What are the treatment options for Metabolic Associated Fatty Liver Disease (MAFLD)?

Treatment of MAFLD (Metabolic-Associated Fatty Liver Disease)

Lifestyle modification with structured weight loss targets is the cornerstone of MAFLD treatment, aiming for ≥5% weight reduction to reduce liver fat, 7-10% to improve inflammation, and ≥10% to improve fibrosis, combined with Mediterranean dietary patterns and ≥150 minutes weekly of moderate-intensity exercise. 1

Non-Pharmacological Therapy (First-Line Treatment)

Weight Loss Targets

• Achieve sustained weight reduction of ≥5% to reduce hepatic steatosis 1, 2
• Target 7-10% weight loss to improve liver inflammation and resolve steatohepatitis 1, 2
• Aim for ≥10% weight loss to achieve fibrosis regression 1, 2
• Weight loss demonstrates dose-dependent histological improvements in steatosis, inflammation (necro-inflammation), and fibrosis 1

Dietary Interventions

• Adopt a Mediterranean dietary pattern as the primary dietary approach, characterized by high intake of vegetables, fruits, low-fat dairy, nuts, olive oil, legumes, and unprocessed fish or poultry 1, 2
• Eliminate sugar-sweetened beverages completely 1, 3
• Minimize ultra-processed foods rich in sugars and saturated fat 1, 3
• Tailor the specific diet type to individual preferences and clinical condition to maximize adherence 1

Physical Activity

• Prescribe ≥150 minutes per week of moderate-intensity exercise OR 75 minutes per week of vigorous-intensity physical activity 1, 2
• Exercise should be tailored to individual preference and ability to ensure sustainability 1
• Physical activity reduces steatosis even without significant weight loss 3
• Aerobic exercise can improve fibrosis and hepatocyte ballooning independent of achieving 7-10% weight loss targets 4

Special Populations

• Normal-weight patients with MAFLD: Diet and exercise interventions should still be recommended to reduce liver fat, though evidence for histological improvement is limited 1
• MAFLD cirrhosis with sarcopenia or decompensation: High-protein diet and late-evening snack 1
• Compensated cirrhosis with obesity: Moderate weight reduction plus high-protein intake and physical activity 1

Pharmacological Therapy

MAFLD-Targeted Therapy

• Resmetirom is the only guideline-recommended MAFLD-targeted therapy with strong evidence, indicated for adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) if locally approved 2, 5
• Resmetirom demonstrated histological efficacy on steatohepatitis and fibrosis in large phase III trials with acceptable safety 5
• No MAFLD-targeted pharmacotherapy is recommended for cirrhotic stage disease 5

Medications for Comorbidities (Safe and Beneficial in MAFLD)

• GLP-1 receptor agonists (semaglutide, tirzepatide) 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, 5
• SGLT2 inhibitors should be used for approved indications (diabetes, heart failure, chronic kidney disease) as they are safe in MASLD and improve cardiometabolic outcomes 5
• Statins are safe and should be used for dyslipidemia in patients with MAFLD 3

Medications NOT Currently Recommended as MAFLD-Targeted Therapy

• Vitamin E cannot be recommended due to lack of robust demonstration of histological efficacy in large phase III trials and potential long-term risks 5
• Pioglitazone cannot be recommended as MAFLD-targeted therapy given lack of robust demonstration of histological efficacy in large phase III trials, though it has metabolic benefits 5, 6
• GLP-1 receptor agonists are not recommended as MAFLD-targeted therapies in the absence of formal demonstration of histological improvement in large phase III trials, though they should be used for their approved indications 5

Bariatric Surgery

• Consider bariatric surgery for patients with MAFLD and class II-III obesity (BMI >35 kg/m²), particularly when lifestyle modification and pharmacotherapy have been insufficient 2
• Bariatric surgery is especially appropriate for individuals with clinically significant fibrosis and obesity with comorbidities 3

Multidisciplinary Care Approach

• A multidisciplinary approach is mandatory to ensure all components are appropriately targeted to improve both liver-related and extrahepatic outcomes 1, 2
• The care team should include hepatology/gastroenterology, endocrinology, cardiology, nutrition/dietetics, and behavioral therapy 2
• Aggressively screen and manage diabetes, dyslipidemia, and hypertension given the bidirectional connections between MAFLD and cardiometabolic comorbidities 3

Monitoring and Risk Stratification

• Use non-invasive tests (FIB-4, liver stiffness measurement) to assess fibrosis progression in a tailored fashion 1, 3
• High-risk patients have FIB-4 >2.67, LSM >12.0 kPa, or significant fibrosis on biopsy 3
• Liver biopsy is not suited for monitoring in routine clinical practice due to invasiveness and procedure-related limitations 1
• Liver biopsy can be used to monitor disease progression or response to treatment in individual cases and clinical trials 1
• Patients with advanced fibrosis (F3) require hepatocellular carcinoma surveillance with imaging every 6 months 3

Treatment Goals

• Prioritize quality of life and survival, cardiometabolic benefits, and prevention of cirrhosis, hepatocellular carcinoma, type 2 diabetes, and cardiovascular disease as the ultimate treatment goals 2

Important Caveats

• Long-term adherence to behavioral changes is often insufficient, with maximal weight loss at 6 months followed by gradual weight regain 1
• Avoid medications that worsen steatosis including corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid 3
• Evidence for lifestyle modification effects on advanced fibrosis or cirrhosis is insufficient due to minority representation in clinical trials 1
• Smoking should be avoided and alcohol discouraged or avoided in advanced fibrosis or cirrhosis 1