PHOENIX, AZ—It may be the best little cardiometabolic risk marker you’ve never heard of. And at under 10 bucks a pop, it may very well be the cheapest.

Gamma glutamyl transferase (GGT), also known as gamma glutamyl transpeptidase, is a liver enzyme involved in the production and secretion of bile. Hepatologists measure it when they evaluate liver function.

There’s a growing body of evidence that this simple test is among the strongest serum predictors of insulin resistance, imminent type 2 diabetes, and cardiovascular events, reported Ryan Bradley, ND, at the annual meeting of the American Association of Naturopathic Physicians.

“GGT is a biomarker of oxidative stress and cardiometabolic risk,” said Dr. Bradley, of the Diabetes & Cardiovascular Wellness Center at Bastyr University, Seattle. “Graded elevations of GGT correlate with increased risk of type 2 diabetes, hypertension and cardiovascular events. You can measure it for under $10, and it correlates well with much more expensive tests like C-reactive protein (CRP) and fibrinogen, which can be as much as $150–$300 per test.”

GGT, Metabolic Syndrome & Diabetes

Investigators at Yonsei University’s Wonju College of Medicine, Korea, recently published a study of more than 3,500 patients, mean age of 57 years, showing significantly higher GGT among those diagnosed with metabolic syndrome. Mean GGT was 23 IU/L in those with metabolic syndrome, compared with 19 IU/L among controls, a statistically significant difference. Metabolic syndrome prevalence was highest in the highest versus lowest GGT quartiles (Lee MY, et al. Diabet Med. 2008; 25(4): 469–475).

Data from 3,451 subjects in the Framingham Heart Study (mean age 44 years old) also showed a strong correlation between GGT and metabolic syndrome, which developed in 968 (28%) of the participants over a 19-year period. After adjusting for other risk factors, the hazard ratio was 1.26 for each standard deviation (SD) increase in GGT.

In both studies, mean GGT levels—even those in the highest quartiles—were within normal ranges (0–51 IU/L) from a liver function point of view.

Several years ago, investigators at Inje University, Korea, analyzed medical records from nearly 30,000 subjects, and deliberately excluded those with GGTs higher than three times the upper limit of normal. They saw a profound association between GGT and diabetes (OR = 3.16), metabolic syndrome (OR = 2.88), impaired fasting glucose (OR = 2.24), obesity (OR = 1.93), and dyslipidemia (OR = 1.38) in men in the highest versus lowest GGT quartiles. Among women, the pattern was similar (Kim DJ, et al. Diabet Med. 2005; 22(9): 1134–1140).

An Independent Risk Factor

Christa Meisinger at the Central Hospital of Augsburg, Germany, looked at 15-year follow-up data from 3,687 patients (mean age 25–64 at baseline) in the MONICA (Monitoring Trends and Determinants on Cardiovascular Disease) cohort. Adjusting for other diabetes risk factors like age and body mass index, they found a 4-fold increased likelihood of diabetes in the highest versus lowest GGT quartile among the men. For the women, the difference was 2.4-fold (Meisinger C, et al. J Intern Med. 2005; 258(6): 527–535).

Data from the Coronary Artery Risk Development in Young Adults (CARDIA) study also show a 4-fold increased hazard ratio for developing diabetes within 15 years among people in the highest versus lowest GGT quartile (Lee DH, et al. Clin Chem. 2003; 49(8): 1358–1366). Dr. Bradley said these risk relationships held firm even after adjusting for fasting glucose and insulin sensitivity, strongly suggesting that GGT is an independent risk predictor.

To some extent, GGT status can soften the impact of obesity on diabetes risk. Lim and colleagues, analyzing 4,011 subjects in the National Health and Nutrition Examination Survey (NHANES) database, found that if GGT was in the range of 26–35 IU/L, and BMI was over 35, the odds ratio for diabetes was 7.5. However, if GGT was under 22 IU/L, the odds ratio was only 2.4, even if BMI was over 35 (Lim JS, et al. Clin Chem. 2007; 53(6): 1092–1098).

This is still a high risk compared with non-obese people, but it is far lower than that of high-GGT patients. “This has huge clinical implications,” said Dr. Bradley.

Impact on Cardiovascular Risk

Rising GGT also correlates with risk of coronary events. Meisinger’s group looked at data from 1,878 men who were free of coronary disease at baseline in 1984–85. By 2002, there were 150 acute events. Mean baseline GGTs were higher in those who had heart attacks than those who did not (28.4 IU/L ± 2 IU versus 22.4 IU/L ± 2.1).

Moreover, baseline GGT quartile was highly predictive of future CV events. For those with baseline GGT’s under 13 IU, odds of a cardiac event were nil. For the men in the 20–35 IU range, the odds ratio was 2.2; for those with GGT’s over 35 IU, it increased to 3.08. Even after adjusting for hypertension, lipid levels, BMI, smoking, and socioeconomic variables, there was still a 2-fold higher CV risk in those with the highest versus lowest GGTs (Meisinger C, et al. Atherosclerosis. 2006; 189(2): 297–302). Lee’s group at the University of Toronto saw a 13% increase in CV event risk, and a 26% increased risk of death per SD increase in GGT, in the Framingham population (Lee DS, et al. Arterioscler Thromb Vasc Biol. 2007; 27(1): 127–133).

Dietary Influences

GGT can be influenced, both positively and negatively, by nutritional factors, said Dr. Bradley. In general, diets high in vegetables, fruits, whole grains and antioxidants reduce GGT, while diets high in red meat, iron, and saturated fats raise it. According to NHANES data, serum carotenoids correlate inversely with GGT; the higher the carotenoid levels, the lower the GGT.

Recently, researchers at the University of Parma, Italy, showed that a diet high in specific antioxidant and poyphenol-rich foods could reduce markers of inflammation and oxidative stress, including CRP and GGT, in 33 healthy adults. The foods included red beans, plums, pineapple, spinach, beets, chard, radicchio, red berries, olive oil, coffee, tea, dark chocolate, and red wine (Valtuena S, et al. Am J Clin Nutr. 2008; 87(5): 1290–1297).

The GGT changes were not huge, said Dr. Bradley. But they were statistically significant and clinically meaningful, and they were achieved in just two weeks.

Pomegranates are among the most antioxidant-rich fruits. While there’s no evidence showing a direct GGT effect, daily consumption of 2 oz pomegranate juice was able to reduce other inflammation markers, as well as lowering systolic pressure and reducing carotid intimal medial thickness in a cohort of 10 patients with confirmed carotid stenosis (Aviram M, et al. Clin Nutr. 2004; 23(3): 423–433). The study was sponsored by the POM juice company.

Many different drugs and diseases affect GGT. It tends to run high in people with congestive heart failure, and among heavy drinkers. NSAIDs, lipid-lowering drugs, antibiotics, histamine blockers, antifungals, seizure medications, anti-depressants and testosterone increase GGT; oral contraceptives and clofibrate lower it.

Reducing GGT

Research on therapies aimed at reducing GGT and the risk it represents is still in early stages. Though there are no definitive therapies, either nutraceutical or drug-based, there are a few good candidates, said Dr. Bradley.

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Milk Thistle: Whole-plant extract of Milk Thistle (Silybum marianum) is a common natural therapy for hepatic disorders. At a dose of 200 mg, thrice daily, for 4 months, it reduced hemoglobin a1C from 7.8% to 6.8%, in a cohort of 51 type 2 diabetics. “That’s comparable to what you see with conventional drugs,” Dr. Bradley said. While GGT was not specifically measured, the herb reduced related enzymes like ALT and AST (Huseini HF, et al. Phytother Res. 2006; 20(12): 1036–1039).
Earlier, Velussi and colleagues showed a mean reduction in glycosylated hemoglobin from 7.9% to 7.2% in 30 diabetics with alcoholic cirrhosis treated with 600 mg Milk Thistle per day (Velussi M, et al. J Hepatol. 1997; 26(4): 871–879).

N-Acetyl Cysteine (NAC): Another common nutrient used for hepatic problems, NAC may reduce cardiometabolic risk. A study of patients with non-alcoholic liver disease showed that 600 mg NAC per day could reduce GGT from 62.7 to 46.3 IU/L. Dr. Bradley said he has tried treating diabetics with 1,800 mg NAC per day, and saw no reduction in GGT at 12 weeks. “These were patients with already advanced disease. NAC certainly makes sense, but the jury’s still out.”

Statin Drugs: Though there’s no evidence that statins reduce GGT, they do reduce CRP, which correlates strongly with GGT. “It is difficult to tease out the antioxidant and anti-inflammatory effects of statins from the anti-lipid effects,” said Dr. Bradley. “I’m not necessarily advocating wider use of statins, but they do provoke very interesting questions.”

Future Directions

Dr. Bradley is participating in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort trial that will look at, among other things, the relationship between GGT, insulin resistance, and vascular inflammation in a multi-ethnic, multi-racial diabetic population. He noted that people of African ancestry generally have GGTs 2 times higher than people of European ancestry. MESA could shed much-needed light on ethnic differences like this.

He is also working with his wife, Erica Oberg, ND, in a study comparing a “naturopathic” diet versus the American Diabetes Association’s recommended diet in a cohort of type 2 diabetic patients.

Science on the clinical application of GGT is still at a very early stage. Dr. Bradley said he welcomes case reports, findings from small cohort studies, and clinical anecdotes. Reach him at: rbradley@bastyr.edu.