Gamma-Glutamyltransferase Activity (GGT) Is a Long-Sought Biomarker of Redox Status in Blood Circulation: A Retrospective Clinical Study of 44 Types of Human Diseases

Abstract

Background and Aim. Redox equilibria are critical for life, but the biomarkers of redox status are currently unavailable. Gamma-glutamyltransferase (GGT) is an essential factor for modulating redox equilibrium through glutathione. In clinical practice, increased circulating GGT activity is used as a hepatobiliary disease biomarker. However, increased circulating GGT activities have also been observed in cancers, heart disease, diabetes, hyperuricemia, inflammation, renal insufficiency, and other diseases, explained by its role in maintaining redox equilibrium inside and outside cells. Previous studies on GGT were mainly limited to one type of disease at one time. In the current study, we systematically compared the GGT levels in 44 different human diseases to test if it could serve as a redox status biomarker in blood circulation. Methods. The clinical GGT data from 168,858 patients with 44 diseases and 132,357 healthy control in the clinical laboratory of our hospital over the past five years were retrieved. All data were analyzed with SPSS, RStudio V.1.3.1073, and python libraries 3.8. Results. Thirty-eight out of 44 diseases had significantly increased ( $p<0.001$ ) circulating GGT activities, whereas gastric cancer, anemia, renal cyst, cervical cancer, preeclampsia, and knee-joint degenerative diseases had significantly decreased ( $p<0.001$ ) GGT activities compared to the healthy control. ROC analyses showed that GGT was an excellent biomarker for liver cancer ( $\text{AUC}=0.86$ ), pancreatitis ( $\text{AUC}=0.84$ ), or hepatic encephalopathy ( $\text{AUC}=0.80$ ). All pancreas-related diseases had more than 8-fold increases in GGT activity span than the healthy control, while pancreatic cancer had a 12-fold increase (1021 U/L vs. 82 U/L). The knee-joint degenerative disease had the lowest median and narrowest GGT activity range (63 U/L). Furthermore, most diseases’ lowest to highest GGT activities were beyond the healthy control in both directions. Conclusions. Thirty-eight out of 44 diseases were in overall oxidative states defined by the increased GGT median values. In contrast, knee-joint degenerative disease, gastric cancer, anemia, renal cyst, cervical cancer, and preeclampsia were in overall antioxidative states. Moreover, most diseases swing between oxidative and antioxidative states, evidenced by the increased lowest to highest GGT activity ranges than the healthy control. Liver- and pancreas-related abnormalities were responsible for significantly increased GGT activities. Our overall results suggested that circulating GGT was a redox status biomarker.