BACKGROUND & AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) have increased in prevalence alongside the global epidemics of obesity and type 2 diabetes and now represent one of the leading causes of chronic liver disease. Patients with MASLD and significant fibrosis (≥F2) are at increased risk for adverse outcomes. With advances in noninvasive tests (NITs) and the recent approval of resmetirom and semaglutide for noncirrhotic MASH with F2-F3 fibrosis, we provide updated consensus guidance on standardized risk stratification, treatment initiation, and response monitoring. METHODS:A structured Delphi process was conducted following a systematic updated literature review (January 2025-November 2025), covering the period since publication of the initial consensus recommendations, and included iterative anonymous voting among 40 international experts representing hepatology, gastroenterology, endocrinology, internal medicine, and primary care. Consensus was predefined as ≥70% agreement. RESULTS:Forty-two statements were developed; 86% achieved consensus in the first round, and all remaining statements reached consensus after refinement and the second round. The panel endorsed a sequential risk-stratification strategy beginning with Fibrosis-4 Index (FIB-4) as the first-line assessment, followed by vibration-controlled transient elastography or Enhanced Liver Fibrosis (ELF) testing for secondary stratification. Treatment consideration with resmetirom or semaglutide was supported for noncirrhotic MASLD with liver stiffness measurement values of 10 to 20 kPa or ELF values of 9.2 to 11.3, after exclusion of cirrhosis. Upfront combination therapy with both drugs was not recommended. Selection of pharmacologic therapy was to be determined through shared decision-making between patient and provider and individualized according to the patient's cardiometabolic profile. Treatment response at 1 year was defined as a ≥30% reduction in liver stiffness or a ≥0.5-point reduction in ELF. CONCLUSIONS:This updated international consensus provides practical algorithms that integrate most commonly used noninvasive testing with recently approved pharmacologic therapies for MASLD, addressing current variability in clinical practice and supporting standardized implementation of risk-based care.

Steatotic liver disease (SLD) is a spectrum of highly prevalent liver diseases encountered at many different healthcare levels. Awareness about metabolic dysfunction-associated SLD (MASLD), MetALD (MASLD and increased alcohol intake) and ALD (alcohol-related liver disease) is increasing beyond hepatology, as reflected by the various SLD guidelines issued by scientific societies from different disciplines, including endocrinology. The guidance presented here aims to improve cross-disciplinary knowledge and know-how by providing guidance to healthcare professionals from a global, holistic, multi-society and multi-stakeholder perspective. The patient trajectory was used as an overarching anchor point to ensure uniform guidance at all points along the SLD spectrum, with the ultimate goal of improving patient identification and optimising care. This consensus guidance covers patient identification and risk stratification, relevant cross-disciplinary primary and secondary care approaches, referral to and from tertiary care and strategies for disease management and monitoring.

Weight reduction (≥5% to improve steatosis and ≥7-10% to improve inflammation and fibrosis) through lifestyle modifications is a first-line treatment of metabolic dysfunction-associated steatotic liver disease. Although the Mediterranean diet is the most evidence-based and recommended diet, similar plant-based diets are also acceptable. Physical activity and exercise (aerobic and resistance) are effective in steatosis reduction, independent of weight loss. However, the uptake of lifestyle interventions is challenging, and to enhance adherence, clinicians, policymakers, and stakeholders should support individuals by increasing awareness and promoting a healthier environment. Behavioral support, personalization, and sustainability of recommendations are key factors in individualized treatment.

AIM:To explore changes in body composition in adolescents with obesity treated with glucagon-like peptide-1 receptor agonist (GLP-1 RA) and their association with metabolic syndrome (MetS) components. METHODS:This real-world retrospective study included adolescents (12-18 years) with obesity who received multidisciplinary lifestyle-based obesity care between 2020 and 2024. GLP-1 RA therapy (liraglutide or semaglutide) was prescribed and dosed on an individualised basis. BMI and muscle-to-fat ratio (MFR) z-scores (by bioimpedance), and MetS components (glucose intolerance, hypertension, and dyslipidemia) were evaluated and compared with patients not receiving GLP-1 RA at corresponding time points. Multivariable regression analyses adjusted for sex, age, physical activity, and length of follow-up evaluated contributors for improvement in body composition. RESULTS:Of 67 eligible adolescents, 41 (61.2%) received GLP-1 RA therapy. The GLP-1 RA-treated group experienced greater improvements in BMI z-scores (-0.34 [-0.57, -0.07] vs. -0.07 [-0.17, 0.05], p < 0.001), and MFR z-scores (0.41 [0.12, 0.56] vs. 0.13 [0.01, 0.25], p = 0.007) compared to those without GLP-1 RA therapy. GLP-1 RA treatment duration was identified as the sole contributor to BMI and MFR z-score improvements (R2 = 0.515, p < 0.001 and R2 = 0.231, p = 0.012, respectively). A 0.25-unit decrease in BMI z-score and a 0.25-unit increase in MFR z-score were associated with 2.8-fold and 1.8-fold higher odds of MetS component improvement, respectively. CONCLUSION:Adolescents with obesity under GLP-1 RA therapy combined with lifestyle intervention demonstrated improvements in body composition and MetS components.

Liver disease causes substantial global morbidity and mortality, with a growing burden from steatotic liver disease driven by alcohol use and metabolic dysfunction, alongside persisting challenges from chronic viral hepatitis. Liver disease burden is unequal between and within countries, with high rates in people with low socioeconomic status and marginalised groups due to increased exposure to risk factors and compounded by reduced access to prevention, diagnosis, and treatment. Liver disease frequently coexists with multimorbidity-including diabetes, cancer, and mental illness-with bidirectional relationships that demand integrated, person-centred pathways of care. Primary care, as the cornerstone of first-contact, comprehensive health care, is uniquely positioned to deliver population-level prevention, early detection, and management of liver disease while reducing health disparities. However, despite increasing emphasis on prevention and long-term condition management globally, liver disease has received scarce attention within primary care policy, training, and system design. This Commission brings together multidisciplinary global expertise to review current evidence and provide recommendations to strengthen primary care-led liver health care. Central themes include reducing inequalities in liver care, defining a minimum package of primary care services, embedding liver health within non-communicable disease strategies, leveraging digital innovation, enhancing multidisciplinary collaboration, and advancing a coordinated research and implementation agenda focused on real-world care pathways and stigma reduction.

BACKGROUND/AIMS:The pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) is multifactorial, with evidence suggesting a protective role for the soluble receptor for advanced glycation end-products (sRAGE). While gut microbiota dysbiosis and MASLD have been linked, evidence of their association with sRAGE remains limited. We aimed to test the prospective association between serum sRAGE levels and MASLD and to explore associated patterns of gut microbiota composition. METHODS:A prospective cohort study assessed serum sRAGE levels and MASLD at two time points, with new-onset or persistence of MASLD evaluated by ultrasonography or controlled attenuation parameter. A cross-sectional analysis was performed on a sub-sample with gut microbiota measurements using 16S rRNA sequencing (V3-V4, Illumina MiSeq). RESULTS:Among 289 subjects in the prospective analysis (mean follow-up: 6.67 ± 0.73 years, mean age: 58.54 ± 6.54 years, 57.8% men), low sRAGE levels were associated with 2.22-fold greater odds of new-onset/persistent MASLD (95% CI 1.15-4.26, p = 0.017), with a dose-response association across sRAGE tertiles. The cross-sectional analysis with a subsample of 136 subjects showed significant α- and β-diversity differences between MASLD and non-MASLD groups. Moreover, β-diversity variation across sRAGE groups resembled that observed between the MASLD groups. Shared taxa linked to low sRAGE levels and MASLD included Streptococcaceae, Enterobacteriaceae, Streptococcus, Dorea, and Klebsiella. Non-MASLD and high sRAGE levels were associated with Christensenellaceae, Akkermansiaceae, Christensenellaceae R-7 group and Akkermansia. CONCLUSIONS:Low sRAGE levels are associated with higher odds of MASLD. MASLD and low sRAGE levels share a similar gut microbiota signature, suggesting a potential biological link that warrants further investigation.

BACKGROUND & AIMS:Structural features of national food systems shape metabolic risk, yet their pathways to metabolic dysfunction-associated steatotic liver disease (MASLD) across development levels remain poorly characterized. We examined food-system pathways to MASLD prevalence and liver-related mortality across 204 countries. METHODS:A cross-national ecological study harmonized data from the Global Burden of Disease study, NCD Risk Factor Collaboration, and FAOSTAT. Exposures were anchored to 2005-2011, metabolic mediators to 2013-2015, MASLD prevalence to 2019-2021, and liver mortality to 2023. Countries were stratified by Socio-Demographic Index (SDI; low <0.60 vs. high ≥0.60). Structural equation models estimated direct and indirect path associations among food-system characteristics, metabolic mediators, and liver outcomes. RESULTS:In low-SDI countries (n = 101), urbanization was associated with higher ultra-processed food retail exposure (β = +0.41), which was associated with higher obesity prevalence (β = +0.17). Food price burden was inversely associated with caloric surplus (β = -0.44). Caloric surplus was associated with MASLD prevalence (β = +0.46). Political stability was inversely associated with MASLD prevalence (β = -0.31). In high-SDI countries (n = 103), ultra-processed food exposure was associated with higher sugar kilocalorie share (β = +0.35), which was associated with higher obesity (β = +0.54). Cereal kilocalorie share was independently associated with higher type 2 diabetes (T2D) prevalence (β = +0.17). T2D was the dominant structural correlate of MASLD (β = +0.80). Healthcare Access and Quality index was positively associated with MASLD prevalence (β = +0.28) and inversely associated with MASLD mortality (β = -0.33). Healthcare quality was inversely associated with hepatitis B and hepatitis C mortality in both strata, but not alcohol-related liver disease mortality. CONCLUSIONS:Structural pathways to MASLD differ by development level: ultra-processed food exposure and caloric surplus dominate in low-SDI settings, whereas T2D dominates in high-SDI settings. These findings identify development-specific intervention targets for reducing liver disease burden. IMPACT AND IMPLICATIONS:Food-system structural characteristics including ultra-processed food retail exposure, dietary composition, and food price burden are differentially associated with MASLD prevalence through development-stratified pathways, providing a cross-national structural framework that extends beyond individual metabolic risk factors. These findings are relevant to global health researchers, epidemiologists, and policymakers working to understand and reduce rising liver disease burden in diverse economic settings. In low-SDI countries, efforts to monitor and moderate ultra-processed food retail expansion may warrant priority alongside caloric sufficiency programs; in high-SDI countries, structural findings reinforce the centrality of type 2 diabetes detection and management as a liver disease prevention strategy. Because this study is ecological and cross-sectional in design, associations reflect country-level structural patterns and should not be interpreted as individual-level causal effects; prospective and interventional research is needed to evaluate whether modifying these structural antecedents translates to reductions in MASLD burden.

Steatotic liver disease (SLD) comprises metabolic dysfunction-associated SLD, metabolic and alcohol-related liver disease, and alcohol-related liver disease, conditions that frequently overlap rather than fall into distinct categories. Cardiometabolic risk factors (CMRFs), including obesity, type 2 diabetes, hypertension and dyslipidaemia, are highly prevalent across SLD subtypes, with most patients exhibiting multiple metabolic abnormalities. These risks interact synergistically with alcohol exposure, accelerating fibrosis progression to cirrhosis and liver mortality. Importantly, both alcohol consumption and metabolic risks are dynamic and can fluctuate over time, leading to transitions across the SLD spectrum that static diagnostic thresholds might not adequately capture. Misclassification is common, particularly due to under-reporting of alcohol intake, underscoring the value of objective alcohol biomarkers such as phosphatidylethanol. Accurate risk stratification, therefore, requires an integrated approach combining systematic alcohol screening, structured evaluation of CMRFs and non-invasive fibrosis assessment. Management must be multidisciplinary, combining alcohol reduction strategies, optimization of metabolic control and liver-directed therapies. However, most emerging pharmacotherapies for metabolic dysfunction-associated steatohepatitis exclude individuals with concurrent alcohol use, creating a gap between clinical trial populations and real-world practice. A dynamic, spectrum-based framework incorporating repeated reassessment of alcohol and metabolic risks offers the most pragmatic path for diagnosis, treatment and equitable care delivery in SLD.

Background & Aims High intake of ultra-processed food (UPF) and its subcategories of processed meats, snacks, and beverages is associated with increased cardiometabolic risk. This study aimed to assess the validity of a Short Processed Food Questionnaire (SPFQ) against a validated food frequency questionnaire (FFQ) and to explore the predictive validity for metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic outcomes. Methods A validation and a prospective cohort study, including adults who participated in a metabolic and hepatic screening survey at Tel-Aviv Medical Center and arrived to follow-up at least five years later. MASLD was evaluated by ultrasound/controlled attenuation parameter. At baseline, participants completed a 118-item FFQ; 49 items were classified as UPF (NOVA 4). The 23-item SPFQ includes 15 UPF items, which were mapped to FFQ data to simulate responses. Relative validity was assessed by comparing UPF estimates using paired t-tests, Pearson correlation, and tertile agreement with weighted kappa. Predictive validity was evaluated by multivariable logistic regression. Results A total of 789 subjects were included. Correlations between the two questionnaires were strong for total UPF and its subcategories processed meat, snacks, and beverages (r≥0.91; all P<0.001). Tertile agreement across total UPF and subcategories was high, with 78.3%, 90.0%, 94.6%, and 96.5% classified in the same tertile by both questionnaires (kappa≥0.81; all P<0.001). In the prospective cohort (n=316; mean follow-up 6.7 years), the highest UPF tertile by SPFQ was associated with higher odds of new-onset/persistent metabolic syndrome (OR=2.05, 95%CI 1.10–3.83), hypertension (2.37, 1.03–5.41), and low HDL-C (2.19, 1.06–4.50). A similar, non-significant trend was observed for MASLD (1.83, 0.82–4.07). Conclusion The SPFQ has a strong relative validity for estimating UPF intake and suggests predictive utility for cardiometabolic outcomes.

BACKGROUND & AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) affects women and men differently, and both perceived and self-stigma may contribute to care avoidance. This study aimed to assess gender-specific patterns of stigma and their associations with care avoidance in MASLD. METHODS:A cross-sectional, international survey was administered in 2023 by the Global MASH/NASH Council (GNC) among adults with a confirmed diagnosis of MASLD. The survey collected sociodemographic and clinical data, assessed perceived stigma and self-stigma using the validated Self-Stigma Scale-Short Form, generating domain-specific and total scores. Severe self-stigma (simply named self-stigma) was defined as a total score above the 75th percentile, stratified by gender. Care avoidance in primary or secondary care (gastroenterology, hepatology, and endocrinology) was reported. RESULTS:Among 1,313 respondents with MASLD (51% men; 50% aged ≥55 years; 28% Europe, 26% USA/Canada, 30% South East/West Asia, 16% MENA), care avoidance was more frequent among men (23.6% vs. 18.9%, p=0.04), occurring predominantly in the primary care. Women reported higher self-stigma scores (all p<0.001) and more discrimination-related perceived stigma (27.8% vs. 19.1%). In adjusted analyses, both perceived stigma [adjusted OR(95%CI): 1.84(1.07-3.18)] and self-stigma [1.84(1.19-2.85)] were associated with care avoidance in men, whereas only perceived stigma was associated with care avoidance in women [2.29(1.25-4.22)]. In women, perceived stigma was linked to younger age, multimorbidity, and history of medical weight loss (p<0.05), while no predictors were identified in men. Lower socioeconomic status and advanced fibrosis predicted self-stigma in both genders. CONCLUSIONS:Stigma emerges as a major, gender-specific barrier to care in MASLD, with distinct mechanisms in men and women. Integrating gender-sensitive, stigma-informed strategies into MASLD care may improve access and continuity of care. IMPACT AND IMPLICATIONS:The presence of stigma due to liver disease is associated with avoiding care. However, despite women reporting a higher degree of stigma than men, men more often avoided healthcare visits especially when self-stigma was present. These differences in stigma and care avoidance by gender necessitates that healthcare providers who treat patients with MASLD develop gender-sensitive interventions to help ensure continued engagement with the healthcare system.