Portal hypertension and its prognostic implications in patients with Wilson's disease.

BACKGROUND AND AIMS: Wilson's disease may progress to cirrhosis and clinically significant portal hypertension (CSPH). We aimed to assess the prevalence and prognostic impact of CSPH-related features on hepatic decompensation and transplant-free survival in patients with Wilson's disease. METHODS AND RESULTS: About 137 patients with Wilson's disease (Leipzig score ≥4), followed for a median observation period of 9.0 (3.9-17.7) years at the Vienna General Hospital, were included in this retrospective study. Overall, 49 (35.8%) developed features of CSPH: 14 (10.2%) varices, 40 (29.2%) splenomegaly, 20 (14.6%) ascites, 18 (13.1%) hepatic encephalopathy and 3 (2.2%) experienced acute variceal bleeding. Overall, 8 (5.8%) patients died, including three deaths caused by CSPH-related complications. Within 10 years, compensated patients with features of CSPH developed more decompensation events (8.3% vs. 1.5% in patients without CSPH, p = 0.3) and had worse transplant-free-survival (91.7% vs. 98.6%), which further declined in patients with hepatic decompensation (26.7%, log-rank: p < 0.0001). Patients with liver stiffness <15 kPa and normal platelets (≥150 G/L) were less likely to decompensate within 10 years (2.6% vs. 8.4%, p = 0.002) and had a better 10-year transplant-free-survival (97.7% vs. 83.9%, p = 0.006). CONCLUSIONS: Patients with Wilson's disease developing features of CSPH are at an increased risk for hepatic decompensation and liver-related mortality, warranting for regular screening and timely initiation of effective CSPH-directed treatments.

The deep abdominal ultrasound transducer (DAX) increases the success rate and diagnostic accuracy of shear wave elastography for liver fibrosis assessment in patients with obesity-A prospective biopsy-controlled study.

BACKGROUND: Obesity impacts the diagnostic accuracy of shear wave elastography (SWE). A deep abdominal ultrasound transducer (DAX) capable of point (pSWE) and two-dimensional (2D)-SWE has recently been introduced to address this issue. METHODS: We performed a prospective study in a cohort of mostly patients with obesity undergoing liver biopsy with a high prevalence of metabolic dysfunction-associate steatotic liver disease (MASLD). Liver stiffness measurement (LSM) was measured using vibration-controlled transient elastography (VCTE), as well as pSWE and 2D SWE on the standard (5C1) and the DAX transducers. RESULTS: We included 129 patients with paired LSM and liver biopsy: median age 44.0 years, 82 (63.6%) women, median BMI: 43.2 kg/m2. Histologic fibrosis stages: F0: N = 55 (42.6%), F1: N = 14 (10.9%), F2: N = 50 (38.8%), F3: N = 2 (1.6%), F4: N = 8 (6.2%). VCTE-LSM failed (N = 13) or were unreliable (IQR/median ≤30% in ≥7.1 kPa, N = 14) in 20.9% of patients. The Pearson correlation of reliable VCTE-LSM with both pSWE and 2D SWE was strong (all >0.78). The diagnostic accuracy for all LSM techniques was poor for significant fibrosis (≥F2, AUC: 0.54-0.63); however, it was good to excellent for advanced fibrosis (≥F3, AUC: 0.87-0.99) and cirrhosis (F4, AUC: 0.86-1.00). In intention-to-diagnose analysis, pSWE on DAX was significantly superior to VCTE-LSM. CONCLUSIONS: pSWE- and 2D-SWE enable the non-invasive identification of advanced fibrosis and cirrhosis in patients with obese MASLD. The use of the DAX transducer for acoustic radiation force imaging (ARFI)-LSM avoids technical failures in an obese population and subsequently offers advantages over VCTE-LSM for the evaluation of fibrosis in an obese MASLD population at risk for fibrosis.

Association between endoscopist adenoma detection rate and serrated polyp detection: Retrospective analysis of over 200,000 screening colonoscopies.

Background and study aims Serrated lesions have been identified as precursor lesions for 20% to 35% of colorectal cancers (CRCs) and may contribute to a significant proportion of interval-cancer. Sessile-serrated-lesions (SSLs), in particular, tend to be flat and located in the proximal colon, making their detection challenging and requiring expertise. It remains unclear whether the detection rate for serrated polyps should be considered as a quality indicator in addition to the adenoma detection rate (ADR). This study sought to assess whether the ADR has an effect on the detection rate for serrated polyps. atients and methods In this retrospective analysis, prospectively collected data from 212,668 screening colonoscopies performed between 2012 and September 2018 were included. Spearman correlation and Whitney-Mann U-test were used to assess the association of ADR and the detection rate of SSLs with (SDR) and without hyperplastic polyps (SPADRs), the sessile serrated detection rate (SSLDR) as well as the clinically relevant serrated detection rate (CRSDR), including all SSLs and traditional serrated adenoma, hyperplastic polyps (HPs) >10 mm anywhere in the colon or HPs > 5 mm proximal to the sigmoid. Results The overall mean ADR was 21.78% (standard deviation [SD] 9.27), SDR 21.08% (SD 11.44), SPADR 2.19% (SD 2.49), and CRSDR was 3.81% (3.40). Significant correlations were found between the ADR and the SDR, SPADR, SSLDR, and CRSDR (rho=0.73 vs. rho=0.51 vs. rho=0.51 vs. rho=0.63; all P <0.001). Endoscopists with a mean ADR ≥25% had significantly higher SDR, SPADR, and CRSDR than endoscopists with a mean ADR <25% (all P <0.001; Mann-Whitney U-Test). Conclusions This study shows that endoscopists with higher ADR detect significantly more serrated lesions than those with a lower ADR.

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.

Transcriptomic signatures of progressive and regressive liver fibrosis and portal hypertension.

Persistent liver injury triggers a fibrogenic program that causes pathologic remodeling of the hepatic microenvironment (i.e., liver fibrosis) and portal hypertension. The dynamics of gene regulation during liver disease progression and early regression remain understudied. Here, we generated hepatic transcriptome profiles in two well-established liver disease models at peak fibrosis and during spontaneous regression after the removal of the inducing agents. We linked the dynamics of key disease readouts, such as portal pressure, collagen area, and transaminase levels, to differentially expressed genes, enabling the identification of transcriptomic signatures of progressive vs. regressive liver fibrosis and portal hypertension. These candidate biomarkers (e.g., Tcf4, Mmp7, Trem2, Spp1, Scube1, Islr) were validated in RNA sequencing datasets of patients with cirrhosis and portal hypertension, and those cured from hepatitis C infection. Finally, deconvolution identified major cell types and suggested an association of macrophage and portal hepatocyte signatures with portal hypertension and fibrosis area.

Von Willebrand factor for outcome prediction within different clinical stages of advanced chronic liver disease.

BACKGROUND AND AIMS: The prognostic performance of von Willebrand factor (VWF) may vary across clinical stages of advanced chronic liver disease (ACLD). Therefore, we investigated the evolution of VWF and other biomarkers throughout the full ACLD spectrum and evaluated their stage-specific prognostic utility. METHODS: We retrospectively included Viennese ACLD patients with available information on hepatic venous pressure gradient (HVPG), C-reactive protein (CRP)/VWF levels and outcomes. ACLD stages were defined according to D'Amico et al. We included an external validation cohort from Padua. RESULTS: We observed gradual increases in VWF throughout ACLD stages. In contrast, HVPG levelled off in decompensated ACLD (dACLD), whereas MELD showed only minor changes in the early stages and CRP did not increase until stage 3. VWF was associated with hepatic decompensation/liver-related death in compensated ACLD (cACLD) in a fully adjusted model, while it was not independently predictive of ACLF/liver-related death in dACLD. After backward selection, HVPG/CRP/VWF remained the main predictors of hepatic decompensation/liver-related death in cACLD. Notably, the performance of the non-invasive CRP/VWF-based model was comparable to invasive HVPG-based models (C-index:0.765 ± 0.034 vs. 0.756 ± 0.040). The discriminative ability of the CRP/VWF-based model was confirmed in an external validation cohort using another VWF assay which yielded systematically lower values. CONCLUSION: VWF is the only biomarker that gradually increases across all ACLD stages. It is of particular prognostic value in cACLD, where a CRP/VWF-based model is equivalent to an invasive HVPG-based model. Systematic differences in VWF underline the importance of interlaboratory surveys. Moreover, our findings reinforce the notion that, already in cACLD, inflammation is a key disease-driving mechanism.

MASLD is related to impaired alcohol dehydrogenase (ADH) activity and elevated blood ethanol levels: Role of TNFα and JNK.

Elevated fasting ethanol levels in peripheral blood frequently found in metabolic dysfunction-associated steatohepatitis (MASLD) patients even in the absence of alcohol consumption are discussed to contribute to disease development. To test the hypothesis that besides an enhanced gastrointestinal synthesis a diminished alcohol elimination through alcohol dehydrogenase (ADH) may also be critical herein, we determined fasting ethanol levels and ADH activity in livers and blood of MASLD patients and in wild-type ± anti-TNFα antibody (infliximab) treated and TNFα-/- mice fed a MASLD-inducing diet. Blood ethanol levels were significantly higher in patients and wild-type mice with MASLD while relative ADH activity in blood and liver tissue was significantly lower compared to controls. Both alterations were significantly attenuated in MASLD diet-fed TNFα-/- mice and wild-type mice treated with infliximab. Moreover, alcohol elimination was significantly impaired in mice with MASLD. In in vitro models, TNFα but not IL-1ß or IL-6 significantly decreased ADH activity. Our data suggest that elevated ethanol levels in MASLD patients are related to TNFα-dependent impairments of ADH activity.

Simple blood tests to diagnose compensated advanced chronic liver disease and stratify the risk of clinically significant portal hypertension.

BACKGROUND AND AIMS: Compensated advanced chronic liver disease (cACLD) identifies patients at risk for clinically significant portal hypertension (CSPH), and thus, for liver-related complications. The limited availability of liver stiffness measurements (LSM) impedes the identification of patients at risk for cACLD/CSPH outside of specialized clinics. We aimed to develop a blood-based algorithm to identify cACLD by fibrosis-4 (FIB-4) and CSPH by von Willebrand factor/platelet count ratio (VITRO). APPROACH AND RESULTS: Patients with (suspected) compensated chronic liver disease undergoing FIB-4+LSM were included in the LSM/FIB-4 cohorts from Vienna and Salzburg. The HVPG/VITRO cohorts included patients undergoing HVPG-measurement + VITRO from Vienna and Bern.LSM/FIB-4-derivation-cohort: We included 6143 patients, of whom 211 (3.4%) developed hepatic decompensation. In all, 1724 (28.1%) had LSM ≥ 10 kPa, which corresponded to FIB-4 ≥ 1.75. Importantly, both LSM (AUROC:0.897 [95% CI:0.865-0.929]) and FIB-4 (AUROC:0.914 [95% CI:0.885-0.944]) were similarly accurate in predicting hepatic decompensation within 3 years. FIB-4 ≥ 1.75 identified patients at risk for first hepatic decompensation (5 y-cumulative incidence:7.6%), while in those <1.75, the risk was negligible (0.3%).HVPG/VITRO-derivation cohort: 247 patients of whom 202 had cACLD/FIB-4 ≥ 1.75 were included. VITRO exhibited an excellent diagnostic performance for CSPH (AUROC:0.889 [95% CI:0.844-0.934]), similar to LSM (AUROC:0.856 [95% CI:0.801-0.910], p = 0.351) and the ANTICIPATE model (AUROC:0.910 [95% CI:0.869-0.952], p = 0.498). VITRO < 1.0/ ≥ 2.5 ruled-out (sensitivity:100.0%)/ruled-in (specificity:92.4%) CSPH. The diagnostic performance was comparable to the Baveno-VII criteria.LSM/FIB-4-derivation cohort findings were externally validated in n = 1560 patients, while HVPG/VITRO-derivation-cohort findings were internally (n = 133) and externally (n = 55) validated. CONCLUSIONS: Simple, broadly available laboratory tests (FIB-4/VITRO) facilitate cACLD detection and CSPH risk stratification in patients with (suspected) liver disease. This blood-based approach is applicable outside of specialized clinics and may promote early intervention.

Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of Ursodeoxycholic Acid (UDCA). Up to 40% of patients do not, however, respond adequately to UDCA and therefore still remain at risk of disease progression to cirrhosis. The introduction of Obeticholic acid (OCA) as second-line therapy for patients failing UDCA has improved outcomes for PBC patients. There remains, however, a need for better treatments for higher risk patients. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorisation for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcomes trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with OCA, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcomes trials when a licensed drug is commercially available. New PBC therapies in development such as the PPAR agonists, face even greater challenges in demonstrating outcomes benefit through randomized placebo-controlled studies once following conditional marketing authorisation, 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 recognise the importance of Real-World Data in providing evidence of outcomes 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.

Validation of Baveno VII criteria and other non-invasive diagnostic algorithms for clinically significant portal hypertension in hepatitis delta.

BACKGROUND & AIMS: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) require validation in patients with hepatitis D virus (HDV)-related compensated advanced chronic liver disease (cACLD). Therefore, we aimed to validate existing NIT algorithms for CSPH in this context. METHODS: Patients with HDV-cACLD (LSM ≥10 kPa or histological METAVIR F3/F4 fibrosis) who underwent paired HVPG and NIT assessment at Medical University of Vienna or Hannover Medical School between 2013 and 2023 were retrospectively included. Liver stiffness measurement (LSM), von Willebrand factor to platelet count ratio (VITRO), and spleen stiffness measurement (SSM) were assessed. Individual CSPH risk was calculated according to previously published models (ANTICIPATE, 3P/5P). The diagnostic performance of Baveno VII criteria and refined algorithms (Baveno VII-VITRO, Baveno VII-SSM) was evaluated. The prognostic utility of NITs was investigated in the main cohort and an independent, multicenter, validation cohort. RESULTS: Fifty-one patients (HVPG ≥10 mmHg/CSPH prevalence: 62.7%, varices: 42.2%) were included. Patients with CSPH had significantly higher LSM (25.8 [17.2-31.0] vs. 14.0 [10.5-19.8] kPa; p < 0.001), VITRO (n = 31, 3.5 [2.7-4.5] vs. 1.3 [0.6-2.0] %/[G/L]; p < 0.001), and SSM (n = 20, 53.8 [41.7-75.5] vs. 24.0 [17.0-33.9] kPa; p < 0.001). Composite CSPH risk models yielded excellent AUROCs (ANTICIPATE: 0.885, 3P: 0.903, 5P: 0.912). Baveno VII criteria ruled out CSPH with 100% sensitivity and ruled in CSPH with 84.2% specificity. The Baveno VII 'grey zone' (41.1%) was significantly reduced by Baveno VII-VITRO or Baveno VII-SSM algorithms, which maintained diagnostic accuracy. Hepatic decompensation within 2 years only occurred in patients who had CSPH or met Baveno VII rule-in criteria. The prognostic value of NITs was confirmed in the validation cohort comprising 92 patients. CONCLUSIONS: Standalone and composite NIT/diagnostic algorithms are useful for CSPH diagnosis in patients with HDV-cACLD. Thus, NITs may be applied to identify and prioritize patients with CSPH for novel antiviral treatments against chronic hepatitis D. IMPACT AND IMPLICATIONS: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) have been developed to identify patients with compensated advanced chronic liver disease (cACLD) at risk of decompensation, but conflicting data has been published regarding the accuracy of liver stiffness measurement (LSM) for the staging of fibrosis in patients infected with hepatitis D virus (HDV). In our study, including 51 patients with HDV-cACLD, LSM- and lab-based NITs yielded high AUROCs for CSPH. Moreover, only patients with CSPH or high non-invasively assessed CSPH risk were at risk of decompensation within 2 years, with the prognostic value of NITs confirmed in a validation cohort. Thus, NITs should be applied and updated in yearly intervals in clinical routine to identify patients with HDV-cACLD at short-term risk of clinical events; NITs may also guide prioritization for novel antiviral treatment options.

[Primary sclerosing cholangitis-Diagnosis and treatment 2024]. / Primär sklerosierende Cholangitis ­ Diagnose und Therapie 2024.

The etiology of primary sclerosing cholangitis (PSC) remains unclear, which explains in part the lack of a causal treatment. The differential diagnostic distinction from the even rarer immunoglobulin 4 (IgG4)-associated cholangitis (IAC) is becoming increasingly more successful. Advances in the understanding of different clinical courses, improvements in noninvasive diagnostics through modern magnetic resonance imaging (MRI) and the introduction of liver elastography have led to the development of improved prognostic models. The evidence for recommendations on medicinal (e.g., ursodeoxycholic acid) or endoscopic treatment (e.g., balloon dilatation and/or stent insertion) for PSC is still low. In contrast, the long-term results of liver transplantation in PSC patients are constantly improving. Due to the lack of highly sensitive and specific screening methods the early recognition of cholangiocellular carcinoma (CCC) as the most important complication is rarely successful. The continuous improvement of endoscopic retrograde cholangiopancreatography (ERCP) and direct cholangioscopy in combination with molecular biological and fluorescence in situ hybridization (FISH) analyses of bile duct tissue samples are promising for refined diagnostics. Due to the significantly increased risk of colorectal cancer, an annual colonoscopy is recommended in the presence of inflammatory bowel disease. Improvement of the early diagnostics of PSC and successful testing of new treatment strategies raise hope for a continuous improvement in the medical support of these complex patients.

A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway.

BACKGROUND: Ductular reactivity is central to the pathophysiology of cholangiopathies. Mechanisms underlying the reactive phenotype activation by exogenous inflammatory mediators and bile acids are poorly understood. METHODS: Using human extrahepatic cholangiocyte organoids (ECOs) we developed an injury model emulating the cholestatic microenvironment with exposure to inflammatory mediators and various pathogenic bile acids. Moreover, we explored roles for the bile acid activated Sphingosine-1-phosphate receptor 2 (S1PR2) and potential beneficial effects of therapeutic bile acids UDCA and norUDCA. RESULTS: Synergistic exposure to bile acids (taurocholic acid, glycocholic acid, glycochenodeoxycholic acid) and TNF-α for 24 hours induced a reactive state as measured by ECO diameter, proliferation, lactate dehydrogenase activity and reactive phenotype markers. While NorUDCA and UDCA treatments given 8 hours after injury induction both suppressed reactive phenotype activation and most injury parameters, proliferation was improved by NorUDCA only. Extrahepatic cholangiocyte organoid stimulation with S1PR2 agonist sphingosine-1-phosphate reproduced the cholangiocyte reactive state and upregulated S1PR2 downstream mediators; these effects were suppressed by S1PR2 antagonist JET-013 (JET), downstream mediator extracellular signal-regulated kinase 1/2 inhibitor, and by norUDCA or UDCA treatments. JET also partially suppressed reactive phenotype after bile acid injury. CONCLUSIONS: We developed a novel model to study the reactive cholangiocyte state in response to pathological stimuli in cholestasis and demonstrated a contributory role of S1PR2 signaling in both injury and NorUDCA/UDCA treatments. This model is a valuable tool to further explore the pathophysiology of human cholangiopathies.

FXR-FGF19 signaling in the gut-liver axis is dysregulated in patients with cirrhosis and correlates with impaired intestinal defence.

BACKGROUND AND AIMS: Experimental studies linked dysfunctional Farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling to liver disease. This study investigated key intersections of the FXR-FGF19 pathway along the gut-liver axis and their link to disease severity in patients with cirrhosis. METHODS: Patients with cirrhosis undergoing hepatic venous pressure gradient measurement (cohort-I n = 107, including n = 53 with concomitant liver biopsy; n = 5 healthy controls) or colonoscopy with ileum biopsy (cohort-II n = 37; n = 6 controls) were included. Hepatic and intestinal gene expression reflecting FXR activation and intestinal barrier integrity was assessed. Systemic bile acid (BA) and FGF19 levels were measured. RESULTS: Systemic BA and FGF19 levels correlated significantly (r = 0.461; p < 0.001) and increased with cirrhosis severity. Hepatic SHP expression decreased in patients with cirrhosis (vs. controls; p < 0.001), indicating reduced FXR activation in the liver. Systemic FGF19 (r = -0.512, p < 0.001) and BA (r = -0.487, p < 0.001) levels correlated negatively with hepatic CYP7A1, but not SHP or CYP8B1 expression, suggesting impaired feedback signaling in the liver. In the ileum, expression of FXR, SHP and FGF19 decreased in patients with cirrhosis, and interestingly, intestinal FGF19 expression was not linked to systemic FGF19 levels. Intestinal zonula occludens-1, occludin, and alpha-5-defensin expression in the ileum correlated with SHP and decreased in patients with decompensated cirrhosis as compared to controls. CONCLUSIONS: FXR-FGF19 signaling is dysregulated at essential molecular intersections along the gut-liver axis in patients with cirrhosis. Decreased FXR activation in the ileum mucosa was linked to reduced expression of intestinal barrier proteins. These human data call for further mechanistic research on interventions targeting the FXR-FGF19 pathway in patients with cirrhosis. CLINICAL TRIAL NUMBER: NCT03267615.

Microbiota modulation by dietary oat beta-glucan prevents steatotic liver disease progression.

Background & Aims: Changes in gut microbiota in metabolic dysfunction-associated steatotic liver disease (MASLD) are important drivers of disease progression towards fibrosis. Therefore, reversing microbial alterations could ameliorate MASLD progression. Oat beta-glucan, a non-digestible polysaccharide, has shown promising therapeutic effects on hyperlipidemia associated with MASLD, but its impact on gut microbiota and most importantly MASLD-related fibrosis remains unknown. Methods: We performed detailed metabolic phenotyping, including assessments of body composition, glucose tolerance, and lipid metabolism, as well as comprehensive characterization of the gut-liver axis in a western-style diet (WSD)-induced model of MASLD and assessed the effect of a beta-glucan intervention on early and advanced liver disease. Gut microbiota were modulated using broad-spectrum antibiotic treatment. Results: Oat beta-glucan supplementation did not affect WSD-induced body weight gain or glucose intolerance and the metabolic phenotype remained largely unaffected. Interestingly, oat beta-glucan dampened MASLD-related inflammation, which was associated with significantly reduced monocyte-derived macrophage infiltration and fibroinflammatory gene expression, as well as strongly reduced fibrosis development. Mechanistically, this protective effect was not mediated by changes in bile acid composition or signaling, but was dependent on gut microbiota and was lost upon broad-spectrum antibiotic treatment. Specifically, oat beta-glucan partially reversed unfavorable changes in gut microbiota, resulting in an expansion of protective taxa, including Ruminococcus, and Lactobacillus followed by reduced translocation of Toll-like receptor ligands. Conclusions: Our findings identify oat beta-glucan as a highly efficacious food supplement that dampens inflammation and fibrosis development in diet-induced MASLD. These results, along with its favorable dietary profile, suggest that it may be a cost-effective and well-tolerated approach to preventing MASLD progression and should be assessed in clinical studies. Impact and Implications: Herein, we investigated the effect of oat beta-glucan on the gut-liver axis and fibrosis development in a mouse model of metabolic dysfunction-associated steatotic liver disease (MASLD). Beta-glucan significantly reduced inflammation and fibrosis in the liver, which was associated with favorable shifts in gut microbiota that protected against bacterial translocation and activation of fibroinflammatory pathways. Together, oat beta-glucan may be a cost-effective and well-tolerated approach to prevent MASLD progression and should be assessed in clinical studies.

Evaluation of potential hepatic recompensation criteria in patients with PBC and decompensated cirrhosis.

BACKGROUND: Aetiological therapy improves liver function and may enable hepatic recompensation in decompensated cirrhosis. AIMS: We explored the potential for recompensation in patients with decompensated primary biliary cholangitis (PBC) - considering a biochemical response to ursodeoxycholic acid (UDCA) according to Paris-II criteria as a surrogate for successful aetiological treatment. METHODS: Patients with PBC were retrospectively included at the time of first decompensation. Recompensation was defined as (i) resolution of ascites and hepatic encephalopathy (HE) despite discontinuation of diuretic/HE therapy, (ii) absence of variceal bleeding and (iii) sustained liver function improvement. RESULTS: In total, 42 patients with PBC with decompensated cirrhosis (age: 63.5 [IQR: 51.9-69.2] years; 88.1% female; MELD-Na: 13.5 [IQR: 11.0-15.0]) were included and followed for 41.9 (IQR: 11.0-70.9) months after decompensation. Seven patients (16.7%) achieved recompensation. Lower MELD-Na (subdistribution hazard ratio [SHR]: 0.90; p = 0.047), bilirubin (SHR per mg/dL: 0.44; p = 0.005) and alkaline phosphatase (SHR per 10 U/L: 0.67; p = 0.001) at decompensation, as well as variceal bleeding as decompensating event (SHR: 4.37; p = 0.069), were linked to a higher probability of recompensation. Overall, 33 patients were treated with UDCA for ≥1 year and 12 (36%) achieved Paris-II response criteria. Recompensation occurred in 5/12 (41.7%) and in 2/21 (9.5%) patients with vs. without UDCA response at 1 year, respectively. Recompensation was linked to a numerically improved transplant-free survival (HR: 0.46; p = 0.335). Nonetheless, 4/7 recompensated patients presented with liver-related complications after developing hepatic malignancy and/or portal vein thrombosis and 2 eventually died. CONCLUSIONS: Patients with PBC and decompensated cirrhosis may achieve hepatic recompensation under UDCA therapy. However, since liver-related complications still occur after recompensation, patients should remain under close follow-up.

A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

Management of varices but not anticoagulation is associated with improved outcome in patients with HCC and macrovascular tumour invasion.

BACKGROUND & AIMS: The value of bleeding prophylaxis and anticoagulation in patients with hepatocellular carcinoma (HCC) and macrovascular tumour invasion (MVI) is unclear. We evaluated the impact of anticoagulation on thrombosis progression, bleeding events, and overall mortality, and assessed the efficacy of adequate management of varices as recommended for patients with cirrhosis. METHODS: HCC patients with MVI who had Child-Turcotte-Pugh A-B7 were included between Q4/2002 and Q2/2022. Localization of the tumour thrombus and changes at 3-6 months were evaluated by two radiologists. Univariable and multivariable logistic/Cox regression analyses included time-dependent variables (i.e., anticoagulation, systemic therapy, non-selective beta blocker treatment). RESULTS: Of 124 patients included (male: n = 110, 89%), MVI involved the main portal vein in 47 patients (38%), and 49 individuals (40%) had additional non-tumorous thrombus apposition. Fifty of 80 patients (63%) with available endoscopy had varices. Twenty-four individuals (19%) received therapeutic anticoagulation and 94 patients (76%) were treated with effective systemic therapies. The use of therapeutic anticoagulation did not significantly affect the course of the malignant thrombosis at 3-6 months. Systemic therapy (aHR: 0.26 [95%CI: 0.16-0.40]) but not anticoagulation was independently associated with reduced all-cause mortality. In patients with known variceal status, adequate management of varices was independently associated with reduced risk of variceal bleeding (aHR: 0.12 [95%CI: 0.02-0.71]). In the whole cohort, non-selective beta blockers were independently associated with reduced risk of variceal bleeding or death from any cause (aHR: 0.69 [95%CI: 0.50-0.96]). CONCLUSION: Adequate bleeding prophylaxis and systemic anti-tumour therapy but not anticoagulation were associated with improved outcomes in patients with HCC and MVI.

Differences between men and women with respect to colorectal cancer mortality despite screening colonoscopy.

BACKGROUND AND AIMS: Women aged 55 to 59 years have a similar prevalence rate and number needed to screen for colorectal adenomas as men at a 10-year younger age. The aim of this study was to determine sex-specific differences in colorectal cancer mortality and estimate the association with adenomas at screening colonoscopy. METHODS: This retrospective study analyzed 323,139 individuals who underwent colonoscopy within a national colorectal cancer screening program in Austria between January 2007 and December 2020. RESULTS: Median patient age was 60 years (interquartile range, 54-67), and the sex distribution in all age groups was nearly identical. Men had significantly higher odds of having an adenoma or serrated polyp, low-risk polyp, high-risk polyp, or colorectal cancer detected at colonoscopy than women (odds ratio [OR] 1.83; 95% confidence interval [CI], 1.80-1.86; OR, 1.46; 95% CI, 1.44-1.49; OR, 1.74; 95% CI, 1.69-1.80; and OR, 1.87; 95% CI, 1.70-2.05, respectively). Strikingly, male sex, when compared with female sex, was associated with an almost 2-fold (hazard ratio, 1.67; 95% CI, 1.05-2.67) increased risk to die from colorectal cancer when an adenoma or serrated polyp was found at the screening colonoscopy and a 4-fold (hazard ratio, 4.14; 95% CI, 2.72-6.3) increased risk when a high-risk polyp was found at the screening colonoscopy. The cumulative incidence for death of colorectal cancer for 60-year-old individuals was 8.5-fold higher in men as compared with women. Markedly, this sex gap narrowed with increasing age, whereas the difference in deaths of other causes remained similar in all age groups. CONCLUSIONS: Our findings strengthen the necessity of sex-specific screening recommendations. Importantly, further prospective studies should focus on sex differences in tumor biology to propose personalized surveillance guidelines.