What is the recommended treatment approach for an adult patient with hepatic steatosis, potentially associated with metabolic syndrome, obesity, diabetes, or high cholesterol?

Treatment of Hepatic Steatosis (MASLD)

The cornerstone of treatment for hepatic steatosis is achieving sustained weight loss of 7-10% through dietary modification and physical activity, with the Mediterranean diet pattern being the most strongly recommended dietary approach. 1

Lifestyle Modifications: The Foundation of Treatment

Weight Loss Targets

• Aim for ≥5% weight reduction to reduce liver fat 1
• Target 7-10% weight loss to improve liver inflammation and steatohepatitis 1
• Achieve ≥10% weight loss to improve fibrosis 1
• Implement a 500-1000 kcal/day caloric deficit to achieve gradual weight loss (maximum 1 kg/week) 2

These weight loss thresholds are dose-dependent—greater weight loss produces greater histological improvement. Even modest weight loss of 5% can reduce hepatic fat content, but more substantial weight loss is required to reverse inflammation and fibrosis. 1

Dietary Recommendations

Adopt a Mediterranean dietary pattern that includes: 1, 3, 2

• Vegetables, fruits, whole grains, legumes, nuts, and olive oil
• Fish or white meat as primary protein sources
• Minimize or eliminate ultra-processed foods rich in sugars and saturated fats 1, 3
• Completely avoid sugar-sweetened beverages 1, 3
• Minimize processed meat consumption 1, 3

Coffee consumption may be beneficial, as observational studies show associations with improved liver damage and reduced liver-related clinical outcomes. 3, 2

Physical Activity

Prescribe ≥150 minutes/week of moderate-intensity physical activity OR 75 minutes/week of vigorous-intensity physical activity 1, 3, 2

Physical activity reduces steatosis even when weight loss goals are not achieved, making it independently beneficial. 2 Tailor the exercise regimen to the patient's preference and physical ability to maximize adherence. 1

Alcohol and Tobacco

• Minimize alcohol consumption to no more than 1 drink/day for women or 2 drinks/day for men 1
• Completely avoid alcohol in patients with advanced fibrosis or cirrhosis, as it increases hepatocellular carcinoma risk and liver-related mortality 2
• Recommend smoking cessation to reduce hepatocellular carcinoma development 2

Pharmacological Management

For Patients with MASH and Significant Fibrosis (Stage ≥2)

Consider resmetirom for adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) 1, 3, 2, 4

Resmetirom is a liver-directed thyroid hormone receptor β-selective agonist that demonstrated histological efficacy on steatohepatitis and fibrosis in phase III trials with acceptable safety. 3, 2 It is conditionally FDA-approved for this indication. 4

For Patients with Comorbid Type 2 Diabetes or Obesity

Prefer GLP-1 receptor agonists (semaglutide, liraglutide, tirzepatide) as first-line therapy 1, 3, 5, 2, 4

These agents provide dual benefits: significant weight loss and direct improvements in hepatic steatosis and inflammation. 2 They are safe in MASLD, including compensated cirrhosis. 2 Semaglutide is conditionally FDA-approved for MASH with moderate to advanced fibrosis. 4

SGLT2 inhibitors can be used in patients with Child-Pugh class A and B cirrhosis 1

Management of Cardiometabolic Comorbidities

Use statins for dyslipidemia in all patients with MASLD, as they reduce hepatocellular carcinoma risk by 37% and are safe even in compensated cirrhosis. 1, 5, 2

Metformin can be used in compensated cirrhosis with preserved renal function but avoid in decompensated cirrhosis due to lactic acidosis risk. 1

Avoid sulfonylureas in hepatic decompensation due to hypoglycemia risk. 1

Pioglitazone may have hepatic benefits according to phase II data, though it is not a first-line agent. 5, 6

What NOT to Use

Do not use ursodeoxycholic acid (UDCA) for MASLD/NASH treatment—the AASLD strongly recommends against it (Grade B evidence). 5

Nutraceuticals cannot be recommended due to insufficient evidence. 1

Bariatric Surgery

Consider bariatric surgery for patients with MASLD and BMI >35 kg/m² who do not respond to lifestyle interventions 1, 3, 5, 2

For patients listed for liver transplantation, aim to reduce BMI <40 kg/m² and ideally <35 kg/m² through dietary modification and supervised physical exercise first. 1 Sleeve gastrectomy may be considered in compensated cirrhosis without clinically significant portal hypertension. 1

Multidisciplinary Approach

Implement a multidisciplinary care model given the bidirectional connections between MASLD and cardiometabolic comorbidities (diabetes, hypertension, dyslipidemia, cardiovascular disease). 1, 3, 5

This approach ensures all metabolic components are appropriately targeted to improve both liver-related and extrahepatic outcomes, as cardiovascular disease is the leading cause of death in MASLD patients. 1, 4

Monitoring and Risk Stratification

Initial Assessment

• Obtain baseline liver ultrasound, complete blood count, comprehensive metabolic panel (AST, ALT, bilirubin, alkaline phosphatase), INR, and creatinine 1
• Assess cardiovascular risk factors: lipid profile, fasting glucose and/or HbA1c, waist circumference, BMI 1
• Use FIB-4 score as initial non-invasive test for fibrosis assessment 3, 2
• Follow with vibration-controlled transient elastography (liver stiffness measurement) if FIB-4 is elevated 3, 4

Ongoing Monitoring

Non-invasive tests may be repeatedly used to assess fibrosis progression but provide limited information about treatment response 1, 3

Follow-up with liver enzyme tests (particularly ALT) every 3-6 months, as ALT reduction of ≥17 U/L has been associated with resolution of steatohepatitis. 1, 2

Liver biopsy is not suited for routine monitoring due to invasiveness but may be used in individual cases to assess disease progression or treatment response. 1, 3

High-Risk Patients Requiring Liver Biopsy Consideration

Consider referral for liver biopsy if: 1

• Patient has diabetes and/or metabolic syndrome (risk factors for NASH and advanced fibrosis)
• Findings suggest cirrhosis: thrombocytopenia, AST>ALT, or hypoalbuminemia
• Patient is undergoing cholecystectomy or bariatric surgery where intraoperative biopsy is low risk

Cirrhosis Surveillance

For patients with MASH-related cirrhosis: 1, 3, 2

• Perform right upper quadrant ultrasound every 6 months for hepatocellular carcinoma screening
• Screen for esophageal varices with upper endoscopy
• Use liver stiffness measurement <15 kPa plus platelet count >150 × 10⁹/L to rule out clinically significant portal hypertension 1
• If liver stiffness measurement >20 kPa and/or platelet count <150 × 10⁹/L, perform upper gastrointestinal endoscopy to screen for varices 1
• Consider non-selective beta-blockers if clinically significant portal hypertension is present 1

Special Considerations for Cirrhosis

In compensated cirrhosis with obesity, pursue moderate weight reduction with emphasis on high protein intake and physical activity to maintain muscle mass and reduce sarcopenia risk. 1

In sarcopenia, sarcopenic obesity, or decompensated cirrhosis, provide a high-protein diet and late-evening snack 1

Adapt dietary and lifestyle recommendations to the severity of liver disease, nutritional status, and presence of sarcopenia. 1

Medications to Discontinue

Stop medications that may worsen steatosis: corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, valproic acid 1

Common Pitfalls to Avoid

• Do not expect rapid results—sustained lifestyle changes over months are required to achieve meaningful histological improvement 1
• Do not use liver biopsy for routine monitoring; reserve it for diagnostic uncertainty or clinical trial settings 1
• Do not neglect cardiovascular risk assessment and management, as cardiovascular disease is the leading cause of death in MASLD 4
• Do not prescribe weight loss in patients with sarcopenia or decompensated cirrhosis without careful nutritional assessment 1
• Do not assume that improving diet quality alone will impact clinical liver-related outcomes—weight loss is essential 1