What is the recommended treatment for non-alcoholic fatty liver disease (NAFLD)?

Treatment of Non-Alcoholic Fatty Liver Disease

Primary Treatment Approach

All patients with NAFLD should undergo structured lifestyle intervention as the foundation of treatment, targeting 7-10% weight loss through Mediterranean diet and 150-300 minutes weekly of moderate-to-vigorous exercise, with pharmacotherapy reserved exclusively for patients with biopsy-proven NASH and significant fibrosis. 1, 2, 3

Risk Stratification Algorithm

Step 1: Calculate FIB-4 Score

• FIB-4 <1.3: Low risk—lifestyle intervention only, no hepatology referral needed 2, 3
• FIB-4 1.3-2.67: Intermediate risk—proceed to liver stiffness measurement 2
• FIB-4 >2.67: High risk—immediate hepatology referral 2, 3

Step 2: Liver Stiffness Measurement (for intermediate-risk patients)

• <8.0 kPa: Confirms low risk—lifestyle intervention only 2
• 8.0-12.0 kPa: Remains intermediate—consider hepatology consultation 2
• >12.0 kPa: Clinically significant fibrosis—hepatology referral mandatory 2

Lifestyle Intervention Protocol

Weight Loss Targets

• Target 7-10% total body weight reduction to achieve histological improvement in steatohepatitis and fibrosis 1, 2, 3
• Create a 500-1000 kcal/day deficit to achieve gradual weight loss of 0.5-1 kg per week 3
• Critical warning: Weight loss must not exceed 1 kg per week, as rapid weight loss can precipitate acute liver failure, especially in patients with advanced disease 4, 3
• Weight loss of 3-5% improves steatosis alone, but 7-10% is required to improve inflammation and fibrosis 3

Dietary Recommendations

• Adopt Mediterranean diet pattern with daily consumption of vegetables, fresh fruits, fiber-rich whole grains, legumes, nuts, fish, and olive oil as the primary fat source 1, 2, 3
• Eliminate processed foods and beverages containing added fructose 1, 3
• Minimize refined carbohydrates, simple sugars, and red/processed meat 1, 3
• Referral to weight management services should be considered if weight loss goals are not achieved 1

Exercise Prescription

• Prescribe 150-300 minutes per week of moderate-intensity exercise (3-6 METs) or 75-150 minutes of vigorous-intensity exercise (≥6 METs) 3
• Vigorous exercise (≥6 METs) is superior to moderate exercise for improving NASH severity and fibrosis 4, 3
• Both aerobic exercise and resistance training effectively reduce liver fat, even without significant weight loss 1, 5
• Exercise improves quality of life, cardiorespiratory fitness, and weight beyond liver-specific benefits 5

Alcohol Consumption

• Patients with NAFLD and cirrhosis must abstain completely from alcohol 1
• Patients with pre-cirrhotic NAFLD should minimize or abstain from alcohol, as consumption accelerates disease progression 1
• Daily alcohol intake of 9-20 g doubles the risk of adverse liver outcomes 3

Pharmacological Treatment (Biopsy-Proven NASH with Fibrosis Only)

Patient Selection Criteria

Pharmacotherapy should be limited to patients with biopsy-proven NASH and fibrosis—those without steatohepatitis or fibrosis have excellent prognosis and require lifestyle intervention only 4, 3

First-Line Pharmacotherapy for Diabetic Patients

• GLP-1 receptor agonists (liraglutide or semaglutide) are first-line glucose-lowering agents for diabetic patients with MASLD, achieving 39% NASH resolution versus 9% placebo 2, 3
• Pioglitazone 30 mg daily is an alternative for patients who cannot tolerate or afford GLP-1 receptor agonists 2

Pharmacotherapy for Non-Diabetic Patients

• Vitamin E 800 IU daily for patients with biopsy-proven NASH without diabetes or cirrhosis improves liver histology 1, 4, 3
• Pioglitazone 30 mg daily can be used in patients with biopsy-proven NASH without cirrhosis, with or without diabetes 1, 4, 3

Critical Limitations

• No pharmacotherapy has been approved by regulatory agencies specifically for NAFLD—all current options are off-label 4
• Metformin improves insulin sensitivity but has no significant effect on liver histology and is not recommended as specific treatment for NASH 4, 3

Management of Metabolic Comorbidities

Cardiovascular Risk Management

• Statins should be used for dyslipidemia management in all NAFLD patients, including those with compensated cirrhosis, as hepatotoxicity is very rare and benefits significantly outweigh risks 1, 2, 3
• Statins are associated with 37% reduction in hepatocellular carcinoma risk and 46% reduction in hepatic decompensation 2, 3
• Patients with hypertension should be managed according to standard guidelines 1

Diabetes Management

• Metformin is first-line for diabetes management when liver function is not severely impaired and eGFR >45 mL/min/1.73 m² 4
• Avoid aggressive glycemic targets (A1C <7%) in advanced liver disease due to elevated hypoglycemia risk from impaired gluconeogenesis 4

Bariatric Surgery Consideration

Referral for bariatric surgery should be considered in NAFLD patients with obesity who meet national eligibility criteria, particularly high-risk patients who have not achieved weight loss goals through lifestyle intervention 1, 3

Multidisciplinary Management for Advanced Disease

Hepatology Referral Criteria

• Patients with cirrhosis or significant-advanced fibrosis require ongoing secondary care management by multidisciplinary teams with expertise in hepatology, diabetes management, cardiovascular risk, and lifestyle intervention 1, 3
• Patients with decompensated liver disease should be considered for transplant assessment 1, 3

Hepatocellular Carcinoma Surveillance

• Perform abdominal ultrasound every 6 months (with or without serum AFP) for HCC screening in patients with advanced fibrosis (F3) or cirrhosis 2, 3
• Lifelong HCC surveillance is required even after metabolic improvement 4, 3

Variceal Screening

• Perform esophagogastroduodenoscopy to screen for esophageal varices in patients with known cirrhosis 4, 3

Nutritional Support in Decompensated Disease

• Provide 1.2-1.5 g/kg daily protein intake with branched-chain amino acids from chicken, fish, eggs, nuts, legumes, or soy to prevent sarcopenia 4, 3
• Patients should eat frequent small meals, avoiding gaps longer than 4-6 hours between meals 4, 3
• A bedtime snack containing protein and at least 50 g of complex carbohydrates is essential to prevent overnight catabolism 4, 3
• Supplement vitamin D to achieve levels above 30 ng/mL, as deficiency correlates with disease severity 4, 3
• Consider vitamin K supplementation in patients with jaundice or cholestatic features 4, 3
• Water-soluble multivitamin supplementation is reasonable in decompensated patients 4, 3

Critical Pitfalls to Avoid

• Never pursue rapid weight loss exceeding 1 kg per week—this can precipitate acute hepatic failure in patients with advanced disease 4, 3
• Do not withhold statins from NAFLD patients, including those with compensated cirrhosis, due to unfounded hepatotoxicity concerns 1, 2
• Do not use metformin as specific treatment for NAFLD histology—it lacks efficacy for liver-specific outcomes despite metabolic benefits 4, 3
• Do not prescribe pharmacotherapy to patients without biopsy-proven NASH and fibrosis—lifestyle intervention alone is appropriate for simple steatosis 4, 3

Patient Education and Follow-Up

• Patients should be provided with written information about NAFLD and weight management in appropriate formats and signposted to credible sources 1
• Patients with NAFLD should have regular reassessment of alcohol consumption 1
• Patients discharged to primary care require clear recommendations on triggers for re-referral to secondary care liver services 1
• Patients with NAFLD should be considered for research studies and clinical trials where available 1