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(Stroke. 2002;33:1163.)
© 2002 American Heart Association, Inc.

Letters to the Editor

Serum Gamma-Glutamyltransferase as a Risk Factor of Ischemic Stroke Might Be Independent of Alcohol Consumption

Michele Emdin, MD, PhD; Claudio Passino, MD Luigi Donato, MD

Institute of Clinical Physiology, National Research Council - CNR, Pisa, Italy

Aldo Paolicchi, MD Alfonso Pompella, MD

Department of Experimental Pathology, University of Pisa Medical School, Pisa, Italy

To the Editor:

In a recent issue of Stroke, Jousilahti et al reported on the association of stroke with serum levels of gamma-glutamyltransferase (GGT) and alcohol consumption in a cohort of more than 14 000 subjects.¹ In particular, the authors observed that the incidence of ischemic stroke had a good correlation with serum GGT—which they interpreted as a surrogate marker of alcohol consumption—in both genders (relative risk in men 1.29, 95% CI 1.04 to 1.60; in women 1.42, 95% CI 1.10 to 1.84). On the other hand, no correlation of ischemic stroke was observed with the self-reported individual alcohol intakes, although "a significant linear increasing trend in the mean levels of self-reported alcohol drinking by quartiles of the serum GGT" was found. The obvious conclusion is that GGT is an independent risk factor for ischemic stroke, irrespective of alcohol drinking, whereas the authors concluded that answers given by patients to questionnaires concerning their lifestyles are unreliable and that serum GGT is a more faithful indicator of alcohol consumption, ie, the actual determinant of stroke occurrence.

We would like to suggest an alternative explanation to the findings of this study, based on previous evidence in the literature in favor of a direct GGT involvement in atherosclerotic plaque complication. GGT, present in serum and on the surface of most cell types, is the enzyme responsible for the extracellular catabolism of glutathione, the main antioxidant in mammalian cells, and its role in cardiovascular diseases may be more complex than currently thought.² While it is certainly true that serum GGT is a well-assessed marker of alcohol abuse, higher GGT levels are also found to be independently correlated with conditions associated with increased atherosclerosis, such as obesity, elevated serum cholesterol, high blood pressure, and myocardial infarction.^3–5 Epidemiologic studies have reported a positive correlation between GGT levels and cardiovascular mortality, namely from ischemic heart disease, irrespective of alcohol consumption.^5–7 A recent study by us has shown that serum GGT level is an independent risk factor for cardiac death and reinfarction in patients with angiographically documented coronary artery disease. Remarkably, its strong predictive value is independent from self-reported alcohol consumption,⁸ which instead has a protective effect on survival, confirming previous observations.⁹

Which mechanisms can underlie the association of serum GGT with atherosclerotic disease and its consequences? Our previous studies documented that GGT, in the presence of iron, can catalyze the oxidation of LDL,¹⁰ a process involved in pathogenesis of atherosclerosis. Moreover, serum GGT is partially adsorbed onto circulating LDL,¹¹ which can carry GGT activity inside atheromatous plaques. Active GGT is colocalized with oxidized LDL¹⁰ (see Figure), and free iron was present at levels sufficient to catalyze LDL oxidation.¹² Also, available evidence is in favor of a pathogenetic role of GGT activity in the evolution and instability of atherosclerotic plaques in different vascular districts. It thus seems appropriate to suggest that the significance of serum GGT should not be restricted to that of a mere "biological marker"¹ of alcohol consumption, when evaluated in a context of atherosclerosis and cardiovascular disease.

View larger version (106K): [in this window] [in a new window]   Colocalization of GGT activity with oxidized LDL in human atherosclerotic plaques. A, GGT activity (histochemical azocoupling reaction). B, colocalization of oxidized LDL (arrows, adjacent section, indirect immunofluorescence with a monoclonal antibody against human oxidized LDL). The sample shown is from a cerebral artery plaque revealed during the autopsy of a 62-year-old patient.

References

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4. Daeppen JB, Smith TL, Schuckit MA. Influence of age and body mass index on -glutamyltransferase activity: a 15-year follow-up evaluation in a community sample. Alcohol Clin Exp Res. 1998; 22: 941–944.[CrossRef][Medline] [Order article via Infotrieve]

5. Betro MG, Oon RC, Edwards JB. Gamma-glutamyl transpeptidase and other liver function tests in myocardial infarction and heart failure. Am J Clin Pathol. 1973; 60: 679–683.[Medline] [Order article via Infotrieve]

6. Wannamethee G, Ebrahim S, Shaper AG. Gamma-glutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes. Am J Epidemiol. 1995; 142: 699–708.[Abstract/Free Full Text]

7. Brenner H, Rothenbacher D, Arndt V, Schuberth S, Fraisse E, Fliedner TM. Distribution, determinants, and prognostic value of gamma-glutamyltranspeptidase for all-cause mortality in a cohort of construction workers from south Germany. Prev Med. 1997; 26: 305–310.[CrossRef][Medline] [Order article via Infotrieve]

8. 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 in patients with ischaemic heart disease. Eur Heart J. 2001; 22: 1802–1807.[Abstract/Free Full Text]

9. Muntwyler J, Hennekens CH, Buring JE, Graziano JM. Mortality and light to moderate alcohol consumption after myocardial infarction. Lancet. 1998; 352: 1882–1885.[CrossRef][Medline] [Order article via Infotrieve]

10. Paolicchi A, Minotti G, Tonarelli P, Tongiani R, De Cesare D, Mezzetti A, Dominici S, Comporti M, Pompella A. Gamma-glutamyl transpeptidase-dependent iron reduction and low density lipoprotein oxidation: a potential mechanism in atherosclerosis. J Invest Med. 1999; 47: 151–160.[Medline] [Order article via Infotrieve]

11. Watanabe M, Taketa K, Izumi M, Nagashima H. Association of gamma-glutamyltransferase with plasma lipoprotein and lipid-protein complex in cholestasis. Hepatogastroenterology. 1984; 31: 204–207.[Medline] [Order article via Infotrieve]

12. Pang JH, Jiang MJ, Chen YL, Wang FW, Chu SH, Chan LY. Increased ferritin gene expression in atherosclerotic lesions. J Clin Invest. 1996; 97: 2204–2212.[Medline] [Order article via Infotrieve]

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