher in the right colon than in the left colon ( P < 0.05). In conclusion, patients with PSC-UC exhibit increased histologic inflammation in the right colon compared with the left colon, regardless of the presence of dysplasia. Although this may provide an explanation for the predominance of right-sided colorectal neoplasia in patients with PSC-UC, increased histologic inflammation does not reliably predict an elevated risk of dysplasia in patients with PSC-UC. These findings reinforce the current recommendation for annual endoscopic surveillance for all patients with PSC-UC, irrespective of the extent and severity of inflammation., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: A new definition of dominant stricture (NDS) has recently been defined for patients with primary sclerosing cholangitis (PSC). Prevalence and clinical features of this, compared to traditional dominant stricture (TDS), have not been reported., Methods: In this single-centre longitudinal prospective cohort study, all PSC patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between October 2021 and 2022 were recruited. Symptoms of cholestasis, laboratory values (P-alkaline phosphatase, P-Bilirubin), Helsinki PSC-score, brush cytology findings and need for endoscopic therapy (i.e. dilation, stenting) were prospectively collected., Results: Overall, 228 patients with PSC underwent 248 ERCPs. NDS was detected in 43 (17%; 36 patients) and TDS without NDS (TDS group) was detected in 62 (25%; 58 patients) ERCPs, respectively; in the remaining 143 ERCPs, neither TDS nor NDS was seen (no dominant stricture [NoDS] group). PSC duration (median 8 years) and patient's age did not differ between the three groups; males presented more often with NDS. Patients with NDS were more often symptomatic, had higher cholestatic liver enzymes, advanced bile duct disease and markers of biliary inflammation (p < .001). Patients with NDS needed dilation (81%) and stenting (21%) more often than the TDS group (60% and 5%, respectively). Dysplasia in brush cytology was more common in TDS (5%) and NDS (9%) than in NoDS (3%) groups (p = .04), but did not differ between TDS and NDS groups., Conclusions: Dominant stricture according to the new definition developed in 17% of PSC patients in our cohort and identifies patients with more advanced disease, biliary inflammation and need of endo-therapy., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background: Glycoprotein-2 (GP2) IgA is a predictor of disease severity in primary sclerosing cholangitis (PSC). We examined GP2's occurrence in the biliary tract, the site of inflammation., Methods: GP2 was analyzed using ELISA, immunoblotting, mass spectrometry, and immunohistochemistry. The samples included: 20 bile and 30 serum samples from PSC patients, 23 bile and 11 serum samples from patients with gallstone disease (GD), 15 bile samples from healthy individuals undergoing liver-donation surgery (HILD), 20 extracts of gallstones (GE) obtained during cholecystectomy, and 101 blood-donor sera., Results: Biliary GP2 concentrations were significantly higher in patients with PSC and GD than in HILD (p < 0.0001). Serum GP2 levels were similar in PSC and GD patients, and controls, but lower than in bile (p < 0.0001). GP2 was detected in all 20 GEs. Mass spectrometry identified GP2 in the bile of 2 randomly selected GD and 2 PSC patients, and in none of 2 HILD samples. GP2 was found in peribiliary glands in 8 out of 12 PSC patients, showing morphological changes in acinar cells, but not in GD-gallbladders., Conclusions: GP2 is present in bile of PSC and GD patients. It is synthesized in the peribiliary glands of PSC patients, supporting a pathogenic role for biliary GP2 in PSC., Competing Interests: Declaration of competing interest PM served as a speaker supported by Alfa Wasserman and Chiesi. CS has served as a speaker for the Falk Foundation, as a consultant for BiomX and Pliant and has received research funding from Galapagos and BiomX. SL is an employee at Medipan GmbH. KG is an employee of GA Generic Assays. DR is an employee at GA Generic Assays and Medipan and owns stocks and shares of both companies., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Immune-related adverse event-sclerosing cholangitis caused by treatment with immune checkpoint inhibitors is rare, and the diagnostic criteria and treatment strategy remain unclear. In this study, we confirmed the clinicopathological features of immune-related adverse event-sclerosing cholangitis and clarified its diagnosis and appropriate management., Methods: We retrospectively evaluated 10 patients diagnosed with immune-related adverse event-sclerosing cholangitis and identified by electronic database searches., Results: Blood tests revealed liver dysfunction with a predominance of biliary tract enzymes in all patients; however, jaundice was present in only one patient. Contrast-enhanced computed tomography revealed diffuse hypertrophy of the extrahepatic bile duct wall as the most frequent finding; however, endoscopic retrograde cholangiopancreatography showed various imaging features, such as the pruned-tree appearance of intrahepatic bile ducts, in all patients. Transpapillary bile duct biopsy showed inflammatory cell infiltration using immunostaining, with a predominance of cluster of differentiation 8-positive T cells in 63% of the cases. Initial steroid therapy was effective in two cases. Mycophenolate mofetil and tacrolimus were used in steroid-refractory cases. Although six patients showed improvements, all of the remaining patients died owing to immune-related adverse event-sclerosing cholangitis., Conclusions: Various bile duct imaging findings of immune-related adverse event-sclerosing cholangitis were revealed; transpapillary bile duct biopsy may be useful in the diagnosis of immune-related adverse event-sclerosing cholangitis. Despite the combination of multiple immunosuppressive agents, prognosis of immune-related adverse event-sclerosing cholangitis remains poor. Longer follow-up and larger clinical studies are necessary to establish its treatment strategy., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We report on two cases of orthotopic liver transplantation (OLTX) due to SARS-Cov2-associated secondary sclerosing cholangitis (SSC) following long-term artificial respiration and extra-corporal membrane oxygenation in intensive care. Under these conditions, SSC is a rapidly progredient biliary disease featuring degenerative cholangiopathy, loss of bile ducts, ductular and parenchymal cholestasis, biliary fibrosis, and finally cirrhosis. Reduced perfusion and oxygenation of the peribiliary plexus, severe concurrent infections, and secondary medico-toxic effects appear to play a crucial role in the pathogenesis of the disease. A direct cytopathic effect of SARS-Cov2 on endothelial cells followed by thrombosis and fibrosing obliteration in all parts of the vascular bed of the liver may enhance the virus-associated liver disease and particularly SSC., (© 2024. The Author(s).)

Aims: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease that affects the hepatic bile ducts, leading to hepatic inflammation and fibrosis. PSC can also impact skeletal muscle through the muscle-liver axis, resulting in sarcopenia, a complication characterized by a generalized loss of muscle mass and strength. The underlying mechanisms and therapy of PSC-induced sarcopenia are not well understood, but one potential regulator is the transcription factor forkhead box protein O1 (FOXO1), which is involved in the ubiquitin proteasome system. Thus, the aim of this study is to assess the pharmacological potential of FOXO1 inhibition for treating PSC-induced sarcopenia., Materials and Methods: To establish diet-induced PSC model, we provided mice with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 4 weeks. Mice were intramuscularly injected with AS1842856 (AS), a FOXO1 inhibitor, at a dose of 3.5 mg/kg twice a week for last two weeks. C2C12 myotubes with cholic acid (CA) or deoxycholic acid (DCA) were treated with AS., Key Findings: We observed a decrease in muscle size and performance in DDC-fed mice with upregulated expression of FOXO1 and E3 ligases such as ATROGIN1 and MuRF1. We found that myotube diameter and MyHC protein level were decreased by CA or DCA in C2C12 myotubes, but treatment of AS reversed these reductions. We observed that intramuscular injection of AS effectively mitigates DDC diet-induced sarcopenia in a rodent PSC model., Significance: Our study suggests that a FOXO1 inhibitor could be a potential leading therapeutic drug for relieving PSC-induced sarcopenia., Competing Interests: Declaration of competing interest The authors declare that there are no conflict of interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background & Aims: Primary sclerosing cholangitis (PSC), often associated with inflammatory bowel disease (IBD), presents a multifactorial etiology involving genetic, immunologic, and environmental factors. Gut dysbiosis and bacterial translocation have been implicated in PSC-IBD, yet the precise mechanisms underlying their pathogenesis remain elusive. Here, we describe the role of gut pathobionts in promoting liver inflammation and fibrosis due to the release of bacterial outer membrane vesicles (OMVs)., Methods: Preclinical mouse models in addition to ductal organoids were used to acquire mechanistic data. A proof-of-concept study including serum and liver biopsies of a patient cohort of PSC (n = 22), PSC-IBD (n = 45), and control individuals (n = 27) was performed to detect OMVs in the systemic circulation and liver., Results: In both preclinical model systems and in patients with PSC-IBD, the translocation of OMVs to the liver correlated with enhanced bacterial sensing and accumulation of the NLRP3 inflammasome. Using ductal organoids, we were able to precisely attribute the pro-inflammatory and pro-fibrogenic properties of OMVs to signaling pathways dependent on Toll-like receptor 4 and NLRP3-gasdermin-D. The immunostimulatory potential of OMVs could be confirmed in macrophages and hepatic stellate cells. Furthermore, when we administered gut pathobiont-derived OMVs to Mdr2 -/- mice, we observed a significant enhancement in liver inflammation and fibrosis. In a translational approach, we substantiated the presence of OMVs in the systemic circulation and hepatic regions of severe fibrosis using a PSC-IBD patient cohort., Conclusions: This study demonstrates the contribution of gut pathobionts in releasing OMVs that traverse the mucosal barrier and, thus, promote liver inflammation and fibrosis in PSC-IBD. OMVs might represent a critical new environmental factor that interacts with other disease factors to cause inflammation and thus define potential new targets for fibrosis therapy., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4 + T (CD4 + T N ) cells in people with PSC. Mechanistically, rs56258221 leads to an increased expression of miR4464, in turn causing attenuated translation of BACH2, a major gatekeeper of T cell quiescence. Thereby, the fate of CD4 + T N is skewed toward polarization into pro-inflammatory subsets. Clinically, people with PSC carrying rs56258221 show signs of accelerated disease progression. The data presented here highlight the importance of assigning functional outcomes to disease-associated genetic polymorphisms as potential drivers of diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events., Methods: Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test., Results: Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001)., Conclusions: Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: In primary sclerosing cholangitis (PSC), it is important to understand the cholangiographic findings suggestive of malignancy, but it is difficult to determine whether cholangiocarcinoma is present due to modifications caused by inflammation. This study aimed to clarify the appropriate method of pathological specimen collection during endoscopic retrograde cholangiopancreatography for surveillance of PSC., Methods: A retrospective observational study was performed on 59 patients with PSC. The endpoints were diagnostic performance for benign or malignant on bile cytology and transpapillary bile duct biopsy, cholangiographic findings of biopsied bile ducts, diameters of the strictures and upstream bile ducts, and their differences., Results: The sensitivity (77.8% vs. 14.3%, P = 0.04), specificity (97.8% vs. 83.0%, P = 0.04), and accuracy (94.5% vs. 74.1%, P = 0.007) were all significantly greater for bile duct biopsy than for bile cytology. All patients with cholangiocarcinoma with bile duct stricture presented with dominant stricture (DS). The diameter of the upstream bile ducts (7.1 (4.2-7.2) mm vs. 2.1 (1.2-4.1) mm, P < 0.001) and the diameter differences (6.6 (3.1-7) mm vs. 1.5 (0.2-3.6) mm, P < 0.001) were significantly greater in the cholangiocarcinoma group than in the noncholangiocarcinoma group with DS. For diameter differences, the optimal cutoff value for the diagnosis of benign or malignant was 5.1 mm (area under the curve = 0.972)., Conclusion: Transpapillary bile duct biopsy should be performed via localized DS with upstream dilation for the detection of cholangiocarcinoma in patients with PSC. Especially when the diameter differences are greater than 5 mm, the development of cholangiocarcinoma should be strongly suspected., (© 2024. Japanese Society of Gastroenterology.)

Background: Primary sclerosing cholangitis (PSC) is a progressive liver disease associated with inflammatory bowel disease (IBD). The percentage of PSC patients diagnosed with concomitant IBD varies considerably between studies. This raises the question whether all PSC patients would show intestinal inflammation if screened thoroughly, even in the absence of symptoms., Methods: To address this question, we collected intestinal biopsies of healthy controls (n = 34), PSC (n = 25), PSC-IBD (n = 41), and IBD (n = 51) patients in a cross-sectional study and carried out cytokine expression profiling, 16S sequencing, in-depth histology, and endoscopy scoring., Results: We found that the vast majority of PSC patients even without clinically manifest IBD showed infiltration of immune cells and increased expression of IL17A and IFNG in intestinal biopsies. However, expression of IL10 and FOXP3 were likewise increased, which may explain why these PSC patients have intestinal inflammation only on a molecular level. This subclinical inflammation in PSC patients was focused in the distal colon, whereas PSC-IBD patients showed inflammation either at the distal colon or on the right side of the colon and the terminal ileum. Furthermore, we observed that PSC patients without IBD showed signs of dysbiosis and exhibited a distinct microbial profile compared with healthy controls., Conclusions: We found a gradient of intestinal inflammation in the vast majority of PSC patients even in the absence of IBD. Thus, further studies evaluating the effect of anti-inflammatory therapies in PSC patients and their impact on the emergence of clinically manifest IBD and colorectal cancer development are needed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: Patients diagnosed with primary sclerosing cholangitis (PSC) but with characteristics of immunoglobulin G4 (IgG4)-associated cholangitis (IAC) have been described. IAC often presents with biliary IgG4-positive plasma cell (IgG4+ PC) infiltration and responds to corticosteroids. In PSC, the frequencies or implications of biliary IgG4+ PC are unknown. We aimed to characterize the phenomenon of biliary IgG4+ PC in patients with an established PSC diagnosis., Methods: Bile duct biopsies from 191 surveillance or therapeutic endoscopic retrograde cholangiography of 58 PSC patients were retrospectively analyzed for IgG4+ PC infiltration. Patients with ≥10 IgG4+ PC per high-power field (HPF) were identified and characterized by clinical parameters, including serum IgG4 and cholangiographic presentations., Results: Altogether 39.7% of the PSC patients showed ≥10 IgG4+ PC/HPF in bile duct biopsies. Patients with biliary IgG4+ PC infiltration were significantly younger at diagnosis of PSC (P = 0.023). There was no association between biliary IgG4+ PC infiltration and transplant-free survival (P = 0.618). Patients with IgG4+ PC infiltration in bile duct biopsies showed significantly higher baseline (P = 0.002) and maximum (P = 0.001) serum IgG4 compared to those without. Biliary IgG4+ PC infiltration was associated with high-grade bile duct strictures (P = 0.05). IgG4-positive plasma cell infiltrations were found multifocally in 72.7% of this subgroup of PSC patients., Conclusions: IgG4+ PC ≥10/HPF can be found abundantly in bile duct biopsies in PSC. Histological findings correlated with serum IgG4, age, and high-grade bile duct strictures. IgG4+ PC was located multifocally, hinting at a systemic biliary phenotype., (© 2024 The Author(s). Journal of Digestive Diseases published by Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Primary sclerosing cholangitis (PSC) is a rare cholestatic disease characterized by biliary infiltration, hepatic fibrosis and bile duct destruction. To date, treatment options for PSC are very limited. Therefore, the current study is aimed to investigate the therapeutic potential of berberine (BBR) against PSC. The disease was induced by feeding the mice with 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine (DDC) for four weeks. The serum biochemistry and liver histology were analyzed. Furthermore, the expression of farnesoid X receptor (FXR) was also evaluated by real-time PCR. The results indicated that berberine prevents the progression of PSC by modulating the expression of FXR which ultimately regulates other genes (including Cyp7A1 and BSEP) thus maintaining bile acids homeostasis. Furthermore, the docking analysis showed that berberine interacts with the binding pocket of FXR to activate the protein thus acting as an FXR agonist. In conclusion, data indicate that berberine protects the liver from PSC-related injury. This effect might be due to the modulation of FXR activity., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones 1-5 . However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco + immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco + macrophages. Functional ablation of Marco + macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco + immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Biliary-pattern injury in the liver (eg, duct injury, ductular reaction, cholestasis) can occur in several conditions, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), large duct obstruction (LDO), and drug-induced liver injury (DILI). While the histologic changes in these conditions have been individually well described, distinguishing among them remains often challenging, particularly when biopsy samples are limited in size, robust clinical information is unavailable, and/or the pathologist does not feel confident in evaluating liver disease. This study evaluated histologic features that could aid the diagnosis of biliary-pattern injury on biopsy. We reviewed 121 liver biopsies from clinically confirmed cases of PBC, PSC, chronic LDO, or DILI for multiple clinical and histologic parameters. The rates of these histologic findings were then compared among different entities. Onion-skin fibrosis was seen in 14% of PSC in comparison to 0%, 5%, and 0% of PBC, DILI, and chronic LDO (P = 0.031). Florid duct lesions were identified in 21% of PBC compared to 2% of PSC and 0% of DILI and LDO (P = 0.0065). Similarly, 42% of PBC showed lobular granulomas, compared to 7% of PSC, 11% of DILI, and 33% of chronic LDO (P = 0.0001). Cholestasis was more commonly seen in DILI (42%) and chronic LDO (83%) than in PBC (4%) and PSC (16%) (P < 0.0001). Lobular chronic inflammation was found in a significantly higher percentage of PBC and LDO than of PSC and DILI (P = 0.0009). There were significantly fewer cases of PBC showing neutrophils in ductular reaction than PSC, DILI, and LDO (P = 0.0063). Histologic findings that can help suggest a diagnosis in liver biopsies with biliary-pattern injury include florid duct lesions, lobular granulomas, lack of neutrophils in ductular reaction, and lobular chronic inflammation in PBC; onion-skin fibrosis in PSC; cholestasis and feathery degeneration in DILI; and lobular granulomas, lobular chronic inflammation, cholestasis, and feathery degeneration in chronic LDO. These findings are likely most helpful when complicating factors interfere with biopsy interpretation., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background & Aims: Chronic inflammation surrounding bile ducts contributes to the disease pathogenesis of most cholangiopathies. Poor efficacy of immunosuppression in these conditions suggests biliary-specific pathologic principles. Here we performed biliary niche specific functional interpretation of a causal mutation (CD100 K849T) of primary sclerosing cholangitis (PSC) to understand related pathogenic mechanisms., Methods: Biopsy specimens of explanted livers and endoscopy-guided sampling were used to assess the CD100 expression by spatial transcriptomics, immune imaging, and high-dimensional flow cytometry. To model pathogenic cholangiocyte-immune cell interaction, splenocytes from mutation-specific mice were cocultured with cholangiocytes. Pathogenic pathways were pinpointed by RNA sequencing analysis of cocultured cells and cross-validated in patient materials., Results: CD100 is mainly expressed by immune cells in the liver and shows a unique pattern around PSC bile ducts with RNA-level colocalization but poor detection at the protein level. This appears to be due to CD100 cleavage as soluble CD100 is increased. Immunophenotyping suggests biliary-infiltrating T cells as the major source of soluble CD100, which is further supported by reduced surface CD100 on T cells and increased metalloproteinases in cholangiocytes after coculturing. Pathogenic T cells that adhered to cholangiocytes up-regulated genes in the T-helper 17 cell differentiation pathway, and the CD100 mutation boosted this process. Consistently, T-helper 17 cells dominate biliary-resident CD4 T cells in patients., Conclusions: CD100 exerts its functional impact through cholangiocyte-immune cell cross talk and underscores an active, proinflammatory role of cholangiocytes that can be relevant to novel treatment approaches., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Cell death and inflammation play critical roles in chronic tissue damage caused by cholestatic liver injury leading to fibrosis and cirrhosis. Liver cirrhosis is often associated with kidney damage, which is a severe complication with poor prognosis. Interferon regulatory factor 3 (IRF3) is known to regulate apoptosis and inflammation, but its role in cholestasis remains obscure. In this study., Approach and Results: We discovered increased IRF3 phosphorylation in the liver of patients with primary biliary cholangitis and primary sclerosing cholangitis. In the bile duct ligation model of obstructive cholestasis in mice, we found that tissue damage was associated with increased phosphorylated IRF3 (p-IRF3) in the liver and kidney. IRF3 knockout ( Irf3-/- ) mice showed significantly attenuated liver and kidney damage and fibrosis compared to wide-type mice after bile duct ligation. Cell-death pathways, including apoptosis, necroptosis, and pyroptosis, inflammasome activation, and inflammatory responses were significantly attenuated in Irf3-/- mice. Mechanistically, we show that bile acids induced p-IRF3 in vitro in hepatocytes. In vivo , activated IRF3 positively correlated with increased expression of its target gene, Z-DNA-Binding Protein-1 (ZBP1), in the liver and kidney. Importantly, we also found increased ZBP1 in the liver of patients with primary biliary cholangitis and primary sclerosing cholangitis. We discovered that ZBP1 interacted with receptor interacting protein 1 (RIP1), RIP3, and NLRP3, thereby revealing its potential role in the regulation of cell-death and inflammation pathways. In conclusion., Conclusions: Our data indicate that bile acid-induced p-IRF3 and the IRF3-ZBP1 axis play a central role in the pathogenesis of cholestatic liver and kidney injury., (Copyright © 2023 American Association for the Study of Liver Diseases.)

With the growing recognition of IgG4-related hepatobiliary disease, establishing a definitive diagnosis relies mainly on a combination of clinical findings, serological markers, and imaging modalities. However, the role of histopathological evaluation remains indispensable, particularly in cases necessitating differential diagnosis or malignancy exclusion. While diagnosing IgG4-related hepatobiliary disease through surgical resection specimens is often straightforward, pathologists encounter substantial challenges when evaluating biopsies. The increasing rarity of surgical interventions exacerbates this due to improved disease recognition and suspicion. Numerous confounding factors, including the absence of the characteristic histologic features, limited tissue sample size, biopsy artifacts, and the limited value of IgG4 counts, further complicate the diagnostic process. Additionally, many other disorders exhibit clinical and histological features that overlap with IgG4-related disease, intensifying the complexity of interpreting biopsy specimens. This article explores the clinical and histomorphologic features of IgG4-related hepatobiliary disease and its potential mimickers. It offers valuable insights for pathologists and clinicians when confronted with biopsy specimens from hepatobiliary organs., Competing Interests: Declaration of competing interest The authors have no conflict of interest or funding to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Enteroblastic carcinoma is clinically characterized by an elevated serum level of alpha-fetoprotein (AFP) and is histologically characterized by cancer cells with a clear cytoplasm and 'blastic' coarse chromatin. It sometimes has an element of hepatoid carcinoma; therefore, these two neoplasms are often regarded as sister entities. Although hepatoid carcinoma in the biliary tree has been reported, enteroblastic cholangiocarcinoma is extremely uncommon. In the present study, four cases of enteroblastic cholangiocarcinoma were examined. Tumors were located inside the liver (n = 2) or common bile duct (n = 2). The two intrahepatic cases had a history of primary sclerosing cholangitis, and serum AFP levels were elevated in both. One unresectable case was diagnosed by needle liver biopsy, while the remaining three underwent surgical resection. Histologically, all cases showed similar microscopic features. Cuboidal or polygonal cancer cells with the characteristic clear cytoplasm and subnuclear vacuoles were arranged in a papillary, micropapillary, tubular, or solid architecture. One case had an element of pancreatobiliary-type adenocarcinoma, while a hepatoid carcinoma element was not observed in any cases. All cases were positive for AFP, glypican 3, and SALL4, with SALL4 being the most widely expressed. Heppar-1 and arginase-1 were negative, except for one case, which was positive for Heppar-1. In conclusion, enteroblastic cholangiocarcinoma is an uncommon subtype of biliary tract malignancy. These cases may have been categorized as 'clear cell' cholangiocarcinoma. Although enteroblastic cholangiocarcinoma seems to occur more commonly in extrahepatic regions, including the gallbladder, it may also develop in the liver, particularly in patients with primary sclerosing cholangitis., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: There is a lack of biliary epithelial molecular markers for primary sclerosing cholangitis (PSC). We analyzed candidates from disease susceptibility genes identified in recent genome-wide association studies (GWAS)., Methods: Expression levels of GWAS genes were analyzed in archival liver tissues of patients with PSC and controls. Immunohistochemical analysis was performed to evaluate expression levels in the biliary epithelia of PSC (N = 45) and controls (N = 12). Samples from patients with primary biliary cholangitis (PBC) were used as disease controls (N = 20)., Results: Hepatic expression levels of ATXN2, HHEX, PRDX5, MST1, and TNFRSF14 were significantly altered in the PSC group. We focused on the immune-related receptor, TNFRSF14. Immunohistochemistry revealed that high expression of TNFRSF14 in biliary epithelial cells was observed only in the PSC group. In addition, the expression of LIGHT, which encodes a TNFRSF14-activating ligand, was increased in PSC liver. Immunohistochemistry showed that high expression of LIGHT was more common in PSC biliary epithelia (53%) than in the PBC (15%) or control (0%) groups; moreover, it was positively associated with fibrotic progression, although it was not an independent prognostic factor., Conclusions: TNFRSF14 and LIGHT are promising candidate markers for PSC., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which pharmacological treatment options are currently unavailable. PSC is strongly associated with colitis and a disruption of the gut-liver axis, and macrophages are involved in the pathogenesis of PSC. However, how gut-liver interactions and specific macrophage populations contribute to PSC is incompletely understood., Approach and Results: We investigated the impact of cholestasis and colitis on the hepatic and colonic microenvironment, and performed an in-depth characterization of hepatic macrophage dynamics and function in models of concomitant cholangitis and colitis. Cholestasis-induced fibrosis was characterized by depletion of resident KCs, and enrichment of monocytes and monocyte-derived macrophages (MoMFs) in the liver. These MoMFs highly express triggering-receptor-expressed-on-myeloid-cells-2 ( Trem2 ) and osteopontin ( Spp1 ), markers assigned to hepatic bile duct-associated macrophages, and were enriched around the portal triad, which was confirmed in human PSC. Colitis induced monocyte/macrophage infiltration in the gut and liver, and enhanced cholestasis-induced MoMF- Trem2 and Spp1 upregulation, yet did not exacerbate liver fibrosis. Bone marrow chimeras showed that knockout of Spp1 in infiltrated MoMFs exacerbates inflammation in vivo and in vitro , while monoclonal antibody-mediated neutralization of SPP1 conferred protection in experimental PSC. In human PSC patients, serum osteopontin levels are elevated compared to control, and significantly increased in advanced stage PSC and might serve as a prognostic biomarker for liver transplant-free survival., Conclusions: Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as a prognostic marker and future therapeutic target in PSC., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aims: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and severe fibrosis for which effective treatment options are currently lacking. In this study, we explored the potential of beta-lapachone (βL) as a drug candidate for PSC therapy., Materials and Methods: We employed an animal model fed a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to assess the preventive and therapeutic effects of βL. The beneficial effects of βL on PSC pathogenic characteristics, including blood biomarkers, inflammation, and fibrosis, were determined by assessing relevant parameters. Differential gene expression between each group was analyzed by RNA sequencing of liver tissues. Mdr2 -/- mice were utilized to explore the involvement of Abcb4 in the βL-induced improvement of PSC pathogenesis., Key Findings: βL effectively inhibited key features of PSC pathogenesis, as demonstrated by reduced blood biomarkers and improved pathogenic characteristics. Treatment with βL significantly mitigated DDC-induced apoptosis, cell proliferation, inflammation, and fibrosis. Analysis of differential gene expression confirmed a new insight that βL could stimulate the expression of genes related to NAD synthesis and Abcb4. Indeed, βL-induced NAD exhibited effective functioning, as evidenced by enhanced sirt1/3 and acetyl-lysine levels, leading to improved mitochondrial stability. The role of Abcb4 in response to βL was confirmed in Mdr2/Abcb4 KO mice, where the beneficial effects of βL were abolished., Significance: This study provided a new concept for PSC treatment, suggesting that pharmacological stimulation of the NAD synthetic pathway and Abcb4 via βL ameliorates PSC pathogenesis., Competing Interests: Declaration of competing interest The authors declare that the content in this article have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Spiny keratoderma is a rare dermatological manifestation that occurs sporadically or hereditarily. These are millimetric hyperkeratotic lesions on the palms and/or soles, usually asymptomatic. Histopathologically, they consist of well-defined columns of parakeratosis on a thinned stratum corneum. Sporadic cases can be associated with chronic diseases or neoplasms. We present a case of palmar spiny keratoderma in a man in the seventh decade of life with cirrhosis due to primary sclerosing cholangitis, and hepatocellular carcinoma. He had remission of the skin lesions two months after performing a liver transplant. This behavior favors the interpretation of spiny keratoderma as a paraneoplastic manifestation of hepatocellular carcinoma. We have not found previous reports of spiny keratoderma from Argentina. We review the literature on this entity.

Background: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammatory fibrosis usually involving the whole biliary tree. However, there are very limited treatment options to treat this disease. Our previous study found a lipid-protein rCsHscB from a liver fluke - Clonorchis sinensis , which had full capacities of immune regulation. Therefore, we investigated the role of rCsHscB in a mouse model of sclerosing cholangitis induced by xenobiotic 3,5- diethoxycarbonyl-1,4-dihydrocollidine (DDC) to explore whether this protein had potential therapeutic value for PSC., Methods: Mice were fed 0.1% DDC for 4 weeks and treated with CsHscB (30 μg/mouse, intraperitoneal injection, once every 3 days); the control group was given an equal amount of PBS or CsHscB under normal diet conditions. All the mice were sacrificed at 4 weeks for the evaluation of biliary proliferation, fibrosis, and inflammation., Results: rCsHscB treatment attenuated DDC-induced liver congestion and enlargement and significantly decreased the upregulation of serum AST and ALT levels. The administration of rCsHscB to DDC-fed mice significantly decreased cholangiocyte proliferation and pro-inflammatory cytokine production compared to mice fed with DDC alone. Also, rCsHscB treatment showed a decreased expression of α-SMA in the liver and other markers of liver fibrosis (Masson staining, Hydroxyproline content, and collagen deposit). More interestingly, DDC-fed mice treated with rCsHscB showed a significant up-regulation of PPAR-γ expression, which was similar to control mice, indicating the involvement of PPAR-γ signaling in the protective action of rCsHscB., Conclusion: Overall, our data show that rCsHscB attenuates the progression of cholestatic fibrosis induced by DDC and supports the potential for manipulating the parasite-derived molecule to treat certain immune-mediated disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Aims: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease characterized by the infiltration of intrahepatic tissue-resident memory CD8 + T cells (T RM ). Itaconate has demonstrated therapeutic potential in modulating inflammation. An unmet need for PSC is the reduction of biliary inflammation, and we hypothesized that itaconate may directly modulate pathogenic T RM ., Approach and Results: The numbers of intrahepatic CD103 + T RM were evaluated by immunofluorescence in PSC (n = 32), and the serum levels of itaconate in PSC (n = 64), primary biliary cholangitis (PBC) (n = 60), autoimmune hepatitis (AIH) (n = 49), and healthy controls (n = 109) were determined by LC-MS/MS. In addition, the frequencies and immunophenotypes of intrahepatic T RM using explants from PSC (n = 5) and healthy donors (n = 6) were quantitated by flow cytometry. The immunomodulatory properties of 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) on CD103 + T RM were studied in vitro. Finally, the therapeutic potential of itaconate was studied by the administration of 4-OI and deficiency of immune-responsive gene 1 (encodes the aconitate decarboxylase producing itaconate) in murine models of PSC. Intrahepatic CD103 + T RM was significantly expanded in PSC and was positively correlated with disease severity. Serum itaconate levels decreased in PSC. Importantly, 4-OI inhibited the induction and effector functions of CD103 + T RM in vitro. Mechanistically, 4-OI blocked DNA demethylation of RUNX3 in CD8 + T cells. Moreover, 4-OI reduced intrahepatic CD103 + T RM and ameliorated liver injury in murine models of PSC., Conclusions: Itaconate exerted immunomodulatory activity on CD103 + T RM in both in vitro and murine PSC models. Our study suggests that targeting pathogenic CD103 + T RM with itaconate has therapeutic potential in PSC., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Introduction: The advances of minimally invasive endoscopy-guided procedures that usually yield limited diagnostic material changed pancreaticobiliary cytopathology into one of the most challenging areas of cytopathology given the abundance of differential diagnoses to be considered when dealing with limited specimens., Case Presentation: We describe a few challenging examples of potential pitfalls in pancreatobiliary cytopathology evaluation collected from a busy academic hospital (tertiary) center. Case 1 illustrates the challenges in handling paucicellular specimens from pancreatic solid lesions in which differential diagnoses may include acinar cell carcinoma, neuroendocrine tumors, adenocarcinoma, or even benign pancreatic tissue, among others. Case 2 illustrates the pitfalls in evaluating limited specimens from patients with chronic pancreatitis, specially when distinguishing exuberant reactive atypia from dysplastic changes is mandatory. Case 3 illustrates pitfalls in distinguishing malignancy from reactive changes in biliary brushing specimens from patients with primary sclerosing cholangitis. Finally, cases 4 and 5 highlight the importance of including the possibility of pancreatic metastasis in the differential diagnoses of some pancreatic lesions., Conclusion: Over time, there has been an increasing demand for pathologists to render diagnoses on limited specimens obtained through minimally invasive procedures which can be frequently challenging even for the most experienced professionals. In many difficult cases, salvaging additional material for a cell block can turn out to be extremely helpful given the possibility of utilizing additional ancillary tests for diagnostic confirmation., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Cellular senescence and biliary fibrosis are prototypical features of obliterative cholangiopathies, such as primary sclerosing cholangitis (PSC). Telomere dysfunction can lead to senescence either through telomere erosion or damaged telomeres. Our goal was to investigate a mechanistic relationship between telomere damage and biliary fibrosis in PSC. Telomere attrition was observed in the bile ducts of patients with PSC along with a reduction in telomerase reverse transcriptase (TERT) expression, compared with that in normal livers. Similarly, liver tissue from mouse models of biliary fibrosis showed telomere attrition with increased damage at telomeres measured as telomere-associated foci (TAF). Cellular models of senescence induction increased the TAF in cholangiocytes. This coincided with decreased TERT expression and increased senescence, which was rescued by modulating TERT levels. Epigenetic analysis revealed increased acquisition of repressive histone methylation at the TERT promoter, which correlated with decreased TERT transcription. Cholangiocyte-selective deletion of TERT in mice exacerbated fibrosis, whereas androgen therapy toward telomerase rescued liver fibrosis and liver function in a genetic mouse model of PSC. Our results demonstrate a mechanistic role for telomere dysfunction in cellular senescence and fibrosis that characterize PSC. This suggests that PSC may be, in part, a telomere biology disorder, and identifies TERT as a potential therapeutic target.

Exploring the pathogenesis of and developing therapies for cholestatic liver diseases such as primary sclerosing cholangitis (PSC) remains challenging, partly due to a paucity of in vitro models that capture the complex environments contributing to disease progression and partly due to difficulty in obtaining cholangiocytes. Here we report the development of a human vascularized bile duct-on-a-chip (VBDOC) that uses cholangiocyte organoids derived from normal bile duct tissue and human vascular endothelial cells to model bile ducts and blood vessels structurally and functionally in three dimensions. Cholangiocytes in the duct polarized, formed mature tight junctions and had permeability properties comparable to those measured in ex vivo systems. The flow of blood and bile was modeled by perfusion of the cell-lined channels, and cholangiocytes and endothelial cells displayed differential responses to flow. We also showed that the device can be constructed with biliary organoids from cells isolated from both bile duct tissue and the bile of PSC patients. Cholangiocytes in the duct became more inflammatory under the stimulation of IL-17A, which induced peripheral blood mononuclear cells and differentiated Th17 cells to transmigrate across the vascular channel. In sum, this human VBDOC recapitulated the vascular-biliary interface structurally and functionally and represents a novel multicellular platform to study inflammatory and fibrotic cholestatic liver diseases., (Creative Commons Attribution license.)

Background: It is estimated that 6% to 20% of all cholangiocarcinoma (CCA) diagnoses are explained by primary sclerosing cholangitis (PSC), but the underlying risk factors in the absence of PSC are unclear. We examined associations of different risk factors with intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) in the United States., Methods: We conducted a case-control study of 121 patients with ECC and 308 patients with ICC treated at MD Anderson Cancer Center between May 2014 and March 2020, compared with 1,061 healthy controls. Multivariable logistic regression analysis was applied to estimate the adjusted OR (AOR) and 95% confidence interval (CI) for each risk factor., Results: Being Asian, diabetes mellitus, family history of cancer, and gallbladder stones were associated with higher odds of developing ICC and ECC. Each 1-unit increase in body mass index in early adulthood (ages 20-40 years) was associated with a decrease in age at diagnosis of CCA (6.7 months, P < 0.001; 6.1 months for ICC, P = 0.001; 8.2 months for ECC, P = 0.007). A family history of cancer was significantly associated with the risk of ICC and ECC development; the AORs (95% CI) were 1.11 (1.06-1.48) and 1.32 (1.01-2.00) for ICC and ECC, respectively., Conclusions: In this study, early adulthood onset of obesity was significantly associated with CCA and may predict early diagnosis at younger age than normal weight individuals., Impact: The study highlights the association between obesity and CCA, independent of PSC. There is a need to consider the mechanistic pathways of obesity in the absence of fatty liver and cirrhosis., (©2023 American Association for Cancer Research.)

Pathologists face many challenges when diagnosing sclerosing biliary lesions on liver biopsy. First, histologic findings tend to be nonspecific with similar to identical features seen in numerous conditions, from benign to outright malignant. In addition, the patchy nature of many of these entities amplifies the inherent limitations of biopsy sampling. The end result often forces pathologists to issue descriptive sign outs that require careful clinical correlation; however, certain clinical, radiologic, and histologic features may be of diagnostic assistance. In this article, we review key elements of four sclerosing biliary processes whose proper identification has significant prognostic and therapeutic implications., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are 2 major liver autoimmune diseases. PBC is common in women and primarily affects intrahepatic small bile duct epithelial cells, known as cholangiocytes. In contrast, PSC is dominant in men and primarily affects medium and big intrahepatic and extrahepatic bile duct epithelial cells. Cholangiocarcinoma (CCA) is a malignancy arising from cholangiocytes, and its incidence is increasing worldwide in both men and women. Numerous retrospective and clinical studies have suggested that PBC patients rarely develop CCA compared to PSC patients. CCA is accountable for the higher deaths in PSC patients due to ineffective therapies and our inability to diagnose the disease at an early stage. Therefore, it is paramount to understand the differences in immune surveillance mechanisms that render PBC patients more resistant while PSC patients are susceptible to CCA development. Here, we review several potential mechanisms contributing to differences in the susceptibility to CCA in PBC versus PSC patients., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of unknown etiology that affects the intra- and extrahepatic bile ducts. The present study examined the utility of a bile proteome analysis using a high-sensitivity mass spectrometer to comprehensively screen for novel PSC biomarkers., Methods: Bile endoscopically collected from patients with PSC, common bile duct stones, and biliary tract cancer were subjected to high-precision liquid chromatography/mass spectrometry. Some of the proteins specifically up-regulated in the bile of the PSC group were re-examined by an enzyme-linked immunosorbent assay., Results: A total of 8094 proteins were successfully identified and 332 were specifically up-regulated in the PSC group. The bioinformatics analysis showed that proteins involved in the proliferation and activation of diverse inflammatory cells were up-regulated in the PSC group. A receiver operating characteristic curve analysis showed good area under the curve values for interleukin-8 and annexin A1 (ANXA1) (0.836 and 0.914, respectively). Immunostaining for ANXA1 revealed its strong expression in inflammatory cells infiltrating the peripheral biliary tract in PSC livers., Conclusion: A bile proteome analysis is a useful tool for elucidating the pathogenesis of PSC and developing new diagnostic approaches. Therefore, ANXA1 has potential as a bile biomarker for PSC., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background & Aims: We reported that cholangiocyte senescence, regulated by the transcription factor ETS proto-oncogene 1 (ETS1), is a pathogenic feature of primary sclerosing cholangitis (PSC). Furthermore, histone 3 lysine 27 is acetylated at senescence-associated loci. The epigenetic readers, bromodomain and extra-terminal domain (BET) proteins, bind acetylated histones, recruit transcription factors, and drive gene expression. Thus, we tested the hypothesis that BET proteins interact with ETS1 to drive gene expression and cholangiocyte senescence., Methods: We performed immunofluorescence for BET proteins (BRD2 and 4) in liver tissue from liver tissue from PSC patients and a mouse PSC model. Using normal human cholangiocytes (NHCs), NHCs experimentally induced to senescence (NHCsen), and PSC patient-derived cholangiocytes (PSCDCs), we assessed senescence, fibroinflammatory secretome, and apoptosis after BET inhibition or RNA interference depletion. We assessed BET interaction with ETS1 in NHCsen and tissues from PSC patient, and the effects of BET inhibitors on liver fibrosis, senescence, and inflammatory gene expression in mouse models., Results: Tissue from patients with PSC and a mouse PSC model exhibited increased cholangiocyte BRD2 and 4 protein (∼5×) compared with controls without disease. NHCsen exhibited increased BRD2 and 4 (∼2×), whereas PSCDCs exhibited increased BRD2 protein (∼2×) relative to NHC. BET inhibition in NHCsen and PSCDCs reduced senescence markers and inhibited the fibroinflammatory secretome. ETS1 interacted with BRD2 in NHCsen, and BRD2 depletion diminished NHCsen p21 expression. BET inhibitors reduced senescence, fibroinflammatory gene expression, and fibrosis in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine-fed and Mdr2 -/- mouse models., Conclusion: Our data suggest that BRD2 is an essential mediator of the senescent cholangiocyte phenotype and is a potential therapeutic target for patients with PSC., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aims: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD, termed PSC-IBD) have a higher risk of harbouring nonconventional and/or invisible dysplasias, especially in the right/proximal colon, than those with IBD alone. We postulated that DNA content abnormality may be frequently detected in the right/proximal colon in PSC-IBD patients, even in the absence of dysplasia, and that this may predispose to progression to nonconventional and/or invisible dysplasias that are often associated with increased rates of aneuploidy and advanced neoplasia., Methods and Results: DNA flow cytometry was performed on 96 morphologically benign colon biopsies taken throughout the colon from 25 PSC-IBD patients during the surveillance colonoscopy that preceded the next procedure that detected dysplasia. Thirty (31%) of the 96 benign colon biopsies in this dysplasia group demonstrated abnormal DNA content, with a propensity for the right/proximal colon (70%) (P < 0.001). In contrast, only one (1%) of 87 benign colon biopsies from 20 IBD patients without neoplasia (control group) demonstrated DNA content abnormality, and it was from the left colon. For analysis per patient, 48% (12 of 25) of the patients in the dysplasia group had abnormal DNA content compared with 5% (1 of 20) of the control group (P = 0.002). Of the 12 PSC-IBD patients with DNA content abnormality, invisible dysplasia was detected in 10 (83%) patients on follow-up, nine (75%) of whom had nonconventional dysplasia., Conclusion: PSC-IBD patients have an increased risk of developing abnormal DNA content in the right/proximal colon, predating the detection of dysplasia., (© 2023 John Wiley & Sons Ltd.)

Background and Aims: The progression of chronic liver diseases towards liver cirrhosis is accompanied by drastic tissue changes. This study combines elaborate transcriptomic and histological methods aiming at spatially resolving the hepatic immune microenvironment in NAFLD (including NASH, primary sclerosing cholangitis, primary biliary cholangitis, and severe alcoholic hepatitis)., Approach and Results: Human liver samples were subjected to RNA-sequencing (n=225) and imaging cytometry (n=99) across 3 independent patient cohorts. Liver samples from alcoholic hepatitis and primary biliary cholangitis patients were used for comparison. Myeloid populations were further characterized in corresponding mouse models. Imaging, clinical, and phenotypical data were combined for multidimensional analysis. NAFLD/NASH and primary sclerosing cholangitis disease stages were associated with loss of parenchymal areas, increased ductular cell accumulation, and infiltration of immune cells. NASH patients predominantly exhibited myeloid cell accumulation, whereas primary sclerosing cholangitis patients additionally had pronounced lymphoid cell responses. Correlating to disease stage, both etiologies displayed intense IBA1 + CD16 low CD163 low macrophage aggregation in nonparenchymal areas, with a distinct spatial proximity to ductular cells. Mouse models revealed that disease-associated IBA1 + hepatic macrophages originated from bone marrow-derived monocytes. Using an unbiased, machine learning-based algorithm, IBA1 in combination with hepatocyte and ductular cell immunostaining-predicted advanced cirrhosis in human NASH, primary sclerosing cholangitis, and alcoholic hepatitis., Conclusions: Loss of hepatocytes and increased ductular reaction are tightly associated with monocyte-derived macrophage accumulation and represent the most prominent common immunological feature revealing the progression of NAFLD, primary sclerosing cholangitis, primary biliary cholangitis, and alcoholic hepatitis, suggesting IBA1 + CD163 low macrophages are key pathogenic drivers of human liver disease progression across diverse etiologies., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Backgrounds: Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases., Methods: We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2 -/- mice injured by DDC, and P4HA2 -/- /MDR2 -/- double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation., Results: The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2 -/- mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2 -/- /MDR2 -/- mice compared with MDR2 -/- mice. Cholangiocytes isolated from P4HA2 -/- /MDR2 -/- mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP., Conclusions: P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC., (Copyright © 2023 American Association for the Study of Liver Diseases.)

The close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) provides a good opportunity to comprehend the gut-liver axis. The gut and the liver have reciprocal interactions, including how gut inflammation influences the liver through immune cells and the microbiota and how the microbiota in the gut modifies bile acids, which are produced and secreted from the liver. PSC-IBD shows distinct clinical findings from classical IBD. In addition, a distinct genetic predisposition and unique microbiota composition suggest that PSC-IBD is an independent disease entity. Understanding the pathogenesis of PSC-IBD helps to develop novel and effective therapeutic agents. Given the high risk of malignancies associated with PSC-IBD, it is critical to identify patients at high risk and implement appropriate surveillance and monitoring strategies. In this review, we provide an overview of PSC-IBD, which exemplifies the gut-liver axis., (© 2023. The Author(s).)

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tree and a risk factor for development of cholangiocarcinoma (CCA). The pathogenesis of PSC-related CCA is largely unclear, although it is assumed that chronic inflammatory environment plays a pivotal role. We aimed to investigate the effect of inflammation-related cytokines in PSC on the proliferation rate of cancer cells. For this, the proliferation index in PSC-CCA and sporadic CCA was determined by Ki-67 immunohistochemistry. The percentage of Ki-67 positivity in cancer cells was significantly higher in PSC-CCA than in sporadic CCA (41.3% ± 5.7% vs 25.8% ± 4.1%; P = .038). To assess which cytokines in the inflammatory environment have the potential to stimulate cancer cell proliferation, patient-derived CCA organoids (CCAOs) were exposed to five cytokines related to PSC (Interleukin (IL)-1β, IL-6, IL-17A, interferon gamma and tumor necrosis factor alpha). Only IL-17A showed a significant stimulatory effect on cell proliferation in CCAOs, increasing organoid size by 45.9% ± 16.4% (P < .01) and proliferation rate by 38% ± 16% (P < .05). IL-17A immunohistochemistry demonstrated that PSC-CCA might express more IL-17A than sporadic CCA. Moreover, correlation analysis in sporadic CCA and PSC-CCA found a significant correlation between IL-17A expression and proliferation. In conclusion, tumor cell proliferation is increased in PSC-CCA cells compared with sporadic CCA cells. IL-17A increases CCA cell proliferation in vitro and may contribute to the high proliferation rate in PSC-CCA in situ. Therefore, IL-17A represents a new potential therapeutic target in (PSC-)CCA, to be tested in future trials., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Primary sclerosing cholangitis (PSC) is an immune-mediated disease of the bile ducts that co-occurs with inflammatory bowel disease (IBD) in almost 90% of cases. Colorectal cancer is a major complication of patients with PSC and IBD, and these patients are at a much greater risk compared to patients with IBD without concomitant PSC. Combining flow cytometry, bulk and single-cell transcriptomics, and T and B cell receptor repertoire analysis of right colon tissue from 65 patients with PSC, 108 patients with IBD and 48 healthy individuals we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time to dysplasia in patients with PSC. This inflammatory signature is characterized by antigen-driven interleukin-17A (IL-17A) + forkhead box P3 (FOXP3) + CD4 T cells that express a pathogenic IL-17 signature, as well as an expansion of IgG-secreting plasma cells. These results suggest that the mechanisms that drive the emergence of dysplasia in PSC and IBD are distinct and provide molecular insights that could guide prevention of colorectal cancer in individuals with PSC., (© 2023. The Author(s).)

Purpose: To assess longitudinal changes in quantitative MRI metrics in pediatric and young adult patients with autoimmune liver disease (AILD)., Methods: This prospective, IRB-approved study included 20 children and young adults (median age = 15 years) with primary sclerosing cholangitis (PSC)/autoimmune sclerosing cholangitis (ASC) and 19 (median age = 17 years) with autoimmune hepatitis (AIH). At a field strength of 1.5-T, T2*-corrected T1 mapping (cT1), 3D fast spin-echo MRCP, and 2D gradient recalled echo MR elastography (MRE) were performed at baseline, one year, and two years. cT1 and quantitative MRCP were processed using LiverMultiScan and MRCP + , respectively (Perspectum Ltd, Oxford, UK). Linear mixed models were used to assess longitudinal changes in quantitative MRI metrics. Spearman rank-order correlation was used to assess relationships between changes in quantitative MRI metrics., Results: Changes in quantitative MRI metrics greater than established repeatability coefficients were measured in six (cT1) and five (MRE) patients with PSC/ASC as well as in six patients (cT1 and MRE) with AIH, although linear mixed models identified no significant changes for the subgroups as a whole. For PSC/ASC, there were positive correlations between change in liver stiffness and changes in bile duct strictures (ρ = 0.68; p = 0.005) and bile duct dilations (ρ = 0.70; p = 0.004) between baseline and Year 2., Conclusion: On average, there were no significant changes in quantitative MRI metrics over a two-year period in children and young adults with AILD. However, worsening cholangiopathy was associated with increasing liver stiffness by MRE in patients with PSC/ASC., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Liver cirrhosis due to secondary sclerosing cholangitis caused by Langerhans cell histiocytosis (LCH) has a poor prognosis, and liver transplantation is the definitive treatment. However, the optimal timing has not been established. We report a 2-year-old girl with LCH-related liver cirrhosis who successfully underwent liver transplantation before progressing to severe liver dysfunction. Physical examination revealed a tumor on her palate. Biopsy was performed, and a diagnosis of LCH was established, together with hepatomegaly, splenomegaly, and rashes. Percutaneous liver biopsy before treatment revealed extreme fibrosis and absence of LCH cells. After beginning chemotherapy, she experienced several delays in treatment and dose reductions because of unacceptable bone marrow suppression, worsening liver dysfunction, and cholangitis. However, tumor shrinkage was observed in both magnetic resonance imaging and BRAF V600E mutant allele titers in her plasma. Given the good treatment response, liver transplantation was conducted. The postoperative course was uneventful, and chemotherapy was resumed 34 days after liver transplantation. Subsequent maintenance treatment was completed with no severe adverse effects. To prevent perioperative complications due to exacerbation of liver dysfunction and possible discontinuation of chemotherapy, liver transplantation should be considered before development of end-stage liver failure, provided that the original disease is well controlled., (© 2022. Japanese Society of Hematology.)

Since its emergence in 2019, it has become apparent that coronavirus 2019 (COVID-19) infection can result in multi systemic involvement. In addition to pulmonary symptoms, hepatobiliary involvement has been widely reported. Extent of hepatic involvement ranges from minor elevation in liver function tests (LFTs) to significant hepatocellular or cholestatic injury. In majority of cases, resolution of hepatic injury or improvement in LFTs is noted as patients recover from COVID-19 infection. However, severe biliary tract injury progressing to liver failure has been reported in patients requiring prolonged intensive care unit stay or mechanical ventilation. Due to the timing of its presentation, this form of progressive cholestatic injury has been referred to as COVID-19 cholangiopathy or post-COVID-19 cholangiopathy, and can result in devastating consequences for patients. COVID-19 cholangiopathy is recognized by dramatic elevation in serum alkaline phosphatase and bilirubin and radiologic evidence of bile duct injury. Cholangiopathy in COVID-19 occurs weeks to months after the initial infection and during the recovery phase. Imaging findings and pathology often resemble bile duct injury associated with primary or secondary sclerosing cholangitis. Etiology of COVID-19 cholangiopathy is unclear. Several mechanisms have been proposed, including direct cholangiocyte injury, vascular compromise, and cytokine release syndromes. This review summarizes existing data on COVID-19 cholangiopathy, including reported cases in the literature, proposed pathophysiology, diagnostic testing, and long-term implications., Competing Interests: Conflict-of-interest statement: The authors declare that there is no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The presence of diffuse biliary stricturing in Primary Sclerosing Cholangitis (PSC) makes the diagnosis of early Cholangiocarcinoma (CCA) in this context difficult. A finding of incidental CCA on liver explant is associated with poor oncological outcomes, despite this; there remains no international consensus on how best to outrule CCA in this group ahead of transplantation. The objectives of this study were to report the Irish incidence of incidental CCA in individuals with PSC undergoing liver transplantation, and to critically evaluate the accuracy of diagnostic modalities in outruling CCA in our wait-listed PSC cohort., Methods: We conducted a retrospective analysis of our prospectively maintained database, which included all PSC patients wait-listed for liver transplant in Ireland., Results: 4.41% of patients (n = 3) were found to have an incidental finding of CCA on liver explant. Despite only being performed in 35.06% of wait-listed PSC patients (n = 27), Endoscopic Retrograde Cholangiopancreatogram (ERCP) with brush cytology was found to be the most effective tool in correctly outruling CCA in this context; associated with a specificity of 96.15%., Conclusion: Our findings support a future role for routine surveillance of PSC patients awaiting liver transplantation; however further research is required in order to identify which investigative modalities are of optimal diagnostic utility in this specific context., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2022 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Primary sclerosing cholangitis (PSC) is an idiopathic chronic immune-mediated cholestatic liver disease characterized by fibro-inflammatory bile duct strictures, progressive hepatobiliary fibrosis, and gut-liver axis disruption. The pathophysiology of PSC remains insufficiently characterized, which hampers the development of effective therapies. Hepatic macrophages (MFs) such as Kupffer cells (KCs) are implicated in PSC pathogenesis, but their exact role is unclear. Using the latest markers to discriminate resident KCs (ResKCs) from their monocyte-derived counterparts (MoKCs), and two models of intrahepatic and extrahepatic cholestasis, respectively, this study showed that CLEC4F + TIM4 + ResKCs were depleted after chronic cholestatic liver injury. The infiltrating CLEC4F + TIM4 - MoKCs were already enriched during the acute phase of PSC. Transcriptional profiling of hepatic MF subsets during early cholestatic injury indicated that ResKCs were indeed activated and that MoKCs expressed higher levels of pro-inflammatory and proliferative markers compared with those of ResKCs. As indicated in experiments with Clec4f DTR transgenic mice, conditional depletion of KCs, before and during early cholestasis induction, had no effect on the composition of the hepatic myeloid cell pool following injury progression and did not affect disease outcomes. Taken together, these results provide new insights into the heterogeneity of the MF pool during experimental PSC and evidence that depletion of resident and activated KCs during sclerosing cholangitis does not affect disease outcome in mice., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Primary sclerosing cholangitis (PSC) is a chronic liver disorder commonly affecting young patients and associated with uncertain prognosis and elevated risk of end-stage liver disease and hepatobiliary cancer. Rate of progression in PSC is heterogeneous and accurately predicting the disease course is of paramount importance to clinical practice and interventional trial design. So far, efforts have brought to the development of models looking at short-to-middle-term outcome using composite models including clinical, laboratory, radiological and histological parameters with limited performance. In the era of whole genome sequencing and digital innovation, the time is ripe for the development of stratified medicine in PSC. Efforts should be directed toward developing well-phenotyped cohorts of patients with longitudinal follow-up across sustained periods of time, application of novel image-processing technology, and biomarker discovery using multiomics platforms.