Treatment of Metabolic Associated Fatty Liver Disease (MAFLD/MASLD)
Lifestyle modification targeting ≥7-10% sustained weight loss through Mediterranean diet and structured exercise (≥150 min/week moderate-intensity) is the cornerstone treatment for MAFLD, with resmetirom as the only guideline-recommended pharmacotherapy for non-cirrhotic patients with significant fibrosis (stage ≥2). 1, 2
Weight Loss Targets Based on Disease Severity
The magnitude of weight reduction directly correlates with histological improvement 3:
- ≥5% weight loss: Reduces hepatic steatosis/liver fat 3, 1
- 7-10% weight loss: Improves liver inflammation and achieves steatohepatitis resolution 3, 1
- ≥10% weight loss: Improves fibrosis regression 3, 1
Critical caveat: Most patients struggle to achieve and sustain >5% weight loss long-term, with maximal weight loss typically occurring at 6 months followed by gradual regain 3. This emphasizes the need for ongoing behavioral support and consideration of adjunctive therapies 4.
Dietary Interventions
Implement a Mediterranean dietary pattern as the primary nutritional approach 1, 5:
- High intake: vegetables, fruits (not juice), low-fat dairy, nuts, olive oil, legumes, unprocessed fish and poultry 3, 1
- Eliminate completely: sugar-sweetened beverages 3, 5
- Minimize: processed meat, ultra-processed foods rich in sugars and saturated fat 3, 5
Important note: Diet quality improvements provide cardiometabolic and hepatic benefits even without significant weight loss 6, 4.
Exercise Prescription
Prescribe structured exercise programs with specific targets 3, 1:
- ≥150 minutes/week of moderate-intensity physical activity OR 75 minutes/week of vigorous-intensity activity 3, 1
- Tailor to individual preference and ability 3, 1
- Add resistance training for patients losing weight (to minimize lean mass loss) and those with sarcopenia 6
Physical activity reduces steatosis even without significant weight loss 5, 6.
Pharmacological Therapy
MASH-Targeted Therapy
Resmetirom is the only guideline-recommended MASH-targeted therapy with strong evidence 1, 2:
- Indication: Non-cirrhotic MASH with significant liver fibrosis (stage ≥2) 1, 2
- Evidence: Large phase III trials demonstrated histological efficacy on steatohepatitis and fibrosis with acceptable safety 2
- Contraindication: Not recommended for cirrhotic stage disease 2
Cardiometabolic Medications
Use GLP-1 receptor agonists (semaglutide, tirzepatide) for their approved indications (type 2 diabetes, obesity) 1, 2:
- These agents improve cardiometabolic outcomes and are safe in MASH, including compensated cirrhosis 5, 2
- However: Not formally recommended as MASH-targeted therapy due to lack of large phase III histological endpoint trials 2
Statins are safe and should be used for dyslipidemia in patients with MAFLD 5.
Agents NOT Recommended
- Vitamin E: Cannot be recommended due to lack of robust phase III efficacy data and potential long-term risks 2
- Pioglitazone: Cannot be recommended given lack of robust phase III histological efficacy demonstration 2
Bariatric Surgery
Consider bariatric surgery for patients with MAFLD and class II-III obesity (BMI >35 kg/m²) when lifestyle modification and pharmacotherapy have been insufficient 1, 5.
Special Populations
Normal Weight Patients with MAFLD
- Recommend diet and exercise interventions to reduce liver fat 3
- Target: 3-5% weight reduction 3
- Insufficient evidence for histological benefit 3
MASH Cirrhosis
Adapt lifestyle to severity of liver disease and nutritional status 3:
- Sarcopenia or decompensated cirrhosis: High-protein diet and late-evening snack 3
- Compensated cirrhosis with obesity: Moderate weight reduction plus high-protein intake and physical activity 3
Multidisciplinary Care Model
A multidisciplinary approach is mandatory to address both liver-related and extrahepatic outcomes 3, 1:
This approach is essential given the bidirectional connections between MAFLD and cardiometabolic comorbidities 3, 5.
Monitoring Treatment Response
Use non-invasive tests to assess fibrosis progression 3, 1:
- Two-step approach: Calculate FIB-4 first, then proceed to vibration-controlled transient elastography for elevated scores 1
- High-risk criteria: FIB-4 >2.67, liver stiffness measurement >12.0 kPa, or significant fibrosis on biopsy 5
- Liver biopsy can be used to monitor disease progression or response to treatment in individual cases and clinical trials 3, 1
Patients with advanced fibrosis (F3) require hepatocellular carcinoma surveillance with imaging every 6 months 5.
Additional Lifestyle Factors
- Smoking: Complete avoidance 3
- Alcohol: Discouraged; complete avoidance in advanced fibrosis or cirrhosis 3
- Coffee consumption: Associated with improvements in liver damage in observational studies 5
Ultimate Treatment Goals
Prioritize quality of life and survival, cardiometabolic benefits, and prevention of cirrhosis, hepatocellular carcinoma, type 2 diabetes, and cardiovascular disease 3, 1.