What is the treatment for hepatic steatosis?

Treatment for Hepatic Steatosis

Risk Stratification Determines Treatment Pathway

All patients with hepatic steatosis require lifestyle modification as first-line therapy, but pharmacologic treatment should be reserved exclusively for those with confirmed steatohepatitis (NASH) and significant fibrosis (≥F2). 1

• Calculate FIB-4 score and obtain liver stiffness measurement (LSM) by transient elastography to stratify fibrosis risk 2, 1
• Low-risk patients (FIB-4 <1.3, LSM <8.0 kPa, or F0-F1 fibrosis) require lifestyle interventions only—no pharmacotherapy 1
• High-risk patients (FIB-4 >2.67, LSM >12.0 kPa, or ≥F2 fibrosis on biopsy) should be referred to hepatology for multidisciplinary management and consideration of pharmacologic therapy 2, 1, 3

Lifestyle Interventions: The Foundation for All Patients

Weight Loss Targets

Achieve 7–10% sustained body weight reduction to improve steatohepatitis and potentially reverse fibrosis. 1, 3, 4

• A 5% weight loss reduces hepatic steatosis 1, 3
• A 7–10% weight loss improves liver inflammation and resolves steatohepatitis 1, 3, 4
• Weight loss >10% can reverse fibrosis 3, 4
• Weight should be lost gradually at <1 kg/week to avoid worsening liver disease 1

Dietary Modifications

Adopt a Mediterranean dietary pattern emphasizing vegetables, fruits, fiber-rich cereals, nuts, fish or white meat, and olive oil. 1, 3, 4

• Completely eliminate sugar-sweetened beverages 3, 4
• Minimize ultra-processed foods rich in sugars and saturated fats 3, 4
• Structured weight loss programs are more effective than office-based counseling alone 2

Physical Activity

Prescribe 150–300 minutes of moderate-intensity or 75–150 minutes of vigorous-intensity aerobic exercise per week. 1, 3, 4

• Exercise reduces steatosis and improves liver enzymes even without significant weight loss 1, 3

Pharmacologic Treatment for Advanced Disease (≥F2 Fibrosis)

First-Line Pharmacotherapy

Resmetirom is the preferred agent for non-cirrhotic patients with biopsy-proven NASH and significant fibrosis (stage F2-F3), demonstrating histologic improvement in steatohepatitis and fibrosis with acceptable safety. 1, 3, 4

• FDA-approved specifically for non-cirrhotic MASH with moderate-to-advanced fibrosis (F2-F3) 4
• Contraindicated in decompensated cirrhosis (F4) 4
• Monitor liver enzymes at 12 weeks to detect drug-induced liver injury 4
• Educate patients about gallbladder complications (cholelithiasis, acute cholecystitis) 4
• Limit rosuvastatin or simvastatin to ≤20 mg/day and pravastatin or atorvastatin to ≤40 mg/day when co-administered 4

GLP-1 Receptor Agonists (Dual Benefit for Diabetes/Obesity)

For patients with type 2 diabetes or obesity, GLP-1 receptor agonists (semaglutide, liraglutide) are preferred as they improve both glycemic control and liver histology. 2, 1, 4

• Semaglutide 0.4 mg/day achieved NASH resolution without worsening fibrosis in 59% of patients versus 17% with placebo 2, 1
• Liraglutide demonstrated reversal of steatohepatitis and amelioration of fibrosis progression in proof-of-concept studies 2
• Dose-dependent gastrointestinal adverse effects (nausea, constipation, vomiting) occur more frequently than placebo 2
• Can be safely combined with resmetirom 4

Pioglitazone

Pioglitazone improves liver histology in patients with biopsy-proven NASH, increasing odds of NASH resolution (OR 3.22) and reversal of advanced fibrosis (OR 3.15). 2, 1

• Effective in patients with or without type 2 diabetes 2
• Associated with average weight gain of 2.7%, which can be mitigated by combining with SGLT2 inhibitors or GLP-1 receptor agonists 2, 1
• Reduces cardiovascular events and prevents progression from prediabetes to diabetes 2

Vitamin E

Vitamin E 800 IU/day improves steatohepatitis in non-diabetic patients with biopsy-proven NASH, though safety concerns limit routine use. 2, 1

• A large randomized trial showed improvement in steatohepatitis in patients without type 2 diabetes 2
• Results were mixed in patients with type 2 diabetes 2
• Retrospective data suggest improved transplant-free survival in patients with advanced fibrosis or cirrhosis 2

Agents NOT Recommended

• Metformin has no major effect on steatohepatitis histology, though it may reduce HCC risk 2
• Dipeptidyl peptidase IV inhibitors showed no benefit in randomized controlled trials 2
• Sulfonylureas have not been adequately tested 2

Management of Metabolic Comorbidities

Diabetes Management

Prioritize GLP-1 receptor agonists and SGLT2 inhibitors for glycemic control in patients with hepatic steatosis. 1, 4

• These agents provide dual metabolic and hepatic benefits 1, 4
• Metformin should be continued in compensated cirrhosis (if eGFR >30 mL/min) as discontinuation may increase mortality 4
• Insulin is the preferred agent in decompensated cirrhosis 4

Dyslipidemia Management

Statins are safe, effective, and recommended for all patients with hepatic steatosis and dyslipidemia, reducing HCC risk by 37%. 1

• Do not withhold statins solely because of liver disease 4

Bariatric Surgery for Appropriate Candidates

Bariatric surgery should be considered for individuals with clinically significant fibrosis and obesity (BMI >40 kg/m² or BMI >35 kg/m² with comorbidities) when lifestyle interventions fail. 2, 1, 3, 4

• Yields durable liver improvement, diabetes remission, and better cardiometabolic risk profiles 4
• Requires multidisciplinary assessment for portal hypertension in compensated cirrhosis 4

Special Considerations for Cirrhotic Disease

No MASH-targeted pharmacotherapy is recommended for patients with cirrhosis; management focuses on metabolic drug adaptation, nutritional counseling, surveillance, and transplant evaluation. 1, 4

• Provide high-protein diet (1.2–1.5 g/kg/day) with total calories ≥35 kcal/kg/day 4
• Offer late-evening snack to reduce overnight fasting and preserve muscle mass 4
• Conduct HCC surveillance with imaging every 6 months 1, 3
• Screen for gastroesophageal varices if LSM ≥20 kPa or thrombocytopenia present 1
• Evaluate for liver transplantation in decompensated cirrhosis 4

Monitoring Strategy

High-risk patients (≥F2) require close hepatology follow-up for cirrhosis, HCC, and related complications using transient elastography with CAP and liver stiffness measurements. 1

• Low-risk patients undergo annual follow-up with repeated non-invasive tests 1
• Non-invasive tests have limited ability to assess treatment response; liver biopsy may be reserved for select cases 4

Common Pitfalls to Avoid

• Do not prescribe pharmacotherapy for simple steatosis without confirmed NASH and significant fibrosis (≥F2) 1
• Do not impose aggressive caloric restriction in patients with sarcopenia or decompensated cirrhosis, as it worsens muscle loss 4
• Do not prescribe metformin in decompensated cirrhosis or when eGFR <30 mL/min due to lactic acidosis risk 4
• Do not discontinue metformin in compensated cirrhosis with type 2 diabetes, as this may increase mortality 4
• Do not use nutraceuticals, as evidence of effectiveness is insufficient 4