What is the initial workup for a patient with elevated Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)?

Workup for Elevated AST and ALT

For patients with elevated AST and ALT, begin with repeat testing within 1-2 weeks for mild elevations (<5× ULN) to confirm the abnormality, followed by a complete liver panel, viral hepatitis serologies, and abdominal ultrasound as first-line imaging. 1

Initial Laboratory Testing

Repeat liver enzymes within 1-2 weeks to establish the trend and confirm the elevation, as a single measurement may not represent true baseline. 1, 2 If the two ALT values differ by >50% and the higher value is >2× ULN, perform a third test to determine the direction of change. 3

Once elevation is confirmed, obtain:

• Complete liver panel: ALT, AST, alkaline phosphatase (ALP), GGT, total and direct bilirubin, albumin, and prothrombin time/INR 3, 1, 2
• Viral hepatitis serologies: HBsAg, anti-HBc (hepatitis B core antibody), and anti-HCV (hepatitis C antibody) 1, 2, 4
• Fasting lipid profile and glucose to assess for metabolic syndrome components 4
• Serum iron, ferritin, and total iron-binding capacity to screen for hemochromatosis 4
• Thyroid function tests (TSH, free T4) to exclude thyroid disorders as a cause of transaminase elevation 1, 5, 2
• Creatine kinase (CK) to rule out muscle disorders, particularly important since AST is present in cardiac muscle, skeletal muscle, and red blood cells 1, 5, 2, 6, 7

Clinical History Assessment

Obtain detailed information on:

• Alcohol consumption: Use validated screening tools like the AUDIT questionnaire; a score ≥8 or heavy drinking days (≥14-21 drinks/week in men, ≥7-14 drinks/week in women) suggests alcoholic liver disease 1, 5
• Complete medication review: Include prescription medications, over-the-counter drugs, and herbal supplements, as medication-induced liver injury accounts for 8-11% of cases with mildly elevated liver enzymes 1, 2, 4
• Metabolic syndrome components: Assess for obesity, diabetes, and hypertension as risk factors for nonalcoholic fatty liver disease (NAFLD), which affects up to 30% of the population 1, 2, 4
• Risk factors for viral hepatitis: Including intravenous drug use, high-risk sexual behavior, and occupational exposures 2, 4
• Recent excessive exercise or muscle injury: Can elevate AST more than ALT and may be mistaken for liver injury 1, 7

First-Line Imaging

Abdominal ultrasound is the recommended first-line imaging test, with sensitivity of 84.8% and specificity of 93.6% for detecting moderate to severe hepatic steatosis. 1, 2 It can identify:

• Hepatic steatosis (fatty liver)
• Biliary obstruction
• Focal liver lesions
• Structural abnormalities 1, 2

Interpretation of AST/ALT Pattern

• AST/ALT ratio <1: Characteristic of NAFLD, viral hepatitis, or medication-induced liver injury 1
• AST/ALT ratio >2: Highly suggestive of alcoholic liver disease; in approximately 70% of alcoholic hepatitis cases, the ratio exceeds 2 5
• Isolated AST elevation with normal ALT: Check CK first to exclude muscle or cardiac origin before pursuing extensive liver workup 5, 6, 8

Additional Testing Based on Initial Results

If initial workup is unrevealing, consider:

• α₁-antitrypsin level for α₁-antitrypsin deficiency 4
• Ceruloplasmin for Wilson disease (particularly in patients <40 years) 4
• Autoimmune markers: Antinuclear antibody (ANA), smooth muscle antibody (ASMA), and liver/kidney microsomal antibody type 1 for autoimmune hepatitis 1, 4
• Serum protein electrophoresis if immunoglobulin abnormalities are suspected 4

Monitoring Schedule Based on Severity

• Mild elevations (<5× ULN): Repeat within 1-2 weeks 1, 2
• Moderate elevations (5-10× ULN): Repeat within 2-5 days 1, 2
• Severe elevations (>10× ULN) or ALT >3× ULN with bilirubin ≥2× ULN: Repeat within 2-3 days with immediate comprehensive evaluation 1, 2

Once confirmed, monitor 2-3 times weekly initially, then reduce to once every 1-2 weeks as clinical condition stabilizes. 3, 2

Referral Criteria

Refer to hepatology if:

• Transaminases remain elevated for ≥6 months without identified cause 1, 2, 4
• ALT increases to >5× ULN (>235 IU/L for males using upper limit of 47 IU/L; >125 IU/L for females using upper limit of 25 IU/L) 1
• Evidence of synthetic dysfunction develops (elevated INR, low albumin, elevated bilirubin) 1, 2
• Suspicion for autoimmune hepatitis or advanced fibrosis 1

Important Considerations and Pitfalls

• ALT is more liver-specific than AST: ALT is primarily concentrated in liver tissue, while AST is present in cardiac muscle, skeletal muscle, kidney, and red blood cells 1, 5, 6, 8
• Normal ALT ranges differ by sex: 29-33 IU/L for males and 19-25 IU/L for females; what appears "normal" by laboratory standards may represent mild elevation in women 1, 5
• Don't assume benign etiology without proper evaluation: ALT elevation ≥5× ULN is rare in NAFLD alone and warrants investigation for viral hepatitis, autoimmune hepatitis, or drug-induced liver injury 1
• Consider macro-AST in isolated persistent AST elevation: A benign condition where AST is bound to immunoglobulins; confirm with polyethylene glycol (PEG) precipitation test 9
• Check CK before extensive workup for isolated AST elevation: Muscle disorders, including Duchenne's and Becker's muscular dystrophy, can cause marked elevations in AST, ALT, and LDH that mimic liver disease 7