What is Gamma-Glutamyl Transferase (GGT)?

What is GGT (Gamma-Glutamyl Transferase)?

GGT (gamma-glutamyl transferase or gamma-glutamyl transpeptidase) is a liver enzyme located on plasma membranes of most cells and organ tissues (particularly hepatocytes) that plays a key role in glutathione metabolism and serves as a valuable biomarker for liver dysfunction, alcohol consumption, and oxidative stress. 1

Physiological Function of GGT

• Primary role: Catalyzes the extracellular catabolism of glutathione, the major thiol antioxidant in mammalian cells 2
• Cellular defense: Plays an important role in protecting cells against oxidants produced during normal metabolism 2
• Dual nature: While primarily involved in antioxidant defense mechanisms through glutathione recycling, GGT can paradoxically also have pro-oxidant effects, particularly in the presence of iron 3, 4

Clinical Significance and Diagnostic Value

As a Biomarker for Liver Disease

• GGT is a sensitive indicator of liver injury but has limited specificity for particular etiologies 1
• Elevated in various liver conditions:
  • Alcoholic liver disease (ALD)
  • Non-alcoholic fatty liver disease (NAFLD)
  • Biliary obstruction
  • Viral hepatitis
  • Drug-induced liver injury (DILI)

As a Marker for Alcohol Consumption

• One of the most frequently used markers to detect previous alcohol consumption with a sensitivity of 73% for detecting daily ethanol consumption >50g 5
• Higher specificity (75%) compared to AST (82%) and ALT (86%) for alcohol detection 5
• Remains the most frequently used marker for early detection of chronic alcohol misuse due to its ease of measurement and low cost 5

Interpretation Considerations

• GGT loses specificity in advanced liver disease as it becomes elevated with extensive fibrosis regardless of cause 5
• Influenced by multiple factors beyond alcohol:
  • Body mass index (BMI)
  • Sex
  • Medications (enzyme-inducing drugs)
  • Metabolic conditions 5, 1

Beyond Liver Disease: GGT as a Predictor of Other Conditions

GGT has emerged as a predictive biomarker for multiple conditions:

• Cardiovascular disease: Independent predictor of coronary heart disease risk, arterial stiffness and plaque 1, 6
• Metabolic disorders: Associated with metabolic syndrome, type 2 diabetes, and gestational diabetes 1, 7
• Mortality risk: Linked to all-cause mortality, with higher GGT levels correlating with increased risk 7, 6
• Oxidative stress: Considered a biomarker for oxidative stress associated with glutathione metabolism 6

Evaluation of Elevated GGT

When GGT is elevated, the following patterns can help with diagnosis:

• Elevated GGT + normal ALP: Consider alcohol use, medication effect, or early liver disease 1
• Elevated GGT + elevated ALP: Suggests cholestatic liver disease 1
• Elevated GGT + elevated AST/ALT (ratio >2): Suggests alcoholic liver disease 1

Monitoring and Follow-up

• Mild isolated elevation of GGT should be repeated in 3-6 months 1
• GGT >2× upper limit of normal warrants immediate investigation, especially with symptoms 1
• Combining GGT with other biomarkers and clinical assessment provides more accurate diagnosis 1

Clinical Applications

GGT measurement is valuable in:

• Screening for alcohol-related liver disease
• Evaluating unexplained liver enzyme elevations
• Risk stratification for cardiovascular and metabolic diseases
• Monitoring response to lifestyle modifications in patients with metabolic syndrome
• Detecting early drug-induced liver injury, even when conventional thresholds aren't reached 1

GGT has evolved from being merely a liver function test to an important biomarker with significant implications for predicting and monitoring a wide range of diseases beyond the liver.