What are the treatment options for non-alcoholic fatty liver disease (NAFLD)?

Treatment of Non-Alcoholic Fatty Liver Disease

First-Line Treatment: Lifestyle Modification for All Patients

All patients with NAFLD should undergo structured lifestyle intervention targeting 7-10% weight loss through caloric restriction and regular physical activity, as this is the only intervention proven to improve liver histology including steatosis, inflammation, and fibrosis. 1, 2

Weight Loss Targets and Approach

• Target 7-10% total body weight loss to achieve improvement in liver inflammation, hepatocyte ballooning, and fibrosis 1, 3
• Weight loss of 3-5% improves steatosis alone, but greater loss (7-10%) is required for histological improvement of necroinflammation 1, 2
• Critical safety consideration: Limit weight loss to less than 1 kg per week (500-1000g weekly), as rapid weight loss can precipitate acute hepatic failure, particularly in patients with advanced disease 1, 4, 2
• Achieve this through a daily caloric deficit of 500-1000 kcal 1, 2

Dietary Recommendations

Implement a Mediterranean diet pattern emphasizing vegetables, fruits, whole grains, legumes, fish, and olive oil as the principal fat source, with minimal red meat and processed foods. 1, 3, 2

• The Mediterranean diet reduces liver fat even without weight loss 1, 3
• Strictly avoid fructose-containing beverages and foods with added sugars, as high fructose intake is independently associated with NAFLD development 1, 2
• Replace saturated fats with monounsaturated and polyunsaturated fats, particularly omega-3 fatty acids 3
• Alcohol restriction is mandatory: Keep intake below 30g/day for men and 20g/day for women; complete abstinence is required in NASH-cirrhosis to reduce HCC risk 1, 2

Exercise Prescription

Prescribe vigorous-intensity exercise (≥6 METs) for at least 150 minutes per week, as moderate-intensity exercise does not improve NASH severity or fibrosis. 4, 2

• Alternative: 150-300 minutes of moderate-intensity aerobic exercise or 75-150 minutes of vigorous-intensity exercise weekly 3, 2
• Include resistance training as complement to aerobic exercise 1, 3
• Exercise alone can reduce hepatic steatosis independent of weight loss by improving insulin sensitivity 1, 2

Risk Stratification for Treatment Intensity

Low-Risk Patients (No NASH or Fibrosis)

Patients without steatohepatitis or fibrosis should receive only lifestyle counseling and no pharmacotherapy for their liver condition, as they have excellent prognosis from a liver standpoint. 1, 2

• Focus solely on lifestyle modifications without medication for liver disease 1, 2
• Manage cardiovascular risk factors including dyslipidemia with statins, which are safe in NAFLD 1, 3, 2

High-Risk Patients (NASH with Fibrosis)

Pharmacotherapy should be reserved exclusively for patients with biopsy-proven NASH and significant fibrosis (≥F2), as this population has risk of progression to cirrhosis and liver-related complications. 1, 4, 2

Pharmacological Treatment Options (Off-Label)

Vitamin E

Consider vitamin E 800 IU daily for patients with biopsy-confirmed NASH without diabetes or cirrhosis. 1, 4, 2

• Improves liver histology in non-diabetic patients with NASH 1, 2
• Should not be used in patients with diabetes or established cirrhosis 2

Pioglitazone

Consider pioglitazone 30 mg daily for patients with biopsy-confirmed NASH without cirrhosis, with or without diabetes. 1, 4, 2

• Improves all histological features except fibrosis and achieves NASH resolution more often than placebo 1
• Side effects include weight gain, bone fractures in women, and rarely congestive heart failure 1
• Can treat both diabetes and NASH simultaneously in appropriate candidates 4

GLP-1 Receptor Agonists

Consider liraglutide or semaglutide for patients with biopsy-proven NASH, as these agents improve liver histology and may reduce HCC risk. 2

• Liraglutide 1.8 mg daily achieved NASH resolution in 39% vs 9% placebo in a 48-week trial 1

What NOT to Use

Metformin has no significant effect on liver histology and is not recommended as specific treatment for liver disease in adults with NASH. 1, 4, 2

• Use metformin as first-line agent for diabetes management when liver and renal function permit (eGFR >45 mL/min/1.73m²), but not for treating NASH itself 4

Management of Metabolic Comorbidities

Cardiovascular Risk Management

Statins should not be withheld from patients with NAFLD, including those with compensated cirrhosis, as hepatotoxicity is very rare and cardiovascular benefits significantly outweigh risks. 1, 2

• Statins may reduce HCC risk by 37% 2
• Treat hypertension according to standard guidelines 1
• Patients with T2DM or QRISK-3 >10% should receive statin therapy 1

Diabetes Management

In patients with NAFLD and type 2 diabetes, prioritize glucose-lowering agents that promote weight loss and reduce cardiovascular risk (GLP-1 agonists, SGLT2 inhibitors). 1

Special Considerations for Advanced Disease and Cirrhosis

Nutritional Support in Decompensated Disease

Provide protein intake of 1.2-1.5 g/kg daily with branched-chain amino acids from sources like chicken, fish, eggs, nuts, lentils, or soy to prevent sarcopenia. 4, 2

• Eat frequent small meals, avoiding gaps longer than 4-6 hours between meals 4, 2
• Mandatory bedtime snack containing protein and at least 50g complex carbohydrates to prevent overnight catabolism 4, 2
• Sodium restriction should not fall below 60 mmol/day in patients with ascites 4

Micronutrient Repletion

• Supplement vitamin D to achieve levels above 30 ng/mL, as deficiency correlates with disease severity 4, 2
• Consider vitamin K supplementation in patients with jaundice or cholestatic features 4, 2
• Water-soluble multivitamin supplementation is reasonable in decompensated patients 4, 2

Monitoring Requirements

Perform right upper quadrant ultrasound with or without serum AFP every 6 months in patients with cirrhosis for HCC surveillance. 4, 3, 2

• Lifelong HCC surveillance is required even after metabolic improvement 4, 2
• Perform esophagogastroduodenoscopy (EGD) screening for esophageal varices in patients with known cirrhosis 4, 3, 2

Liver Transplantation

Refer patients with liver failure from NAFLD for transplantation evaluation when the first major complication of cirrhosis occurs or when evidence of hepatic dysfunction develops. 4, 2

• Patients with hepatorenal syndrome type I require expedited transplant referral 4

Critical Pitfalls to Avoid

• Never pursue rapid weight loss (>1 kg/week) in obese NAFLD patients with advanced disease—this can precipitate acute hepatic failure 1, 4, 2
• Do not use metformin as specific treatment for NAFLD histology—it has no significant effect on liver histology despite metabolic benefits 1, 4
• No pharmacotherapy has been approved by regulatory agencies specifically for NAFLD treatment—all current options are off-label 1, 4, 3
• Avoid aggressive glycemic targets (A1C <7%) in advanced liver disease due to elevated hypoglycemia risk from impaired gluconeogenesis 4

Multidisciplinary Management

Management of patients with advanced NAFLD in secondary care should be by multidisciplinary teams with expertise in clinical hepatology, diabetes management, cardiovascular risk factors, and lifestyle intervention. 1