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Background: Patients with autoimmune liver diseases require individualized long-term immunosuppressive therapy, whose discontinuation is possible after complete histological remission and that requires repeated liver biopsy. In view of this, the search for non-invasive markers is essential for patients with autoimmune liver disease., Purpose: The purpose of this research is to assess the possibility of predicting the recurrence of autoimmune liver disease in children., Method: The biological material used in the study was blood serum from 80 children diagnosed with autoimmune hepatitis and autoimmune sclerosing cholangitis. Patients were divided into four groups according to disease activity and therapeutic approach., Results: The percentage of monocyte subpopulations was determined by flow cytometry, and disease activity, inflammation, and fibrosis markers were analyzed to study the relationship and diagnostic value of the parameters studied in detail. The results of the study indicate a significant relationship between disease activity and changes in the distribution of the percentage of monocyte subpopulations in the blood. The percentage of intermediate CD14++/CD16+ monocytes was found to correlate with disease activity, and non-classical CD14lowCD16+ monocytes were found to be of high diagnostic value in the diagnosis of disease relapse., Conclusions: These findings not only expand the understanding of the pathogenesis of autoimmune liver disease but also point to the prospects of using monocyte subpopulations as potential biomarkers for predicting relapse, contributing to the development of more effective clinical management strategies., Competing Interests: Declaration of Competing Interest The authors confirm, that they have no conflicts of interest to disclose, (Copyright © 2024 Elsevier GmbH. 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.)

The microbiome plays a crucial role in integrating environmental influences into host physiology, potentially linking it to autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. All autoimmune liver diseases are associated with reduced diversity of the gut microbiome and altered abundance of certain bacteria. However, the relationship between the microbiome and liver diseases is bidirectional and varies over the course of the disease. This makes it challenging to dissect whether such changes in the microbiome are initiating or driving factors in autoimmune liver diseases, secondary consequences of disease and/or pharmacological intervention, or alterations that modify the clinical course that patients experience. Potential mechanisms include the presence of pathobionts, disease-modifying microbial metabolites, and more nonspecific reduced gut barrier function, and it is highly likely that the effect of these change during the progression of the disease. Recurrent disease after liver transplantation is a major clinical challenge and a common denominator in these conditions, which could also represent a window to disease mechanisms of the gut-liver axis. Herein, we propose future research priorities, which should involve clinical trials, extensive molecular phenotyping at high resolution, and experimental studies in model systems. Overall, autoimmune liver diseases are characterized by an altered microbiome, and interventions targeting these changes hold promise for improving clinical care based on the emerging field of microbiota medicine., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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.)

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.)

Background: Patients with isolated IgG4-related sclerosing cholangitis (IgG4-SC) often undergo unnecessary resection. The aim of this study was to validate the revised Japanese diagnostic criteria for isolated IgG-4-SC and to improve awareness about this condition in the population., Methods: This was a Japanese retrospective multicenter study. We focused on the data and diagnostic yield obtained using the Japanese diagnostic criteria published initially in 2012 and revised later in 2020 for the diagnosis of isolated IgG4-SC., Results: Patients with isolated IgG4-SC could be classified into two groups based on the primary location of the lesion: the hilar type (n = 40) and the extrahepatic type (n = 13). In total, 10 patients with the hilar type had undergone unnecessary resection. The revised 2020 criteria are useful for the diagnosis of extrahepatic lesions, which are not included in the 2012 criteria. The need for a steroid trial was reduced from 37.7% when the diagnosis was based on the 2012 criteria to 7.6% when the diagnosis was based on the revised 2020 criteria. The diagnostic specificity also improved from 58.5% for the 2012 criteria to 88.7% for the revised 2020 criteria., Conclusion: Our validation of the 2020 criteria for the diagnosis of IgG4-SC could contribute to avoiding unnecessary resection in patients with isolated IgG4-SC, which can be classified into the hilar and extrahepatic types. The 2020 criteria can enhance the diagnosis rate of isolated IgG4-SC and uncover this tough-to-diagnose entity based on inclusion of the imaging findings and decrease the dependence on a steroid trial., (© 2024 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Autoimmune and immune-mediated biliary diseases represent a small proportion of biliary disorders, but owing to their progressive nature, lead to end-stage liver disease, necessitating liver transplantation for definitive management., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. 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.)

Background: Primary sclerosing cholangitis (PSC) is a chronic liver disease leading to inflammation with scaring and strictures of bile ducts, which can lead to liver cirrhosis. A subtype of PSC characterized by high serum IgG4 (sIgG4) levels has been reported to be associated with poor outcomes, but the exact role and the longitudinal development of sIgG4 levels in PSC progression remains to be clarified. The aim of this study was to investigate if subsequent analysis of sIgG4 levels allows the identification of the PSC phenotype with high sIgG4., Methods: sIgG4 values were repeatedly analysed in a well-characterized European PSC cohort of 110 individuals. Biochemical parameters, clinical endpoints, death and liver transplantation were compared between PSC subgroups., Results: 12.7% (n = 14) of PSC patients showed increased sIgG4 levels (PSC-IgG4). The values normalized in 57.1% (n = 8; PSC-IgG4 norm ) during follow-up measurements, whereas the values remained permanently elevated in 42.9% (n = 6; PSC-IgG4 const ). Serum values of AP and γGT were significantly higher in PSC-IgG4 const compared to PSC-IgG4 norm at final blood sampling. Furthermore, mean age at PSC diagnosis was markedly lower in PSC-IgG4 const compared to PSC-IgG4 norm ., Conclusions: This is the first study analyzing longitudinal development of sIgG4 in PSC. Our data indicate that only sequential determination of sIgG4 levels allow to accurately distinguish between the PSC phenotype with high sIgG4 and PSC with low sIgG4., (© 2024. The Author(s).)

Background: The epigenome, the set of modifications to DNA and associated molecules that control gene expression, cellular identity, and function, plays a major role in mediating cellular responses to outside factors. Thus, evaluation of the epigenetic state can provide insights into cellular adaptions occurring over the course of disease., Methods: We performed epigenome-wide association studies of primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) using the Illumina MethylationEPIC Bead Chip., Results: We found evidence of increased epigenetic age acceleration and differences in predicted immune cell composition in patients with PSC and PBC. Epigenetic profiles demonstrated differences in predicted protein levels including increased levels of tumor necrosis factor receptor superfamily member 1B in patients with cirrhotic compared to noncirrhotic PSC and PBC. Epigenome-wide association studies of PSC discovered strongly associated 5'-C-phosphate-G-3' sites in genes including vacuole membrane protein 1 and SOCS3, and epigenome-wide association studies of PBC found strong 5'-C-phosphate-G-3' associations in genes including NOD-like receptor family CARD domain containing 5, human leukocyte antigen-E, and PSMB8. Analyses identified disease-associated canonical pathways and upstream regulators involved with immune signaling and activation of macrophages and T-cells. A comparison of PSC and PBC data found relatively little overlap at the 5'-C-phosphate-G-3' and gene levels with slightly more overlap at the level of pathways and upstream regulators., Conclusions: This study provides insights into methylation profiles of patients that support current concepts of disease mechanisms and provide novel data to inspire future research. Studies to corroborate our findings and expand into other -omics layers will be invaluable to further our understanding of these rare diseases with the goal to improve and individualize prognosis and treatment., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

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.)

Objective: There is a strong clinical association between IBD and primary sclerosing cholangitis (PSC), a chronic disease of the liver characterised by biliary inflammation that leads to strictures and fibrosis. Approximately 60%-80% of people with PSC will also develop IBD (PSC-IBD). One hypothesis explaining this association would be that PSC drives IBD. Therefore, our aim was to test this hypothesis and to decipher the underlying mechanism., Design: Colitis severity was analysed in experimental mouse models of colitis and sclerosing cholangitis, and people with IBD and PSC-IBD. Foxp3 + Treg-cell infiltration was assessed by qPCR and flow cytometry. Microbiota profiling was carried out from faecal samples of people with IBD, PSC-IBD and mouse models recapitulating these diseases. Faecal microbiota samples collected from people with IBD and PSC-IBD were transplanted into germ-free mice followed by colitis induction., Results: We show that sclerosing cholangitis attenuated IBD in mouse models. Mechanistically, sclerosing cholangitis causes an altered intestinal microbiota composition, which promotes Foxp3 + Treg-cell expansion, and thereby protects against IBD. Accordingly, sclerosing cholangitis promotes IBD in the absence of Foxp3 + Treg cells. Furthermore, people with PSC-IBD have an increased Foxp3 + expression in the colon and an overall milder IBD severity. Finally, by transplanting faecal microbiota into gnotobiotic mice, we showed that the intestinal microbiota of people with PSC protects against colitis., Conclusion: This study shows that PSC attenuates IBD and provides a comprehensive insight into the mechanisms involved in this effect., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background/aims:  Inborn errors of immunity (IEI) may associate with autoimmune diseases, including autoimmune liver diseases (AILD). However, both the IEI frequency and secondary effects of immunosuppressives are unknown in patients with AILD due to the lack of data. We aimed to evaluate the ratio of IEI in AILD., Materials and Methods:  A total of 82 patients with AILD (39 autoimmune hepatitis, 32 primary biliary cholangitis, 7 variant syndromes (VS), and 4 primary sclerosing cholangitis patients) were included in this single-center, cross-sectional, and descriptive study. The patients were evaluated and classified according to diagnostic criteria for IEI., Results:  Out of 82 patients with AILD, female/male ratio was 3.6. Median age of diagnosis of AILD was 45 years. We diagnosed 15 (18%) patients with immunodeficiency (ID). Inborn errors of immunity ratio was highest in VS patient group (29%). Out of 15 patients with ID, 4 (4.8%) patients had common variable immunodeficiency, 4 (4.8%) had partial immunoglobulin A deficiency, 4 (4.8%) had selective immunoglobulin M deficiency, and 3 (3.6%) had combined immunodeficiency., Conclusion:  We detect ID in about one-fifth of the patients with AILD. The present study showed a significant risk of IEI that is blurred by the shadow of immune suppressive treatments. We suggest that the AILD patients with ID will benefit from the individualized and targeted therapeutic options used in IEI. Further research with larger patient groups and long-term follow-up are desperately needed to elucidate the diagnostic, therapeutic, and prognostic impacts of IEI-related individualized therapy on AILD patients.

Background: Observational studies have indicated that immune dysregulation in primary sclerosing cholangitis (PSC) primarily involves intestinal-derived immune cells. However, the causal relationship between peripheral blood immune cells and PSC remains insufficiently understood., Methods: A bidirectional two-sample Mendelian randomization (MR) analysis was implemented to determine the causal effect between PBC and 731 immune cells. All datasets were extracted from a publicly available genetic database. The standard inverse variance weighted (IVW) method was selected as the main method for the causality analysis. Cochran's Q statistics and MR-Egger intercept were performed to evaluate heterogeneity and pleiotropy., Results: In forward MR analysis, the expression ratios of CD11c on CD62L+ myeloid DC (OR = 1.136, 95% CI = 1.032-1.250, p = 0.009) and CD62L-myeloid DC AC (OR = 1.267, 95% CI = 1.086-1.477, p = 0.003) were correlated with a higher risk of PSC. Each one standard deviation increase of CD28 on resting regulatory T cells (Treg) (OR = 0.724, 95% CI = 0.630-0.833, p < 0.001) and CD3 on secreting Treg (OR = 0.893, 95% CI = 0.823-0.969, p = 0.007) negatively associated with the risk of PSC. In reverse MR analysis, PSC was identified with a genetic causal effect on EM CD8+ T cell AC, CD8+ T cell AC, CD28- CD127- CD25++ CD8+ T cell AC, CD28- CD25++ CD8+ T cell AC, CD28- CD8+ T cell/CD8+ T cell, CD28- CD8+ T cell AC, and CD45 RA- CD28- CD8+ T cell AC., Conclusion: Our study indicated the evidence of causal effects between PSC and immune cells, which may provide a potential foundation for future diagnosis and treatment of PSC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Xie, Cai, Liu, Lv, Yang, He, Yin, Lan and Wu.)

Background & Aims: Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD., Methods: Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations., Results: Most EIMs occurred more commonly in female subjects (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated., Conclusions: We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Primary sclerosing cholangitis (PSC), a chronic cholestatic liver condition, is frequently associated with inflammatory bowel disease. Specific immune cells have been implicated in PSC pathogenesis with the emergence of the "microbiota" and "gut lymphocyte homing" hypotheses, albeit their identities remain controversial. The first genome-wide association analysis leveraged nonoverlapping data from 3757 Europeans to evaluate 731 immunophenotypes. A genome-wide association analysis comprising 2871 cases and 12,019 controls yielded summary statistics for PSC. An inverse-variance weighted (IVW) analysis was performed to identify immunophenotypes causally related to PSC, and the results were validated using weighted mode, MR-Egger, and weighted median methods. Comprehensive sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. IVW analysis revealed 26 immune traits exhibiting causal associations with PSC. CD3 on HLA-DR+ CD4+ (IVW odds ratio [OR]: 0.904; 95% confidence interval [CI]: 0.828-0.986, P = .023) and CD3 on secreting Treg (IVW OR: 0.893; 95% CI: 0.823-0.969, P = .007) were negatively associated with PSC susceptibility and demonstrated high consistency across the 3 validation methods. Moreover, 7 other immune traits, including CD39+ resting Treg absolute cell (IVW OR = 1.083, 95% CI: 1.013-1.157, P = .019), CD39+ secreting Treg absolute cell (IVW OR = 1.063, 95% CI: 1.012-1.118, P = .015), CD3 on naive CD8br (IVW OR = 0.907, 95% CI: 0.835-0.986, P = .022), CD3 on CD39+ activated Treg (IVW OR = 0.927, 95% CI: 0.864-0.994, P = .034), CD28 on resting Treg (IVW OR = 0.724, 95% CI: 0.630-0.833, P = 5.95E-06), and CD39 on CD39+ CD4+ (IVW OR = 1.055, 95% CI: 1.001-1.112, P = .044) exhibited consistent results in the Weighted Median and Weighted Mode validation methods. Moreover, no significant heterogeneity or horizontal pleiotropy was observed across the single nucleotide polymorphisms. The leave-one-out results revealed that sequentially eliminating each single nucleotide polymorphism had no significant influence on model effect estimates or qualitative inference. This study evaluated potential causal links between 731 immune traits and PSC susceptibility. Twenty-six immune traits were identified using the IVW method. Verification across multiple methods revealed 9 immune traits with a plausible causal connection to PSC. These findings may uncover mechanistic pathways and novel therapeutic approaches., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The pathogenesis of primary sclerosing cholangitis (PSC) is unclear, although studies implicate IL-17A as an inflammatory mediator in this disease. However, a direct assessment of IL-17 signaling in PSC cholangiocytes is lacking. In this study, we aimed to investigate and characterize the response of PSC extrahepatic cholangiocyte organoids (ECO) to IL-17A stimulation., Methods: Cholangiocytes obtained from patients with PSC and without PSC by endoscopic retrograde cholangiography were cultured as ECO. The ECO were treated with vehicle or IL-17A and assessed by transcriptomics, secretome analysis, and genome sequencing., Results: Unsupervised clustering of all integrated single-cell RNA sequencing data identified 8 cholangiocyte clusters that did not differ between PSC and non-PSC ECO. However, PSC ECO cells demonstrated a robust response to IL-17 treatment, as noted by an increased number of differentially expressed genes by transcriptomics and more abundant chemokine and cytokine expression and secretion. After rigorous filtering, genome sequencing identified candidate somatic variants shared among PSC ECO from unrelated individuals. However, no candidate rare variants in genes regulating the IL-17 pathway were identified, but rare variants regulating the MAPK signaling pathway were present in all PSC ECO., Conclusions: PSC and non-PSC patient-derived ECO respond differently to IL-17 stimulation, implicating this pathway in the pathogenesis of PSC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Primary sclerosing cholangitis (PSC) is an (auto)immune-mediated cholestatic liver disease with a yet unclear etiology. Increasing evidence points to an involvement of neutrophils in chronic liver inflammation and cirrhosis but also liver repair. Here, we investigate the role of the neutrophil extracellular trap (NET) component myeloperoxidase (MPO) and the therapeutic potential of DNase I and of neutrophil elastase (NE) inhibitor GW311616A on disease outcome in the multidrug resistance 2 knockout (Mdr2 -/- ) mouse, a PSC animal model. Initially, we observed the recruitment of MPO expressing cells and the formation of NETs in liver biopsies of PSC patients and in Mdr2 -/- livers. Furthermore, sera of Mdr2 -/- mice contained perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA)-like reactivity similar to PSC patient sera. Also, hepatic NE activity was significantly higher in Mdr2 -/- mice than in wild type littermates. Flow cytometry analyses revealed that during disease development a highly active neutrophil subpopulation established specifically in the liver of Mdr2 -/- mice. However, absence of their MPO activity, as in MPO-deficient Mdr2 -/- mice, showed no effect on hepatobiliary disease severity. In contrast, clearance of extracellular DNA by DNase I reduced the frequency of liver-resident neutrophils, plasmacytoid dendritic cells (pDCs) and CD103 + conventional DCs and decreased cholangiocyte injury. Combination of DNase I with a pDC-depleting antibody was additionally hepatocyte-protective. Most importantly, GW311616A, an orally bioavailable inhibitor of human NE, attenuated hepatobiliary injury in a TNFα-dependent manner and damped hyperproliferation of biliary epithelial cells. Further, hepatic immigration and activity of CD11b + DCs as well as the secretion of IFNγ by hepatic CD4 and CD8 T cells were reduced. Our findings delineate neutrophils as important participants in the immune cell crosstalk that drives cholestatic liver disease and identify NET components as potential therapeutic targets., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.)

Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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.)

Rationale: Immunoglobulin G4-related disease (IgG4-RD) can involve various organs throughout the body, primarily manifesting as endocrine dysfunction, visual impairment, jaundice, and limited sexual function. IgG4-related autoimmune pancreatitis is triggered by autoimmune reactions and characterized by structural changes in the pancreas and pancreatic ducts. The disease mainly affects middle-aged and elderly males, typically presenting as progressive painless jaundice and misdiagnosed as cholangiocarcinoma or pancreatic cancer., Patient Concerns: This study reports a 54-year-old male who consulted with different institutions multiple times due to diabetes, pancreatitis, elevated liver enzymes, and jaundice., Diagnoses: Magnetic resonance imaging revealed swollen head of the pancreas and atrophic tail. Liver and pancreatic tissue pathology showed IgG4 plasma cell infiltration, while liver biopsy indicated interface hepatitis, liver fibrosis, and pseudolobule formation, with no evidence of bile duct damage., Interventions: Following hormone therapy, the patient's serum IgG4 levels and liver enzyme levels returned to normal., Outcomes: The disease relapsed 2 years after maintaining hormone therapy, and the patient underwent additional hormone-induced remission therapy combined with azathioprine., Lessons: The purpose of this research report is to enhance the awareness and understanding of IgG4-RD, emphasizing the necessity for personalized treatment strategies that take into account its recurrence, associations, and imaging features. This report provides valuable insights and guidance for clinicians in managing and diagnosing patients with IgG4-RD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

There was evidence that perinuclear antineutrophil cytoplasmic antibodies (pANCA) in autoimmune liver diseases react with human beta-tubulin-5 (TBB5). Here, we reevaluate the specificity and clinical relevance of anti-TBB5 antibodies. Patients with untreated autoimmune hepatitis (AIH; n = 53), AIH under immunosuppressive therapy (AIH-IS; n = 125), primary sclerosing cholangitis (PSC; n = 40), primary biliary cholangitis (PBC; n = 250), nonautoimmune liver diseases (n = 158), inflammatory bowel diseases (IBD; n = 30), and healthy individuals (n = 62) were tested by enzyme-linked immunosorbent assay for IgG- and IgA-antibodies against recombinant human TBB5. pANCA were detected by immunofluorescence test. Sera were absorbed with TBB5 coupled to cyanogen bromide-activated sepharose. Prevalence and reactivity of IgG anti-TBB5 were significantly higher in patients with untreated AIH (68%; arbitrary units [AU] median: 369) than in PSC (28%; AU median: 84, P < 0.001), other liver diseases (14%; AU median: 185, P < 0.0001), IBD (3%; AU median: 111, P < 0.0001), and healthy controls (3%; AU median: 135; P < 0.0001). Anti-TBB5 did not correlate with pANCA, and immunoprecipitation with TBB5 did not abolish pANCA reactivity. In untreated AIH, anti-TBB5-reactivity was significantly higher than in AIH-IS. Transaminases decreased under IS preferentially in anti-TBB5-negative patients. There was no correlation between anti-TBB5-reactivity and histological stages. IgA-anti-TBB5 was mainly found in alcohol-associated liver disease (ALD; 39%). Our data do not support TBB5 as an autoantigenic target of pANCA. However, IgG-anti-TBB5 showed high specificity for (untreated) AIH. While they did not correlate with histological and laboratory parameters, their presence may indicate a poor response to IS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: The "gut homing" hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here, we examine "the gut homing theory" in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases., Approach and Results: Expression of MAdCAM-1, CCL25, and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from patients with CLD undergoing OLT and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T cells was assessed using flow cytometry. Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was up-regulated in all CLDs compared with normal liver. There were no differences between disease groups. Frequencies of α4β7, αEβ7, CCR9, and GPR15 expressing hepatic T cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. β7 expressing hepatic T cells displayed an increased inflammatory phenotype compared with β7 negative cells, although this inflammatory cytokine profile was present in both the inflamed and normal liver., Conclusions: These findings refute the widely accepted "gut homing" hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T cells is not unique to PSC, but is a panetiological feature of CLD., (© 2021 American Association for the Study of Liver Diseases.)

Background Immune-related hepatotoxicity is often regarded as immune-related hepatitis (irHepatitis) despite including immune-related sclerosing cholangitis (irSC). This study examined the clinical differences between irSC and irHepatitis. Methods A single-center retrospective study of 530 consecutive patients who received immunotherapy between August 2014 and April 2020 was performed. IrSC and irHepatitis were respectively defined as the radiological presence and absence of bile duct dilation and wall thickness. Results Forty-one patients (7.7%) developed immune-related hepatotoxicity. A CT scan was performed on 12 patients, including 11 of 12 with ≥ grade 3 aminotransferase elevations. IrSC and irHepatitis were diagnosed in 4 (0.8%) and 8 (1.5%) patients, respectively. All the irSC patients had been treated with anti-PD-1. IrHepatitis was more common among patients receiving anti-CTLA-4 than among those receiving anti-PD-1/PD-L1 inhibitors (14%, 7/50 vs. 0.2%, 1/480, P < 0.001). A ≥ grade 2 alkaline phosphatase (ALP) elevation resulting in a cholestatic pattern was seen in all 4 irSC patients. Among the irSC patients, 3 (3/4, 75%) developed ≥ grade 3 aminotransferases elevation. The median duration from the start of immunotherapy until ≥ grade 2 liver enzymes elevation was 257 and 55.5 days in irSC and irHepatitis patients. The median times for progression from grade 2 to 3 liver enzyme elevation were 17.5 and 0 days, respectively. Conclusions IrSC and irHepatitis have different characteristics in the class of immune checkpoint inhibitor and onset pattern. Radiological examination for the diagnosis of irSC should be considered for patients with ≥ grade 2 ALP elevation resulting in a cholestatic pattern. (Registration number J2020-36, Date of registration June 3, 2020)., (© 2021. The Author(s).)

Objectives: To evaluate the prevalence and clinical significance of autoantibodies in children with overweight and obesity with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) compared with those with autoimmune liver disease (ALD)., Study Design: This was a retrospective, cross-sectional study of children with a biopsy-proven diagnosis of NAFL, NASH, autoimmune hepatitis (AIH), or primary sclerosing cholangitis (PSC) and a body mass index (BMI) >85th percentile treated between 2007 and 2016., Results: A total of 181 patients were identified, including 31 (17%) with NAFL, 121 (67%) with NASH, 12 (6.6%) with ALD (AIH, PSC, or overlap), and 17 (9.4%) with combined ALD and NAFLD. Antinuclear antibody (ANA), anti-actin antibody, and anti-liver kidney microsomal (LKM) antibody were positive in 16.1%, 13.8%, and 0%, respectively, of the patients with NAFL and in 32.8%, 15.5%, and 0%, respectively, of those with NASH. Total immunoglobulin G (IgG) was elevated in 27.3% of the patients with NAFL and in 47.7% of those with NASH, but in 100% of those with ALD. The positive predictive value of LKM was 100% for ALD but only 29% for ANA and 46% for anti-actin antibody., Conclusions: False-positive rates of autoantibodies were higher in pediatric patients with overweight and obesity with NAFLD compared with the general adult population. Positive LKM had the highest specificity and positive predictive value, and elevated IgG level had the highest sensitivity for ALD. The presence of autoantibodies does not signal more severe NAFLD in children. BMI >98th percentile seems to be an important breakpoint above which ALD is less likely., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aims: Cholestasis is characterized by increased total bile acid (TBA) levels, which are regulated by farnesoid X receptor (FXR)/FGF15. Patients with primary sclerosing cholangitis (PSC) typically present with inflammatory bowel disease (IBD). Mast cells (MCs) (i) express FXR and (ii) infiltrate the liver during cholestasis promoting liver fibrosis. In bile-duct-ligated (BDL) MC-deficient mice (B6.Cg-Kit W-sh /HNihrJaeBsmJ [Kit W-sh ]), ductular reaction (DR) and liver fibrosis decrease compared with BDL wild type, and MC injection exacerbates liver damage in normal mice., Approach and Results: In this study, we demonstrated that MC-FXR regulates biliary FXR/FGF15, DR, and hepatic fibrosis and alters intestinal FXR/FGF15. We found increased MC number and biliary FXR expression in patients with liver injury compared with control. Histamine and FGF19 serum levels and small heterodimer partner expression increase in patients PSC and PSC-IBD compared with healthy controls. MC injection increased liver damage, DR, inflammation, biliary senescence/senescence-associated secretory phenotype (SASP), fibrosis, and histamine in Kit W-sh mice. Inhibition of MC-FXR before injection reduced these parameters. BDL and Kit W-sh mice injected with MCs displayed increased TBA content, biliary FXR/FGF15, and intestinal inflammation, which decreased in BDL Kit W-sh and Kit W-sh mice injected with MC-FXR. MCs increased ileal FXR/FGF15 expression in Kit W-sh mice that was reduced following FXR inhibition. BDL and multidrug resistance 2/ATP-binding cassette family 2 member 4 knockout (Mdr2 -/- ) mice, models of PSC, displayed increased intestinal MC infiltration and FXR/FGF15 expression. These were reduced following MC stabilization with cromolyn sodium in Mdr2 -/- mice. In vitro, MC-FXR inhibition decreased biliary proliferation/SASP/FGF and hepatic stellate cell activation., Conclusions: Our studies demonstrate that MC-FXR plays a key role in liver damage and DR, including TBA regulation through alteration of intestinal and biliary FXR/FGF15 signaling., (© 2021 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Autoimmune liver diseases are attributed to a complex interplay of biologic, acquired, and environmental factors. Increased prevalence, later stage at presentation, worse response to standard therapy, and transplant-related disparities have all been reported in racial and ethnic minorities such as Black and Latinx patients with autoimmune liver diseases. While biology and inherited genetic predispositions may partly explain these disparities, definitive and universal genetic variations underlying these differences in outcomes have not been defined. Nonetheless, socioeconomic status, access to health care, environmental and societal factors, and implicit provider bias can all contribute to poor patient outcomes. There remains an unmet need to understand and mitigate the factors contributing to health inequity in autoimmune liver diseases. In this review, we summarize the data on racial and ethnic disparities in presentation, treatment response, and outcomes pertaining to autoimmune liver diseases in minority populations, on the premise that understanding disparities is the first step toward reaching health equity., (© 2021 by the American Association for the Study of Liver Diseases.)

We have recently introduced multiple reaction monitoring (MRM) mass spectrometry as a novel tool for glycan biomarker research and discovery. Herein, we employ this technique to characterize the site-specific glycan alterations associated with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Glycopeptides associated with disease severity were also identified. Multinomial regression modelling was employed to construct and validate multi-analyte diagnostic models capable of accurately distinguishing PBC, PSC, and healthy controls from one another (AUC = 0.93 ± 0.03). Finally, to investigate how disease-relevant environmental factors can influence glycosylation, we characterized the ability of bile acids known to be differentially expressed in PBC to alter glycosylation. We hypothesize that this could be a mechanism by which altered self-antigens are generated and become targets for immune attack. This work demonstrates the utility of the MRM method to identify diagnostic site-specific glycan classifiers capable of distinguishing even related autoimmune diseases from one another., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The tight relationship between the gut and liver on embryological, anatomical and physiological levels inspired the concept of a gut-liver axis as a central element in the pathogenesis of gut-liver axis diseases. This axis refers to the reciprocal regulation between these two organs causing an integrated system of immune homeostasis or tolerance breakdown guided by the microbiota, the diet, genetic background, and environmental factors. Continuous exposure of gut microbiome, various hormones, drugs and toxins, or metabolites from the diet through the portal vein adapt the liver to maintain its tolerogenic state. This is orchestrated by the combined effort of immune cells network: behaving as a sinusoidal and biliary firewall, along with a regulatory network of immune cells including, regulatory T cells and tolerogenic dendritic cells (DC). In addition, downregulation of costimulatory molecules on hepatic sinusoids, hepatocytes and biliary epithelial cells as well as regulating the bile acids chain also play a part in hepatic immune homeostasis. Recent evidence also demonstrated the link between changes in the gut microbiome and liver resident immune cells in the progression of cirrhosis and the tight correlation among primary sclerosing cholangitis (PSC) and also checkpoint induced liver and gut injury. In this review, we will summarize the most recent evidence of the bidirectional relationship among the gut and the liver and how it contributes to liver disease, focusing mainly on PSC and checkpoint induced hepatitis and colitis. We will also focus on completed therapeutic options and on potential targets for future treatment linking with immunology and describe the future direction of this research, taking advantage of modern technologies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bozward, Ronca, Osei-Bordom and Oo.)

Introduction: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 virus, is a predominantly respiratory tract infection with the capacity to affect multiple organ systems. Abnormal liver tests, mainly transaminase elevations, have been reported in hospitalized patients. We describe a syndrome of cholangiopathy in patients recovering from severe COVID-19 characterized by marked elevation in serum alkaline phosphatase (ALP) accompanied by evidence of bile duct injury on imaging., Methods: We conducted a retrospective study of COVID-19 patients admitted to our institution from March 1, 2020, to August 15, 2020, on whom the hepatology service was consulted for abnormal liver tests. Bile duct injury was identified by abnormal liver tests with serum ALP > 3x upper limit of normal and abnormal findings on magnetic resonance cholangiopacreatography. Clinical, laboratory, radiological, and histological findings were recorded in a Research Electronic Data Capture database., Results: Twelve patients were identified, 11 men and 1 woman, with a mean age of 58 years. Mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 118 days. Peak median serum alanine aminotransferase was 661 U/L and peak median serum ALP was 1855 U/L. Marked elevations of erythrocyte sedimentation rate, C-reactive protein, and D-dimers were common. Magnetic resonance cholangiopacreatography findings included beading of intrahepatic ducts (11/12, 92%), bile duct wall thickening with enhancement (7/12, 58%), and peribiliary diffusion high signal (10/12, 83%). Liver biopsy in 4 patients showed acute and/or chronic large duct obstruction without clear bile duct loss. Progressive biliary tract damage has been demonstrated radiographically. Five patients were referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. One patient underwent successful living donor liver transplantation., Discussion: Cholangiopathy is a late complication of severe COVID-19 with the potential for progressive biliary injury and liver failure. Further studies are required to understand pathogenesis, natural history, and therapeutic interventions., (Copyright © 2021 by The American College of Gastroenterology.)

Background: Immunoglobulin G subclass 4 (IgG4) is hypothesized to play an immunomodulatory role, downregulating humoral immune responses. The role of this anti-inflammatory molecule in inflammatory bowel disease (IBD) has not been fully characterized. We sought to define alterations in serum IgG4 in patients with IBD and their association with multiyear disease severity., Methods: We analyzed metadata derived from curated electronic health records from consented patients with IBD prospectively followed at a tertiary center over a 10-year time period. Patients with IBD with IgG4 serum levels available formed the study population. Demographics and multiyear clinical data were collected and analyzed. We stratified patients with IBD with low, normal, or high serum IgG4 levels., Results: We found IgG4 characterized in 1193 patients with IBD and low IgG4 levels in 233 patients (20%) and elevated IgG4 levels in 61 patients (5%). An IgG4 deficiency did not significantly correlate with other antibody deficiencies. In a multiple Poisson regression analysis, low IgG4 was associated with more years on biologic agents (P = 0.002) and steroids (P = 0.049) and more hospital admissions (P < 0.001), clinic visits (P = 0.010), outpatient antibiotic prescriptions (P < 0.001), and CD-related surgeries (P = 0.011) during the study period after controlling for certain confounders. Elevated IgG4 was only associated with primary sclerosing cholangitis (P = 0.011). A cohort of patients with IgG4-deficient severe IBD received intravenous Ig replacement therapy, which benefited and was continued in 10 out of 11 individuals., Conclusions: An IgG4 subclass deficiency, distinct from other antibody deficiencies, occurred commonly in a referral IBD population and was associated with multiple markers of disease severity. This is the first association of IgG4 subclass deficiency with an inflammatory disease process. Further work is needed to define the mechanistic role of IgG4 deficiency in this severe IBD subgroup., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: A 60-year-old woman with surgically confirmed immunoglobulin G4-related sclerosing cholangitis underwent 18F-FDG PET/CT due to significantly elevated serum CA-19-9 level, which revealed a hypermetabolic lesion in the residual liver. 68Ga-FAPI PET/MR was performed to further evaluate whether the FDG-avid lesion is a malignant tumor. Astonishingly, diffuse intense radioactivity was revealed throughout the liver, suggesting involvement of active immunoglobulin G4-related sclerosing cholangitis, but nonfocal elevated 68Ga-FAPI accumulation in the FDG-avid lesion indicated postoperative change. From this case, we speculated that FAPI imaging could be used for evaluation of chronic liver disease because fibroblast activation protein has a profibrogenic role in chronic liver injury., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

B cells form a branch of the adaptive immune system, essential for the body's immune defense against pathogens. B cell dysfunction has been implicated in the pathogenesis of immune mediated liver diseases including autoimmune hepatitis, IgG4-related hepatobiliary disease, primary biliary cholangitis and primary sclerosing cholangitis. B cells may initiate and maintain immune related liver diseases in several ways including the production of autoantibodies and the activation of T cells via antigen presentation or cytokine production. Here we comprehensively review current knowledge on B cell mechanisms in immune mediated liver diseases, exploring disease pathogenesis, B cell therapies, and novel treatment targets. We identify key areas where future research should focus to enable the development of targeted B cell therapies., Competing Interests: EC is on the advisory board for Viela Bio for IgG4-realted disease. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cargill and Culver.)

Introduction: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterized by bile duct inflammation and fibrosis. The role of macrophages in PSC development and progression is less studied. Macrophage activation markers soluble (s)CD163 and mannose receptor (sMR) are associated with disease severity and outcome in other liver diseases, but not previously investigated in PSC. We evaluated sCD163 and sMR regarding disease severity and prognosis in patients with PSC., Methods: We investigated 2 independent PSC cohorts from Oslo (n = 138) and Helsinki (n = 159) and analyzed blood sCD163 and sMR levels. The Mayo score, Enhanced Liver Fibrosis Test, and Amsterdam-Oxford model were assessed for comparison., Results: Median (interquartile range) sCD163 was 3.32 (2.27-5.60) and 1.96 (1.47-2.70) mg/L in the Oslo and Helsinki cohorts, respectively, reflecting differences in disease severity between cohorts. Median sMR was similar in both cohorts, 0.28 (0.22-0.44) and 0.28 mg/L (0.20-0.36), respectively. In both cohorts, sCD163 and sMR levels raised with increasing disease severity (liver enzymes, Mayo score, and enhanced liver fibrosis test). Patients with high baseline levels of sCD163 had shorter transplant-free survival than patients with low baseline levels. Furthermore, sCD163 was associated with transplant-free survival in univariate cox-regression analyses. Both sCD163 and sMR performed better in the Oslo cohort of more severely diseased patients than those in the Helsinki cohort of more mildly diseased patients., Discussion: Macrophage activation markers are elevated according to disease severity suggesting an important role of macrophages in PSC. Furthermore, sCD163 was identified as a prognostic marker and predictor of transplant-free survival in PSC (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A516)., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Atezolizumab is an immune checkpoint inhibitor that is a key drug in non-small-cell lung cancer treatment. However, it can cause immune-related adverse events, including liver injury. Several patterns of liver injury associated with immune checkpoint inhibitor therapy have been reported; however, not much is known about sclerosing cholangitis. We present here a case of lung adenocarcinoma with atezolizumab-induced secondary sclerosing cholangitis diagnosed using needle biopsy of the liver. A 77-year-old woman with lung adenocarcinoma, cT3N2M0, stage IIIA, was treated with concurrent chemoradiotherapy involving carboplatin and paclitaxel, which markedly reduced the tumor diameter. However, 5 months later, the lesion regrew, and she underwent 39 cycles of pemetrexed monotherapy. As pulmonary metastasis progressed, she was treated with atezolizumab. After 13 cycles of atezolizumab therapy, she complained of nausea. Laboratory tests showed elevated levels of the biliary tract and hepatic enzymes. Nevertheless, abdominal computed tomography and ultrasonography revealed no underlying related cause. Ultrasound-guided needle biopsy of the liver was performed, and histopathological analysis of biopsy samples showed features of sclerosing cholangitis. Further examinations were performed, and a diagnosis of atezolizumab-induced secondary sclerosing cholangitis without strictures and dilatations of the large bile ducts was established. Prednisolone was administered orally, after which the biliary tract and hepatic enzyme levels improved immediately. In patients presenting with a hepatic injury during immune checkpoint inhibitor therapy, clinicians should be aware of the possibility of immune checkpoint inhibitor-induced sclerosing cholangitis, even if the large bile ducts have no strictures and dilatations., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background/aims: Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are the 3 main autoimmune liver diseases (AILDs). The epidemiology of AILD in Turkey is not known. To determine the scientific status, we performed a scientometric analysis of AILD-related original articles that originated from Turkey., Materials and Methods: We searched the Web of Science database, the Science Citation Index Expanded (SCI-E), and the Social Sciences Citation Index (SSCI) by using the keywords "autoimmune hepatitis," "primary biliary cholangitis/primary biliary cirrhosis," and "primary sclerosing cholangitis" in conjunction with "Turkey." A scientometric analysis was done on the search results., Results: We identified 117 AILD-related papers that were published in Turkey from 1997 to 2019. Among these, 70 case reports, letters, and reviews and 2 original articles that were not cited in SCI-E/SSCI were excluded. The remaining 45 original articles were further analyzed. These studies were related to AIH (n=22), PBC (n=7), PSC (n=9), PBC-AIH overlap (n=5), and others (n=2). Four of the publications originated in pediatric settings; 9 of 45 papers were published from 1997 to 2008 and 36 papers were published from 2009 to 2019. Most papers (75%) were reported from 5 centers; 9 papers (20%) were published in journals with an impact factor of 3 or higher., Conclusion: The overall number and quality of AILD-related papers in Turkey are unexpectedly low, although a number of papers have received considerable international recognition. More epidemiologic, prospective, and multicenter research projects are warranted to advance AILD knowledge and to produce high-quality research from Turkey.

IgG4-related disease (IgG4 RD) is a multisystem disorder characterized by tumefactive (mass forming) lesions, storiform fibrosis, and IgG4-positive plasma cell infiltration. IgG4 sclerosing cholangitis (IgG4 SC) is the biliary manifestation of IgG4 RD, often in association with autoimmune pancreatitis (AIP). Here, we report two patients with IgG4-related cholangitis mimicking primary sclerosing cholangitis.

Background and Aims: Extraintestinal manifestations are common in inflammatory bowel disease patients, although there are few data available on their diagnosis, management and follow-up. We systematically reviewed the literature evidence to evaluate tools and investigations used for the diagnosis and for the assessment of the treatment response in inflammatory bowel disease patients with extraintestinal manifestations., Methods: We searched in PubMed, Embase and Web of Science from January 1999-December 2019 for all interventional and non-interventional studies published in English assessing diagnostic tools and investigations used in inflammatory bowel disease patients with extraintestinal manifestations., Results: Forty-five studies (16 interventional and 29 non-interventional) were included in our systematic review, enrolling 7994 inflammatory bowel disease patients. The diagnostic assessment of extraintestinal manifestations was performed by dedicated specialists in a percentage of cases ranging from 60-100% depending on the specific condition. The clinical examination was the most frequent diagnostic strategy, accounting for 35 studies (77.8%). In patients with primary sclerosing cholangitis or rheumatological symptoms, biochemical and imaging tests were also performed. Anti-TNF agents were the most used biological drugs for the treatment of extraintestinal manifestations (20 studies, 44.4%), and the treatment response varied from 59.1% in axial spondyloarthritis to 88.9% in ocular manifestations. No benefit was detected in primary sclerosing cholangitis patients after treatment with biologics., Conclusions: In the clinical management of inflammatory bowel disease patients with extraintestinal manifestations the collaboration of dedicated specialists for diagnostic investigations and follow-up is key to ensure the best of care approach. However, international guidelines are needed to homogenise and standardise the assessment of extraintestinal manifestations.

Competing Interests: Conflict of interest GMH reports consultancy and/or speaker fees for Genfit, Cymabay, Intercept, Falk Pharma, GSK, Pliant. Please refer to the accompanying ICMJE disclosure forms for further details.

Background: The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) are not well known., Methods: The outcomes of patients with IgG4-SC at Mayo Clinic (1999-2018) were compared to an age- and gender-matched (1:1 ratio) group of patients with primary sclerosing cholangitis (PSC)., Results: We identified 89 patients with IgG4-SC; median age at diagnosis was 67 years, 81% were males, and the median follow-up was 5.7 years. Seventy-eight patients received prednisone for induction of remission, and 53 received at least one other immunosuppressive agent for maintenance of remission. Of the IgG4-SC group, 10 died (median time from diagnosis until death was 6.5 years): 2 due to cirrhosis, 3 due to cholangiocarcinoma (CCA), and 5 due to non-hepatobiliary causes. Eleven patients in the PSC group underwent liver transplantation, while none did in the IgG4-SC group. The incidence of a hepatobiliary adverse event (cirrhosis or CCA) was 3.4 times greater in the PSC compared to the IgG4-SC group (events per 1000 person-years: 52.6; 95% CI 38-73; vs. 15.6; 95% CI 7-32). The probability of development of a hepatobiliary adverse event within 10 years was 11% in the IgG4-SC compared to 45% in the PSC group (P = 0.0001). The overall survival tended to be higher in the IgG4-SC compared to the PSC group (10-year: 79% vs. 68%, respectively; P = 0.11)., Conclusions: In a cohort of IgG4-SC patients, 88% of whom were treated with immunosuppressive drugs, the risk of cirrhosis and CCA was significantly lower compared to an age- and gender-matched group with PSC.

Background and Aims: T cells from patients with primary sclerosing cholangitis (PSC) show a prominent interleukin (IL)-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant T-helper 17 (Th17) response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T-cell response toward Th17., Approach and Results: Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using transwell experiments with cholangiocytes. Cytokine production was measured using flow cytometry, enzyme-linked immunosorbent assay, RNA in situ hybridization, and quantitative real-time PCR. Genetic polymorphisms were obtained from ImmunoChip analysis. Following ex vivo stimulation with phorbol myristate acetate/ionomycin, PSC patients showed significantly increased numbers of IL-17A-producing peripheral blood CD4 + T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo. Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL-1β and IL-6, cytokines known to drive Th17 cell differentiation. Moreover, microbe-activated monocytes induced the secretion of Th17 and monocyte-recruiting chemokines chemokine (C-C motif) ligand (CCL)-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14 hi CD16 int and CD14 lo CD16 hi monocytes/macrophages were increased compared to alcoholic cirrhosis, and monocytes were found to be located around bile ducts., Conclusions: PSC patients show increased Th17 differentiation already in vivo. Microbe-stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC., (© The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

Background & Aims: There are insufficient population-level data on the effects of primary sclerosing cholangitis (PSC) in patients with inflammatory bowel disease (IBD)., Methods: We identified incident cases of IBD, with PSC (PSC-IBD) and without, from April 2006 to April 2016 and collected data on outcomes through April 2019. We linked data from national health care registries maintained for all adults in England on hospital attendances, imaging and endoscopic evaluations, surgical procedures, cancer, and deaths. Our primary aim was to quantify the effects of developing PSC in patients with all subtypes of IBD and evaluate its effects on hepatopancreatobiliary disease, IBD-related outcomes, and all-cause mortality, according to sex, race, and age., Results: Over 10 years, we identified 284,560 incident cases of IBD nationwide; of these, 2588 patients developed PSC. In all, we captured 31,587 colectomies, 5608 colorectal cancers (CRCs) 6608 cholecystectomies, and 41,055 patient deaths. Development of PSC was associated with increased risk of death and CRC (hazard ratios [HRs], 3.20 and 2.43, respectively; P < .001) and a lower median age at CRC diagnosis (59 y vs 69 y without PSC; P < .001). Compared to patients with IBD alone, patients with PSC-IBD had a 4-fold higher risk of CRC if they received a diagnosis of IBD at an age younger than 40 years; there was no difference between groups for patients diagnosed with IBD at an age older than 60 years. Development of PSC also increased risks of cholangiocarcinoma (HR, 28.46), hepatocellular carcinoma (HR, 21.00), pancreatic cancer (HR, 5.26), and gallbladder cancer (HR, 9.19) (P < .001 for all). Risk of hepatopancreatobiliary cancer-related death was lower among patients with PSC-IBD who received annual imaging evaluations before their cancer diagnosis, compared to those who did not undergo imaging (HR, 0.43; P = .037). The greatest difference in mortality between the PSC-IBD alone group vs the IBD alone group was for patients younger than 40 years (incidence rate ratio >7), in contrast to those who received a diagnosis of IBD when older than 60 years (incidence rate ratio, <1.5). Among patients with PSC-IBD we observed 173 first liver transplants. Liver transplantation and PSC-related events accounted for approximately 75% of clinical events when patients received a diagnosis of PSC at an age younger than 40 years vs 31% of patients who received a diagnosis when older than 60 years (P < .001). African Caribbean heritage was associated with increased risks of liver transplantation or PSC-related death compared with white race (HR, 2.05; P < .001), whereas female sex was associated with reduced risk (HR, 0.74; P = .025)., Conclusions: In a 10-year, nationwide study, we confirmed that patients with PSC-IBD have increased risks of CRC, hepatopancreatobiliary cancers, and death compared to patients with IBD alone. In the PSC-IBD group, diagnosis of IBD at age younger than 40 years was associated with greater risks of CRC and all-cause mortality compared with diagnosis of IBD at older ages. Patients who receive a diagnosis of PSC at an age younger than 40 years, men, and patients of African Caribbean heritage have an increased incidence of PSC-related events., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Glycosylation of antibodies, particularly in the Fc domain, critically modulate the ability of antibodies to bind to FcRs, maintaining immune quiescence to achieve a finely orchestrated immune response. The removal of sialic acid and galactose residues dramatically alters the physiological function of IgGs, and alterations of Ig glycosylation have been associated with several autoimmune disorders. However, Ig glycosylation has not been extensively studied in autoimmune cholangitis. We applied triple quadruple mass spectroscopy with subsequent multiple reaction monitoring to elucidate the profile, composition and linkage of sugar residues of antibody glycans in patients with primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and healthy controls (HC). Agalactosylated, HexNAc terminated IgG1 glycoforms were enriched in both PBC and PSC. Levels of IgM glycans at site N439 and fucosylated glycans in J chain, were significantly decreased in PBC compared to PSC and HC. PSC patients had decreased bisecting glycoforms and increased biantennary glycoforms on IgA compared to PBC. Importantly, our data demonstrate the association of distinct branching and composition patterns of Ig glycoforms with disease severity and liver cirrhosis, which highlight the importance of glycan biology as a potential mechanism and/or a disease specific signal of inflammation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: To describe the clinical characteristics, biochemical and histological features, outcomes and predictors of prognosis of children with autoimmune hepatitis (AIH) from a paediatric centre in South Africa., Methods: Thirty-nine children diagnosed with AIH at Red Cross War Memorial Children's Hospital between 2005 and 2015 were included. Relevant patient's data were retrieved from the hospital's medical records and database. Liver biopsy slides were reviewed. Ethical approval was obtained. Data were analysed using SPSS., Results: Females were 29 (74%). Mean age at presentation was 7.27 ± 3.35 years and the mean follow-up was 4.5 ± 2.4 years. Jaundice was present in 97% of patients at presentation. An acute presentation was observed in 26 (67%) even though cirrhosis was detected in 22 (56%). Autoantibody screening was completed in 35 patients, 20 (57%) were AIH-1, 1 (3%) was AIH-2 and 14 (40%) were seronegative AIH. Of the 25 patients who underwent magnetic resonance cholangiography 17 (68%) had associated autoimmune sclerosing cholangitis. The remission rate was 79%. However, 11 children relapsed later. One child required liver transplantation and one demised. Seronegative and seropositive patients have comparable characteristics and outcomes. While a higher alanine transaminase (ALT) level at presentation is a significant predictor of remission, a lower ALT level and cirrhosis are significant risk factors for unfavourable outcome. Overall survival rate was 97%., Conclusion: AIH responds well to therapy with excellent survival. Hence, it should be considered in any child presenting with viral screen negative hepatitis and start therapy timeously to prevent disease progression., (© The Author(s) [2020]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Immune mediated liver diseases entail a broad category which are associated with increased morbidity and mortality amongst the paediatric population. Programmed Death 1 (PD1) is an inhibitory receptor mainly expressed by T cells, and when activated shed into plasma as soluble PD1(sPD1). The AIM of this study was to evaluate sPD1 levels in plasma of paediatric patients with Autoimmune Hepatitis (AIH), Primary Sclerosing Cholangitis (PSC), AIH and PSC overlap, Inflammatory Bowel Disease (IBD) alone, and concurrent PSC/IBD and AIH/IBD in order to identify a biomarker to response or predict relapse verses remission. Methods: Plasma samples were collected from 41 paediatric patients. AIH patients were further categorized into active, incomplete responders and responders, based on response to standard therapy. sPD1 levels were measured and compared between PSC, PSC/AIH, IBD alone, PSC/IBD and AIH/IBD patients and between active AIH, incomplete responders and responders. Flow cytometry was performed to further analyze CD45RA+, CD3CD4, CD8, CCR7, CXCR3, CD38 and PD1. Results: In the AIH group, those with active disease demonstrated a significantly higher sPD1 levels in comparison to responders (* p  > .001). However, the incomplete responders didn't show a reduction in sPD1 in comparison to active AIH and patients with IBD alone. Interestingly, patients with PSC showed significantly lower level of sPD1 compared to active AIH (* p  < .002), whereas, patients with PSC in conjunction with AIH (* p  < .006) or IBD (* p  < .02) demonstrated a significant increase in sPD1. In addition, we have observed increased levels of circulating CD4 and CD8 bound PD1 in active AIH but not in PSC or responders suggesting T cells activation. CD4+ PD1 double positive cells demonstrated increased expression of CXCR3. Thus, suggesting the activation of PD1 + T cells is mediating through CXCR3 in Autoimmune hepatitis. Conclusions: Our study demonstrates that sPD1 levels correlate with active disease state of AIH and IBD. sPD1 levels did not correlate with PSC. However, PSC in conjunction with AIH or IBD showed higher levels of sPD1. This suggests that T cell activation plays a critical role in active AIH and IBD but not in PSC. Soluble PDI levels could be used as a clinical biomarker to assess response in patients with AIH and for prospectively monitoring PSC patients for development of IBD or AIH.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and stricturing. Exploration of the pathogenesis of PSC in light of its association with inflammatory bowel disease (IBD) and the "gut-liver" axis is an emerging area of interest. A growing number of studies have begun to elucidate the role of the gut microbiota, its metabolites and its influence on host immune responses in the development of PSC and PSC-IBD. Studies of the fecal microbiota have highlighted enriched levels of certain species, including Veillonella , Streptococcus and Enterococcus , among others. A heightened immune response to enteric dysbiosis and bacterial translocation have also been implicated. For example, Klebsiella pneumoniae strains derived from gnotobiotic mice transplanted with PSC-IBD microbiota were found to induce pore formation in human intestinal epithelial cells and enhanced Th17 responses. Gut microbes have additionally been hypothesized to be implicated in PSC pathogenesis through their role in the synthesis of various metabolites, including bile acids (BAs), which function as signaling molecules with important gut and hepatic effects. An expanded knowledge of the gut microbiome as it relates to PSC offers critical insight into the development of microbe-altering therapeutic interventions, such as antibiotics, nutritional interventions and fecal microbial transplantation. Some of these have already shown some preliminary evidence of benefit. Despite exciting progress in the field, much work remains to be done; areas that are particularly lacking include functional characterization of the microbiome and examination of pediatric populations. In this review, we summarize studies that have investigated the microbiome in PSC and PSC-IBD as well as putative mechanisms, including the potential role of metabolites, such as BAs. We then briefly review the evidence for interventions with microbe-altering properties for treating PSC., Competing Interests: Conflict-of-interest statement: Dr. Kamath BM reports - Consultant Shire, Albireo and Mirum since they make ASBT inhibitors. All other authors no disclosures to report., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)