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.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30% of adults, with about 30% of cases progressing to metabolic dysfunction-associated steatohepatitis (MASH), which can lead to cirrhosis and hepatocellular carcinoma. Cardiovascular disease is the leading cause of death in patients with MASH, highlighting the need for integrated heart-liver co-management. MASLD and cardiovascular disease share common pathophysiological mechanisms, including insulin resistance, low-grade inflammation, atherogenic dyslipidaemia, and oxidative stress, creating a bidirectional interplay that drives disease progression. Effective management of MASLD requires addressing not only hepatic steatosis, inflammation, and fibrosis, but also managing cardiovascular risk. Current clinical practice and trials face several challenges, including the underdiagnosis of MASLD, poor collaboration between hepatologists and cardiologists, and a paucity of pharmacological options that safely target both the liver and heart. This Review covers three main pharmacological approaches: metabolic-targeted therapies, which improve the upstream metabolic milieu; liver-targeted therapies, which focus on MASH and fibrosis, but require further evaluation for cardiovascular safety; and cardiovascular therapies, which might provide hepatoprotective effects, but need further study. This Review discusses the benefits and limitations of these pharmacotherapies, emphasising the importance of an integrated heart-liver co-management approach to improve clinical outcomes for patients living with MASLD.

The redefinition of steatotic liver disease, including metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH), has sharpened the distinction between benign hepatic fat accumulation and true liver pathology. MASLD has a global prevalence of 25-30%, but this should not be regarded as the prevalence of individuals with liver disease requiring diagnosis and treatment, as only a minority will progress to advanced disease with liver-related morbidity or mortality. Steatosis alone is often a phenotype or risk marker for liver disease or cardiometabolic disease - not a disease per se in the conventional sense. Clinically relevant liver disease arises when steatosis progresses to steatohepatitis and fibrosis -conditions identifiable by emerging non-invasive tests or histology. MASH has a substantial global prevalence of around 5%. The risk of adverse liver outcomes in MASLD/MASH is primarily determined by the stage of liver fibrosis (e.g. liver stiffness >10 kPa by elastography), severity of metabolic dysfunction (e.g. type 2 diabetes) and other risk factors (e.g. alcohol, genetics, age and sex). From a therapeutic perspective, this distinction underscores that isolated steatosis warrants primarily cardiometabolic management, whereas both established MASH and MASLD with fibrosis require liver-targeted interventions. Recognising the difference between steatosis (not a standalone liver disease) and MASH/fibrosis (true driver of liver-related risk) enables more precise risk communication, guides targeted surveillance and treatment, and helps to avoid unnecessary alarm and inefficient use of resources in already strained healthcare systems. This paradigm shift supports credible, evidence-based public health strategies focused on metabolic health and fibrosis prevention.

Metabolic dysfunction associated steatotic liver disease (MASLD) and metabolic dysfunction associated steatohepatitis (MASH) are accelerating global priorities, yet pivotal clinical trial activity remains concentrated in North America and Europe despite substantial burden in the Middle East and North Africa (MENA). Building on prior work quantifying MENA underrepresentation, we provide a policy and operational analysis informed by contemporary epidemiological, regulatory, and clinical trial literature and practical experience in trial delivery. We argue that underselection is driven less by scientific feasibility than by predictable, modifiable operational constraints. Key barriers include prolonged and fragmented contracting and budget negotiations, limited and inconsistent endpoint delivery capacity (imaging, noninvasive tests, and biopsy workflows), uneven pharmacy infrastructure for investigational product handling, shortages of stable research staffing with protected time, and variable ethics and regulatory review pathways. Commercial incentives to prioritize FDA and EMA approval in high profitability markets can reinforce these patterns, raising scientific and ethical concerns when high burden populations remain underrepresented. We propose actionable reforms across stakeholders, including earlier feasibility that funds readiness, standardized contracting pathways with clear timelines, shared regional endpoint support for pathology and imaging, and regulatory reliance models that reduce redundant review without weakening protections. Strengthening trial delivery as a measurable health system function is essential for MENA inclusion and for global credibility of emerging MASLD and MASH therapeutics.

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.