Assessment of fatigue and its impact in chronic liver disease.

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 such as primary biliary cholangitis (PBC), chronic hepatitis C viral infection (HCV) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), 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 PBC, HCV and MASLD. As such, 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 fatigue is comprised of peripheral (neuromuscular failure, often in conjunction with sub-maximal 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 HCV and MASLD can improve levels of fatigue and HRQL, but current treatments for PBC do not seem to affect levels of fatigue. We conclude that obtaining PRO data to include HRQL and fatigue are essential for determining the comprehensive burden of CLD and its potential treatments. IMPACT AND IMPLICATIONS: Fatigue is a complex phenomenon associated with both a peripheral cause (neuromuscular failure and sub-maximal cardiorespiratory function) and a central cause (central nervous system dysfunction). Although fatigue is common among patients with CLD, it does not always correlate with the severity of the liver disease, but fatigue is related with significant decreases in patients' health related quality of life (HRQL). Appreciating the impact of fatigue using validated self-report measurements is important to better understand the burden of CLD and the effectiveness of treatment.

Metabolic dysfunction-associated steatotic liver disease: An opportunity for collaboration between cardiology and hepatology.

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.

Treatment response and clinical event-free survival in autoimmune hepatitis: a Canadian multicentre cohort study.

BACKGROUND & AIMS: We sought to identify predictors of outcome for people living with autoimmune hepatitis (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 immunoglobulin G (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 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, uses continuous measurements over follow-up, and our findings help inform risk stratification of patients. We provide evidence for treating clinicians, as well as those developing and evaluating new therapies, to seek evidence of good treatment response by keeping aminotransferase activity values within the reference range. 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 of treatment for patients.

Cholestatic liver disease leads to significant adaptative changes in neural circuits regulating social behavior in mice to enhance sociability.

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.

Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis.

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.

Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

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.).

Avenues within the gut-liver-brain axis linking chronic liver disease and symptoms.

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.

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

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.

Impact of depression and antidepressant use on clinical outcomes of hepatitis B and C: a population-based study.

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.

A qualitative patient interview study to understand the experience of patients with nonalcoholic steatohepatitis.

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.

Impact of setanaxib on quality of life outcomes in primary biliary cholangitis in a phase 2 randomized controlled trial.

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.

Anti-Valosin-Containing Protein (VCP/p97) Autoantibodies in Inclusion Body Myositis and Other Inflammatory Myopathies.

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.

Multimodal Brain MRI of Deep Gray Matter Changes Associated With Inflammatory Bowel Disease.

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.

Magnetic resonance imaging revealed structural and functional changes within the brains of inflammatory bowel disease patients, in regions known to be involved in processing brain signals associated with behavioral symptoms, anxiety, pain, stress, and cognitive deficits.

Race and Ethnicity in Non-Alcoholic Fatty Liver Disease (NAFLD): A Narrative Review.

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.

Current considerations for clinical management and care of non-alcoholic fatty liver disease: Insights from the 1st International Workshop of the Canadian NASH Network (CanNASH).

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.

The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.

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 (I2=99·9%) and NAFLD incidence (I2=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.

A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis.

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.

Recruitment of α4ß7 monocytes and neutrophils to the brain in experimental colitis is associated with elevated cytokines and anxiety-like behavior.

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 α4ß7 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-α4ß7 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 α4ß7 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-α4ß7 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-1ß and CCL2 levels were elevated in the brain and treatment with anti-α4ß7 significantly reduced them. Enhanced anxiety-like behavior in mice with colitis was reversed by treatment with interleukin 1 receptor antagonist. CONCLUSIONS: In experimental colitis, α4ß7 integrin-expressing monocytes direct the recruitment of neutrophils to the cerebral vasculature, leading to elevated cytokine levels. Increased interleukin-1ß mediates anxiety-like behavior.

Colitis-associated microbiota drives changes in behaviour in male mice in the absence of inflammation.

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.

Impact of the COVID-19 Pandemic on Hospitalizations for Alcoholic Hepatitis or Cirrhosis in Alberta, Canada.

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.