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

Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD)

Lifestyle modification targeting 7-10% total body weight loss through caloric restriction and regular exercise is the only proven first-line treatment for all NAFLD patients, with pharmacotherapy reserved exclusively for biopsy-proven NASH with significant fibrosis (≥F2). 1

Treatment Algorithm Based on Disease Severity

For Patients with Simple Steatosis or Mild NAFLD (No NASH, No Fibrosis)

Do not prescribe any pharmacologic therapy—these patients require only lifestyle modification. 2, 1 Patients without steatohepatitis or fibrosis have excellent prognosis from a liver standpoint, and cardiovascular disease—not liver disease—is their primary mortality risk. 2, 1

• Counsel on healthy diet and physical activity only 2
• Monitor annually for type 2 diabetes using HbA1c, hypertension, and dyslipidemia 2
• Reassess alcohol consumption regularly 2

For Patients with Biopsy-Proven NASH and Significant Fibrosis (≥F2)

Implement aggressive lifestyle modification PLUS consider pharmacotherapy. 1 This includes patients with bridging fibrosis, cirrhosis, or early-stage NASH with increased risk factors (age >50 years, diabetes, metabolic syndrome, elevated ALT). 2

Weight Loss Targets and Expected Outcomes

The magnitude of weight loss directly correlates with histological improvement: 1

• ≥5% weight loss: Decreases hepatic steatosis in 65% of patients 1
• ≥7% weight loss: Achieves NASH resolution in 64% of patients 2, 1
• ≥10% weight loss: Results in fibrosis regression in 45% and stabilization in the remaining 55% 1

Critical caveat: Avoid rapid weight loss exceeding 1 kg per week—this can worsen liver disease or precipitate acute hepatic failure. 1, 3

Dietary Interventions

Adopt a Mediterranean diet pattern as the primary dietary approach, which reduces liver fat even without weight loss. 1, 4 This emphasizes vegetables, fruits, whole grains, legumes, olive oil as the principal fat source, moderate fish consumption, and minimal red meat. 3

• Create a 500-1000 kcal daily energy deficit 1, 4
• Completely eliminate fructose-containing beverages and sugar-sweetened drinks 1
• Reduce refined carbohydrates and processed foods 2
• Replace saturated fats with monounsaturated and polyunsaturated fats, especially omega-3 fatty acids 4

The macronutrient composition matters less than sustained weight loss over months to years, but the Mediterranean pattern has the strongest evidence base. 2

Exercise Prescription

Prescribe 150-300 minutes per week of moderate-intensity aerobic exercise OR 75-150 minutes per week of vigorous-intensity exercise. 1, 4 However, the evidence shows a critical distinction:

• Moderate-intensity exercise (brisk walking, stationary cycling) alone does NOT improve NASH severity or fibrosis 2
• Vigorous-intensity exercise (≥6 METs, such as running) is required for benefit on fibrosis 2, 3
• Doubling the vigorous activity recommendations provides additional fibrosis benefit 2
• Include resistance training as it promotes musculoskeletal fitness and affects metabolic risk factors 2, 1

Any increase in physical activity is better than continuing inactivity, but set realistic expectations about intensity requirements. 2

Pharmacologic Treatment Options (Only for Biopsy-Proven NASH with Fibrosis ≥F2)

No drug has been approved by regulatory agencies specifically for NAFLD—all current options are off-label. 2, 3

Vitamin E

• 800 IU daily in non-diabetic, non-cirrhotic patients with biopsy-confirmed NASH 1, 3
• This is the most established option for appropriate candidates 5

Pioglitazone

• 30 mg daily improves all histological features except fibrosis and achieves NASH resolution more often than placebo 1
• Can be used in patients with or without diabetes 3
• Treats both diabetes and NASH simultaneously in appropriate candidates 3

GLP-1 Receptor Agonists

• For patients with type 2 diabetes and NASH, liraglutide or semaglutide demonstrate NASH resolution in 39% versus 9% with placebo 1
• These agents promote weight loss and reduce cardiovascular risk 2

Metformin

Do not use metformin as specific NAFLD treatment—it has weak effect on liver fat and scarce evidence for histological efficacy. 2, 1, 3 While it may be used as first-line agent for diabetes management when liver and renal function permit (eGFR >45 mL/min/1.73 m²), it should not be prescribed to treat the liver disease itself. 3

Management of Metabolic Comorbidities

Aggressively treat all components of metabolic syndrome, as cardiovascular disease is the primary cause of mortality in NAFLD patients without cirrhosis. 1

Dyslipidemia

Statins are safe and should be used to treat dyslipidemia despite liver disease—they reduce hepatocellular carcinoma risk by 37% and hepatic decompensation by 46%. 1 Hepatotoxicity is very rare and benefits significantly outweigh risks, even in patients with compensated cirrhosis. 2, 4

Hypertension

Manage according to standard guidelines (NICE guidelines in UK settings). 2

Diabetes

Use glucose-lowering agents that promote weight loss and reduce cardiovascular risk. 2 GLP-1 agonists are preferred in patients with NASH. 1

Alcohol Consumption

• Keep alcohol strictly below risk threshold (30 g for men, 20 g for women) in pre-cirrhotic NAFLD 2
• Total abstinence is mandatory in NASH-cirrhosis to reduce HCC risk 2, 1
• Alcohol consumption accelerates disease progression even in pre-cirrhotic stages 2

Bariatric Surgery

Consider bariatric surgery for patients with BMI ≥35 kg/m² who fail lifestyle modifications, though effectiveness and safety have not been established in cirrhosis. 1, 4 Referral should be made for patients meeting national eligibility criteria. 2

Medications to Avoid

Discontinue medications that worsen steatosis: corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid. 1, 4

Monitoring Strategy

For All NAFLD Patients

• Use non-invasive tests (NAFLD Fibrosis Score, FIB-4) to identify patients at risk for advanced fibrosis 1
• Monitor liver enzymes (ALT, AST) periodically 1
• Screen annually for type 2 diabetes, hypertension, and dyslipidemia 2

For Patients with Cirrhosis

• Right upper quadrant ultrasound every 6 months for HCC screening 1, 3
• EGD screening for esophageal varices 1, 3
• Transplant referral when appropriate 1

When to Refer to Secondary Care

Patients with cirrhosis or significant-advanced fibrosis should continue management in secondary care with multidisciplinary teams having expertise in clinical hepatology, diabetes management, cardiovascular risk factors, and lifestyle intervention. 2, 4

Critical Pitfalls to Avoid

1. Never pursue rapid weight loss exceeding 1 kg per week in obese NAFLD patients—this can precipitate acute hepatic failure 1, 3

2. Do not prescribe pharmacotherapy for mild NAFLD without biopsy-proven NASH and significant fibrosis 1, 3

3. Do not withhold statins due to unfounded hepatotoxicity concerns—they are safe and beneficial 2, 4

4. Do not use metformin as specific NAFLD treatment despite its metabolic benefits 2, 1, 3

5. Ensure sustainability of lifestyle interventions—choose dietary and exercise regimens that can be maintained long-term rather than extreme short-term approaches 4