Concise review: gamma-glutamyl transferase - evolution from an indiscriminate liver test to a biomarker of cardiometabolic risk

Abstract

This concise review article critically examines the recent medical literature regarding gamma glutamyl transferase (GGT) with a special emphasis on newly proposed indications for GGT use, including cardiovascular risk assessment. GGT is a ubiquitous glycosylated protein embedded in the outer surface of cell membranes, which catalyzes the transfer of glutamyl groups from various substrates and plays a key role in the antioxidant/pro-oxidant balance. In the past, the enzyme was considered a non-specific liver test. Current evidence supports the role of GGT in the assessment of portal hypertension in cystic fibrosis, porto-sinusoidal vascular disease, malignant mesothelioma, and incident type 2 diabetes and as a biomarker of cardiometabolic risk and cardiovascular disease. Several specific points including the use of GGT in hepatology as a sensitive but poorly specific test and the association of GGT with metabolic syndrome, nonalcoholic fatty liver disease and its fibrotic stages, cardiometabolic risk, chronic kidney disease, neurodegenerative disorders and dementia, idiopathic pulmonary arterial hypertension, and Corona Virus Disease 2019 (COVID-19) are addressed based on the most recent research in these fields. Putative mechanisms linking GGT with increased metabolic stress and the effects of various therapeutic interventions on GGT values are also discussed. We conclude that GGT has evolved from an indiscriminate liver test and an index of alcohol consumption to a biomarker of cardiometabolic health. The proper interpretation of GGT values (i.e., of hepatic vs. extrahepatic origin) is deeply affected by the clinical and epidemiological context. We propose that GGT may be utilized in public health campaigns, in the research arena, and in clinical practice to identify those individuals who can benefit most from the proactive preventive and therapeutic approaches, given that they are at high cardiometabolic risk.

Thyroid function, adipokines and mitokines in metabolic dysfunction‐associated steatohepatitis: A multi‐centre biopsy‐based observational study

“…Considering that GGT has also been proposed to have similar effects on cardiometabolic profile, 62 separate GGT-adjusted models were created; however, no alterations of the association between thyroid function and MASLD staging were observed with GGT not altering the examined associations. In addition, sex dimorphisms in the pathophysiology of MASLD have been previously discussed.…”

“…We also evaluated the novel mitokine total GDF‐15 as a promising molecule associated with MASLD development and progression 33 to generate hypotheses about potential causal pathways that might mediate the association between thyroid dysfunction and MASLD severity. Considering that GGT has also been proposed to have similar effects on cardiometabolic profile, 62 separate GGT‐adjusted models were created; however, no alterations of the association between thyroid function and MASLD staging were observed with GGT not altering the examined associations. In addition, sex dimorphisms in the pathophysiology of MASLD have been previously discussed 34–39 .…”

Prevalence of hepatic steatosis and fibrosis in Turner syndrome: A prospective case–control study

“…14,15 Elevated GGT has also been suggested to predict the development of portal hypertension in cardiometabolic disease in the general population. [16][17][18] It is hypothesized that GGT elevation is not just due to release from injured cells in the setting of chronic liver disease, but also accelerated synthesis of GGT and/or release of GGT into the bloodstream. [16][17][18] GGT has low specificity, and its role in TS will need continued study, but our results suggest that it may assist in SLD risk assessment in TS.…”

Liver stiffness as a cornerstone in heart disease risk assessment

“…Gamma glutamyl transferase has been as well highlighted as a marker of cardiometabolic health, although interpretation of its elevation is highly unspecific and can be the result of multiple other liver-related conditions including cholestatic and alcoholic liver disease. 129 Regardless of targeting common pathophysiological pathways, the link between (advanced) MASLD and the increased incidence and prevalence of heart disease with resulting mortality fuels the need for an approved anti-MASH drug in the multidisciplinary treatment of metabolically compromised patients. [130][131][132] In addition, both entities are typified by impaired quality of life [133][134][135][136][137] along with financial pressure on healthcare systems 138,139 which further emphasizes the need for holistic management of these patients (Figure 2).…”

“…Fetuin‐A has been earlier proposed as a biomarker for liver and vascular fibrosis progression in MASLD, 127 and hepatic hypoperfusion and cardiac outcomes in HF, 128 but requires validation for these purposes. Gamma glutamyl transferase has been as well highlighted as a marker of cardiometabolic health, although interpretation of its elevation is highly unspecific and can be the result of multiple other liver‐related conditions including cholestatic and alcoholic liver disease 129 …”