What labs to order if alkaline phosphatase (ALP) is elevated?

Laboratory Workup for Elevated Alkaline Phosphatase

When alkaline phosphatase (ALP) is elevated, a comprehensive laboratory workup should include gamma-glutamyl transferase (GGT) to confirm hepatobiliary origin, complete liver panel, bone markers, and abdominal ultrasound as first-line imaging. 1

Initial Laboratory Tests

• Confirm hepatobiliary origin:

  • Gamma-glutamyl transferase (GGT) - essential to differentiate between liver and bone sources 1, 2

• Basic laboratory workup:

  • Complete blood count with differential
  • C-reactive protein
  • Comprehensive liver panel (AST, ALT, bilirubin, albumin)
  • Serum creatinine
  • Calcium and phosphate levels 1

• Bone-related markers (especially if GGT is normal):

  • Bone-specific alkaline phosphatase
  • Parathyroid hormone (PTH)
  • Vitamin D levels 1

Additional Testing Based on Initial Results

• If hepatobiliary origin suspected (elevated GGT):

  • Autoimmune markers: ANA, ASMA, AMA, anti-LKM antibodies
  • Viral hepatitis panel (hepatitis A, B, C serologies) 1

• If bone origin suspected (normal GGT with elevated ALP):

  • Osteocalcin (highly correlated with bone ALP, r = 0.78) 3
  • Consider bone imaging if Paget's disease or metastases suspected 1, 4

Imaging Studies

• First-line imaging:

  • Abdominal ultrasound (sensitivity 73%, specificity 91% for biliary pathology) 1

• Second-line imaging (if ultrasound inconclusive):

  • MRI with MRCP (sensitivity 86%, specificity 94%) - gold standard for biliary tract evaluation
  • CT scan or MRI for detailed liver assessment
  • Transient elastography (FibroScan) for fibrosis evaluation 1

Clinical Considerations

Common Causes of Markedly Elevated ALP

1. Malignancy (57% of cases with isolated elevated ALP):

   • Infiltrative intrahepatic malignancy
   • Bony metastases
   • Combined hepatic and bone metastases 4

2. Biliary obstruction:

   • Malignant obstruction (e.g., cholangiocarcinoma)
   • Benign obstruction (e.g., common bile duct stones) 5, 6

3. Sepsis:

   • Can cause extremely high ALP even with normal bilirubin 5

4. Bone disease (29% of isolated elevated ALP):

   • Paget's disease
   • Metabolic bone disorders 4

5. Other causes:

   • Primary biliary cholangitis
   • Primary sclerosing cholangitis
   • Drug-induced liver injury
   • Infiltrative liver diseases 1

Special Populations

• Chronic kidney disease patients: Consider bone-specific ALP to diagnose mineral and bone disorders 1
• Children: ALP naturally elevated due to bone growth; GGT helps identify biliary disease 1
• Pregnant women: Consider placental production as cause of elevated ALP 1

Pitfalls and Caveats

• GGT alone may incorrectly identify the source of ALP elevation in approximately 10% of cases; consider direct measurement of bone isoenzyme in uncertain cases 3
• An isolated elevated ALP of unclear etiology is associated with poor prognosis (47% mortality within 58 months) and requires thorough evaluation 4
• Extremely high ALP levels (>1000 IU/L) are most commonly seen in sepsis, malignant biliary obstruction, and infiltrative diseases 5, 6
• Patients with sepsis can present with markedly elevated ALP despite normal bilirubin levels 5