A Randomised Controlled Tria of Low-calorie Ketogenic Diet Versus Mediterranean Diet in Patients With Compensated Advanced Chronic Liver Disease (cACLD) Secondary to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

The rationale of the study stems from evidence that patients with "compensated advanced chronic liver disease" (cACLD) secondary to MASLD have higher risk of liver-related morbidity (liver decompensation, hepatocellular carcinoma) and mortality. However, todate the only approved drug by FDA in patients with MASH and F2-F3 fibrosis is Resmetirom, but it is still not available in clinical practice outside US. As a consequence, currently and in the future the first-line treatment of MASLD involved weight loss and lifestyle modification, such as physical exercise and dietary regimens based on calorie restriction. In this context the Mediterranean diet is considered the standard, but over the last decade, the Very low-carbohydrate ketogenic diets (VLCKD) has gained immense popularity for its short-term positive effects on weight loss, even if data on MASLD cACLD are lacking.

Therefore, considering recent evidence, the investigator hypothesize that VLCKD could represent a new therapeutic option in the management of patients with MASLD and cACLD. Specifically, the investigator propose a randomized controlled study that evaluates the 48 week impact of two dietary protocols, the MD and the VLCKD, in individuals with cACLD secondary to MASLD, with specific focus on weight loss >=10% and on liver-related (changes in liver stiffness by TE, MRE and MRI-PDFF, AST, ALT) and metabolic parameters (see section on outcomes) Here the investigators report the detailed proposed nutritional protocols

• MEDITERRANEAN DIET This equilibrated diet has a caloric value 10% below the total metabolic expenditure of each individual. The total metabolic expenditure is calculated from the basal metabolic expenditure (based on the formula FAO/WHO/UN) multiplied by the coefficient of activity, which is calculated according to the physical activity of each participant. The calories provide to this group range between 1,400 and 1,800 kcal/day. The ration of macronutrients provided is 45-55 % arbohydrates,15-25 % proteins, and 25-35 % fat, in addition to a recommended intake of 20-40 g/day of fiber in the form of vegetables and fruits.
• VERY LOW-CARBOHYDRATE KETOGENIC DIETS The VLCKD ketogenic protocol entails: a caloric intake < 800 calories, a protein intake calculated based on individual needs: 1.2 + 0.2 g/kg/ideal body weight, low carbohydrate content (approximately 45-55 g of carbohydrates per day), and low lipids (10-15g/day). Vitamins and minerals, Unlimited vegetables.

The Kalibra protocol consists of 3 stages:

WEIGHT LOSS: Ketogenic metabolism is activated by reduced carbohydrate intake. As an accessory phenomenon to lipolysis and the catabolism of fat reserves in adipose tissue, there is a physiological production of ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone), which represent a water-soluble and readily available energy source for many tissues in the body (brain, heart, and muscles). Continuous ketogenesis, in addition to providing adequate energy intake, is important to ensure the absence of hunger and a feeling of overall well-being throughout the weight loss period.