How do I diagnose non‑alcoholic fatty liver disease?

Diagnosing Non-Alcoholic Fatty Liver Disease

Diagnose NAFLD by confirming hepatic steatosis (≥5% of hepatocytes) through imaging or histology, excluding significant alcohol consumption (>21 drinks/week for men, >14 drinks/week for women), and systematically ruling out competing causes of chronic liver disease. 1, 2

Initial Clinical Assessment

Alcohol History and Risk Factor Evaluation

• Obtain a detailed alcohol consumption history to exclude alcoholic liver disease, defining significant consumption as >21 standard drinks per week for men or >14 drinks per week for women 2, 3, 4
• Assess for metabolic risk factors including obesity, type 2 diabetes mellitus, dyslipidemia, metabolic syndrome, hypertension, polycystic ovary syndrome, hypothyroidism, and obstructive sleep apnea 2, 3
• Review complete medication history including prescribed medications, over-the-counter drugs, herbal products, and supplements that may cause hepatic steatosis 3, 4

Critical Pitfall to Avoid

• Do not rely solely on liver enzyme elevations to diagnose or exclude NAFLD, as up to 50% of NAFLD patients have normal aminotransferase levels, and patients with advanced fibrosis may have minimal or no enzyme elevation 2, 4, 5

Laboratory Testing to Confirm Diagnosis

Essential Initial Laboratory Panel

• Complete liver chemistry panel including ALT, AST, alkaline phosphatase, total bilirubin, albumin, and prothrombin time/INR 2, 4
• Complete blood count with platelet count for fibrosis risk assessment, as thrombocytopenia suggests advanced disease 2
• Fasting glucose, HbA1c, and complete lipid profile to identify metabolic comorbidities 2, 3

Excluding Competing Etiologies (Mandatory)

• Viral hepatitis serology (hepatitis B surface antigen, hepatitis C antibody) to exclude chronic viral hepatitis 1, 2, 4
• Iron studies (serum ferritin and transferrin saturation) to exclude hemochromatosis 1, 2, 4
  • If ferritin is persistently elevated with high transferrin saturation, test for HFE gene mutations (C282Y) 1
  • Consider liver biopsy in patients with homozygote or compound heterozygote C282Y mutations to assess hepatic iron and exclude significant injury 1
• Autoimmune markers (ANA, anti-smooth muscle antibodies) if clinically indicated 2, 4
  • Low-titer autoantibodies (ANA >1:160 or ASMA >1:40) occur in 21% of NAFLD patients and are generally an epiphenomenon without clinical significance 1
  • Only pursue autoimmune workup if very high aminotransferases, elevated globulin, or other features strongly suggest autoimmune liver disease 1

Imaging Studies for Steatosis Detection

First-Line Imaging

• Abdominal ultrasonography is the primary screening test and should be performed as the first-line imaging modality to detect hepatic steatosis 2, 4
• Ultrasound, CT, and conventional MRI do not reliably assess steatohepatitis or fibrosis and cannot distinguish simple steatosis from NASH 1

Advanced Imaging When Indicated

• MRI or MR elastography can provide more accurate quantification of steatosis and fibrosis when ultrasonography is inadequate or inconclusive 2

Non-Invasive Fibrosis Assessment (Critical for Risk Stratification)

Calculate Fibrosis Risk Scores

Use NAFLD Fibrosis Score (NFS) calculated from age, BMI, presence of diabetes/impaired fasting glucose, AST/ALT ratio, platelet count, and albumin 1, 2:

• NFS <-1.455: Low risk of advanced fibrosis (90% sensitivity, 60% specificity to exclude advanced fibrosis)
• NFS >0.676: High risk of advanced fibrosis (67% sensitivity, 97% specificity to identify advanced fibrosis)

Use FIB-4 Index calculated from age, AST, ALT, and platelet count 1, 2:

• FIB-4 <1.45: Low risk of advanced fibrosis
• FIB-4 >3.25: High risk of advanced fibrosis

Additional Non-Invasive Tools

• Vibration-controlled transient elastography (VCTE/FibroScan) measures liver stiffness and is clinically useful for identifying advanced fibrosis, with AUROC of 0.88 for detecting bridging fibrosis and cirrhosis 1, 2
• Enhanced Liver Fibrosis (ELF) panel (hyaluronic acid, TIMP-1, PIIINP) has AUROC of 0.90 with 80% sensitivity and 90% specificity for advanced fibrosis 1

Liver Biopsy Indications

Liver biopsy remains the gold standard for characterizing histological alterations, distinguishing NASH from simple steatosis, and staging fibrosis, but should be reserved for specific situations due to cost, sampling error, and procedure-related morbidity 1

When to Consider Liver Biopsy

• Patients at increased risk of steatohepatitis and/or advanced fibrosis based on metabolic syndrome presence, elevated fibrosis scores, or elevated liver stiffness measurements 1, 2
• Uncertain diagnosis when competing etiologies cannot be excluded without histological confirmation 1, 2
• Persistently elevated serum ferritin with increased iron saturation, especially with C282Y HFE mutations 1, 2
• Persistently abnormal liver biochemistries in patients with metabolic syndrome who would benefit from diagnostic and prognostic information 1

Biopsy Technical Considerations

• Use large needle size (2-3 cm length, 16 gauge) and obtain at least one core biopsy to minimize sampling error 1

Diagnostic Algorithm Summary

1. Confirm alcohol consumption is below threshold (<21 drinks/week men, <14 drinks/week women) 2, 4
2. Perform comprehensive laboratory testing to exclude viral hepatitis, hemochromatosis, and autoimmune liver disease 1, 2, 4
3. Obtain abdominal ultrasound to detect hepatic steatosis (≥5% involvement required for diagnosis) 2, 4
4. Calculate NFS and/or FIB-4 to stratify fibrosis risk 1, 2
5. Consider VCTE or MR elastography for patients with indeterminate fibrosis risk 1, 2
6. Reserve liver biopsy for high-risk patients, uncertain diagnosis, or when histological confirmation would change management 1, 2

Common Diagnostic Pitfalls

• Assuming normal liver enzymes exclude significant disease: Many patients with advanced fibrosis have normal or minimally elevated aminotransferases 2, 4, 5
• Misinterpreting low-titer autoantibodies: These are common epiphenomena in NAFLD and do not indicate autoimmune liver disease unless accompanied by very high aminotransferases and elevated globulin 1
• Overinterpreting mildly elevated ferritin: This is common in NAFLD and does not necessarily indicate iron overload unless accompanied by elevated transferrin saturation 1
• Failing to assess metabolic comorbidities: The presence of metabolic syndrome strongly predicts steatohepatitis and should guide decisions about liver biopsy 1