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

Treatment of MAFLD by Disease Stage

For all stages of MAFLD, lifestyle modification targeting 7-10% weight loss through Mediterranean diet and 150+ minutes weekly of moderate-intensity exercise forms the foundation of treatment, with resmetirom now available for non-cirrhotic MASH with significant fibrosis (stage ≥2). 1, 2

Stage-Specific Treatment Algorithm

Simple Steatosis (MASL)

• Target ≥5% weight reduction to achieve steatosis reduction 1
• Implement Mediterranean dietary pattern with minimization of processed meats, ultra-processed foods, and sugar-sweetened beverages 1, 2
• Prescribe ≥150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity physical activity 1, 2
• No pharmacological therapy specifically indicated at this stage 2
• Smoking avoidance and alcohol discouragement are essential 1

MASH Without Significant Fibrosis (F0-F1)

• Target ≥7-10% weight reduction for MASH resolution and fibrosis improvement 1, 2
• Continue intensive lifestyle interventions with multidisciplinary care approach 1
• Consider incretin-based therapies (semaglutide, tirzepatide) if comorbid type 2 diabetes or obesity present 2
• Bariatric surgery may be considered for patients with obesity who fail lifestyle interventions 2
• Pharmacological MASH-targeted therapy not yet standard at this stage 2

MASH With Significant Fibrosis (F2-F3)

• Resmetirom is recommended as first-line pharmacological therapy, having demonstrated histological efficacy on steatohepatitis and fibrosis in phase III trials 2
• Maintain ≥7-10% weight reduction target through continued lifestyle modification 1
• High-protein intake should be emphasized to prevent sarcopenia during weight loss 1
• Incretin-based therapies remain appropriate for metabolic comorbidity management 2
• Non-invasive tests (FIB-4, transient elastography) should be used for repeated fibrosis assessment rather than serial liver biopsies 1, 2

Compensated MASH Cirrhosis

• Moderate weight reduction (3-5%) with high-protein diet and physical activity to prevent sarcopenia 1
• Late-evening snack recommended to optimize nutritional status 1
• Liver stiffness measurement ≤15 kPa plus platelets ≥150×10⁹/L rules out clinically significant portal hypertension 1
• Upper gastrointestinal endoscopy required if LSM ≥20 kPa and/or platelets <150×10⁹/L to screen for varices 1
• Non-selective beta-blockers initiated if clinically significant portal hypertension present 1
• Hepatocellular carcinoma surveillance mandatory 2
• Alcohol avoidance is critical at this stage 1

Decompensated Cirrhosis

• High-protein diet with late-evening snack to address sarcopenia and nutritional deficiency 1
• Lifestyle interventions adapted to severity of liver disease 1
• Bariatric surgery is contraindicated in decompensated cirrhosis 1
• Liver transplantation evaluation should be initiated 1
• Pre-transplant weight optimization targets BMI <40 kg/m² (ideally <35 kg/m²) through dietary modification and supervised exercise 1
• Pharmacological weight-loss strategies may be considered after careful risk-benefit assessment regarding sarcopenia and liver function 1

Critical Monitoring Considerations

Non-invasive tests provide limited information about individual treatment response despite their utility in population-level studies 1. Longitudinal FIB-4 and transient elastography can assess fibrosis progression but should not be the sole determinant of treatment efficacy 1, 2.

For clinical trial contexts or individual cases requiring definitive assessment, liver biopsy remains the gold standard for monitoring disease progression or treatment response, though it is not suited for routine practice 1, 2.

Common Pitfalls to Avoid

The most critical error is failing to implement multidisciplinary care addressing both hepatic and cardiometabolic components simultaneously 1. Treatment of cardiometabolic comorbidities (with statins, aspirin, renin-angiotensin-aldosterone modulators) may modify disease progression and reduce liver-related events 1.

Another pitfall is setting unrealistic weight loss expectations—even 3-5% weight reduction provides metabolic benefits in cirrhotic patients, while higher targets risk worsening sarcopenia 1. The type of weight-loss diet should be tailored to individual preferences and clinical condition rather than applying rigid protocols 1.