Management of De Novo Metabolic-Associated Steatohepatitis Liver Disease (MASLD)

Introduction to MASLD Management

• The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver recommend treatment of de novo MASLD focusing on aggressive lifestyle modifications, optimal management of metabolic comorbidities, and consideration of pharmacological interventions like resmetirom for those with significant fibrosis (stage ≥2) 1, 2

Lifestyle Modifications

• Complete alcohol abstinence is recommended for patients with de novo MASLD 1, 2
• Aggressive treatment of hypertension, with optimal blood pressure control (<140/<90 mmHg), reduces all-cause mortality by 42% 1
• A Mediterranean-style diet rich in vegetables, fruits, whole grains, legumes, and healthy fats, with a daily caloric intake of 1200-1500 kcal, and a gradual weight loss of up to 1 kg/week is recommended for improving liver histology and cardiometabolic health, with a high strength of evidence 3, 4, 5, 6, 7, 8, 9
• A hypocaloric diet with a 500-1000 kcal daily reduction from baseline, and a target weight loss of 3-5% to improve steatosis, 7-10% to improve liver inflammation and biochemistry, and >10% to improve fibrosis, is recommended, with a high strength of evidence 3, 4, 10, 6, 7, 9
• The American College of Gastroenterology suggests replacing saturated fats with monounsaturated and polyunsaturated fatty acids, emphasizing omega-3 rich foods, and using extra virgin olive oil as the primary fat source, with a high strength of evidence 4, 8, 9
• A minimum protein intake of 1.2-1.5 g/kg body weight, focusing on branched-chain amino acids, is recommended, and consideration of consultation with a specialized nutritionist is advised, as suggested by the American Gastroenterological Association, with a moderate strength of evidence 4, 9
• At least 150-200 minutes/week of moderate-intensity aerobic activities in 3-5 sessions is recommended, with a combination of aerobic exercise and resistance training effective for improving metabolic risk factors, as suggested by the American Heart Association and the American Gastroenterological Association, with a high strength of evidence 11, 7, 12, 9

Pharmacological Interventions

• Resmetirom is recommended as first-line therapy for non-cirrhotic MASH with significant fibrosis (stage ≥2) due to demonstrated histological efficacy on steatohepatitis and fibrosis, with a low strength of evidence 9
• GLP-1 receptor agonists (semaglutide, dulaglutide) can be used for weight management and glycemic control in patients with obesity or type 2 diabetes, but are not recommended as first-line treatment for liver disease in NASH, with a low strength of evidence 1, 9
• Pioglitazone has demonstrated efficacy in reversing steatohepatitis in patients with prediabetes or type 2 diabetes, improving glucose and lipid metabolism, and may slow fibrosis progression, although it is not recommended as a specific therapy due to lack of robust demonstration of histological efficacy, with a low strength of evidence 6, 13, 14, 1, 9
• Vitamin E (800 IU/day) may be considered for non-diabetic adults with biopsy-proven NASH, improving steatosis in patients without diabetes, but is not recommended as a targeted therapy for steatohepatitis, with a low strength of evidence 14, 1, 9
• SGLT2 inhibitors (such as empagliflozin, dapagliflozin) are safe to use in MASH, but should be used for their indications (type 2 diabetes, heart failure, chronic kidney disease), with insufficient evidence to recommend as MASH-targeted therapy, as recommended by the European Association for the Study of the Liver (EASL) guidelines, with a low strength of evidence 9
• Metformin can be used with compensated cirrhosis if glomerular filtration rate >30 ml/min, while insulin is preferred for decompensated cirrhosis, and GLP-1 receptor agonists can be used in Child-Pugh class A cirrhosis, as recommended by the European Association for the Study of the Liver (EASL) guidelines, with a low strength of evidence 9

Surgical Interventions

• Bariatric surgery can be considered for non-cirrhotic MASH with obesity, with improvements in steatosis, steatohepatitis, and fibrosis, and is associated with remission of type 2 diabetes and improvement of cardiometabolic risk factors, as recommended by the European Association for the Study of the Liver (EASL) guidelines, with a moderate strength of evidence 15, 7, 16, 9
• For compensated cirrhosis, bariatric surgery requires careful evaluation by a multidisciplinary team with experience in bariatric surgery, as recommended by the European Association for the Study of the Liver (EASL) guidelines, with a moderate strength of evidence 9

Monitoring and Follow-up

• Regular evaluation of diet, alcohol intake, and physical activity is essential for patients with de novo MASLD 2
• Consider consultation with a dietician and physical activity specialist for patients with de novo MASLD 2
• A multidisciplinary approach involving a cardiologist, diabetologist/endocrinologist, and obesity treatment team is recommended for patients with metabolic risk factors 2
• Liver enzymes should be monitored every 3 months in patients with MASH, as recommended by the American Association for the Study of Liver Diseases, with a moderate strength of evidence 11, 12, 9
• Imaging should be repeated at 6-12 months in patients with MASH, as recommended by the American Association for the Study of Liver Diseases, with a moderate strength of evidence 11, 12, 9
• Biopsy should be considered after 1-2 years of therapy to assess histological response in patients with MASH, as recommended by the American Association for the Study of Liver Diseases, with a moderate strength of evidence 11, 12, 9
• HCC surveillance with ultrasound examination every 6 months is recommended for patients with advanced fibrosis or cirrhosis, as suggested by the American Association for the Study of Liver Diseases and the American College of Gastroenterology, with a moderate strength of evidence 16, 7, 12, 9
• Non-invasive fibrosis assessment (e.g., FibroScan, FIB-4) should be considered every 1-2 years to monitor for disease progression, as recommended by the American Association for the Study of Liver Diseases, with a moderate strength of evidence 17

Prognosis and Complications

• De novo MASLD post-liver transplantation can progress rapidly, with advanced fibrosis/cirrhosis developing in 20% of cases within 3 years 1
• Post-transplant obesity is independently associated with a 2-fold higher mortality risk 1
• Cardiovascular complications are the second most common cause of non-hepatic mortality in liver transplant recipients 1
• Technical difficulties due to adhesions may limit surgical feasibility of bariatric procedures post-transplantation 1

Treatment Recommendations