Gamma Glutamyltranspeptidase and Long-Term Survival: Is It Just the Liver?

Background: Increased gamma glutamyltranspeptidase (GGT) is associated with cardiovascular disease. To date, however, few studies with sufficient sample size and follow-up have investigated the association of GGT with all-cause mortality. Methods: The relation of GGT to the risk of death was examined in a cohort of 283 438 first attendants (inpatients or outpatients) of the Vienna General Hospital with request for GGT analysis as part of a routine screening panel and was then monitored for up to 13 years. To evaluate GGT as a predictor, Cox proportional hazards models were calculated, which were adjusted for age and sex. Results: In both men and women, GGT above the reference category (GGT >9 U/L in women, >14 U/L in men) was significantly (P <0.001) associated with allcause, cancer, hepatobiliary, and vascular mortalities. Hazard ratios (HRs) for men and women were similar in all categories. Among patients who presented with GGT above the reference category for the first time, those younger than 30 years had higher all-cause mortality rates than did those older than 80 years (HR 1.5–3.3 vs HR 1–1.3 >80 years, respectively). Conclusions: GGT is associated with mortality in both men and women, especially in patients younger than 30 years, and even high-normal GGT is a risk factor for all-cause mortality. © 2007 American Association for Clinical Chemistry The glycoprotein gamma glutamyltranspeptidase (GGT) is located on membranes of cells with high secretory or absorptive activities, such as liver, kidney, pancreas, intestine, heart, brain, and prostate cells, but not in bone cells or erythrocytes (1, 2). Serum GGT is increased in hepatobiliary diseases, with highest concentrations in cholestatic conditions (1, 3). Increased serum GGT has been reported in a wide variety of clinical conditions, including pancreatic disease, myocardial infarction, renal failure, chronic obstructive pulmonary disease, diabetes, and alcoholism (1, 4–6). Alterations in serum GGT concentrations are also found in patients who are taking medications such as phenytoin and barbiturates (1 ), as well as in people with increased meat intake (7 ). Serum GGT activity is affected by genetic and environmental factors, with heritability estimated at 0.52 (8 ). The widespread availability and frequent use of liver chemistry tests have resulted in a dramatic increase in the number of abnormal GGT values that must be judged by physicians. Although GGT is mainly seen as an indicator for hepatobiliary disease and alcohol consumption, several studies have shown its association with morbidity and mortality from other causes, especially cardiovascular disease (CVD) (9 ). There have also been important advances in the definition of the associations of serum GGT with type 2 diabetes (4, 10) and with stroke (11 ). Serum GGT concentrations are associated with increased risk of myocardial infarction and cardiac death (9, 12–14). An independent prognostic role of GGT for all-cause mortality in males has also been reported (15, 16). In the present study we addressed the value of GGT as a marker for the identification of men and women with unfavorable prognoses for long-term survival. Early identification of high-risk patients would allow for optimiza1 Institute of Medical and Chemical Laboratory Diagnostics and the Departments of 2 Internal Medicine IV, Division of Gastroenterology and Hepatology, and 3 Internal Medicine I, Division of Infectious Diseases, Medical University of Vienna, Vienna, Austria. † These authors contributed equally to the article. * Address correspondence to this author at: Medical University of Vienna, Institute of Medical and Chemical Laboratory Diagnostics, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Fax 43-1-40400-5389; e-mail Oswald.wagner@ meduniwien.ac.at. Received October 10, 2006; accepted January 19, 2007. Previously published online at DOI: 10.1373/clinchem.2006.081620 4 Nonstandard abbreviations: GGT, gamma glutamyltranspeptidase; CVD, cardiovascular disease; IQR, interquartile range; CI, confidence interval; HR, hazard ratio. Clinical Chemistry 53:5 000–000 (2007) General Clinical Chemistry