CONTEXT:Multiparametric magnetic resonance iron-corrected T1 mapping (cT1) may help identification and risk-stratification of steatohepatitis (MASH). OBJECTIVE:In type 2 diabetes, metabolic dysfunction-associated steatotic liver disease frequently advances to steatohepatitis with significant fibrosis and increased risk of developing cirrhosis. cT1 allows MASH risk-stratification by measuring liver disease activity (fibro-inflammation) but its association with cardiometabolic risk factors that drive liver disease progression in T2D (insulin resistance, lipotoxicity, and metabolic syndrome) remains unclear. METHODS:We recruited 109 participants with T2D from primary care settings who were classified into four groups according to cT1 and liver fat content (LiverMultiScan): (1) without steatosis; (2) steatosis only without MASH; (3) mild-moderate MASH (cT1 ≥ 800 to ≤875 ms); and (4) severe MASH (cT1 > 875 ms). We also measured insulin resistance (HOMA-IR), adipose tissue dysfunction (Adipo-IR, plasma adiponectin), and several noninvasive tests of MASH necroinflammation or fibrosis severity (NIS2+®, CK-18, FAST, and MRE). RESULTS:Higher MASH disease activity (cT1) was associated with more severe features of the metabolic syndrome as well as increased insulin resistance (HOMA-IR) and adipose tissue dysfunction (higher Adipo-IR and decreased adiponectin levels; all P < .01). Elevated cT1 correlated with worse hepatic necroinflammation (FAST, NIS2+®, and CK-18) and more severe steatosis and fibrosis (all P < .001). CONCLUSION:In people with T2D, worse MASH disease activity (measured by cT1) is associated with unfavorable cardiometabolic risk factors that are known to drive liver disease progression. Use of cT1 in this population may help early identification of at-risk individuals who would benefit from earlier aggressive intervention in primary care.

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.

The American Gastroenterological Association gathered a group of interdisciplinary experts to develop an updated Clinical Care Pathway on how to best screen for, diagnose, and treat metabolic dysfunction-associated steatotic liver disease. The complementary clinical application was also updated to reflect the changes in the clinical guidance: MASLD/MASH Clinical Care Pathway mobile application at gastro.org/MASLD.

The clinical management of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) is undergoing rapid evolution, driven by advances in noninvasive diagnostics and the recent approval of liver-directed therapies. Multiple professional societies have issued guidelines and clinical care pathways to address screening, risk stratification, treatment initiation, and monitoring; however, substantial heterogeneity exists across these documents. In this review, we systematically compare major contemporary guidelines from hepatology, gastroenterology, endocrinology, and diabetes societies, highlighting areas of consensus as well as key differences in target populations for screening, noninvasive test thresholds, treatment eligibility criteria, and monitoring strategies. We analyse the methodological underpinnings of these recommendations, emphasising important limitations related to reliance on trial-derived populations, the absence of head-to-head comparisons, and the use of noninvasive test cutoffs extrapolated from highly selected randomised controlled trials. We also discuss how subjective interpretation of emerging evidence, variable consideration of cardiometabolic comorbidities, and limited integration of cost and access considerations contribute to divergent recommendations. Finally, we propose a framework for improving future guidelines, including greater transparency regarding evidence limitations, adoption of prevalence- and outcome-informed thresholds, clearer guidance on therapy sequencing and combination strategies, and a more holistic approach that aligns liver-specific outcomes with broader cardiometabolic risk reduction. As the therapeutic landscape continues to expand, more adaptive and objective guideline frameworks will be essential to optimise real-world implementation and equity of care.

ImportanceCurrent guidance from the American Diabetes Association recommends liver stiffness measurement (LSM) only when the Fibrosis-4 (FIB-4) index is elevated. However, LSM may provide additional valuable information compared with FIB-4, which is known to underperform in certain populations, such as individuals with type 2 diabetes.ObjectiveTo assess whether liver fibrosis evaluated by LSM is associated with increased mortality in individuals with and without diabetes.Design, Setting, and ParticipantsThis cohort study included adult patients with complete vibration-controlled transient elastography (VCTE) and controlled attenuation parameter (CAP) data. Baseline data, including demographics and routine laboratory tests, were obtained from the 2017 to 2018 National Health and Nutrition Examination Survey and linked to data from the National Center for Health Statistics and National Death Index up to December 31, 2019. Patients with a history of liver disease other than metabolic dysfunction-associated steatotic liver disease were excluded. Data were analyzed from December 2024 to December 2025, accounting for the complex survey design using examination weights.ExposuresLiver disease based on CAP results and LSM by VCTE. CAP results 274 dB/m or higher indicate a diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and LSM results 9.7 kPa or higher indicate advanced liver fibrosis.Main Outcomes and MeasuresAll-cause mortality. Mortality risk was expressed as hazard ratios (HRs) with 95% CIs calculated using Cox proportional hazards regression models.ResultsA total of 4102 adult patients (mean [SEM] age, 47 [1] years; 50.7% female), were included in the study. The mean (SEM) body mass index (BMI), calculated as weight in kilograms divided by height in meters squared, was 29.5 (0.3). Diabetes was present in 14.5% of participants. After a mean (SEM) follow-up of 24 (2) months, 59 patients (1.4%) had died. Patients who died during follow-up vs those who did not were older (mean [SEM] age, 62 [3] years vs 47 [1] years; P < .001), had a higher prevalence of diabetes (35.7% vs 14.2%; P = .01), and were more likely to be of non-Hispanic White race (85.1% vs 62.7%, P = .002). Increased risk of all-cause mortality was associated with the coexistence of diabetes with MASLD (adjusted hazard ratio [AHR], 2.77; 95% CI, 1.16-6.65; P = .03) and diabetes with advanced liver fibrosis (AHR 6.41; 95% CI, 1.03-39.85; P = .047). In patients with diabetes, LSM (AHR, 1.06; 95% CI, 1.04-1.09; P < .001) but not FIB-4 index remained associated with all-cause mortality even after adjusting for other clinical variables, such as age, sex, BMI, and hemoglobin A1c.Conclusions and RelevanceIn this cohort study, LSM was an independent risk factor for all-cause mortality in individuals with diabetes, even after a relatively short follow-up. Implementing LSM to screen for liver fibrosis as part of routine diabetes management could aid in early identification of patients with high mortality risk.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most prevalent liver disease among children and is closely associated with insulin resistance and increased risk of developing type 2 diabetes. Early intervention in children with MASLD is essential to prevent progression to advanced liver disease and other metabolic disorders. The goal of this ongoing trial is to determine the effect of a weight-maintaining low glycaemic, moderately carbohydrate-restricted diet (CRD) v. fat-restricted diet (FRD) on changes in hepatic lipid content, insulin sensitivity and metabolomic profile over a 6-month period in adolescents with MASLD. Eligible participants will be children aged 10-17 years with a BMI > 75th percentile and a clinical diagnosis of MASLD. This randomised control trial consists of two 12-week phases: a controlled feeding phase, during which food will be provided to the family, and a free-living phase. The CRD has a macronutrient composition of < 25 % carbohydrate (CHO), 25 % protein and > 50 % fat, while the FRD is composed of 55 % CHO, 25 % protein and 20 % fat. Primary outcomes include change in hepatic lipid measured by MRI and magnetic resonance spectroscopy (MRS); insulin sensitivity measured via euglycaemic clamp; and metabolomic profiling measured from fasting blood. Diet tolerance, body weight and compliance were measured weekly by a Registered Dietitian during the controlled feeding phase and then monthly in the free-living phase. Changes in study endpoints will be assessed between intervention groups and across study time points, assessing for effects by group, time and the group-by-time interaction.

Introduction and Objective: Recent ADA guidance recommends screening individuals with T2D for liver fibrosis with FIB-4 index followed by confirmatory testing. However, implementation of these recommendations remains low. This project assessed whether an electronic health record (EHR) alert for elevated FIB-4 improved screening for liver fibrosis. Methods: Pre-intervention data were gathered from all new patients seen in a weight loss clinic in July-August 2025. An EHR alert flagged patients with BMI≥30kg/m2, A1c≥5.7%, and FIB-4≥1.3. Post-intervention data were collected from 12/2025 to 2/2026. Outcomes included documentation of FIB-4 in clinic notes and orders placed for fibrosis-related labs (e.g., ELF) or imaging studies (e.g., elastography). A 1-hour education session for providers has recently been conducted, and similar data gathering for a post-education phase is ongoing. Results: Pre-intervention data included 178 new patients (45±13 years, 78.7% female, BMI 41.8±9.6 kg/m2, A1c 6.0±1.2%, 23% had diabetes, 7% had elevated FIB-4). FIB-4 was mentioned in only 2 (1.1%) notes. Additionally, 88 (49.4%) patients had labs within 1 year prior to calculate FIB-4, while 41 (23%) had the required CBC and CMP ordered on the day of visit. Post-intervention data included 111 new patients (45±15 years, 82.9% female, BMI 41±8.3 kg/m2, A1c 5.8±1.2%, 18% had diabetes, 9% had elevated FIB-4). FIB-4 referenced in notes significantly increased to 9%, p=0.002 compared to preintervention. Fifty-six (50.5%) of these patients had labs required to calculate FIB-4 within 1 year prior, while 15 (13.5%) had labs ordered on the day of visit. No significant changes in ELF or elastography orders were observed. Conclusion: Implementation of a FIB-4 alert increased awareness about liver fibrosis screening, but it did not substantially change providers’ practices. Alerts alone may not be sufficient to improve fibrosis screening in obesity clinics. Ongoing efforts include targeted provider education to assess whether combined strategies enhance liver fibrosis screening. Disclosure S. Bobba: None. J. Nammi: None. K. Cohn: None. M.E. Gray: Consultant; Current; Novo Nordisk, Boehringer Ingelheim International GmbH, Madrigal Pharmaceuticals, Inc. Consultant; Ended; Intercept Pharmaceuticals, Inc. F. Bril: Consultant; Current; Novo Nordisk. Advisory Panel; Current; Novo Nordisk. Consultant; Current; Madrigal Pharmaceuticals, Inc. Advisory Panel; Current; Madrigal Pharmaceuticals, Inc. Consultant; Current; Boehringer Ingelheim International GmbH. Advisory Panel; Current; Boehringer Ingelheim International GmbH. Funding Petauri Kinetix

BACKGROUND:This retrospective study compared healthcare resource utilization (HCRU) and costs between patients with probable metabolic dysfunction-associated steatohepatitis (MASH) and those without MASH or those with diagnosed MASH in the United States. RESEARCH DESIGN AND METHODS:Patients from Komodo Healthcare Map data (2017-2022) were divided into 3 groups: probable MASH (hepatic steatosis index >36 or ICD-10-CM K76.0 plus ≥1 cardiometabolic risk factor), diagnosed MASH (ICD-10-CM K75.81), and without MASH (none of the aforementioned characteristics). Propensity score weighting adjusted for baseline differences. HCRU and costs were calculated for all-cause, major adverse liver outcomes (MALO), and major adverse cardiovascular events (MACE). RESULTS:Patients with probable MASH (n = 1 549 485) had higher all-cause, MALO-related, and MACE-related HCRU than those without MASH (n = 513 862). However, patients with probable MASH had lower HCRU than those with diagnosed MASH (n = 15 000). Associated costs per patient per year were higher in patients with probable MASH vs those without MASH (rate ratio, 1.27; 95% CI, 1.26-1.28), but lower than in patients with diagnosed MASH (rate ratio, 0.70; 95% CI, 0.67-0.72). CONCLUSIONS:HCRU and costs were higher in patients with probable MASH than in patients without MASH. Results highlight the economic burden associated with probable MASH and the importance of early diagnosis.

AIMS:Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of cirrhosis. NIS2+ is a recently approved serum-based test combining two biomarkers (miR-34a-5p and YKL-40) to identify at-risk MASH (i.e., MASH and significant fibrosis). OBJECTIVE:To assess the prevalence of at-risk MASH by NIS2+ in individuals from primary care or endocrinology clinics. MATERIALS AND METHODS:798 participants recruited from outpatient clinics were risk-stratified by NIS2+ into low-risk, intermediate-risk or having at-risk MASH (NIS2+ score < 0.46, ≥ 0.46 and < 0.68 or ≥ 0.68, respectively). Presence of steatosis (CAP ≥ 288 dB/m) and clinically significant liver fibrosis (VCTE- ≥ 8.0 kPa) was established by transient elastography (FibroScan). RESULTS:At-risk MASH affected 29% of individuals with both obesity and T2D compared to 3% of those without either condition (p < 0.001). People with at-risk MASH, compared to those at low-risk, more often had steatosis (81% vs. 40%), clinically significant fibrosis (42% vs. 5%), AST or ALT ≥ 40 IU/L, hepatic insulin resistance (by HOMA-IR) and adipose tissue insulin resistance (by adipo-IR) (all p < 0.001). NIS2+ strongly correlated with diagnosis of at-risk MASH by FAST (r = 0.67; p < 0.001), as well as CK-18, ALT and AST and liver fibrosis by VCTE-LSM (all p < 0.001). CONCLUSION:The prevalence of at-risk MASH is high in individuals with obesity and T2D attending outpatient primary care and endocrinology clinics. Their progression to cirrhosis may be prevented with early risk-stratification and timely intervention.

OBJECTIVE:This study compared in vivo changes in hepatic phosphate metabolites using phosphorus magnetic resonance spectroscopy (31P-MRS) in patients with vs without metabolic dysfunction-associated steatotic liver disease (MASLD) after oral fructose consumption. METHODS:Thirty-seven overweight or obese patients without diabetes underwent a 2-hour oral glucose tolerance test, a fasting liver proton magnetic resonance spectroscopy, and a 31P-MRS before and during 60 minutes after an oral 75-gram fructose challenge. RESULTS:Before fructose consumption, there were no differences in ATP, phosphomonoesters (PME), or phosphodiesters between groups. After fructose, patients without MASLD had a rapid increase in PME (from 15.5 ± 4.8 to 19.3 ± 5.1 within 15 minutes, P = .033). In these patients, inorganic phosphate (Pi) decreased during the first 30 minutes but then increased, leading to higher than baseline levels (from 10.2 ± 1.9 to 11.8 ± 2.8, P = .037). ATP significantly dropped in patients without MASLD within 15 minutes (from 21.8 ± 3.4 to 19.9 ± 4.0, P = .018), with persistently lower levels after 60 minutes (19.1 ± 4.1, P = .006 vs baseline). However, all these responses to oral fructose appeared blunted in patients with MASLD, with unchanged PME levels and only showing an Pi increase 45 minutes after fructose consumption. ATP levels showed a nonsignificant drop in the first 15 minutes with recovery of baseline levels at minute 30. CONCLUSION:Following fructose consumption, patients with MASLD exhibited distinct patterns of change in phosphate metabolites, reflecting differences in hepatic metabolic responses. These findings suggest altered hepatic metabolic handling of fructose in MASLD, which may have implications for disease progression.