What labs should be ordered for a patient suspected of having fatty liver disease?

Laboratory Evaluation for Fatty Liver Disease

For patients with suspected fatty liver disease, order a comprehensive metabolic panel with liver enzymes (AST, ALT, alkaline phosphatase, bilirubin), complete blood count with platelets, fasting glucose or hemoglobin A1c, fasting lipid panel, INR/PT, albumin, and a standard liver etiology screen including hepatitis B surface antigen, hepatitis C antibody, iron studies (ferritin and transferrin saturation), and autoimmune markers (ANA, anti-smooth muscle antibody, anti-mitochondrial antibody). 1, 2

Primary Assessment Panel

Core Liver Function Tests

• Liver enzymes: AST, ALT, alkaline phosphatase, total and direct bilirubin to assess hepatocellular injury and cholestasis 2, 3
• Synthetic function markers: Serum albumin, prothrombin time, and INR to evaluate hepatic synthetic capacity 1, 2
• Complete blood count with platelets: Essential to detect thrombocytopenia (platelet count <150,000), which suggests portal hypertension and likely cirrhosis 2, 3
• Serum creatinine: To assess renal function, particularly important in advanced disease 2

Note that ALT thresholds for abnormality should be ALT >20 U/L for women and >30 U/L for men, not the traditional laboratory upper limits, as these better identify clinically significant NAFLD 1. However, normal ALT does not exclude fatty liver disease or even advanced fibrosis—approximately 50% of NAFLD patients have normal transaminases 3, 4.

Metabolic Risk Assessment

• Fasting glucose and/or hemoglobin A1c: To evaluate for diabetes mellitus, a major risk factor for NASH and advanced fibrosis 2, 3
• Fasting lipid profile: To assess dyslipidemia as part of metabolic syndrome 2, 3
• Document BMI and waist circumference: Essential obesity parameters that correlate with disease severity 2

Exclusion of Alternative Liver Diseases

This is critical because other chronic liver diseases require different management and can coexist with fatty liver:

• Hepatitis B surface antigen: To exclude chronic hepatitis B 1, 2
• Hepatitis C antibody (with reflex PCR if positive): To screen for hepatitis C infection 1, 2
• Iron studies: Simultaneous serum ferritin and transferrin saturation (>45% suggests hemochromatosis) 1, 2
• Autoimmune markers: ANA, anti-smooth muscle antibody, and anti-mitochondrial antibody to exclude autoimmune hepatitis and primary biliary cholangitis 1, 2
• Serum immunoglobulins: Part of the autoimmune workup 1

Important caveat: An isolated elevated ferritin is commonly seen in dysmetabolic iron overload syndrome in the setting of NAFLD itself and does not reflect hemochromatosis—you need both elevated ferritin AND transferrin saturation >45% to suspect hemochromatosis 1.

Fibrosis Risk Stratification

First-Line Fibrosis Assessment: FIB-4 Index

Calculate the FIB-4 index using age, AST, ALT, and platelet count as the initial point-of-care test for fibrosis risk 1, 2:

• FIB-4 <1.3 (or <2.0 if age >65 years): Low risk for advanced fibrosis—can be managed in primary care with reassessment every 2 years 1, 3
• FIB-4 1.3-2.67 (or 2.0-3.25 if age >65): Indeterminate risk—requires second-tier testing with Enhanced Liver Fibrosis (ELF) panel, vibration-controlled transient elastography (VCTE/FibroScan), or magnetic resonance elastography (MRE) 1
• FIB-4 >2.67 (or >3.25): High risk for advanced fibrosis—consider specialist referral and possible liver biopsy 1

The NAFLD Fibrosis Score (NFS) is an alternative first-line test using age, BMI, hyperglycemia, platelet count, albumin, and AST/ALT ratio, with cutoffs of <-1.455 (low risk) and >0.676 (high risk) 1.

Pattern Recognition for Advanced Disease

Look for these laboratory patterns that suggest cirrhosis or advanced fibrosis:

• AST > ALT ratio: Suggests more advanced fibrosis or cirrhosis (the ratio reverses in advanced disease) 2, 3
• Thrombocytopenia: Platelet count <150,000 suggests portal hypertension 2
• Hypoalbuminemia: Low albumin suggests decreased synthetic function and advanced disease 2
• Elevated INR or prolonged PT: Indicates impaired hepatic synthetic capacity 2
• Elevated bilirubin: Suggests advanced liver dysfunction 2

High-Risk Populations Requiring Sequential Testing

Patients with type 2 diabetes or 2+ features of metabolic syndrome are at higher risk for hepatic fibrosis and should have sequential or consecutive testing with a second noninvasive test even if FIB-4 is in the indeterminate range 1.

Common Pitfalls to Avoid

• Do not exclude fatty liver disease based on normal ALT alone—half of NAFLD patients have normal transaminases, and advanced fibrosis can present with normal liver enzymes 2, 3, 4
• Do not use isolated GGT elevation as the sole marker of liver injury—it is insufficient for diagnosis 2
• Do not assume AST:ALT >1 excludes NAFLD—this ratio actually reverses in advanced disease and suggests cirrhosis 2, 3
• Review medications for hepatotoxic agents: Corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid can cause medication-induced steatosis 2
• Recognize that ALT levels in NAFLD are typically between normal and 250 IU/L, usually <5× upper limit of normal, with ALT typically higher than AST until advanced disease develops 2

When to Consider Liver Biopsy

Liver biopsy should be considered when 1, 3:

• NASH or advanced liver fibrosis is suspected based on noninvasive tests
• Noninvasive tests are indeterminate or discordant
• Concurrent other chronic liver diseases cannot be excluded
• Clinical suspicion of more advanced disease despite reassuring noninvasive tests

Imaging Considerations

While not strictly "labs," abdominal ultrasonography should be part of the standard liver etiology screen to visualize hepatic steatosis and exclude structural abnormalities like dilated bile ducts 1. Ultrasound is the most economical and widely available modality for detecting steatosis, though it has limited sensitivity for mild steatosis (<30% hepatic fat content) 1, 3.