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Background & AimsCholangiocarcinoma (CCA), heterogeneous biliary tumors with dismal prognosis, lacks accurate early diagnostic methods, especially important for individuals at high-risk (i.e., primary sclerosing cholangitis (PSC)). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs).MethodsEVs from patients with isolated PSC (n=45), concomitant PSC-CCA (n=44), PSC who developed CCA during follow-up (PSC to CCA; n=25), CCAs from non-PSC etiology (n=56), hepatocellular carcinoma (HCC; n=34) and healthy individuals (n=56) were characterized by mass-spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA or CCAs regardless etiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumors at single-cell level. Prognostic EV-biomarkers for CCA were investigated.ResultsHigh-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and HCC, that were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease (LD)) vs isolated PSC (AUC=0.947;OR=36.9), and combined with CA19-9, overpowers CA19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs healthy individuals (AUC=0.992;OR=387.5). Noteworthy, CRP/FRIL accurately diagnosed LD Pan-CCA (AUC=0.941;OR=89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidences of malignancy. Multi-organ transcriptomic analysis revealed that serum EV-biomarkers were mostly expressed in hepatobiliary tissues, and scRNA-seq and immunofluorescence analysis of CCA tumors showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV-prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively or positively to patients’ survival, respectively.ConclusionsSerum EVs contain protein biomarkers for the prediction, early diagnosis and prognosis estimation of CCA detectable using total serum, representing a tumor cell-derived liquid biopsy tool for personalized medicine.Impact and ImplicationsThe accuracy of current imaging tests and circulating tumor biomarkers for cholangiocarcinoma (CCA) diagnosis is far from satisfactory. Most CCAs are considered sporadic, although up to 20% of patients with primary sclerosing cholangitis (PSC) develop CCA during their lifetime, constituting a major cause of PSC-related death. This international study has proposed protein-based and etiology-related logistic models with predictive, diagnostic or prognostic capacities by combining 2-4 circulating protein biomarkers, moving a step forward into personalized medicine. These novel liquid biopsy tools may allow the: i) easy and non-invasive diagnosis of sporadic CCAs, ii) identification of patients with PSC with higher risk for CCA development, iii) establishment of cost-effective surveillance programs for the early detection of CCA in high-risk populations (e.g., PSC), and iv) prognostic stratification of patients with CCA, which, altogether, may increase the number of cases eligible for potentially curative options or to receive more successful treatments, decreasing CCA-related mortality.

Unlabelled: The principal limitations of the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. Methods: A modified Delphi process was led by three large pan-national liver associations. Consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Results: A total of 236 panellists from 56 countries participated in four online surveys and two hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83% and 78%, respectively. 74% of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms 'non-alcoholic' and 'fatty' were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD. A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350g/week and 210 to 420g/week for females and males respectively). Conclusions: The new nomenclature and diagnostic criteria are widely supported, non-stigmatising and can improve awareness and patient identification.

Patients with benign recurrent intrahepatic cholestasis (BRIC) suffer from recurrent episodes of cholestatic jaundice. Treatment options remain limited and are mainly symptomatic. In case reports rifampicin, plasmapheresis, and nasobiliary drainage have been reported to be effective. In this case series, we present long-term experience indicating disease-modifying effects of non-invasive treatment with rifampicin for recurrent cholestasis in BRIC type 1 (BRIC1).We included all adult BRIC1 patients diagnosed and followed up at a single centre in Bergen, Norway. Data regarding clinical and biochemical features during BRIC attacks with and without rifampicin treatment were retrieved from medical journals and a data registry.Five males with BRIC1 were included. Median age at diagnosis was 22 years (range 15-41). Together they had suffered from 65 cholestatic attacks (including four documented abortive attacks). Twenty-eight attacks were treated with rifampicin alone over the last 12 years; all cases showed symptomatic relief and reduction in the levels of bilirubin and alkaline phosphatase in blood. The attacks treated with rifampicin seemed to have shorter duration and were less likely to result in complications or hospitalization compared to attacks prior to the introduction of rifampicin. No side effects attributable to rifampicin were noted.Episodic treatment of recurrent BRIC1 attacks with rifampicin seems to ameliorate severity and shorten the duration of attacks. Timely diagnosis and effective treatment are of major importance in BRIC, not only to decrease complications but also improving patients' quality of life.

Background and Aims: There is an unmet need for new biomarkers to improve diagnostics and prognostics in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Inter-α-inhibitor heavy chain 4 (ITIH4) is an abundant, liver-produced protein, and its synthesis may be altered in liver diseases. We investigated whether ITIH4 plasma concentrations were affected in PBC and PSC patients.Methods: We developed an immunoassay specific for ITIH4 and determined ITIH4 plasma concentrations in 66 PBC, 126 PSC, 92 autoimmune hepatitis (AIH), 67 chronic hepatitis C (CHC), 33 alcoholic hepatitis (AH) patients and 138 healthy controls (HCs). Hepatic ITIH4 expression was investigated by immunohistochemistry in PBC.Results: The mean plasma concentration of ITIH4 was almost doubled in PBC [409 µg/mL (95% CI: 388-431)] and 35% higher in PSC [308 µg/mL, (95% CI: 296-319)] compared with HCs [226 µg/mL (95% CI: 221-231); pConclusions: The plasma concentration of ITIH4 was highly elevated in patients with PBC and PSC, suggesting that ITIH4 should be further investigated as a biomarker in cholestatic liver disease.

Background and aims Biomarkers of inflammation may be of clinical utility in primary sclerosing cholangitis (PSC). We aimed to investigate the interferon gamma-related biomarkers neopterin and kynurenine–tryptophanratio (KT-ratio) in PSC. Methods Circulating neopterin, tryptophan and kynurenine were measured with LC-MS/MS in multiple cross-sectional cohorts comprising in total of 524 PSC patients and 100 healthy controls from Norway, Germany and Sweden. Results Neopterin and KT-ratio were significantly increased in PSC patients compared with controls in both a discovery and a validation cohort from Norway. Furthermore, high neopterin and KT-ratio levels were associated with a shorter transplantation-free survival in the PSC patients in the Norwegian discovery cohort and the German validation cohort. However, in the validation PSC cohort from Sweden, no relationship between neopterin and KT-ratio and liver transplantation-free survival was observed. The correlations between neopterin and KT-ratio were moderate to strong and similar in all cohorts (rho 0.50–0.67). Neopterin and KT-ratio also correlated with C-reactive protein (rho 0.17-0.63) and revised Mayo risk score (rho 0.23–0.42) in all cohorts. Conclusions Neopterin and KT-ratio were elevated in PSC and associated with liver transplantation-free survival in two independent PSC cohorts, highlighting a possible role of interferon gamma-driven inflammation in the pathogenesis. However, the lack of association with survival in one of the cohorts reduces the potential clinical value of neopterin and KT-ratioas biomarkers and highlights the need to validate new biomarkers in PSC in multiple cohorts. publishedVersion

Purpose Ultrasound elastography is a noninvasive method for liver stiffness measurement (LSM) with the aim of reflecting approximate liver fibrosis load. Despite minimal evidence, current guidelines recommend 10 min of rest and breath hold prior to measurements and offer no advice concerning recent alcohol consumption, leading to challenges in clinical practice. We aimed to investigate how LSM in healthy adults is influenced by physical exercise, recent alcohol consumption, and respiration. Materials and Methods 42 healthy subjects aged 21–36 years were included. LSM using point shear wave elastography (pSWE) was performed in five stages: baseline, after physical activity, after registration of alcohol consumption, and during breath hold compared to free breathing. Results LSM values were significantly increased following physical exercise compared to baseline values (4.1±0.8 vs. 3.8±0.8 kPa, p=0.01). Alcohol consumption during the last 72 h (0–27 alcohol units) did not significantly affect LSM. There was no significant difference between LSM during breath hold and free breathing. Conclusion In healthy subjects, LSM increased after recent physical exercise, while alcohol consumption 24–72 h prior to examination did not have a significant impact. There was no clinically significant effect of breath hold on LSM. Our study supports present guidelines recommending rest prior to LSM, while indicating that breath hold may not be mandatory. Recent moderate alcohol exposure may affect LSM to a lesser extent than commonly believed.

Primary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. Patients bear a significant risk of cholangiocarcinoma and colorectal cancer, and frequently have concomitant inflammatory bowel disease and autoimmune disease manifestations. To date, no medical therapy has proven significant impact on clinical outcomes and most patients ultimately need liver transplantation. Several treatment strategies have failed in the past and whilst prescription of ursodeoxycholic acid (UDCA) prevails, controversy regarding benefits remains. Lack of statistical power, slow and variable disease progression, lack of surrogate biomarkers for disease severity and other challenges in trial design serve as critical obstacles in the development of effective therapy. Advances in our understanding of PSC pathogenesis and biliary physiology over recent years has however led to a surge of clinical trials targeting various mechanistic compartments and currently raising hopes for imminent changes in patient management. Here, in light of pathophysiology, we outline and critically evaluate emerging treatment strategies in PSC, as tested in recent or ongoing phase II and III trials, stratified per a triad of targets of nuclear and membrane receptors regulating bile acid metabolism, immune modulators, and effects on the gut microbiome. Furthermore, we revisit the UDCA trials of the past and critically discuss relevant aspects of clinical trial design, including how the choice of endpoints, alkaline phosphatase in particular, may affect the future path to novel, effective PSC therapeutics.

[Background & Aims]: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent, yet largely underappreciated liver condition which is closely associated with obesity and metabolic disease. Despite affecting an estimated 1 in 4 adults globally, NAFLD is largely absent on national and global health agendas., [Methods]: We collected data from 102 countries, accounting for 86% of the world population, on NAFLD policies, guidelines, civil society engagement, clinical management, and epidemiologic data. A preparedness index was developed by coding questions into 6 domains (policies, guidelines, civil awareness, epidemiology and data, NAFLD detection, and NAFLD care management) and categorising the responses as high, medium, and low; a multiple correspondence analysis was then applied., [Results]: The highest scoring countries were India (42.7) and the United Kingdom (40.0), with 32 countries (31%) scoring zero out of 100. For 5 of the domains a minority of countries were categorised as high-level while the majority were categorised as low-level. No country had a national or sub-national strategy for NAFLD and, [Conclusions]: Although NAFLD is a pressing public health problem, no country was found to be well prepared to address it. There is a pressing need for strategies to address NAFLD at national and global levels., The data collection and analysis were funded by the EASL International Liver Foundation with support from, Intercept, Bristol-Myers-Squibb Company, Genfit, and MSD. Data collection for the original European data was funded by the EASL International Liver Foundation supported by Gilead Sciences Europe Ltd., Allergan Pharmaceutical International Ltd., Bristol-Myers-Squibb Company, Pfizer Inc., and Resoundant Inc.

Autoimmune hepatitis is a chronic liver disease which, if untreated, can lead to cirrhosis of the liver and liver failure. The majority of patients respond well to standard immunosuppressive therapy, but some experience adverse effects, or lack of treatment efficacy. Diagnosis, assessment of therapeutic response and choice of second-line therapy may be challenging. This article provides a summary of updated knowledge concerning diagnosis and treatment of patients with complex autoimmune hepatitis.

Objectives: Noninvasive tests for the evaluation of liver fibrosis are particularly helpful in children to avoid general anesthesia and potential complications of invasive tests. We aimed to establish reference values for 2 different elastography methods in a head-to-head comparison for children and adolescents 4 to 17 years, using transient elastography as common reference in a subset. Methods: A total of 243 healthy participants aged 4 to 17 years were examined by a single observer with a full liver B-mode scan before elastography, following a minimum of 3 hours fasting. Liver stiffness measurements (LSMs) using 2-dimensional shear wave elastography (2D-SWE, GE Logiq E9) and point shear wave elastography (pSWE, Samsung RS80A with Prestige) were performed in all participants, and compared to transient elastography (TE, FibroScan) in a subset (n = 87). Interobserver agreement was evaluated in 50 children aged 4 to 17 years. Results: Valid measurements were obtained in 242 of 243 (99.6%) subjects for 2D-SWE, 238 of 243 (97.9%) for pSWE, and in 83 of 87 (95.4%) for TE. Median liver stiffness overall was 3.3 (interquartile range [IQR] 2.7–4.3), 4.1 (IQR 3.6–4.7), and 4.1 kPa (IQR 3.5–4.6) for 2D-SWE, pSWE, and TE, respectively. Intraclass correlation coefficients between observers were 0.84 and 0.83 for 2D-SWE and pSWE, respectively. LSM values were significantly lower for 2D-SWE compared to pSWE and TE, and increased with advancing age. Higher LSM values in males were observed in adolescents. Conclusions: All methods showed excellent feasibility. 2D-SWE showed significantly lower LSM values than pSWE and TE, and lower failure rate compared to TE. Our results further indicate an age and sex effect on LSM values. publishedVersion

Improved methods are needed to risk stratify and predict outcomes in patients with primary sclerosing cholangitis (PSC). Therefore, we sought to derive and validate a prediction model and compare its performance to existing surrogate markers. The model was derived using 509 subjects from a multicenter North American cohort and validated in an international multicenter cohort (n = 278). Gradient boosting, a machine-based learning technique, was used to create the model. The endpoint was hepatic decompensation (ascites, variceal hemorrhage, or encephalopathy). Subjects with advanced PSC or cholangiocarcinoma (CCA) at baseline were excluded. The PSC risk estimate tool (PREsTo) consists of nine variables: bilirubin, albumin, serum alkaline phosphatase (SAP) times the upper limit of normal (ULN), platelets, aspartate aminotransferase (AST), hemoglobin, sodium, patient age, and number of years since PSC was diagnosed. Validation in an independent cohort confirms that PREsTo accurately predicts decompensation (C-statistic, 0.90; 95% confidence interval [CI], 0.84-0.95) and performed well compared to Model for End-Stage Liver Disease (MELD) score (C-statistic, 0.72; 95% CI, 0.57-0.84), Mayo PSC risk score (C-statistic, 0.85; 95% CI, 0.77-0.92), and SAP

Background & Aims Primary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin. Methods We included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin. Results At baseline, the median (range) ELF test was 9.3 (7.5–12.9) and median LSM 1.26 m/s (0.66–3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p = 0.005, vs. 0.12 point/year, 95% CI [0.03, 0.21], p = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86). Conclusions ELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC. Lay summary Primary sclerosing cholangitis (PSC) is characterised by substantial disease variability between patients and fluctuating liver biochemistries. Hence, new biomarkers are needed to identify individuals with an increased risk of developing end-stage liver disease. We explore the change over time of 2 putative prognostic biomarkers in PSC, the serum Enhanced Liver Fibrosis (ELF®) test and LSMs by ultrasound, demonstrating differences that may reflect differing abilities to discriminate risk., Graphical abstract, Highlights • ELF and LSM increased in patients with PSC, but only in patients with ALP >1.5× ULN. • ELF may be more reliable for PSC risk stratification (low within-patient variation). • A subgroup showed concomitant spontaneous reduction in ALP, ELF, and LSM.

Autoimmune hepatitis is a chronic liver disease which, if untreated, can lead to cirrhosis of the liver and liver failure. The majority of patients respond well to standard immunosuppressive therapy, but some experience adverse effects, or lack of treatment efficacy. Diagnosis, assessment of therapeutic response and choice of second-line therapy may be challenging. This article provides a summary of updated knowledge concerning diagnosis and treatment of patients with complex autoimmune hepatitis.

Background & Aims To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD). Methods Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses. Results Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Qfdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation–free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD. Conclusions The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC. publishedVersion

Purpose Controlled attenuation parameter (CAP) is a non-invasive method to assess the presence of liver steatosis. It has been evaluated in children and adults, mainly in either the obese or in subjects with suspected liver disease. Our aim was to describe CAP in healthy non-obese subjects without suspected liver steatosis and to suggest cutoff levels for steatosis. Materials and Methods We prospectively recruited 187 individuals aged 8–70 years. All underwent clinical examination, including height and weight measurement. Body mass index (BMI) was calculated and converted into z-scores. To exclude liver pathology, B-mode ultrasound and liver stiffness measurements were performed in all prior to CAP measurement. Blood was drawn for liver biochemistry in adults. Results CAP was associated with BMI z-score across all ages. CAP started to rise alongside BMI z-score already in subjects with a BMI below average. CAP values were higher in adults than in children (p Conclusion CAP was correlated with BMI z-score, even in individuals with a below-average BMI . We found CAP above published cutoff values in a substantial proportion of presumably healthy, non-obese children and adults, warranting further research to clarify whether this represents non-obese non-alcoholic fatty liver disease or if reference values need adjustment.

Background and Aims: Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. Approach and Results: Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86). Conclusions: Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials. acceptedVersion

The aim of the study described here was to characterize three different liver elastography methods in primary sclerosing cholangitis (PSC) patients, for the first time exploring 2-D shear wave elastography (2-D-SWE) in PSC patients and its putative advantages over point shear wave elastography (pSWE). Sixty-six adult PSC patients (51 males, 77%) underwent liver elastography: Transient elastography (TE), pSWE and 2-D-SWE were applied head-to-head after B-mode ultrasonography and blood tests. Liver stiffness measurements (LSMs) by pSWE yielded lower values than those by TE; 2-D-SWE had less steep slope but was overall not significantly different from TE. Correlation between LSMs by pSWE and TE was excellent (intraclass correlation coefficient = 0.92); correlation for 2-D-SWE with either pSWE or TE was moderate but improved with exclusion of overweight individuals. LSMs correlated with the Enhanced Liver Fibrosis test (ELF) across all scanner systems. Our study indicates that LSM by different systems is feasible in PSC patients and that 2-D-SWE tends to underestimate stiffness compared with TE. publishedVersion

Background & Aims Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are phenotypically distinct autoimmune liver diseases that progress to cirrhosis and liver failure; however, their histological fibrosis distribution differs. We investigated the extracellular matrix (ECM) profiles of patients with PSC, PBC, and AIH to establish whether the diseases display differential patterns of ECM turnover. Methods Serum samples were retrospectively collected from the UK (test cohort; PSC n = 78; PBC n = 74; AIH n = 58) and Norway (validation cohort; PSC n = 138; PBC n = 28; AIH n = 27). Patients with ulcerative colitis without liver disease (n = 194) served as controls. We assessed specific serological biomarkers of ECM turnover: type III and V collagen formation (PRO-C3, PRO-C5), degradation of type III and IV collagen (C3M, C4M), biglycan (BGM) and citrullinated vimentin (VICM). Results Most of the ECM markers showed elevated serum levels in PBC compared with PSC or AIH (p, Graphical abstract, Highlights • Serological biomarkers specifically targeting extracellular matrix remodelling enable evaluation of the dynamics of fibrosis evolution. • ECM turnover was increased in PBC compared with PSC and AIH. • ECM markers, particularly PRO-C3, were associated with disease stage in the autoimmune liver diseases and with clinical outcome in PSC.

Most patients with autoimmune hepatitis respond well to standard immunosuppressive therapy with steroids and azathioprine, and while untreated disease is usually fatal, patients who respond well to therapy have an excellent prognosis. However, insufficient response to standard therapy or intolerable side effects requiring dose adaptions or treatment changes occur in 10–20% of patients. While there is fairly good agreement on second-line treatment options, there is very wide variation in the indication and use of possible third-line therapies. Herein, the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the International Autoimmune Hepatitis Group (IAIHG) outline a treatment algorithm for both children and adults that should help to standardise treatment approaches, in order to improve patient care and to enable the comparison of treatment results between scientific publications. acceptedVersion

Background Magnetic resonance enterography (MRE) has become an important tool in the diagnosis and follow-up of Crohn’s disease (CD). MRE findings are used in the calculation of the Lémann index (LI), a score that quantifies accumulated bowel damage. However, calculating the score is demanding; thus, serum biomarkers reflecting tissue damage and fibrosis are warranted for monitoring purposes. Increased extracellular matrix (ECM) remodelling and collagen tissue deposition is the result of accumulated bowel damage, eventually leading to intestinal fibrosis; particularly, the basement membrane and interstitial matrix are affected. We aimed to investigate ECM serum biomarkers of type III collagen formation (PRO-C3), type IV collagen degradation (C4M), degradation of citrullinated vimentin (VICM) and their association with LI and the degree of bowel wall fibrosis assessed by contrast-enhanced MRE in CD patients. Methods Serum from CD patients was analysed (n = 85, part of IBSEN population). Competitive ELISA was applied for the quantification of PRO-C3, C4M and VICM in the serum samples. The LI score was calculated based on the surgical history, MRE findings and the endoscopy findings. The suggested cut-off for substantial bowel damage is LI >/= 2. Increased contrast enhancement of the bowel wall at 5 min and the presence of stenosis on MRE was considered severe fibrosis. Student’s t-test, Spearman’s r correlation and one-way-ANOVA with FDR correction was applied for statistical analysis. Results Serum levels of C4M were elevated in patients with confirmed fibrosis by contrast MRE compared with patients without fibrosis (p = 0.031, AUC: 0.61) (Figure 1A). VICM correlated to the LI score in CD patients (r = 0.26, p = 0.015) and serum VICM levels were elevated in patients with an LI score >2 (p = 0.005, AUC: 0.67) (Figure 1B). VICM was significantly associated with intestinal damage for LI > 20 (LI 0 vs. >20: p = 0.005, AUC: 0.72). PRO-C3 was not associated with intestinal damage or intestinal fibrosis. Conclusion Our results indicate that the accumulated intestinal damage and the bowel wall fibrosis in CD are associated with elevated serum levels of VICM and C4M, respectively. Thus, serological biomarkers of basement membrane degradation and inflammation may be a useful tool to monitor intestinal tissue damage and fibrosis development.

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation.

Background & Aims: One important hypothesis in primary sclerosing cholangitis pathophysiology suggests that bacterial products from an inflamed leaky gut lead to biliary inflammation. We aimed to investigate whether circulating markers of bacterial translocation were associated with survival in a Norwegian primary sclerosing cholangitis cohort. Methods: Serum levels of zonulin, intestinal fatty acid binding protein, soluble CD14, lipopolysaccharide and lipopolysaccharide‐binding protein were measured in 166 primary sclerosing cholangitis patients and 100 healthy controls. Results: Lipopolysaccharide‐binding protein and soluble CD14 were elevated in primary sclerosing cholangitis compared with healthy controls (median 13 662 vs 12 339 ng/mL, P = 0.010 and 1657 vs 1196 ng/mL, P optimal cut‐off using receiver operating characteristics) were associated with reduced liver transplantation–free survival (P

Autotaxin has been associated with liver disease severity and transplant-free survival. This study aimed to validate autotaxin as a biomarker in two cohorts of Norwegian large-duct PSC patients, one discovery panel (n = 165) and one validation panel (n = 87). Serum activity of autotaxin was measured in diluted sera by a fluorometric enzymatic assay. Patients reaching an end-point, liver transplantation or death, (discovery panel: n = 118 [71.5%]; validation panel: n = 35 [40.2%]), showed higher autotaxin activity compared with the other patients, P P = 0.004, respectively. Kaplan-Meier survival analyses showed a strong association between increasing autotaxin activity and shorter liver transplant-free survival (discovery panel: P P = 0.001). There was no relationship between autotaxin activity and the presence of inflammatory bowel disease or occurrence of hepatobiliary malignancy. In a multivariable analysis, high autotaxin activity was associated with an increased risk of liver transplantation or death (hazard ratio 2.03 (95% confidence interval 1.21–3.40), P

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). [GRAPHICS]

Several different platforms providing ultrasound elastography have emerged in recent years. In this in vitro study on a single tissue-mimicking phantom (CIRS Model 49), we aimed to compare the performance of quantitative elastography measurements from platforms running strain elastography and others running shear wave elastography. We evaluated five different elastography platforms using both linear and curvilinear probes. All measurements were performed in parallel by two independent investigators who recorded the elasticity quantitatively. We investigated intra- and inter-observer agreement by intra-class correlation analysis and coefficient of variation, by correlation and limits of agreement. The reproducibility of elasticity measurements was good to excellent for shear wave and strain elastography. All five elastography platforms had high intra-observer (intra-class correlation coefficient: 0.932–1.0) and inter-observer correlation (intra-class correlation coefficient: 0.845–0.996). All inclusions could be differentiated by quantitative elastography by all systems (p

Point shear wave elastography (pSWE) is an ultrasound-based method for non-invasive quantification of liver fibrosis. The objective of this study was to explore liver pSWE in patients with primary sclerosing cholangitis (PSC) for assessment of fibrosis. Fifty-five non-transplant patients with PSC (38 males, 17 females; mean age: 46.4 y) were included and compared with 24 matched controls. Median (range) PSC duration was 8.1 (0–33) y. Ultrasonographic scanning followed by liver stiffness measurement by pSWE was performed using a conventional ultrasound system (Philips iU22). Signs of liver fibrosis on B-mode were identified in 21 patients (38%). Splenomegaly was found in 19 patients (35%) and ascites in two patients (4%). Successful pSWE measurements were achieved in the right liver lobe of all individuals and in the left liver lobe of 36 patients (65.5%). PSC patients had significantly higher median shear wave velocity (SWV) than controls in the right liver (median [range] SWV 1.26 [0.73–2.57] m/s vs. 1.09 [0.88–1.25] m/s, p