Gamma-glutamyl transferase - GGT
Gamma-glutamyl transpeptidase, GGTP

This enzyme cleaves C-terminal glutamyl groups from amino acids and transfers them to another peptide or to an amino acid. It is important in glutathione metabolism, amino acid absorption and protection against oxidant injury. Although GGT is found in many tissues, the main source is the liver (primarily biliary epithelium), thus GGT is used mainly as a sensitive indicator of cholestasis (interpretation, in general, is similar to ALP). It has a half life of 72-96 hours (equine).

Organ specificity

GGT is found primarily in the membrane and in microsomes (from SER) as aggregates. A small portion (< 5%) is found in the cytoplasm. Disaggregation (solubilization) and increased synthesis result in increased activity in serum.
  • Biliary tract - source of serum activity in health and disease.
  • Pancreas, gastrointestinal tract - GGT does not increase in serum in disorders involving these tissues (it is usually shed into the lumen of these organs).
  • Kidney - proximal renal tubules. GGT is shed into urine, rather than blood.
  • Mammary glands - GGT is excreted into milk.
  • Reproductive tract - Epididymis (GGT is secreted into semen).
Causes of increased GGT
  1. Drug effects
    Increases in GGT occur secondary to therapeutic drugs causing cholestasis. Increases may also be seen with anticonvulsant or corticosteroid therapy, presumably secondary to liver injury causing localized cholestasis or biliary hyperplasia. Induction of GGT synthesis may also contribute to high GGT levels with corticosteroids. Increases in GGT occur as soon as 5 days after corticosteroid administration.

  2. Physiologic
    a) Neonates: Colostrum in all species, except for horses. contains high GGT concentrations. Increases in GGT occur within 24 hours of suckling and are a sensitive indicator of passive transfer. Very high levels of GGT may be observed (up to 1000 x adult levels in 2-3 day old puppies) that gradually decrease with time (over 10 days in dogs, 4- 6 weeks in lambs and calves) and is an expected finding in a neonate (i.e. does not indicate hepatobiliary disease). In calves, the increase in GGT has been used to predict efficacy of passive transfer; in one study, GGT < 200 U/L was 80% sensitive for a diagnosis of failure of passive transfer. Even though foals do not derive GGT from the colostrum of mares, GGT can be higher in neonates. In one study, GGT increased transiently (up to 169 U/L) in the 7-28 days after birth, before decreasing to within reference intervals by 2 months of age. Note that elevations in AP do occur after suckling. This is thought to be derived from intestinal sources in the neonate and is not due to colostrum itself.

    b) Breed: Donkeys and burros have 2-3 x GGT levels of horses.

  3. Disease effects
    Increases in GGT occur secondary to hyperplasia or induction of synthesis.

    a) Hepatobiliary disease: In small animals, GGT is a sensitive indicator of biliary hyperplasia and cholestasis. In the cat, GGT increases may precede increases in ALP and is a more sensitive indicator of liver disease in this species (not in all circumstances; hepatic lipidosis is a notable exception). GGT does not increase in small animals treated with CCl4 toxicity (which causes centrilobular heptocyte necrosis).
    In large animals, GGT is a sensitive test for biliary hyperplasia (it is a good marker for pyrrolizidine alkaloid toxicity in ruminants) and cholestasis (which is relatively uncommon in large animals, with the exception of cholangiohepatitis and cholelithiasis in horses). In horses, higher fold increases in GGT compared to AST and ALP are seen in cholangiohepatitis. In this species, monitoring of GGT levels is useful in assessing response to antibiotic therapy in this disorder. GGT has been shown to increase with hepatocellular necrosis due to CCL4 toxicity. However, it is not clear if this is truly due to necrosis (of biliary epithelium or hepatocytes) or is secondary to cholestasis/biliary hyperplasia induced by the necrosis. GGT is considered a better marker of biliary tract disorders in large animals than ALP.
    Although very low levels of GGT are normally found in hepatocytes from adults (fetal hepatocytes do express GGT), liver disease (viral disease, neoplasia) can induce GGT expression in hepatocytes (often on their sinusoidal surface), so increases in serum GGT can reflect biliary (primarily) or hepatocellular disease.

    b) Renal disease: GGT is expressed on the membranes of proximal renal tubular epithelial cells. Cell injury causes GGT to be shed into the urine and not into blood. Urinary GGT:creatinine ratio has been studied as an early indicator of renal tubular injury, especially due to aminoglycoside toxicity.
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