Gamma-glutamyltransferase, atherosclerosis, and cardiovascular disease: triggering oxidative stress within the plaque.

The serum determination of gamma-glutamyltransferase (γ-GT) activity is a low-cost, highly sensitive and accurate, and frequently used laboratory test. Although it is considered to be an index of hepatobiliary dysfunction and alcohol abuse,1 recent epidemiology and pathology studies have suggested its independent role in the pathogenesis and clinical evolution of cardiovascular diseases brought on by atherosclerosis.1,2 Article p 2130 The prospective study by Ruttman and colleagues in 163 944 Austrian adults studied for 17 years shows that γ-GT is independently associated with cardiovascular mortality.3 Serum γ-GT activity had a prognostic impact on fatal events of chronic forms of coronary heart disease, congestive heart failure, and ischemic or hemorrhagic stroke. This was found to be true in both sexes, with a clear dose-response relationship, and with a stronger prognostic significance of γ-GT in younger participants. These findings from a large unselected cohort unequivocally confirm previous observations that γ-GT is associated with overall mortality and cardiovascular events, in both unselected populations4–7 and patients with ascertained coronary artery disease, independent of all confounders including liver function and alcohol use.8,9 γ-GT is the enzyme responsible for the extracellular catabolism of glutathione (GSH, γ-glutamyl-cisteinyl-glycine), the main thiol intracellular antioxidant agent in mammalian cells.1 It is present, linked through a small lipophilic sequence of its larger subunit, on the cell surface membrane of most cell types; although the same protein is produced in all tissues, differences in the sugar moieties allow that only the liver γ-GT is detectable in serum.10 Most serum γ-GT is bound to carriers, such as α- and β-lipoproteins and albumin.1 This association is likely to occur within hepatocytes, before γ-GT releases in serum, through still-unknown mechanisms. Serum γ-GT activity is affected by genetic and environmental factors, with heritability estimated at 0.52.11 Within its …