What is the clinical use of Gamma-Glutamyl Transferase (GGT) in liver disease?

Clinical Use of GGT in Liver Disease

GGT serves three primary clinical roles in liver disease: confirming hepatobiliary origin of elevated alkaline phosphatase, screening for alcohol-related liver disease, and assessing disease severity in specific conditions like chronic hepatitis delta, though it should never be used in isolation due to its low specificity. 1

Primary Diagnostic Applications

Confirming Hepatobiliary Origin of Elevated Alkaline Phosphatase

• GGT is most valuable when used to determine whether elevated ALP originates from liver or other tissues (bone, intestine). 2
• When ALP is elevated, concomitantly elevated GGT confirms hepatobiliary origin and indicates cholestasis. 2
• This is critical because GGT is found in liver, kidneys, intestine, prostate, and pancreas, but not in bone. 2

Screening for Alcohol-Related Liver Disease

• GGT has 73% sensitivity for detecting daily ethanol consumption >50g, which is higher than AST (50%) or ALT (35%). 2
• Alcohol consumption is the most common cause of elevated GGT, occurring in about 75% of habitual drinkers. 2
• However, an isolated increase in GGT is not associated with major liver pathology and is not an adequate indication on its own for liver biopsy. 1
• GGT combined with elevated MCV increases sensitivity for detecting alcohol consumption. 2
• In alcohol-associated liver disease, GGT is inadequate on its own to establish alcohol use and should be combined with other biomarkers, physical exam, and clinical interview. 1

Role in Initial Liver Disease Evaluation

Standard Liver Blood Test Panel

• Initial investigation for potential liver disease should include bilirubin, albumin, ALT, ALP, and GGT, together with a full blood count. 1
• The British Society of Gastroenterology analysis showed that routine addition of GGT led to marginal increase in sensitivity but at cost of loss of specificity and higher false-positive rate. 1
• However, addition of GGT increases likelihood of detecting adults with abnormal liver blood tests from 15% to 30%, and raised GGT is associated with increased liver and all-cause mortality. 1

Disease-Specific Applications

Cholestatic Liver Diseases

• GGT increases occur earlier and persist longer than ALP elevations in cholestatic disorders. 2
• Very high GGT activities are measured in cholestatic conditions including primary biliary cholangitis and primary sclerosing cholangitis. 2, 3
• In primary biliary cholangitis and cholestatic drug-induced liver injury, GGT is positively correlated with ALP and total cholesterol, reflecting cholestasis. 4

Chronic Hepatitis Delta

• In chronic hepatitis delta, GGT is incorporated into the delta-4 fibrosis score (D4FS), where it is combined with transient elastography, platelet count, and ALT to identify cirrhosis with an AUROC of 0.94. 1
• High GGT levels in patients with chronic hepatitis delta independently predict clinical outcomes. 2

Non-Alcoholic Fatty Liver Disease

• NAFLD patients typically have GGT levels ranging from low normal to >400 U/L. 2
• Isolated elevation of GGT is considered a poor indicator of liver injury in NAFLD. 2
• In NAFLD, GGT is positively correlated with ALT, AST, and triglycerides, reflecting oxidative stress. 4

Alcoholic Liver Disease

• In alcoholic liver disease, GGT is associated with both oxidative stress and cholestasis. 4
• GGT is positively correlated with ALT, AST, ALP, triglycerides, and total cholesterol in this condition. 4
• The highest level of GGT can exceed 2000 U/L in alcoholic liver disease. 4

Critical Limitations and Caveats

Low Specificity

• GGT elevation alone has low specificity and must be interpreted in context with other liver enzymes. 2
• GGT loses specificity in advanced liver disease because it elevates regardless of etiology once extensive fibrosis develops. 2
• Isolated GGT elevations can occur in the absence of underlying liver disease, and therefore GGT should not be used as an exclusion criterion or sole marker of liver disease. 2

Non-Hepatic Causes

• Common medications that elevate GGT include interferon, antipsychotics, beta-blockers (atenolol), bile acid resins, estrogens, protease inhibitors, retinoic acid drugs, sirolimus, steroids, tamoxifen, and thiazides. 2
• Other causes include diabetes, insulin resistance, obesity, and cystic fibrosis-related hepatobiliary disease. 2

Monitoring and Follow-Up

Timing of Repeat Testing

• In suspected cholestatic drug-induced liver injury, blood tests should be repeated within 7-10 days. 2
• For suspected hepatocellular drug-induced liver injury, testing should be repeated within 2-5 days. 2
• Patients with advanced liver disease should undergo comprehensive liver function tests including GGT at least every 6 months. 2

Response to Treatment

• GGT levels recover slowly following abstinence from alcohol. 2
• For alcohol-related elevations, complete abstinence is recommended as recovery is gradual. 2

Prognostic Value

• Even mildly elevated GGT independently predicts increased risk for cardiovascular disease, diabetes, metabolic syndrome, and all-cause mortality. 2
• GGT is rarely low in advanced fibrosis or cirrhosis, where values are typically much higher, suggesting its potential as a marker for disease severity. 2