Welcome to our GGT Science Library. In this section we will demonstrate how moderately elevated to high levels of GGT contribute to the disease process by depleting glutathione levels leading to increased oxidative stress, causing cell damage, lipid peroxidation, DNA mutagenisis and major life-threatening diseases affecting the body's vital organs.
As in our IRON Science Library, we will not present a lengthy narrative on each affected body system, but rather we will briefly summarize or quote the relevant take-home points and/or research conclusions from each study. Article titles are linked to abstracts archived at the U.S. National Library of Science. Many articles also have Full free text PDF links . Our GGT Science Library pages include:
GGT: Your Heart, Cardiovascular System, Oxidative Stress and Mortality
γ-Glutamyltransferase, Hepatic Enzymes, and Risk of Incident Heart Failure in Older Men (1) Free full text
In this 2012 study of a cohort of 3,494 men in the U.K., ages 60 to 79 with no diagnosis of myocardial infarction, who were followed for nine years, there were 168 incident heart failure cases. GGT of 38 and above, was associated with an elevated risk of heart failure of nearly two-fold that of men with GGT below 38 U/L in men 70 years of age and younger, following a wide range of adjustment for known and novel risk factors. The research team's conclusion, "Elevated GGT was associated with increased risk of heart failure in men aged <70 years." [Health-e-Iron note: a portion of Table #4 from this study appears below:]
Association between serum gamma-glutamyltransferase and cardiovascular mortality varies by age: the Minnesota Heart Survey (2) Free full text
This 2009 based on data from the Minnesota Heart Survey, researchers reported that for subjects below age 70 only, and compared to the lowest 1/3rd of the normal range, elevated GGT doubled mortality risk for those in the middle-normal range, more than tripled the risk in the top-normal range, and presented nearly a five-fold risk when GGT was more than the upper end of normal. The researchers concluded, "Our findings suggest that serum GGT within its normal range can predict CVD (cardiovascular disease) mortality in those aged less than 70 years, but may have limited usefulness for risk assessment in older adults." [Health-e-iron note: a table demonstrating these results appears directly below.This is a relatively small case-control study. The trends demonstrated by this study are consistent with other findings described on this site, however, the magnitude of risk comparisons could be distorted by the size of the study]
Gamma-Glutamyltransferase, Atherosclerosis, and Cardiovascular Disease Triggering Oxidative Stress Within the Plaque (3) Free full text
This 2005 paper describes the mechanism in which elevated GGT triggers oxidative stress within arterial plaque and suggests how GGT and iron metabolism interact in the process leading to fatal cardiac events.
Serum γ-Glutamyltransferase: Independent Predictor of Risk of Diabetes, Hypertension, Metabolic Syndrome, and Coronary Disease (4) Free full text
In this 2012 research from Turkey set out to determine "The extent to which its value in determining incident cardiometabolic risk (coronary heart disease (CHD), metabolic syndrome (MetS), hypertension and type 2 diabetes) is independent of obesity
needs to be further explored in ethnicities." "After appropriate exclusions, a cohort of 1,667 adults of a general population (age 52 ±11 years) was evaluated prospectively at 4 year's follow-up using partly Cox proportional hazard regressions. GGT activity was measured: "GGT activity was 24.9 (17.0; 35.05) U/l in men, 17.0 (12.3; 24.0) U/l in women. In linear regression analysis, while smoking status was not associated, (male) sex, sex-dependent age, alcohol usage, BMI, fasting triglycerides and C-reactive protein (CRP) were significant independent determinants of circulating GGT. "Each 1-s.d. increment in (= 0.53 ln GGT) GGT activity significantly predicted in each sex incident hypertension (hazard ratio (HR) 1.20 ..., and similarly MetS, after adjustment for age, alcohol usage, smoking status, BMI and menopause. Strongest independent association existed with diabetes (HR 1.3 (95% CI 1.1; 1.5)) whereas GGT activity tended to marginally predict CHD independent of total bilirubin but not of BMI. The researchers concluded, "that elevated serum GGT confers, additively to BMI, risk of hypertension, MetS, and type 2 diabetes but only mediates adiposity against CHD risk."
Gamma-glutamyltransferase to determine cardiovascular risk: shifting the paradigm forward (5) Free full text
This 2011 review states, "It is likely that the process entails the oxidation of low-density lipoprotein through GSH (glutathione)/GGT-dependent iron reduction (i.e. oxidation) within the plaque. In this context, oxidative stress is a probable mediator." And..."Recent insights into the pathophysiological background of GGT in the precipitation and progression of atherosclerosis appear to be supported by relevant epidemiological observations as a cardiovascular risk predictor." And..."...GGT... has potential implications for identifying those at increased cardiovascular risk who may benefit from preventive measures..."
Gamma glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults (6) Free full text
In study published in 2005 covering an Austrian population monitored over 17 years, "In both men and women, high GGT was significantly (P<0.001) associated with total mortality from cardiovascular disease, showing a clear dose-response relationship." Overall, the relative mortality risk for men and women below age 60 (at study entry), and when comparing the highest versus the lowest GGT quintiles, was 2.03 in men and 2.60 in women. For older subjects, the respective relative risks were 1.42 and 1.52. The researchers concluded, "This study demonstrates in a large, prospectively observed cohort that GGT is independently associated with cardiovascular mortality." [Health-e-Iron note: a table and figure illustrating these results appear directly below]
A figure from this study appears below:
Gamma Glutamyl Transferase and Metabolic Syndrome,Cardiovascular Disease, and Mortality RiskThe Framingham Heart Study (7) Free full text
The results for this 2007 U.S. study covering 3,451 Framingham Heart Study participants, indicated, "An increase in serum GGT predicts onset of metabolic syndrome, incident CVD (cardiovascular disease), and death..." A dose-response relationship was observed above the lowest GGT levels. "Individuals in the highest GGT quartile experienced a 67% increase in cardiovascular disease incidence." [Health-e-Iron note: a table demonstrating these results, Table 2 and Figures 1 & 2 from this paper appear directly below]
Two figures from this study appear below:
Increased serum gamma-glutamyltransferase activity in patients with metabolic syndrome (8) Free full text
In this 2011 study from Turkey the investigators enrolled "232 patients (mean age 60.4 years) from our (their) outpatient cardiology clinic, 117 with and 115 without MetS (control group) as defined by the ATP-III criteria. The results of serum liver function tests including serum GGT and C-reactive protein (CRP) levels were compared between the two groups. "The two groups were similar with regard to age, sex, smoking, and family history of coronary artery disease (p>0.05). The prevalences of hypertension and dyslipidemia were significantly higher in patients with MetS. Compared with controls, patients with MetS had significantly higher serum GGT [(median 21, interquartile range (16-33) vs. 19 (14-26) U/l; p=0.008] and C-reactive protein levels [6.2 (3.6-9.4) vs. 5.0 (3.1-7.0) U/l; p=0.044]. A high GGT activity (>40 U/l) was determined in 14.5% of the patients with MetS and in 4.4% of the control subjects (p=0.012). The researchers concluded, "Our findings suggest that patients with MetS have higher serum GGT and CRP levels compared with controls. This increased GGT level might be a marker of increased oxidative stress and premature atherosclerosis." [Health-e-Iron note: Tables 1,2 and 3 from this study are below]
Comparison of serum gamma-glutamyltransferase levels between patients with cardiac syndrome X and healthy asymptomatic individuals (9) Free full text
In this 2012 study from Turkey the researchers aimed "to compare serum GGT levels between patients with cardiac syndrome X and asymptomatic healthy individuals." "Fifty consecutive patients (29 female, 21 male, aged 28-81 years) who underwent coronary angiography due to objective ischaemia and were eventually diagnosed with cardiac syndrome X between July 2009 and January 2010, and 50 healthy asymptomatic control individuals (28 female, 22 male, aged 30-78 years) were studied." "Serum total cholesterol, LDL-cholesterol, and triglyceride levels were significantly elevated in the cardiac syndrome X patients and also "serum GGT levels were also significantly higher in the cardiac syndrome X patients than in the control group (30.48 ± 16.36 and 17.88 ± 6. 89 U/L, p < 0.001)." The researchers concluded, "GGT activity in patients with cardiac syndrome X was higher than in healthy controls. Moreover, GGT activity was further increased in those patients with cardiac syndrome X who had also MS." [Health-e-iron note: Table 1 below demonstrates laboratory and physical differences between Cardiac syndrome X patients and controls]
Gamma Glutamyltransferase and Long-Term Survival: Is It Just the Liver? (10) Free full text
In this 2007 Austrian study, among a cohort of 283,438 patients (inpatients or outpatients) monitored for up to 13 years, both men and women having initial GGT above 14 U/L and 9 U/L respectively experienced the following relative risk increases of death across four elevations of GGT categories when compared to the lowest GGT category: +20%, +40%, +60% and +100%. "GGT is associated with mortality in both men and women, especially in patients younger than 30 years (at entry) and even high-normal GGT is a risk factor for all-cause mortality." [Health-e-iron note: a table and several charts graphically demonstrate these results below]
Figure 3 from this study appears directly below and two addition figures (2&4) below that:
Fig. 3. Adjusted mortality among patients according to subgroups of GGT. GGT was classified as described in Materials and Methods. The lowest category served as reference category.
Figure 2 from this study appears below:
Fig. 2. Overall survival among patients according to subgroups of GGT in 283,438 patients.
Figure 4 from this study appears below:
Fig. 4. Hepatobiliary and hepatoma mortality according to subgroups of GGT. [Health-e-Iron note: this figure 4 and above figure 3 clearly demonstrate the association of even mildly elevated GGT with premature mortality for the major primary causes of death in the U.S. Note, the Austrian population has a greater than two year life expectancy advantage over the U.S.]
Serum gamma-glutamyl transferase and risk of heart failure in the community (11) Free full text
In this analysis of Framingham Heart Study participants reported in 2010, the investigators "related serum GGT to the incidence of heart failure in 3,544 (mean age, 44.5 years; 1,833 women and 1,711 men)." All participants ... were followed for a mean period of 23.6 years. After the model "was adjusted for age, sex, body mass index, diabetes mellitus, smoking, systolic blood pressure, treatment for hypertension, alcohol intake, total to high-density lipoprotein cholesterol ratio, valve disease, and history of myocardial infarction and updated every four years for changes, the investigators determined, "Participants with a serum GGT level at the median or greater (men ≤ 16 U/L and women ≤
9 U/L) had a 1.71-fold risk of heart failure (95% CI, 1.21 to 2.41) compared with individuals with GGT concentrations less than the median." When adjustment were made for age and sex only, the risk of heart failure was 119% greater for those with GGT above the median, The researchers concluded, "In this prospective study of a large community-based sample, higher serum GGT concentrations within the "normal" range were associated with greater risk of heart failure and incrementally improved prediction of heart failure risk." [Health-e-iron note: a table derived from this stud, Table 1 and Figure 2 from the study are below]
Figure 2. Age- and sex-adjusted cumulative incidence of heart failure by serum GGT median levels (at or greater than and less than the median).
Serum Gamma-Glutamyaltransferase Concentrations Correlates with Framingham Score in Koreans (12) Free full text
In this study reported in 2011, "This study examined the association between serum GGT concentration and Framingham risk score (FRS) in the Korean population. This cross-sectional study was performed on 30,710 Koreans. Besides FRS, body mass index, fasting blood glucose, liver enzymes, lipid profile, uric acid and high sensitive C-reactive protein data were used. The study subjects were grouped into quartiles according to the levels of GGT. Analyses relating GGT to FRS ≥ 20% utilized multiple confounders adjusted logistic regression. Positive correlations were established between log-transformed GGT concentration and FRS (r = 0.38; P < 0.001). Increasing the quartile of serum GGT concentration was significantly associated with linear increasing trends in FRS (P-trend < 0.001). "Compared to the lowest baseline GGT category, age-gender adjusted odd ratios for FRS ≥ 20% were significantly increased from the lowest to highest GGT quartiles; these results remained significantly after adjustments for multiple confounders. Increased GGT concentration is associated with the increase in FRS. Serum GGT may be helpful to predict the future risk of CAD (coronary artery disease)." The researchers determined that GGT concentration correlated very well with Framingham risk scores. [Health-e-Iron note: figure #1 demonstrating these results appears directly below]
Fig. 1. The relationship between the 10-yr CAD risk and the quartile of serum GGT concentration. Increasing quartiles of serum GGT concentration are significantly associated with linear increasing trends in 10-yr CAD risk (P trend < 0.001). Vertical bar indicates 95% confidence interval. White circle indicates the mean.
Serum gamma glutamyl transferase: a novel biomarker for screening of premature coronary artery disease (13)
In this 2011 research from Pakistan the investigators "aimed to elucidate the association between gamma glutamyl transferase (GGT) activity with prevalence of premature coronary artery disease (CAD) in young Pakistani patients undergoing diagnostic coronary angiography." "A total of 218 young adults (age ≤ 45 years) underwent diagnostic angiography. Serum samples were taken from all the patients and analyzed for serum GGT activity, cholesterol and triglycerides." "Coronary artery disease patients had significantly increased GGT activity (P = .001) and exhibited a significant positive correlation with blood pressure, cholesterol, blood glucose, and smoking and negative correlation with total antioxidant status (P < .01)."
Socioeconomic status, antioxidant micronutrients, and correlates of oxidative damage: the Coronary Artery Risk Development in Young Adults (CARDIA) study (14) Free full text
In this 2009 study covering a population of young adults in the U.S. the researchers examined "whether socioeconomic status (SES) (education, occupation, income), is associated both cross sectionally and prospectively with circulating concentrations of a) two correlates of oxidative damage, F(2)-isoprostanes (F(2)-IsoPs) and gamma-glutamyltransferase (GGT); and b) antioxidant nutrients (ascorbic acid and carotenoids)." "We also examine whether the proposed associations are mediated by smoking, alcohol consumption, and depression. Risk for chronic disease increases with decreasing SES. One pathway by which low SES might influence disease risk is by promoting oxidative stress." "Data from 1,278 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were used to examine the association of SES with oxidation correlates and antioxidant nutrients. Education, occupation, health behaviors, and body mass index (BMI) were assessed during Years 0, 10, and 15 of the study; income and depression were evaluated at Years 10 and 15. F(2)-isoprostanes were measured at Year 15, gamma-glutamyltransferase (GGT) at Years 0 and 10, carotenoids at Years 0 and 15, and ascorbic acid at Years 10 and 15." "Cross sectionally, oxidation correlates decreased and antioxidant nutrients increased with increasing SES, estimated in several ways, independent of age, sex, race, and BMI. Prospectively, lower Year 0 education and occupation predicted greater increases in GGT and greater decreases in carotenoids over 10 to 15 years. The researchers concluded, "Circulating oxidation correlates increase and antioxidant nutrients decrease with decreasing SES, both cross sectionally and prospectively."
Association between gamma-glutamyltransferase and coronary artery calcification (15)
In this 2012 report out of Turkey the researchers first noted, "The exact mechanisms behind the association between atherosclerosis and gamma-glutamyltransferase (GGT) are unclear. Coronary artery calcification (CAC) detected by computerized tomography is an important marker of atherosclerosis and its severity correlates with coronary plaque burden. The aim of this study was to investigate if serum GGT levels are associated with CAC in patients without known coronary heart disease (CHD) who had low-intermediate risk for CHD." "Two hundred and seventy two patients who had low-intermediate risk for coronary artery disease were included in the study. Serum GGT levels were measured spectrophotometrically. CACS (Agatston method) were performed using a 64-slice computerized tomography scanner. The patients were grouped according to their GGT values in four quartiles." "Patients in higher GGT quartiles had elevated CAC score (P<0.001). Patients in higher GGT quartiles were predominantly males (P<0.001) and were more likely to be smoking (P=0.004), and have elevated uric acid (P<0.001), fasting blood glucose (P<0.001), CRP levels (P=0.003) and 10-year total cardiovascular risk (P=0.007) and low HDL levels (P<0.001). Positive correlations were found between log GGT and CAC (r=0.233, P<0.001). In the multivariate analysis GGT, age, smoking and serum uric acid levels appeared as independent factors predictive of presence of CAC." The researchers concluded, "We demonstrated a significant correlation between serum GGT levels and CAC and CHD risk factors. Serum GGT level was an independent marker of CAC."
Association of coronary artery calcification and serum gamma-glutamyl transferase in Korean (16) Free full text
This study from Korea was reported in 2012. The investigators noted, "Elevated serum gamma-glutamyl transferase (GGT) has been known to be associated with the cardiovascular disease. However, there is a lack of researches on direct examination of relevance between serum GGT and coronary artery calcification (CAC). Accordingly, the aim of this study was to investigate the association between serum GGT levels and the prevalence of CAC in Korean." "The study population consisted of 14,439 male and female adults without coronary artery disease, who were conducted health examination from January 2010 to December 2010. The prevalence of CAC in relation to the quartile groups of serum GGT levels and odds ratio and 95% CI of CAC were analyzed using multiple logistic regression model." "The prevalence of CAC increased with increasing GGT quartile (4.6%, 8.7%, 11.8% and 14.7% in the lowest, second, third, highest GGT quartiles, respectively; p < 0.001). In the logistic regression analysis adjusted for multiple variables, odds ratio (95% CI) for the prevalence of CAC comparing the 1st GGT quartile to the 4th quartile were 2.43 (1.94-3.05) for all subjects, 1.49 (1.21-1.85) for men and
1.33 (0.62-2.87) for women. The investigators concluded, "Elevated serum GGT levels were independently associated with the prevalence of CAC. Physicians and health care providers should be observant regarding future development of coronary artery disease among people with increasing concentration of serum GGT." [Health-e-Iron note: Table #4 from this study appears below]
Gamma-glutamyl transferase and metabolic risk factors for cardiovascular disease (17) Free full text
The researchers in this 2005 study concluded, "...a significant association was observed between serum GGT activity and the cardiovascular risk factors studied including total cholesterol, triglycerides, fasting plasma glucose, total homocysteine and systolic blood pressure, independent of lifestyle factors." The researchers concluded. "The observed association between serum GGT and cardiovascular risk factors may partly explain the reported relationship between serum GGT activity and cardiovascular disease. Serum GGT activity may be regarded as a marker of cardiovascular risk factors or oxidative stress rather than a mere indicator of excessive ethanol consumption or obesity."
Serum gamma glutamyltransferase as a marker of metabolic syndrome and coronary disease likelihood in nondiabetic middle-aged and elderly adults (18)
In this 2006 study reported in Turkey, "754 men and 802 women were available for analysis who were followed up briefly yielding only 16% of overall cases of coronary heart disease (CHD). GGT activity was measured kinetically. In multivariate analysis across 12 variables, waist circumference, sex, complement C3, moderate alcohol intake and uric acid were significant independent covariates of serum GGT." "By analyzing the sample in tertiles, doubling in GGT activity was found associated with a rise of 74% in metabolic syndrome (MS) likelihood-independent of salient confounders (P < 0.001). This association was mediated by waist circumference. Individuals in the top versus the bottom tertile exhibited an odds ratio for CHD likelihood of 1.81 (95% CI 1.09; 3.02)-independent of age, sex, total cholesterol, systolic blood pressure, impaired fasting glucose, smoking status, alcohol usage and, notably, of waist circumference." "This indicated that a doubling in serum GGT activity corresponded to a 45% excess in CHD likelihood, after adjustment for standard risk factors." The researchers stated, "In conclusion, waist circumference is a major determinant of serum GGT activity among Turkish adults. Doubling in activity is associated with a (largely waist girth mediated) rise by over one-half in the multiadjusted MS likelihood, and by nearly one-half in the CHD likelihood, independent of waist girth and major risk factors."
Serum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28 838 middle-aged men and women (19) Free full text
In a 2006 study of 28,838 Finnish men and women studied up to 11.9 years hazard ratios increased in each of four ascending GGT categories. "Serum GGT cutpoints were the 25th, 50th, 75th, and 90th sex-specific percentiles. After adjustment for known cardiovascular risk factors, compared with the lowest GGT category, hazard ratios (HR) were 1.15, 1.25, 1.27, and 1.57 among men and 1.03, 1.22, 1.32, and 1.44 among women in other four GGT categories (P for trend <0.01, respectively)." "However, stronger associations were observed among subjects aged <60 and among alcohol drinkers." "Among subjects with type-2 diabetes, the corresponding adjusted HRs were 1.29, 1.57, 1.88, and 1.78 (P trend=0.03, men and women combined)." [Health-e-Iron note: Table #3 illustrating some of these results appears below]
Gamma-glutamyltransferase as a cardiovascular risk factor (20) Free full text
This 2006 review covers the evidence on GGT as a risk factor for cardiovascular disease based on prior published research.[Health-e-Iron note: The author provided Figure 1 below to demonstrate the relationship of GGT activity with arterial plaque and foam cell production]
Serum gamma-glutamyltransferase is a predictor of incident coronary events in apparently healthy men from the general population (21)
In this 2006 study of 1,878 men in Germany (age 25-64 years), the authors conclude, "Serum GGT is a strong predictor of acute coronary events in apparently healthy men from the general population, independent of other risk factors for cardiovascular disease." Across quartiles of GGT, the relative risk of a coronary event, in increments above a GGT reference of less than 13 U/L, increased to 1.84, 2.02 and 3.08 (for trend 0.0001). When further fully adjusted for multiple risk factors, the hazard ration in the highest GGT quartile was then 2.34. The researchers concluded, "Serum GGT is a strong predictor of acute coronary events in apparently healthy men from the general population, independent of other risk factors for cardiovascular disease."
Gamma-glutamyltransferase is associated with incident vascular events independently of alcohol intake: analysis of the British Women's Heart and Health Study and Meta-analysis (22) Free full text
In this 2007 report based on 2,961 participants in the British Women's Heart and Health study that included a meta-analysis of nine other studies, the researchers concluded, "GGT is associated with incident vascular events independently of alcohol intake." [Health-e-Iron note: Figure 3 below illustrates the results of the meta-analysis associating GGT with incident CHD or stroke.]
Gamma-glutamyl transpeptidase-dependent iron reduction and LDL oxidation--a potential mechanism in atherosclerosis (23)
In this 1999 reported study the researchers preformed "a series of experiments showed that the gamma-glutamate residue of GSH affected interactions of the juxtaposed cysteine thiol with iron, precluding Fe(III) reduction and hence LDL oxidation." "Both processes increased remarkably after addition of purified gamma-GT, which acts by removing the gamma-glutamate residue. GSH-dependent LDL oxidation was similarly promoted by gamma-GT associated with the plasma membrane of human monoblastoid cells, and this process required iron traces that can be found in advanced or late stage atheromas. Collectively, these findings suggested a possible role for gamma-GT in the cellular processes of LDL oxidation and atherogenesis. Histochemical analyses confirmed that this may be the case, showing that gamma-GT activity is expressed by macrophage-derived foam cells within human atheromas, and that these cells colocalize with oxidized LDL." The researchers concluded, "Biochemical and histochemical correlates indicate that gamma-GT can promote LDL oxidation by hydrolyzing GSH into more potent iron reductants. These findings may provide mechanistic clues to the epidemiologic evidence for a possible correlation between persistent elevation of gamma-GT and the risk of fatal reinfarction in patients with ischemic heart disease." [Health-e-Iron note: This relative early (1999) study suggested a process that appears to have been confirmed by an extensive body of more recent research]
Is serum gamma glutamyltransferase a marker of oxidative stress? (24) Free full text
In this 2004 analysis of results from the third U.S. National Health and Nutrition Examination Survey, these researchers found that GGT was inversely associated with six acknowledged antioxidants, but did not find it associated with vitamin E. "Fig. 1
shows a clear inverse association of the sum of carotenoids (acarotene, h-carotene, h-cryptoxanthin, lutein/zeaxanthin, and lycopene) with serum GGT levels. All these associations were not materially different after additional adjustment for total energy intake, BMI, smoking status, smoking amount, alcohol intake, and exercise..." "The researchers concluded, "...the current and previous studies strongly suggest that serum GGT level within its normal range may be an early marker of oxidative stress." [Health-e-Iron note: Below Figure 1 and Table 1 from this paper demonstrate the inverse relationship of these antioxidants with GGT]
Association of serum carotenoids and tocopherols with gamma-glutamyltransferase: the Cardiovascular Risk Development in Young Adults (CARDIA) Study (25) Free full text
Also in 2004, and similar to the previous study, the researchers examined data from 3,128 black and white participants (men and women 17–35 years of age in 1985–1986). The researchers noted, "Our present and previous studies with CARDIA participants consistently suggest that serum GGT might be one of the enzymes related to oxidative stress. One reason for this conclusion is that dietary heme iron positively predicted future serum GGT concentration; free iron, which would cause oxidative stress, might mediate this association, although free iron was not measured. They concluded, "Circulating concentrations of alpha-carotene, beta-carotene, and beta-cryptoxanthin inversely predicted the serum GGT concentration measured 10 years later in a dose-response manner (P for trend <0.01)." "...we found that baseline serum antioxidants were strongly and inversely associated with future serum GGT concentrations"...and, "Our present findings support the contention that serum GGT concentration is a marker related with oxidative stress." [Health-e-Iron note: Below Table 1 from this paper demonstrates the inverse relationship of these antioxidants with GGT]
Prevalence and Prognostic Significance of Elevated Gamma-Glutamyltransferase in Chronic Heart Failure (26) Free full text
In this 2009 study of 1,033 consecutive heart failure patients in Austria, the prevalence of elevated GGT was significantly higher in patients than in sex and age-matched healthy control subjects. The authors concluded, "Prevalence of elevated GGT is high in patients with chronic heart failure. The GGT levels are associated with disease severity. Increased GGT is an independent predictor of death or heart transplantation. GGT may provide additional prognostic information, especially in patients with mild heart failure." [Health-e-Iron note: Figure 2 from this paper appears below:]
Figure 2. Correlation between GGT in quintiles and combined end point. Cumulative 5-year event rates were estimated by univariate sex-stratified Cox proportional hazard regression analysis in 998 patients with CHF according to quintiles of GGT levels at the study entry. Numbers of patients at risk and event rates are shown below the graphs.
Plasma Gamma-Glutamyltransferase, Cysteinyl-Glycine, andOxidized Low-Density LipoproteinA Pathway Associated With Myocardial Infarction Risk? (27) Free full text
In this prospective study of more than 27,000 subjects reported in Germany in 2010, the researchers found virtually the same results for myocardial infarction as has been demonstrated above in many other studies. They ascertained that GGT predicted myocardial infarction, and concluded, "The positive association between GGT activity and MI risk appears to be independent of circulating cysteinyl-glycine and oxidized LDL levels." "In summary, we demonstrated that GGT activity in plasma is positively associated with incident MI" "However, contrary to our hypothesis, plasma levels of Cys-Gly and oxLDL appear to have a negligible influence on the relationship between GGT and the end point." [Health-e-Iron note: the below figure from this paper demonstrates the relative hazard rations for Myocardial I of GGT, cysteinyl-glycine and Oxidized LDL]
Figure. The HRs (95% CIs) of myocardial infarction per 1-SD increase in log-transformed plasma GGT activity, Cys-Gly, and oxLDL, as derived from Cox proportional hazards regression analysis, with age as the underlying time variable. Model 3 is stratified by age at recruitment and adjusted for sex, body mass index, smoking status, educational attainment, physical activity, alcohol consumption, hypertension, and TC/HDL-C ratio.
Gamma-glutamyl transferase: a novel cardiovascular risk biomarker (28) Free full text
This 2010 review was published by researchers from the Berkeley heart Lab and the American Heart Association. They noted, with respect to several of the studies on this page: "In the upper reference (i.e. normal) range, GGT was found to be an independent biomarker of the metabolic syndrome, with a 20% per GGT quartile trend rise. Additionally, GGT was positively correlated with an 18% per quartile risk of cardiovascular events and a 26% per quartile increased risk of all-cause mortality." And they suggested, "GGT is becoming an important addition to the multimarker approach to cardiovascular risk evaluation. It should be considered a valuable adjunct in stratifying patient risk and in assessing the aggressiveness of appropriate treatment, with hopes of preventing unnecessary cardiac events and deaths in future years." [Health-e-Iron note: Table 1 from this report is replicated below]
Ten year trends in chronic disease risk factors in the Republic of Karelia, Russia (29) Free full text
In this 2008 reported study from the Republic of Karelia (near St. Petersburg), North-West Russia. The researchers noted "In Russia, non-communicable diseases are leading cause of death. The aim of this article is to describe changes in chronic disease risk factors (RFs) in Pitkäranta district in Russia during ten year period of time from 1992 to 2002." "Independent random samples, age 25-64, were taken from the population registers. Blood pressure, weight and height were measured. Serum cholesterol, HDL-cholesterol, triglyceride and GGT values were determined from serum samples. Smoking and alcohol consumption were asked. The total number of respondents was 2,766." "Systolic and diastolic blood pressure decreased in Pitkäranta from 1992 to 2002. Total serum cholesterol increased slightly. There was no significant change in BMI or in physical activity. Smoking did not change in males but increased among females. Self-reported alcohol use increased, as also mean GGT." The researchers concluded, "The study gives valuable information on developments of RFs in Russia. Some alarming tendencies in lifestyle were seen and chronic disease RF situation has generally worsened. The results also show how big is the challenge to change lifestyles deep in culture--and in the situation where preventive work and policies do not receive strong support. A reliable monitoring of RFs and behaviours is obviously a back bone for drawing necessary attention and to steer intervention." [Health-e-Iron note: Table #4 from this study appears below. Note that the highlighted text and GGT measures in this population are significantly higher (both in 1992 and 2002-3) than those reported in all other studies on this web site. A good way to gauge this is by comparing the lowest GGT measures from the highest quartile GGT noted in the Framingham Offspring Study (Table #1 directly above, i.e., men; 25 U/L; women; 14 U/L) to the average or mean GGT measures highlighted below (men; 27.0 - 43.6 U/L; women; 22.3 - 26.0 U/L) . Not surprisingly, life expectancy in Russia is nearly ten years less than in the U.S. and approximately 11-13 years less than in Germany, Austria, and France.]
Metabolic syndrome in Russian adults: associated factors and mortality from cardiovascular diseases and all causes (30) Free full text
This is another study conducted in Russia that was reported in 2010. The investigators reported, "Russia has one of the highest CVD mortality in the world, but its association with MetS remains unknown." "Data on 3555 adults aged 18-90 years were collected in a cross-sectional study in 2000." "After adjustment for all studied factors except BMI, age, serum GGT, C-reactive protein and AST-to-ALT ratio were associated with MetS in both genders. Additionally, MetS was associated with sedentary lifestyle in women and with smoking in men. In the same regression model drinking alcohol 2-4 times a month and consumption of five or more alcohol units at one occasion in men, and drinking alcohol 5 times or more a month in women were inversely associated with MetS. After a 9-year follow-up, MetS was associated with higher risk of death from stroke (RR = 3.76, 95% CI:1.35-10.46) and from either stroke or myocardial infarction (MI, RR = 2.87, 95% CI:1.32-6.23) in men." The researchers concluded, "Factors associated with MetS in both genders were age, GGT, C-reactive protein, and AST-to-ALT ratio. Moderate frequency of alcohol consumption and binge drinking in men and higher leisure time physical activity in women, were inversely associated with MetS. Positive associations between MetS and mortality were only observed for deaths from stroke and either stroke or MI in men." [Health-e-Iron note similar to the study directly above, mean GGT levels (men; 43.7 U/L and women; 28.4 U/L) in this study were also quite high compared to other populations studied]
Persistent elevation of liver function enzymes within the reference range is associated with increased cardiovascular risk in young adults: the Bogalusa Heart Study (31)
In this 2007 reported by researchers from Tulane University Health Sciences Center, liver enzymes were tracked over time for 12 years in 489 young adults (40% male, 73% white at baseline). "Both at baseline and follow-up, males vs females had higher ALT (P < .01 to .0001) and GGT (P < .0001); blacks vs whites had higher GGT (P < .0001)." Enzyme levels over time were persistently high for those in the highest quartile at baseline. "...based on a multivariate analysis using 2 separate models for ALT and GGT, baseline levels of both enzymes were independent predictors of follow-up; insulin resistance index and baseline GGT were also predictive of follow-up systolic blood pressure. Elevations in liver enzymes ALT and GGT, within "reference" range, persist over time and relate to clinically relevant adverse CV risk profile in young adults."
Increased γ-glutamyl transferase levels predict early mortality in patients with acute pulmonary embolism (32)
In this 2012 reported study of early mortality in Turkey, GGT was measured in 127 consecutive patients with confirmed pulmonary embolism. Eighteen patients died during follow-up, of which 17 had GGT above 55 U/L. the research team concluded, "We have shown that a high GGT level is associated with worse hemodynamic parameters, and it seems that GGT helps risk stratification in patients with acute PE."
Longitudinal change in serum gamma-glutamyltransferase and cardiovascular disease mortality: a prospective population-based study in 76,113 Austrian adults (33) Free full text
This 2008 Austrian study included 76,113 men and women and 455,331 serial GGT measurements. A pronounce increase in GGT over time was significantly associated with cardiovascular disease mortality in men when compared to men with relatively stable GGT during the period. Women demonstrated similar but less significant results, and only with respect to coronary artery disease. As in several of the above studies, the risks were observed to be markedly stronger for younger individuals. The researchers concluded, "Our study is the first to demonstrate that a longitudinal increase in GGT, independently of baseline GGT and even within its normal range, significantly increases risk of fatal CVD." [Health-e-Iron note: Figure 1 from this study is replicated below]
Figure 1. Adjusted cumulative survival from all cardiovascular events according to categories of 7-year increase of serum -glutamyltransferase (GGT) among 26,105 male (A) and 36 822 female (B) Austrian adults. Participants with baseline GGT 60 U/L in men and 36 U/L in women or participants increasing into the abnormal range of GGT were excluded.
Longitudinal increase in gamma-glutamyltransferase within the reference interval predicts metabolic syndrome in middle-aged Korean men (34)
A study similar to the above one was reported in 2010 by researchers on Korea. "...we examined the association between longitudinal changes in serum gamma-glutamyltransferase (GGT) levels and the risk for metabolic syndrome (MetS). A MetS-free cohort of 9,148 healthy male workers, who had participated in a health checkup program in 2002, was followed until September 2007." "During 37,663.4 person-years of follow-up, 1,056 men developed MetS. The risk of incident MetS increased across the baseline GGT quartiles, even after further updating GGT values during the follow-up." "A longitudinal increase in GGT as a time-dependent variable as well as a non-time-dependent variable was significantly related to MetS after adjusting for age plus the elapsed time from visit 1 to visit 2, baseline MetS traits, uric acid, regular exercise, alcohol consumption, and smoking." "Even within the GGT reference interval (<40 U/L), the fourth quartile of GGT change predicted the development of MetS (adjusted hazard risk, 1.61; 95% confidence interval, 1.26-2.07)." "Furthermore, these associations were consistently observed within the subgroups-those with body mass index less than 23 kg/m(2), C-reactive protein less than 3.0 mg/L, homeostasis model assessment of insulin resistance less than 2.04, alcohol intake not exceeding 20 g/d, alanine aminotransferase less than 35 U/L, an absence of ultrasonographically detected fatty liver, and an absence of any MetS traits." The researchers concluded, "A longitudinal increase in the GGT level, even within the GGT reference interval, may be an independent predictor for MetS, regardless of the baseline GGT."
Cross-sectional and longitudinal association of serum alanine aminotransaminase and gamma-glutamyltransferase with metabolic syndrome in middle-aged and elderly Chinese people (35) Free full Text
In this 2011 reported study from China "5,404 subjects aged ≥ 40 years were recruited from two urban communities in Shanghai for cross-sectional analyses. A subgroup of 681 participants without MetS at baseline was included in the longitudinal analyses." "Both GGT and ALT were strongly and positively associated with MetS risks in simple and multivariate analyses. Further adjustment for HOMA-IR and ALT did not change the association of GGT and MetS materially, whereas adjustment for HOMA-IR and GGT substantially attenuated the ALT-MetS association. In longitudinal analyses, risks of developing MetS were increased across GGT quartiles in a dose-dependent manner after extensive adjustments (odds ratios were 1.00, 1.38, 1.62, and 2.29
for GGT, quartile 1 through quartile 4; P for trend = 0.01). In contrast, ALT was no longer associated with MetS development after final adjustment for GGT (P for trend = 0.09)." The investigators concluded, "Our study confirmed significant and independent associations of GGT and ALT with MetS in adult Chinese people. Moreover, GGT might be more effective for indicating the future development of MetS." [Health-e-Iron note: Tables 1 and 3 from this paper appear below]
Role of GGT in diagnosis of metabolic syndrome: a clinic-based cross-sectional survey (36) Free full text
This study adult men and women in Turkey was published in 2010 and was aimed to determine "if the liver function tests (LFT), especially gamma glutamyl transferase (GGT), have a predictive value in diagnosis of metabolic syndrome (MS). A cross-sectional, single-center study was carried out with 908 subjects. Four hundred and forty two of these subjects were diagnosed with MS with IDF criteria; while other 466 were sex and age matched healthy control subjects. Blood pressure, liver function tests, fasting blood glucose levels and lipid profile of the subjects were recorded." "The mean values of ... (ALT), ...(AST) and GGT levels were statistically significantly higher in MS group. ..." When the sample is divided into quartiles of the GGT levels, increase in GGT is positively correlated with increased MS prevalence. In ROC analysis GGT is as strongly associated with the IDF (International Diabetes Federation) diagnostic components as is each individual IDF component, except elevated systolic blood pressure." "In multivariance analysis, in MS group, a high GGT was positively associated with CVD prevalance (odds ratio: 2.011, 95% CI 1.10-4.57) compared to low GGT group independent of age, sex and smoking habits." The researchers concluded, "Elevated liver enzymes, although in normal ranges, especially at upper quartiles, play a central role in early diagnosis of fat overflow to the liver. Regarding the availability and simplicity of these tests in routine clinical practice, they, especially GGT, have potential to be considered in algorithms for metabolic syndrome." [Health-e-Iron note: Table 1 from this Table appears below]
The value of gamma-glutamyltransferase in cardiovascular risk prediction in men without diagnosed cardiovascular disease or diabetes (37)
This 2008 study covering 6,997 men age 40-59 from 24 British towns followed for up to 24 years reported results consistent with the findings shown above. "GGT was significantly and positively associated with increased risk of fatal (but not non-fatal CHD events), major stroke events and total CVD mortality after adjustment for established CVD risk factors. Risk of fatal CHD and CVD mortality was only elevated in the top quarter (≥22IU/L); risk of stroke tended to increase with increasing GGT. The adjusted relative risks (Q4 vs. Q1) were
1.43 (1.09,1.84) for fatal CHD events, 1.56 (1.20,2.04) for stroke incidence and
1.40 (1.16,1.70) for CVD
mortality. When stratified by age groups stronger associations were seen between GGT and CVD mortality in the younger men (<55 years) (p=0.01 for interaction). GGT significantly predicted CVD outcomes especially in those at low and medium CHD risk based on Framingham risk score (FRS)." The researchers concluded, "Elevated GGT is associated with significantly increased risk of stroke, fatal CHD events and CVD mortality independent of established CVD risk factors and may be a useful additional marker for long-term CVD risk."
Gamma-glutamyltransferase, cardiovascular disease and mortality in individuals with diabetes mellitus (38) Free full text
Reported in 2012, this was a study based on data from the Investigation into Cancer and Nutrition in Potsdam (Germany), Bilthoven and Utrecht (the Netherlands). Data used were from 1,280 participants, aged 35-70 years, with a confirmed diagnosis of diabetes mellitus. Participants with high GGT activity had an increased mortality risk: Hazard Ratio in the highest quartile was 3.96 (95% CI 1.74, 9.00). The researchers concluded, "Higher GGT plasma activity is associated with increased all-cause mortality in individuals with diabetes."
Serum gamma-glutamyl transferase, self-reported alcohol drinking, and the risk of stroke (39) Free full text
In this 2000 research report from Finland, "A prospective cohort study of 14, 874 Finnish men and women aged 25 to 64 years who participated in a cardiovascular risk-factor survey in 1982 or 1987." "Serum GGT concentration was associated with the risk of total and ischemic stroke in both genders. The risk ratios...in men and women were 1.45 and 1.48 for total stroke and 1.51 and 1.59 for ischemic stroke, respectively" (Table 2 in full paper) "There was also a significant association among men between GGT and the risk of intracerebral hemorrhage and among women between GGT and the risk of subarachnoid hemorrhage. The relationships remained statistically significant also after adjustment for other risk factors. Self-reported alcohol drinking did not associate with any type of stroke." [Health-e-Iron note: Tables 1 and 2 from this report are below]
Association between serum gamma-glutamyltransferase and acute ischemic nonembolic stroke in elderly subjects (40)
This was a 2009-published study from Greece. "A total of 163 patients >70 years of age (88 men) admitted due to a first-ever acute ischemic/nonembolic stroke and 166 volunteers (87 men) without a history of cardiovascular disease were included." "Stroke patients showed higher concentrations of GGT compared with controls. In univariate analysis, crude odds ratio (OR) for GGT was 1.06/1 IU/L increase (95% CI, 1.03-1.09; p<0.001). Compared to subjects with GGT levels in the lowest quartile, those within the highest quartile had a 4.7-times increase in the odds of experiencing an ischemic stroke (95% CI 2.39-9.11, p<0.001). This association remained significant after controlling for all potential confounders (adjusted OR, 2.90, 95% CI, 1.35-6.27; p=0.007). Analysis of interaction between MetS and GGT showed that subjects with MetS had a 1.08 higher odds/1 IU/L increase in GGT to experience an ischemic stroke [adjusted OR, 1.08 (95% CI, 1.04-1.12; p<0.001)." The researchers concluded, "There are positive associations between serum GGT and first ischemic/nonembolic stroke in individuals >70 years of age independent of established risk factors for cardiovascular disease and concurrent metabolic abnormalities."
Gamma-glutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes (41)
In this 1995 study of 7,613 British men followed for 11.5 years, "GGT levels were strongly associated with all-cause mortality, largely due to a significant increase in deaths from ischemic heart disease and other non-cardiovascular disease causes, i.e., non-cancer deaths, in the top quintile of the GGT distribution" "After adjustment for these personal characteristics and biologic variables, elevated GGT (highest quintile > or = 24 unit/liter vs. the rest) was still associated with a significant increase in mortality from all causes (relative risk (RR) = 1.22, 95% confidence interval (CI) 1.01-1.42; n = 818 deaths) and from ischemic heart disease (RR = 1.42, 95% CI 1.12-1.80; n = 332 deaths)." In 1995 the researchers concluded, "...many factors other than alcohol intake are associated with increased levels of GGT, in particular body mass index, diabetes mellitus, and serum total cholesterol." [Health-e-Iron note: This early paper (i.e. 1995) established a firm footing for what would later be discovered. In comparing the top 20% quintile to "the rest" only, the knowledge respecting increased mortality risks within the "normal range" had not yet been published. Also at that time the evidence indicating GGT''s direct involvement in the oxidative stress process had not been thoroughly investigated. This evidence is discussed in detail in many of the journal articles referenced on this web site.]
Serum γ-glutamyltransferase and the risk of heart failure in men and women in Finland (42) Free full text
The objective of this 2012 reported study was "to evaluate the association of serum γ-glutamyltransferase (GGT) levels with heart failure (HF) risk in the Finnish population." "The present study, which is a part of FINRISK study, was carried out in Finland.Subject study cohorts included 18 353 Finnish men and 19 726 women who were 25-74 years of age and free of HF at baseline. Main outcome measures HF (636 men and 445 women) during a mean follow-up of 14.5 years." "The multivariable-adjusted (age, sex, study area, study year, smoking, education, alcohol consumption, physical activity, valvular heart disease, body mass index (BMI), systolic blood pressure, total cholesterol at baseline, myocardial infarction and diabetes at baseline and during follow-up) HRs of HF at five GGT groups (using the 25th, 50th, 75th and 90th percentiles) were 1.00, 1.16 (95% CI: 0.97 to 1.38), 1.20 (1.00 to 1.45), 1.29 (1.04 to 1.60) and 1.82 (1.45 to 2.29) (P (trend) <0.001). Stratification by smoking status, alcohol consumption and BMI gave similar results, while stronger association was observed among subjects aged <60 years (P(trend)=0.001) compared with subjects 60+ years of age (P(trend)=0.173). The researchers concluded, "Moderate to high levels of serum GGT (from the 50th to the 90th percentiles) were significantly associated with incident HF in men and women in Finland, and the predictive power was stronger in subjects aged <60 years."
Serum gamma-glutamyltransferase as a risk factor of ischemic stroke might be independent of alcohol consumption (43) Free full text
The significant points made in this 2002 editorial review were that GGT in the presence of of iron can catalyze the oxidation of LDL, when free iron was present in sufficient levels to do so. The authors concluded, "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” of alcohol consumption, when evaluated in a context of atherosclerosis and cardiovascular disease." [Health-e-Iron note: the below slide from this article provides an example of the iron-catalyzed from an autopsy]
"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."
Gamma-glutamyltransferase and prognosis in patients with stable coronary heart disease followed over 8 years (44)
In this 2010 study done in Germany, of 1,152 patients (age 30-70 years at baseline) who participated in an in-patient rehabilitation program after acute coronary syndrome, 147 participants had experienced a non-fatal or fatal secondary cardiovascular disease event. Hazard ratios ascended over the second, third and fourth quartiles of GGT respectively: 1.21, 1.32 and 1.75. All all-cause mortality as a secondary outcome was stronger (HR 1.97 Ptrend=0.017). The researchers concluded, "In patients with stable coronary heart disease, serum gamma-GT was associated with prognosis independent of a variety of established risk markers. The association appeared similar to that reported for primary cardiovascular disease, which should motivate additional studies of its clinical utility in cardiovascular patient care." [Health-e-Iron note: the outcomes from this study are summarized in the below chart]
Association of gamma-glutamyltransferase with cardiovascular risk: a prognostic outlook (45)
An opinion rendered from this 2009 review stated, "...supplementary GGT determination to conventional testing has potential implications for screening those at increased cardiovascular risk who may benefit from prophylactic measures and require enhanced therapeutic effort."
Gamma-Glutamyltransferase Level and Risk of Hypertension: A Systematic Review and Meta-Analysis (46) Free full text
This is a 2012 published "systematic review and meta-analysis to evaluate the exact association between GGT level and subsequent development of hypertension." "A total of 13 prospective cohort studies including 43314 participants and 5280 cases of hypertension were included. The pooled RR of hypertension was 1.94 (95%CI: 1.55-2.43; P<0.001) when comparing the risk of hypertension between the highest versus lowest category of GGT levels. Moreover, the risk of hypertension increased by 23% (summary RR: 1.23; 95%CI: 1.13-1.32; P<0.001) per 1 SD logGGT increment. Subgroup analyses showed significant positive associations in each subgroup except in ≧160/95 subgroup (RR: 2.56, 95%CI: 0.87-7.54; P = 0.088) and nondrinkers subgroup (RR: 1.76, 95%CI: 0.88-3.53; P = 0.113). Sensitivity analyses showed no single study significantly affects the pooled RRs. No publication bias was found in our meta-analysis." The researchers concluded, "GGT level is positively associated with the development of hypertension. Further studies are needed to confirm our findings and elucidate the exact mechanisms between GGT level and the incidence of hypertension." Health-e-Iron note: Table 2 "Meta-analysis of risk of hypertension between highest vs lowest category of GGT" is below]
Association between serum gamma-glutamyltransferase level and prehypertension among US adults (47) Free full text
This was a 2007 report to determine whether "Higher serum gamma-glutamyltransferase (GGT) levels, a marker of oxidative stress, are implicated in the development and progression of hypertension..." "This was a "cross-sectional study among 5,827 National Health and Nutrition Examination Survey 1999–2002 participants aged ≥18 years without cardiovascular disease (CVD) and hypertension." "The researchers found "higher serum GGT levels were positively associated with prehypertension, independent of smoking, waist circumference, diabetes, cholesterol levels and other confounders. The multivariable odds ratio (95% confidence intervals) comparing quartile 4 of GGT (>29 U/L) to quartile 1 (<13 U/L) was 1.84 (1.37–2.46), p<0.0001." "This association persisted in separate analyses among men and women. The results were consistent in subgroup analyses by race-ethnicity, age, smoking, alcohol intake, body mass index, waist circumference and diabetes. In non-parametric models, the positive association between serum GGT and prehypertension appeared to be present across the full range of GGT, without any threshold effect. The researchers concluded, "Higher serum GGT levels are associated with prehypertension in a nationally representative sample of US adults, free of CVD and hypertension." [Health-e-Iron note: Table 2 from this study appears below]
Body fat distribution, liver enzymes, and risk of hypertension: evidence from the Western New York Study
Free full text
This was a study from New York reported in 2005 to determine the association of GGT with hypertension. It was "a 6-year longitudinal investigation among 1,455 men and women who returned for the follow-up visit. Baseline variables included serum GGT, blood pressure, and anthropometric measures. Incident HTN (hypertension) was defined as blood pressure > or =140/90
or on antihypertensive medication at the follow-up visit. To eliminate individuals with potential liver pathology, analyses focused only on individuals with GGT within its normal range (n=897). Participants were divided in quintiles (Q) based on their baseline GGT levels." "Multiple logistic regression analyses [odds ratio (95% confidence intervals)] revealed a significant association of GGT with incident hypertension [2.1 (1.1 to 4.0) Q5 versus Q1]. In subgroup analyses, GGT and HTN were significantly associated among both noncurrent and current drinkers, but only for participants above the median of anthropometric measures [eg, body mass index >26.4, 2.3 (0.9 to 5.7), waist circumference >86.1 cm, 3.7 (1.4 to 9.9), and abdominal height >19.8 cm, 3.1 (1.2 to 8.5), for Q5 versus Q1, in fully adjusted models]. The researchers concluded, "that the association between GGT and hypertension is not caused solely by alcohol consumption and indicate that serum GGT, within its normal range, may predict hypertension among individuals with increased central fat distribution, suggesting that fatty liver may represent an important underlying mechanism for this association." [health-e-Iron note: Table #3 from this study appears below]
gamma-Glutamyltransferase predicts cardiovascular death among Japanese women (49) Free full text
This was a 2007-reported study undertaken in Japan. The researchers noted, "Since Japanese women are known to have a lower prevalence of alcohol consumption, we examined whether GGT predicts CVD mortality in never-drinkers. We followed 2,724 Japanese men and 4,122 Japanese women without prior CVD or liver dysfunction for 9.6 years and observed 83 and 82 CVD deaths, respectively. Current alcohol drinkers comprised 59% of men and 7% of women. Among women, the multiple adjusted hazard ratio (HR) for CVD mortality compared with the reference group (GGT: 1-12 U/L) was 2.88 (95% confidence interval (CI), 1.14-7.28) for the elevated group (GGT>or=50 U/L). This positive relationship was unchanged in the never-drinkers subgroup (HR for log-transformed GGT, 1.62 (95% CI, 1.11-2.37)). No significant relationships were observed in men." The researchers concluded, "GGT displays a strong positive association with CVD mortality among Japanese women, for whom the prevalence of ever-drinkers is very low."
Serum gamma-glutamyltransferase is associated with arterial stiffness in healthy individuals (50)
In this 2011 study reported in Korea serum GGT, brachial-ankle pulse wave velocity (baPWV) "and conventional risk factors were measured in 10,988 apparently healthy subjects (7,248 men, 3,740 women) who participated in a routine health screening examination." "In both men and women, we observed positive linearity between GGT quartiles and body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, total cholesterol, LDL cholesterol, triglycerides, uric acid, high-sensitive C-reactive protein (hsCRP) and homeostatic model assessment of insulin resistance (HOMA-IR) score (P for trends < 0·001). The proportion of individuals with diabetes, hypertension increased as the GGT quartile increased (P for trends < 0·001). Age-adjusted mean baPWV increased gradually in both males and females according to GGT quartiles (P for trends < 0·001 in both genders). The odds for higher baPWV (i.e. >75th percentile in each sex) were significantly higher in the highest compared with the lowest GGT quartiles, after adjustment for confounding variables, in both men [odds ratio (OR) = 1·63, 95% CI = 1·21-2·20] and women (OR = 1·56, 95% CI = 1·08-2·27). The researchers concluded, "These results suggest that GGT is independently associated with the increased level of arterial stiffness both in men and in women and the association between them appears to be stronger in men compared to women."
Fatty liver index, gamma-glutamyltransferase, and early carotid plaques (51) Free full text
This is a 2012 report by an Italian research team. The researchers noted, "An association between fatty liver and carotid atherosclerosis has been established; however, it is not clear whether this relationship is a consequence of shared conventional risk factors or whether it is determined by specific circulating factors originating from liver or adipose tissue." "To identify the factors possibly linking fatty liver and atherosclerosis, we assessed, in 1,012 subjects free of confounding diseases (e.g., hypertension, diabetes, cardiovascular diseases, and dyslipidemia) and metabolic syndrome, the relationship between the presence of early plaques at carotid bifurcation and fatty liver index (FLI; a validated surrogate marker of fatty liver), as well as the associations between carotid plaque presence and established atherosclerotic risk factors, family history of cardiovascular disease (FH-CVD) or diabetes, insulin sensitivity, serum liver enzymes, adipokines, fatty free acids, and high-sensitivity C-reactive protein (hsCRP). A total of 55 of 1,012 subjects (5.4%) had small plaque at carotid bifurcation. Subjects with plaque were older and had higher prevalence of FLI ≥60 and FH-CVD, higher blood pressure, plasma low-density lipoprotein cholesterol, glucose, gamma-glutamyltransferase (GGT), and hsCRP, as compared to subjects without plaques (P < 0.05). In a logistic regression model, adjusted for sex, liver transaminase, and alcohol consumption, the independent predictors of plaque presence were age (P < 0.0005), FLI ≥60 (P < 0.0005), and current smoking (P < 0.05). When FLI in the model was replaced by variables used in its equation (e.g., body mass index, waist circumference, plasma triglycerides, and GGT), the independent determinants of plaque presence were age (P < 0.001), GGT (P = 0.001), and current smoking (P < 0.05)." The researchers concluded, "Our cross-sectional study suggests that subjects with FLI ≥60 are at higher risk of atherosclerotic lesions, independently of established risk factors, and that serum GGT may represent a link between fatty liver and the development of early atherosclerosis." [Health-e-Iron note: Table 1 from this study is below]
The significance of serum gamma-glutamyltransferase in cardiovascular diseases (52) Free full text
This review from Italy published in 2004, provided a parallel suggestion, "the recently recognized functions of GGT in the generation of reactive oxygen species, indicate that serum GGT represents a true marker of cardiovascular diseases and underlying atherosclerosis." The authors stated in their concluding remarks that: "...with regard to ischemic heart and brain disease, serum GGT appears to have all the features of a true prognostic marker:"
Optimal sensitivity-specificity of the diagnostic assay
Epidemiological evidence of its presence in apparently healthy people before the occurrence of events; and
Real improvement in the ability to predict subsequent events
Additive prognostic value of gamma-glutamyltransferase in coronary artery disease (53) Free full text
This 2009 study first noted that, "Serum gamma-glutamyltransferase activity (GGT) has been documented as an independent cardiovascular risk factor. However, to-date its value has not been compared with C-reactive protein (CRP) and other indexes in a multimarker prognostic strategy in patients with coronary artery disease." "We prospectively evaluated 474 subjects with angiographically documented CAD. GGT and traditional humoral and clinical parameters were measured at hospital admission. A multivariate model was used to predict all-cause and cardiac mortality." "GGT showed an independent prognostic value after adjustment for possible confounders, including alcohol consumption, and beyond established risk factors, such as extent of coronary atherosclerotic disease, left ventricular ejection fraction, age, serum glucose, cholesterol subfractions, and C-reactive protein (CRP). At a 3-year follow-up, cardiac mortality was 9% in patients with serum GGT activity >25 U/L vs. 3.5% in those with serum GGT<25 U/L (p=0.028). The association of three independent biomarkers (higher GGT, CRP, fasting glucose) identified a subgroup of 45 patients with the highest risk of cardiac death at 3 years (26.6%, vs. no event or 2.7% in the subsets of 87 and 198 patients with, respectively, no/one risk factor above cut-off value, p<0.0001)." The researchers concluded, "GGT is confirmed as independent risk factor in patients with established coronary artery disease. GGT, CRP, fasting glucose show an additive prognostic value, whereas low values of these biomarkers identify a subset of patients with the lowest risk of cardiac death." [Health-e-Iron note: Figure 2 from the above paper is below]
Fig. 2. P-spline analysis (the lines reflect the 95% confidence intervals) of the association of biomarkers with the risk of cardiac death shows a dose–response relationship for serum gamma-glutamyltransferase (GGT) activity (top left), glucose level (top right), C-reactive protein (CRP) level (bottom).
Gamma-glutamyltransferase and risk of cardiovascular disease mortality in people with and without diabetes: Pooling of three British Health Surveys (54)
In this 2012 reported study the researchers "examined (a) the association of GGT with cardiovascular disease (CVD) and all-cause mortality in people with and without diabetes; and (b) the predictive validity observed when adding GGT to a CVD risk algorithm." "In an analytical sample of 17,852 participants, 583 (3.3%) had baseline diabetes. During 10.1years of follow-up, there were 235 deaths from all causes (77 from CVD) in diabetics. Corresponding results for non-diabetics were 2859 and 719. The age- and sex-adjusted HR (95%CI) for a one SD increase in log(e)(GGT) in relation to CVD mortality risk in participants with diabetes was 1.43 (1.13-1.81) and in those without diabetes was 1.27 (1.18-1.37). Corresponding results for total mortality were 1.24 (1.08-1.44) and 1.30 (1.25-1.34)." The researchers concluded, "Higher GGT levels are a risk factor for all-cause and cardiovascular disease death in people with and without diabetes. However, knowledge of GGT does not improve cardiovascular predictions beyond traditional risk factors."
gamma-Glutamyltransferase dependent generation of reactive oxygen species from a glutathione/transferrin system (55)
The results of this 1998 laboratory study from Poland reported, "In comparison with GGT negative V79 cells, only recombinant cells expressing a high level of GGT on the cell membrane were able to generate Reactive Oxygen Species." The researchers summarized these findings as follows: "We further confirmed the hypothesis that cysteinylglycine (CysGly), a product of GGT/GSH reaction, ... but not GSH (glutathione), was responsible for ROS formation initiated by the reductive release of iron from transferrin. These data clearly indicate that under physiological conditions, GGT is directly involved in ROS generation." [This was among the first reports to describe how GGT "was responsible for ROS formation initiated by the reductive release of iron from transferrin."]
Gamma-glutamyltransferase activity in human atherosclerotic plaques--biochemical similarities with the circulating enzyme (56)
This 2009 study was reported by a research team in Italy. Based on a n analysis of 18 consecutive patients undergoing carotid endoarteriectomy, "The results obtained suggest the presence in plaques of a serum-like GGT protein, indicating that a direct contribution of serum GGT to enzyme activity found within atherosclerotic lesions is possible. Data also indicate the occurrence of GGT-mediated redox reactions within plaque environment, which might influence plaque progression."
Study of the pro-oxidant and antioxidant properties of glutathione on proteins and lipids oxidative damage : the relevance to atherogenesis (no abstract) (57)
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The full text of this article published in 2000 describes the author's laboratory study of the antioxidant and pro-oxidant properties of GGT/glutathione interaction the presence of iron. "We proposed to study in vitro the pro-oxidant role of GGT/GSH (glutathione) and the oxidative modifications that it induces on proteins and lipids, known vulnerable targets of free radical attack." "We found a significant increase (1.3 to 5 fold) for different carbonyl compounds in the samples containing GGT in the oxidation mixture, as compared to the control, that clearly proves the role of GGT in lipid peroxidation." "In addition, generation of highly reactive 4-hydroxyalkenals (such as 4-hydroxynonenal) with known toxic effects on cell membranes and functions (Comporti, 1998) suggests that the GSH metabolism by GGT in the presence of iron might represent a biological way for a LPO (lipid peroxidation) toxic process."
Evidence for the pro-oxidant effect of gamma-glutamyltranspeptidase-related enzyme
The author of the above study and several colleagues published this study later in 2000 and first noted, "It has been previously reported that the metabolism of reduced glutathione (GSH) by gamma-glutamyltranspeptidase (GGT) in the presence of chelated metals leads to free radical generation and lipid peroxidation (LPO)." "The present study demonstrates for the first time that an established cell line expressing GGT-rel, a human GGT-related enzyme, metabolizes extracellular GSH to cysteinylglycine (CysGly) in a time-dependent manner when cells were incubated in a medium containing 2.5 mM GSH and 25 mM glycylglycine. Supplementation with 150-165 microM Fe(3+)-EDTA resulted in a reactive oxygen species (ROS) generation process. The researchers concluded, "Our data clearly indicate that in the presence of iron, not only GGT, but also GGT-rel has a pro-oxidant function by generation of a reactive metabolite (CysGly) and must be taken into account as a potential physiopathological oxidation system."
Role of gamma-glutamyl transferase (GGT) in diagnosis of impaired glucose tolerance and metabolic syndrome: A prospective cohort research from the Kerman Coronary Artery Disease Risk Study (KERCADRS) (59)
In this 2012-reported study from Iran, the investigators noted "The important role of raised serum gamma-glutamyl transferase (GGT) for predicting diabetes mellitus and insulin resistance is clear; however relationship between increased level of GGT and impaired glucose tolerance (IGT) is now hypothesized. We aimed to show the importance of GGT measurement in diagnosis of IGT." "Two hundred persons were randomly selected from the Kerman Coronary Artery Disease Risk Study (KERCADRS), as a population-based study. All participants underwent GGT analysis test, besides measuring risk factors and components of metabolic syndrome (MS)." "The area under curve (AUC) for GGT was 0.722 for discriminating IGT from normal condition, and 0.847 for discriminating MS from normal status. In ROC curve analysis, the optimal cut-off value for GGT to discriminate IGT from normal condition was 20.5 IU
with the sensitivity of 71.6% and the specificity of 66.1%. The best cutoff value for GGT to discriminate MS from normal condition was also 16.5 IU with the sensitivity and specificity of 78.4% and 78.4%, respectively." The investigators concluded, "The measuring GGT can be a sensitive method for early diagnosis and predicting IGT and MS from normal condition. Because this diagnostic test is a low-cost, highly sensitive, accurate and frequently used laboratory test, its measurement is recommended as a useful marker of both IGT and MS."
Synergistic effect of gamma glutamyltransferase and obesity on metabolic syndrome, independent of hepatic steatosis (60)
This 2012 reported study was undertaken in Taiwan. The researchers first noted, "Both obesity and gamma glutamyltransferase (GGT) are individually considered to be closely associated with metabolic syndrome (MetS). Whether the 2 factors synergistically associate with MetS is not yet confirmed. The purpose of this study was to investigate whether obesity and GGT are interactively associated with MetS." "A cross-sectional study of 7390 adults (age 32-62 years old) was conducted from 2009 to 2010." The "results showed that greater serum GGT quartiles were positively associated with all MetS components and fatty liver (P < .001). The odds ratio of MetS increased significantly along with quartiles of GGT and obesity. In comparison with subjects with normal body mass index and first quartile GGT, the odds ratio of MetS in obese groups with 1st, 2nd, 3rd, and 4th quartile GGT were 6.8, 14.5, 20.3, and 45.2, respectively, and it remained tenable after adjustment for fatty liver. The synergy index of GGT and obesity on MetS is 2.2 (95% confidence interval, 1.9-2.6)." The researchers concluded, "Serum GGT level in combination with obesity can be a simple but useful tool for risk stratification of developing MetS. Obese individuals with high-normal GGT levels require close monitoring for high risk of MetS."
Serum levels of γ-glutamyltransferase and progression of coronary atherosclerosis (61)
The researchers in this 2012-reported study from Italy noted, "Progression of coronary atherosclerosis (ATS) has clinical implications. Serum levels of γ-glutamyltransferase (GGT), a marker of oxidative stress, predict the risk of cardiovascular events. However, the role of GGT levels in the progression of coronary ATS has never been established." 100 consecutive patients (age ~64 years, 68% men) underwent coronary angiographs (CAs) separated by at least 6 months. All of the patients were on statin treatment. Following a multiple regression analysis, and as assessed by increases in stenosis score between each CA, GGT was the only independent predictor of progression of coronary atherosclerosis. The researchers concluded, "GGT is associated with angiographic coronary ATS progression in patients with ischemic heart disease on statin treatment, suggesting that oxidative stress may be another therapeutic target for preventing ATS progression beyond that of lipid-lowering therapies."
Serum gamma-glutamyl transferase and mortality in persons undergoing coronary angiography-The Ludwigshafen Risk and Cardiovascular Health Study (62) Free full text
This study was undertaken in Germany and reported in 2010. The researchers noted, "Serum gamma-glutamyl transferase (GGT) seems to be a predictor for coronary artery disease (CAD). The objective of this study was to elucidate the relationship between GGT and total as well as cardiovascular mortality." "Serum levels of GGT were determined in 2,556 subjects with and 699 subjects without angiographic evidence of CAD in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study." "Serum GGT was positively associated with male gender, alcohol consumption and markers of the metabolic syndrome (triglycerides, blood pressure, waist circumference and insulin resistance). It was positively related to aspartate aminotransferase, alanine aminotransferase, C-reactive protein, interleukin-6, and negatively related to glutathione and increased age. During a mean follow-up period of 7.75 years, 754 subjects died. Compared with subjects in the lowest quartile of GGT, the unadjusted hazard ratios (95% CI) for all-cause death were 1.2 (0.9-1.5), 1.4 (1.1-1.8) and 1.9 (1.5-2.3), respectively, in other GGT quartiles. Hazard ratios (CI) for death from cardiovascular causes were 1.4 (1.0-2.0), 1.8 (1.4-2.5) and 2.2 (1.6-2.9). After adjustment for age, gender and cardiovascular risk factors GGT remained a significant predictor for total and cardiovascular mortality. In angiographic CAD the predictive value of GGT was also significant and similar to that in the entire cohort. The researchers concluded, "Serum GGT is predictive of all-cause and cardiovascular mortality in individuals with CAD independently of other cardiovascular risk factors."
Association between serum γ-glutamyltransferase levels and coronary microvascular function (63)
This 2013 study was reported in Turkey. The investigators "aimed to determine whether the serum GGT level is independently and specifically associated with coronary flow reserve (CFR) impairment in normal individuals." "We examined healthy individuals who did not have any major CV risk factors (277), of whom CFR was achieved in 263 (95%). They were divided into three groups according to serum GGT levels." "Participants with high GGT levels had significantly impaired CFR compared with those with intermediate and low GGT levels (2.82±0.49 vs. 2.71±0.51 and 2.44±0.48 U/l; P<0.0001). After adjusting for potential confounders, including sex, BMI, blood pressure, lipids, and glucose, we found that the serum GGT and high-sensitivity C-reactive protein levels were associated independently with CFR impairment (b=-0.205, P=0.007; b=-0.172, P=0.024). We also found that the serum GGT level was a good predictor of low CFR at the receiver-operating characteristic curve. The area under the curve was 75% [95% confidence interval, 0.65-0.86], and the serum GGT level was significantly predictive of a low CFR (P<0.0001)." The researchers concluded, "These results support a role for the serum GGT level as an independent marker of coronary microvascular damage and inflammation in normal individuals without concomitant risk factors."
The relation of serum gamma-glutamyl transferase levels with coronary lesion complexity and long-term outcome in patients with stable coronary artery disease (64)
This was a 2012-reported study undertaken in Turkey. The investigators "evaluated the relationship between GGT levels and coronary complexity, severity and extent assessed by SYNTAX score and long-term adverse events." "We enrolled 442 consecutive patients with stable angina pectoris who underwent coronary angiography. Baseline serum GGT levels were measured and SYNTAX score was calculated from the study population. Median follow-up duration was 363 days. Endpoints were all cause mortality and any revascularization." "In multivariate analysis serum GGT, diabetes mellitus, HDL-cholesterol,
eGFR and ejection fraction were found to be independent predictors of high SYNTAX score. The survival analysis showed that long-term revascularization rates were comparable between the GGT groups (for 36 U/l cut point) of the overall population (7.7% vs 8.6% logrank, p = 0.577), whereas long-term all cause mortality rate was higher in the GGT ≥ 36 U/l group (3.6% vs 11.6%
logrank, p = 0.001). In Cox proportional hazards regression model, GGT ≥ 36 U/l group was found to be an independent predictor of long-term all cause mortality in the unadjusted (HR 2.54, 95% CI 1.17-5.48, p = 0.018) and age- and gender-adjusted (HR 2.58, 95% CI 1.19-5.58, p = 0.016) models." The investigators concluded, "Serum GGT level was independently associated with coronary complexity and long-term mortality in patients with stable coronary artery disease."
Serum gamma-glutamyltransferase levels are inversely related to endothelial function in chronic kidney disease (65) Free full text
This 2012-published report was based on a study that was undertaken in Turkey. The researchers noted that, "Gamma-glutamyltransferase (GGT) is an enzyme responsible for the extracellular catabolism of the antioxidant glutathione and recently implicated in the pathogenesis of atherosclerosis. Endothelial dysfunction is a prodromal feature of atherogenesis. Since oxidative stress is highly present in uremia and causally linked to endothelial dysfunction, we hypothesized that GGT may be a factor implicated in this process." "Serum GGT and C-reactive protein (CRP) levels, estimated glomerular filtration rate (eGFR), and 24-h proteinuria were measured in 214 nondiabetic stages 3-5 CKD patients. The endothelium-dependent vasodilatation (FMD) of the brachial artery was assessed by using high-resolution ultrasound. We investigated the relationship between FMD and circulating serum GGT." "Serum GGT levels were negatively associated with FMD (r = -0.41, p < 0.001) and eGFR (r = -0.34, p < 0.001) in univariate analysis. Multivariate regression analysis showed that the association between GGT and FMD persisted after adjustment for age, sex, smoking, renal function (eGFR), inflammation (CRP), proteinuria, and homeostatic model assessment index." The researchers concluded, "Circulating GGT levels significantly associate with endothelial dysfunction, an important early feature of the atherogenic process. GGT might be an early marker of oxidative or other cellular stress that it is possibly directly related to the pathogenesis of endothelial dysfunction."
Gammaglutamyltransferase in ESRD as a predictor of all-cause and cardiovascular mortality: another facet of oxidative stress burden (66) Free full text
This 2009-reported study was undertaken in Italy. The researchers noted, "GGT...represents the major factor responsible for the extra-cellular catabolism of the main antioxidant in mammalian cells, Glutathione. (end stage renal disease) ESRD is a condition characterized by a high risk of death and cardiovascular (CV) complications and with a high prevalence of liver disease but the link between GGT and clinical outcomes has never been studied in this population." "We tested the predictive power of GGT for overall and cardiovascular mortality in a cohort study in 584 ESRD patients. Over a 4 years follow up 194 patients died. GGT was higher in non-survivors (median 25 UI/l, interquartile range 16-45 UI/l) than in survivors (22, 15-33 UI/l) (P=0.006). On univariate Cox regression analysis plasma GGT predicted both all-cause [HR (10 UI/l increase): 1.04, 95% CI: 1.01-1.06, P=0.006] and cardiovascular mortality [HR: 1.03, 95% CI: 1.00-1.05, P=0.04]. These relationships held true in multivariate Cox regression analyses [HR: 1.06, 95% CI: 1.03-1.10 (P<0.001) and 1.05, 95% CI: 1.01-1.10, P=0.01] adjusting for liver disease as well as Framingham risk factors and non traditional risk factors including C reactive Protein (CRP). The researchers concluded, "High GGT in ESRD patients is a strong, independent risk marker for all cause and cardiovascular death. The predictive power of GGT for these outcomes likely reflects the involvement of this enzyme in oxidative stress mechanisms."