What are the management steps for non-alcoholic chronic liver disease (NASH)?

Management of Non-Alcoholic Fatty Liver Disease (NAFLD/NASH)

Lifestyle modification targeting 7-10% weight loss is the cornerstone of NAFLD treatment, with pharmacotherapy reserved exclusively for biopsy-proven NASH with significant fibrosis (≥F2). 1, 2

Risk Stratification Determines Treatment Intensity

Your first step is determining disease severity, as this dictates whether lifestyle modification alone suffices or pharmacotherapy is warranted:

• Patients without NASH or fibrosis (F0-F1): Lifestyle modification only—no liver-directed pharmacotherapy 1, 2
• Patients with biopsy-proven NASH and significant fibrosis (≥F2): Intensive lifestyle modification PLUS pharmacotherapy 1, 3, 2
• Patients with cirrhosis: Refer for liver transplantation evaluation when first major complication occurs or hepatic dysfunction develops 3

The evidence is unequivocal: patients with simple steatosis have excellent prognosis and should not receive pharmacotherapy for their liver condition. 1

Lifestyle Modifications: The Non-Negotiable Foundation

Weight Loss Targets

Achieve 7-10% total body weight reduction to improve liver histology, inflammation, and potentially reverse fibrosis. 1, 3, 2

The dose-response relationship is clear from prospective trials with paired liver biopsies:

• 5% weight loss: Improves hepatic steatosis 1
• 7% weight loss: Improves NAS (NAFLD Activity Score) 1
• ≥10% weight loss: Achieves near-universal NASH resolution and fibrosis improvement by at least one stage 4

Critical pitfall: In patients with cirrhosis, weight loss must be gradual (<1 kg/week), as rapid weight loss can precipitate acute hepatic failure. 3

Caloric Restriction Strategy

Implement a 500-1000 kcal/day energy deficit to induce weight loss of 500-1000 g/week. 1, 5 This caloric restriction drives weight loss and reduction of liver fat independent of macronutrient composition. 1

Dietary Pattern: Mediterranean Diet

Follow a Mediterranean diet pattern—this is the most evidence-based dietary approach and can reduce liver fat even without weight loss. 1, 3, 2, 4

Specific components include:

• Reduced carbohydrates (40% of calories vs. 50-60% in typical low-fat diet), especially avoiding processed foods and fructose-containing beverages 1, 5, 4
• Increased monounsaturated and omega-3 fatty acids (40% of calories as fat vs. up to 30% in typical low-fat diet) 4
• Emphasis on: vegetables, fruits, whole grains, legumes, nuts, and olive oil as principal fat source 3, 2
• Moderate fish consumption, minimal red meat 3

Alcohol restriction: Keep below risk threshold (30 g/day for men, 20 g/day for women); total abstinence is mandatory in NASH-cirrhosis to reduce HCC risk 1

Coffee consumption has no liver-related limitations and may be protective. 1

Exercise Prescription

Prescribe 150-200 minutes/week of moderate-intensity aerobic exercise (brisk walking, stationary cycling) in 3-5 sessions. 1, 2

The evidence shows a dose-effect relationship: vigorous exercise (≥6 METs) provides greater benefit than moderate exercise for NASH and fibrosis improvement. 1 However, any increase in physical activity over previous levels is better than continuing inactivity. 1

Resistance training is also effective and promotes musculoskeletal fitness with beneficial effects on metabolic risk factors. 1

Combined diet and exercise is superior to either intervention alone in improving liver enzymes and HOMA-IR. 6

Pharmacological Treatment: Only for Biopsy-Proven NASH with Fibrosis

No drug has been approved by regulatory agencies for NASH—all pharmacotherapy is off-label. 1, 3 Therefore, pharmacological treatment should be limited to patients with biopsy-proven NASH and significant fibrosis (≥F2). 1, 3, 2

For Non-Diabetic Patients with NASH and Fibrosis (≥F2)

Vitamin E 800 IU daily is recommended for non-diabetic patients with biopsy-confirmed NASH without cirrhosis. 3, 2

For Diabetic Patients with NASH and Fibrosis (≥F2)

Pioglitazone 30 mg daily is first-line pharmacotherapy for diabetic patients with biopsy-confirmed NASH, with or without cirrhosis. 3, 2

GLP-1 receptor agonists (e.g., semaglutide) should be considered for diabetic NASH patients, particularly those with significant fibrosis (≥F2). 2

Important caveat: Metformin has no significant effect on liver histology despite metabolic benefits and should not be used as specific treatment for NAFLD. 3

Management of Metabolic Comorbidities

Statins are safe and should be used to treat dyslipidemia in NAFLD/NASH patients—they have beneficial pleiotropic properties. 3, 2

For diabetes management, prioritize medications with dual benefits:

• GLP-1 receptor agonists 2
• SGLT2 inhibitors 2
• Pioglitazone (treats both diabetes and NASH simultaneously) 3, 2

Metformin is appropriate as first-line agent when liver function is not severely impaired and renal function is preserved (eGFR >45 mL/min/1.73 m²). 3

Special Considerations for Cirrhosis

Nutritional Management in Decompensated Disease

Provide protein intake of 1.2-1.5 g/kg daily with branched-chain amino acids from chicken, fish, eggs, nuts, lentils, or soy to prevent sarcopenia. 1, 3

Patients should:

• Eat frequent small meals, avoiding gaps >4-6 hours between meals 1, 3
• Consume a bedtime snack containing protein and at least 50 g of complex carbohydrates 1, 3
• Limit sodium restriction to no less than 60 mmol/day in patients with ascites 3

Micronutrient Supplementation

• Vitamin D: Supplement to achieve levels >30 ng/mL, as deficiency correlates with disease severity 3
• Vitamin K: Consider in patients with jaundice or cholestatic features 3
• Water-soluble multivitamins: Reasonable in decompensated patients due to diminished hepatic storage capacity 3

Surveillance and Monitoring

For Patients with Cirrhosis

Perform right upper quadrant ultrasound with or without serum AFP every 6 months for HCC surveillance—this is required lifelong even after metabolic improvement. 3

Perform esophagogastroduodenoscopy (EGD) screening for esophageal varices in patients with known cirrhosis. 3

Evaluate bone densitometry in patients with previous fragility fractures, corticosteroid treatment, or before liver transplantation. 3

For Patients Without Cirrhosis

Follow up with liver enzyme tests every 3-6 months to assess response to lifestyle interventions. 5

Consider repeat non-invasive fibrosis assessment after 1 year. 5

When to Refer to Hepatology

Patients with FIB-4 >2.67, liver stiffness >12.0 kPa by transient elastography, or biopsy-proven clinically significant fibrosis should be managed by a hepatologist-coordinated multidisciplinary team. 2

High-risk NASH patients (F2-F3 fibrosis) have approximately 10% risk of progression and require hepatologist coordination. 2

Critical Pitfalls to Avoid

• Never pursue rapid weight loss in obese NAFLD patients with advanced disease—this can precipitate acute hepatic failure 3
• Do not use metformin as specific treatment for NAFLD histology—it lacks efficacy on liver pathology 1, 3
• Avoid aggressive glycemic targets (A1C <7%) in advanced liver disease due to substantially elevated hypoglycemia risk from impaired gluconeogenesis and decreased drug clearance 3
• Do not prescribe pharmacotherapy for patients without NASH or fibrosis—they have excellent prognosis with lifestyle modification alone 1, 2