gamma-glutamyl transferase

**Function/biochemistry:** GGT is a membrane-bound enzyme that transfers gamma-glutamyl residues from glutathione and other gamma-glutamyl peptides to amino acids or peptides. It is part of the gamma-glutamyl cycle, which helps with glutathione breakdown and amino acid transport and with cellular protection against oxidative stress. It is located on the cell surface of biliary epithelial cells (canalicular and bile duct), renal proximal tubule, pancreas, and intestine. Serum GGT mostly comes from the liver.

**Clinical significance:** - **Cholestasis/biliary obstruction:** GGT rises in parallel with ALP, and often to a marked degree. Examples include choledocholithiasis, primary biliary cholangitis, primary sclerosing cholangitis, and pancreatic head cancer. - **Confirming the source of ALP:** If ALP is elevated and GGT is also elevated, the source is hepatobiliary. If ALP is elevated and GGT is normal, think bone (Paget disease, osteoblastic metastases, fracture healing, growing children) or the placenta in pregnancy. Alternatively, 5'-nucleotidase can be used. - **Alcohol use:** GGT is elevated in chronic alcohol use because of enzyme induction. An AST:ALT ratio >2 along with raised GGT supports alcoholic liver disease. GGT can be a marker of alcohol use or relapse, but it is not specific. - **Enzyme induction by drugs:** Phenytoin, barbiturates (phenobarbital), carbamazepine, and rifampin can raise GGT without liver injury. Other causes include NAFLD, hepatitis, congestive hepatopathy, hepatic malignancy, diabetes, obesity, and pancreatitis. - **Not elevated in bone disease.** That is why GGT is useful as a discriminator. - **Low or normal GGT with cholestasis:** Consider progressive familial intrahepatic cholestasis types 1 and 2 and benign recurrent intrahepatic cholestasis. These are the classic low-GGT cholestatic conditions, and they are sometimes tested.

**Pattern recognition for boards:** - Cholestatic pattern: ALP and GGT are disproportionately elevated compared with AST/ALT. Bilirubin, especially conjugated, may also rise. - Hepatocellular pattern: AST/ALT are markedly elevated, and GGT is mildly elevated. - Isolated GGT elevation: Suspect alcohol use or drug induction.

**Other associations:** GGT has been studied as a marker of oxidative stress and an independent predictor of cardiovascular risk and metabolic syndrome. It is not routinely used for this purpose. It is also not specific, so interpret it in the clinical context.

**High-yield takeaway:** GGT is a sensitive but nonspecific marker of hepatobiliary disease and alcohol use. It is useful mainly for determining whether an elevated ALP is hepatic in origin.