How should I manage a patient with non‑alcoholic fatty liver disease?

Management of Non-Alcoholic Fatty Liver Disease

All patients with NAFLD require therapeutic lifestyle interventions targeting 7-10% weight loss through Mediterranean diet and 150-300 minutes weekly of moderate-intensity exercise, combined with aggressive management of metabolic comorbidities, while pharmacologic liver-directed therapy should be reserved only for those with biopsy-proven NASH or clinically significant fibrosis (≥F2). 1, 2

Initial Risk Stratification

Calculate FIB-4 score immediately to determine fibrosis risk and guide management intensity:

• FIB-4 <1.3 (Low Risk): Manage in primary care with lifestyle interventions and annual monitoring 1, 2
• FIB-4 1.3-2.67 (Intermediate Risk): Obtain liver stiffness measurement by transient elastography to further stratify 2, 3
  • LSM <8.0 kPa: Continue primary care management with annual follow-up 2, 3
  • LSM 8.0-12.0 kPa: Consider hepatology referral and monitor every 6 months 2, 3
  • LSM >12.0 kPa: Refer to hepatology for multidisciplinary management 2, 3
• FIB-4 >2.67 (High Risk): Immediate hepatology referral for consideration of liver biopsy and intensive management 2, 3

Screen for cirrhosis complications if LSM ≥20 kPa or thrombocytopenia present, including esophagogastroduodenoscopy for varices. 2, 3

Lifestyle Interventions (All Patients)

Weight Loss Strategy

Target 7-10% total body weight reduction, as this magnitude achieves histological improvement in both steatohepatitis and fibrosis. 1, 2, 3 Even 5% weight loss improves steatosis and inflammation, but greater reduction is necessary for fibrosis regression. 1, 3

Create a calorie deficit of 500-1000 kcal/day to achieve gradual weight loss of 500-1000g per week. 2, 3 Avoid rapid weight loss exceeding 1 kg/week, as this may paradoxically worsen portal inflammation and fibrosis. 2

Dietary Prescription

Adopt Mediterranean diet as the primary dietary approach, which reduces liver fat even without weight loss. 1, 2, 3 This includes:

• Daily consumption of vegetables, fresh fruits, fiber-rich whole grains, legumes, nuts, fish or white meat, and olive oil as primary fat source 1, 2, 3
• Strict limitation of simple sugars, fructose-containing beverages, red meat, processed meats, and ultra-processed foods 1, 2, 3

Alcohol Restriction

Complete alcohol abstinence is mandatory, as even low alcohol intake (9-20g daily) doubles the risk for adverse liver-related outcomes in NAFLD patients. 1, 3 This recommendation differs from general population guidance and reflects the heightened vulnerability of fatty liver to alcohol-related injury. 1

Physical Activity

Prescribe a minimum of 150-300 minutes of moderate-intensity aerobic exercise weekly, or 75-150 minutes of vigorous-intensity exercise weekly. 2, 3 Add resistance training, which is particularly beneficial for patients with poor cardiorespiratory fitness. 2

Management of Metabolic Comorbidities

Dyslipidemia

Use statins for dyslipidemia management in all NAFLD patients regardless of fibrosis stage, as they are safe in fatty liver disease and associated with 37% reduction in HCC risk and 46% reduction in hepatic decompensation. 2, 4 The historical concern about statin hepatotoxicity in NAFLD has been definitively refuted. 2, 4

Diabetes Management

Prioritize GLP-1 receptor agonists as first-line glucose-lowering agents for diabetic patients with NAFLD. 4 Semaglutide achieved 59% NASH resolution versus 17% placebo, and liraglutide achieved 39% NASH resolution versus 9% placebo in clinical trials. 2, 4

Consider pioglitazone (30-45 mg/day) as an alternative, particularly for patients who cannot tolerate or afford GLP-1 receptor agonists. 3, 4 Pioglitazone achieved 47% steatohepatitis resolution in biopsy-proven NASH. 4

Avoid sulfonylureas and insulin when possible, as these agents increase HCC incidence by 1.6 and 2.6 times respectively. 1, 4 Metformin is safe but lacks robust evidence for histological improvement. 1

Severe Obesity

Consider bariatric surgery for patients with BMI >35 kg/m² (or >32.5 kg/m² in Asian populations) who meet national eligibility criteria, as it resolves NASH in 85% of patients at 1 year and is safe even in compensated cirrhosis. 3 This intervention remains underutilized despite strong evidence. 1

Pharmacologic Liver-Directed Therapy

Reserve pharmacologic liver-directed therapy for patients with biopsy-proven NASH or clinically significant fibrosis (≥F2), as most patients with simple steatosis have low risk of progression. 1

For Non-Diabetic Patients with Biopsy-Proven NASH

Vitamin E (800 IU/day) can improve steatohepatitis in non-diabetic patients with biopsy-proven NASH, though use caution in those with prostate cancer risk. 3, 4 Evidence for fibrosis improvement is limited, and results are mixed in diabetic patients. 4

Hepatocellular Carcinoma Surveillance

Perform abdominal ultrasound every 6 months for HCC screening in patients with advanced fibrosis (F3) or cirrhosis. 2, 4 Consider CT or MRI in overweight/obese patients where ultrasound quality is limited. 2

Implement smoking cessation programs, as smoking increases HCC risk by 1.5-1.8 times and is associated with liver fibrosis progression. 1, 3

Monitoring Schedule

Monitor low-risk patients (FIB-4 <1.3, LSM <8.0 kPa) annually with repeated FIB-4 and liver stiffness measurement. 2, 3

Monitor intermediate/high-risk patients (FIB-4 ≥1.3, LSM ≥8.0 kPa) every 6 months with liver function tests and non-invasive fibrosis markers. 2, 3

Critical Pitfalls to Avoid

Do not neglect cardiovascular risk assessment, as cardiovascular disease drives mortality in NAFLD patients before cirrhosis develops. 3 Obtain baseline lipid profile, HbA1c, blood pressure, and BMI at initial evaluation. 2

Do not treat steatosis grade as a therapeutic target, as the presence and severity of steatosis does not necessarily correlate with disease severity or prognosis. 1 The critical determinant is fibrosis stage, not steatosis grade. 1

Do not prescribe specific pharmacologic treatment targeting liver steatosis in low-risk patients (FIB-4 <1.3), as this population has excellent prognosis with lifestyle interventions alone. 1

Avoid medications that worsen steatosis, including corticosteroids, amiodarone, methotrexate, and tamoxifen. 3