Background information
Gamma-glutamyl transferase (GGT; EC2.3.2.2.) is an enzyme located on the external surface of membranes of various cells. Mammalian GGT is a dimeric glycoprotein with a molecular weight of 68 kDa consisting of 2 subunits: a 46 kDa large subunit and a 22 kDa small subunit. The large subunit has an intracellular N-terminal sequence, a transmembrane hydrophobic domain and an extracellular domain and is responsible for GGT anchorage on the cellular membrane surface whereas the small subunit harbors the enzyme active center (1). GGT is present in all cells with the exception of erythrocytes. GGT activity was reported to be particularly high in tissues with secretory and absorptive function such as kidney, biliary system, intestine and epididymis and the enzyme activity is greatest in the ductal luminal surface of these tissues (3).
GGT functions are not entirely known. Cleavage of glutathione—the main thiol antioxidant in humans—is the most important physiological function of GGT. Glutathione has profound cellular functions including protection from oxidative stress, redox signaling, detoxification of xenobiotics, cellular proliferation, fibrogenesis, nitric oxide metabolism, storage and transport of cysteine, sulphur metabolism and apoptosis (10). Glutathione is synthesized in the cytoplasm of cells via a cycle of reactions proposed by Meister (9). After synthesis, glutathione is transported out of the cell and is degraded by GGT into glutamyl moiety (transferred to water or other compounds such as amino acids or peptides) and dipeptide cysteinyl-glycine which is further degraded by dipeptidase into free cysteine and glycine (Figure 1). Glutathione breakdown in the extracellular space increases the availability of cysteine which is taken up by the cells and used as an essential precursor for the intracellular synthesis of glutathione and proteins. Thus GGT contributes in maintaining the physiological concentrations of glutathione in cytoplasm and cellular defense against oxidative stress.
Circulating GGT is supposed to originate mostly from the liver (12,13) and is influenced by genetic and environmental factors (14).
The list of GGT involvement in pathological processes is long. Nevertheless, outside the clinical use as a test for hepatobiliary disease and alcohol abuse, GGT has garnered large interest for its association with cardiovascular disease (CVD), diabetes, metabolic syndrome and cancer. The focus of this review is to summarize the existing knowledge on the association of GGT with CVD.
GGT, CVD and mortality
Several population-based studies have investigated the association of GGT with CVD or risk of death. The Framingham Offspring Study (FOS) was one of the first epidemiological studies initiated to test the association of GGT with cardiovascular risk and disease. In its second examination cycle, 3,451 patients were recruited between 1978 and 1982 and followed up to a mean of 19 years. GGT was associated with higher body mass index, blood pressure, low-density lipoprotein (LDL)-cholesterol, triglycerides and glucose. On the follow-up, per each standard deviation (SD) higher log GGT, the risk for metabolic syndrome increased by 26%. After adjustment for cardiovascular risk factors, GGT conferred a 13% and 26% increase in the risk for CVD and mortality for each SD higher log GGT. Subjects in the highest GGT quartile showed a 67% increase in the incidence of CVD. The study clearly showed that increased activity of circulating GGT predicted the onset of metabolic syndrome, incident CVD and mortality hinting a role for GGT as a marker of metabolic and cardiovascular risk (19).
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In aggregate, evidence from epidemiological studies as regards the association of GGT with the risk for CVD or mortality may be summarized as follows: first, epidemiological evidence strongly supports an association between elevated GGT and incident CVD, stroke or all-cause and CVD-related mortality which appears to be stronger in subjects of younger age. Second, there seems to be a strong correlation between elevated GGT and cardiometabolic risk factors which tend to cluster in subjects with higher GGT levels. Consequently, whether GGT provides prognostic information on top of cardiovascular and metabolic risk factors for prediction of CVD or mortality remains unproven. Third, evidence available is not consistent as regards the association between elevated GGT activity and the risk for acute ischemic events, particularly acute myocardial infarction. Fourth, although a significant association between elevated GGT and CVD or mortality is observed in both sexes, more sex-specific analyses are needed to clarify some existing controversy. Whether the association between GGT and CVD or mortality is weaker in Asian population needs further investigation.
GGT and coronary events or mortality in patients with CHD
It has been suggested that the presence CHD may strengthen the association between GGT and mortality (20). Emdin et al. (39) assessed the association of GGT with mortality or mortality plus nonfatal myocardial infarction over a 6-year follow-up in 469 patients with angiography-documented CHD. In a subgroup of 262 patients with previous myocardial infarction, cardiac mortality (25.2% vs. 13.9%; P=0.038) or cardiac mortality plus nonfatal myocardial infarction (32.7% vs. 20.4%; P=0.031) were higher in patients with a GGT >40 U/L versus those with GGT <40 U/L. The association between GGT and cardiac events remained significant after adjustment for potential confounders including alcohol consumption.
In aggregate, evidence for an association of GGT with coronary events and mortality in patients with established CHD is weaker than the evidence obtained from epidemiological studies investigating the association of GGT with incident CHD or mortality. Particularly, whether GGT offers prognostic information that is incremental to the information provided by conventional risk factors remains still questionable. Despite using coronary angiography—the gold standard for diagnosis of CHD—studies that assessed GGT in patients with established CHD included smaller numbers of patients and had a short follow-up.
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Mechanisms of GGT association with CVD
Several putative explanations may be offered to explain the association of elevated GGT with the risk for CVD or CVD-related mortality. GGT is closely associated with established cardiovascular risk factors (which tend to cluster in patients with higher GGT level), metabolic syndrome and insulin resistance (18). Elevated GGT may be a marker of antioxidant inadequacy and of increased oxidative stress (17). Circulating GGT levels are also closely correlated with the markers of inflammation and thus its elevated activity may signify a heightened inflammatory state (80). Ample evidence exists that all these conditions—cardiovascular risk factors, metabolic syndrome, insulin resistance, increased oxidative stress and systemic inflammation are great promoters of CVD and CVD-related mortality. In this regard, elevated GGT may be considered a marker of increased cardiometabolic stress, in general. The close association of GGT with alcohol consumption may also explain the association of GGT and all-cause mortality (81) and cardiac arrhythmias, particularly atrial fibrillation (82). Nevertheless, light and moderate alcohol consumption are inversely associated with myocardial infarction and CVD mortality (81). Nonalcoholic fatty liver—the most common cause of chronic liver disease, with a prevalence up to 70% in diabetic patients—is associated with the increased activity of GGT and other liver enzymes in addition to more prevalent CVD (83). Nonalcoholic fatty liver disease is associated with an array of cardio-metabolic disorders, for which it is considered a metabolic syndrome equivalent. It has been proposed that GGT may indicate a link between fatty liver and early atherosclerotic disease (84). Not surprisingly, the adjustment for fatty liver has attenuated the association between GGT and CVD mortality (58). Nonalcoholic fatty liver disease is associated with the risk of ventricular arrhythmias (85) and atrial fibrillation (86). In particular, elevated GGT is associated with the increased risk for atrial fibrillation either because both conditions share similar risk factors or because of ectopic fat accumulation in atrial myocardium (87) which may modulate the electrophysiological properties and ion currents predisposing for arrhythmogenesis (88). Finally, evidence available suggests a direct participation of GGT in the pathophysiology of CVD, particularly atherosclerosis, on cellular and molecular level. The breakdown of glutathione by GGT in the extracellular space leads to production of cysteinyl-glycine dipeptide—even a stronger reducing agent than glutathione. The cysteinyl-glycine moiety acts as a strong reducing agent of iron from Fe3+ to Fe2+ which subsequently catalyzes formation of super-oxide and hydrogen peroxide. These species promote peroxidation reactions (including low-density lipoproteins) and exert a local pro-oxidant and proinflammatory action (Figure 1). There is evidence that these reactions occur within atherosclerotic plaques and they present the most accepted putative mechanism of a direct participation of GGT in the pathophysiology of atherosclerosis leading to promotion of atherosclerotic process, plaque instability and coronary ischemic events (89). Catalytically active GGT is found in atherosclerotic plaques (90) and the GGT activity within the atherosclerotic plaques was found to correlate with systemic GGT activity (91) and histological indexes of plaque instability (92).
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(1) Ann Transl Med. 2016 Dec; 4(24): 481