What is the recommended management for metabolic dysfunction‑associated steatohepatitis (MASH) in an adult patient with obesity, type‑2 diabetes, dyslipidaemia, and at least stage F2 fibrosis?

Management of MASH with F2 Fibrosis, Obesity, Type 2 Diabetes, and Dyslipidaemia

In an adult with MASH and at least F2 fibrosis plus metabolic comorbidities, initiate resmetirom (if locally approved) alongside GLP-1 receptor agonists or GLP-1/GIP co-agonists for dual hepatic and metabolic benefit, combined with intensive lifestyle modification targeting 7–10% weight loss, statin therapy for dyslipidaemia, and consideration of bariatric surgery if BMI ≥35 kg/m² with comorbidities. 1, 2

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Risk Stratification and Diagnostic Confirmation

• Confirm fibrosis stage ≥F2 using a stepwise approach: calculate FIB-4 score, then perform transient elastography (liver stiffness measurement ≥10 kPa suggests F2 or higher). 1, 3
• If non-invasive tests are discordant or the patient has class III obesity, consider liver biopsy as the gold standard for definitive staging, as ultrasound alone cannot exclude cirrhosis and FibroScan may be less reliable in severe obesity. 2
• Magnetic resonance elastography (MRE) is less affected by obesity and provides reliable fibrosis assessment when FibroScan results are uncertain. 2
• Rule out cirrhosis (F4) before initiating MASH-targeted pharmacotherapy, as resmetirom is contraindicated in decompensated cirrhosis and no MASH-specific drugs are recommended for cirrhotic patients. 1, 2

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Lifestyle Modification: The Foundation for All Patients

Weight Loss Targets

• Achieve 7–10% total body weight reduction to induce MASH resolution and fibrosis regression; even 5% weight loss reduces hepatic steatosis. 1, 3, 2
• Create a 500–1,000 kcal/day deficit to produce gradual weight loss (<1 kg/week), avoiding rapid loss that may worsen liver injury or sarcopenia. 1, 3

Dietary Pattern

• Adopt a Mediterranean diet emphasizing daily vegetables, fruits, whole grains, legumes, nuts, fish or white meat, and olive oil as the primary fat source. 1, 3, 2
• Completely eliminate sugar-sweetened beverages and minimize ultra-processed foods high in sugars and saturated fats. 3, 2

Physical Activity

• Prescribe ≥150 minutes/week of moderate-intensity or ≥75 minutes/week of vigorous-intensity aerobic exercise, as physical activity reduces steatosis and improves liver enzymes even without significant weight loss. 1, 3, 2

Alcohol Avoidance

• Advise complete alcohol abstinence, especially in patients with advanced fibrosis or cirrhosis. 2

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MASH-Targeted Pharmacotherapy (Non-Cirrhotic F2–F3 Fibrosis)

Resmetirom (First-Line MASH-Specific Agent)

• Resmetirom is the first FDA-approved agent (March 2024) for adults with non-cirrhotic MASH and moderate-to-advanced fibrosis (F2–F3); phase III trials demonstrated superior histologic resolution of steatohepatitis and fibrosis regression with acceptable safety. 1, 2
• Use resmetirom only where locally approved and according to the product label; it is contraindicated in decompensated cirrhosis (F4). 1, 2
• Monitor liver enzymes at 12 weeks after initiation to detect drug-induced liver injury; transient ALT/AST elevations may occur, particularly with concurrent statin use. 2
• Educate patients about gallbladder complications (cholelithiasis, acute cholecystitis, obstructive pancreatitis), which occur more frequently with resmetirom; instruct them to report abdominal pain, nausea, vomiting, or fever. 2
• Adjust statin doses during resmetirom therapy: limit rosuvastatin or simvastatin to ≤20 mg/day and pravastatin or atorvastatin to ≤40 mg/day. 2

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Management of Metabolic Comorbidities

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. 1, 3, 2
• Semaglutide has received FDA conditional approval for MASH with moderate-to-advanced fibrosis; in randomized trials, semaglutide 0.4 mg/day achieved MASH resolution without fibrosis worsening in 59% of patients versus 17% with placebo. 3, 2
• Tirzepatide can be continued alongside resmetirom if both are indicated; in the MAESTRO-NASH trial, ~14% of participants used tirzepatide without altering resmetirom's tolerability or efficacy. 2
• SGLT2 inhibitors (empagliflozin, dapagliflozin) are alternative options for type 2 diabetes; trials show moderate reductions in liver fat content and serum ALT. 1, 3
• Metformin should be continued in patients with compensated cirrhosis (if eGFR >30 mL/min), as discontinuation may increase mortality; however, metformin alone does not improve MASH histology. 1, 3, 2
• Non-incretin weight-loss agents (orlistat, phentermine-topiramate, naltrexone-bupropion) are not recommended due to inconclusive efficacy data in MASH. 1, 2

Dyslipidaemia

• Statins are safe, effective, and strongly recommended for all MASH patients with dyslipidaemia; meta-analyses show statins reduce hepatocellular carcinoma risk by 37%. 3, 2
• Do not withhold statins solely because of liver disease; they remain cardioprotective and do not worsen hepatic outcomes. 2

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Bariatric Surgery for Eligible Patients

• Consider bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy) for patients with BMI ≥40 kg/m² or BMI ≥35 kg/m² plus comorbidities who have not responded adequately to lifestyle and pharmacologic interventions. 1, 2
• In the BRAVES trial, 55% of patients achieved histological MASH resolution without fibrosis worsening at 1 year after bariatric surgery versus 15% with lifestyle modification alone; fibrosis improvement by ≥1 stage occurred in 37–39% after surgery versus 23% with lifestyle alone. 1
• In compensated cirrhosis, bariatric surgery may be considered after multidisciplinary assessment for portal hypertension and surgical risk; careful evaluation by an experienced team is required. 1, 2
• Metabolic/bariatric endoscopic procedures are not recommended pending further validation in MASH. 1, 2

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Surveillance and Monitoring

Fibrosis Progression

• Repeat FIB-4 and transient elastography annually for patients with F2–F3 fibrosis to monitor disease progression; recognize that non-invasive tests primarily track fibrosis 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 as surrogate markers of treatment response. 2

Hepatocellular Carcinoma (HCC) Surveillance

• HCC surveillance is not indicated for F2 fibrosis; it is mandatory for cirrhotic patients (F4) with ultrasound ± AFP every 6 months and may be considered for advanced fibrosis (F3) based on individual risk. 2

Portal Hypertension

• Screen for gastroesophageal varices if liver stiffness ≥20 kPa or thrombocytopenia is present. 3

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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. 2, 4
• MASLD is linked to higher rates of cardiovascular events, chronic kidney disease, and extra-hepatic malignancies; coordinate care to manage these systemic risks. 2

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Common Pitfalls and How to Avoid Them

• Do not prescribe metformin in decompensated cirrhosis or when eGFR <30 mL/min due to lactic acidosis risk. 1, 2
• Do not discontinue metformin in compensated cirrhosis with type 2 diabetes, as this may increase mortality. 1, 2
• Do not impose aggressive caloric restriction in patients with sarcopenia or decompensated cirrhosis, as it worsens muscle loss. 2
• Do not use resmetirom in cirrhotic patients (F4), as it is contraindicated and no MASH-targeted pharmacotherapy is recommended for cirrhosis. 1, 2
• Do not rely on ultrasound alone to rule out cirrhosis; use FIB-4, elastography, or MRE for accurate fibrosis staging. 2

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Special Considerations for Cirrhotic Patients (If F4 Is Present)

• No MASH-targeted pharmacotherapy is recommended for cirrhotic patients; management focuses on metabolic drug adaptation, nutritional counseling, surveillance for portal hypertension and HCC, and liver transplantation evaluation in decompensated cirrhosis. 1, 2
• Provide a high-protein diet (1.2–1.5 g/kg body weight/day) with total calories ≥35 kcal/kg/day and a late-evening snack to reduce overnight fasting and preserve muscle mass in sarcopenic or decompensated patients. 1, 2
• In compensated cirrhosis with obesity, a moderate weight-loss plan emphasizing protein intake and physical activity is acceptable to avoid sarcopenia. 1, 2
• Insulin is the preferred glucose-lowering agent in decompensated cirrhosis when other options are unsuitable. 1, 2