Fatty Liver Disease

Introduction Ketogenic diets, characterized by very low carbohydrate intake and increased fat consumption, have gained significant attention as a potential therapeutic strategy in metabolic dysfunction-associated steatotic liver disease. The rationale is biologically appealing: by reducing insulin levels and promoting lipolysis and hepatic β-oxidation, ketogenic diets may rapidly decrease intrahepatic fat and improve metabolic parameters. In an era where lifestyle interventions remain the cornerstone of MASLD management, understanding whether dietary composition—beyond simple caloric restriction—can meaningfully influence liver fat is of major clinical importance. Summary This article critically evaluates a recent mechanistic study suggesting superior reductions in intrahepatic triglyceride content and insulin resistance with ketogenic diets compared to non-ketogenic diets. While the findings support a “starvation-like” metabolic shift with increased fat oxidation and reduced insulin levels, the authors highlight key methodological limitations that challenge causal interpretation. The most important concern is the non-randomized crossover design, where all participants received the ketogenic diet first, followed by the non-ketogenic diet after a prolonged interval, introducing significant time-related confounding. Additionally, a substantial imbalance in protein intake between the two diets raises the possibility that observed metabolic changes may be driven by increased protein rather than ketosis itself. Finally, reliance on HOMA-IR as a surrogate for hepatic insulin sensitivity is questioned, as reductions in insulin and glucose during low-carbohydrate intake may reflect decreased metabolic demand rather than true improvement in insulin signaling. Overall, while ketogenic diets show potential in reducing liver fat, these findings underscore the need for rigorously designed trials before attributing benefits specifically to carbohydrate restriction.

Introduction Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now widely used for type 2 diabetes and obesity, two conditions frequently encountered in gastroenterology practice. Their effects extend far beyond glycemic control and weight loss, influencing the gut, pancreas, liver, biliary system, and peri-endoscopic care. Because these drugs are increasingly prescribed, gastroenterologists need practical, evidence-based guidance on how to use them safely in daily practice. Why This Position Paper Is Needed Although GLP-1RAs have shown major cardiometabolic benefits, clinicians continue to face important questions in gastroenterology: Are they safe in MASLD/MASH and cirrhosis? Do they increase the risk of GI or pancreatic cancers? Should they be routinely stopped before upper GI endoscopy? How should we manage GI side effects, pancreatitis concerns, and gallstone risk? This position paper from the Italian Society of Gastroenterology (SIGE) addresses these common clinical dilemmas and provides a practical framework for day-to-day management. Key Takeaways GLP-1RAs can be safely used in patients with diabetes or obesity and MASLD/MASH. They appear beneficial, especially in non-cirrhotic MASH, and semaglutide is highlighted as a disease-modifying option in selected patients with F2–F3 fibrosis. Semaglutide should be considered in adults with non-cirrhotic MASH and moderate-to-advanced fibrosis. It has shown meaningful benefit in MASH resolution and may improve fibrosis in selected patients. GLP-1RAs appear safe in cirrhosis. In patients with cirrhosis plus diabetes or obesity, these agents seem safe and may even reduce hepatic decompensation. A possible reduction in hepatocellular carcinoma risk is suggested. This is promising, but the evidence remains weak and largely observational. GLP-1RAs do not appear to increase the risk of major GI cancers. Available evidence does not support an increased risk of oesophagal, gastric, or colorectal cancer. Pancreatic cancer risk does not appear to increase. In fact, some studies suggest a possible reduction, but this remains uncertain. Routine discontinuation before upper GI endoscopy is not recommended. Current evidence does not support stopping GLP-1RAs routinely before gastroscopy. A liquid diet the day before upper GI endoscopy may be useful in selected cases. This is particularly relevant for: patients with nausea, vomiting, or dyspepsia longer or more complex endoscopic procedures Suspected retained gastric contents No extra bowel preparation is required before a colonoscopy. Standard colonoscopy preparation appears sufficient in most patients receiving GLP-1RAs. GLP-1RAs do not increase the risk of acute pancreatitis. This is an important reassurance for clinicians, although caution remains sensible in very high-risk patients. GLP-1RAs do increase the risk of cholelithiasis. This is one of the clearest safety signals and should be kept in mind, especially in rapid weight loss or pre-existing biliary risk. Mild GI adverse events are common, especially early after starting therapy. Nausea, vomiting, diarrhoea, constipation, and reflux symptoms are the most frequent issues. GI side effects are usually mild, transient, and dose-dependent. Most occur early and improve with time and gradual dose escalation. Severe GI complications are not increased. Serious events such as major obstruction, perforation, or severe complications are uncommon and not clearly more frequent than with placebo. GERD symptoms may worsen. Clinicians should ask about reflux symptoms, particularly in predisposed patients. Patient education is central to successful use. Practical advice includes: smaller meals avoiding high-fat meals good hydration slow dose titration temporary symptomatic treatment when needed Dose escalation matters. Slower titration can improve tolerability and reduce treatment discontinuation. Evidence quality remains limited for many recommendations. Much of the guidance is based on low or very low quality evidence, highlighting the need for better prospective studies. Conclusion This SIGE position paper supports the growing integration of GLP-1RAs into gastroenterology and hepatology practice. Overall, these drugs appear safe, clinically useful, and increasingly relevant, particularly in patients with obesity, diabetes, and MASLD/MASH. Routine discontinuation before upper endoscopy is generally unnecessary, pancreatitis risk is not increased, and cancer concerns are largely unsupported. The key practical issues are GI tolerability, reflux symptoms, and cholelithiasis, all of which can usually be managed with careful monitoring and thoughtful clinical judgment.

Introduction Metabolically associated steatotic liver disease (MASLD) has become one of the most common causes of chronic liver disease worldwide, closely linked to the global epidemics of obesity and type 2 diabetes. The progressive form, metabolic dysfunction–associated steatohepatitis (MASH), can lead to fibrosis, cirrhosis, hepatocellular carcinoma, and liver transplantation. Until recently, treatment options were limited mainly to lifestyle modification. Resmetirom, a selective thyroid hormone receptor-β (THR-β) agonist, represents a new pharmacologic therapy targeting hepatic steatosis and inflammation and is now approved for MASH with F2–F3 fibrosis. Beyond histologic improvements, its effect on health-related quality of life (HRQL) across the MASLD spectrum remained uncertain. Summary This analysis from the MAESTRO-NAFLD-1 trial and its open-label extension evaluated HRQL outcomes in patients with early MASH and MASH cirrhosis treated with resmetirom. A total of 1143 patients with early MASH and 180 with MASH cirrhosis were included. HRQL was assessed using disease-specific instruments, including CLDQ-NAFLD and LDQoL. Patients with MASH cirrhosis had significantly poorer baseline quality-of-life scores compared with those with earlier disease. Treatment with resmetirom (80–100 mg) resulted in meaningful improvements in several HRQL domains, particularly worry, abdominal symptoms, and health distress, beginning by week 24 and sustained through week 52 and into year 2. Improvements were more pronounced in patients who achieved MRI-PDFF response, indicating a reduction in hepatic fat. Overall, the study demonstrates that resmetirom not only improves liver pathology but also enhances disease-specific quality of life in patients across the MASLD spectrum, including those with cirrhosis, supporting its broader clinical benefit beyond histologic endpoints.

Metabolically–dysfunction–associated steatotic liver disease (MASLD) is strongly linked to cardiometabolic disorders, and cardiovascular disease (CVD) remains the leading cause of mortality in these patients. However, it is unclear whether commonly used cardiovascular risk prediction tools accurately estimate risk in this population. This study evaluated the performance of three widely used models—the Framingham Risk Score (FRS), Pooled Cohort Equation (PCE), and the American Heart Association PREVENT equation—in predicting cardiovascular events among patients with MASLD. Using data from the TARGET-NASH real-world cohort, the study included 1,090 US adults aged ≥30 years with MASLD. Researchers assessed the ability of these models to predict 5–10 year cardiovascular risk and compared predicted risk with actual observed cardiovascular events. The results showed that all commonly used tools performed poorly in this population. The FRS demonstrated weak discrimination (C-statistic 0.58), while the PREVENT model also showed limited predictive ability (C-statistic 0.60). In addition, both FRS and PCE showed significant calibration errors, meaning they overestimated risk in high-risk groups and underestimated risk in lower-risk groups. Importantly, the study also demonstrated that cardiovascular event rates increased progressively from MASLD to cirrhosis, suggesting that liver disease severity contributes independently to cardiovascular risk. Overall, these findings indicate that standard cardiovascular risk calculators are inadequate for patients with MASLD. Given the high cardiovascular mortality in this population, new risk assessment tools incorporating liver disease–specific factors are urgently needed to improve prediction, prevention, and clinical management.

Introduction – MASLD in Normal-Weight Individuals Metabolically dysregulated steatotic liver disease (MASLD) is commonly linked with obesity and metabolic syndrome. However, a significant subset of patients develop MASLD despite having a normal body mass index (BMI)—often referred to as lean or normal-weight MASLD. These individuals may still have metabolic abnormalities such as insulin resistance, visceral adiposity, or sedentary lifestyles. Current global MASLD guidelines recommend 3–5% weight reduction even in normal-weight individuals to reduce liver fat. However, emerging evidence suggests that focusing primarily on weight loss in this population may be misguided and clinically impractical. Why Weight Reduction May Not Help in Lean MASLD For patients already within a healthy weight range, further weight loss may provide limited metabolic benefit and can be difficult to achieve or sustain. More importantly, exercise exerts powerful liver-specific metabolic effects independent of body weight changes. Physical activity improves insulin sensitivity, enhances mitochondrial function, and increases hepatic fatty acid oxidation—mechanisms that directly reduce liver fat without requiring weight loss. Clinical studies show that structured aerobic or resistance exercise can reduce intrahepatic fat by 10–30%, even when body weight remains unchanged. Meta-analyses confirm that ≥150 minutes of moderate exercise weekly significantly improves hepatic steatosis independent of weight reduction. These findings suggest that in lean MASLD, lifestyle interventions should prioritise regular physical activity rather than weight-centric goals, reframing exercise as a direct therapeutic strategy rather than merely a tool for weight loss.