What laboratory tests are recommended for a patient with potential liver disease, considering their medical history and risk factors?

Laboratory Testing for Potential Liver Disease

Initial investigation for potential liver disease should include bilirubin, albumin, ALT, ALP, and GGT, together with a full blood count if not already performed within the previous 12 months. 1

First-Line Core Laboratory Panel

The British Society of Gastroenterology establishes a standardized initial panel that serves as the foundation for evaluating suspected liver disease:

Basic Liver Chemistry Tests

• Bilirubin - assesses hepatic excretory function and cholestasis 1
• Albumin - reflects hepatic synthetic function and chronicity of disease 1
• Alanine aminotransferase (ALT) - primary marker of hepatocellular injury 1
• Alkaline phosphatase (ALP) - indicates cholestatic or infiltrative disease 1
• Gamma-glutamyl transferase (GGT) - increases sensitivity for detecting alcohol-related and fatty liver disease, and is associated with increased liver and all-cause mortality 1
• Full blood count - platelet count helps assess for portal hypertension and advanced fibrosis 1

Critical Addition: AST for Fibrosis Assessment

• Aspartate aminotransferase (AST) should be obtained reflexively on the same sample when ALT or GGT is abnormal to calculate the AST:ALT ratio 1
• An AST:ALT ratio >1 indicates advanced fibrosis/cirrhosis, even when both values are within normal reference ranges 1
• This ratio is essential for risk stratification and referral decisions 1

Second-Line Etiologic Testing

Once abnormal liver tests are confirmed, proceed with a comprehensive etiologic screen based on the clinical context:

Viral Hepatitis Serologies

• Hepatitis B surface antigen (HBsAg) and hepatitis B core IgM 2
• Hepatitis C antibody (HCV Ab) 2
• For marked elevations (ALT >1000 U/L), add hepatitis A, hepatitis E, and cytomegalovirus serologies 2

Autoimmune Markers

• Serum immunoglobulin G (IgG) - elevated in autoimmune hepatitis 2
• Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-liver kidney microsome (LKM) antibodies 1, 2
• Antimitochondrial antibody (AMA) - for primary biliary cholangitis 1

Iron Studies

• Ferritin and transferrin saturation 2
• Transferrin saturation >45% suggests hemochromatosis and warrants genetic testing 2
• Isolated elevated ferritin without elevated transferrin saturation does not indicate hemochromatosis 2

Metabolic Parameters (for NAFLD Assessment)

• Fasting glucose or hemoglobin A1c 2
• Lipid panel (triglycerides, cholesterol) 2
• Assessment for metabolic syndrome components (waist circumference, BMI, blood pressure) 1

Additional Metabolic Testing (When Core Panel Negative)

• Alpha-1-antitrypsin level - for alpha-1-antitrypsin deficiency 1
• Thyroid function tests - thyroid disease can cause liver enzyme elevation 1, 2
• Ceruloplasmin (age >3 and <40 years) with 24-hour urinary copper - for Wilson's disease 1, 2
• Creatine kinase - to exclude muscle source of transaminase elevation 2

Clinical History Requirements

Obtain specific details that guide testing interpretation:

• Alcohol consumption - quantify grams per day (>20-30 g/day suggests alcohol-related disease) 1, 2
• Medication review - identify hepatotoxic drugs (corticosteroids, amiodarone, methotrexate, tamoxifen, valproic acid) 1, 2
• Risk factors for viral hepatitis - injection drug use, blood transfusions before 1992, country of origin, sexual history 1, 2
• Metabolic syndrome features - obesity, diabetes, hypertension, dyslipidemia 1, 2
• Family history - hemochromatosis, Wilson's disease, autoimmune conditions 2

Non-Invasive Fibrosis Assessment

After establishing etiology, assess fibrosis stage using validated scores:

First-Line Fibrosis Scores

• FIB-4 score - values <1.3 indicate low risk of advanced fibrosis (<2.0 for age >65 years) 1
• NAFLD Fibrosis Score - values ≤-1.455 indicate low risk (≤-0.12 for age >65 years) 1
• These should be automatically calculated and reported in primary care for patients with metabolic risk factors 1

Second-Line Fibrosis Tests (When Scores Indeterminate)

• Enhanced Liver Fibrosis (ELF) test - serum biomarker panel 1
• Transient elastography (FibroScan) - values >7.8 kPa suggest advanced fibrosis 1
• ARFI elastography - cut-offs vary by manufacturer 1

Imaging Recommendations

• Abdominal ultrasound with Doppler is the initial imaging modality of choice, with 84.8% sensitivity and 93.6% specificity for moderate to severe hepatic steatosis 2
• Ultrasound also excludes biliary obstruction, focal lesions, and assesses for cirrhosis features 1, 2
• CT abdomen/pelvis with IV contrast may be considered for moderate to severe elevations or when ultrasound is inadequate 2

Monitoring Strategy

Important caveat: The goal is etiologic diagnosis, not monitoring alone, as 84% of abnormal tests remain elevated at 1 month and 75% at 2 years 2. Repeat testing without pursuing diagnosis is inefficient.

• For confirmed abnormal results, proceed directly to etiologic testing rather than simply repeating basic tests 2
• Monthly clinical evaluation during treatment includes questioning about symptoms of hepatotoxicity and physical assessment 1

Referral Criteria

Immediate Specialist Referral

• Unexplained clinical jaundice 2
• Suspicion of hepatic or biliary malignancy 2
• Evidence of hepatitis B, HCV, autoimmune hepatitis, or hemochromatosis 2
• Findings concerning for cirrhosis - thrombocytopenia, AST>ALT, hypoalbuminemia, elevated INR 1

Routine Hepatology Referral

• Transaminases elevated ≥6 months without identified cause 2
• Negative extended liver aetiology screen even without NAFLD risk factors 1
• Evidence of synthetic dysfunction (low albumin, elevated INR) 2
• High-risk fibrosis scores requiring further evaluation 1

Common Pitfalls to Avoid

• Do not rely on GGT alone - while it increases sensitivity, it has lower specificity and higher false-positive rates 1
• Do not assume isolated ferritin elevation indicates hemochromatosis - transferrin saturation >45% is required 2
• Do not use AST:ALT ratio in isolation - it retains utility even when both values are normal 1
• Do not screen unselected general populations - non-invasive fibrosis tests should be used in at-risk populations (metabolic risk factors, harmful alcohol use) where prevalence justifies testing 1
• Do not delay etiologic workup - prolonged monitoring without diagnosis is not cost-effective given persistence of abnormalities 2