Treatment of MASLD with Advanced Fibrosis
For patients with MASLD and advanced fibrosis, prioritize sustained weight loss of ≥10% through intensive lifestyle modification combined with GLP-1 receptor agonists (semaglutide or liraglutide), and consider resmetirom for non-cirrhotic patients with stage ≥2 fibrosis. 1, 2
Lifestyle Modification: The Foundation
Target ≥10% sustained weight reduction to achieve fibrosis improvement, as this threshold demonstrates the strongest evidence for reversing fibrosis in patients with advanced disease 1. The dose-response relationship is clear: 5% weight loss reduces steatosis, 7-10% improves inflammation, but ≥10% is required for fibrosis regression 1, 2.
Dietary Interventions
- Adopt a Mediterranean dietary pattern including vegetables, fruits, unsweetened high-fiber cereals, nuts, fish or white meat, and olive oil 1, 2
- Eliminate all sugar-sweetened beverages completely 1, 2
- Minimize ultra-processed foods rich in sugars and saturated fat 1
- Implement a 500-1000 kcal/day deficit to achieve gradual weight loss 3, 4
Exercise Prescription
- Prescribe ≥150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity physical activity 1, 2
- Physical activity reduces steatosis even without significant weight loss 2
Critical caveat: Long-term adherence to lifestyle changes is challenging, with maximal weight loss typically occurring at 6 months followed by gradual regain 1. This emphasizes the need for structured, affordable long-term programs and consideration of pharmacotherapy 1.
Pharmacological Treatment
GLP-1 Receptor Agonists (First-Line Pharmacotherapy)
GLP-1 receptor agonists (semaglutide, liraglutide) should be used for their approved indications (type 2 diabetes, obesity) as they improve cardiometabolic outcomes and are safe in MASH, including compensated cirrhosis 2. These agents effectively improve histological features of MASLD and provide substantial weight loss 5, 6. Semaglutide is conditionally FDA-approved for adults with MASH and moderate to advanced fibrosis 7.
Resmetirom (Liver-Targeted Therapy)
Resmetirom should be considered for non-cirrhotic patients with significant liver fibrosis (stage ≥2) if approved locally, as it demonstrated histological efficacy in phase III trials with acceptable safety 2. This thyroid hormone receptor β-selective agonist is conditionally FDA-approved and improves both steatohepatitis and fibrosis without requiring weight loss 7, 5.
Pioglitazone (Alternative Option)
Pioglitazone can be considered for patients with biopsy-proven steatohepatitis and significant fibrosis, particularly those with type 2 diabetes 3, 6. Despite causing moderate weight gain, it improves adipose tissue function and MASLD with potential benefit on fibrosis 5.
Multidisciplinary Management of Cardiometabolic Comorbidities
A multidisciplinary approach is essential to address both liver-related and extrahepatic outcomes, given the bidirectional connections between MASLD and cardiometabolic disease 1, 2.
Cardiovascular Risk Management
- Statins are safe and should be used for dyslipidemia in all patients with MASLD, reducing hepatocellular carcinoma risk by 37% 2, 4
- Consider renin-angiotensin-aldosterone modulators and aspirin, as treatment of cardiometabolic comorbidities may reduce liver-related events 1
Diabetes Management
- Prefer GLP-1 receptor agonists or SGLT2 inhibitors for patients with type 2 diabetes 3, 6
- Optimize glycemic control to reduce liver fat 2
Medications to Avoid
Avoid medications that worsen steatosis including corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid 2.
Monitoring and Surveillance
Fibrosis Assessment
- Use FIB-4 score, liver stiffness measurement (LSM), or liver biopsy for risk stratification 2, 3
- High-risk patients have FIB-4 >2.67, LSM >12.0 kPa, or significant fibrosis on biopsy 2
- Non-invasive tests may be repeatedly used to assess fibrosis progression but provide limited information about treatment response 1
Hepatocellular Carcinoma Surveillance
Patients with advanced fibrosis (F3) require hepatocellular carcinoma surveillance with imaging every 6 months 2.
Bariatric Surgery
Consider bariatric surgery for appropriate individuals with clinically significant fibrosis and obesity with comorbidities (BMI >35 kg/m²) 2, 3, 7. Bariatric surgery achieves substantial sustained weight loss and improves histological outcomes 8, 5.
Special Considerations for Advanced Disease
Compensated Cirrhosis with Obesity
- Target moderate weight reduction (3-5%) plus high-protein intake and physical activity 1
- Lifestyle must be adapted to severity of liver disease and nutritional status 1
Alcohol Consumption
Alcohol should be discouraged or avoided completely in advanced fibrosis or cirrhosis 1.
Coffee Consumption
Coffee consumption has been associated with improvements in liver damage and reduced liver-related clinical outcomes in observational studies 2.
Long-Term Goals
The ultimate objectives are quality of life and survival, cardiometabolic benefits, and prevention of cirrhosis, hepatocellular carcinoma, type 2 diabetes, and cardiovascular disease 1. However, improved mortality has not yet been demonstrated for any treatment-induced histological changes, emphasizing the need for long-term follow-up studies 1.