What is the significance of elevated alkaline phosphatase (ALP) and normal Gamma-Glutamyl Transferase (GGT) in a patient, potentially an adult with risk factors for liver disease?

Elevated Alkaline Phosphatase with Normal GGT: Bone Origin Most Likely

Your patient's alkaline phosphatase of 133 U/L (mildly elevated) with a normal GGT of 11.8 U/L almost certainly indicates a non-hepatic source, most likely from bone, and you should pursue a bone-directed evaluation rather than hepatobiliary imaging. 1

Why This Pattern Matters

The normal GGT is the critical discriminating factor here. GGT is present in liver, kidneys, intestine, prostate, and pancreas, but is critically absent in bone tissue, making it the key discriminator between hepatic and bone sources of ALP elevation. 1 Cholestatic liver diseases typically elevate both ALP and GGT together, so isolated ALP elevation with normal GGT makes hepatobiliary diagnoses unlikely. 1

Immediate Next Steps

Do not order abdominal ultrasound or MRCP as the first step when GGT is normal, as this wastes resources and delays correct diagnosis. 1 Instead:

• Verify that ALT, AST, and bilirubin are truly normal to confirm this is isolated ALP elevation 1
• Repeat ALP and GGT together to confirm the dissociation pattern 1
• Order ALP isoenzyme analysis to definitively determine the percentage derived from liver versus bone or intestinal sources 1
• Obtain bone-specific alkaline phosphatase (B-ALP) if available, as it's a sensitive marker for bone turnover and metastases 1

Differential Diagnosis Priority

With this pattern, consider:

• Paget's disease of bone (causes marked ALP elevation, often >5× ULN) 1
• Bone metastases, particularly from breast, prostate, or lung primaries 1
• Osteomalacia or vitamin D deficiency, especially in elderly or those with malabsorption 1
• Recent fractures or fracture healing 1
• Osteoporosis with active bone turnover 1
• Physiologic elevation if patient is pregnant (2nd/3rd trimester) or pediatric age 1

Targeted Bone Workup

• Assess for bone pain, recent trauma, or localized skeletal symptoms 1
• Check 25-OH vitamin D, calcium, phosphate, and PTH levels to evaluate for osteomalacia or metabolic bone disease 1
• Consider bone scan (technetium-99m scintigraphy) as first-line imaging for suspected bone pathology, particularly if localized symptoms or concern for metastases 1

Age-Specific Considerations

• In elderly patients, strongly consider bone metastases and Paget's disease as these are the most common causes 1
• In postmenopausal women with bone pain or radiographic abnormalities, bone scan is indicated 1
• In patients under 40 with suspected bone pathology, urgent referral to a bone sarcoma center may be required 1

Critical Pitfall

Do not assume benign etiology without investigation—in one retrospective study of 260 patients with isolated elevated ALP, 57% were due to underlying malignancy (with 61 having infiltrative intrahepatic malignancy, 52 having bony metastasis, and 34 having both). 2 Additionally, 47% of patients died within an average of 58 months after identification of isolated elevated ALP. 2

When to Reconsider Hepatobiliary Disease

If bone workup is completely negative, then consider hepatic metastases or infiltrative diseases, as normal liver enzymes do not exclude infiltrative liver disease. 1 However, this should be a secondary consideration only after bone sources are ruled out given the normal GGT.

Medication Review

Do not overlook medication review, as bisphosphonates and denosumab can alter ALP levels despite underlying bone pathology. 1