What is the recommended diagnostic work‑up and treatment plan for an adult patient with suspected non‑alcoholic fatty liver disease (NAFLD), especially if they are overweight, have type 2 diabetes, dyslipidaemia, hypertension, or a sedentary lifestyle?

Non-Alcoholic Fatty Liver Disease: Diagnostic Work-Up and Treatment

Initial Diagnostic Approach

In adults with suspected NAFLD who have metabolic risk factors (overweight, type 2 diabetes, dyslipidemia, hypertension), begin by quantifying alcohol intake—consumption exceeding 21 standard drinks per week in men or 14 drinks per week in women excludes NAFLD—then obtain comprehensive metabolic screening, viral hepatitis serology, and abdominal ultrasound to confirm hepatic steatosis. 1, 2

Mandatory Initial Investigations

• Alcohol assessment: Use the NIAAA definition where one standard drink equals 14g of pure alcohol; ongoing consumption above thresholds indicates alcoholic liver disease, not NAFLD 1, 2
• Viral hepatitis screening: Test for hepatitis B surface antigen and hepatitis C antibody to exclude viral etiologies 2, 3
• Complete metabolic panel: Include CBC, comprehensive metabolic panel, fasting glucose or HbA1c, and lipid panel 4, 2
• Abdominal ultrasound: First-line imaging modality for detecting moderate-to-severe steatosis, though sensitivity is only 53-65% for mild steatosis 2

Exclude Competing Etiologies

• Iron studies: Obtain serum ferritin and transferrin saturation; modestly elevated ferritin alone in obese patients is common in NAFLD and does not indicate hemochromatosis unless both ferritin and transferrin saturation are elevated 1, 2, 3
• Autoimmune markers: Check ANA and anti-smooth muscle antibodies; titers >1:160 or >1:40 respectively occur in 21% of NAFLD patients as an epiphenomenon, but very high titers (>5x ULN aminotransferases) with elevated globulins warrant autoimmune hepatitis work-up 1
• Additional testing: Alpha-1 antitrypsin level and ceruloplasmin (if age <40) to exclude Wilson disease 2, 3
• Medication review: Assess for drug-induced hepatotoxicity 2

Assessment of Metabolic Comorbidities

Document the presence of metabolic syndrome components, as these predict steatohepatitis severity and drive adverse outcomes. 1

• Central obesity: Measure BMI and waist circumference 1
• Diabetes/insulin resistance: Screen with fasting glucose and HbA1c; 70% of type 2 diabetics have NAFLD 4, 3
• Dyslipidemia: Obtain fasting lipid panel including triglycerides and HDL cholesterol 1
• Hypertension: Document blood pressure readings 1
• Additional conditions: Screen for hypothyroidism, polycystic ovary syndrome, and obstructive sleep apnea 1

Risk Stratification for Advanced Fibrosis

Immediately calculate the FIB-4 score using age, AST, ALT, and platelet count to stratify fibrosis risk, as advanced fibrosis is the major predictor of liver-related mortality. 4, 2, 3

FIB-4 Score Calculation and Interpretation

• Formula: (Age × AST) / (Platelet count × √ALT) 3
• Low risk (<1.3): Repeat non-invasive testing every 2-3 years 3
• Indeterminate risk (1.3-2.67): Consider additional testing with vibration-controlled transient elastography (VCTE) or Enhanced Liver Fibrosis (ELF) panel 1, 4
• High risk (>2.67): Refer to hepatology for further evaluation and possible liver biopsy 4, 3

Alternative Non-Invasive Tools

• NAFLD Fibrosis Score (NFS): Based on age, BMI, hyperglycemia, platelet count, albumin, and AST/ALT ratio; AUROC of 0.85 for advanced fibrosis 1
• Vibration-controlled transient elastography: Useful for confirming high-risk patients identified by clinical scores 1
• MR elastography: Superior accuracy but limited by cost and availability 1

When to Consider Liver Biopsy

• Persistently elevated ferritin with increased iron saturation in the context of C282Y HFE mutation (homozygote or heterozygote) 1
• High-risk fibrosis scores requiring definitive staging 1
• Need to exclude co-existing chronic liver diseases when non-invasive tests are inconclusive 1

Important caveat: Liver biopsy has limitations including sampling error, cost, and procedure-related morbidity/mortality, so reserve it for cases where results will change management. 1, 5

Treatment Strategy

Weight loss of 7-10% total body weight is the cornerstone of therapy and the only proven treatment for NAFLD, achieved through gradual reduction of 0.5-1 kg per week maximum. 4, 5, 6

Lifestyle Modifications

• Dietary pattern: Adopt a Mediterranean diet with reduced saturated fats and refined carbohydrates; replace processed foods, fast food, and commercial bakery goods with unprocessed foods high in fiber including whole grains, vegetables, fruits, legumes, nuts, and seeds 1, 4
• Physical activity: 150-200 minutes per week of moderate-intensity aerobic exercise in 3-5 sessions 4
• Weight loss targets: 3-5% body weight improves hepatic steatosis; 5-10% reduces hepatic inflammation 1, 5
• Alcohol: Avoid excess consumption; complete abstinence if advanced fibrosis is present 1, 3

Pharmacotherapy

For patients with type 2 diabetes and NAFLD, initiate GLP-1 receptor agonists (liraglutide or semaglutide) as first-line therapy, as these agents improve liver histology and promote weight loss. 4, 3

• Metformin: Use as initial or adjunctive therapy if liver function is not severely impaired 4
• Pioglitazone: Improves steatohepatitis in non-diabetic patients with biopsy-proven NASH, but long-term safety data are lacking 1, 5
• Vitamin E: Improves steatohepatitis in non-diabetic patients with biopsy-proven NASH at doses of 800 IU daily, but concerns exist regarding long-term safety 1, 5, 7

Critical limitation: No FDA-approved pharmacotherapy specifically for NAFLD exists; pioglitazone and vitamin E are recommended only in selected patients with biopsy-proven NASH. 1, 5

Management of Metabolic Comorbidities

• Type 2 diabetes: Preferentially use GLP-1 receptor agonists; screen all NAFLD patients for diabetes with fasting glucose or HbA1c 4, 3
• Dyslipidemia: Treat according to cardiovascular risk guidelines 8
• Hypertension: Manage per standard protocols 8

Monitoring Protocol

Initial Monitoring

• Liver enzymes (AST, ALT) 4
• Metabolic parameters: Fasting glucose, HbA1c, lipid panel 4
• Anthropometrics: Weight and BMI 4

Long-Term Surveillance

• Low-risk patients (FIB-4 <1.3): Repeat FIB-4 every 2-3 years, annual cardiovascular risk assessment, annual diabetes screening with HbA1c 3
• Cirrhosis patients: Hepatocellular carcinoma surveillance with ultrasound every 6 months; variceal screening if liver stiffness measurement >20 kPa or platelets <150,000/mm³ 3

Specialist Referrals

Refer to hepatology/gastroenterology for high-risk fibrosis scores (FIB-4 >2.67), indeterminate scores requiring additional testing, or when liver biopsy is needed. 4, 3

• Endocrinology/diabetes clinic: For optimization of diabetes management, particularly when initiating GLP-1 receptor agonists 4
• Nutrition/weight management program: For structured dietary counseling and weight loss support 4

Special Considerations

Incidentally Discovered Hepatic Steatosis

Patients with incidental steatosis on imaging who have normal liver biochemistries should be assessed for metabolic risk factors and alternate causes for steatosis; if metabolic risk factors are present, calculate FIB-4 score as 11% may be at high risk for advanced fibrosis. 1, 2

Screening Recommendations

Routine screening for NAFLD in primary care, diabetes, or obesity clinics is not advised due to uncertainties surrounding diagnostic tests, treatment options, and lack of cost-effectiveness data. 1

However, maintain a high index of suspicion in patients with type 2 diabetes, as they have higher prevalence of NASH and advanced fibrosis. 1

Family Screening

Systematic screening of family members for NAFLD is not recommended currently, despite evidence suggesting familial clustering and heritability. 1

Common Pitfalls to Avoid

• Do not assume normal aminotransferases exclude NAFLD or NASH: Liver enzymes can be normal in patients with significant disease 1
• Do not pursue extensive hemochromatosis work-up for isolated ferritin elevation: Modestly elevated ferritin is common in NAFLD and does not indicate iron overload unless transferrin saturation is also elevated 1, 2
• Do not interpret low autoantibody titers as autoimmune hepatitis: Elevations up to 1:160 (ANA) or 1:40 (ASMA) occur in 21% of NAFLD patients without atypical features 1
• Do not recommend rapid weight loss: Gradual reduction of 0.5-1 kg per week is optimal; rapid weight loss may not improve fatty liver as effectively 1, 4