What is the best treatment approach for an adult patient with hepatic steatosis, possibly associated with metabolic syndrome, obesity, diabetes, and high cholesterol?

Treatment of Hepatic Steatosis (MASLD)

The cornerstone of treatment for hepatic steatosis is achieving 7-10% sustained weight loss through dietary modification and physical activity, with a Mediterranean diet pattern as the primary dietary approach. 1, 2

Lifestyle Modification: The Foundation

Weight Loss Targets

• 5% weight reduction: Reduces liver fat content 1
• 7-10% weight reduction: Improves liver inflammation and steatohepatitis 1, 2
• >10% weight reduction: Improves fibrosis 1

These targets are dose-dependent—greater weight loss produces greater hepatic benefit, with clinical trials consistently demonstrating histological improvements at these thresholds. 1

Dietary Recommendations

• Mediterranean diet is the primary dietary pattern: emphasize vegetables, fruits, whole grains, legumes, nuts, and olive oil 1, 3
• Minimize ultra-processed foods, processed meats, and sugar-sweetened beverages 1, 3
• Increase monounsaturated fats (particularly extra virgin olive oil) which improve hepatic steatosis and metabolic parameters 3
• Coffee consumption (>3 cups daily) is associated with reduced liver damage and improved outcomes 2, 3
• Alcohol restriction: limit to ≤20 g/day (1 drink/day for women, 2 drinks/day for men), though complete avoidance is recommended in advanced fibrosis or cirrhosis 1, 3

Physical Activity

• ≥150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity aerobic exercise 1, 2
• Exercise should be tailored to individual preference and ability to maximize adherence 1

Pharmacological Management

First-Line Pharmacotherapy for MASH with Significant Fibrosis

Resmetirom is recommended for adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2), demonstrating histological efficacy on steatohepatitis and fibrosis in phase III trials. 1, 4

GLP-1 Receptor Agonists

Semaglutide (and other GLP-1 receptor agonists like tirzepatide) should be considered for patients with comorbid type 2 diabetes or obesity, as they provide beneficial effects on MASLD while addressing metabolic comorbidities. 1, 2, 4

Diabetes-Specific Agents

• Pioglitazone 30 mg daily can be used in patients with biopsy-proven NASH, particularly those with type 2 diabetes, showing hepatic benefit in phase II data 1, 5, 6
• SGLT2 inhibitors can be used in patients with Child-Pugh class A and B cirrhosis 1
• Metformin can be used in compensated cirrhosis with preserved renal function but is contraindicated in decompensated cirrhosis due to lactic acidosis risk 1

Cardiovascular Risk Management

Statins are safe and should be prescribed according to cardiovascular risk guidelines in patients with MASLD, including those with compensated cirrhosis—they reduce cardiovascular events and should not be withheld due to liver concerns. 1, 3

Bariatric Surgery

Bariatric surgery should be considered for patients with non-cirrhotic MASLD who have an approved indication (typically BMI >35), as it induces long-term beneficial effects on the liver and is associated with remission of type 2 diabetes. 1, 2

For patients with compensated advanced chronic liver disease/compensated cirrhosis, bariatric surgery can be considered but requires careful evaluation by a multidisciplinary team with expertise in this population. 1

Management of Cardiometabolic Comorbidities

A multidisciplinary approach is essential given the complex interplay between MASLD and cardiometabolic disease. 1, 2

Assess and Treat:

• Dyslipidemia: Use statins per cardiovascular risk guidelines 1, 3
• Type 2 diabetes: Optimize glycemic control with agents that may benefit the liver (GLP-1 agonists, pioglitazone, SGLT2 inhibitors) 1, 2
• Hypertension: Control blood pressure; renin-angiotensin-aldosterone modulators may contribute to reduction in liver-related events 1
• Obesity: Structured weight-loss programs, obesity pharmacotherapy, or bariatric surgery 2, 6

Monitoring and Risk Stratification

Non-Invasive Fibrosis Assessment

• FIB-4 score followed by transient elastography for stepwise fibrosis assessment 2
• Liver stiffness measurement (LSM) <15 kPa plus platelet count >150 × 10⁹/L may rule out clinically significant portal hypertension 1
• LSM >20 kPa and/or platelet count <150 × 10⁹/L: Perform upper gastrointestinal endoscopy to screen for varices 1

Surveillance in Cirrhosis

• Hepatocellular carcinoma surveillance: Right upper quadrant ultrasound every 6 months 1
• Esophageal varices screening: EGD per AASLD guidelines 1
• Non-selective beta-blockers may be started if clinically significant portal hypertension is present 1

Special Considerations for Cirrhosis

Nutritional Management in MASH Cirrhosis

• High-protein diet with late-evening snack for patients with sarcopenia, sarcopenic obesity, or decompensated cirrhosis 1
• Moderate weight reduction can be suggested in compensated cirrhosis with obesity, emphasizing high protein intake and physical activity to maintain muscle mass 1
• Dietary recommendations must be adapted to disease severity and nutritional status 1, 2

Critical Pitfalls to Avoid

• Do not delay lifestyle intervention: Early dietary modification prevents progression—refer for dietary consultation immediately upon diagnosis 3
• Do not prescribe pharmacotherapy for simple steatosis: Lifestyle modification is the sole recommended treatment for early-stage disease without inflammation or fibrosis 3
• Do not withhold statins: They are safe in MASLD and reduce cardiovascular mortality, which is the leading cause of death in this population 1, 3, 4
• Do not discontinue medications that worsen steatosis without considering alternatives: corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, valproic acid 1