Alanine aminotransferase and gamma-glutamyl transferase are associated with the metabolic syndrome but not with angiographically determined coronary atherosclerosis

Methods We enrolled 1000 consecutive patients undergoing coronary angiography for the evaluation of suspected or established stable CAD. The metabolic syndrome (MetS) was defined according to ATP-III criteria; significant CAD was diagnosed in the presence of coronary stenoses with lumen narrowing ≥ 50%. Results Serum alanine aminotransferase (ALT), the ALT/aspartate aminotransferase (AST) ratio, and serum gamma-glutamyl transferase (GGT) were significantly higher in patients with the MetS than in subjects without the MetS (34 ± 21 vs. 29 ± 20 U/l; p < 0.001, 1.16 ± 0.39 vs. 1.00 ± 0.36 U/l, p < 0.001; and 53 ± 88 vs. 43 ±57 U/l, p = 0.001, respectively) but were similar in patients with significant CAD as in those who did not have significant CAD at angiography ( p = 0.592; p = 0.731, and p = 0.716, respectively). Analysis of covariance after multivariate adjustment including alcohol consumption confirmed that ALT, ALT/AST ratio, and GGT were significantly and independently associated with the MetS but not with significant CAD. Conclusions ALT, the ALT/AST ratio, and GGT are associated with the MetS but not with angiographically determined coronary atherosclerosis. Abbreviations CAD coronary artery disease MetS metabolic syndrome ALT alanine aminotransferase AST aspartate aminotransferase GGT gamma-glutamyl transferase NAFLD non-alcoholic fatty liver disease T2DM type 2 diabetes BMI body mass index ATP-III Adult Treatment Panel III HDL high density lipoprotein LDL low densitylipoprotein CRP C-reactive protein IDF International diabetes Federation HbA1c Haemoglobin A1c ANCOVA analysis of covariance VLDL very low density lipoprotein. Keywords Liver enzymes Atherosclerosis Coronary angiography Metabolic syndrome Alanine aminotransferase Aspartate aminotransferase Gamma-glutamyl transferase 1 Introduction Recently, associations between elevated serum levels of liver enzymes and increased cardiovascular risk have attracted much interest. Indeed, serum alanine aminotransferase (ALT) and serum gamma-glutamyl transferase (GGT) have been shown to predict cardiovascular events in prospective studies independently from conventional cardiovascular risk factors [1–5] . The most frequent cause of elevated liver enzymes in current clinical practice is non-alcoholic fatty liver disease (NAFLD) [6] , which affects as much as 15–20% of the general population and up to 90% of patients with type 2 diabetes (T2DM) [7] . Pathophysiologically, NAFLD is strongly related to insulin resistance and to the metabolic syndrome (MetS), the cluster of cardiovascular risk factors associated with insulin resistance [8–11] . Indeed, elevated GGT is a predictor of incident MetS [4] . Both insulin resistance and the clinical entity of the MetS predict vascular events [12] ; it is a matter of debate in as far elevated liver enzymes are associated with cardiovascular events independent of the clinical diagnosis of the MetS. Myocardial infarction, a frequently applied endpoint in clinical studies, does not optimally reflect the atherogenicity of metabolic parameters. It is the last step in the development of atherothrombotic CAD, and thrombogenic factors ultimately determine whether or not infarction occurs [13,14] . By coronary angiography, to the opposite, preferentially atherosclerosis is assessed. Therefore, it appears important to also investigate the association of risk factors with angiographically determined coronary atherosclerosis. The association of elevated liver enzymes with the angiographically determined coronary artery state is uncertain. In the present study we therefore aimed at investigating the associations of ALT, of aspartate aminotransferase (AST), of the ALT/AST ratio and of GGT with angiographically determined coronary atherosclerosis and with the MetS in a large series of consecutive angiographied coronary patients. We hypothesized that both the MetS and coronary atherosclerosis are independently associated with these parameters of liver function. 2 Materials and methods 2.1 Study subjects From August 2005 through December 2007 we enrolled 1004 consecutive Caucasian patients who were referred to coronary angiography for the evaluation of established or suspected stable CAD on the basis of current guidelines [15] . Patients who had suffered myocardial infarctions or acute coronary syndromes within three months prior to the baseline angiography and patients testing positive for viral hepatitis as well as patients with autoimmune hepatitis were not enrolled in our study. Four patients with type 1 diabetes were excluded from the analyses. Data thus are reported for 1000 patients. Information on conventional cardiovascular risk factors was obtained by a standardized interview; and systolic/diastolic blood pressure was measured by the Riva–Rocci method under resting conditions in a sitting position at the day of hospital entry at least 5 h after hospitalization. Smoking categorically was defined as any positive or negative history of smoking. Hypertension was defined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [16] , and T2DM was diagnosed according to World Health Organization criteria [17] . Height and weight were recorded, and body mass index (BMI) was calculated as body weight (kg)/height (m) 2 . Overall, 69.5% of our patients were on aspirin, 49.7% on statins, 1.4% on fibrates, 11.9% on calcium antagonists, 55.2% on beta adrenoreceptor blocking agents, 24.9% on diuretics, 35.4% on angiotensin converting enzyme inhibitors, and 18.7% on angiotensin II receptor blocking agents. Among patients with T2DM, 25.7%, 33.7%, 53.7%, 0.6%, and 3.4% were receiving – alone or in combination – insulin, sulfonylurea, metformin, acarbose, and glitazones, respectively. According to National Cholesterol Education Programme Adult Treatment Panel III (ATP-III) criteria [18] , the MetS was diagnosed in the presence of any three of: waist circumference > 102 cm in men and > 88 cm in women, triglycerides ≥150 mg/dl (1.7 mmol/l), HDL cholesterol < 40 mg/dl (1.0 mmol/l) in men and < 50 mg/dl (1.3 mmol/l) in women, blood pressure ≥ 130/≥ 85 mmHg, or fasting glucose ≥110 mg/dl (6.1 mmol/l). Using International Diabetes Federation (IDF) criteria [19] , the MetS was diagnosed in patients who had a high waist circumference (≥ 94 cm in men and ≥ 80 cm in women) plus any two of: triglycerides ≥150 mg/dl (1.7 mmol/l) or specific treatment for this lipid abnormality, high density lipoprotein (HDL) cholesterol < 40 mg/d (1.0 mmol/l) in males and < 50 mg/dl (1.3 mmol/l) in females or specific treatment for this lipid abnormality, systolic blood pressure≥130 or diastolic blood pressure ≥ 85 mmHg or treatment of previously diagnosed hypertension, and fasting plasma glucose ≥100 mg/dl (5.6 mmol/l) or previously diagnosed T2DM. Coronary angiography was performed with the Judkin's technique. The angiographic analyses were conducted by two independent investigators who were blinded to serologic assays. Coronary artery stenoses with lumen narrowing of 50% or more were considered significant, and coronary arteries were defined as normal in the absence of any visible lumen narrowing at angiography, as described previously [20] . The Ethics Committee of the University of Innsbruck approved the present study, and all participants gave written informed consent. 2.2 Laboratory analyses Venous blood samples were collected after an overnight fast of 12 h before angiography was performed, and laboratory measurements were performed from fresh serum samples, as described previously [21] . ALT, AST, and GGT all were measured on a Cobas Integra 800 ® at 37° centigrade. For ALT and AST the enzymatic tests Test ALTL ID 0–595 (Roche, Basel, Switzerland) and Test ASTL ID 0–594 (Roche, Basel, Switzerland) were used, respectively, according to the International Federation of Clinical Chemistry (IFCC) with pyridoxal-5′-phosphate. For GGT, the enzymatic Test GGTI-2 ID 0–498 (Roche, Basel, Switzerland) was used, which is standardized against the IFCC method. Also serum triglycerides, total cholesterol, low density lipoprotein (LDL) cholesterol, HDL cholesterol, apolipoprotein B, apolipoprotein A1, CRP, and plasma glucose were determined on a Cobas Integra 800 ® (Roche, Basel, Switzerland). Haemoglobin A1c (HbA1c) was determined by high-performance liquid chromatography on a Menarini-Arkray KDK HA 8140 ® (Arkray KDK, Kyoto, Japan). 2.3 Statistical analysis Differences in patient characteristics were tested for statistical significance with the Chi square test for categorical variables; the Mann–Whitney–U and Kruskal–Wallis tests were used for continuous variables, as appropriate. The Hochberg correction for multiple testing was applied where appropriate. Spearman rank correlation coefficients were calculated. To test for independent determinants of continuous variables, analysis of covariance (ANCOVA) was performed, using a general linear model approach. Daily alcohol consumption was entered into the multivariate models as a continuous variable. Results are given as mean ± standard deviation if not denoted otherwise. Statistical analyses were performed with the software package SPSS 10.0 for Windows (SPSS, Inc., Chicago, IL). 3 Results 3.1 Patient characteristics Overall, the characteristics of our study population were typical for a cohort undergoing coronary angiography for the evaluation of CAD, with a preponderance of male gender (64.3%), and a high prevalence of type 2 diabetes (24.9%), hypertension (70.7%), and smoking (58.8%). From our patients, 295 (29.5%) had the MetS as defined by ATP-III criteria, and in 553 patients (55.3 %) coronary angiography revealed significant CAD. From our patients, 323 had neither the MetS (ATP-III definition) nor significant CAD, 124 had the MetS, but not significant CAD, 382 did not have the MetS but had significant CAD, and 171 had both, the MetS and significant CAD. Table 1 summarizes characteristics of our patients in these four groups. 3.2 Liver enzymes in study subgroups Serum ALT, the ALT/AST ratio, and serum GGT were significantly higher in patients who had the ATP-III MetS than in subjects without the MetS according to ATP-III criteria (34 ± 21 vs. 29 ± 20 U/l; p < 0.001, 1.16 ± 0.39 vs. 1.00 ± 0.36 U/l, p < 0.001; and 53 ± 88 vs. 43 ± 57 mg/dl U/l, p = 0.001, respectively). In contrast, these parameters of liver function did not differ significantly between patients with significant CAD and subjects without significant CAD (30 ± 22 vs. 30 ± 19 U/l, p = 0.592; 1.05 ± 0.39 vs. 1.05 ± 0.36; p = 0.731, and 44 ± 61 vs. 48 ± 75 U/l; p = 0.716, respectively) nor between those with coronary stenoses > 70% ( n = 446) and those without such lesions (30 ± 22 vs. 30 ± 19 U/l; p = 0.513; 1.05 ± 0.39 vs. 1.05 ± 0.36; p = 0.994; 43 ± 46 vs. 48 ± 81 U/l; p > 0.229). Serum AST was similar in patients with the MetS as in patients who did not have the MetS (29 ± 13 vs. 28 ± 14 U/l; p = 0.500) and also did not differ between patients with significant CAD and those who did not have significant CAD (28 ± 14 vs. 28 ± 12 U/l; p = 0.887) nor between those with coronary stenoses > 70% and those without such lesions (28 ± 16 vs. 28 ± 12 U/l; p = 0.280). When both the presence of the MetS and the presence of significant CAD were considered, ALT, ALT/AST ratio, and GGT were significantly higher in patients with the MetS both among those without significant CAD (33 ± 19 vs. 29 ± 19 U/l, p = 0.003; 1.14 ± 0.35 vs. 1.01 ± 0.35 U/l, p < 0.001; and 51 ± 78 vs. 47 ± 74 U/l, p = 0.016, respectively) and among those with significant CAD (34 ± 23 vs. 29 ± 21 U/l, p < 0.001; 1.17 ± 0.41 vs. 0.99 ± 0.36 U/l, p < 0.001; 54 ± 94 vs. 39 ± 37 U/l, p = 0.034, respectively). In contrast ALT, the ALT/AST ratio, and GGT did not differ significantly between those with significant CAD and those who did not have significant CAD among subjects without the MetS ( p = 0.407, p = 0.462, and p = 0.572, respectively) nor among subjects with the MetS ( p = 0.996, p = 0.722, p = 0.805, respectively). ALT, ALT/AST ratio, and GGT were significantly higher in MetS patients who did not have significant CAD than in patients with significant CAD who did not have the MetS ( p < 0.001; p < 0.001; p = 0.020, respectively). Both among patients with significant CAD and among subjects who did not have significant CAD, fasting insulin was significantly higher in patients with the MetS than in those without the MetS ( Table 1 ; p < 0.001 for both comparisons). Fasting insulin correlated significantly with ALT ( r = 0.274; p < 0.001), with the ALT/AST ratio ( r = 0.328; p < 0.001), and with GGT ( r = 0.155; p < 0.001). 3.3 Results of multivariate analyses In line with our univariate results, analysis of covariance adjusting for age, gender, smoking, LDL cholesterol, and alcohol consumption showed that serum ALT, the ALT/AST ratio, and GGT were significantly associated with the MetS as diagnosed by ATP-III criteria ( F = 13.87, p < 0.001; F = 19.94, p < 0.001; and F = 8.55, p = 0.004, respectively) but not with significant CAD ( F = 1.005, p = 0.317; F = 0.11, p = 0.741; and F = 2.07, p = 0.151). Interaction terms MetS⁎CAD were not significant for any of these three parameters ( p = 0.178, p = 0.172, and p = 0.657, respectively). Further, for ALT, for the ALT/AST ratio, and for GGT interaction terms MetS⁎gender ( p = 0.955, p = 0.137, and p = 0.453, respectively), and CAD⁎gender ( p = 0.787, p = 0.283, p = 0.948, respectively) were non-significant, indicating that gender did not significantly affect the associations between these parameters and the MetS or CAD, respectively. Concordantly, ALT, ALT/AST ratio, and GGT neither among men ( F = 2.11, p = 0.148, F = 0.01, p = 0.919 and F = 1.22, p = 0.269, respectively) nor among women ( F = 0.04, p = 0.852; F = 1.31, p = 0.254; F = 0.61, p = 0.436, respectively) were significantly associated with significant CAD. Additional adjustments for physical exercise, serum CRP, and use of statins, metformin, and glitazones confirmed our results: Serum ALT, the ALT/AST ratio, and GGT were significantly associated with the MetS as diagnosed by ATP-III criteria ( F = 9.25, p = 0.002; F = 10.97, p = 0.001 and F = 6.86, p = 0.009, respectively) but not with significant CAD ( F = 0.27, p = 0.606; F = 2.82, p = 0.094; and F = 1.74, p = 0.188; respectively). Regarding individual ATP-III MetS criteria, ALT was significantly associated with the high triglycerides ( F = 6.62, p = 0.010) and the high blood pressure ( F = 5.30, p = 0.022) traits, the ALT/AST ratio with the high glucose ( F = 11.63, p = 0.001) and the high triglycerides ( F = 3.94, p = 0.048) traits, and GGT with the high glucose trait ( F = 19.73, p < 0.001) after adjustment for age, gender, smoking, presence of significant CAD, LDL cholesterol, serum CRP, alcohol consumption, physical activity, and use of statins, metformin, or glitazones. In logistic regression analyses adjusting for age, gender, smoking, LDL cholesterol, alcohol consumption, physical exercise, serum CRP, and use of statins, metformin, and glitazones, ALT, the ALT/AST ratio, and GGT proved to be significant determinants of the MetS ( Fig. 1 A ) but not of significant CAD ( Fig. 1 B). 3.4 IDF definition of the MetS The prevalence of the MetS according to the IDF definition was 46.7%. Considering both the IDF MetS and the presence of significant CAD, 251 patients had neither the IDF MetS nor significant CAD, 196 had the MetS, but not significant CAD, 282 did not have the MetS but had significant CAD, and 271 had both, the MetS according to IDF criteria and significant CAD. As with the ATP-III definition of the MetS, ALT, the ALT/AST ratio, and GGT were significantly higher in patients with the IDF MetS than in subjects who did not have the IDF MetS both in subjects without significant CAD (32 ± 19 vs. 28 ± 19 U/l, p = 0.004; 1.12 ± 0.36 vs. 0.99 ± 0.34 U/l, p < 0.001, and 53 ± 78 vs. 44 ± 72 U/l, p = 0.002, respectively) and among patients with significant CAD (33 ± 26 vs. 28 ± 16 U/l, p = 0.002; 1.12 ± 0.43 vs. 0.98 ± 0.33 U/l, p < 0.001 and 51 ± 80 vs. 37 ± 33 U/l, p = 0.006), whereas ALT, the ALT/AST ratio, and GGT did not differ significantly between patients with significant CAD and those without significant CAD both among subjects without the IDF MetS ( p = 0.601, p = 0.734, and p = 0.493, respectively) and among patients who had the MetS according to IDF criteria ( p = 0.570, p = 0.743, p = 0.725, respectively). 4 Discussion From our results we conclude that serum ALT, the ALT/AST ratio, and serum GGT are significantly associated with the MetS but not with angiographically determined coronary atherosclerosis. To the best of our knowledge, this is the first report on the association between liver enzymes and the MetS in patients characterized by coronary angiography. Previous studies had described associations between serum levels of liver enzymes and the MetS in other patient populations and, importantly, without taking into consideration the coronary artery state [9,22,23] . In extension to these reports we found that serum ALT, the ALT/AST ratio, and serum GGT are significantly associated with the MetS in angiographied coronary patients irrespective of the presence of significant CAD and irrespective of whether the ATP-III or IDF criteria for the diagnosis of the MetS are applied. Hardly any data on the association between liver enzymes and angiographically determined coronary atherosclerosis are available from the literature. A single small study from Iran [24] , while failing to show an association between liver enzymes and coronary atherosclerosis in the total study population, described an association of liver enzymes with severe CAD in the subgroup of women only; formal interaction analyses were not performed in this study. In our larger population of angiographically characterized patients, we neither among women nor among men observed an association between liver enzymes and coronary atherosclerosis. Further, interaction analyses in our investigation did not suggest a significant gender difference with respect to the association between liver enzymes and coronary atherosclerosis. CAD is the leading cause of mortality worldwide, and, due to the current epidemic of obesity and sedentary lifestyle in industrialized countries, the prevalence of the MetS is very high in large parts of the world [25] . Screening for CAD and for the MetS therefore is important. Given the availability and simplicity of liver enzyme testing, these parameters may appear attractive for this purpose. However, in the light of our data increases in ALT, ALT/AST ratio, and GGT may help to identify individuals with the MetS, but do not appear useful for the identification of patients with coronary atherosclerosis. The most common cause of elevated liver enzymes in current clinical practice is NAFDL [6] , and several pathophysiological links between NAFDL and the MetS have been elucidated. The fatty liver is insulin resistant [26] and overproduces both glucose and very low density lipoproteins (VLDL) [27,28] , which leads to hyperglycemia, hypertriglyceridemia, and, consequently, to low HDL cholesterol. These MetS stigmata, however, promote atherosclerosis. Also, associations of NAFLD with emerging metabolic syndrome related cardiovascular risk markers such as low serum adiponectin [29] and increased oxidative stress [30] have been demonstrated. Why, then, are ALT, AST, the ALT/AST ratio, and GGT not associated with angiographically determined coronary atherosclerosis? It should be considered that a lack of association between these parameters with coronary atherosclerosis does not refute the concept of an association between NAFLD and atherosclerotic disease. In the Dallas Heart Study, almost 80% of the subjects with a fatty liver had normal serum ALT [31] . Indeed, serum ALT correlates with liver fat, but explains less than 20% of the variation in liver fat as determined by magnetic resonance spectroscopy [32] . Correlations of serum AST and GGT with liver fat content are even weaker than those of ALT [22] . In particular, AST – which was not associated with the MetS in our investigation – is a poor indicator of NAFLD, and rather an elevated ALT/AST ratio is typical for patients with NAFLD [33] . From the background of these considerations, future studies addressing the association of liver fat as determined by sensitive methods such as 1 H-magnetic resonance spectroscopy with coronary atherosclerosis would be of great interest. Also, the association of coronary atherosclerosis with more sensitive and specific biochemical markers of liver fat content than ALT, AST, ALT/AST ratio, and GGT would be interesting in this context. In our investigation liver enzymes were not associated with coronary atherosclerosis, irrespective of whether patients with coronary stenoses ≥ 50% or patients with coronary stenoses > 70% were compared to those without the respective lesions. However, our data do not exclude a correlation between liver enzymes and atherosclerosis as diagnosed by intravascular ultrasound (IVUS). Whereas our results do not at all point towards such an association, it would be of interest to address this issue in an IVUS study. In ostensible contradiction to the results from our large population of angiographically characterised patients, earlier studies have reported significant associations of ALT and GGT with the incidence of vascular events [1–3] . In this context, it should be considered that visualisation of coronary atherosclerosis by angiography does not reflect the same aspects of atherothrombotic disease as the clinical cardiovascular event, which is precipitated by plaque instability and thrombosis. It is therefore important to study not only the association between risk factors and clinical endpoints but also their association with angiographically determined atherosclerosis. In synthesis of our results with the previously reported associations of liver enzymes with coronary events, it appears possible that these parameters are more strongly associated with the plaque instability and thrombosis precipitating the acute atherothrombotic coronary event than with coronary atherosclerosis per se. Important strengths of our investigation are its large sample size and the meticulous characterisation of the enrolled subjects. Further, our investigation is characterized by the typical strengths and limitations of studies enrolling patients who undergo coronary angiography for the evaluation of CAD. The angiographical characterisation of the coronary artery state was an essential feature of our study design. Of course, patients undergoing coronary angiography for the evaluation of CAD are a selected group of patients the results from which are not necessarily applicable to the general population. However, the population we chose to investigate is at a high vascular risk and therefore deserves particular clinical attention. Therapeutically, liver steatosis in NAFLD can be effectively improved (and, thus, liver enzymes can be reduced) by weight loss [34] . Importantly, weight loss not only improves NAFLD and liver enzymes, but also the whole cluster of metabolic syndrome risk factors, for which as our data show elevated liver enzymes are an important marker. It is less clear whether physical exercise independent from weight loss can improve liver steatosis [22] . Pharmaceutically, the insulin sensitizing pioglitazone been shown to decrease liver steatosis [35] . Overall, however, available data for the pharmaceutical treatment of NAFLD are limited. A number of randomized controlled trials using metformin, glitazones, ACE inhibitors, pentoxifylline, fenofibrate, niacin, vitamin E, poly-unsaturated fatty acids, and the CB1 receptor antagonist rimonabant are currently being tested in NAFLD. In conclusion we found that ALT, the ALT/AST ratio, and GGT are significantly associated with the MetS but not with angiographically determined coronary atherosclerosis in the clinically important high-risk population of angiographied coronary patients. While the association between NAFLD with atherosclerosis certainly merits further investigation, these simple parameters should not too enthusiastically be embraced as novel tools for cardiovascular risk stratification. Acknowledgements The VIVIT institute thanks Dr. Egmond Frommelt and the Innovationsstiftung of the Liechtenstein Global Trust (LGT) Bank (Bendern, Liechtenstein), Dr. Karl Josef Hier and the Peter Goop Stiftung (Vaduz, Liechtenstein), the Fachhochschule Dornbirn (Dornbirn, Austria), and the Institute for Clinical Chemistry at the Academic Teaching Hospital Feldkirch (Feldkirch, Austria) for providing us with generous research grants. We are grateful to Franz Rauch and the Vorarlberger Industriellenvereinigung (Bregenz, Austria), to Dr. Peter Woess and the Vorarlberger Aerztekammer (Dornbirn, Austria), to Mag. Gabriela Dür and the Vorarlberger Landesregierung (Bregenz, Austria), to Dr. Elmar Bechter and the Vorarlberger Landessanitätsrat (Bregenz, Austria) and to Luis Patsch, Director, Vorarlberger Landeskrankenhaus-Betriebsgesellschaft (Feldkirch, Austria), for continuously supporting our Research Institute. References [1] R.K. Schindhelm J.M. Dekker G. Nijpels Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study Atherosclerosis 191 2007 391 396 [2] E. Ruttmann L.J. Brant H. Concin G. Diem K. Rapp H. Ulmer Gamma-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults Circulation 112 2005 2130 2137 [3] C. Meisinger A. Doring A. Schneider H. Lowel Serum gamma-glutamyltransferase is a predictor of incident coronary events in apparently healthy men from the general population Atherosclerosis 189 2006 297 302 [4] D.S. Lee J.C. Evans S.J. 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