Initial Evaluation and Work-Up for Abnormal Liver Function Tests
All patients with abnormal liver blood tests—regardless of the magnitude of elevation—should undergo a comprehensive liver aetiology screen that includes abdominal ultrasound, viral hepatitis serologies (HBsAg, HCV antibody with reflex PCR), autoimmune markers (anti-mitochondrial, anti-smooth muscle, and antinuclear antibodies), serum immunoglobulins, and simultaneous ferritin with transferrin saturation. 1
Step 1: Confirm the Abnormality and Review Context
Repeat the abnormal liver tests within 2–4 weeks to establish whether the elevation is persistent or transient, as single abnormal values may reflect temporary physiologic variation rather than true liver disease. 1, 2
Review all previous liver test results, past medical history, current medications (including over-the-counter drugs and herbal supplements), and alcohol consumption before interpreting the significance of any abnormality. 1
Recognize that the magnitude of elevation does not predict clinical significance; even mild abnormalities warrant investigation, while the specific pattern (hepatocellular vs. cholestatic) and clinical context determine the urgency and direction of the work-up. 1
Step 2: Determine the Pattern of Liver Injury
Hepatocellular Pattern (ALT/AST Predominance)
Calculate the R-value: (ALT ÷ ULN for ALT) / (ALP ÷ ULN for ALP). An R ≥ 5 defines hepatocellular injury, R ≤ 2 indicates cholestatic injury, and 2 < R < 5 suggests mixed injury. 2
Assess the AST:ALT ratio to differentiate etiologies: a ratio <1 is characteristic of non-alcoholic fatty liver disease (NAFLD) or viral hepatitis, while a ratio ≥2 is highly suggestive of alcoholic liver disease. 1, 2
Common causes to investigate: NAFLD (most common in patients with metabolic syndrome), viral hepatitis (HBV, HCV), medication-induced liver injury, autoimmune hepatitis, hemochromatosis, and Wilson disease (in patients <40 years). 1, 2
Cholestatic Pattern (ALP/GGT Predominance)
Confirm hepatic origin of ALP elevation by checking GGT; if GGT is also elevated, the source is hepatobiliary rather than bone. 3, 4
Order abdominal ultrasound immediately to distinguish extrahepatic biliary obstruction (dilated bile ducts, gallstones, masses) from intrahepatic cholestasis (primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis). 1
If ultrasound shows biliary dilation or a mass, arrange urgent referral to gastroenterology or hepatobiliary surgery, as extrahepatic obstruction may require endoscopic or surgical intervention. 1
Step 3: Order the Standard Liver Aetiology Screen
For all adults with any abnormal liver test, obtain the following panel simultaneously to avoid diagnostic delays and reduce the need for repeat venipuncture: 1, 3
| Test | Purpose |
|---|---|
| Abdominal ultrasound | Detect hepatic steatosis, biliary obstruction, focal lesions, portal hypertension features, and structural abnormalities (sensitivity 84.8%, specificity 93.6% for moderate-to-severe steatosis) [1,2] |
| HBsAg, HCV antibody (with reflex PCR if positive) | Screen for chronic viral hepatitis, a common cause of persistent transaminase elevation [1] |
| Anti-mitochondrial antibody | Diagnose primary biliary cholangitis [1] |
| Anti-smooth muscle antibody | Identify autoimmune hepatitis [1] |
| Antinuclear antibody (ANA) | Screen for autoimmune liver disease [1] |
| Serum immunoglobulins (IgG, IgM, IgA) | Detect hypergammaglobulinemia associated with autoimmune hepatitis or cirrhosis [1] |
| Ferritin and transferrin saturation (simultaneous) | Screen for hereditary hemochromatosis; transferrin saturation >45% is clinically significant [1,2] |
For children, modify the panel to include anti-liver-kidney microsomal antibody, coeliac antibodies, alpha-1-antitrypsin level, and caeruloplasmin (age >3 years), and discuss any abnormalities with a metabolic disease specialist. 1
Step 4: Assess Metabolic Risk Factors and Alcohol Use
Measure waist circumference, blood pressure, fasting glucose (or HbA1c), and fasting lipid panel to identify metabolic syndrome components (obesity, diabetes, hypertension, dyslipidemia), which are the primary drivers of NAFLD. 2
Obtain a detailed, quantitative alcohol history using validated tools (e.g., AUDIT or AUDIT-C); consumption ≥14–21 drinks/week in men or ≥7–14 drinks/week in women suggests alcoholic liver disease. 2
Review all prescription medications, over-the-counter drugs, and herbal supplements against the LiverTox® database, as medication-induced liver injury accounts for 8–11% of cases with mildly elevated liver enzymes. 2
Step 5: Risk-Stratify for Advanced Fibrosis
Calculate the FIB-4 score using age, ALT, AST, and platelet count to determine the need for hepatology referral: 1, 2
FIB-4 <1.3 (or <2.0 if age >65 years): Low risk for advanced fibrosis (negative predictive value ≥90%); continue monitoring and address underlying etiology. 1, 2
FIB-4 >2.67: High risk for advanced fibrosis; refer to hepatology for further evaluation, which may include transient elastography or liver biopsy. 1, 2
FIB-4 between 1.3 and 2.67: Indeterminate risk; consider second-line non-invasive tests (e.g., NAFLD Fibrosis Score, transient elastography) or hepatology consultation based on clinical context. 1, 2
Step 6: Determine Urgency and Referral Criteria
Urgent Referral to Secondary Care (Same Day or Within 48 Hours)
ALT or AST >10× ULN (severe elevation) or >20× ULN (life-threatening elevation). 2, 4
ALT or AST ≥3× ULN plus total bilirubin ≥2× ULN (Hy's Law pattern), which predicts high risk of acute liver failure. 2
Evidence of synthetic dysfunction: elevated INR, low albumin (<3.5 g/dL), or thrombocytopenia (<150 × 10⁹/L) suggesting advanced liver disease or acute liver failure. 1, 2
Clinical signs of hepatic decompensation: jaundice, ascites, encephalopathy, or variceal bleeding. 2, 4
Routine Hepatology Referral (Within 4–6 Weeks)
ALT >5× ULN (>235 IU/L for males, >125 IU/L for females) on repeat testing. 1, 2
Persistent elevation ≥6 months without an identified cause despite completion of the aetiology screen. 1, 2
FIB-4 score >2.67 indicating high risk for advanced fibrosis. 1, 2
Suspicion for autoimmune hepatitis (elevated immunoglobulins, positive autoantibodies) or other complex liver diseases requiring specialist evaluation. 1, 2
Step 7: Monitoring Strategy for Mild Elevations
For ALT <2× ULN: Repeat liver enzymes in 2–4 weeks to establish trend; if stable or improving, continue monitoring every 4–8 weeks until normalized. 2
For ALT 2–3× ULN: Repeat testing within 2–5 days and intensify the diagnostic evaluation (broaden infectious, metabolic, and medication reviews). 2
For ALT ≥3× ULN or doubling from baseline: Escalate monitoring frequency and consider urgent hepatology referral if no reversible cause is identified. 2
Common Pitfalls to Avoid
Do not assume mild elevations are benign without proper evaluation; even modest increases can reflect significant pathology, especially in women whose normal ALT range (19–25 IU/L) is lower than men (29–33 IU/L). 2
Do not overlook non-hepatic causes of elevated transaminases, such as intensive exercise, muscle injury (check creatine kinase), cardiac injury, hemolysis, or thyroid disorders, which can all elevate AST in particular. 2
Do not delay the aetiology screen based on the magnitude of abnormality; 75% of patients with abnormal liver enzymes remain abnormal at 2 years, so any abnormality warrants investigation. 3
Do not forget to calculate the FIB-4 score, a simple tool that identifies patients needing urgent specialist assessment and prevents missed diagnoses of advanced fibrosis. 1, 2
Normal ALT does not exclude significant liver disease; up to 50% of patients with NAFLD and 10% with advanced fibrosis may have normal ALT using conventional thresholds. 2