What is the recommended evaluation and management approach for metabolic dysfunction‑associated steatotic liver disease (MASLD) in patients with overweight/obesity, type 2 diabetes, dyslipidaemia, hypertension, or other features of metabolic syndrome?

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

All patients with overweight/obesity, type 2 diabetes, dyslipidemia, hypertension, or metabolic syndrome should undergo systematic case-finding for MASLD using a stepwise non-invasive algorithm: calculate FIB-4 score first, then confirm with transient elastography if elevated, targeting fibrosis stage ≥ F2 as the threshold for both increased liver-related risk and eligibility for disease-modifying therapy. 1, 2

Risk Stratification and Diagnostic Pathway

Who to Screen

• Proactively screen all adults with type 2 diabetes, obesity (BMI > 30 kg/m²), metabolic syndrome, or persistently elevated liver enzymes rather than waiting for incidental imaging findings. 1, 3
• Approximately 60–70% of individuals with type 2 diabetes and 70–80% of those with obesity have MASLD. 4
• Screen patients with prediabetes or any combination of metabolic risk factors (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism). 2, 3

Stepwise Fibrosis Assessment

• Step 1: Calculate FIB-4 score (age, AST, ALT, platelet count) as the initial blood-based screening tool. 1, 4
• Step 2: If FIB-4 is elevated or intermediate, perform transient elastography (FibroScan) to measure liver stiffness; a value ≥ 10 kPa indicates at least stage F2 fibrosis. 1, 2
• Use magnetic resonance elastography (MRE) when FibroScan is unreliable, particularly in class III obesity where ultrasound-based methods are less accurate. 1
• Liver biopsy remains the gold standard for definitive staging when non-invasive tests are discordant or when precise histologic confirmation is required before initiating pharmacotherapy. 1, 2

Assess All Cardiometabolic Comorbidities at Diagnosis

• Systematically evaluate for dyslipidemia, hypertension, chronic kidney disease, sleep apnea, and polycystic ovary syndrome to inform staging and guide comprehensive management. 1
• Cardiovascular disease is the leading cause of death in MASLD, followed by extrahepatic cancers (gastrointestinal, breast, gynecologic) and liver-related complications. 4, 5

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Lifestyle Interventions (Foundation for All Patients)

Weight-Loss Targets

• Achieve 7–10% total body-weight reduction to promote MASH resolution and fibrosis regression. 1, 2
• A 5% weight loss is sufficient to reduce hepatic steatosis, though greater loss yields more robust histologic improvement. 1, 4
• 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. 1

Dietary Pattern

• Adopt a Mediterranean dietary pattern emphasizing vegetables, fruits, whole grains, legumes, nuts, fish/white meat, and olive oil as the primary fat source. 1, 4
• Eliminate sugar-sweetened beverages completely and minimize ultra-processed foods high in sugars and saturated fats. 1
• Coffee consumption is associated with reduced liver damage and improved liver-related outcomes in observational studies. 1

Physical Activity

• Prescribe ≥ 150 minutes per week of moderate-intensity or ≥ 75 minutes per week of vigorous-intensity aerobic exercise, which reduces steatosis and improves liver enzymes even without substantial weight loss. 1, 4

Alcohol Avoidance

• Advise complete alcohol avoidance, especially in patients with advanced fibrosis or cirrhosis. 1
• MASLD is defined by alcohol consumption < 140 g/week in women (< 2 standard drinks/day) and < 210 g/week in men (< 3 standard drinks/day). 4

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Pharmacologic Management: Non-Cirrhotic MASLD (Fibrosis F2–F3)

MASH-Targeted Therapy

• Resmetirom is the first FDA-approved disease-modifying 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, 4
• Resmetirom is contraindicated in decompensated cirrhosis (stage F4). 1
• Semaglutide (subcutaneous GLP-1 agonist) received FDA conditional approval for MASH with fibrosis F2–F3; in randomized trials, 0.4 mg daily achieved MASH resolution without fibrosis worsening in 59% of patients versus 17% with placebo. 1, 4

Management of Type 2 Diabetes and Obesity

• GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) and 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, 4
• Tirzepatide was present in ~14% of MAESTRO-NASH trial participants and did not alter resmetirom's tolerability or efficacy; maintaining tirzepatide while adding resmetirom is advised for patients with confirmed F2–F3 fibrosis. 1
• SGLT2 inhibitors (empagliflozin, dapagliflozin) are viable alternatives; trials show moderate reductions in liver fat content and serum ALT. 1
• Continue metformin in patients with compensated cirrhosis (eGFR > 30 mL/min); discontinuation may increase mortality, although metformin alone does not improve MASH histology. 1
• Non-incretin weight-loss agents (orlistat, phentermine-topiramate, naltrexone-bupropion) are not recommended due to insufficient efficacy data in MASH. 1

Management of Dyslipidemia

• Statins are safe, effective, and strongly recommended for all MASH patients with dyslipidemia; meta-analyses show a 37% reduction in hepatocellular carcinoma risk. 1
• Do not withhold statins solely because of liver disease; they remain cardioprotective and do not worsen hepatic outcomes. 1
• When using resmetirom, limit rosuvastatin or simvastatin to ≤ 20 mg/day and pravastatin or atorvastatin to ≤ 40 mg/day due to drug interactions. 1

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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. 1, 4
• In the BRAVES trial, 55% of surgically treated patients achieved histologic MASH resolution without fibrosis worsening at 1 year versus 15% with lifestyle alone; fibrosis improvement by ≥ 1 stage occurred in 37–39% after surgery versus 23% with lifestyle alone. 1
• Bariatric surgery may be considered in compensated cirrhosis after multidisciplinary assessment of portal hypertension and surgical risk. 1
• Metabolic/bariatric endoscopic procedures are not recommended pending further validation. 1

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Pharmacologic Management: Cirrhotic MASLD (Stage F4)

• No MASH-targeted pharmacotherapy is recommended for patients with cirrhosis; management focuses on metabolic optimization, nutritional support, HCC surveillance, and transplant evaluation when indicated. 1, 2
• Continue metformin in compensated cirrhosis if eGFR > 30 mL/min; it is contraindicated in decompensated disease. 1
• Insulin is the preferred glucose-lowering agent in decompensated cirrhosis when other options are unsuitable. 1
• GLP-1 agonists and SGLT2 inhibitors can be used cautiously in compensated cirrhosis with close monitoring. 1

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 preserve muscle mass. 1
• Offer a late-evening snack to reduce overnight fasting and prevent sarcopenia in decompensated patients. 1
• In compensated cirrhosis with obesity, a moderate weight-loss plan emphasizing adequate protein intake and physical activity is acceptable to avoid sarcopenia. 1

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Surveillance and Monitoring

Hepatocellular Carcinoma (HCC) Surveillance

• Perform ultrasound ± AFP every 6 months for cirrhotic MASLD (stage F4). 1
• Consider HCC surveillance for advanced fibrosis (stage F3) based on individual risk assessment. 1
• HCC surveillance is not recommended for fibrosis stages F0–F2. 1
• In obese patients with cirrhosis, combine AFP with ultrasound due to reduced sonographic sensitivity; employ MRI when ultrasound visualization remains inadequate. 1
• HCC can develop in MASLD patients without cirrhosis, warranting heightened awareness. 6

Fibrosis Progression Monitoring

• Repeat FIB-4 and elastography annually for patients with stage F2/F3 and every 2–3 years for stages F0/F1. 1
• Non-invasive tests primarily track fibrosis progression and have limited ability to gauge treatment response. 1, 2
• A relative reduction in MRI-PDFF > 30% and an ALT decrease > 17 U/L are associated with histologic resolution of steatohepatitis in MASLD. 1

Portal Hypertension Monitoring

• Conduct regular endoscopic or imaging assessment for varices and decompensation in cirrhotic patients. 1
• Evaluate the application of Baveno VII criteria for clinically significant portal hypertension and the role of spleen stiffness measurement in MASLD. 6

Safety Monitoring for Resmetirom

• Measure liver enzymes at 12 weeks after starting resmetirom to detect drug-induced liver injury; transient ALT/AST rises are possible, especially with concurrent statin use. 1
• Gallbladder complications (cholelithiasis, acute cholecystitis, obstructive pancreatitis) occur more frequently with resmetirom; educate patients to report abdominal pain, nausea, vomiting, or fever. 1

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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 extrahepatic outcomes. 1, 5
• MASLD is linked to higher rates of cardiovascular events, chronic kidney disease, and extrahepatic malignancies; coordinate care across specialties to manage systemic implications. 1, 5
• Encourage extrahepatic cancer screening in patients with obesity and type 2 diabetes, reflecting their elevated risk profile. 1

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Common Pitfalls and Caveats

• Do not impose aggressive caloric restriction in patients with sarcopenia or decompensated cirrhosis, as it worsens muscle loss. 1
• Do not prescribe metformin in decompensated cirrhosis or when eGFR < 30 mL/min due to lactic-acidosis risk. 1
• Do not discontinue metformin in compensated cirrhosis with type 2 diabetes, as withdrawal may increase mortality. 1
• Do not withhold statins solely because of liver disease; they remain safe and cardioprotective. 1
• Do not use resmetirom in cirrhotic patients (F4); it is contraindicated in decompensated cirrhosis. 1
• Do not rely on ultrasound alone to exclude cirrhosis; employ FIB-4, elastography, or MRE for accurate staging. 1
• Nutraceuticals should not be used in MASLD because evidence of effectiveness is insufficient. 1
• No mortality benefit has been demonstrated for treatment-induced histologic improvements in MASLD; long-term outcome data are lacking. 1