What is the treatment for MASLD (Macrophage Activation Syndrome with Liver Dysfunction)?

Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

For patients with MASLD, a comprehensive treatment approach should focus on lifestyle modifications as first-line therapy, with pharmacological interventions reserved for those with significant fibrosis (stage ≥2), prioritizing resmetirom when available for non-cirrhotic patients. 1

Diagnosis and Disease Staging

MASLD has evolved from a diagnosis of exclusion to a positive diagnosis with specific criteria. Disease staging is crucial for treatment decisions:

• MASLD without fibrosis or with mild fibrosis (F0-F1): Lifestyle modifications only
• MASLD with significant fibrosis (F2-F3): Lifestyle modifications plus pharmacotherapy
• MASLD with cirrhosis (F4): Lifestyle modifications plus individualized pharmacotherapy with close monitoring 2

First-Line Treatment: Lifestyle Modifications

Diet Recommendations

• Target weight loss: 7-10% of body weight for histological improvement
• Rate of weight loss: <1 kg/week to avoid worsening portal inflammation and fibrosis
• Caloric restriction: 500-1000 kcal energy deficit daily
• Diet pattern: Mediterranean diet focusing on:
  • Vegetables, fruits, and fiber-rich foods
  • Limited saturated fats
  • Minimal commercially produced fructose and added sugars
  • Complete alcohol abstinence, especially for advanced disease 2

Physical Activity

• Minimum recommendation: 150-200 minutes/week of moderate-intensity aerobic activities in 3-5 sessions
• Optimal approach: Combination of aerobic exercise and resistance training 2

Nutritional Considerations

• Protein intake: Minimum 1.2-1.5 g/kg body weight daily
• Special considerations for cirrhosis:
  • High-protein diet (1.2-1.5 g/kg body weight/day)
  • Caloric intake of at least 35 kcal/kg body weight/day
  • Late-evening snack for patients with sarcopenia or decompensated cirrhosis 1

Pharmacological Treatment

MASH-Targeted Therapies

• Resmetirom: First choice for non-cirrhotic MASH with significant liver fibrosis (stage ≥2)
  • Demonstrated histological efficacy on steatohepatitis and fibrosis
  • Acceptable safety and tolerability profile
  • Currently no data on sustainability of benefits or long-term safety 1

Medications for Comorbidities with Potential Liver Benefits

For Patients Without Cirrhosis (F0-F3)

• GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) and co-agonists (tirzepatide):

  • Safe to use in MASH including compensated cirrhosis
  • Indicated for type 2 diabetes and obesity
  • Substantial weight loss may provide hepatic histological benefit 1, 2

• SGLT2 inhibitors (empagliflozin, dapagliflozin):

  • Safe to use in MASLD
  • Should be used for their indications: type 2 diabetes, heart failure, chronic kidney disease
  • Insufficient evidence to recommend as MASH-targeted therapy 1

For Patients With Compensated Cirrhosis (F4)

• Metformin: Can be used with compensated cirrhosis if glomerular filtration rate >30 ml/min
• Insulin: Preferred for decompensated cirrhosis
• GLP-1 receptor agonists: Can be used in Child-Pugh class A cirrhosis
• SGLT2 inhibitors: Can be used in Child-Pugh class A and B cirrhosis 1

Medications Not Recommended as MASH-Targeted Therapies

• Pioglitazone: Lack of robust demonstration of histological efficacy in large Phase III trials
• Vitamin E: Lack of robust demonstration of histological efficacy and potential long-term risks
• Non-incretin-based weight-loss agents: Insufficient evidence
• Nutraceuticals: Insufficient evidence of effectiveness and safety 1, 2

Special Considerations for Cirrhosis

Medication Cautions

• Metformin: Contraindicated in decompensated cirrhosis or renal impairment due to risk of lactic acidosis
• Sulfonylureas: Avoid in hepatic decompensation due to risk of hypoglycemia
• Statins: Can be used in chronic liver disease, including compensated cirrhosis 1

Surgical Options

• Bariatric surgery:
  • Should be considered for non-cirrhotic MASLD with approved indications
  • Can induce long-term beneficial liver effects
  • Associated with remission of type 2 diabetes and improvement of cardiometabolic risk factors
  • For compensated cirrhosis: requires careful evaluation by a multidisciplinary team with experience in bariatric surgery 1

Monitoring and Follow-up

• Liver enzymes: Every 3 months
• Imaging: Repeat at 6-12 months
• Biopsy: Consider repeat after 1-2 years of therapy to assess histological response
• HCC surveillance: Ultrasound examination every 6 months for patients with advanced fibrosis or cirrhosis 2

Common Pitfalls to Avoid

1. Underestimating weight loss importance: 5% can improve steatosis, but 7-10% is needed for histological improvement
2. Prescribing medications without proper disease staging: Treatment should be tailored based on fibrosis stage
3. Allowing alcohol consumption: Even moderate alcohol use can double the risk of adverse liver-related outcomes
4. Using metformin in decompensated cirrhosis: High risk of lactic acidosis
5. Using sulfonylureas in hepatic decompensation: Increased risk of hypoglycemia 1, 2