What is the treatment for severe hepatic steatosis?

Treatment of Severe Hepatic Steatosis

The cornerstone of treatment for severe hepatic steatosis is achieving sustained weight loss of at least 7-10% through dietary modification and exercise, with Mediterranean-style dietary patterns and at least 150 minutes weekly of moderate-intensity physical activity being the most strongly recommended interventions. 1

Lifestyle Interventions: The Foundation of Treatment

Weight Loss Targets

• Aim for >10% sustained weight reduction to improve fibrosis in patients with severe steatosis, particularly those with overweight or obesity 1
• Weight loss of 5% reduces liver fat 1
• Weight loss of 7-10% improves liver inflammation 1
• Weight loss >10% is needed to improve fibrosis and potentially achieve disease remission 1, 2
• The correlation between weight reduction and histological improvement is dose-dependent, with participants achieving ≥7% weight loss showing significant improvements in steatosis, lobular inflammation, and ballooning injury 2

Dietary Modifications

• Adopt a Mediterranean dietary pattern including vegetables, fruits, unsweetened high-fiber cereals, nuts, fish or white meat, and olive oil 1, 3
• Eliminate sugar-sweetened beverages completely 1
• Limit ultra-processed foods rich in sugars and saturated fat 1
• High saturated fat and simple sugar (particularly fructose) consumption are established risk factors for worsening steatosis 4

Physical Activity Requirements

• Prescribe at least 150 minutes per week of moderate-intensity exercise or 75 minutes per week of vigorous-intensity activity 1
• Physical activity reduces steatosis even without significant weight loss 1, 3
• Tailor exercise to individual preference and ability to maximize adherence 1

Pharmacological Considerations

MASH-Targeted Therapy

• Resmetirom should be considered for non-cirrhotic patients with significant liver fibrosis (stage ≥2) if approved locally, as it demonstrated histological efficacy in phase III trials with acceptable safety 1
• Resmetirom may be considered for patients with advanced fibrosis, at-risk steatohepatitis with significant fibrosis, or high risk of adverse liver-related outcomes 1
• No MASH-targeted pharmacotherapy is currently recommended for cirrhotic patients 1

Medications for Comorbidities

• GLP-1 receptor agonists (semaglutide, liraglutide) should be used for their approved indications (type 2 diabetes, obesity) as they improve cardiometabolic outcomes and are safe in MASH, including compensated cirrhosis 1, 3
• While GLP-1RAs cannot currently be recommended as MASH-targeted therapies due to lack of phase III histological data, substantial weight loss induced by these agents could provide hepatic histological benefit 1
• Statins are safe and should be used for dyslipidemia in patients with hepatic steatosis 3, 5
• SGLT2 inhibitors and metformin should be used for their approved indications (diabetes, heart failure, chronic kidney disease) but cannot be recommended as MASH-targeted therapies 1, 3

Medications NOT Recommended

• Vitamin E cannot be recommended as MASH-targeted therapy despite prior use, due to lack of robust phase III efficacy data and potential long-term risks 1
• Pioglitazone cannot be recommended as MASH-targeted therapy despite being safe to use, due to insufficient phase III evidence 1
• Nutraceuticals cannot be recommended due to insufficient evidence of effectiveness and safety 1

Monitoring and Risk Stratification

Assessment of Disease Severity

• Stratify patients using FIB-4 score, liver stiffness measurement (LSM), or liver biopsy 3
• High-risk patients have FIB-4 >2.67, LSM >12.0 kPa, or significant fibrosis on biopsy 3
• Patients with advanced fibrosis (F3) require hepatocellular carcinoma surveillance with imaging every 6 months 5

Follow-up Strategy

• Non-invasive tests (MRI-PDFF, ALT) can be used to monitor treatment response, though liver biopsy remains the gold standard in clinical trials 1
• MRI-PDFF relative reduction >30% or ALT reduction >17 U/L has been associated with resolution of steatohepatitis in trials 1

Multidisciplinary Approach

A multidisciplinary approach is essential to address both liver-related and extrahepatic outcomes, given the bidirectional connections between steatotic liver disease and cardiometabolic comorbidities 1

Management of Cardiometabolic Risk Factors

• Screen and manage diabetes, dyslipidemia, and hypertension aggressively 3
• Optimize glycemic control in diabetic patients to reduce liver fat 3
• Avoid medications that worsen steatosis including corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid 3

Special Considerations

Bariatric Surgery

• Consider bariatric surgery for appropriate individuals with clinically significant fibrosis and obesity with comorbidities 3
• Bariatric surgery is associated with decreased cardiovascular risk, improved overall mortality, and reduction in hepatic steatosis, inflammation, and fibrosis 6

Coffee Consumption

• Coffee consumption has been associated with improvements in liver damage and reduced liver-related clinical outcomes in observational studies 1

Critical Pitfall

The most common pitfall is treating severe steatosis with pharmacotherapy alone without aggressive lifestyle modification. Weight loss through diet and exercise remains the only intervention with Level 1 evidence for improving liver injury 1, and no medication can substitute for this foundational approach. Even in patients receiving resmetirom or other therapies, lifestyle interventions must remain the primary treatment strategy.