BACKGROUND AND AIMS:New obesity definitions beyond body mass index (BMI) have recently been proposed. This study aimed to assess the proportion of obesity under these frameworks and their associations with liver-related events (LREs). APPROACH AND RESULTS:We analyzed data from the multinational vibration-controlled transient elastography (VCTE)-prognosis cohort of 12,583 patients with metabolic dysfunction-associated steatotic liver disease. Obesity was defined using 3 frameworks: BMI alone, the European Association for the Study of Obesity (EASO) criteria (BMI-defined obesity or overweight with waist-to-height ratio ≥0.5 plus comorbidity), and the Lancet Commission criteria (BMI-defined obesity plus ≥1 elevated anthropometric measure, or ≥2 elevated anthropometric measures, or BMI ≥40 kg/m²). LRE incidence per 1000 person-years was 2.4 (95% CI: 1.5-3.7), 3.4 (95% CI: 2.6-4.5), and 5.2 (95% CI: 4.3-6.3) for BMI-defined normal weight, overweight, and obesity. Overall, 20.4% and 34.1% of patients were not classified as obese by BMI but met obesity criteria under the EASO and Lancet definitions. These newly classified obese groups did not have higher LRE risk compared with their nonobese counterparts (adjusted subdistribution HR 1.15 [0.64-2.08] for EASO; 0.75 [0.42-1.34] for Lancet ), with incidence rates of 2.9 (95% CI: 1.9-4.3) and 2.7 (95% CI: 1.8-3.9) per 1000 person-years. LRE risk increased significantly only when the waist-to-height ratio approached 0.6. CONCLUSIONS:New obesity definitions broadened the obesity population but did not improve LRE prediction over BMI alone. Higher waist-based thresholds warrant further evaluation.

Background and Aims: Lifestyle intervention aiming at weight loss (WL) is the cornerstone of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) management, but treatment response by non-invasive tests (NITs) is not yet established. Here, we aim to assess antifibrotic response to WL by collagen and non-collagen fibrogenesis markers.Methods: We included 146 patients with MASLD (median age 52 [46-61] years, 63% male) undergoing 6-month randomized dietary trial (2021-2023): Mediterranean Diet (n=49) or Low-Charb Diet (n=49) or nutritional advice (n=48). Inclusion criteria: MASLD and LSM (VCTE)<10 kPa, Body Mass Index (BMI) of 25-35 kg/m2, age<65 years. Exclusion criteria: HbA1c>9.5%, type 2 diabetes (T2D) treated with insulin of GLP1-RA. All parameters were assessed at baseline and 6 months. Serum non-collagen (TSP2, CD163 and IGFB7 - Mainz) and collagen (C4M, PRO-C3, PRO-C4, PRO-C6 and PRO-C8 - Nordic Bioscience) markers were measured through in-house standardized ELISA assay. Primary endpoint was changes in NIT levels between patients achieving <5% WL (group A n=91), compared to those achieving 5-10% WL (group B n=38) and ≥10% WL (group C n=17).Results: Median BMI was 30,4 [28,7–33,4] kg/m2, T2D and PNPLA3 GG were present in 31% and 21,8% of cases. PRO-C4 levels fell significantly in group B (p=0,041) and C (p=0,015), but not in group A (p=0,147). TSP2 levels fell substantially in group B (p=0,046) and in group C (p=0,004) but not in group A (p=0,714). FIB-4 and VCTE did not show clinically significant changes. Delta PRO-C4 showed a stepwise negative increase across the 3 groups: from mean -71,7 (SD 510,3) ng/ml to mean -228,7 (634,2) ng/ml to mean -695,5 (1735,8) ng/ml (ANOVA p=0,011). Delta TSP2 varied from mean -0,2 (13,5) ng/ml to mean -4,2 (14,5) ng/ml to mean -12,6 (15,8) ng/ml (ANOVA p=0,004). PRO-C4 and TSP2 showed significant association with delta weight changes: R2 0,05 (p=0,003) and 0,08 (p=0,0002). Delta TSP2> -1,96 ng/ml and delta PRO-C4> -703 ng/ml (both by Youden Index) were associated with WL >5% after adjustment for age, male sex, obesity, T2D and PNPLA3 GG: aOR 0,16 (0,04-0,63, p=0,008) and aOR 0,29 (0,29-0,96, p=0,043) respectively.Conclusion: In patients with MASLD without advanced fibrosis undergoing dietary intervention, serum TSP2 and PRO-C4 levels fell significantly in correlation to WL and were associated with WL>5%. This evidence suggests their clinical utility to monitor attenuation of hepatic fibrogenesis.

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.

Introduction: In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), the Fibrosis-4 (FIB-4) score is the recommended first-line screening test for initial risk stratification of advanced fibrosis. Values in the intermediate-risk range (1.3-2.67) are associated with a high proportion of false positives, resulting in a substantial downstream second-line testing burden. Current guidelines suggest two possible approaches in this group: proceeding directly to liver stiffness measurement (LSM) or repeating FIB-4 in one year after a lifestyle change intervention. Since up to 40% of MASLD patients fall into this category, identifying strategies that optimise referral is needed.Aim: To compare two different referral strategies in patients with intermediate FIB-4 values and evaluate their ability to predict progression to advanced fibrosis over approximately 5-10 years.Methods: We retrospectively analysed 92 patients with baseline FIB-4 between 1.3 and 2.67. Advanced fibrosis at follow-up was defined by liver biopsy showing F3-F4, when available, or by LSM ≥12 kPa. Two referral strategies were compared: (1) immediate referral if baseline LSM ≥8 kPa; (2) referral if FIB-4 remained ≥1.3 at 1-2 years. Diagnostic performance was assessed through sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and confusion matrices.Results: Advanced fibrosis over a median follow up of 6 (2.7-13.2) years was detected in 25 patients (27%). When applied at baseline, LSM ≥8 kPa had the best diagnostic performance (Se 0.95; Sp 0.7, PPV 0.45, NPV 0.97) in predicting advanced fibrosis at last follow-up. In 19 (21%) patients, FIB-4 values declined below <1.3 at 1-2 years, despite no structured lifestyle change intervention, and none of these patients developed advanced fibrosis during follow up. Therefore, repeating FIB-4 at 1-2 years and performing LSM only if FIB-4 remains ≥1.3, would have avoided 21% of FibroScan® examinations, without any missed cases of advanced fibrosis (Se 1; Sp 0.22, PPV 0.25, NPV 100%).Conclusions: In FIB-4 intermediate-risk patients, repeating FIB-4 at 1-2 years prior to second-line testing can reduce unnecessary LSM by 21%, without missing advanced fibrosis cases at follow-up.

BACKGROUND & AIMS:Dietary interventions are a cornerstone of management for metabolic dysfunction-associated steatotic liver disease (MASLD). However, it remains unclear whether specific dietary patterns confer benefits beyond weight loss. We aimed to compare the effects of different dietary strategies on liver fat and metabolic health in patients with MASLD. METHODS:We conducted a 6-month, three-arm, parallel-group randomized controlled trial including patients with MASLD and overweight or obesity who were naïve to structured nutritional counselling. Participants were randomized to Mediterranean diet (MeD), low-carbohydrate, high-protein diet (LCHO), or standard nutritional recommendations. Liver fat content was assessed by controlled attenuation parameter (CAP). Secondary outcomes included changes in anthropometric and metabolic parameters, body composition, and ultra-processed food (UPF) consumption. Structural equation modelling was used to investigate pathways linking dietary allocation, weight loss, and UPF intake with changes in CAP. RESULTS:Of 173 enrolled participants, 148 (85.5%) completed the study. CAP decreased significantly within the LCHO and control groups (Δ -19.5 [-48.8 to 8.0], p = 0.004 and -11.0 [-32.0 to 12.0], p <0.001), with no significant between-group differences. All study arms achieved significant improvements in body weight, BMI, adiposity measures, metabolic profile, and dietary quality, including reductions in UPF intake. Structural equation modelling analyses showed no direct or total effect of dietary pattern on changes in CAP. In contrast, reductions in BMI and UPF consumption independently and significantly predicted CAP improvements: β = 14.34 (95% CI 10.55-18.13), and β = 0.64 (95% CI 0.25-1.03). CONCLUSIONS:In patients with MASLD, weight loss and reductions in UPF intake, rather than diet type, were the main drivers of improvements in liver fat and metabolic health. These findings support a patient-centered dietary approach in MASLD management. CLINICAL TRIAL NUMBER:NCT073043336. IMPACT AND IMPLICATIONS:This randomized controlled trial shows that weight loss and reductions in ultra-processed food intake, rather than the specific dietary pattern, are the primary factors associated with improvements in liver fat and metabolic health in MASLD. These findings challenge the emphasis on prescriptive dietary models and support a more flexible, patient-centered approach focused on sustainable weight reduction and improved dietary quality. Prioritizing reduction of ultra-processed foods may represent a practical and scalable strategy to enhance adherence and maximize long-term clinical benefit in routine care.

Background and aims The evolution of non-invasive tests of liver fibrosis during follow-up of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains difficult to interpret in clinical practice. We aimed to translate the dynamics of non-invasive tests into a personalized prediction of liver-related events (LRE) in MASLD. Methods We used the international multicentre VCTE-Prognosis cohort including adult patients with MASLD who underwent liver stiffness measurements (LSM) by vibration-controlled transient elastography. The study outcome was LRE, a composite endpoint including cirrhosis decompensation or hepatocellular carcinoma. A joint latent class model (JLCM) was used to compute dynamic predictions resulting in a personalized estimation of the risk of LRE (0-100% at chosen time horizons). Results 13,627 patients were included, with 238 LRE occurring during the median follow-up of 4.0 years (IQR: 2.1-5.9). LSM trajectory adjusted on FIB-4 and sex (longitudinal part) and age with platelets (survival part) were selected by the JLCM for LRE prediction. Calibration plots showed very good agreement between the predicted and the observed risk of LRE. The JLCM provided excellent discrimination for LRE with integrated AUROCs increasing from 88.2% at baseline to 92.2% at the 5-year follow-up visit. At the different study visits, 61-80% of the patients who experienced LRE were identified as high risk by the JLCM, versus 39-56% with LSM and 32-60% with FIB-4. Conclusion By automatically integrating and interpreting the dynamics of non-invasive tests of liver fibrosis, JLCM enables the personalised prediction of the risk of hard outcomes, rather than the imperfect evaluation of histological surrogates.

Early identification of patients with metabolic dysfunction-associated steatohepatitis (MASH) and significant fibrosis (≥F2) is critical to optimize patient care and prevent both hepatic and extra-hepatic complications. Current international guidelines consistently recommend a screening in high-risk populations using 2-step algorithms based on noninvasive tests. This review will examine the recommended risk stratification algorithms for MASH, summarize the evidence supporting their clinical use, and highlight the potential benefits for patient management. Finally, we will discuss the key barriers to their implementation in routine clinical practice.

BACKGROUND & AIMS:The availability of new drugs for the treatment of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) underlines the need of early predictors of response to such therapies. This study evaluated the impact of 1-year changes in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE), controlled attenuation parameters (CAP), and serum alanine aminotransferase (ALT) on liver outcomes in patients with MASLD. METHODS:A large multicenter cohort of MASLD patients with LSM ≥8 kPa and prospective follow-up was enrolled. Liver-related events (LREs), including hepatocellular carcinoma (HCC) and liver decompensation (LD), were evaluated during follow-up. LSM, CAP, ALT, and Fibrosis-4 Index (FIB-4) were assessed at baseline and at 1-year follow-up. Cause-specific Cox regression analyses were performed to correlate 1-year variation in LSM, CAP, ALT, and FIB-4 with the risk of developing LRE, LD, and HCC, in terms of cause-specific hazard ratios (csHRs). RESULTS:We included 1744 patients with LSM ≥8 kPa (median age, 55 years; 52.1% male; 58.3% obese; 55.8% with diabetes) and 989 with LSM ≥10 kPa (median age, 56 years; 50.2% male; 54.7% obese; 51% with diabetes), followed for a median of 28.2 and 32 months, respectively. LREs occurred in 39 patients with LSM ≥8 kPa (26 LD, 22 HCC) and in 35 with LSM ≥10 kPa (25 LD, 19 HCC). A 1-year variation in LSM, but not in CAP, ALT, or FIB-4, was independently associated with LRE in patients with MASLD and LSM ≥8 kPa (csHR, 1.007; 95% confidence interval [CI], 1.001-1.014). Likewise, 1-year LSM variation (csHR, 1.009; 95% CI, 1.000-1.018) independently predicted LD in this population, whereas no 1-year changes in CAP, ALT, or FIB-4 were associated with LD risk. No independent associations were observed between 1-year changes in LSM, CAP, ALT, or FIB-4 and the risk of HCC. All findings were confirmed in patients with LSM ≥10 kPa and in those at high risk of progression with type 2 diabetes. CONCLUSIONS:In patients with MASLD and LSM ≥8 or ≥10 kPa, the % LSM reduction at 1 year was independently associated with lower risk of LRE and LD.