What are the implications and management of elevated Gamma-Glutamyl Transferase (GGT) levels?

From the Guidelines

Elevated Gamma-Glutamyl Transferase (GGT) levels require investigation of underlying liver or biliary disease, with management focused on treating the root cause rather than the enzyme elevation itself. GGT is an enzyme primarily found in the liver, biliary tract, and kidneys, and elevations typically indicate liver or biliary dysfunction. Common causes include alcohol consumption, fatty liver disease, medications (like phenytoin, carbamazepine, and barbiturates), biliary obstruction, viral hepatitis, and less commonly, pancreatic disease or heart failure. Initial management involves lifestyle modifications such as alcohol cessation, weight loss through diet and exercise for fatty liver disease, and discontinuation of hepatotoxic medications when possible. No specific medication directly lowers GGT; instead, treatment targets the underlying condition. For alcoholic liver disease, complete abstinence is essential. Non-alcoholic fatty liver disease requires weight loss of 7-10% through caloric restriction and regular exercise. Patients with viral hepatitis may need antiviral medications, while biliary obstruction might require endoscopic or surgical intervention. GGT elevation warrants further diagnostic workup including comprehensive liver function tests, hepatitis serology, imaging studies (ultrasound, CT, or MRI), and occasionally liver biopsy. GGT serves as a sensitive but non-specific marker of hepatobiliary disease, often rising before other liver enzymes and thus serving as an early indicator of liver stress or damage, as supported by recent studies 1.

Key Considerations

• GGT elevation is a sensitive but non-specific marker of hepatobiliary disease
• Common causes of elevated GGT include alcohol consumption, fatty liver disease, medications, biliary obstruction, and viral hepatitis
• Initial management involves lifestyle modifications and discontinuation of hepatotoxic medications
• Treatment targets the underlying condition, rather than the enzyme elevation itself
• Further diagnostic workup is necessary to determine the underlying cause of GGT elevation, including comprehensive liver function tests, hepatitis serology, imaging studies, and occasionally liver biopsy

Diagnostic Approach

• Monitor liver function tests, including GGT, before each infusion and/or consider weekly if grade 1 LFT elevations 1
• Review medications and supplements that may cause hepatotoxicity and rule out abnormal liver enzymes from development or progression of liver metastases
• Consider liver biopsy if the patient is steroid-refractory or if concern for other differential diagnoses that would alter medical management
• Use additional tests, such as gamma-glutamyl transferase (GGT) testing, 5′nucleotidase levels, and DBIL, to inform the aetiology of ALP elevations 1

From the Research

Implications of Elevated GGT Levels

• Elevated Gamma-Glutamyl Transferase (GGT) levels can indicate liver dysfunction, and it is often used as a marker of alcohol intake 2.
• Conditions that increase serum GGT, such as obstructive liver disease, high alcohol consumption, and use of enzyme-inducing drugs, can lead to increased free radical production and the threat of glutathione depletion 2.
• Elevated GGT levels have been associated with an increased risk of coronary heart disease, Type 2 diabetes, and stroke, and people with high serum GGT have higher mortality 2.

Management of Elevated GGT Levels

• The evaluation of elevated GGT levels should include a complete medical history, physical examination, and non-invasive diagnostic tests such as serology, iron levels, autoimmunity, or abdominal ultrasound 3.
• The degree of elevation of GGT and other liver enzymes, such as ALT and AST, can help guide the evaluation and management of liver disease 4.
• Statin treatment has been shown to reduce GGT levels in patients with non-alcoholic fatty liver disease (NAFLD), suggesting liver safety of statins in these patients 5.
• Abnormal liver biochemical tests, including elevated GGT, should be categorized based on the pattern and magnitude of aminotransferase elevation, and further workup and treatment should be guided by the underlying cause of the abnormality 6.

Diagnostic Approach

• The diagnostic approach to elevated GGT levels should include testing for viral hepatitis, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency 4.
• A liver biopsy may be considered when serologic testing and imaging fail to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible 4.
• The evaluation of albumin and prothrombin levels can help assess hepatic function and differentiate between acute and chronic diseases 3.