What is Gamma Glutamyl Transferase (GGT)?

Gamma-Glutamyl Transferase (GGT)

Gamma-glutamyl transferase (GGT) is a liver enzyme located on plasma membranes of most cells and organ tissues (particularly hepatocytes) that plays a primary role in extracellular glutathione catabolism, serving as an important marker of liver injury and oxidative stress. 1, 2

Biochemical Properties and Function

• GGT is a transferase enzyme involved in the transpeptidation of gamma-glutamyl groups to various receptor molecules 3
• Primary physiological functions:
  • Extracellular catabolism of glutathione (the major cellular antioxidant)
  • Plays crucial role in cellular defense against oxidative stress
  • Involved in xenobiotic metabolism
  • Paradoxically can also have pro-oxidant effects 2, 3

Clinical Utility

Liver Disease Assessment

• GGT is a sensitive marker for liver injury, though lacks specificity for particular etiologies 3
• Often used in conjunction with other liver enzymes:
  • Elevated GGT + normal ALP may indicate alcohol use, medication effects, or early liver disease
  • Elevated GGT + elevated ALP suggests cholestatic liver disease 1
• An isolated increase in GGT is not associated with major liver pathology and is not an adequate indication on its own for liver biopsy 4

Cholestatic Disease Evaluation

• GGT is elevated in cholestatic liver disease, with significant elevations in obstructive jaundice 1
• In acute calculous cholecystitis, GGT has been identified as the most reliable liver function test for detecting common bile duct stones, with a sensitivity of 80.6% and specificity of 75.3% using a cut-off level of 224 IU/L 4

Beyond Liver Disease

GGT has emerged as an important biomarker for multiple conditions:

1. Cardiovascular Disease:

   • Independent biomarker associated with increased cardiovascular risk and mortality 1, 5, 6
   • Associated with atrial fibrillation and exacerbation of congestive heart failure 5

2. Metabolic Disorders:

   • Strong predictor of metabolic syndrome and its components 5, 6
   • Associated with abnormal BMI, HDL cholesterol, glucose, triglycerides, and blood pressure 6
   • Linked to nonalcoholic fatty liver disease (NAFLD) 2

3. Other Conditions:

   • Early predictive marker for atherosclerosis, heart failure, arterial stiffness and plaque 7
   • Associated with gestational diabetes 7
   • Linked to obstructive sleep apnea 5
   • Predictor of various cancers and all-cause mortality 7, 3

Interpretation Considerations

• GGT lacks specificity for hepatobiliary disease and can be elevated in various conditions 1
• Medications can affect GGT levels, potentially leading to false interpretations 1
• GGT >2× upper limit of normal should be considered for immediate investigation, especially with symptoms 1
• When elevated, GGT should be interpreted in context with other liver enzymes and clinical presentation

Pitfalls in GGT Interpretation

• Assuming normal transaminases rule out significant liver disease (cholestatic disorders can progress with minimal transaminase elevation) 1
• Failing to consider drug-induced cholestatic liver injury, which can occur 2-12 weeks after starting a medication 1
• Attributing elevated alkaline phosphatase solely to liver disease without confirming hepatic origin via GGT 1

GGT has evolved from being considered merely a marker of alcohol consumption and liver dysfunction to a valuable biomarker with significant predictive utility across multiple disease states, particularly in cardiovascular and metabolic conditions.