What are the most common causes of elevated Gamma-Glutamyl Transferase (GGT) and Alkaline Phosphatase (ALP)?

Most Common Causes of Elevated GGT and ALP

Primary Causes of Elevated GGT

Alcohol consumption is the most common cause of elevated GGT, occurring in approximately 75% of habitual drinkers, with daily consumption exceeding 60g leading to elevation. 1

• GGT has 73% sensitivity for detecting daily ethanol consumption >50g, which is higher than AST (50%) or ALT (35%), making it an early detection marker for alcohol use 1
• GGT levels recover slowly following abstinence from alcohol 1
• The AST/ALT ratio exceeding 2 (or 3) combined with elevated GGT suggests alcoholic hepatitis 1

Primary Causes of Elevated ALP

Cholestatic liver diseases (primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis) and extrahepatic biliary obstruction (particularly choledocholithiasis) are the major hepatic causes of chronic ALP elevation. 2

• Bone disorders, including Paget's disease, bony metastases, and fractures, are significant non-hepatic sources of ALP elevation 2
• Physiologic causes include childhood (due to bone growth) and pregnancy (due to placental production) 2

Common Causes Affecting Both GGT and ALP

Biliary Obstruction

• Choledocholithiasis (gallstones in the bile duct) causes both GGT and ALP elevation, with approximately 18% of adults undergoing cholecystectomy having choledocholithiasis 1, 2
• GGT increases occur earlier and persist longer than ALP elevations in cholestatic disorders 1
• In acute calculus cholecystitis, GGT is the most reliable liver function test for detecting common bile duct stones, with sensitivity of 80.6% and specificity of 75.3% using a cut-off of 224 IU/L 1

Cholestatic Liver Diseases

• Primary biliary cholangitis and primary sclerosing cholangitis cause elevation of both markers 1, 2
• In patients with inflammatory bowel disease, elevated ALP should raise suspicion of primary sclerosing cholangitis 2

Infiltrative Liver Diseases

• Sarcoidosis, amyloidosis, and hepatic metastases can cause elevation of both GGT and ALP 1, 2

Chronic Liver Disease

• Viral hepatitis, cirrhosis, and chronic hepatitis can elevate both markers 1, 2

Medication-Induced Elevations

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. 1

• Older patients (≥60 years) are more prone to cholestatic drug-induced liver injury, which can comprise up to 61% of cases in this age group 2
• Marked increase of GGT may indicate drug-induced liver injury even when conventional DILI threshold levels are not reached 3

Metabolic Causes

• Diabetes, insulin resistance, and obesity can cause elevated GGT 1
• Nonalcoholic fatty liver disease (NAFLD) patients typically have GGT levels ranging from low normal to >400 U/L 1
• Even mildly elevated GGT independently predicts increased risk for cardiovascular disease, diabetes, metabolic syndrome, and all-cause mortality 1

Diagnostic Approach to Differentiate Sources

Confirming Hepatic Origin of ALP

Measuring GGT concurrently with ALP helps determine the source of ALP elevation: elevated GGT confirms hepatic origin, while normal GGT suggests bone or other non-hepatic sources. 2

• Concomitantly elevated GGT confirms that elevated ALP originates from the liver and indicates cholestasis 1
• GGT is found in the liver, kidneys, intestine, prostate, and pancreas, but not in bone 1
• However, GGT has limited utility as a predictor of ALP isoform elevation overall, with an area under the ROC curve of only 0.68 for hepatic isoform elevation 4

Severity Classification

• Mild ALP elevation: <5 times the upper limit of normal 2
• Moderate elevation: 5-10 times ULN 2
• Severe elevation: >10 times ULN (requires expedited workup) 2

Important Clinical Pitfalls

• GGT elevation alone has low specificity and should be interpreted in context with other liver enzymes 1
• Isolated GGT elevations can occur in the absence of underlying liver disease and should not be used as the sole marker of liver disease 1
• In patients with advanced liver disease, GGT loses specificity because it elevates regardless of etiology once extensive fibrosis develops 1
• 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