Gamma glutamyl transferase ‘To be or not to be’ a liver function test?

Liver function tests or LFTs are commonly requested blood tests, usually as a panel or group request rather than as individual components. The term is a misnomer, since many of the individual analytes measured as part of the panel have no relationship to liver function, but reflect tissue damage to the liver and other organs. Liver function testing has become almost a routine reflex test added on to any venepuncture performed on a patient, often being used as a test of ‘wellness’; this has led to an explosion in the number of patients tested. In Tayside, Scotland, over 60% of the resident population had LFTs checked in a 20-year period. As the rate of testing has increased, the proportion of abnormality has remained the same at 17–20%. In tandem with this increase in testing, there has been a significant rise in liver disease, being the only major cause of death to be increasing in those under the age of 65. So there are calls for initiatives to use LFTs to identify significant liver disease early, when interventions for alcohol, antiviral treatment for hepatitis C or B virus (HCV) and weight loss for non-alcoholic fatty liver disease (NAFLD) can have significant beneficial effects. The composition of the ‘LFT’ panel varies, but bilirubin, albumin, alanine aminotransferase (ALT) and alkaline phosphatase are almost ubiquitous; aspartate aminotransferase (AST) and gamma glutamyl transference (GGT) are only occasionally included. GGT is present in the cell membranes of many tissues, including kidneys, bile duct, pancreas, gallbladder, spleen, heart, brain and seminal vesicles. It consists of two polypeptide chains, a heavy and a light subunit, with the active site in the light subunit. GGT is involved in the transfer of amino acids across the cellular membrane and leukotriene metabolism. It is also involved in glutathione metabolism by transferring the glutamyl moiety, leaving the cysteine product to preserve intracellular homeostasis of oxidative stress. The contraction of the LFT panel has been driven in part by cost considerations. For example with respect to evidence of hepatocyte damage, the argument is that the clinical information derived from AST is similar and less specific for liver than for ALT, so that only the ALT is required to be measured. A similar argument is advanced for the GGT and alkaline phosphatase, both reflecting biliary disease. However, this view of AST and GGT as simple surrogates of ALT and alkaline phosphatase, respectively, is an over-simplification that only holds true if each test is looked at in isolation, which is not what happens in clinical practice. GGT has a sensitivity for the diagnosis and prognosis of liver disease beyond its association with biliary disease and the alkaline phosphatase. This may be due to its function in the control of redox status. It is a well-known marker of alcohol excess; more recently, slightly elevated serum GGT has also been found to correlate with cardiovascular disease and is under active investigation as a cardiovascular risk marker. GGT in fact accumulates in atherosclerotic plaques, suggesting a potential role in pathogenesis of cardiovascular diseases. This correlates with its strong association with the metabolic syndrome and NAFLD. It remains unclear if NAFLD drives the cardiovascular risk, with GGT merely a surrogate biomarker, or if GGT has a more direct pathogenetic role. GGT can be used in different diagnostic and prognostic algorithms or scores for liver disease. It is one of