Diagnosis -- Idiopathic Isolated Elevation of GGT


Idiopathic isolated elevation of GGT


GGT is a well-established serum marker for alcohol related liver disease. However, GGT's predictive utility applies beyond liver disease. Elevated GGT can be linked to a multitude of diseases and conditions ranging from cardiovascular disease, diabetes and metabolic syndrome [1]. GGT is an enzyme located in hepatocytes as well as cells of bile duct, gallbladder, pancreas, spleen, kidney, heart, brain and seminal vesicles. GGT mainly originates from the liver and places an important role in the extracellular catabolism of glutathione by transferring the glutamyl moiety and isolating the cysteine product to preserve the intracellular homeostasis of oxidative stress [2, 3] The first American epidemiologic study to test GGT concentrations was conducted between 1978 and 1982 where 3,853 participants were evaluated for standard heart disease risk factors including body mass index (BMI), blood pressure, lipids, liver enzymes (including GGT), fasting glucose, serum creatinine, C-reactive protein (CRP) and the presence of diabetes mellitus [4]. In addition to the pilot study, several large population-based studies were conducted over the last decades from Austria, Finland, Korea and the United states, all of which show the increased risk of disease and mortality to elevated GGT concentrations with links to cardiovascular disease, heart failure, cancer, diabetes and all-cause mortality [5, 6].

Isolated elevation of GGT concentrations
Elevated GGT concentrations often raises concern for several diseases such as liver and cardiovascular conditions. GGT concentrations are sensitive however have a low specificity [7]. While GGT concentration concentrations are highest in the liver, they are found throughout different organ systems. Elevations of the enzyme can occur in a number of clinical scenarios- liver disease (fatty liver, viral hepatitis, bile duct obstruction and drug reactions) as well as in rare situations of isolated elevated GGT concentrations with no true underlying cause. Elevated GGT concentrations are also related to cardiovascular and hepatic conditions.

It has been speculated that diet may also be involved in relation to increased GGT concentration concentrations. A prospective study was conducted to understand the relationship between several food items such as: alcohol, meats, poultry, fish, dairy, fresh/frozen vegetables, French fries, fruit, fruit juice, refined grains, whole grains, legumes, nuts, and coffee to GGT concentration concentrations. The study showed alcohol and meat were the only food groups whose consumption was associated with high concentrations of GGT, after the adjustment for lifestyle factors and other dietary factors. When nutrients in meat were examined, iron (heme) was strongly associated with increased serum GGT concentrations. On the contrary, saturated, monounsaturated, and polyunsaturated fats showed a nonsignificant inverse association with GGT. Consumption of plant associated foods consistently had an inverse association [8].

In addition to understanding dietary relationships with GGT, the study also observed associations with supplements. Specifically, they observed that vitamin A, vitamin C, folate and α-tocopherol from supplements were associated with high concentrations of serum GGT concentrations. These findings were not confounded by iron which is commonly consumed together. The explanation of such findings relies on the understanding of antioxidants which is naturally present in food [9, 10]. Antioxidants are formed during redox reactions whereas supplements often lack the balance of oxidized and reduced forms of a substance. The body's defense against oxidative stress requirements antioxidants, thus a high dose of a single antioxidant could perturb the physiologic balance of nutrients [11].

Laboratory testing
Due to the myriad of causes of increased GGT concentrations, clinical testing for the following analytes can aid in identifying the underlying cause(s): GGT, alkaline phosphatase, ALT, AST, total bilirubin, direct bilirubin, and albumin. Infectious work-up including hepatitis and other infections may be informative. Extensive work-up if clinically warranted may include urine organic acid panel. Specifically, assessment of the alpha ketoglutarate and tyrosine catabolites (4-hydroxyphenyllactate, 4-hydroxyphenylpyruvate).

Clinical management
In deciding whether to evaluate the patient's liver further, consider risk factors for liver disease, symptoms, physical exam, and imaging.


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  2. Wannamethee G, Ebrahim S, Shaper AG. Gamma-glutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes. Am J Epidemiol 1995; 142: 699-708.
  3. Potter JD. Cancer prevention: epidemiology and experiment. Cancer Lett 1997; 114: 7-9.
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  7. Carey WD. How should a patient with an isolated GGT elevation be evaluated? Cleve Clin J Med 2000; 67: 315-316.
  8. Lee D-H, Steffen LM, Jacobs DR. Association between serum gamma-glutamyltransferase and dietary factors: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Am J Clin Nutr 2004; 79: 600-605.
  9. Kugelman A, Choy HA, Liu R, et al. gamma-Glutamyl transpeptidase is increased by oxidative stress in rat alveolar L2 epithelial cells. Am J Respir Cell Mol Biol 1994; 11: 586-592.
  10. Karp DR, Shimooku K, Lipsky PE. Expression of gamma-glutamyl transpeptidase protects ramos B cells from oxidation-induced cell death. J Biol Chem 2001; 276: 3798-3804.
  11. Eastwood MA. Interaction of dietary antioxidants in vivo: how fruit and vegetables prevent disease? QJM 1999; 92: 527-530.

Contributed by Simmi Patel, MD and Octavia Peck Palmer, PhD

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