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Introduction: Patient, clinician, and system-related barriers may affect adherence to hepatocellular carcinoma (HCC) surveillance programmes. The impact of a dedicated automated recall HCC surveillance programme on retention rates in patients eligible for screening is unknown. We aimed to describe and evaluate a large HCC surveillance programme in a publicly funded healthcare system., Methods: Data were collected from January 1, 2013, to December 31, 2022, from a retrospective cohort of subjects enrolled in a publicly funded automated recall semi-annual surveillance programme as per the American Association for the Study of Liver Disease HCC guidance in the Calgary Health Zone (~1.6 million), Canada. Patients were excluded if there was incomplete data or did not meet indications for surveillance. Cox regression was used to identify predictors of non-retention to surveillance., Results: A total of 7269 patients were included. The median was age 55.5 years (IQR: 45.5-63.8), 60% were male, 46% were of Asian descent, 51% had HBV infection, and 36% had cirrhosis (35% alcohol-related). Median follow-up was 4.9 years (IQR: 1.5-7.2). Overall, 52% (n = 3768) of patients were retained in the surveillance programme, while 8.3% (n = 603) left for potential medical reasons, and 40% (n = 2898) were lost in follow-up. The median time in the programme for those lost in follow-up was 0.81 years (IQR: 0.0-2.8) compared to 6.75 years if retained (IQR: 5.6-8.6; p < 0.001). In multivariable Cox regression analysis, HCV aetiology (HR 1.41; CI 1.23-1.62, p < 0.01), African ethnicity (HR 1.20, CI 1.02-1.42, p = 0.03), and cirrhosis (HR 1.16, CI 1.05-1.28, p < 0.01) increased risk of dropout. On interaction analysis, Hepatitis B amongst cirrhotic patients also increased risk of dropout (HR 1.48, CI 1.05-2.07, p = 0.02)., Conclusion: A dedicated automated recall HCC surveillance programme has a high retention rate in a large multi-ethnic cohort of patients while identifying certain marginalised patient populations, such as those with viral liver disease, cirrhosis, or African ethnicity, as particularly vulnerable to loss to follow-up., (© 2025 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Introduction and Objectives: Prevalence estimates are crucial for enhancing preparedness to prevent and manage chronic diseases. This is the first study to estimate the prevalence of hepatic steatosis and advanced fibrosis in Canada, leveraging a nationally representative survey and multiple validated non-invasive tests (NITs)., Materials and Methods: The Canadian Health Measures Survey (CHMS) is Canada's largest direct health measures survey, which collects data on sociodemographic, clinical factors, and blood chemistry. We determined steatosis using two NITs: the Hepatic Steatosis Index (HSI) and the NAFLD Ridge Score (NRS). The FIB-4 Index and NAFLD fibrosis score (NFS) were used to assess the risk of advanced fibrosis among adults with steatosis. Survey weights were incorporated to account for oversampling, survey nonresponse, and post-stratification., Results: Between 2009 and 2019, 1365 children (55 % males, median age 13 (IQR: 10-15) and 4664 adults (51 % males, median age 45 (IQR: 34-62), 57 % reporting weekly alcohol consumption) were included in our study. The weighted steatosis prevalence ranged from 9 to 11 % among children to 38-48 % among adults based on the NRS and HSI, respectively. Between 86-87 % of adults with type 2 diabetes and 65-72 % with hypertension had evidence of steatosis. Overall, 1.2-2.4 % of adults with steatosis were at risk of advanced liver fibrosis., Conclusions: We estimate between 1 in 3 and 1 in 2 adults have hepatic steatosis, and 195,000-406,200 are at high risk of advanced liver fibrosis in Canada. No routine screening guidelines for liver fibrosis exist in Canada, and most patients are unaware of their condition. Prevalence studies are essential for raising awareness and advocating for the inclusion of steatotic liver disease on national public health agendas., Competing Interests: Declaration of interests Giada Sebastiani has acted as speaker for Merck, Gilead, Abbvie, Novo Nordisk, Pfizer, served as an advisory board member for Pfizer, Merck, Novo Nordisk, Gilead, and has received unrestricted research funding from Theratecnologies Inc. Mark Swain has served in an advisory role for Ipsen, Novo Nordisk, GSK, Abbott, Advanz, as a speaker for Abbott, and has received clinical trial or research support from Gilead, BMS, CymaBay, Intercept, Genfit, Pfizer, Novartis, Astra Zeneca, GSK, Celgene, Novo Nordisk, Axcella Health Inc., Merck, Galectin Therapeutics, Calliditas Therapeutics, Madrigal, AbbVie, Altimmune, Roche, Kowa, Ipsen, Intercept, 89Bio. Keyur Patel Advisor/Consultant- Novo Nordisk, Merck, Resalis; DSMB- Gilead Sciences, Galectin. Alnoor Ramji has acted as an advisor /consultant for Abbvie, Gilead, Intercept/ Advanz, Janssen, Novo-Nordisc, Pfizer and has grant/research support from Abbvie, Galmed, Gilead, Intercept, Janssen, Merck, Novartis, Novo-Nordisk. Sahar Saeed has served as an advisory board member for Novo Nordisk., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Primary sclerosing cholangitis is a chronic liver disease associated with significant morbidity, mortality, and healthcare utilization. We conducted a systematic review and meta-analysis of population-based studies of the incidence and prevalence of primary sclerosing cholangitis., Methods: Medline and Embase were systematically searched to identify population-based studies of a defined geographic area and reported the incidence or prevalence of primary sclerosing cholangitis in the general population. Meta-analyses, using random-effects, were performed to calculate overall and country-specific incidence (per 100 000 persons/year) and prevalence rates (per 100 000 persons) with 95% confidence intervals., Results: The 14 studies on incidence and the 12 for prevalence originated from North America, Asia, Europe, and Oceania. Incidence and prevalence rates of primary sclerosing cholangitis were 0.87 (95% confidence interval, 0.59-1.29) and 13.53 (95% confidence interval, 10.20-17.94) per 100 000 persons, respectively., Conclusions: Both the prevalence and incidence of primary sclerosing cholangitis is low in the general population. Future studies on the incidence and prevalence of primary sclerosing cholangitis in the general population should be directed at Asia, Africa, and Latin America to allow for a more robust assessment of the global epidemiology of primary sclerosing cholangitis., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To evaluate health system use, health outcomes, and avoided costs when patients with chronic gastrointestinal (GI) conditions are managed in the medical home., Design: A retrospective, observational cohort study was conducted through a single-point-of-entry referral system., Setting: Calgary, Alta., Participants: Patients with referrals for any of 7 nonurgent indications., Main Outcome Measures: Patients with referrals for any of 7 nonurgent indications were returned to primary care for management, guided by evidence-based primary care pathways. Patients were linked to administrative databases to extract indications, re-referral rates, endoscopy findings and outcomes, number of emergency department and urgent care visits, and number of hospital admissions. Costs avoided were estimated using Canadian Institute for Health Information data for health care use, consultation, and endoscopy., Results: Between July 1, 2018, and May 31, 2020, a total of 3435 routine referrals were closed for 3274 patients. The most common pathway used was dyspepsia (1154 of 3435, 33.6%). A total of 362 patients (11.1%) had 616 GI-related emergency department or urgent care visits; 52 (1.6%) patients experienced 68 GI-related hospitalizations. A total of 396 patients (12.1%) underwent endoscopy; of the 348 patients with findings available for analysis, 7.8% exhibited a clinically significant finding. The estimated total cost avoided was $1,477,237., Conclusion: The implementation of co-developed primary care pathways safely supports the care of patients with common, nonurgent GI conditions within the medical home. In this population, rates of re-referral and health care use were low, resulting in avoidance of substantial costs and improved overall appropriateness of care., (Copyright © 2024 the College of Family Physicians of Canada.)

Patient-reported outcomes (PROs), such as health-related quality of life (HRQL), are important outcome measures for patients with chronic liver diseases (CLDs). Presence of cirrhosis and advanced liver disease have been associated with worsened HRQL and fatigue. On the other hand, some patients with earlier stages of CLD also experience fatigue, causing PRO impairment. Treatment for some CLDs may improve HRQL and, sometimes, levels of fatigue. We aimed to provide an in-depth expert review of concepts related to fatigue and HRQL in patients with primary biliary cholangitis, hepatitis C virus and MASLD (metabolic dysfunction-associated steatotic liver disease). A panel of experts in fatigue and CLD reviewed and discussed the literature and collaborated to provide this expert review of fatigue in CLD. Herein, we review and report on the complexity of fatigue, highlighting that it is comprised of peripheral (neuromuscular failure, often in conjunction with submaximal cardiorespiratory function) and central (central nervous system dysfunction) causes. Fatigue and HRQL are measured using validated self-report instruments. Additionally, fatigue can be measured through objective tests (e.g. grip strength). Fatigue has deleterious effects on HRQL and one's ability to be physically active and socially engaged but does not always correlate with CLD severity. Treatments for hepatitis C virus and MASLD can improve levels of fatigue and HRQL, but current treatments for primary biliary cholangitis do not seem to affect levels of fatigue. We conclude that obtaining PRO data, including on HRQL and fatigue, is essential for determining the comprehensive burden of CLD and its potential treatments., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Treatment outcomes for people living with autoimmune hepatitis (AIH) are limited by a lack of specific therapies, as well as limited well-validated prognostic tools and clinical trial endpoints. We sought to identify predictors of outcome for people living with AIH., Methods: We evaluated the clinical course of people with AIH across 11 Canadian centres. Biochemical changes were analysed using linear mixed-effect and logistic regression. Clinical outcome was dynamically modelled using time-varying Cox proportional hazard modelling and landmark analysis., Results: In 691 patients (median age 49 years, 75.4% female), with a median follow-up of 6 years (25th-75th percentile, 2.5-11), 118 clinical events occurred. Alanine aminotransferase (ALT) normalisation occurred in 63.8% of the cohort by 12 months. Older age at diagnosis (odd ratio [OR] 1.19, 95% CI 1.06-1.35) and female sex (OR 1.94, 95% CI 1.18-3.19) were associated with ALT normalisation at 6 months, whilst baseline cirrhosis status was associated with reduced chance of normalisation at 12 months (OR 0.52, 95% CI 0.33-0.82). Baseline total bilirubin, aminotransferases, and IgG values, as well as initial prednisone dose, did not predict average ALT reduction. At baseline, older age (hazard ratio [HR] 1.25, 95% CI 1.12-1.40), cirrhosis at diagnosis (HR 3.67, 95% CI 2.48-5.43), and elevated baseline total bilirubin (HR 1.36, 95% CI 1.17-1.58) increased the risk of clinical events. Prolonged elevations in ALT (HR 1.07, 95% CI 1.00-1.13) and aspartate aminotransferase (HR 1.13, 95% CI 1.06-1.21), but not IgG (HR 1.01, 95% CI 0.95-1.07), were associated with higher risk of clinical events. Higher ALT at 6 months was associated with worse clinical event-free survival., Conclusion: In people living with AIH, sustained elevated aminotransferase values, but not IgG, are associated with poorer long-term outcomes. Biochemical response and long-term survival are not associated with starting prednisone dose., Impact and Implications: Using clinical data from multiple Canadian liver clinics treating autoimmune hepatitis (AIH), we evaluate treatment response and clinical outcomes. For the first time, we apply mixed-effect and time-varying survival statistical methods to rigorously examine treatment response and the impact of fluctuating liver biochemistry on clinical event-free survival. Key to the study impact, our data is 'real-world', represents a diverse population across Canada, and uses continuous measurements over follow-up. Our results challenge the role of IgG as a marker of treatment response and if normalisation of IgG should remain an important part of the definition of biochemical remission. Our analysis further highlights that baseline markers of disease severity may not prognosticate early treatment response. Additionally, the initial prednisone dose may be less relevant for achieving aminotransferase normalisation. This is important for patients and treating clinicians given the relevance and importance of side effects., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Biochemical response to ursodeoxycholic acid (UDCA) therapy is associated with good prognosis in people living with primary biliary cholangitis (PBC). Biochemical response is typically assessed early in disease and it is not known what proportion of patients lose previously attained biochemical response, nor whether this impacts long-term liver transplant (LT)-free survival., Methods: We identified all UDCA-treated patients with PBC from the Canadian Network for Autoimmune Liver disease with biochemical measurements at 1 year, and evaluated their liver biochemistry over time. Inadequate biochemical response was defined as serum alkaline phosphatase ≥1.67x the upper limit of normal or abnormal serum total bilirubin at 1 year of UDCA therapy and all time points thereafter. Multistate Markov models were used to estimate transition rates between biochemical response states and from each state to LT or death. Results were validated in an external cohort (GLOBAL PBC registry)., Results: A total of 823 patients from eight centers were included. Mean age at diagnosis was 53 years, 91% were female, 33% had inadequate biochemical response to UDCA at 1 year (n = 269). Patients who retained initial adequate response had lower rates of LT or death compared to patients who subsequently lost response (relative rate 0.102, 95% CI 0.047-0.223). Patients who regained adequate response had lower rates than patients who did not (0.016, 95% CI 0.001-0.568), and patients who lost response once more (0.010, 95% CI 0.001-0.340). Patients who regained adequate response for a third time also had lower rates than patients who did not (0.151, 95% CI 0.040-0.566). Analyses in the GLOBAL PBC registry (n = 2,237) validated these results., Conclusion: Loss of biochemical response at any time is associated with heightened risks of LT or death in people living with PBC. Achievement of biochemical response is an important goal throughout follow-up, regardless of biochemical response profile early in therapy., Impact and Implications: Early biochemical response to ursodeoxycholic acid is associated with good prognosis in patients with primary biliary cholangitis (PBC). Our work demonstrates that patients with PBC transition between biochemical response states over time, and that these transitions correspond with changes in risk of liver transplantation or death. Clinicians should re-evaluate risk and optimize treatment decisions for patients with PBC throughout follow-up, regardless of early biochemical response to therapy., (© 2024 The Author(s).)

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease worldwide. The current and projected cost of treating individuals with MASLD in Canada remains unknown. Our objective was to calculate the projected liver-specific and total health-care costs for people living with MASLD in Canada from 2020 to 2050., Methods: The health-care usage of a cohort of patients diagnosed with MASLD in Calgary, Alberta was calculated using administrative data. Liver-specific encounters were identified and the average costs per year per patient were calculated. Projected costs were calculated by multiplying the average cost per patient within each health state by the projected prevalence of each health state., Results: There were 6358 patients in the cohort. The annual average liver-specific cost per patient was $7.02 for F0/F1, $35.30 for F2, $60.46 for F3, and $72.55 for F4. The projected Canada-wide liver-specific cost was $85.5 million in 2020 and was expected to increase by $51 million by 2050. The average annual total health-care cost per patient was $397.90 for F0/F1, $781.53 for F2, $2881.84 for F3, and $1598.82 for F4. Thus, the projected Canada-wide total health-care cost was $3.76 billion in 2020 and was expected to increase by almost $2 billion by 2050., Conclusion: These estimates underscore the need for a MASLD framework that focuses on both prevention and innovative care models to change the predicted trajectory of health-care costs., (© 2024 The Authors.)

Altered metabolic function has many detrimental effects on the body that can manifest as cardiovascular and liver diseases. Traditional approaches to understanding and treating metabolic dysfunction-associated disorders have been organ-centered, leading to silo-type disease care. However, given the broad impact that systemic metabolic dysfunction has on the human body, approaches that simultaneously involve multiple medical specialists need to be developed and encouraged to optimize patient outcomes. In this review, we highlight how several of the treatments developed for cardiac care may have a beneficial effect on the liver and vice versa, suggesting that there is a need to target the disease process, rather than specifically target the cardiovascular or liver specific sequelae of metabolic dysfunction., Competing Interests: Declaration of competing interest GG received research grants from Gilead, ViiV, MERCK, Jansen and Pfizer; attended advisory boards and received speaker honoraria from Gilead, ViiV, MERCK and Pfizer. JM received speaker honoraria from Gilead and ViiV. MGS has served as an advisor for Gilead, Ipsen, Advanz, Pfizer, Roche, Abbott and Novo Nordisk; as speaker for Abbott; and has received clinical trial or research grant support from Gilead, BMS, CymaBay, Intercept, Genfit, Pfizer, Ipsen, Novartis, Astra Zeneca, GSK, Celgene, Novo Nordisk, Axcella Health Inc., Merck, Galectin Therapeutics, Calliditas Therapeutics, AbbVie, Kowa. Giada Sebastiani has acted as speaker for Merck, Gilead, AbbVie, Novo Nordisk, Pfizer, served as an advisory board member for Pfizer, Merck, Novo Nordisk, Gilead, and has received unrestricted research funding from Theratecnologies Inc. PR is a member of the advisory board of Amgen, Novo Nordisk, and Novartis., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Cholestatic liver diseases (CLD) are commonly associated with behavioral changes, including social isolation, that negatively affects patient quality of life and remains unaltered by current therapies. It remains unclear whether CLD-associated social dysfunction stems from a direct effect on the brain, or from the psychological impact of CLD. The psychological component of disease is absent in animals, so we investigated the impact of CLD on social behavior and gene expression profiles in key social behavior-regulating brain regions in a mouse model., Methods: CLD due to bile duct ligation was used with the three-chamber sociability test for behavioral phenotyping. Differentially expressed gene (DEG) signatures were delineated in 3 key brain regions regulating social behavior using RNA-seq. Ingenuity Pathway Analysis (IPA®) was applied to streamline DEG data interpretation and integrate findings with social behavior-regulating pathways to identify important brain molecular networks and regulatory mechanisms disrupted in CLD., Results: CLD mice exhibited enhanced social interactive behavior and significantly altered gene expression in each of the three social behavior-regulating brain regions examined. DEG signatures in BDL mice were associated with key IPA®-identified social behavior-regulating pathways including Oxytocin in Brain Signaling, GABA Receptor Signaling, Dopamine Receptor Signaling, and Glutamate Receptor Signaling., Conclusions: CLD causes complex alterations in gene expression profiles in key social behavior-regulating brain areas/pathways linked to enhanced social interactive behavior. These findings, if paralleled in CLD patients, suggest that CLD-associated reductions in social interactions predominantly relate to psychological impacts of disease and may inform new approaches to improve management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown., Methods: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable])., Results: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting., Conclusions: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects., Aims: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC., Methods: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years., Results: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2., Conclusions: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year., Clinicaltrials: gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16., (© 2023 CymaBay Therapeutics, Inc and The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA)., Approach and Results: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events., Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Symptoms of fatigue, social withdrawal and mood disturbances are commonly encountered in patients with chronic liver disease and have a detrimental effect on patient quality of life. Treatment options for these symptoms are limited and a current area of unmet medical need. In this review, we will evaluate the potential mechanistic avenues within the gut-liver-brain axis that may be altered in the setting of chronic liver disease that drive the development of these symptoms. Both clinical and pre-clinical studies will be highlighted as we discuss how perturbations in host immune response, microbiome, neural responses, and metabolites composition can affect the central nervous system., 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 © 2023 Nguyen and Swain.)

Background: Behavioral symptoms, including mood disorders, substantially impact the quality of life of patients with inflammatory bowel disease (IBD), even when clinical remission is achieved. Here, we used multimodal magnetic resonance imaging (MRI) to determine if IBD is associated with changes in the structure and function of deep gray matter brain regions that regulate and integrate emotional, cognitive, and stress responses., Methods: Thirty-five patients with ulcerative colitis (UC) or Crohn's disease (CD) and 32 healthy controls underwent 3 Tesla MRIs to assess volume, neural activity, functional connection strength (connectivity), inflammation, and neurodegeneration of key deep gray matter brain regions (thalamus, caudate, pallidum, putamen, amygdala, hippocampus, and hypothalamus) involved in emotional, cognitive and stress processing. Associations with sex, presence of pain, disease activity, and C-reactive protein (CRP) concentration were examined., Results: Significantly increased activity and functional connectivity were observed in cognitive and emotional processing brain regions, including parts of the limbic system, basal ganglia, and hypothalamus of IBD patients compared with healthy controls. Inflammatory bowel disease patients exhibited significantly increased volumes of the amygdala and hypothalamus, as well as evidence of neurodegeneration in the putamen and pallidum. Hippocampal neural activity was increased in IBD patients with active disease. The volume of the thalamus was positively correlated with CRP concentration and was increased in females experiencing pain., Conclusions: Patients with IBD exhibit functional and structural changes in the limbic and striatal systems. These changes may be targets for assessing or predicting the response to therapeutic interventions aimed at improving comorbid emotional and cognitive symptoms., (© The Author(s) 2022. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is a real unmet need for primary biliary cholangitis (PBC) treatments that can improve quality of life impacting symptoms. In this post hoc analysis, we evaluated potential effects of the NADP oxidase 1/4 inhibitor, setanaxib, on patient-reported quality of life from a phase 2 trial in PBC., Patients and Methods: The underpinning double-blind, randomized, placebo-controlled trial (NCT03226067) recruited 111 patients with PBC and inadequate response/intolerance to ursodeoxycholic acid. Patients self-administered oral placebo (n=37), setanaxib 400 mg once daily (OD; n=38), or setanaxib 400 mg twice daily (BID; n=36), in addition to ursodeoxycholic acid for 24 weeks. Quality of life outcomes were assessed using the validated PBC-40 questionnaire. Patients were stratified post hoc by baseline fatigue severity., Results: At week 24, patients treated with setanaxib 400 mg BID reported greater mean (SE) absolute reductions from baseline in PBC-40 fatigue domain score [-3.6 (1.3)] versus those receiving setanaxib 400 mg OD [-0.8 (1.0)]) or placebo [0.6 (0.9)]. Similar observations were made across all PBC-40 domains except itch. In the setanaxib 400 mg BID arm, patients with moderate-to-severe fatigue at baseline had a greater reduction in mean fatigue score at week 24 [-5.8 (2.1)] versus those with mild fatigue [-0.6 (0.9)]; results were similar across all domains. Reduced fatigue was correlated with emotional, social, symptom, and cognitive improvements., Conclusions: These results support further investigation of setanaxib as a treatment for patients with PBC, particularly for those with clinically significant fatigue., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Depression is common in patients with chronic viral hepatitis. We evaluated the impact of major depressive disorder (MDD) and antidepressant use on survival among patients with HBV and HCV., Methods: We used The Health Improvement Network database, the largest medical database in the UK, to identify incident HBV (n=1401) and HCV (n=1635) in patients between 1986 and 2017. Our primary composite outcome was the development of decompensated cirrhosis or death. MDD and each class of antidepressants were assessed in multivariate Cox proportional hazards models. Models were adjusted for age, sex, and clinical comorbidities., Results: The prevalence of MDD among HCV patients was higher compared with HBV patients (23.5% vs. 9.0%, p<0.001, respectively). Similarly, HCV patients were more likely to use antidepressants (59.6%) compared with HBV patients (27.1%), p>0.001. MDD was not an independent predictor for decompensated cirrhosis-free survival or mortality. However, the use of tricyclic and tetracyclic antidepressants (TCAs) was associated with poor decompensated cirrhosis-free survival in HBV and HCV cohorts (adjusted HR: 1.80, 95% CI, 1.00-3.26 and 1.56, 95% CI, 1.13-2.14, respectively). Both TCAs in the HBV cohort and selective serotonin reuptake inhibitors among the HCV cohort were associated with poor overall survival (adjusted HR: 2.18, 95% CI, 1.16-4.10; 1.48, 95% CI, 1.02-2.16, respectively)., Conclusions: Although prevalent among viral hepatitis patients, MDD did not affect disease progression or survival in either HBV or HCV cohorts. TCA use was associated with poor decompensated cirrhosis-free survival. Therefore, its use should be further studied among viral hepatitis patients., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

NASH is a potentially progressive form of NAFLD characterized by hepatocyte injury and liver inflammation which can cause fibrosis. Currently, there are limited data on the patient experience of NASH. Our aim was to use both literature review and patient interviews to understand the signs/symptoms and life impacts of NASH fibrosis stages F1-F4 that are important to patients, as well as begin to investigate the applicability of an instrument (ie, questionnaire) that may be used to capture patients' experiences. The literature review identified concepts (signs/symptoms and impacts) related to NASH fibrosis stages F1-F4 and the NASH-specific patient-reported outcome instrument (NASH-CHECK) for reporting patient experience of NASH. Interviews with 22 patients from Canada and the USA with NASH fibrosis stages F1-F4 revealed 27 signs/symptoms and 32 impacts that they felt were important, including fatigue, pain in the abdomen, worry, and frustration. Three concepts reported during patient interviews were not identified in the literature review. No concepts appeared to be exclusive to a specific fibrosis stage or presence/absence of obesity and no linear trends were identified between fibrosis stage or presence/absence of obesity and level of disturbance reported for concepts. The patient interviews supported the concepts included in the NASH-CHECK overall, demonstrating that it could be used to report the patient experience of NASH fibrosis stages F1-F4. Interviews with patients with NASH fibrosis stages F1-F4 revealed patients can self-report and elaborate on signs/symptoms and impacts related to the disease regardless of fibrosis stage. The NASH-CHECK was identified as a suitable instrument that could be used by patients with fibrosis stages F1-F4., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Objective: The rationale for this study was based on reports that valosin-containing protein (VCP) mutations are found in hereditary inclusion body myositis (IBM) and VCP was detected in rimmed vacuoles of sporadic IBM (sIBM) muscle biopsies. Autoantibodies to VCP have not been reported in sIBM or other inflammatory myopathies (IIMs). The aim of this study was to determine the frequency and clinical significance of anti-VCP antibodies in sIBM and other IIMs., Methods: Sera were collected from 73 patients with sIBM and 383 comparators or controls, including patients with IIM (n = 69), those with juvenile dermatomyositis (JDM) (n = 67), those with juvenile idiopathic arthritis (JIA) (n = 47), those with primary biliary cholangitis (PBC) (n = 105), controls that were age matched to patients with sIBM (similarly aged controls [SACs]) (n = 63), and healthy controls (HCs) (n = 32). Immunoglobulin G antibodies to VCP were detected by addressable laser bead immunoassay using a full-length recombinant human protein., Results: Among patients with sIBM, 26.0% (19/73) were positive for anti-VCP. The frequency in disease controls was 15.0% (48/320). Among SACs, the frequency was 1.6% (1/63), and in HCs 0% (0/32). Frequencies were 17.5% (11/63) for IIM, 25.7% (27/105) for PBC, 3.0% (2/67) for JDM, and 17.0% (8/47) for JIA. The sensitivity, specificity, positive predictive value, and negative predictive value of anti-VCP for sIBM were 26.0%, 87.2%, 28.4%, and 85.9%, respectively. Of patients with sIBM, 15.1% (11/73) were positive for both anti-VCP and anti-cytosolic 5'-nucleotidase 1A (NT5c1A). Eleven percent of patients (8/73) were positive for anti-VCP, but negative for anti-NT5c1A., Conclusion: Anti-VCP has low sensitivity and moderate specificity for sIBM but may help fill the seronegative gap in sIBM. Further studies are needed to determine whether anti-VCP is a biomarker for a clinical phenotype that may have clinical value., (© 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

BACKGROUND: Identifying strategies for stopping nucleos(t)ide analogues (NUC) in patients with chronic hepatitis B (CHB) is a major goal in CHB management. Our study describes our tertiary-centre experience stopping nucleos(t)ide analogues (NUC) in CHB. METHODS: We conducted a retrospective cohort study of all individuals with CHB seen at the Calgary Liver Unit between January 2009 and May 2020 who stopped NUC. We collected baseline demographics and HBV lab parameters before and after stopping NUC with results stratified by off-treatment durability. Clinical flare was defined as alanine aminotransferase (ALT) over twice the upper limit of normal and virological flare as HBV DNA >2000 IU/mL. RESULTS: Forty-seven (3.5%) of the 1337 individuals with CHB stopped NUC therapy. During follow-up, six patients (12.8%) restarted NUCs because of a flare. All flares occurred within six months of discontinuation. Median time to restart treatment was 90 days (Q1 65, Q3 133). Upon restarting, all showed suppression of HBV DNA and ALT normalization. Factors associated with restarting NUC therapy included hepatitis B e antigen (HBeAg) positive status at first appointment and longer NUC consolidation therapy. Age, sex, ethnicity, liver stiffness measurement, choice of NUC, and quantitative hepatitis B surface antigen (qHBsAg) level at stopping were not associated with sustained response off-treatment. Six patients had functional cure with HBsAg loss. CONCLUSIONS: Stopping long-term NUC is feasible in HBeAg negative CHB. Hepatic flares can occur despite low levels of qHBsAg. Finite NUC therapy can be considered in eligible patients who are adherent to close monitoring and follow-up, particularly in the first six months after stopping NUC therapy., (Copyright © 2022 Canadian Association for the Study of the Liver.)

Non-alcoholic fatty liver disease (NAFLD) is a significant public health concern worldwide with a complex etiology attributed to behavioural, environmental, and genetic causes. The worldwide prevalence of NAFLD is estimated to be 32.4% and constantly rising. Global data, however, indicate considerable heterogeneity among studies for both NAFLD prevalence and incidence. Identifying variables that affect the estimated epidemiological measures is essential to all stakeholders, including patients, researchers, healthcare providers, and policymakers. Besides helping with the research on disease etiology, it helps to identify individuals at risk of the disease, which in turn will outline the focus of the preventive measures and help to fittingly tailor individualized treatments, targeted prevention, screening, or treatment programs. Several studies suggest differences in the prevalence and severity of NAFLD by race or ethnicity, which may be linked to differences in lifestyle, diet, metabolic comorbidity profile, and genetic background, among others. Race/ethnicity research is essential as it can provide valuable information regarding biological and genetic differences among people with similar cultural, dietary, and geographical backgrounds. In this review, we examined the existing literature on race/ethnicity differences in susceptibility to NAFLD and discussed the contributing variables to such differences, including diet and physical activity, the comorbidity profile, and genetic susceptibility. We also reviewed the limitations of race/ethnicity studies in NAFLD.

Background & Aims: Colonoscopy quality indicators provide measurable assessments of performance, but significant provider-level variations exist. We performed a systematic review and meta-analysis to assess whether endoscopist specialty is associated with adenoma detection rate (ADR) - the primary outcome - or cecal intubation rate, adverse event rates, and post-colonoscopy colorectal cancer rates., Methods: We searched EMBASE, Google Scholar, MEDLINE, and the Cochrane Central Registry of Controlled Trials from inception to December 14, 2020. Two reviewers independently screened titles and abstracts. Citations underwent duplicate full-text review, with disagreements resolved by a third reviewer. Data were abstracted in duplicate. The DerSimonian and Laird random effects model was used to calculate pooled odds ratios (ORs) with respective 95% confidence intervals (CIs). Risk of bias was assessed using Risk of Bias in Non-randomised Studies of Interventions., Results: Of 11,314 citations, 36 studies representing 3,500,832 colonoscopies were included. Compared with colonoscopies performed by gastroenterologists, those by surgeons were associated with lower ADRs (OR, 0.81; 95% CI, 0.74-0.88) and lower cecal intubation rates (OR, 0.76; 95% CI, 0.63-0.92). Compared with colonoscopies performed by gastroenterologists, those by other (non-gastroenterologist, non-surgeon) endoscopists were associated with lower ADRs (OR, 0.91; 95% CI, 0.87-0.96), higher perforation rates (OR, 3.02; 95% CI, 1.65-5.51), and higher post-colonoscopy colorectal cancer rates (OR, 1.23; 95% CI, 1.14-1.33). Substantial to considerable heterogeneity existed for most analyses, and overall certainty in the evidence was low according to the Grading of Recommendations, Assessment, Development, and Evaluations framework., Conclusion: Colonoscopies performed by surgeons or other endoscopists were associated with poorer quality metrics and outcomes compared with those performed by gastroenterologists. Targeted quality improvement efforts may be warranted., (Published by Elsevier Inc.)

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and the leading cause of liver-related morbidity and mortality. We aimed to predict the burden of NAFLD by examining and estimating the temporal trends of its worldwide prevalence and incidence., Methods: In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, Scopus, and Web of Science without language restrictions for reports published between date of database inception and May 25, 2021. We included observational cross-sectional or longitudinal studies done in study populations representative of the general adult population, in whom NAFLD was diagnosed using an imaging method in the absence of excessive alcohol consumption and viral hepatitis. Studies were excluded if conducted in paediatric populations (aged <18 years) or subgroups of the general population. Summary estimates were extracted from included reports by KR and independently verified by HA using the population, intervention, comparison, and outcomes framework. Primary outcomes were the prevalence and incidence of NAFLD. A random-effects meta-analysis was used to calculate overall and sex-specific pooled effect estimates and 95% CIs., Findings: The search identified 28 557 records, of which 13 577 records were screened; 299 records were also identified via other methods. In total, 72 publications with a sample population of 1 030 160 individuals from 17 countries were included in the prevalence analysis, and 16 publications with a sample population of 381 765 individuals from five countries were included in the incidence analysis. The overall prevalence of NAFLD worldwide was estimated to be 32·4% (95% CI 29·9-34·9). Prevalence increased significantly over time, from 25·5% (20·1-31·0) in or before 2005 to 37·8% (32·4-43·3) in 2016 or later (p=0·013). Overall prevalence of NAFLD was significantly higher in men than in women (39·7% [36·6-42·8] vs 25·6% [22·3-28·8]; p<0·0001). The overall incidence of NAFLD was estimated to be 46·9 cases per 1000 person-years (36·4-57·5); 70·8 cases per 1000 person-years (48·7-92·8) in men and 29·6 cases per 1000 person-years (20·2-38·9) in women (p<0·0001). There was considerable heterogeneity between studies of both NAFLD prevalence (I 2 =99·9%) and NAFLD incidence (I 2 =99·9%)., Interpretation: Worldwide prevalence of NAFLD is considerably higher than previously estimated and is continuing to increase at an alarming rate. Incidence and prevalence of NAFLD are significantly higher among men than among women. Greater awareness of NAFLD and the development of cost-effective risk stratification strategies are warranted to address the growing burden of NAFLD., Funding: Canadian Institutes of Health., Competing Interests: Declaration of interests MGS declares receiving research grants from Gilead, Intercept, CymaBay, Genkyotex, GlaxoSmithKline, Genfit, Novartis, Pfizer, Galectin Therapeutics, Celgene, Astra Zeneca, Novo Nordisk, and AbbVie; and honoraria from Abbott, Gilead Roche, Intercept, Gilead, Abbott, and Novo Nordisk. SEC declares receiving research grants from Gilead, Boehringer Ingelheim, Genfit, Allergan, and Axcella Health; and honoraria from Interceot and AstraZeneca. A-AS declares receiving research grants from Gilead and Intercept; and honoraria from SCOPE Canada. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Primary biliary cholangitis (PBC) is a rare, chronic autoimmune, cholestatic liver disease affecting approximately 318 per million Canadians. There is limited information regarding the characterization of this patient population in Canada. Consequently, we aim to describe a cohort of PBC patients managed across liver centres serving this type of population., Methods: A cross-sectional examination of 1,125 PBC patient charts at 15 liver centres across Canada was conducted between January 2016 and September 2017., Results: Data from 1,125 eligible patients were collected from 7 Canadian provinces. The patient population was largely female (90.2%), had a median overall age of 61.3 years, and a median overall time since diagnosis of 6.4 years. Of the patients included in the study, 89% were on ursodeoxycholic acid (UDCA) therapy at a median dose of 14.0 mg/kg/day and 4.4% were previously treated with UDCA, whereas 6.6% were never treated with UDCA. Of the patients with available data (n = 1067), 289 (27.1%) presented with alkaline phosphatase (ALP) levels ≥200 IU/L and/or total bilirubin levels ≥21 µmol/L. Assessment of UDCA treatment response revealed that 26.6% and 38.3% of patients were inadequate responders according to the Toronto and Paris-II criteria, respectively. Mortality occurred in 1.2% (14) of patients, with liver-related adverse outcomes being more commonly observed in patients who discontinued UDCA compared to those who are currently on treatment (36.3% and 19.6%, respectively)., Conclusion: This study showed that Canadian PBC patients present with demographics and features commonly reported in the literature for this disease. Over one third of PBC patients had inadequate response to UDCA treatment or were not currently being treated with UDCA. Consequently, there is a significant unmet therapeutic need in this Canadian PBC population., Competing Interests: EM Yoshida has received an unrestricted research grant from Paladin Laboartories and clinical trials sponsorship from Gilead Sciences, Intercept, Abbvie, Merck, Genfit, Pfizer, Celgene, Allergan, and Madrigal. He has also received honoraria for CME/Ad Board lectures from Intercept, Gilead, and Merck. He is President of the Vancouver Medical Dental Allied Staff Association; C Tsien received grants/contracts from Lupin, and payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Abbvie and Intercept; MG Swain received grants/contracts for research studies from Gilead, Intercept, CymaBay, Genkyotex, GSK, Genfit, Novartis, Pfizer, Celgene, AstraZeneca, AbbVie, and Novo Nordisk, payment or honoraria for lectures and presentations from Gilead, Intercept, and AbbVie, and participated on the advisory boards for Gilead, Novartis, and Intercept; KM Peltekian participated on the advisory board for Intercept and has held a leadership or fiduciary role on the Canadian Liver Foundation board; MA Puglia has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Intercept as well as support from them for attending meetings and/or travel and participating on their advisory board; M Elkhashab has received consulting fees and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AbbVie, Gilead, and Merck, as well as participated on the advisory boards for AbbVie, Gilead, and Merck; M O’Brien has received payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Intercept; HH Ko has received payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Intercept and has held a leadership or fiduciary role on the Intercept advisory board; E Tam has received consulting fees from Intercept as well as payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Intercept; A Ramji has received grants/contracts from AbbVie, Allergan, Assembly, Galmed, Gilead, Janssen, Intercept, Novartis, and Merck, as well as payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AbbVie, Allergan, Amgen, Celgene, Gilead, Intercept, Amgen, Janssen, Novartis, and Merck. He has participated on advisory board for AbbVie, Gilead, Janssen, Intercept, Novartis, Merck, and Novo Nordisk; the other authors have nothing to disclose., (Copyright © 2022 Canadian Association for the Study of the Liver.)

Background and Aims: We investigated associations between ethnicity, survival, and disease severity in a diverse Canadian cohort of patients with primary biliary cholangitis (PBC)., Approach and Results: Patients with PBC were included from the Canadian Network for Autoimmune Liver Disease. Ethnicity was defined using a modified list adopted from Statistics Canada, and ethnicities with small samples were grouped. Clinical events were defined as liver decompensation, HCC, liver transplantation, or death. Clinical event-free and liver transplantation-free survival were analyzed using Cox regression. Trajectories of serum liver function tests were assessed over time using mixed-effects regression. Health-related quality of life was assessed using the Short Form 36, the PBC-40 questionnaire, and the 5-D Itch scale and analyzed using mixed-effects regression. The cohort included 1538 patients with PBC from six sites and was comprised of 82% White, 4.7% Indigenous, 5.5% East Asian, 2.6% South Asian, and 5.1% miscellaneous ethnicities. Indigenous patients were the only ethnic group with impaired liver transplant-free and event-free survival compared to White patients (HR, 3.66; 95% CI, 2.23-6.01; HR, 3.09; 95% CI, 1.94-4.92). Indigenous patients were more likely to have a clinical event before diagnosis (10%) than all other ethnic groups despite similar age at diagnosis. Indigenous patients presented with higher alkaline phosphatase, total bilirubin, and GLOBE scores than White patients; and these relative elevations persisted during follow-up., Conclusions: Indigenous Canadians with PBC present with advanced disease and have worse long-term outcomes compared to White patients., (© 2022 American Association for the Study of Liver Diseases.)

Background & Aims: We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid., Methods: In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8., Results: Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events., Conclusions: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus., Gov Number: NCT02955602 CLINICALTRIALSREGISTER., Eu Number: 2016-002996-91 LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores., Competing Interests: Conflict of interest Christopher Bowlus has received grants from Arena Pharmaceuticals, Cara Therapeutics, Genfit, Genkyotex, and Novartis and grants and personal fees from CymaBay Therapeutics, Eli Lilly, Gilead, GlaxoSmithKline, and Intercept. Michael Galambos has received consulting and investigator fees from CymaBay Therapeutics. Richard Aspinall owns stock in CymaBay Therapeutics. Gideon M. Hirschfield has received personal fees from CymaBay Therapeutics, Genfit, GlaxoSmithKline, HighTide, Intercept Pharma, Mirum, and Pliant. David E. Jones has received personal fees from Abbott and Falk and personal fees and a grant from Intercept. Stuart C. Gordon has received personal fees and advisory board compensation from CymaBay Therapeutics and research support was paid to his institution by AbbVie, Brigham and Women’s Hospital, CymaBay Therapeutics, DURECT, Eiger, Genfit, Gilead, GlaxoSmithKline, Intercept, Merck, Pliant, Shire, and Viking. Stephen A. Harrison has received personal fees from AgonAB, Altimmune, Boston Pharmaceuticals, B Riley FBR, Canfite Biopharma, Echosens North America, Fibronostics, Foresite Labs, Fortress Biotech, GNS Healthcare, Histoindex Pte, Inipharm, Ionis, Kowa Research Institute, Medpace, Microba Pty, Nutrasource, Piper Sandler & Co, Prometic Pharma Smt, Ridgeline Therapeutics, Sonic Incytes Medical Corporation, and Terns; grants from Cirius Therapeutics, Galmed Research & Development, Hepion Pharmaceuticals, and Pathai; personal fees and grants from Akero Therapeutics, Axcella Health, Civi Biopharma, CymaBay Therapeutics, Enyo Pharma S.A., Galectin Therapeutics, Genfit, Gilead Sciences, High Tide, Intercept, Madrigal Pharmaceuticals, Metracrine, NGM Biopharmaceuticals, Northsea Therapeutics B.V., Novartis, Novo Nordisk, Poxel, Sagimet Biosciences, and Viking Therapeutics; advisory board compensation from 89Bio, Akero Therapeutics, Altimmune, Arrowhead Pharmaceuticals, Axcella Health, Civi Biopharma, CymaBay Therapeutics, Echosens North America, Foresite Labs, Galectin Therapeutics, Galmed Research & Development, Genfit, Gilead, Hepion Pharmaceuticals, High Tide, Histoindex Pte, Indalo Therapeutics, Intercept, Madrigal Pharmaceuticals, Medpace, Metacrine, NGM Biopharmaceuticals, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Prometic Pharma Smt, Ridgeline Therapeutics, Sagimet Biosciences, Terns, and Theratechnologies; and owns stock in Akero Therapeutics, Cirius Therapeutics, Galectin Therapeutics, Genfit, Hepion Pharmaceuticals, Histoindex Pte, Metacrine, NGM Biopharmaceuticals, Northsea Therapeutics B.V., and Pathai. Andreas E. Kremer has received personal fees from AbbVie, Bayer, CymaBay Therapeutics, Eisai, Eli Lilly, Escient, Falk, FMC, Gilead, GlaxoSmithKline, Mirum, MSD, Myr, Newbridge, Novartis, and Zambon and personal fees and a grant from Intercept. Marlyn J. Mayo has received consulting and investigator fees from CymaBay Therapeutics. Paul J. Thuluvath has received a grant from CymaBay Therapeutics. Cynthia Levy has received grants from Genkyotex, Gilead, High Tide, Intercept, Novartis, and Zydus and grants and personal fees from Cara Therapeutics, CymaBay Therapeutics, Genfit, and GlaxoSmithKline. Mark Swain has received grants from CymaBay Therapeutics and Genfit and a grant and personal fees from Intercept. Yvonne Dörffel, Guy Neff, David Sheridan, Carmen Stanca, Christoph Berg, and Aparna Goel have nothing to disclose. Mitchell L. Shiffman has received grants from CymaBay Therapeutics, High Tide, and Genfit and grants and personal fees from Intercept. John M. Vierling has received grants from Gilead, GlaxoSmithKline, and Intercept; personal fees from Intercept and Novartis; and personal fees and grants from CymaBay Therapeutics. Pol Boudes is a former employee of CymaBay Therapeutics who owns stock in CymaBay Therapeutics and holds a patent broadly relevant to this work. Alexandra Steinberg is a former employee of CymaBay Therapeutics who owns stock in CymaBay Therapeutics. Yun-Jung Choi is an employee of and owns stock in CymaBay Therapeutics. Charles McWherter is an employee of and owns stock in CymaBay Therapeutics and holds patents broadly relevant to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Autoimmune cholestatic liver disease includes both Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). Both conditions result in impairment of hepatic bile flow ultimately leading to chronic liver injury, liver fibrosis and eventually end stage cirrhosis. Early and accurate diagnosis are important for the risk stratification, follow up and management of these patients. The underlying pathogenesis of these conditions have not been completely resolved and poses a barrier for the development of new diagnostic and prognostics tools. Current research work suggests that the pathogenesis of autoimmune cholestatic liver disease results from environmental, genetic, and a large component of underlying immune dysfunction. While the current available serum biomarkers and imaging modalities showcases progression in precision medicine for the management of autoimmune cholestatic liver disease, development of new biomarkers are still an area of need in this field. In this review, we will discuss the current and emerging biomarkers in patients with PBC, PSC, and a special population that exhibit overlap syndrome with autoimmune hepatitis (AIH). The use of these biomarkers for diagnosis and prognosis of these patients will be reviewed through the lens of the current understanding of the complex immune pathophysiology of these conditions., Competing Interests: MJF is the Medical Director of Mitogen Diagnostics Corporation and has received honoraria and consulting fees from Werfen International, Aesku Diagnostics GmbH and Alexion Canada. MGS is a member of advisory boards for Gilead, Intercept and Roche, has served as a speaker for Gilead, Intercept and Abbott and receives clinical trial research support from Gilead, BMS, CymaBay, Intercept, Genfit, Pfizer, Novartis, Astra Zeneca, GSK, Celgene, Novo Nordisk, Axcella Health Inc., Merck, Galectin Therapeutics. 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 © 2022 Nguyen, Fritzler and Swain.)

Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract. IBD are associated with a high prevalence of cognitive, behavioural and emotional comorbidities, including anxiety and depression. The link between IBD and the development of behavioural comorbidities is poorly understood. As the intestinal microbiota profoundly influences host behaviour, we sought to determine whether the altered gut microbiota associated with intestinal inflammation contributes to the development of behavioural abnormalities. Using the dextran sulphate sodium (DSS) model of colitis, we characterized intestinal inflammation, behaviour (elevated plus maze and tail suspension test) and the composition of the microbiota in male mice. Cecal contents from colitic mice were transferred into germ-free (GF) or antibiotic (Abx)-treated mice, and behaviour was characterized in recipient mice. Gene expression was measured using qPCR. DSS colitis was characterized by a significant reduction in body weight and an increase in colonic inflammatory markers. These changes were accompanied by increased anxiety-like behaviour, an altered gut microbiota composition, and increased central Tnf expression. Transfer of the cecal matter from colitic mice induced similar behavioural changes in both GF and Abx-treated recipient mice, with no signs of colonic or neuroinflammation. Upon characterization of the microbiota in donor and recipient mice, specific taxa were found to be associated with behavioural changes, notably members of the Lachnospiraceae family. Behavioural abnormalities associated with intestinal inflammation are transmissible via transfer of cecal matter, suggesting that alterations in the composition of the gut microbiota play a key role in driving behavioural changes in colitis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background & Aims: Coronavirus disease 2019 (COVID-19) pandemic lockdown and restrictions had significant disruption to patient care. We aimed to evaluate the impact of COVID-19 restrictions on hospitalizations of patients with alcoholic and nonalcoholic cirrhosis as well as alcoholic hepatitis (AH) in Alberta, Canada., Methods: We used validated International Classification of Diseases (ICD-9 and ICD-10) coding algorithms to identify liver-related hospitalizations for nonalcoholic cirrhosis, alcoholic cirrhosis, and AH in the province of Alberta between March 2018 and September 2020. We used the provincial inpatient discharge and laboratory databases to identify our cohorts. We used elevated alanine aminotransferase or aspartate aminotransferase, elevated international normalized ratio, or bilirubin to identify AH patients. We compared COVID-19 restrictions (April-September 2020) with prior study periods. Joinpoint regression was used to evaluate the temporal trends among the 3 cohorts., Results: We identified 2916 hospitalizations for nonalcoholic cirrhosis, 2318 hospitalizations for alcoholic cirrhosis, and 1408 AH hospitalizations during our study time. The in-hospital mortality rate was stable in relation to the pandemic for alcoholic cirrhosis and AH. However, nonalcoholic cirrhosis patients had lower in-hospital mortality rate after March 2020 (8.5% vs 11.5%; P = .033). There was a significant increase in average monthly admissions in the AH cohort (22.1/10,000 admissions during the pandemic vs 11.6/10,000 admissions before March 2020; P < .001)., Conclusions: Before and during COVID-19 monthly admission rates were stable for nonalcoholic and alcoholic cirrhosis; however, there was a significant increase in AH admissions. Because alcohol sales surged during the pandemic, future impact on alcoholic liver disease could be detrimental., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Behavioral comorbidities, such as anxiety and depression, are a prominent feature of IBD. The signals from the inflamed gut that cause changes in the brain leading to these behavioral comorbidities remain to be fully elucidated. We tested the hypothesis that enhanced leukocyte-cerebral endothelial cell interactions occur in the brain in experimental colitis, mediated by α4β7 integrin, to initiate neuroimmune activation and anxiety-like behavior., Methods: Female mice treated with dextran sodium sulfate were studied at the peak of acute colitis. Circulating leukocyte populations were determined using flow cytometry. Leukocyte-cerebral endothelial cell interactions were examined using intravital microscopy in mice treated with anti-integrin antibodies. Brain cytokine and chemokines were assessed using a multiplex assay in animals treated with anti-α4β7 integrin. Anxiety-like behavior was assessed using an elevated plus maze in animals after treatment with an intracerebroventricular injection of interleukin 1 receptor antagonist., Results: The proportion of classical monocytes expressing α4β7 integrin was increased in peripheral blood of mice with colitis. An increase in the number of rolling and adherent leukocytes on cerebral endothelial cells was observed, the majority of which were neutrophils. Treatment with anti-α4β7 integrin significantly reduced the number of rolling leukocytes. After anti-Ly6C treatment to deplete monocytes, the number of rolling and adhering neutrophils was significantly reduced in mice with colitis. Interleukin-1β and CCL2 levels were elevated in the brain and treatment with anti-α4β7 significantly reduced them. Enhanced anxiety-like behavior in mice with colitis was reversed by treatment with interleukin 1 receptor antagonist., Conclusions: In experimental colitis, α4β7 integrin-expressing monocytes direct the recruitment of neutrophils to the cerebral vasculature, leading to elevated cytokine levels. Increased interleukin-1β mediates anxiety-like behavior., (© 2022. The Author(s).)

Non-alcoholic fatty liver disease (NAFLD) affects approximately 8 million Canadians. NAFLD refers to a disease spectrum ranging from bland steatosis to non-alcoholic steatohepatitis (NASH). Nearly 25% of patients with NAFLD develop NASH, which can progress to liver cirrhosis and related end-stage complications. Type 2 diabetes and obesity represent the main risk factors for the disease. The Canadian NASH Network is a national collaborative organization of health care professionals and researchers with a primary interest in enhancing understanding, care, education, and research around NAFLD, with a vision of best practices for this disease state. At the 1st International Workshop of the CanNASH network in April 2021, a joint event with the single topic conference of the Canadian Association for the Study of the Liver (CASL), clinicians, epidemiologists, basic scientists, and community members came together to share their work under the theme of NASH. This symposium also marked the initiation of collaborations between Canadian and other key opinion leaders in the field representative of international liver associations. The main objective is to develop a policy framework that outlines specific targets, suggested activities, and evidence-based best practices to guide provincial, territorial, and federal organizations in developing multidisciplinary models of care and strategies to address this epidemic., Competing Interests: G Sebastiani has acted as a speaker for Pfizer, Merck, Novo Nordisk, Novartis, Gilead, and AbbVie, served as an advisory board member for Merck, Gilead, Pfizer, Allergan, Novo Nordisk, Intercept Pharmaceuticals, and Novartis, and has received research funding from Merck and Theratec. K Patel is a speaker for Gilead Sciences, Intercept, and Abbott, an advisory board/consultant for Gilead Sciences, Intercept, Novartis, and Allergan, and has received research funding from Gilead Sciences. V Ratziu consults for Genfit, Intercept, Galmed, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, and Madrigal. He has received grants from Gilead. JJ Feld is a consultant/advisor and/or has received research support from AbbVie, Arbutus, Antios, Enanta, Eiger, Finch, Gilead Sciences, GSK, Janssen, and Roche. BA Neuschwander-Tetri is a consultant for Allergan, Allysta, Arrowhead, ARTham, Axcella, Blade, Boehringer Ingelheim, BMS, Coherus, Consynance, Durect, Enanta, Fortress, Gelesis, Gilead, HistoIndex, Intercept, Lipocine, Madrigal, Medimmune, Merck, Metacrine, Mundipharma, NGM, pH-Pharma, Prometheus, and Siemens. He has received institutional research grants from Allergan, BMS, Cirius, CymaBay, Enanta, Galectin, Genfit, Gilead, Intercept, Madrigal, NGM, and Prometheus. M Pinzani is an advisory board/consultant for Promethera (Belgium), Chemomab (Israel), Takeda (USA), LimmaTech Biologics (Switzerland), Resolution Therapeutics (UK), Dicerna (USA), Astra Zeneca (UK). He is a co-founder/director and shareholder of Engitix Therapeutics Ltd (UK) and 3P-Sense Ltd (UK). He is Chief Medical Officer of Hepatotargets/BitBio Ltd (UK). S Petta has been a speaker and/or advisor for AbbVie, Gilead, and Intercept. A Berzigotti has been an advisory board member for Inventiva, Bracco, General Electrics, and Boehringer Ingelheim. EM Brunt has been a study pathologist for CymaBay, Histoindex, and NGM, a consultant for Alnylam/Regeneron Therapeutics, Arrowhead Pharmaceutical, and Perspectum Diagnostics, and a member of the advisory board for Pfizer. A Tang is a speaker for Eli Lilly and has received research support from Siemens. JF Cobbold has received consultancy fees from Novo Nordisk and speaker fees from Intercept. P Ghali has been a consultant for Merck and Gilead. QM Anstee reports grants from AbbVie, Allergan/Tobira, AstraZeneca, GlaxoSmithKline, Glympse Bio, Novartis Pharma AG, Pfizer Ltd., and Vertex. He also reports consultancy for 89Bio, Abbott Laboratories, Acuitas Medical, Allergan/Tobira, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Celgene, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Imperial Innovations, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Madrigal, MedImmune, Metacrine, NewGene, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Servier, Terns, and Viking Therapeutics. He is a speaker for Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, and MedScape. He further reports royalties from Elsevier Ltd. H Bajaj reports receiving grant support from Amgen, Kowa, and Sanofi US Services, and grant support and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen Global Services, and Novo Nordisk. MG Swain served on an advisory board and speakers bureaus for Gilead, Intercept, Abbott, Novartis. He has also received clinical trial funding from Gilead, Intercept, CymaBay, Genkyotex, GSK, and Novartis. A Ramji served on advisory boards and speakers bureaus for Gilead, Intercept, AbbVie, Celgene, Merck, and Novartis. He has also received clinical trial funding AbbVie, Assembly, Gilead, Intercept, Galmed, Janssen, Springbanks, Allergan, and Novartis. The other coauthors have nothing to disclose related to this publication., (Copyright © 2022 Canadian Association for the Study of the Liver.)

Background & Aims: Acute pancreatitis is a common disease with significant associated morbidity and mortality. We performed a systematic review and meta-analysis of population-based studies to explore the changing temporal trends of acute pancreatitis incidence globally., Methods: We performed a systematic literature search to identify population-based studies reporting the annual incidence of acute pancreatitis. Abstracts were assessed independently to identify applicable articles for full-text review and data extraction. Joinpoint temporal trend analyses were performed to calculate the average annual percent change (AAPC) with 95% confidence intervals (CIs). The AAPCs were pooled in a meta-analysis to capture the overall and regional trends in acute pancreatitis incidence over time. Temporal data were summarized in a static map and an interactive, web-based map., Results: Forty-four studies reported the temporal incidence of acute pancreatitis (online interactive map: https://kaplan-acute-pancreatitis-ucalgary.hub.arcgis.com/). The incidence of acute pancreatitis has increased from 1961 to 2016 (AAPC, 3.07%; 95% CI, 2.30% to 3.84%; n = 34). Increasing incidence was observed in North America (AAPC, 3.67%; 95% CI, 2.76% to 4.57%; n = 4) and Europe (AAPC, 2.77%; 95% CI, 1.91% to 3.63%; n = 23). The incidence of acute pancreatitis was stable in Asia (AAPC, -0.28%; 95% CI, -5.03% to 4.47%; n = 4)., Conclusions: This meta-analysis provides a comprehensive overview of the global incidence of acute pancreatitis over the last 56 years and demonstrates a steadily rising incidence over time in most countries of the Western world. More studies are needed to better define the changing incidence of acute pancreatitis in Asia, Africa, and Latin America., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Autoimmune liver disease (AILD) spans a spectrum of chronic disorders affecting the liver parenchyma and biliary system. Three main categories of AILD are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). This review condenses the presentation and discussions of the Single Topic Conference (STC) on AILD that was held in Ottawa, Ontario, in November 2019. We cover generalities regarding disease presentation and clinical diagnosis; mechanistic themes; treatment paradigms; clinical trials, including approaches and challenges to new therapies; and looking beyond traditional disease boundaries. Although these diseases are considered autoimmune, the etiology and role of environmental triggers are poorly understood. AILDs are progressive and chronic conditions that affect survival and quality of life. Advances have been made in PBC treatment because second-line treatments are now available (obeticholic acid, bezafibrate); however, a significant proportion still present suboptimal response. AIH treatment has remained unchanged for several decades, and data suggest that fewer than 50% of patients achieve a complete response and as many as 80% develop treatment-related side effects. B-cell depletion therapy to treat AIH is in an early stage of development and has shown promising results. An effective treatment for PSC is urgently needed. Liver transplant remains the best option for patients who develop decompensated cirrhosis or hepatocellular carcinoma within specific criteria, but recurrent AILD might occur. Continued efforts are warranted to develop networks for AILD aimed at assessing geo-epidemiological, clinical, and biochemical differences to capture the new treatment era in Canada., Competing Interests: The authors have nothing to disclose., (Copyright © 2021 Canadian Association for the Study of the Liver.)

The intestinal microbiota plays an important role in regulating brain functions and behaviour. Microbiota-dependent changes in host physiology have been suggested to be key contributors to psychiatric conditions. However, specific host pathways modulated by the microbiota involved in behavioural control are lacking. Here, we assessed the role of the aryl hydrocarbon receptor (Ahr) in modulating microbiota-related alterations in behaviour in male and female mice after antibiotic (Abx) treatment. Mice of both sexes were treated with Abx to induce bacterial depletion. Mice were then tested in a battery of behavioural tests, including the elevated plus maze and open field tests (anxiety-like behaviour), 3 chamber test (social preference), and the tail suspension and forced swim tests (despair behaviour). Behavioural measurements in the tail suspension test were also performed after microbiota reconstitution and after administration of an Ahr agonist, β-naphthoflavone. Gene expression analyses were performed in the brain, liver, and colon by qPCR. Abx-induced bacterial depletion did not alter anxiety-like behaviour, locomotion, or social preference in either sex. A sex-dependent effect was observed in despair behaviour. Male mice had a reduction in despair behaviour after Abx treatment in both the tail suspension and forced swim tests. A similar alteration in despair behaviour was observed in Ahr knockout mice. Despair behaviour was normalized by either microbiota recolonization or Ahr activation in Abx-treated mice. Ahr activation by β-naphthoflavone was confirmed by increased expression of the Ahr-target genes Cyp1a1, Cyp1b1, and Ahrr. Our results demonstrate a role for Ahr in mediating the behaviours that are regulated by the crosstalk between the intestinal microbiota and the host. Ahr represents a novel potential modulator of behavioural conditions influenced by the intestinal microbiota., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aims: The effect of major depression and antidepressant use on patient survival in chronic liver disease is unknown. We evaluated the impact of major depressive disorder (MDD) and antidepressants on survival among patients with alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD)., Methods: The Health Improvement Network database, the largest medical database in the United Kingdom, was used to identify incident ALD (n = 4148) and NAFLD (n = 19 053) in patients between 1986 and 2017. Our primary outcome was development of decompensated cirrhosis or death. MDD and each class of antidepressants were assessed in multivariate Cox proportional hazards models as time-varying covariates. Models were adjusted for age, sex, socio-economic status and comorbidities., Results: MDD rate was higher among patients with ALD (22.8%) compared to those with NAFLD (16.1%), P < .01. Antidepressant usage was common in patients with ALD (47.4%) and NAFLD (40.8%). After adjusting for covariates, MDD (adjusted hazard ratio [AHR]: 0.80, 95% CI: 0.63-1.02 for NAFLD; and AHR 1.01, 0.88-1.15 for ALD) was not associated with improved decompensated cirrhosis-free survival. The antidepressant mirtazapine was associated with worse decompensated cirrhosis-free survival among NAFLD (AHR 2.16, 95% CI: 1.32-3.52) and ALD (AHR 1.53, 1.09-2.15) cohorts. Similarly, mirtazapine was associated with mortality in both cohorts., Conclusions: MDD was not associated with worse outcomes for ALD or NAFLD. Mirtazapine was associated with an increased risk of decompensated cirrhosis or death, which was not observed with other antidepressants. Prospective studies are warranted to confirm these findings., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: The management of chronic liver diseases (CLDs) and cirrhosis is associated with substantial healthcare costs. We aimed to estimate trends in national healthcare spending for patients with CLDs or cirrhosis between 1996 and 2016 in the United States., Methods: National-level healthcare expenditure data developed by the Institute for Health Metrics and Evaluations for the Disease Expenditure Project and prevalence of CLDs and cirrhosis derived from the Global Burden of Diseases Study were used to estimate temporal trends in inflation-adjusted US healthcare spending, stratified by setting of care (ambulatory, inpatient, emergency department, and nursing care). Joinpoint regression was used to evaluate temporal trends, expressed as annual percent change (APC) with 95% confidence intervals (CIs). Drivers of change in spending for ambulatory and inpatient services were also evaluated., Results: Total expenditures in 2016 were $32.5 billion (95% CI, $27.0-$40.4 billion). Over 65% of spending was for inpatient or emergency department care. From 1996 to 2016, there was a 4.3%/year (95% CI, 2.8%-5.8%) increase in overall healthcare spending for patients with CLDs or cirrhosis, driven by a 17.8%/year (95% CI, 14.5%-21.6%) increase in price and intensity of hospital-based services. Total healthcare spending per patient with CLDs or cirrhosis began decreasing after 2008 (APC -1.7% [95% CI, -2.1% to -1.2%]), primarily because of reductions in ambulatory care spending (APC -9.1% [95% CI, -10.7% to -7.5%] after 2011)., Discussion: Healthcare expenditures for CLDs or cirrhosis are substantial in the United States, driven disproportionately by acute care in-hospital spending., (Copyright © 2021 by The American College of Gastroenterology.)

Introduction: To describe the characteristics and outcomes of children with cystic fibrosis (CF) hospitalized with cirrhosis in the United States., Methods: We conducted a population-based cohort study of hospitalizations among children with CF using the 2016 Kid's Inpatient Database., Results: In total, 9,615 admissions were analyzed. Diagnosis of cirrhosis was present in 509 (5.3%) and was significantly associated with increased mortality, length of stay, and hospital charges compared with those without cirrhosis. Hepatic encephalopathy was significantly associated with death in children with cirrhosis., Discussion: Future interventions should be designed to support children with CF who have cirrhosis to improve clinical outcomes., (Copyright © 2021 by The American College of Gastroenterology.)

Background: Choosing Wisely Canada (CWC) recommends not to perform gastroscopy for dyspepsia in otherwise healthy adults less than 55 years of age (2014). The aim of this study was to evaluate the use of gastroscopy in a young, healthy population with uncomplicated dyspepsia., Methods: A retrospective review of gastroscopies completed during 3-month periods in 2015, 2016, and 2017 identified all patients undergoing gastroscopy for the primary indication of dyspepsia. Low-risk patients for dyspepsia were defined as adults, aged 18 to 54 years without alarm symptoms, comorbidities and/or abnormal imaging findings or laboratory values. Gastroscopy and pathology reports were reviewed to identify clinically actionable findings. Clinical outcomes were followed to December 31, 2018 including gastroenterology referrals, emergency room visitation and hospitalization., Results: Among 1358 patients having a gastroscopy for dyspepsia, 480 (35%) were low-risk patients. Sixteen patients 3.3% (16/480) had a clinically actionable result found on gastroscopy or biopsy. No malignant lesions were detected. Low-risk patients were followed up for an average of 2.75 years, 8% (39/480) visited the emergency department (ED), 1% (3/480) of patients were admitted to hospital and 12% (59/480) of patients were re-referred for a dyspepsia-related concern., Interpretation: A high rate of low yield, high cost, invasive endoscopic investigations were performed in this population of otherwise healthy patients under age 55 years. These data suggest limited uptake of current recommendations against the routine use of gastroscopy to investigate dyspepsia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)

Background: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent worldwide. Identifying high-risk patients is critical to best utilize limited health care resources. We established a community-based care pathway using 2D ultrasound shear wave elastography (SWE) to identify high risk patients with NAFLD. Our objective was to assess the cost-effectiveness of various non-invasive strategies to correctly identify high-risk patients., Methods: A decision-analytic model was created using a payer's perspective for a hypothetical patient with NAFLD. FIB-4 [≥1.3], NAFLD fibrosis score (NFS) [≥-1.455], SWE [≥8 kPa], transient elastography (TE) [≥8 kPa], and sequential strategies with FIB-4 or NFS followed by either SWE or TE were compared to identify patients with either significant (≥F2) or advanced fibrosis (≥F3). Model inputs were obtained from local data and published literature. The cost/correct diagnosis of advanced NAFLD was obtained and univariate sensitivity analysis was performed., Results: For ≥F2 fibrosis, FIB-4/SWE cost $148.75/correct diagnosis while SWE cost $276.42/correct diagnosis, identifying 84% of patients correctly. For ≥F3 fibrosis, using FIB-4/SWE correctly identified 92% of diagnoses and dominated all other strategies. The ranking of strategies was unchanged when stratified by normal or abnormal ALT. For ≥F3 fibrosis, the cost/correct diagnosis was less in the normal ALT group., Conclusions: SWE based strategies were the most cost effective for diagnosing ≥F2 fibrosis. For ≥F3 fibrosis, FIB-4 followed by SWE was the most effective and least costly strategy. Further evaluation of the timing of repeating non-invasive strategies are required to enhance the cost-effective management of NAFLD., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SEC reports clinical trial support from Gilead Sciences, Genfit, Boehringer Ingelheim, Allergan, BMS and Sequana and has provided consulting services for Intercept Pharmaceuticals, Eisai, and AstraZeneca and Paladin Labs outside the submitted work. AAS reports research grant support from grants from Gilead Sciences and Intercept Pharmaceuticals and has provided consulting services for Intercept Pharmaceuticals and Gilead Sciences outside the submitted work. MGS reports consulting or speaker services for Intercept Pharmaceuticals, Gilead Sciences, Abbott, Novartis and research and clinical trial support from Gilead Sciences, Intercept, CymaBay, Genkyotex, Novartis, Pfizer, Genfit, GSK, Astra Zeneca outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: In Canada, non-alcoholic fatty liver disease (NAFLD) is the most frequently occurring liver disease, affecting one in four Canadians. NAFLD can in turn evolve into non-alcoholic steatohepatitis (NASH) and cirrhosis. No study in Canada has investigated knowledge of NAFLD among physicians., Methods: Primary care physicians (PCPs); specialists in internal medicine, gastroenterology, and hepatology; and hepatology nurses who were members of the College of Family Physicians of Canada, Canadian Association for the Study of the Liver, or Canadian Association of Hepatology Nurses were invited to participate in this web-based survey., Results: Of 650 invited physicians and nurses, 214 (33%) responded and 171 (26%) completed the whole survey. Overall, 51% of the respondents were PCPs, 38% were specialists, and 11% were nurses. Of these, 58% of PCPs, 28% of specialists, and 39% of nurses responded that they were only somewhat familiar or unfamiliar with NAFLD. Moreover, 53% of PCPs, 20% of specialists, and 35% of nurses thought the prevalence of NAFLD in Canada was 15% or less. Also, 42% of respondents thought that NASH could be diagnosed by imaging or blood tests. Finally, more than 40% of PCPs, 22% of specialists, and 33% of nurses thought that metformin and statin were treatments for NASH., Conclusions: This survey shows that a significant proportion of Canadian physicians and nurses managing patients with NAFLD are not very familiar with the disease. This study emphasizes the need for further provider education, national practice guidelines, and improved treatment options., Competing Interests: GS has acted as speaker for Merck, Gilead, AbbVie, Novonordisk, Novartis, and Pfizer; served as an advisory board member for Pfizer, Merck, Novartis, Gilead, Allergan, and Intercept; and received unrestricted research funding from Merck and Theratec. AR served on advisory boards and speakers bureaus for Gilead, Intercept, AbbVie, Celgene, Merck, and Novartis and received clinical trial funding from AbbVie, Assembly, Gilead, Intercept, Galmed, Janssen, Springbanks, Allergan, and Novartis. MGS served on advisory boards and speakers bureaus for Gilead, Intercept, Abbott, and Novartis and received clinical trial funding from Gilead, Intercept, CymaBay, Genkyotex, GSK, and Novartis. KP is a speaker for Gilead Sciences, Intercept, and Abbott; is advisory board/consultant for Gilead Sciences, Intercept, Novartis, and Allergan; and received research funding from Gilead Sciences., (Copyright © 2021 Canadian Association for the Study of the Liver.)

Introduction: B cells are important regulators of both adaptive and innate immunity. The normal liver contains significant numbers of B cells, and their numbers increase dramatically in immune-mediated liver diseases. Our previous observations suggest a hepatoprotective effect of the antidepressant mirtazapine in human and experimental immune-mediated liver disease. Therefore, we performed a series of experiments to determine the impact of mirtazapine treatment on hepatic B cell homeostasis, as reflected by B cell number, trafficking and phenotype using flow cytometry (FCM) and intravital microscopy (IVM) analysis. Mirtazapine treatment rapidly induced a significant reduction in total hepatic B cell numbers, paralleled by a compositional shift in the predominant hepatic B cell subtype from B2 to B1. This shift in hepatic B cells induced by mirtazapine treatment was associated with a striking increase in total hepatic levels of the chemokine CXCL10, and increased production of CXCL10 by hepatic macrophages and dendritic cells. Furthermore, mirtazapine treatment led to an upregulation of CXCR3, the cognate chemokine receptor for CXCL10, on hepatic B cells that remained in the liver post-mirtazapine. A significant role for CXCR3 in the hepatic retention of B cells post-mirtazapine was confirmed using CXCR3 receptor blockade. In addition, B cells remaining in the liver post-mirtazapine produced lower amounts of the proinflammatory Th1-like cytokines IFNγ, TNFα, and IL-6, and increased amounts of the Th2-like cytokine IL-4, after stimulation in vitro ., Conclusion: Mirtazapine treatment rapidly alters hepatic B cell populations, enhancing hepatic retention of CXCR3-expressing innate-like B cells that generate a more anti-inflammatory cytokine profile. Mirtazapine-induced hepatic B cell shifts could potentially represent a novel therapeutic approach to immune-mediated liver diseases characterized by B cell driven pathology., 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 Almishri, Davis, Shaheen, Altonsy, Jenne and Swain.)

Obesity and cirrhosis are associated with poor hepatitis B virus (HBV) vaccine responses, but vaccine efficacy has not been assessed in nonalcoholic fatty liver disease (NAFLD). Sixty-eight HBV-naïve adults with NAFLD were enrolled through the Canadian HBV network and completed three-dose HBV or HBV/HAV vaccine (Engerix-B ® , or Twinrix ® , GlaxoSmithKline). Anti-HBs titers were measured at 1-3 months post third dose. In 31/68 subjects enrolled at the coordinating-site, T-cell proliferation and follicular T-helper cells (pTFH) were assessed using PBMC. Immune response was also studied in NAFLD mice. NAFLD patients were stratified as low-risk-obesity, BMI < 35 (N = 40) vs. medium-high-risk obesity, BMI > 35 (N = 28). Anti-HBs titers were lower in medium/high-risk obesity, 385 IU/L ± 79 vs. low-risk obesity class, 642 IU/L ± 68.2, p = 0.02. High-risk obesity cases, N = 14 showed lower vaccine-specific-CD3+ CD4+ T-cell response compared to low-risk obesity patients, N = 17, p = 0.02. Low vaccine responders showed dysfunctional pTFH. NAFLD mice showed lower anti-HBs levels and T-cell response vs. controls. In conclusion, we report here that obese individuals with NAFLD exhibit decreased HBV vaccine-specific immune responses.

Background: There are limited long-term data on outcomes of chronic hepatitis B (CHB) in untreated and tenofovir disoproxil fumarate (TDF)-treated women during pregnancy., Aims: To assess clinical outcomes in a multiethnic cohort of patients during pregnancy and post-partum in a low HBV endemic region., Methods: Retrospective real-world study of women with CHB (treated or untreated with TDF) from 2011 to 2019; data including ALT, HBV DNA, HBeAg and liver stiffness measurement were collected during pregnancy and post-partum., Results: In 341 women (446 pregnancies) followed for a median of 33 months (IQR: 26.7-39.5) post-partum, 19% (65/341) received TDF (11 initiated pre-pregnancy, 53 for mother-to-child transmission (MTCT) prevention). During follow-up, 72/341 had subsequent pregnancy, including 18/53 on TDF for MTCT risk, of whom 7/18 were re-treated. In all TDF-treated women, HBV DNA declined but rebounded after TDF withdrawal (median baseline, near birth and early follow-up levels were 7.2, 3.0 and 5.5 log IU/mL respectively [P < 0.01]). In HBeAg+ patients (65/341) ALT flares were more common (P = 0.03), especially for those who stopped TDF post-partum, requiring re-treatment in 21% (11/53). In comparison, 54% (116/215) of untreated women had a post-partum ALT flare; one with fulminant hepatitis underwent transplant 13 months post-partum. HBsAg clearance occurred in 2.6% (9/341, 3/9 HBeAg+, 2/9 TDF treated) at median 30 months (IQR: 23-40) and 37% (24/65) of HBeAg+ patients had HBeAg loss at median 17 months (IQR: 12-26) post-partum., Conclusions: Post-partum ALT flares were common, especially after TDF withdrawal. Overall, 37% achieved HBeAg clearance and 2.9% had HBsAg loss during long-term follow-up., (© 2020 John Wiley & Sons Ltd.)

Background: The greatest risk of chronic hepatitis B (CHB) is from mother-to-child transmission. Approximately 20% of individuals in sub-Saharan Africa are hepatitis B virus (HBV) surface antigen-positive (HBsAg+), but the prevalence of occult hepatitis B (OHB) is unknown. Aim: This study investigated CHB and OHB prevalence and viral variants in a cohort of pregnant women in Gondor, Ethiopia., Methods: Patients were prospectively recruited from the University of Gondar Hospital ( N = 200; median age 27 [inter-quartile range] 8.3y) from March through June 2016. Data were collected using an investigator-administered questionnaire. Plasma was tested for HBsAg and HBV core antibody (anti-HBc), and HBV genotype and presence of HBV variants (ie, vaccine escape mutants [VEMs]) were determined by polymerase chain reaction, Sanger sequencing, and phylogenetic analysis., Results: Of women tested, 1% (2/200) were HBsAg+; 26.8% (47/182) of HBsAg-negative patients were anti-HBc+, of whom 37/47 (78.7%) had detectable HBV DNA. The overall rate of OHB was 20.3%. Both HBsAg+ cases were HBV genotype D, and 36/37 (97.3%) of OHB individuals were genotype D. None carried VEM, but both HBsAg+ cases and 32/37 (86.5%) of the OHB cases showed lamivudine-resistant mutations., Conclusions: Twenty-seven percent of pregnant women in this cohort showed evidence of CHB or prior HBV exposure (ie, HBsAg+ or anti-HBc+) and clinically relevant HBV variants. Data from this single-centre study suggests high HBV prevalence, reinforcing the World Health Organization's recommendation for universal prenatal HBV screening and infant vaccination., Competing Interests: None declared., (Copyright © 2020 Canadian Association for the Study of the Liver.)

Background and Aims: Mirtazapine is an atypical antidepressant with antagonist activity for serotonin and histamine receptors. Clinical and experimental evidence suggests that, in addition to treating depression, mirtazapine also alters liver innate immunity and suppresses immune-driven hepatic macrophage activation. Liver macrophages, Kupffer cells, represent the largest collection of fixed macrophages in the body and are critical in regulating hepatic immunity. In addition to their capacity to regulate inflammation, Kupffer cells are key sentinels for clearing blood-borne pathogens, preventing their dissemination within the body. This process involves pathogen capture, phagocytosis, and activation-induced killing via reactive oxygen species (ROS) production. Therefore, we speculated that mirtazapine might adversely alter Kupffer cell pathogen-associated activation and killing., Methods: Mice were treated with mirtazapine and time-dependent changes in Kupffer cells were characterized using intravital microscopy. Macrophage and neutrophil responses, bacterial dissemination, and liver damage were assessed following i.v. infection with a pathogenic strain of S. aureus ., Results: Mirtazapine rapidly (within 1.5 h) activates Kupffer cells, indicated by a loss of elongated shape with cellular rounding. However, this shape change did not result in impaired pathogen capture function, and, in fact, generated enhanced ROS production in response to S. aureus -induced sepsis. Neutrophil dynamics were altered with reduced cellular recruitment to the liver following infection. Bacterial dissemination post-intravenous administration was not altered by mirtazapine treatment; however, hepatic abscess formation was significantly reduced., Conclusions: Mirtazapine rapidly activates Kupffer cells, associated with preserved bacterial capture functions and enhanced ROS generation capacity. Moreover, these changes in Kupffer cells were linked to a beneficial reduction in hepatic abscess size. In contrast to our initial speculation, mirtazapine may have beneficial effects in sepsis and warrants further exploration., (Copyright © 2020 Davis, Almishri, Jenne and Swain.)

Patients with rheumatoid arthritis experience chronic pain, depression and fatigue, even when inflammation of the joints is well controlled. To study the relationship between arthritis, depression, and sustained pain when articular inflammation is no longer observed, we tested the hypothesis that brain TNF drives post-inflammation depression-like behavior and persistent pain in experimental arthritis. The murine model of antigen-induced arthritis (AIA) was used to evaluate the effects of knee inflammation on sustained pain and depression-like behavior. We measured joint pain using an automated dynamic plantar algesiometer and depression-like behavior with the tail suspension test. Cytokines were measured by Luminex assay and ELISA. TNF in the brain was blocked by intracerebroventricular injection of anti-TNF antibodies. Histological damage and elevated levels of cytokines were observed in the knee 24 h after antigen treatment, but not at 13 days. Reduced pain thresholds were seen 24 h and 13 days after treatment. Depression-like behavior was observed on day 13. Treatment with the antidepressant imipramine reduced both depression-like behavior and persistent pain. However, blocking joint pain with the analgesic dipyrone did not alter depression-like behavior. Elevated levels of TNF, CCL2, and CXCL-1 were observed in the hippocampus 24 h after treatment, with TNF remaining elevated at day 13. Intracerebroventricular infusion of an anti-TNF antibody blocked depression-like behavior and reduced persistent pain. We have demonstrated that depression-like behavior and pain is sustained in AIA mice after the resolution of inflammation. These changes are associated with elevated levels of TNF in the hippocampus and are dependent upon brain TNF. The findings reveal an important mechanistic link between the expression of chronic pain and depression in experimental arthritis. Furthermore, they suggest treating depression in rheumatoid arthritis may positively impact other debilitating features of this condition., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Patients with primary biliary cholangitis (PBC) with incomplete response to ursodeoxycholic acid are at risk of disease progression and need additional therapy. Obeticholic acid (OCA) was approved in Canada in May 2017, but its effectiveness in a real-world setting has not been described. We sought to describe our experience with OCA in a Canadian cohort. OCA-naive patients treated at two Canadian centers were included. Clinical and biochemical data were collected at OCA initiation and during follow-up. Primary outcomes were changes in serum alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (TB) over the duration of therapy. Secondary outcomes were changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), immunoglobulin M (IgM), platelets, and albumin; and achievement of the primary endpoint of the original phase 3 study that led to OCA approval (A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis [POISE]), dose reductions, discontinuations, and tolerability. Repeated-measures models were used to assess changes in biochemistry over time. Sixty-four patients were included; 4 carried a diagnosis of overlap with autoimmune hepatitis. Mean age was 54.6 years, median ALP was 250 U/L, TB was 13 µmol/L, platelet count was 225 × 10 9 /L, and 24% had liver stiffness measurements ≥16.9 kPa. There was a significant reduction in mean ALP of 55 U/L ( P  < 0.001), GGT of 138 U/L ( P  < 0.001), ALT of 11.9 U/L ( P  < 0.001), AST of 5.7 U/L ( P  < 0.05), and IgM of 0.70 g/L ( P  < 0.001) over 12 months; TB remained stable ( P  = 0.98). Forty-four patients met POISE-inclusion criteria, 39% (n = 17) of whom had 12-month biochemical measurements. In this subset, 18% (n = 3/17) met the 12-month POISE primary endpoint, but considering follow-up to 19 months, 43% achieved this target (n = 9/21). Pruritus was the most commonly reported complaint. Conclusion : Use of OCA was associated with improvement in biochemical surrogates of outcome in PBC in a real-world setting., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)