Do you order Gamma-Glutamyl Transferase (GGT) if Alkaline Phosphatase (AP) is mildly elevated?

Should You Order GGT When Alkaline Phosphatase is Mildly Elevated?

Yes, you should order GGT when alkaline phosphatase is mildly elevated to confirm whether the elevation originates from the liver or from non-hepatic sources like bone. 1

Why GGT is Essential for Evaluating Elevated ALP

• GGT confirms hepatobiliary origin because it is present in liver tissue but not in bone, making it the most practical test to differentiate the source of ALP elevation 1, 2
• When ALP is elevated with normal GGT, this strongly suggests a non-hepatic source (most commonly bone), allowing you to avoid unnecessary hepatobiliary imaging 2
• When ALP is elevated with high GGT, this confirms hepatobiliary origin and indicates cholestasis requiring immediate evaluation with abdominal ultrasound 3

The Diagnostic Algorithm

Step 1: Measure GGT concurrently with elevated ALP 1

• If GGT is normal: The ALP elevation is likely from bone, intestine, or other non-hepatic sources 2

  • Consider bone conditions: Paget's disease, bone metastases, fractures, osteomalacia 2
  • Avoid extensive hepatobiliary workup as the first step 2
  • Consider ALP isoenzyme fractionation if diagnosis remains unclear 1, 2

• If GGT is elevated: The ALP elevation is hepatobiliary in origin 3

  • Proceed immediately to transabdominal ultrasound to evaluate for biliary obstruction, gallstones, or infiltrative liver disease 3
  • Review all medications thoroughly, as drug-induced cholestatic liver injury comprises up to 61% of cases in patients ≥60 years 3
  • Screen for alcohol use, as this is the most common cause of elevated GGT (occurring in ~75% of habitual drinkers) 3

Important Clinical Context

• Mild ALP elevation is defined as less than 5 times the upper limit of normal 1
• In NASH patients, ALP is usually normal or only mildly elevated (typically <2× ULN), so ALP ≥2× ULN is atypical and suggests alternative diagnoses 4, 1
• The combination of GGT + ALP has 93.5% sensitivity and 85.1% specificity for detecting asymptomatic choledocholithiasis, making it a valuable screening tool 5

Critical Pitfalls to Avoid

• Don't skip GGT measurement - while some studies suggest GGT has limited sensitivity (46.6%) for hepatic ALP elevation 6, guidelines consistently recommend it as the first-line test because normal GGT effectively rules out hepatobiliary disease 1, 2
• Don't assume liver pathology without confirming with GGT - this leads to unnecessary imaging and workup 2
• Don't order GGT in isolation - isolated GGT elevation is a poor indicator of liver injury and insufficient to diagnose liver disease 4

When to Use Alternative Tests

• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone 1
• 5'-nucleotidase can also be measured, as elevations generally signal hepatobiliary disease, though it is less commonly used than GGT 4