What labs should I order for a patient with elevated Liver Function Tests (LFTs)?

Laboratory Workup for Elevated Liver Function Tests

For any patient with elevated LFTs, order a comprehensive liver aetiology screen that includes: complete metabolic panel (ALT, AST, alkaline phosphatase, total and direct bilirubin, albumin), hepatitis B surface antigen, hepatitis C antibody with reflex PCR, anti-mitochondrial antibody, anti-smooth muscle antibody, antinuclear antibody, serum immunoglobulins, simultaneous serum ferritin and transferrin saturation, plus abdominal ultrasound. 1, 2

Initial Core Laboratory Panel

The first step requires determining the pattern and severity of liver injury through a complete metabolic panel 2, 3:

• Hepatocellular markers: ALT, AST (with ALT:AST ratio >1 suggesting non-alcoholic disease, AST:ALT ratio >1 suggesting alcoholic disease) 2
• Cholestatic markers: Alkaline phosphatase, GGT, total and direct bilirubin 1, 2
• Synthetic function: Albumin, prothrombin time/INR 4
• Complete blood count if not performed within 12 months 1

Severity classification guides urgency: mild to moderate elevations are <3× upper limit of normal (ULN), severe elevations are >3× ULN, and life-threatening elevations are >20× ULN requiring immediate hospitalization 2, 3.

Standard Liver Aetiology Screen

All patients with abnormal LFTs should undergo investigation with a liver aetiology screen irrespective of level and duration of abnormality 1. This comprehensive panel includes:

Infectious Causes

• Hepatitis B surface antigen 1
• Hepatitis C antibody with follow-on PCR if positive 1

Autoimmune Causes

• Anti-mitochondrial antibody (for primary biliary cholangitis) 1
• Anti-smooth muscle antibody (for autoimmune hepatitis) 1
• Antinuclear antibody 1
• Serum immunoglobulins 1

Metabolic Causes

• Simultaneous serum ferritin and transferrin saturation (for hereditary hemochromatosis) 1
• Consider alpha-1-antitrypsin level (especially in younger patients or those with emphysema) 1
• Consider ceruloplasmin for Wilson disease (particularly age <40 years) 1

Essential Imaging

Abdominal ultrasound is mandatory as part of the initial workup for all patients with persistent LFT abnormalities 1, 2, 3. This imaging has 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis and evaluates for 2, 3:

• Hepatic parenchyma and steatosis
• Biliary dilation or obstruction
• Liver masses or cirrhosis
• Splenomegaly suggesting portal hypertension

If cholestatic pattern persists with direct bilirubin, GGT, or alkaline phosphatase elevation and ultrasound is inconclusive, obtain magnetic resonance cholangiopancreatography to detect biliary strictures, stones, or obstruction 1.

Risk Stratification for Fibrosis

Calculate FIB-4 score for all patients to determine risk of advanced fibrosis and need for hepatology referral 1, 2:

• FIB-4 >2.67 indicates high risk for advanced fibrosis and warrants hepatology referral 2
• Alternative: NAFLD Fibrosis Score (NFS) can be used 1
• These non-invasive scores help prioritize patients who need specialist evaluation 2

Additional Testing Based on Clinical Context

For Suspected Alcoholic Liver Disease

• Quantify alcohol consumption using AUDIT-C screening tool 2
• If AUDIT score >19, consider referral to alcohol services 1
• If harmful drinking identified, perform risk stratification with Fibroscan/elastography; refer if >16 kPa 1

For Suspected Drug-Induced Liver Injury

• Obtain detailed medication history including prescription drugs, over-the-counter medications, herbal supplements, and illicit substances 2, 3
• Consider temporal relationship between drug initiation and LFT elevation 5

For Suspected NAFLD

• Document metabolic risk factors: BMI >25, type 2 diabetes, dyslipidemia 1
• Calculate FIB-4 or NFS for fibrosis risk stratification 1, 2

Monitoring and Follow-Up Testing

Repeat testing frequency depends on severity 2, 3:

• Mild elevations (<5× ULN): Repeat within 2-4 weeks 2, 3
• Moderate to severe (5-20× ULN): Repeat every 2-3 days until stable 3
• Life-threatening (>20× ULN): Immediate hospitalization with intensive monitoring 3

Urgent Referral Criteria

Immediate hepatology referral is required for 2:

• ALT >5× ULN or ALT >3× ULN with total bilirubin >2× ULN (Hy's Law criteria)
• Evidence of synthetic dysfunction (low albumin, elevated INR)
• Dilated bile ducts on imaging
• FIB-4 score >2.67 or imaging suggesting advanced fibrosis/cirrhosis
• Persistent elevation >6 months despite addressing modifiable factors

Common Pitfalls to Avoid

Do not interpret LFT abnormalities without reviewing previous results, past medical history, and current clinical context 1. The extent of elevation does not necessarily correlate with clinical significance—the specific analyte that is abnormal and the clinical context determine importance 1.

Do not delay the comprehensive aetiology screen—even mild elevations warrant full investigation, as early detection of treatable conditions like viral hepatitis, hemochromatosis, or autoimmune hepatitis significantly impacts outcomes 1, 6.

For pediatric patients, modify the panel to include anti-liver kidney microsomal antibody, coeliac antibodies, alpha-1-antitrypsin level, and ceruloplasmin (age >3 years), while ferritin and transferrin saturation may not be indicated 1.