What is the cause of elevated Gamma-Glutamyltransferase (GGT) without an increase in bilirubin levels?

From the Guidelines

Elevated gamma-glutamyl transferase (GGT) without increased bilirubin typically indicates liver stress or damage that hasn't progressed to impair bile flow, with common causes including alcohol consumption, non-alcoholic fatty liver disease (NAFLD), and certain medications or infections. The most recent and highest quality study, 1, provides guidance on the management of abnormal liver function tests, including elevated GGT. According to this study, GGT is found in the liver and in the kidneys, intestine, prostate, and pancreas, and its elevation can indicate liver stress or damage. Some key points to consider when evaluating elevated GGT include:

• Alcohol consumption is a common cause of elevated GGT, as it induces GGT production through enzyme induction 1
• NAFLD is another frequent cause of elevated GGT, particularly in those with obesity, diabetes, or metabolic syndrome 1
• Certain medications, such as phenytoin, carbamazepine, and barbiturates, can also elevate GGT levels 1
• Infections like hepatitis or mononucleosis can cause elevated GGT in early stages 1
• Pancreatic disorders can also lead to elevated GGT, as GGT is present in pancreatic tissue 1
• Hyperthyroidism can increase liver enzyme levels, including GGT 1
• Heart failure may also elevate GGT due to liver congestion 1 For accurate diagnosis, a complete medical history, physical examination, and possibly additional tests like ultrasound or other liver function tests are necessary. Lifestyle modifications such as reducing alcohol intake, weight management, and medication adjustments may be recommended depending on the underlying cause.

From the Research

Causes of Increased Gamma-GT without Increase in Bilirubin

• Increased gamma-glutamyltransferase (GGT) without a corresponding increase in bilirubin can be an indicator of drug-induced liver injury (DILI) in patients who do not meet the conventional diagnostic criteria of acute liver injury 2.
• GGT elevation is also associated with cholestasis, oxidative stress, and liver damage in various liver diseases, including primary biliary cholangitis (PBC), DILI, alcoholic liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD) 3.
• Frequently abnormal serum GGT activity is associated with the future development of fatty liver, suggesting that individuals with elevated GGT levels may be at an increased risk of developing fatty liver disease 4.
• GGT is also an underestimated marker for cardiovascular disease and the metabolic syndrome, and its elevation is associated with an increased risk of cardiovascular mortality, atrial fibrillation, and congestive heart failure 5.

Possible Underlying Mechanisms

• GGT has a pro-oxidant activity and a modulating influence on endothelial dysfunction, which may contribute to its association with cardiovascular disease and the metabolic syndrome 5.
• The enzyme is involved in glutathione and cysteine metabolism, and its elevation may reflect oxidative stress and liver damage 3, 5.
• GGT is not specific to the liver, and its elevation can be seen in various conditions, including biliary tract disease, pancreatic disease, and renal disease 6.

Clinical Implications

• Increased GGT without a corresponding increase in bilirubin should be investigated further to rule out underlying liver disease or other conditions that may be causing the elevation 2, 3.
• Patients with elevated GGT levels should be monitored closely for the development of fatty liver disease and cardiovascular disease 4, 5.
• The use of GGT as a biomarker for liver disease and cardiovascular disease requires further assessment and validation 5, 6.