Is Serum-Glutamylatransferase a Biomarker of Xenobiotics Which Are Conjugated by Glutathione?
GGT has long been used as a marker of alcohol consumption. However, we have shown that an association between GGT and cardiovascular disease exists even among nondrinkers.1 What then explains these findings? In their letter, Lee and colleagues explore the evidence supporting their suggestion that GGT is a marker of environmental exposure to xenobiotics. Lee et al present a comprehensive case in support of their hypothesis that GGT levels are determined by exposure to environmental pollutants. We would like to highlight several points that do not contradict the interpretation offered by Lee and colleagues but which may require additional investigation to resolve.
Lee at al argue that nonalcoholic fatty liver diseases (NAFLD) are not a likely determinant of GGT levels as it cannot explain the association of GGT and clinical outcomes in the lower range of the GGT distribution. Liver fat content is a continuum that is dichotomised to define the clinical condition NAFLD. Present evidence does not contradict, nor strongly support, the suggestion that GGT levels are determined by the degree of liver fat content, by which individuals with low-normal levels of GGT having no or very little liver fat. This is because of a lack of present evidence to determine this either way. Very few studies provide information comparing the association of alanine aminotransferase (ALT), the liver enzyme routinely used in screening and diagnosing NAFLD, to the association of GGT with the degree of liver fat content, and results of existing studies are contradictory.2,3
GGT is present in atherosclerotic plaques and therefore may contribute to plaque evolution and rupture.4 GGT levels have been shown to have a negative prognostic value for survival among patients with existing cardiovascular and coronary artery conditions.5,6 This suggests that GGT may be associated with later stages of disease progression and not only with the initial stages. Alternatively these finding may be a result of reverse causality. Whichever the case, it is unlikely that exposure to environmental toxics is the key mechanism underlying the association of GGT with adverse outcomes among patients with existing cardiovascular disease to be explained by, although this would require further investigation.
Finally, we agree with Lee et al that epidemiological population based studies alone will probably not provide a definitive answer to what determines GGT levels or the underlying mechanisms explaining its association with cardiovascular and other health outcomes. A combination of a molecular level approach and epidemiological population based studies will probably be necessary for that. However it may be important to remember that GGT is present in most cell types.4 Therefore, it is likely that more than one factor, as well as the balance between these factors determine circulating GGT levels.
Fraser A, Harris R, Sattar N, Ebrahim S, Smith GD, Lawlor DA. Gamma-glutamyltransferase is associated with incident vascular events independently of alcohol intake: analysis of the British Women’s Heart and Health Study and meta-analysis. Arterioscler Thromb Vasc Biol. 2007; 27: 2729–2735.
Westerbacka J, Corner A, Tiikkainen M, Tamminen M, Vehkavaara S, Hakkinen AM, Fredriksson J, Yki-Jarvinen H. Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk. Diabetologia. 2004; 47: 1360–1369.
Emdin M, Pompella A, Paolicchi A. Gamma-glutamyltransferase, atherosclerosis, and cardiovascular disease: triggering oxidative stress within the plaque. Circulation. 2005; 112: 2078–2080.
Karlson BW, Wiklund O, Hallgren P, Sjolin M, Lindqvist J, Herlitz J. Ten-year mortality amongst patients with a very small or unconfirmed acute myocardial infarction in relation to clinical history, metabolic screening and signs of myocardial ischaemia. J Intern Med. 2000; 247: 449–456.
Emdin M, Passino C, Michelassi C, Titta F, L’abbate A, Donato L, Pompella A, Paolicchi A. Prognostic value of serum gamma-glutamyl transferase activity after myocardial infarction. Eur Heart J. 2001; 22: 1802–1807.