Original article: Evaluation of association between serum gamma glutamyltransferase activity and carotid intima media thickness

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1 Original article: Evaluation of association between serum gamma glutamyltransferase activity and carotid intima media thickness *Dr. Madhulika Mahashabde, **Dr. Suryaprakash Rajesh Kothe *Associate Professor, **PG student Department of Medicine, Dr. D. Y. Patil Medical College, Pimpri, Pune, Maharashtra, India Corresponding author: Dr. Madhulika Mahashabde Abstract: Introduction: Gamma-glutamyltransferase (GGT) is a plasma membrane enzyme that plays a central role in oxidative metabolism. It regulates extracellular catabolism of glutathione. Gamma-glutamyltransferase is usually known as diagnostic marker for hepatobiliary disease and excessive alcohol consumption. Timely assessment of common carotid artery IMT and serum gammaglutamyl transferase can be used to assess the consequences. Therefore, I investigated the association between serum GGT activity and carotid IMT in this study. Materials and methods: Sixty patient admitted in medicine wards are included in this study over a period from July 2012 to September 2014 are included in this study. Institute Ethics Committee Clearance was obtained before start of Study.Measurement of gamma- glutamyltransferase activity: Serum GGT activity was measured by an enzymatic colorimetric test at 37_C, using a Roche/Hitachi analyzer (Mannheim, Germany). The reference range of GGT activity In our laboratory is 8-61 U/L. Observations and results: Above table and below graph shows correlation between CIMT and serum GGT value. It showed positive relation sheep. P value significant (<0.001) and r value (0.783) is positive indicating that CIMT and Serum GGT has significant positive correlation. CIMT increases as Serum GGT level increases. Conclusion: In present study serum GGT activities within the reference range were associated with carotid IMT and serum GGT activities were increased in patients with carotid artery intimal hyperplasia. Carotid IMT is a widely used surrogate marker for atherosclerotic disease. Therefore, the association between carotid IMT and serum GGT activity suggests that serum GGT activity is a marker for atherosclerotic disease. Keywords : Gamma-glutamyltransferase, carotid intima media thickness Introduction acute coronary syndrome (1-4) e. GGT has also been Gamma-glutamyltransferase (GGT) is a plasma identified in atherosclerotic plaques (5-6). Timely membrane enzyme that plays a central role in assessment of common carotid artery IMT and serum oxidative metabolism (1-4). It regulates extracellular gamma-glutamyl transferase can be used to assess the catabolism of glutathione. Gamma-glutamyltransferase consequences. Therefore, I investigated the is usually known as diagnostic marker for association between serum GGT activity and carotid hepatobiliary disease and excessive alcohol IMT in this study. consumption (1-4). Recently, serum GGT activity was Materials and methods found to be associated with cardiovascular diseases Sixty patient admitted in medicine wards are included (CVD), other vascular risk factors, and prognosis of in this study over a period from July 2012 to 104

2 September 2014 are included in this study. Institute Ethics Committee Clearance was obtained before start of Study. Inclusion criteria Sixty patients who had normal liver function test (aspartate aminotransferase, alanineaminotransferase and alkaline phosphatase) were consecutively enrolled in this study. Patient between the age group of years randomly selected irrespective of sex, duration, glycemic control with or without hypertension and with or without diabetic macrovascular complication with normal liver function tests. Exclusion criteria 1. Age>70years. 2. Chronic alcoholic (>30g/day). 3. Pregnant women. 4. Active or chronic Renal/liver disease. 5. Patient on ocp and long term steroids or any hepatotoxic drug. Documented coronary or peripheral artery disease Measurement of gamma- glutamyltransferase activity: Serum GGT activity was measured by an enzymatic colorimetric test at 37_C, using a Roche/Hitachi analyzer (Mannheim, Germany). The reference range of GGT activity In our laboratory is 8-61 U/L. Evaluation ofintimal Media Thickness: All patients were examined in supine position with neck extended with a pillow under the shoulder. Ultrasonography of the common carotid artery, carotid bifurcation, and internal carotid artery of the left and right carotid arteries was performed with a 7.5-MHz linear-array transducer (Siemens Acuson x300). On a longitudinal, two-dimensional ultrasound image of the carotid artery, the anterior (near) and posterior (far) walls of the carotid artery are displayed as two bright white lines separated by a hypoechogenic space. The distance between the leading edge of the first bright line of the far wall (lumen-intima interface) and the leading edge of the second bright line (media-adventitia interface) indicates the intima-media thickness. For the near wall, the distance between the trailing edge of the first bright line and the trailing edge of the second bright line at the near wall provides the best estimate of the near-wall intima-media thickness. Left carotid was examined first and then the right. Three sites were selected in each carotid artery. The carotid artery bulb was traced and the first reading is taken 1 cm proximal to the carotid bulb. The second reading is taken within the bulb and the site with maximum diameter recorded. The third reading is taken 1 cm distal to the carotid bulb along the internal carotid artery. For all three sites both near wall and far wall measurements are taken. The recordings are taken upto 2 decimal points. An average of each artery is computed taking into account all six readings. At the time, a note was made of presence of any plaque or calcification and duly recorded. Statistical Analysis Statistical analyses were performed with SPSS software (Statistical Package for the Social Sciences, version 10.0, SSPS Inc., and Chicago, Illinois). Medworld asia Dedicated for quality research 105

3 Observations and results : Table 1: Correlation between CIMT and Serum GGT level (n=60) Mean Std. Pearson Correlation P value Deviation (r value) Carotid intima media <0.001 thickness (mm) Serum GGT level (U/L) Above table and below graph shows correlation between CIMT and serum GGT value. It showed positive relation sheep. P value significant (<0.001) and r value (0.783) is positive indicating that CIMT and Serum GGT has significant positive correlation. CIMT increases as Serum GGT level increases. Discussion: The present study showed that serum GGT activities within the reference range were associated with carotid IMT and serum GGT activities were increased in patients with carotid artery intimal hyperplasia. Serum GGT level was higher in hyperplasia group (mean 35.46u/L) in comparison to non-hyperplasia group where mean serum GGT level was u/l and this difference was statistically significant. P value significant (<0.001) and r value (0.783) is positive indicating that CIMT and Serum GGT has significant positive correlation. CIMT increases as Serum GGT level increases Carotid IMT is a widely used surrogate marker for atherosclerotic disease. (6,7,8,9) Therefore, the association between carotid IMT and serum GGT activity suggests that serum GGT activity is a marker for atherosclerotic disease. Recent studies (6,10) suggest an independent role of GGT in the pathogenesis of CVD. Gammaglutamyltransferase has been identified in atherosclerotic plaques in the carotid, cerebral, and coronary artery, and histochemical evidence of GGT activity was detected in human atherosclerotic plaques. (6,10,11) Gamma-glutamyltransferase was expressed in CD68 macrophage-derived foam cells, (6,10) and GGT positive foam cells were localized with immunoreactive oxidized LDL in the arterial wall. (10) Furthermore, glutathione hydrolysis by GGT can trigger iron-catalyzed LDL oxidation, (6) as well as production of reactive oxygen species, (6) likely promoting plaque complications.previous findings suggest that serum GGT contributes to the accumulation of GGT within atherosclerotic plaques. (10) Therefore, serum GGT activities could reflect GGT activity in atherosclerotic plaques. The reverse is also possible. In present study proportion of hyperplasia was not significantly differ in male and female. The p value for the same was more than Similar results were

4 also found by Nuti M et al (12) where he concluded that age-adjusted CIMT values did not differ by GGT levels in males or females. The present study showed that hyperplasia was higher in elderly compare to lower aged patients and it was statistically significant. (p<0.001) Results of different studies are inconsistent with the active contribution of GGT in the initiation and progression of atherosclerotic vascular disease, at least to the extent reflected by carotid imaging. This issue has been addressed by a few studies biased by low statistical strength of the reported correlations, limited sample size, and unbalanced male-to-female ratios and, most importantly, missing adjustment for sex and age. (13) This latter limitation is of particular relevance when considering the confounding effect of demographic variables on CIMT in this study. This is in agreement with Volzke et al s study on a large sample of patients with non-alcoholic fatty liver disease (14) in which anatomic alterations ranging from mere liver steatosis to steatohepatitis coexisted with elevated GGT and related metabolic abnormalities. (15) This conclusions are further supported by negative results reported in several series of patients with nonalcoholic fatty liver disease, (16) a condition that affected also an undefined but large portion of our patients, particularly those with higher ALT, a measure of hepatic fat accumulation. (17) It must be recognized, however, that the issue of the nonalcoholic fatty liver disease as a marker of more advanced carotid atherosclerosis is controversial (17) Conclusion In present study serum GGT activities within the reference range were associated with carotid IMT and serum GGT activities were increased in patients with carotid artery intimal hyperplasia. Carotid IMT is a widely used surrogate marker for atherosclerotic disease. Therefore, the association between carotid IMT and serum GGT activity suggests that serum GGT activity is a marker for atherosclerotic disease. References: 1. Wannamethee G, Ebrahim S, Shaper AG. Gammaglutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes. Am J Epidemiol. 1995; 142(7): Lee DH, Jacobs DR Jr, Gross M, et al. Gamma-glutamyltransferaseis a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.Clin Chem. 2003; 49(8): Emdin M, Passino C, Michelassi C, et al. Prognostic value of serum gamma-glutamyltransferase activity after myocardial infarction. Eur Heart J. 2001; 22(19): Emdin M, Passino C, Michelassi C, Donato L, Pompella A,Paolicchi A. Additive prognostic value of gammaglutamyltransferasein coronary artery disease. Int J Cardiol. 2009; 136(1): Paolicchi A, Minotti G, Tonarelli P, et al. Gammaglutamyltranspeptidase-dependent iron reduction and LDL oxidation: a potential mechanism in atherosclerosis. J Investig Med. 1999; 47(3): Paolicchi A, Emdin M, Ghliozeni E, et al. Human atherosclerotic plaques contain gammaglutamyltranspeptidase enzyme activity. Circulation. 2004; 109: Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J. Intimamediathickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens. 2002; 20(2):

5 8. Poredos P. Intima-media thickness: indicator of cardiovascular risk and measure of the extent of atherosclerosis. Vasc Med.2004; 9(1): Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimalmedialthickness is related to cardiovascular risk factors measured from childhood through middle age: the Muscatine Study. Circulation.2001; 104(23): Emdin M, Passino C, Donato L, Paolicchi A, Pompella A. Serum gamma-glutamyltransferase as a risk factor of ischemic stroke might be independent of alcohol consumption. Stroke. 2002; 33(4): FranziniM, Corti A, MartinelliB, et al. Gamma-glutamyltransferase activity in human atherosclerotic plaques biochemical similarities with the circulating enzyme. Atherosclerosis. 2009; 202(1): Nuti M1, Spontoni P, Grigoratos C, Dell'Omo G, Balbarini A, Pedrinelli R. Lack of a relationship between circulating gamma-glutamyltransferase levels and carotid intima media thickness in hypertensive and diabetic patients. Vasc Health Risk Manag. 2012;8: Lee DH, Jacobs DR Jr, Gross M, et al. Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem. 2003;49(8): Angulo P. Nonalcoholic fatty liver disease. N Engl J Med.2002;346: Yagmur J, Ermis N, Acikgoz N, et al. Elevated serum gamma-glutamyl transferase activity in patients with cardiac syndrome X and its relationship with carotid intima media thickness. Acta Cardiol. 2010; 65: Volzke H, Robinson DM, Kleine V, et al. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. World J Gastroenterol. 2005;11: McKimmie RL, Daniel KR, Carr JJ, et al. Hepatic steatosis and subclinical cardiovascular disease in a cohort enriched for type 2 diabetes: the Diabetes Heart Study. Am J Gastroenterol.2008; 103: