What is the appropriate workup for an adult patient with elevated transaminase levels and no known history of liver disease?

Workup for Elevated Transaminase Levels in Adults

Initial Confirmation and Repeat Testing

Repeat liver enzymes within 2-4 weeks to establish true persistence, as single elevations may reflect transient processes or laboratory variation. 1, 2

• A complete liver panel must include ALT, AST, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and prothrombin time/INR to assess for cholestatic patterns and synthetic function 1, 2
• Check creatine kinase to rule out muscle disorders as a cause of AST elevation, particularly if recent intensive exercise or muscle injury occurred 2, 3

First-Line Laboratory Testing

Obtain viral hepatitis serologies (HBsAg, anti-HBc, anti-HCV antibody) and assess metabolic parameters (fasting lipid profile, glucose, hemoglobin A1c) as these identify the most common causes. 1, 2, 4, 5

• Iron studies (serum iron, ferritin, total iron-binding capacity) should be performed to screen for hereditary hemochromatosis 1, 4, 5
• Thyroid function tests to rule out thyroid disorders as a cause of transaminase elevations 2, 3
• Assess alcohol consumption: >21 standard drinks per week in men and >14 standard drinks per week in women suggests alcoholic liver disease 1
• Complete medication review including all prescription drugs, over-the-counter medications, and herbal supplements to identify potential hepatotoxic agents 1, 2, 3

Risk Factor Assessment and Pattern Recognition

• An AST:ALT ratio <1 suggests nonalcoholic fatty liver disease, viral hepatitis, or medication-induced injury 1, 6
• An AST:ALT ratio ≥2 is highly suggestive of alcoholic liver disease 3
• Assess for metabolic syndrome components (obesity, diabetes, hypertension, dyslipidemia) as NAFLD affects up to 30% of the population and is the most common cause 1, 2, 4, 5

Imaging Evaluation

Abdominal ultrasound is the initial imaging modality of choice, with 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis. 1, 2, 3

• Ultrasound identifies fatty liver, biliary obstruction, focal liver lesions, and structural abnormalities 2, 3

Fibrosis Risk Stratification

Calculate the FIB-4 index using age, ALT, AST, and platelets to assess fibrosis risk, with a score >2.67 indicating high risk for advanced fibrosis requiring hepatology referral. 1, 2, 3

• FIB-4 score <1.3 (<2.0 in those older than 65 years) indicates low risk with negative predictive value ≥90% 3

Second-Line Testing (If Initial Workup Negative)

• α₁-antitrypsin level and phenotype for α₁-antitrypsin deficiency 4, 5
• Ceruloplasmin level for Wilson disease (particularly in patients <40 years) 4, 5
• Autoimmune markers: antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and liver/kidney microsomal antibody type 1 for autoimmune hepatitis 4, 5
• Celiac serologies (tissue transglutaminase antibody) as celiac disease can cause elevated transaminases 4, 5

Monitoring Strategy Based on Severity

• For mild elevations (<5× ULN): Repeat liver enzymes in 2-4 weeks to establish trend 1, 2
• For moderate elevations (5-10× ULN): Repeat within 2-5 days with full liver panel 2
• For severe elevations (>10× ULN) or ALT >3× ULN with bilirubin >2× ULN: Immediate evaluation with repeat testing within 2-3 days 2
• For confirmed mild elevations with identified cause (e.g., NAFLD), monitor ALT every 3 months during the first year to verify stability 1

Referral Criteria

Refer to hepatology if transaminases remain elevated for ≥6 months without an identified cause, or if there is evidence of synthetic dysfunction (elevated INR, low albumin), or if FIB-4 score >2.67. 1, 2, 3

• Consider liver biopsy if diagnosis remains unclear after non-invasive evaluation, particularly when results will influence treatment decisions 6, 2, 3

Common Pitfalls to Avoid

• Don't assume mild elevations are benign without proper evaluation—up to 80% of patients with NASH may be identified on the basis of elevated transaminases 6
• Don't overlook non-hepatic causes: intensive exercise, muscle injury, cardiac injury, hemolysis, and thyroid disorders can all elevate transaminases, particularly AST 2, 3
• Don't forget that normal ALT does not exclude significant liver disease—up to 50% of patients with NAFLD have normal liver chemistries 6
• Don't delay hepatitis E testing in patients with suspected drug-induced liver injury and markedly elevated transaminases, as hepatitis E can present identically 7