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.

Abstract The Model for End-Stage Liver Disease (MELD) score is widely used to prioritize patients for liver transplantation and to estimate short-term mortality in end-stage liver disease. Inaccuracies in serum creatinine measurements, particularly interference from bilirubin, both key components of the MELD, may influence clinical decision-making. However, standardized approaches to address such analytical bias are lacking. Here we show that bilirubin-related interference leads to clinically relevant MELD distortions and associated outcomes. We developed a correction model using controlled in vitro matrices and validated it against representative patient samples. The model was applied to a large cohort from registry data and a separate clinical population. After correction, clinically meaningful score shifts occurred in a substantial proportion of patients, with lower corrected scores associated with altered transplantation probability and mortality estimates. These findings highlight the importance of harmonized, interference-resistant creatinine assays to improve fairness and accuracy in liver transplant allocation.

In 2023, new terminology [metabolic dysfunction associated steatotic liver disease (MASLD)] was introduced adressing the shortfalls (stigma/underreporting of alcohol) of nonalcoholic fatty liver disease (NAFLD). MASLD falls within a SLD spectrum dependent upon cardio-metabolic risk factors (CMRFs) and alcohol consumption [MASLD (< 20 g females/30 g males), MetALD (<50g females/<60 g males), and ALD (≥ 50g females/ ≥ 60 g males). HRQL, economic burden, fibrosis, cirrhosis, cancer, and mortality are inversely related with alcohol and presence of multiple CMRFs. Adult prevalence rates of MASLD, Met-ALD and ALD are 30%+, 2.2%-10%, and 1%-3%, respectively. Increased awareness of SLD and decreasing alcohol consumption interventions are needed.

BACKGROUND & AIMS:Noninvasive tests (NITs) are widely used to risk-stratify patients with metabolic dysfunction-associated steatotic liver disease (MASLD); however, their performance may vary according to patient characteristics. We evaluated the accuracy of NITs in a large, multinational MASLD cohort across select subpopulations. METHODS:We analyzed 18,759 adults with biopsy-confirmed MASLD from 41 countries. NITs included FIB-4, liver stiffness measurement (LSM), and Agile-3+. Diagnostic performance for advanced fibrosis (F3-F4) was measured using areas under the curve (AUCs) across subgroups defined by age, sex, type 2 diabetes (T2D), obesity, and alcohol use. Subgroup-specific cutoffs were derived. RESULTS:Advanced fibrosis was present in 37% of patients. Pooled AUCs were 0.79 for FIB-4, 0.83 for LSM, and 0.86 for Agile-3+. FIB-4 accuracy declined with age (AUC 0.70 in ≥65 years vs 0.79 in <65 years, P < .0001) and in middle-aged patients with T2D. The LSM performance remained stable across T2D status but was moderately reduced in patients with obesity and, more profoundly, morbid obesity (body mass index [BMI] >35 kg/m2). Sex and alcohol use had minimal impact on AUCs. Age- and T2D-specific FIB-4 cutoffs varied substantially to maintain predefined accuracy (sensitivity or specificity). The cutoffs for LSM also differed based on patients' BMI, with lower diagnostic cutoffs for advanced fibrosis required in nonobese MASLD (sensitivity 80%: 8.8 kPa in lean, 9.0 kPa overweight, 9.6 kPa in obesity, 11.0 kPa in morbid obesity). CONCLUSIONS:Accuracy of NITs for advanced fibrosis in MASLD is influenced by age, T2D, and obesity. Age-adjusted FIB-4 thresholds may enhance risk stratification. Imaging-based and composite NITs (LSM and Agile-3+) provide more consistent performance across MASLD subpopulations.

BACKGROUND & AIMS:Data on outcomes of hepatitis D virus coinfection in individuals with hepatitis B virus are limited. Clinical characteristics and post-transplant outcomes of patients with hepatitis B virus/hepatitis D virus vs hepatitis B virus monoinfection were compared. METHODS:Adult liver transplant recipients with hepatitis B virus infection from the European Liver Transplant Registry and the United States Scientific Registry of Transplant Recipients between 2000 and 2022 were analyzed. Listing diagnosis determined hepatitis D virus coinfection. Demographic, clinical, peritransplant characteristics, and post-liver transplant mortality were compared between the hepatitis D virus and hepatitis B virus groups. RESULTS:Among 13,093 hepatitis B virus liver transplant recipients, 2327 (18%) had hepatitis D virus. Hepatitis D virus was more frequent in the European Liver Transplant Registry (24%) vs the United States Scientific Registry of Transplant Recipients (2.6%). The proportion of hepatitis B virus/hepatitis D virus liver transplant recipients remained stable over time (P > .05). Compared with patients with hepatitis B virus monoinfection, patients with hepatitis D virus were younger (48 ± 10 vs 54 ± 10 years), had lower body mass index (25.4 ± 4.0 vs 26.3 ± 4.7 kg/m2), were less male (68% vs 83%), were less frequently listed with hepatocellular carcinoma (27% vs 44%), had more ascites (66% vs 55%), and had higher Model for End-stage Liver Disease scores (17.6 ± 7.4 vs 17.0 ± 9.3) (all P < .01). The median follow-up was 5.2 years (interquartile range, 1.3-11.7 years). Post-liver transplant survival was superior in patients with hepatitis D virus: 1-year (92% vs 88%), 3-year (86% vs 80%), 5-year (81% vs 74%), 10-year (68% vs 61%) (all P < .01). Similar trends were noted in patients without hepatocellular carcinoma; outcomes in patients with hepatitis D virus vs patients with hepatitis B virus with hepatocellular carcinoma were similar (all P > .05). CONCLUSIONS:Compared with hepatitis B virus-monoinfected recipients, hepatitis B virus/hepatitis D virus recipients were transplanted younger with more advanced liver disease, underscoring the urgent need for hepatitis D virus-targeted therapies. Despite their worse pretransplant profile, patients with hepatitis D virus achieve comparable or superior post-transplant survival.

Fatigue in chronic viral hepatitis may be associated with decreased health-related quality of life and other patient-reported outcomes (PROs). We evaluated the relationship between fatigue and PROs in patients with chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Patients with CHB and CHC enrolled in the Global Liver Registry completed PRO instruments: FACIT-F, CLDQ (for CHB), CLDQ-HCV (for CHC), and WPAI:SHP. Fatigue was defined as FACIT-F Fatigue Scale (FS) score < 30 (scale range: 0-52). Among 2888 patients from 14 countries, 1561 had CHB (mean age 47 ± 13 years; 60% male; 13% advanced fibrosis; 13% depression; 17% fatigue) and 1327 had CHC (50 ± 13 years; 47% male; 21% advanced fibrosis; 18% depression; 28% fatigue). CHB-fatigue was associated with younger age, female, obesity, anxiety, depression (all p < 0.01) and worse PRO scores: CLDQ (scale 1-7): 4.1 ± 0.9 vs. 5.8 ± 0.9; FACIT score (range 0-108): 67.6 ± 14.5 vs. 87.7 ± 13.7; work productivity impairment (range 0-1): 0.33 ± 0.29 vs. 0.11 ± 0.22 (all p < 0.0001). Multivariable analysis confirmed the association of fatigue with lower PRO scores, impairment up to -23% (p < 0.01). CHC-fatigue was associated with female sex, obesity, type 2 diabetes, anxiety, depression (all p < 0.05) and worse PRO scores: CLDQ-HCV: 3.8 ± 1.0 vs. 5.5 ± 1.0; FACIT: 61.8 ± 14.1 vs. 85.6 ± 14.5; work productivity impairment: 0.49 ± 0.32 vs. 0.17 ± 0.25 (all p < 0.0001). In multivariable models, fatigue remained associated with reduced PRO scores, impairment up to -33% (p < 0.01). Almost one in five patients with chronic viral hepatitis report significant fatigue, which is associated with substantial PRO and work productivity impairment. Routine assessment for and management of fatigue in CHC or CHB care is essential.

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is associated with a substantial symptom burden. However, no validated symptom-focused patient-reported outcome (PRO) instrument exists for this population. We aimed to develop and validate the MASH Symptom Questionnaire. Methods: We analyzed MASLD subjects from the Global NASH/MASH Registry (GNR) with clinical data and completed CLDQ-MASH instruments. For the new instrument development and preliminary validation, we used CLDQ-MASH items supplemented with symptom-related items from other generic instruments (development sample: n=2,066) and expert input. A list of 50 symptom-related items was identified. After removal of redundancy, 36 items were retained and evaluated using exploratory factor analysis. Standard pipeline for validation of a PRO instrument was applied. The instrument was validated using another independent validation sample from GNR (validation sample: n=2541). Results: In the development phase, 36 items were distributed in 8 symptom domains: Mental, Cognitive, Fatigue, Systemic, Abdominal, Health distress, Sleep Disturbance, and Peripheral symptoms domains. Seven of eight domains demonstrated Cronbach’s alpha >0.80 (high internal consistency); the remaining Peripheral symptoms domain included diverse items. The domain scores significantly discriminated across histologic disease severity (early fibrosis vs. F2-F3 vs. cirrhosis), liver stiffness categories (<10 vs. 10-20 vs. >20 kPa) in both development and independent validation samples. The instrument discriminated well based on non-hepatic comorbidities (type 2 diabetes, hypertension, psychiatric, sleep, pruritus, clinically overt fatigue, GERD, other GI disorders). Similar strong validation properties were noted in the independent validation sample. Conclusion: The 36-item, 8-domain CLDQ-MASH Symptom Questionnaire (CLDQ-MASH SQ) represents the first validated, disease-specific symptom questionnaire for patients with MASH showing good psychometric properties. With further external validation, the CLDQ-MASH-SQ has the potential to serve as a standardized tool in both clinical research and routine practice to comprehensively assess disease burden and treatment response.

BACKGROUND:Resmetirom is approved for MASH F2-F3 fibrosis. Health-related quality of life (HRQL) was assessed in patients with MASH treated with resmetirom. METHODS:Patients with MASH enrolled in MAESTRO-NAFLD-1 (NCT04197479) and the 52-week open-label extension study (year 2). HRQL was assessed using LDQoL and CLDQ-NAFLD. Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) response definition for early MASH: a decrease ≥30% from baseline; MASH cirrhosis ≥20% decrease (if baseline MRI-PDFF >5%). RESULTS:MAESTRO-NAFLD-1 included 180 patients with MASH cirrhosis and 1143 with early MASH [baseline MRI-PDFF ≥8%, vibration-controlled transient elastography (VCTE) ≥5.5 kPa <8.5 kPa] treated with 80 mg or 100 mg resmetirom or placebo or 100 mg open-label resmetirom. Baseline HRQL for MASH cirrhosis was significantly lower (up to -15% of score range) for all 6 domains of CLDQ-NAFLD and 13/17 domains of LDQoL (p<0.05). MASH cirrhosis, by week 24 of resmetirom treatment year 1, had improvements in Worry (CLDQ-NAFLD) and Health Distress (LDQoL) up to +4% of score range, sustained through week 52 and throughout year 2 (day 1, week 12, week 28) (p<0.05). Cirrhotic patients with MRI-PDFF response by year 1 week 52, improved in Stigma score (LDQoL): mean change (+3.9 vs. -4.2, p=0.042). Early MASH receiving resmetirom experienced improvement in: Abdominal and Worry (CLDQ-NAFLD) and Health Distress (LDQoL) (up to +5% of score range size); no similar improvements observed in placebo (all p>0.05). Early MASH patients with MRI-PDFF response experienced Abdominal and Worry score (up to +6%) improvements-greater than placebo or nonresponders. CONCLUSIONS:Early MASH and MASH cirrhosis treated with resmetirom experience improvement in some disease-specific HRQL scores.

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: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.