What is the workup for a patient with elevated alkaline phosphatase (ALP)?

Workup for Elevated Alkaline Phosphatase

The initial workup for elevated alkaline phosphatase (ALP) should focus on determining its source (hepatobiliary vs bone) and ruling out serious underlying conditions, particularly malignancy, which is the most common cause of unexplained isolated ALP elevation (57% of cases). 1

Step 1: Confirm Hepatic Origin

• Determine if ALP is of hepatic origin: Order gamma-glutamyl transferase (GGT) and/or ALP isoenzyme fractionation 2
  • Elevated GGT confirms hepatobiliary source
  • Normal GGT suggests bone origin (common in postmenopausal women) 3

Step 2: Basic Laboratory Evaluation

• Complete blood count: To assess for infection, malignancy
• Comprehensive metabolic panel: Including liver function tests (AST, ALT, bilirubin)
• Urinalysis: To evaluate renal function
• Estimated glomerular filtration rate: To assess kidney function 2

Step 3: Specific Testing Based on ALP Origin

If Hepatobiliary Origin:

1. Abdominal imaging:

   • Ultrasound, CT, or MRI of abdomen to evaluate for:
     • Biliary obstruction (common cause of marked ALP elevation) 4
     • Liver metastases
     • Infiltrative liver disease

2. Additional laboratory tests:

   • Viral hepatitis serologies (HAV-IgM, HBsAg, HBcIgM, HCV antibody) 2
   • Antimitochondrial antibody (for primary biliary cholangitis)
   • Antinuclear antibody and anti-smooth muscle antibody (for autoimmune hepatitis) 2

If Bone Origin:

1. Bone-specific tests:

   • Bone-specific alkaline phosphatase (BAP)
   • Calcium, phosphate levels
   • Parathyroid hormone (PTH) 2
   • 25(OH) vitamin D and 1,25(OH)₂ vitamin D 2

2. Imaging:

   • Bone scan is recommended only if:
     • Patient has bone pain
     • ALP is markedly elevated
     • Radiographic findings suggest bone neoplasm 2

Step 4: Additional Testing Based on Clinical Suspicion

• For suspected malignancy (particularly if ALP >1,000 U/L):

  • Age-appropriate cancer screening
  • CT chest/abdomen/pelvis to evaluate for metastatic disease 2

• For neurological symptoms:

  • MRI or CT of brain/spine 2

• For suspected infection:

  • Blood cultures (sepsis is a common cause of markedly elevated ALP) 4

Interpretation and Follow-up

• If initial workup is unrevealing:

  • Repeat ALP in 1-3 months 5
  • 52% of isolated ALP elevations normalize within 1-3 months 5
  • In children, consider transient hyperphosphatasemia which resolves spontaneously 6

• If ALP remains elevated:

  • Consider referral to specialist (hepatology, oncology, or endocrinology)
  • More extensive evaluation may be needed

Common Pitfalls to Avoid

1. Overlooking malignancy: Isolated elevated ALP of unclear etiology is associated with malignancy in 57% of cases, with 47% mortality within 58 months 1

2. Unnecessary bone scans: Avoid bone scans in the absence of bone pain, elevated ALP, or radiographic findings suggesting bone neoplasm 2

3. Missing hepatobiliary causes: Sepsis can cause extremely high ALP with normal bilirubin 4

4. Ignoring age-related factors: ALP and BAP levels are significantly higher in elderly patients (80s vs 60s) 3

5. Excessive testing: In children and some adults, transient elevations may resolve spontaneously 6