Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has emerged as a prevalent health concern, encompassing a wide spectrum of liver-related disorders. Insulin resistance, a key pathophysiological feature of MASLD, can be effectively ameliorated through dietary interventions. The Mediterranean diet, rich in whole grains, fruits, vegetables, legumes, and healthy fats, has shown promising results in improving insulin sensitivity. Several components of the Mediterranean diet, such as monounsaturated fats and polyphenols, exert anti-inflammatory and antioxidant effects, thereby reducing hepatic steatosis and inflammation. Furthermore, this dietary pattern has been associated with a higher likelihood of achieving MASLD remission. In addition to dietary modifications, physical exercise, particularly resistance exercise, plays a crucial role in enhancing metabolic flexibility. Resistance exercise training promotes the utilization of fatty acids as an energy source. It enhances muscle glucose uptake and glycogen storage, thus reducing the burden on the liver to uptake excess blood glucose. Furthermore, resistance exercise stimulates muscle protein synthesis, contributing to an improved muscle-to-fat ratio and overall metabolic health. When implemented synergistically, the Mediterranean diet and resistance exercise can elicit complementary effects in combating MASLD. Combined interventions have demonstrated additive benefits, including greater improvements in insulin resistance, increased metabolic flexibility, and enhanced potential for MASLD remission. This underscores the importance of adopting a multifaceted approach encompassing dietary modifications and regular physical exercise to effectively manage MASLD. This narrative review explores the biological mechanisms of diet and physical exercise in addressing MASLD by targeting insulin resistance and decreased metabolic flexibility.

Background & Aims: There is intense research for drugs able to reduce disease progression in nonalcoholic fatty liver disease. We aimed to test the impact of novel antidiabetic drugs (dipeptidyl‐peptidase‐4 inhibitors – DPP‐4Is, glucagon‐like peptide‐1 receptor agonists – GLP‐1RAs, sodium‐glucose cotransporter‐2 inhibitors – SGLT‐2Is) on non‐invasive biomarkers of steatosis (fatty liver index, FLI) and fibrosis (Fibrosis‐4 score, FIB‐4) in patients with type 2 diabetes (T2D).Methods: Clinical, anthropometric and biochemical parameters were retrospectively analysed in 637 consecutive T2D patients switched from metformin w/wo sulfonylureas and/or pioglitazone to DPP‐4Is, GLP‐1RAs and SGLT‐2Is in a tertiary care setting. 165 patients maintained on original treatments served as controls. The effects on FLI and FIB‐4 at 6‐ and 12‐month follow‐up were analysed by logistic regression after adjustment for baseline differences, computed by propensity scores, and additional adjustment for changes in glycosylated hemoglobin (HbA1c) and body mass index.Results: Body mass index, HbA1c and aminotrasferases significantly decreased following switching to GLP‐1RAs and SGLT2‐Is, compared with both controls and DPP‐4Is, whereas only HbA1c was reduced on DPP‐4Is. FLI and FIB‐4 were reduced on GLP‐1RA and SGLT‐2I; logistic regression analysis confirmed a significant improvement of both biomarkers after adjustment for propensity score. The shift of FIB‐4 values towards the category ruling out advanced fibrosis was maintained after additional adjustment for confounders. These effects were confirmed in a sensitivity analysis on effect size.Conclusions: Glucagon‐like peptide‐1 receptor agonists and SGLT‐2Is improve biomarkers of steatosis and fibrosis, in keeping with beneficial effects on liver disease progression, and should be considered the treatment of choice in T2D.

The current focus of the treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) is lifestyle intervention with the aim of significant weight loss alongside aggressive cardiovascular risk reduction. NAFLD is tightly associated with type 2 diabetes (T2D) and obesity. In patients with T2D, glucose lowering agents that promote weight loss have shown a beneficial impact on NAFLD. However, it remains unclear as to whether glucose lowering can improve NALFD in patients with T2D, independent of weight loss. In a retrospective analysis of data from 637 people with T2D, we examined the longitudinal impact of optimizing glycaemic control with DPP-IV inhibitors, GLP-1RAs and SGLT2 inhibitors on Fatty liver index (FLI) and Fibrosis score 4 (Fib-4) adjusting for changes in BMI and choice of glucose lowering regimen over a 12-month period. Multiple linear regression analysis demonstrated a significant correlation between the change in glycated haemoglobin and change in FLI after adjustment for change in BMI, age, sex, and drug class (R = 0.467, p = 0.031). The greatest reduction in FLI was observed in patients with the largest reduction in glycated haemoglobin (p < 0.0001). The probability of improvements in FLI with optimization of glycaemic control was similar with all 3 glucose lowering agents, despite differences in weight reduction. Similar relationships were observed examining the changes in glycaemic control and Fib-4. Improvements in glucose control that are independent of weight loss are associated with improvement in NAFLD and should form an integral part of the management patients with co-existent NAFLD and T2D.

Advanced chronic liver disease (ACLD) represents a complex and multifactorial clinical entity characterized by liver dysfunction and associated complications. In recent years, the significance of nutritional status in ACLD prognosis has gained considerable attention. This review article delves into the multifactorial pathogenesis of malnutrition in ACLD and its profound consequences for health outcomes. We explore the clinical implications of secondary sarcopenia in ACLD and highlight the critical relevance of frailty in both decompensated and compensated ACLD. A specific focus of this review revolves around branched-chain amino acids (BCAAs) and their pivotal role in managing liver disease. We dissect the intricate relationship between low Fischer’s ratio and BCAA metabolism in ACLD, shedding light on the molecular mechanisms involved. Furthermore, we critically evaluate the existing evidence regarding the effects of BCAA supplementation on outcomes in ACLD patients, examining their potential to ameliorate the nutritional deficiencies and associated complications in this population.

Summary: Background: The long‐term results of web‐based behavioural intervention in non‐alcoholic fatty liver disease (NAFLD) have not been described in patients followed in specialised centres.Aims: To analyse the long‐term effectiveness of web education compared with the results achieved by a group‐based behavioural intervention in the same years 2012–2014.Methods: We followed 679 patients with NAFLD (web‐based, n = 290; group‐based, n = 389) for 5 years. Weight loss ≥10% was the primary outcome; secondary outcomes were attrition, changes in liver enzymes and in biomarkers of steatosis (Fatty liver Index) and fibrosis (Fibrosis‐4 index).Results: The cohorts differed in age, education, working status and presence of diabetes. Attrition was higher in the web‐based cohort (hazard ratio: 1.53; 95% CI: 1.24–1.88), but not different after adjustment for confounders. Among patients in active follow‐up, 50% lost ≥5% of initial body weight and 19% lost ≥10%, without difference between cohorts. Alanine aminotransferase levels fell to within the normal range in 51% and 45% of web‐ and group‐based cohorts, respectively. Fatty Liver Index declined progressively and, by year 5, it ruled out steatosis in 4.8%, whereas 24.9% were in the indeterminate range. Fibrosis‐4 index increased in both cohorts, driven by age, but the prevalence of cases ruling‐in advanced fibrosis remained very low (around 1%). Improvements in the class of both surrogate biomarkers were associated with ≥5% weight loss.Conclusions: Although burdened by attrition, web‐based behavioural intervention is feasible and effective in NAFLD, expanding the cohort involved in behavioural programs and reducing the risk of progressive disease.