What are the recent advances in the management of non‑alcoholic fatty liver disease (NAFLD) and its progressive form non‑alcoholic steatohepatitis (NASH)?

Recent Advances in NAFLD Management

Risk Stratification Now Drives Treatment Decisions

The most important recent advance is the shift from treating all NAFLD patients uniformly to stratifying by fibrosis stage, with pharmacotherapy reserved exclusively for biopsy-proven NASH with significant fibrosis (≥F2). 1, 2, 3

• Use FIB-4 score as the initial screening tool; values >2.67 indicate high risk for advanced fibrosis and mandate hepatology referral. 2, 4
• Transient elastography with liver stiffness >12.0 kPa confirms clinically significant fibrosis requiring multidisciplinary management. 2, 4
• Patients with simple steatosis (F0-F1) have excellent prognosis and should receive only lifestyle modification—no liver-directed pharmacotherapy. 2, 3

Lifestyle Modification Remains the Only Proven First-Line Therapy

• Target 7–10% total body weight loss through combined diet and exercise for all NAFLD patients, regardless of fibrosis stage. 1, 2, 3
• Weight loss of ≥7% achieves NASH resolution in approximately 64% of patients. 2
• Weight loss of ≥10% produces fibrosis regression in 45% and stabilization in the remaining 55%. 1, 2
• Critical pitfall: Avoid rapid weight loss exceeding 1 kg/week, as this can worsen portal inflammation, exacerbate fibrosis, or precipitate acute hepatic failure in severely obese patients. 1, 2, 3, 4

Mediterranean Diet as the Preferred Dietary Pattern

• Adopt a Mediterranean diet (high in vegetables, fruits, whole grains, legumes, olive oil, fish; low in red meat and processed foods) as the primary dietary approach—this reduces liver fat even without weight loss. 1, 2, 3, 4
• Create a daily caloric deficit of 500–1000 kcal (approximately 1200–1500 kcal/day for women; 1500–1800 kcal/day for men). 1, 2, 3
• Completely eliminate fructose-containing beverages and sugar-sweetened drinks. 2, 3, 4

Vigorous Exercise Provides Superior Histologic Benefit

• Prescribe 75–150 minutes per week of vigorous-intensity aerobic exercise (≥6 METs) or 150–300 minutes per week of moderate-intensity exercise. 1, 2, 3, 4
• Key advance: Vigorous-intensity exercise (e.g., running, cycling >16 km/h) is specifically required to improve NASH severity and fibrosis; moderate-intensity activity alone does not alter fibrosis. 2, 3
• Include resistance training to augment metabolic benefits and improve musculoskeletal fitness. 1, 2

Emerging Pharmacologic Options for Biopsy-Proven NASH with ≥F2 Fibrosis

GLP-1 Receptor Agonists: First-Line for Diabetic Patients

GLP-1 receptor agonists (liraglutide, semaglutide) represent the most significant recent pharmacologic advance, achieving NASH resolution in 39–59% of patients versus 9–17% with placebo while simultaneously promoting weight loss and cardiovascular protection. 2, 3, 4

• Prioritize GLP-1 agonists for all patients with type 2 diabetes and biopsy-proven NASH. 2, 3
• These agents provide dual benefits for diabetes control and NASH treatment. 3

Vitamin E and Pioglitazone: Established Off-Label Options

• Vitamin E 800 IU daily is the most established therapy for non-diabetic, non-cirrhotic patients with biopsy-proven NASH, improving steatohepatitis and overall liver histology through antioxidant effects. 2, 3
• Pioglitazone 30 mg daily improves all histologic features except fibrosis and achieves higher NASH-resolution rates than placebo; use in diabetic patients with biopsy-proven NASH. 2, 3

Investigational Agents in Late-Phase Trials

• Obeticholic acid (farnesoid X receptor agonist), lanifibranor (pan-PPAR agonist), and cenicriviroc (CCR2/CCR5 inhibitor) show promise in phase 2b/3 trials, though none are yet approved. 5, 6
• Several candidates failed in late-phase trials (elafibranor, emricasan, selonsertib), highlighting the complexity of NASH pharmacotherapy. 5, 6

Agents NOT Recommended for NAFLD Treatment

• Metformin should not be used as specific NAFLD treatment—it has minimal impact on liver fat and lacks robust histologic benefit, though it may be continued for diabetes management. 2

Aggressive Management of Metabolic Comorbidities

Cardiovascular disease, not liver disease, is the leading cause of death in NAFLD patients without cirrhosis, making metabolic comorbidity management a critical recent emphasis. 1, 2, 3, 4

Statins Are Safe and Hepatoprotective

• Statins should be prescribed to all patients with dyslipidemia—they are safe in NAFLD and reduce hepatocellular carcinoma risk by 37% and hepatic decompensation by 46%. 1, 2, 3, 4
• This represents a major shift from prior concerns about statin use in liver disease. 4

Optimize Diabetes Therapy with Liver-Friendly Agents

• Prioritize GLP-1 receptor agonists or SGLT-2 inhibitors for glycemic control in diabetic NAFLD patients. 2, 3
• Metformin reduces HCC incidence, but sulfonylureas and insulin increase HCC risk by 1.6-fold and 2.6-fold, respectively. 1

Alcohol Abstinence Is Mandatory in Advanced Disease

• In pre-cirrhotic NAFLD, limit alcohol to ≤1 drink/day for women and ≤2 drinks/day for men. 2
• Total abstinence is required in NASH-related cirrhosis to reduce hepatocellular carcinoma risk. 1, 2

Bariatric Surgery for Refractory Obesity

• Consider bariatric surgery for patients with BMI ≥35 kg/m² who fail lifestyle interventions—approximately 85% achieve histologic NASH resolution at one year post-procedure. 2, 3, 4
• Contraindication: Safety and effectiveness have not been established in patients with cirrhosis or very high BMI combined with advanced fibrosis. 2

Hepatocellular Carcinoma Surveillance in Advanced Disease

• Perform abdominal ultrasound every 6 months for HCC screening in patients with advanced fibrosis (F3) or cirrhosis. 1, 2, 4
• Esophagogastroduodenoscopy (EGD) for variceal screening is required in cirrhotic patients. 1, 2
• Refer to transplant center when clinical criteria for transplant eligibility are met. 1, 2

Monitoring Strategy by Risk Category

Low-Risk Patients (FIB-4 <1.3, LSM <8.0 kPa)

• Monitor annually with repeated FIB-4 and liver stiffness measurement. 4
• Periodic monitoring of serum transaminases (ALT, AST). 1, 2

High-Risk Patients (FIB-4 >1.3, LSM >8.0 kPa or ≥F2 Fibrosis)

• Monitor every 6 months with liver function tests and non-invasive fibrosis markers. 4
• Refer to hepatology for multidisciplinary management. 2, 3, 4

Common Pitfalls to Avoid

• Do not prescribe pharmacotherapy for simple steatosis or mild NAFLD without biopsy-proven NASH and significant fibrosis—these patients have excellent prognosis with lifestyle modification alone. 2, 3
• Do not pursue rapid weight loss—gradual reduction (≤1 kg/week) is essential to prevent hepatic decompensation. 1, 2, 3, 4
• Do not withhold statins in NAFLD patients with dyslipidemia—they are safe and provide hepatoprotective benefits. 2, 3, 4
• Do not use metformin as specific NAFLD treatment—reserve it solely for diabetes management. 2