What is the treatment for an adult patient with severe hepatic steatosis and a history of metabolic disorders?

Treatment for Severe Hepatic Steatosis

For adults with severe hepatic steatosis and metabolic disorders, achieve sustained weight loss of at least 10% through dietary modification and structured exercise, as this is the only intervention with Level 1 evidence for improving liver injury, inflammation, and fibrosis. 1

Lifestyle Interventions: The Foundation of Treatment

Weight Loss Targets

• Target ≥10% sustained body weight reduction to improve fibrosis in severe steatosis 1
• Weight loss of 5% reduces liver fat 1
• Weight loss of 7-10% improves liver inflammation 1
• Weight loss >10% is required for fibrosis improvement 1

Dietary Modifications

Adopt a Mediterranean dietary pattern including vegetables, fruits, unsweetened high-fiber cereals, nuts, fish or white meat, and olive oil 1

• Eliminate all sugar-sweetened beverages completely 1
• Limit ultra-processed foods rich in sugars and saturated fat 1
• Increase unprocessed/minimally processed foods 1
• Coffee consumption (>3 cups daily) has been associated with improvements in liver damage and reduced liver-related clinical outcomes 1, 2

Exercise Prescription

Prescribe at least 150 minutes per week of moderate-intensity exercise or 75 minutes per week of vigorous-intensity activity 1, 2

• Physical activity reduces steatosis even without significant weight loss 1, 2
• High-intensity interval training (HIIT) combined with dietary advice significantly decreased cortisol levels in MASLD patients 3
• Aerobic exercise combined with dietary advice was most effective for reducing hepatic steatosis (CAP values) 3

Pharmacological Therapy

MASH-Targeted Therapy

If approved locally, consider resmetirom for non-cirrhotic patients with significant liver fibrosis (stage ≥2), as it demonstrated histological efficacy on steatohepatitis and fibrosis in phase III trials with acceptable safety 1, 2, 4

• Resmetirom is conditionally FDA-approved for adults with MASH and moderate to advanced fibrosis 4
• No MASH-targeted pharmacotherapy can currently be recommended for cirrhotic patients 1
• Vitamin E cannot be recommended despite prior use, given lack of robust demonstration of histological efficacy from large phase III trials and potential long-term risks 1

Metabolic Comorbidity Management

Use GLP-1 receptor agonists (semaglutide, liraglutide) for their approved indications (type 2 diabetes, obesity) as they improve cardiometabolic outcomes and are safe in MASH, including compensated cirrhosis 2, 4

• Semaglutide is conditionally FDA-approved for adults with MASH and moderate to advanced fibrosis 4
• GLP-1 receptor agonists can be used in Child-Pugh class A cirrhosis 1, 5
• SGLT2 inhibitors can be used in Child-Pugh class A and B cirrhosis 1, 5

Statins are safe and should be used for dyslipidemia according to cardiovascular risk guidelines to reduce cardiovascular events 1, 2

• Statins can be used in chronic liver disease, including compensated cirrhosis 1
• Do not withhold statins due to liver concerns 6

Medications to Avoid or Use Cautiously

• Metformin can be used in compensated cirrhosis with preserved renal function but should not be used in decompensated cirrhosis, especially with concomitant renal impairment, due to lactic acidosis risk 1, 5
• Sulfonylureas should be avoided in hepatic decompensation due to hypoglycemia risk 1, 5
• Avoid medications that worsen steatosis: corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, valproic acid 2

Bariatric/Metabolic Surgery

Consider bariatric surgery for patients with severe steatosis, clinically significant fibrosis, and class II or III obesity with comorbidities 1, 2

• Roux-en-Y gastric bypass or sleeve gastrectomy demonstrated histological resolution of MASH without worsening of fibrosis in 55% at 1-year follow-up versus 15% with lifestyle modification alone 1
• Fibrosis improvement by >1 stage was achieved in 37-39% after bariatric surgery versus 23% after lifestyle modification 1
• Approximately 6% of participants had severe adverse events related to surgery 1
• Endoscopic bariatric therapies require further validation and cannot currently be recommended 1

Special Considerations for Cirrhosis

Compensated Cirrhosis

Moderate weight reduction can be pursued with emphasis on high protein intake (1.2-1.5 g/kg/day) and physical activity to maintain muscle mass and reduce sarcopenia risk 1

Decompensated Cirrhosis or Sarcopenia

Provide a high-protein diet (1.2-1.5 g/kg/day) and late-evening snack 1

• Supply at least 35 kcal/kg of body weight/day 1, 5
• Dietary and lifestyle recommendations must be adapted to disease severity, nutritional status, and presence of sarcopenia/sarcopenic obesity 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, 2

• Screen and manage diabetes, dyslipidemia, and hypertension aggressively 2
• Optimize glycemic control in diabetic patients to reduce liver fat 2
• Cardiovascular disease is the leading cause of death in MASLD patients, followed by extrahepatic cancers and liver-related complications 4

Monitoring and Risk Stratification

Stratify patients using FIB-4 score, liver stiffness measurement (LSM), or liver biopsy 2

• High-risk patients have FIB-4 >2.67, LSM >12.0 kPa, or significant fibrosis on biopsy 2
• Patients with advanced fibrosis (F3) require hepatocellular carcinoma surveillance with imaging every 6 months 2
• Non-invasive tests may be repeatedly used to assess fibrosis progression but provide limited information about treatment response 1

Common Pitfalls to Avoid

• Do not delay dietary referral until advanced disease develops—early intervention with dietary modification prevents progression 6
• Do not prescribe pharmacotherapy for simple steatosis—lifestyle modification is the sole recommended treatment for early-stage disease 6
• Do not withhold statins due to liver concerns—they are safe and reduce cardiovascular mortality 6
• Do not use nutraceuticals—insufficient evidence of effectiveness and safety 1