What is the recommended management for metabolic dysfunction‑associated steatotic liver disease (MASLD)?

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

A multidisciplinary approach combining lifestyle modification, pharmacotherapy for metabolic comorbidities, and—in select patients with non-cirrhotic MASH and fibrosis F2–F3—resmetirom is the recommended management strategy for MASLD. 1

Risk Stratification and Diagnostic Approach

• Apply a stepwise non-invasive algorithm in all high-risk adults (type 2 diabetes, obesity, metabolic syndrome, or elevated liver enzymes): calculate FIB-4 score first, then confirm with transient elastography if FIB-4 is elevated. 1
• A liver stiffness measurement ≥10 kPa on elastography indicates at least stage F2 fibrosis, identifying patients at risk for liver-related outcomes and determining eligibility for MASH-targeted therapy. 2
• Liver biopsy is not suitable for routine monitoring due to invasiveness but may be used in individual cases when precise histologic staging is essential, particularly in class III obesity where non-invasive tests may be discordant. 1, 2

Lifestyle Modification: Foundation for All Patients

Weight-Loss Targets

• Aim for ≥7–10% sustained body-weight reduction to achieve MASH resolution and improve liver inflammation; ≥5% loss reduces hepatic steatosis, and ≥10% improves fibrosis. 1
• Create a daily caloric deficit of 500–1,000 kcal to promote gradual weight loss (<1 kg/week) and avoid rapid loss that may worsen liver injury or sarcopenia. 2

Dietary Pattern

• Adopt a Mediterranean dietary pattern emphasizing vegetables, fruits, whole grains, legumes, nuts, olive oil, and unprocessed fish or poultry while minimizing processed meat, ultra-processed foods rich in sugars and saturated fats, and completely eliminating sugar-sweetened beverages. 1
• This dietary approach improves histologically or non-invasively assessed liver injury, though evidence for impact on clinical liver-related outcomes remains limited. 1

Physical Activity

• Prescribe ≥150 minutes/week of moderate-intensity or ≥75 minutes/week of vigorous-intensity aerobic activity, tailored to individual preference and ability, to reduce steatosis even without substantial weight loss. 1
• While physical activity confers well-documented cardiometabolic benefits, evidence for histological and clinical liver outcomes is less robust. 1

Alcohol Abstinence

• Mandate complete alcohol abstinence, especially in patients with significant fibrosis or cirrhosis, as even low alcohol intake doubles the risk for adverse liver-related outcomes. 3, 4

Pharmacological Management: Non-Cirrhotic MASH with Fibrosis F2–F3

MASH-Targeted Therapy

• Resmetirom is the first FDA-approved agent (March 2024) for adults with non-cirrhotic MASH and moderate-to-advanced fibrosis (stage F2–F3); phase III trials demonstrated superior histologic resolution of steatohepatitis and fibrosis regression with an acceptable safety profile. 1, 2
• Resmetirom should be used only where locally approved and according to the label; it is contraindicated in decompensated cirrhosis (stage F4). 1, 2
• Vitamin E cannot be recommended as MASH-targeted therapy given the lack of robust demonstration of histological efficacy from large phase III trials and potential long-term risks. 1
• Pioglitazone cannot be recommended as MASH-targeted therapy despite being safe in non-cirrhotic MASH, due to lack of robust phase III efficacy data. 1

Management of Type 2 Diabetes and Obesity

• GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) or the GLP-1/GIP co-agonist tirzepatide are preferred first-line agents in non-cirrhotic MASH, providing glycemic control, weight loss, and hepatic benefit; semaglutide has received FDA conditional approval for MASH with moderate-to-advanced fibrosis. 2
• SGLT2 inhibitors (empagliflozin, dapagliflozin) are safe alternatives that should be used for their respective indications (type 2 diabetes, heart failure, chronic kidney disease); trials show moderate reductions in liver fat and serum ALT. 1, 2
• Metformin should be continued in patients with compensated cirrhosis (if eGFR >30 mL/min) because discontinuation may increase mortality, although metformin alone does not improve MASH histology. 2
• Incretin-based agents (GLP-1 agonists, tirzepatide) are favored for obesity due to their combined metabolic and hepatic effects; non-incretin weight-loss drugs (orlistat, phentermine-topiramate, naltrexone-bupropion) are not recommended due to inconclusive efficacy data. 2

Management of Dyslipidemia

• Statins are safe, effective, and strongly recommended for all MASLD patients with dyslipidemia; meta-analyses show a 37% reduction in hepatocellular carcinoma risk. 2
• Do not withhold statins solely because of liver disease; they remain cardioprotective and do not worsen hepatic outcomes. 2, 3
• When using resmetirom concurrently, limit rosuvastatin or simvastatin to ≤20 mg/day and pravastatin or atorvastatin to ≤40 mg/day. 2

Bariatric Surgery

• Offer bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy) to patients with BMI ≥40 kg/m² or BMI ≥35 kg/m² with metabolic comorbidities who have failed lifestyle and pharmacologic measures; surgery yields durable liver improvement, diabetes remission, and better cardiometabolic risk profiles. 2
• In compensated cirrhosis, bariatric surgery may be considered after multidisciplinary assessment for portal hypertension and surgical risk. 2, 3
• Metabolic/bariatric endoscopic procedures are not recommended pending further validation. 2

Management of Cirrhotic MASLD (Stage F4)

Pharmacotherapy Limitations

• No MASH-targeted pharmacotherapy is currently recommended for patients with cirrhosis; management focuses on metabolic optimization, nutritional support, surveillance for complications, and transplant evaluation when indicated. 1, 2, 3

Metabolic Comorbidity Management in Cirrhosis

• Metformin may be used in compensated cirrhosis if eGFR >30 mL/min but is contraindicated in decompensated cirrhosis due to lactic acidosis risk. 2, 3
• GLP-1 agonists and SGLT2 inhibitors can be used cautiously in compensated cirrhosis with close monitoring. 2, 3
• Insulin is the preferred glucose-lowering agent in decompensated cirrhosis when other options are unsuitable. 2, 3

Nutritional Management in Cirrhosis

• Provide a high-protein diet (1.2–1.5 g/kg body weight/day) with total calories ≥35 kcal/kg/day to prevent sarcopenia and sarcopenic obesity. 2, 3
• Offer a late-evening snack to reduce overnight fasting and preserve muscle mass in sarcopenic or decompensated patients. 2, 3
• In compensated cirrhosis with obesity, a moderate weight-loss plan emphasizing protein intake and physical activity is acceptable to avoid sarcopenia. 2, 3

Surveillance and Monitoring in Cirrhosis

• Conduct hepatocellular carcinoma surveillance with ultrasound ± AFP every 6 months for all cirrhotic MASLD patients; consider surveillance for advanced fibrosis (F3) based on individual risk assessment. 2, 4
• Perform regular surveillance for portal hypertension through endoscopic or imaging assessment for varices and decompensation. 2
• Evaluate for liver transplantation in all cases of decompensation (ascites, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome) or hepatocellular carcinoma development. 2, 3

Monitoring and Follow-Up for Non-Cirrhotic MASLD

• Repeat FIB-4 and elastography annually for patients with stage F2/F3 and every 2–3 years for stages F0/F1 to monitor fibrosis progression; recognize that non-invasive tests primarily track progression and have limited ability to assess treatment response. 2
• A relative reduction in MRI-PDFF >30% and an ALT decrease >17 U/L are associated with histologic resolution of steatohepatitis and can be used to monitor treatment response. 2

Multidisciplinary Care

• Implement a multidisciplinary team (hepatology, endocrinology, nutrition, cardiology, surgery) to address the intertwined liver disease, diabetes, obesity, and cardiovascular risk, thereby improving both hepatic and extra-hepatic outcomes. 1, 2
• MASLD is linked to higher rates of cardiovascular events, chronic kidney disease, and extra-hepatic malignancies; coordinated care is essential. 2, 5

Common Pitfalls to Avoid

• Do not impose aggressive caloric restriction in patients with sarcopenia or decompensated cirrhosis, as it worsens muscle loss. 2, 3
• Do not prescribe metformin in decompensated cirrhosis or when eGFR <30 mL/min due to lactic acidosis risk. 2, 3
• Do not discontinue metformin in compensated cirrhosis with type 2 diabetes, as withdrawal may increase mortality. 2, 3
• Do not withhold statins solely because of liver disease; they are safe and cardioprotective. 2, 3
• Do not use resmetirom in cirrhotic patients (F4); it is contraindicated. 2
• Do not rely on ultrasound alone to exclude cirrhosis; employ FIB-4, elastography, or magnetic resonance elastography for accurate staging. 2
• Nutraceuticals should not be used in MASLD because evidence of effectiveness and safety is insufficient. 1