What is Gamma-Glutamyl Transferase (Gamma GT)?
Gamma-glutamyl transferase (GGT) is a liver enzyme located on the plasma membranes of most cells and organ tissues, particularly hepatocytes, that plays a primary role in the extracellular catabolism of glutathione and is routinely used in clinical practice as a sensitive marker of liver injury and cholestasis. 1
Biochemical Function and Location
- GGT is found in the liver, kidneys, intestine, prostate, and pancreas, but notably not in bone, which makes it useful for distinguishing the source of elevated alkaline phosphatase 2
- The enzyme's primary physiological role is the extracellular breakdown of glutathione, the major thiol antioxidant in mammalian cells, thereby playing a crucial role in cellular antioxidant defense mechanisms 1, 3
- GGT performs transpeptidation of functional gamma-glutamyl groups to various receptor molecules and is involved in glutathione recycling and xenobiotic metabolism 3
- Most of the enzyme is linked to the microsomal fraction in cells, with very low cytosoluble fraction 4
Clinical Utility as a Diagnostic Marker
- GGT is highly sensitive for detecting liver injury but has poor specificity for particular etiologies, making it most useful when interpreted alongside other liver enzymes 3
- When alkaline phosphatase is elevated, concomitantly elevated GGT confirms that the elevated alkaline phosphatase originates from the liver rather than bone and indicates cholestasis 2
- GGT increases occur earlier and persist longer than alkaline phosphatase elevations in cholestatic disorders 5, 2
- Bilirubin level, prothrombin time, and GGT remain normal throughout pregnancy, and any elevation should be evaluated 5
Common Causes of Elevated GGT
- Alcohol consumption is the most common cause of elevated GGT, occurring in about 75% of habitual drinkers, with daily consumption exceeding 60g leading to elevations 2
- Cholestatic liver diseases including primary biliary cholangitis, primary sclerosing cholangitis, and bile duct obstruction cause elevated GGT 2
- Medications that commonly elevate GGT include interferon, antipsychotics, beta-blockers such as atenolol, bile acid resins, estrogens, protease inhibitors, retinoic acid drugs, sirolimus, steroids, tamoxifen, and thiazides 2
- Metabolic conditions including diabetes, insulin resistance, obesity, and nonalcoholic fatty liver disease can cause elevated GGT 2, 1
- Viral hepatitis, cirrhosis, and other chronic liver diseases elevate GGT 2
Broader Clinical Significance Beyond Liver Disease
- GGT has been linked to a remarkable array of chronic conditions beyond liver disease, including cardiovascular disease, metabolic syndrome, chronic kidney disease, and increased all-cause mortality 1, 6, 7
- Even mildly elevated GGT independently predicts increased risk for cardiovascular disease, diabetes, metabolic syndrome, and all-cause mortality due to its role in oxidative stress and cellular antioxidant defense mechanisms 2
- In the upper reference range, GGT is an independent biomarker of metabolic syndrome, with a 20% per GGT quartile trend rise 6
- GGT was positively correlated with an 18% per quartile risk of cardiovascular events and a 26% per quartile increased risk of all-cause mortality 6
- The enzyme may be considered a biomarker for oxidative stress associated with glutathione metabolism and possibly a proatherogenic marker because of its indirect relationship in the biochemical steps to LDL cholesterol oxidation 6
Important Diagnostic Limitations
- Isolated GGT elevations can occur in the absence of underlying liver disease, and therefore GGT should not be used as an exclusion criterion or sole marker of liver disease 2
- GGT elevation alone has low specificity and should be interpreted in context with other liver enzymes 2
- In advanced liver disease with extensive fibrosis, GGT loses its specificity and becomes elevated regardless of the underlying cause, making it a marker of disease severity rather than etiology in cirrhotic patients 2