Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD)
Lifestyle modification with weight loss and dietary changes is the cornerstone of NAFLD treatment, with pharmacotherapy reserved exclusively for patients with biopsy-proven NASH and significant fibrosis. 1, 2
Risk Stratification Determines Treatment Pathway
Before initiating treatment, you must stratify patients by fibrosis risk, as this fundamentally changes management:
- Low-risk patients (FIB-4 <1.3, liver stiffness <8.0 kPa, or F0-F1 fibrosis on biopsy) should receive lifestyle interventions only—no pharmacotherapy 2, 3
- Intermediate/high-risk patients (FIB-4 >1.3, liver stiffness >8.0 kPa, or ≥F2 fibrosis) require lifestyle interventions plus consideration of pharmacologic therapy and hepatology referral 2, 3
- Patients with compensated cirrhosis need HCC surveillance every 6 months with ultrasound ± AFP and variceal screening with EGD 4, 1
Lifestyle Interventions: The Foundation for All Patients
Weight Loss Targets and Approach
Achieve 7-10% total body weight reduction to improve liver histology, inflammation, and potentially reverse fibrosis. 4, 1, 2 The dose-response relationship is clear: 3-5% weight loss improves steatosis alone, while 5-10% is required to reduce hepatic inflammation and potentially improve fibrosis 4, 5.
Critical pitfall: Weight loss must be gradual at a maximum rate of 0.5-1 kg per week 1, 3. Rapid weight loss in patients with advanced disease can precipitate acute hepatic failure 1. This is especially dangerous in patients with compensated cirrhosis 1.
Implement a hypocaloric diet with 500-1000 kcal daily energy deficit to achieve this target rate 2, 3.
Dietary Pattern Recommendations
Follow a Mediterranean diet pattern, which is the most strongly recommended dietary intervention 4, 1, 2. This emphasizes:
- Vegetables, fruits, whole grains, legumes, nuts, and seeds as primary foods 4
- Olive oil as the principal fat source 1
- Moderate fish consumption with minimal red meat 1
- Replace saturated fats with PUFAs (especially omega-3) and MUFAs 4
Completely avoid fructose-containing beverages and foods, as fructose directly worsens steatosis 4, 2, 3. Replace processed foods, fast food, commercial bakery goods, and sweets with unprocessed high-fiber foods 4.
Limit alcohol consumption to no more than 1 drink/day for women or 2 drinks/day for men, or consider complete abstinence 4, 3.
Exercise Prescription
Prescribe 150-300 minutes per week of moderate-intensity aerobic exercise or 75-150 minutes per week of vigorous-intensity exercise. 2 Notably, vigorous-intensity exercise (≥6 METs) for at least 150 minutes per week is superior to moderate-intensity exercise for improving NASH severity and fibrosis 1.
Combined diet and exercise is superior to either intervention alone for improving liver enzymes and insulin resistance 5.
Pharmacological Treatment: Only for Biopsy-Proven NASH with Fibrosis
Pharmacological treatments should be strictly limited to patients with biopsy-proven NASH and fibrosis (≥F2), as those without steatohepatitis or fibrosis have excellent prognosis from a liver standpoint. 1, 2, 3
First-Line Pharmacotherapy Options
For patients meeting criteria for pharmacotherapy:
Vitamin E (800 IU daily) can be considered in patients with biopsy-confirmed NASH without diabetes or cirrhosis 4, 1. However, caution is warranted in patients with prostate cancer 6.
Pioglitazone (30 mg daily) can be considered in patients with biopsy-confirmed NASH without cirrhosis, with or without diabetes 4, 1. Pioglitazone improves liver histology including fibrosis and simultaneously treats diabetes in appropriate candidates 1, 7.
Important caveat: No pharmacotherapy has been approved by regulatory agencies specifically for NAFLD treatment—all current options are off-label 1. Fewer than 50% of patients with NASH respond to current therapies 4.
GLP-1 Receptor Agonists for Patients with Diabetes
For patients with type 2 diabetes and NASH/fibrosis, GLP-1 receptor agonists (e.g., liraglutide, semaglutide) are preferred, demonstrating NASH resolution in 39% versus 9% with placebo while promoting weight loss 2. These agents treat both diabetes and NASH simultaneously 3.
Management of Metabolic Comorbidities
Aggressively treat all components of metabolic syndrome, as cardiovascular disease—not liver disease—is the primary cause of mortality in NAFLD patients without cirrhosis. 2, 3
Specific Medication Guidance
- Statins are safe, effective, and strongly recommended for patients requiring lipid management, reducing hepatocellular carcinoma risk by 37% and hepatic decompensation by 46% 2, 3
- Metformin is NOT recommended as specific treatment for NAFLD, as it has no significant effect on liver histology despite metabolic benefits 1, 3. However, it remains safe and appropriate for diabetes management when liver function is not severely impaired and eGFR >45 mL/min/1.73 m² 1
- Avoid sulfonylureas and insulin if possible, as they may increase HCC risk 3
Monitoring Strategy
- Low-risk patients: Annual follow-up with repeated non-invasive fibrosis assessment 2
- Intermediate/high-risk patients: Follow-up every 6 months with liver function tests and non-invasive fibrosis markers 2
- Cirrhotic patients: HCC surveillance every 6 months with right upper quadrant ultrasound ± AFP, plus EGD screening for esophageal varices 4, 1, 2
Liver biopsy remains the gold standard for characterizing liver histology but should be reserved for patients at high risk for NASH and advanced fibrosis, including those with diabetes and/or metabolic syndrome, or findings concerning for cirrhosis 4, 3.
Bariatric Surgery Consideration
Consider bariatric surgery for patients with class II-III obesity (BMI ≥35 kg/m²) who fail to achieve adequate weight loss through lifestyle modifications, as significant weight loss from bariatric surgery can improve liver fat and inflammation 2, 6.
Critical Medications to Discontinue
Discontinue medications that may worsen steatosis: corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid 4.