What is the complete evaluation for non‑alcoholic fatty liver disease in an adult patient?

Complete Evaluation of Non-Alcoholic Fatty Liver Disease in Adults

Diagnostic Criteria

NAFLD diagnosis requires four essential components: (1) hepatic steatosis confirmed by imaging or histology, (2) alcohol consumption below threshold levels (≤21 drinks/week in men, ≤14 drinks/week in women), (3) exclusion of competing causes of steatosis, and (4) exclusion of co-existing chronic liver diseases. 1

Initial Clinical Assessment

Alcohol History

• Quantify alcohol consumption using validated questionnaires to ensure intake remains below diagnostic thresholds 1
• If self-reported consumption conflicts with clinical suspicion, confirm with family members or close contacts 1

Metabolic Risk Factor Evaluation

• Screen all patients for metabolic syndrome components: waist circumference >102 cm (men) or >88 cm (women), triglycerides ≥150 mg/dL, HDL <40 mg/dL (men) or <50 mg/dL (women), blood pressure ≥130/85 mmHg, fasting glucose ≥110 mg/dL 1
• Assess for obesity, type 2 diabetes, and dyslipidemia as these significantly increase NAFLD risk 1

Laboratory Workup

Essential Blood Tests

• Complete blood count with platelets (required for FIB-4 calculation) 2, 3
• Comprehensive metabolic panel including AST, ALT, alkaline phosphatase, bilirubin, albumin 2, 3
• Fasting glucose or HbA1c for diabetes screening 2
• Lipid panel (total cholesterol, triglycerides, HDL, LDL) 2

Exclusion of Alternative Diagnoses

• Viral hepatitis serologies: Hepatitis B surface antigen, hepatitis C antibody 1
• Iron studies: Serum ferritin and transferrin saturation to evaluate for hemochromatosis 1
• Autoimmune markers: ANA, anti-smooth muscle antibody (though commonly elevated in NAFLD as epiphenomenon) 1
• Ceruloplasmin for Wilson's disease (especially in patients <40 years) 1, 2
• Alpha-1 antitrypsin level 2

Important caveat: Mildly elevated ferritin is common in NAFLD and does not necessarily indicate iron overload. However, if both ferritin and transferrin saturation are elevated, test for HFE gene mutations (C282Y). Consider liver biopsy if homozygous or compound heterozygous mutations are present to assess hepatic iron and fibrosis. 1

Fibrosis Risk Stratification

First-Tier Assessment: FIB-4 Score

All adults with type 2 diabetes, prediabetes, obesity, or cardiometabolic risk factors should undergo FIB-4 calculation even with normal liver enzymes. 1

• FIB-4 formula: (Age × AST) / (Platelet count × √ALT) 2, 3
• Interpretation:
  • <1.3: Low risk of advanced fibrosis 2, 3
  • 1.3-2.67: Indeterminate risk 2, 3

  • 2.67: High risk of advanced fibrosis 2, 3

Age-specific adjustment: In patients ≥65 years, use higher cutoff of 1.9-2.0 rather than 1.3 to improve specificity 1

Critical limitation: Normal ALT has only 50% sensitivity for NASH and 40% sensitivity for advanced fibrosis—normal liver enzymes do not exclude significant disease. 3

Second-Tier Assessment for Indeterminate or High FIB-4

Patients with FIB-4 ≥1.3 require additional risk stratification with either transient elastography or enhanced liver fibrosis (ELF) blood test. 1

Transient Elastography (Liver Stiffness Measurement)

• <8.0 kPa: Low risk, excludes advanced fibrosis 1, 3
• 8.0-12.0 kPa: Indeterminate risk 3
• >12.0 kPa: High risk of advanced fibrosis 3
• >20 kPa: Suggests cirrhosis, warrants variceal screening 2

Enhanced Liver Fibrosis (ELF) Test

• <7.7: Low risk 3
• 7.7-9.8: Indeterminate risk 3
• >9.8: High risk 3

Do not use a second nonproprietary panel (e.g., NAFLD fibrosis score) as they do not perform better than FIB-4. 1

Imaging Evaluation

Incidentally Discovered Hepatic Steatosis

• If symptoms, signs of liver disease, or abnormal liver biochemistries are present: Evaluate as suspected NAFLD with full workup 1
• If asymptomatic with normal liver biochemistries: Assess for metabolic risk factors and alternative causes of steatosis (alcohol, medications) 1
• Liver biopsy is not recommended in asymptomatic patients with incidental steatosis and normal liver biochemistries 1

Imaging Modalities

• Ultrasound: 84.8% sensitivity and 93.6% specificity for moderate-to-severe steatosis (>30% fat), but sensitivity drops to 53-65% for mild steatosis 3
• MRI-based methods perform better than other modalities for quantifying steatosis and detecting fibrosis 4

Liver Biopsy Indications

Consider liver biopsy in the following scenarios:

• High-risk patients (FIB-4 >2.67, elastography >12.0 kPa, or ELF >9.8) for definitive staging and surveillance planning 3
• Patients with elevated ferritin, elevated transferrin saturation, and HFE gene mutations (homozygous or compound heterozygous C282Y) to assess hepatic iron concentration 1
• When other liver disorders cannot be excluded with noninvasive tests 5
• To distinguish NASH from simple steatosis when management decisions depend on histology 6

Liver biopsy remains the gold standard for staging fibrosis and confirming NASH (defined as ≥5% steatosis plus hepatocyte ballooning and inflammation). 1

Specialist Referral

Refer to gastroenterology or hepatology for:

• Indeterminate or high-risk results on second-tier testing (elastography or ELF) 1
• FIB-4 >2.67 3
• Evidence of cirrhosis or advanced fibrosis 2
• Persistently elevated aminotransferases >6 months with low FIB-4 (to evaluate alternative diagnoses) 1

Interprofessional care is recommended for long-term management of patients with significant fibrosis. 1

Special Populations

Type 2 Diabetes and Prediabetes

• NAFLD prevalence exceeds 70% in adults with type 2 diabetes 1
• 12-20% have clinically significant fibrosis (≥F2) 1
• Screen all patients with diabetes or prediabetes using FIB-4, even with normal liver enzymes 1

Type 1 Diabetes

• Screen only if additional risk factors present (obesity, incidental steatosis on imaging, elevated aminotransferases) 1
• FIB-4 not well validated in this population 1

Surveillance for Low-Risk Patients

For patients with FIB-4 <1.3:

• Repeat noninvasive fibrosis testing every 2-3 years 2
• Annual cardiovascular risk assessment 2
• Annual diabetes screening with HbA1c 2

Screening Recommendations

Routine screening for NAFLD in primary care, diabetes, or obesity clinics is not currently recommended due to uncertainties surrounding diagnostic tests, treatment options, and lack of data on long-term outcomes. 1 However, targeted case-finding using FIB-4 in high-risk populations (type 2 diabetes, obesity, metabolic syndrome) is strongly supported by recent guidelines. 1