Is Serum Gamma-Glutamyltransferase a Biomarker of Xenobiotics, Which Are Conjugated by Glutathione?

Abstract

A meta-analysis of 10 prospective cohort studies,1 including our own,2 reported that serum γ-glutamyltransferase (GGT) predicted incident vascular events. This meta-analysis posed one important, but unsolved question: why does serum GGT predict incident vascular events? In addition to vascular events, serum GGT predicts various important clinical outcomes including type 2 diabetes, metabolic syndrome, and renal problems.3–5 Serum GGT has traditionally been used as a marker of alcohol consumption; however, alcohol consumption cannot explain the disease relationships with serum GGT because these associations have been observed among nondrinkers as well as drinkers. The other prevailing interpretations are that serum GGT predicts clinical outcomes as a marker of nonalcoholic fatty liver disease (NAFLD) or oxidative stress.6–8 Although both of these explanations have some merit, each also has problems. Although not clearly stated in many of the reports,1–5 most associations of serum GGT with clinical outcomes were dose-response relations within the normal range of serum GGT; we submit that this aspect of the association is critical to interpretation. First, even though NAFLD may partially explain the associations among subjects with a relatively high serum GGT activity and NAFLD can present even among subjects with low normal serum GGT, NAFLD is unlikely to fully explain the graded associations with clinical outcomes which were observed among subjects with serum GGT in the low part of its normal range, less than 20 or 30 U/L. However, it is worthwhile to note that serum GGT may be a predictor of the future risk of NAFLD. In a prospective study by our group,9 serum GGT within its normal range strongly predicted the future risk of chronic elevation of serum alanine aminotransferase (ALT), but serum ALT within its normal range did not predict the future risk of chronic elevation of serum GGT. The …