What is the basic workup for patients with elevated Gamma-Glutamyl Transferase (GGT), Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT)?

Evaluation of Elevated GGT, AST, and ALT

The basic workup for elevated GGT, AST, and ALT should begin with abdominal ultrasound and a comprehensive laboratory panel to identify the underlying cause, followed by targeted testing based on initial findings. 1

Initial Laboratory Evaluation

• Complete liver panel:

  • AST, ALT, ALP, GGT, total and direct bilirubin
  • Albumin and PT/INR (to assess synthetic function)
  • Calculate AST:ALT ratio (>2 suggests alcoholic liver disease) 2, 1

• Core laboratory tests:

  • Viral hepatitis serology: HAV-IgM, HBsAg, HBcIgM, HCV antibody 1
  • Metabolic panel and lipid profile (to evaluate for NAFLD/NASH) 1
  • Fasting glucose (to assess for diabetes/insulin resistance) 1

• Imaging:

  • Abdominal ultrasound (first-line investigation with 84.8% sensitivity and 93.6% specificity for moderate-to-severe fatty infiltration) 1

Classification of Liver Enzyme Elevations

Liver enzyme elevations are typically classified as 1:

Classification	Level of Elevation
Mild	<5× ULN
Moderate	5-10× ULN
Severe	>10× ULN

Additional Testing Based on Initial Findings

For suspected autoimmune disease:

• Autoimmune markers: ANA, ASMA, ANCA 1

For suspected metabolic/genetic disorders:

• Iron studies (ferritin, serum iron, TIBC) if hemochromatosis is suspected 1, 3
• Ceruloplasmin if Wilson disease is suspected, especially in younger patients 1
• Alpha-1 antitrypsin levels if deficiency is suspected 1, 3

For suspected alcoholic liver disease:

• Detailed alcohol consumption history (>30g/day for men, >20g/day for women increases risk) 2
• Look for AST:ALT ratio >2 (characteristic of alcoholic liver disease) 1

For medication-related injury:

• Review all current medications, including over-the-counter drugs and supplements 1
• Consider discontinuation of suspected hepatotoxic medications 1

For extrahepatic causes:

• Thyroid function tests (hypothyroidism can cause elevated liver enzymes) 4, 3
• Celiac disease screening 3
• CK levels if muscle disorders are suspected 4

Advanced Assessment

• Calculate FIB-4 score to assess risk of advanced fibrosis 1
• Consider non-invasive fibrosis assessment with elastography (FibroScan/ARFI) if available 1
• Consider liver biopsy if:
  • Diagnosis remains unclear after non-invasive testing 1
  • Suspected autoimmune hepatitis requires confirmation 1
  • Elevated liver enzymes persist for >6 months without clear cause 3

Monitoring and Follow-up

• For mild elevations: repeat liver enzymes in 1-3 months 1
• For moderate to severe elevations or persistent abnormalities: refer to gastroenterology/hepatology 1
• Monitor response to any interventions (medication discontinuation, lifestyle changes) 1

Common Pitfalls to Avoid

• Isolated GGT elevation is not sufficient to qualify as liver injury and may simply indicate enzyme induction 2
• Liver enzyme elevations may not correlate with the degree of liver damage in chronic viral hepatitis 4
• Non-alcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in Western countries (20-30% prevalence) and should be considered early in the workup 1
• When calculating the pattern of liver injury (R value), AST can reliably replace ALT, but GGT can only substitute ALP when the R value scores as hepatocellular 5