What is the significance of Gamma-Glutamyl Transferase (GGT) in the setting of elevated Alkaline Phosphatase (Alk Phos)?

From the Guidelines

GGT is a crucial diagnostic tool in the setting of elevated alkaline phosphatase (ALP), as it helps differentiate between hepatobiliary and bone sources of elevated ALP, with concomitantly elevated GGT suggesting a liver origin for the abnormality. The value of GGT in this context lies in its ability to indicate whether pathologically elevated ALP is of hepatic or nonhepatic origin, as GGT is found in the liver but not in bone 1.

When interpreting GGT results, it is essential to consider the clinical context, including the patient's medical history, medications, and other laboratory findings. Elevated GGT can occur in various conditions, such as cholestasis, biliary obstruction, drug-induced liver injury, alcohol consumption, and pancreatic disease 1.

Key points to consider when evaluating elevated ALP and GGT include:

• Concomitantly elevated GGT and ALP suggest a hepatobiliary origin for the abnormality, pointing to conditions like cholestasis or biliary obstruction 1
• Isolated elevated ALP of hepatic origin may indicate a chronic cholestatic process, such as partial bile duct obstruction or primary biliary cholangitis 1
• Normal GGT levels in the presence of elevated ALP may suggest bone pathology, such as Paget's disease or osteomalacia 1
• Additional liver function tests, like bilirubin, ALT, and AST, are typically ordered alongside GGT and ALP to provide a comprehensive assessment of hepatobiliary function 1.

In clinical practice, elevated GGT in the setting of elevated ALP should prompt further evaluation, including imaging of the biliary tree, to determine the etiology of extrahepatic or intrahepatic cholestasis 1. This approach allows for timely diagnosis and management of underlying conditions, ultimately improving patient outcomes in terms of morbidity, mortality, and quality of life.

From the Research

Value of GGT in Setting of Elevated Alk Phosphatase

• The value of Gamma-Glutamyl Transferase (GGT) in the setting of elevated alkaline phosphatase (ALP) is a topic of interest in hepatobiliary disease diagnosis 2.
• GGT activity is elevated in cholestasis, but it is not liver-specific and can be induced by alcohol and certain drugs 2.
• A study found that GGT as a predictor of hepatic isoform elevation had an area under the ROC curve (AUC) of 0.68, and GGT activity above the upper reference limit was 46.6% sensitive and 85.0% specific for hepatic ALP elevation 3.
• The same study concluded that GGT was reasonably specific but insensitive for hepatic ALP isoform elevation and was a poor predictor of ALP isoform elevation overall, suggesting that its usefulness in evaluating isoenzymes orders is limited 3.
• Another study found that the gamma-glutamyl transpeptidase to alkaline phosphatase ratio (GAPR) combined with gamma-glutamyl transpeptidase to aspartate aminotransferase ratio (GAR) and alanine aminotransferase to aspartate aminotransferase ratio (AAR) was effective in diagnosing alpha-fetoprotein-negative hepatocellular carcinoma 4.
• In general, abnormal liver biochemical tests, including GGT and ALP, can be categorized based on the pattern and magnitude of aminotransferase elevation, and can be indicative of various hepatobiliary diseases 5.

GGT and ALP Elevation Patterns

• Elevated serum levels of transaminases (AST and ALT) usually indicate hepatocellular damage, while serum activities of AP and G-GT are elevated in cholestasis 2.
• A hepatic enzyme pattern (predominant transaminase elevation) should be discriminated from a cholestatic pattern (predominant AP and G-GT elevation) 2.
• The combination of GAPR, GAR, and AAR was most effective in differentiating alpha-fetoprotein-negative hepatocellular carcinoma patients from control groups 4.

Clinical Implications

• Accurate interpretation of liver biochemical tests, including GGT and ALP, is crucial for appropriate further workup, treatment, and referral, as prompt treatment can improve the natural history of several hepatobiliary diseases 5.
• GGT activity should be considered in the context of other laboratory parameters and clinical characteristics to determine its diagnostic value in specific patient populations 3, 4.