What are the current guidelines for managing metabolic‑associated steatohepatitis (MASH)?

MASH Treatment Guidelines

Adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be treated with resmetirom if locally approved, combined with lifestyle modification targeting 7-10% weight loss, while those with type 2 diabetes or obesity should receive incretin-based therapies (semaglutide, tirzepatide) for their dual metabolic and hepatic benefits. 1

Diagnostic and Risk Stratification Approach

Case-finding is essential in high-risk populations using a stepwise non-invasive approach 1, 2:

• Apply case-finding strategies in individuals with cardiometabolic risk factors (particularly type 2 diabetes or obesity), abnormal liver enzymes, and/or radiological signs of hepatic steatosis 1
• Use FIB-4 score as the initial blood-based assessment, followed by transient elastography to rule-in or rule-out advanced fibrosis 1, 2
• Advanced fibrosis (stage ≥F2) is the key threshold that predicts liver-related outcomes and determines treatment eligibility 1

Non-Pharmacological Management (Foundation for All Patients)

Weight Loss Targets

Target 7-10% weight reduction to achieve MASH resolution and fibrosis improvement in patients with overweight/obesity 1, 2:

• 5% weight loss reduces steatosis 1
• 7-10% weight loss achieves MASH resolution and fibrosis regression 1, 2
• Weight loss type should be tailored to individual preferences and clinical condition 1

Dietary Recommendations

Mediterranean diet pattern is strongly recommended 1, 2:

• Minimize processed meat, ultra-processed foods, and sugar-sweetened beverages 1
• Emphasize vegetables, fruits, low-fat dairy, nuts, olive oil, legumes, unprocessed fish and poultry 1
• Coffee consumption is associated with improved liver outcomes in observational studies 2

Physical Activity

Prescribe ≥150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity physical activity 1, 2

Alcohol

Discourage alcohol consumption; mandate avoidance in advanced fibrosis or cirrhosis 1

Pharmacological Management

MASH-Targeted Therapy (Non-Cirrhotic Disease)

Resmetirom is the first approved MASH-targeted therapy for adults with non-cirrhotic MASH and significant fibrosis (F2/F3) 1, 2:

• Demonstrated histological effectiveness on both steatohepatitis and fibrosis with acceptable safety and tolerability 1
• FDA conditionally approved in March 2024 based on phase III trial data showing superior MASH resolution and fibrosis improvement 3, 4
• Should be considered if locally approved and dependent on label 1

Treatment of Comorbidities (Dual Benefit Approach)

Type 2 Diabetes

GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) and coagonists (tirzepatide) are preferred first-line agents in non-cirrhotic MASH 1, 2:

• Provide both glycemic control and hepatic benefit 1, 2
• Semaglutide received FDA conditional approval for MASH with moderate to advanced fibrosis 3, 4

SGLT2 inhibitors (empagliflozin, dapagliflozin) are alternative options 1:

• Show moderate reduction in liver lipid content and ALT in trials 1

Metformin should not be discontinued in patients with compensated cirrhosis (unless contraindicated by hepatic decompensation or renal failure), as discontinuation may increase mortality 1:

• Can be used if glomerular filtration rate >30 ml/min 1
• Does not improve MASH histology as monotherapy 1

Obesity

Incretin-based therapies (GLP-1 agonists, tirzepatide) are preferred for their dual metabolic and hepatic effects 1, 2

Non-incretin-based weight-loss agents (orlistat, phentermine-topiramate, naltrexone-bupropion) are NOT recommended as MASH-targeted therapies due to inconclusive trial data 1

Dyslipidemia

Statins should not be withheld based on liver disease diagnosis alone, as they are safe and reduce cardiovascular risk 5

Bariatric Surgery

Bariatric surgery should be considered in non-cirrhotic MASLD with approved indications (BMI >40 kg/m² or BMI >35 kg/m² with comorbidities) 1, 2:

• Induces long-term beneficial liver effects and remission of type 2 diabetes 1
• Associated with improvement in cardiometabolic risk factors 1

In compensated cirrhosis, bariatric surgery can be considered but requires careful multidisciplinary evaluation for clinically significant portal hypertension 1, 5

Metabolic/bariatric endoscopic procedures cannot currently be recommended due to insufficient validation 1

Management of MASH-Related Cirrhosis

Critical Distinction

No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage 1, 5

Lifestyle Adaptations for Cirrhosis

Dietary recommendations must be adapted to disease severity and nutritional status 1:

• High-protein diet (1.2-1.5 g/kg body weight/day) with total caloric intake ≥35 kcal/kg body weight/day 1, 5
• Late-evening snack to reduce overnight fasting and preserve muscle mass in sarcopenia or decompensated cirrhosis 1, 5
• Moderate weight reduction can be suggested in compensated cirrhosis with obesity, emphasizing high protein intake and physical activity to prevent sarcopenia 1

Pharmacological Management in Cirrhosis

Metformin can be used in compensated cirrhosis with preserved renal function (GFR >30 ml/min) but is contraindicated in decompensated cirrhosis 1, 5

Insulin is the preferred agent in decompensated cirrhosis when other glucose-lowering options are contraindicated 1, 5

GLP-1 receptor agonists and SGLT2 inhibitors should be used cautiously, with careful monitoring in compensated cirrhosis 1

Surveillance and Complications

Management includes 1, 2:

• Surveillance for portal hypertension and hepatocellular carcinoma 1
• Nutritional counseling to prevent sarcopenia 1
• Liver transplantation evaluation in decompensated cirrhosis or HCC development 1, 5

Multidisciplinary Approach

A multidisciplinary team approach is strongly recommended given the bidirectional connections between MASLD and cardiometabolic comorbidities 1, 2:

• Ensures all components (liver disease, diabetes, obesity, cardiovascular risk) are appropriately targeted 1
• Improves both liver-related and extrahepatic outcomes 1

Monitoring Strategy

Non-invasive tests may be repeatedly used to assess fibrosis progression in a tailored fashion 1, 2:

• Provide limited information about treatment response 1
• Liver biopsy can be used in individual cases to monitor disease progression or treatment response 1, 2

Common Pitfalls to Avoid

• Do not use aggressive caloric restriction in patients with sarcopenia or decompensated cirrhosis, as this worsens muscle wasting 5
• Do not prescribe metformin in decompensated cirrhosis or when GFR <30 ml/min due to lactic acidosis risk 1, 5
• Do not withhold statins based on cirrhosis diagnosis alone 5
• Do not discontinue metformin in patients with compensated cirrhosis and type 2 diabetes, as this may increase mortality 1