Gamma Glutamyltransferase and Long-Term Survival: Is It Just the Liver?

Kazemi-Shirazi, Lili; Endler, Georg; Winkler, Stefan; Schickbauer, Thomas; Wagner, Oswald; Marsik, Claudia

doi:10.1373/clinchem.2006.081620

Cited by 127 publications

(137 citation statements)

References 25 publications

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“…The study by Kazemi-Shirazi et al (23) investigated the association of GGT with the risk of mortality in a cohort of 283,438 first attendants (inpatients or outpatients). The median follow-up was 7.6 years.…”

Section: Ggt Cvd and Mortalitymentioning

confidence: 99%

Gamma-glutamyl transferase and cardiovascular disease

Ndrepepa¹,

Kastrati²

2016

Ann. Transl. Med.

103

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Gamma-glutamyl transferase (GGT) is an enzyme located on the external surface of cellular membranes. GGT contributes in maintaining the physiological concentrations of cytoplasmic glutathione and cellular defense against oxidative stress via cleavage of extracellular glutathione and increased availability of amino acids for its intracellular synthesis. Increased GGT activity is a marker of antioxidant inadequacy and increased oxidative stress. Ample evidence suggests that elevated GGT activity is associated with increased risk of cardiovascular disease (CVD) such as coronary heart disease (CHD), stroke, arterial hypertension, heart failure, cardiac arrhythmias and all-cause and CVD-related mortality. The evidence is weaker for an association between elevated GGT activity and acute ischemic events and myocardial infarction. The risk for CVD or CVD-related mortality mediated by GGT may be explained by the close correlation of GGT with conventional CVD risk factors and various comorbidities, particularly non-alcoholic fatty liver disease, alcohol consumption, oxidative stress, metabolic syndrome, insulin resistance and systemic inflammation. The finding of GGT activity in atherosclerotic plaques and correlation of intra-plaque GGT activity with histological indexes of plaque instability may suggest a participation of GGT in the pathophysiology of CVD, particularly atherosclerosis. However, whether GGT has a direct role in the pathophysiology of CVD or it is an epiphenomenon of coexisting CVD risk factors or comorbidities remains unknown and Hill's criteria of causality relationship between GGT and CVD are not fulfilled. The exploration whether GGT provides prognostic information on top of the information provided by known cardiovascular risk factors regarding the CVD or CVD-related outcome and exploration of molecular mechanisms of GGT involvement in the pathophysiology of CVD and eventual use of interventions to reduce circulating GGT activity remain a duty of future studies.

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Section: Ggt Cvd and Mortalitymentioning

confidence: 99%

Gamma-glutamyl transferase and cardiovascular disease

Ndrepepa¹,

Kastrati²

2016

Ann. Transl. Med.

103

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“…During follow-up, 4,884 (5.3%) incident cancers were observed. On average, 3.8 GGT measurements were obtained for each participant (range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Baseline GGT levels ranged from 3.0 to 590.7 U/L, with a median of 17.9 U/L.…”

Section: Characteristics Of Study Populationmentioning

confidence: 99%

“…Kazemi-Shirazi and colleagues 19 demonstrated a significant association of GGT levels and cancer death in a large, retrospective hospital-based study. In type 2 diabetic patients, Monami and colleagues 26 recently found an association between elevated GGT and cancer-related mortality; this relationship was confirmed in a multivariate analysis after adjustment for potential confounding.…”

mentioning

confidence: 99%

“…17 In addition, several large-scale studies indicate an independent role of GGT for premature death from all causes. 9,18,19 The association of GGT with cancer incidence, however, remains largely unexplored. Several experimental models have elucidated the ability of cellular GGT to modulate crucial redoxsensitive functions, such as antioxidant/antitoxic defences and cellular proliferative/apoptotic balance, and its role in tumor progression, invasion and drug resistance has been proposed.…”

mentioning

confidence: 99%

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Prospective study of the association of gamma‐glutamyltransferase with cancer incidence in women

Strasak

Pfeiffer

Klenk

et al. 2008

Intl Journal of Cancer

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Although several epidemiologic studies have shown that gammaglutamyltransferase (GGT) is associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored. In experimental models the ability of cellular GGT to modulate crucial redox-sensitive functions has been established, and it may thus play a role in tumor progression. In the present study, we investigated the association of GGT with overall and site-specific cancer incidence in a population-based cohort of 92,843 Austrian women with 349,674 serial GGT measurements, prospectively followed-up for a median of 13.5 years. The relationship between GGT and cancer incidence was analyzed using adjusted Cox regression models with age as underlying time metric with age as underlying time metric including GGT concentrations at baseline and incorporating repeated GGT measurements as a time-dependent variable. During follow-up, 4,884 incidence cancers were observed. Compared to normal low GGT (<17.99 U/L), cancer risk was elevated for all other GGT categories (p for trend < 0.0001), with adjusted hazard ratios (95% confidence intervals) of 1.06 (0.99-1.13) for GGT levels between 18.00 and 35.99 U/L (normal high), 1.12 (1.02-1.22) for GGT levels between 36.00 and 71.99 U/L (elevated) and 1.43 (1.28-1.61) for highly elevated GGT (>72.00 U/L). Very similar results were seen when GGT was analyzed as a time-dependent variable. In cancer-site specific models, elevated GGT statistically significantly increased the risk for malignant neoplasms of digestive organs, the respiratory system/intrathoracic organs, breast and female genital organs and lymphoid and haematopoietic cancers (all, p < 0.006). Our study is the first to demonstrate in a large population-based cohort that high GGT levels significantly increased cancer risk in women.Published 2008 Wiley-Liss, Inc. This article is a US Government work, and, as such, is in the public domain in the United States of America.Key words: gamma-glutamyltransferase; cancer incidence; risk factor; epidemiology; women Gamma-glutamyltransferase (GGT), present on the external surface of most cells and in serum, is the enzyme responsible for the extracellular catabolism of glutathione (GSH), the main thiol antioxidant in mammalian cells. 1,2 In clinical practice, GGT is commonly used as a diagnostic test to assess liver dysfunction, and as a biological marker of excessive alcohol intake. 1,3,4 However, several recent epidemiologic studies have shown elevated GGT to independently influence morbidity and mortality from causes other than liver disease. Particularly, GGT was independently related to cardiovascular disease, 5-12 it correlated with most cardiovascular risk factors [13][14][15][16] and, more recently, an association with chronic kidney disease was found. 17 In addition, several large-scale studies indicate an independent role of GGT for premature death from all causes. 9,18,19 The association of GGT with cancer incidence, however, remains largely unexplored. Several ex...

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“…Excess serum GGT has been linked to both oxidative stress [146] and increased cancer risk [147] as well as many other diseases [148]. In a study on 283 438 people who were divided into five subgroups based on GGT level, a hazard ratio of 18.5 for risk of hepatic carcinoma was ascertained for the highest level compared to the lowest [149]. Another study based in Korea found an increased risk of multiple cancers in association with elevated GGT: most especially liver cancer, but also cancer of the esophagus, larynx, stomach, bile ducts, lungs and colon [150].…”

Section: Colon and Liver Cancermentioning

confidence: 99%