How do I work up an elevated alkaline phosphatase (alk phos) level?

Diagnostic Approach to Elevated Alkaline Phosphatase

The most effective workup for elevated alkaline phosphatase (ALP) begins with confirming its hepatobiliary origin through GGT measurement, followed by targeted imaging with abdominal ultrasound as first-line, and specific testing based on clinical presentation. 1

Initial Evaluation

1. Confirm hepatobiliary origin:

   • Measure gamma-glutamyl transferase (GGT) to confirm hepatobiliary origin of elevated ALP (sensitivity 80.6%, specificity 75.3%) 1
   • If GGT is normal, consider ALP fractionation to identify bone, intestinal, or placental sources 1

2. Basic laboratory workup:

   • Complete blood count with differential
   • C-reactive protein
   • Serum creatinine
   • Comprehensive liver panel (AST, ALT, bilirubin, albumin)
   • Calcium and phosphate levels (to evaluate for bone disorders) 1, 2

Targeted Testing Based on Clinical Suspicion

For suspected biliary/hepatic disease:

• Autoimmune markers: ANA, ASMA, AMA, anti-LKM antibodies 1
• Viral hepatitis panel: Hepatitis A, B, C serologies 1
• Imaging:
  • Abdominal ultrasound as first-line imaging (sensitivity 73%, specificity 91% for CBD stones) 1
  • If biliary pathology is suspected or ultrasound is inconclusive, proceed to MRI with MRCP (sensitivity 86%, specificity 94%) 1

For suspected bone disease:

• Bone-specific alkaline phosphatase
• Parathyroid hormone (PTH) levels
• Vitamin D levels
• Consider bone imaging if Paget's disease or metastatic disease is suspected 2, 1

Common Causes to Consider

1. Hepatobiliary causes:

   • Biliary obstruction (malignant or benign)
   • Primary biliary cholangitis (PBC)
   • Primary sclerosing cholangitis (PSC)
   • Drug-induced liver injury
   • Infiltrative liver diseases 1, 3

2. Bone-related causes:

   • Paget's disease
   • Bone metastases (accounts for 20% of isolated elevated ALP cases) 3
   • X-linked hypophosphatemia 2
   • Osteomalacia 2

3. Other important causes:

   • Sepsis (can present with extremely high ALP and normal bilirubin) 4
   • Malignancy (accounts for 57% of isolated elevated ALP of unclear etiology) 3
   • Benign familial hyperphosphatasemia (rare genetic condition) 5

Important Clinical Pearls

• An isolated elevated ALP without obvious cause warrants thorough investigation, as 47% of patients with this finding died within an average of 58 months in one study 3
• Extremely high ALP levels (>1000 U/L) are most commonly associated with sepsis, malignant biliary obstruction, and AIDS 4
• In patients with chronic kidney disease, bone-specific alkaline phosphatase can help diagnose mineral and bone disorders 1
• In children, ALP is naturally elevated due to bone growth; measuring GGT helps identify potential biliary disease 1
• In pregnant women, consider placental production as a cause of elevated ALP 1

Follow-up Monitoring

• Mild elevations: repeat in 4-6 weeks
• Moderate elevations: repeat in 2-3 weeks
• Severe elevations: repeat in 1 week or sooner 1

When evaluating elevated ALP, maintain a high index of suspicion for malignancy, as metastatic disease (both hepatic and bone) is the most common cause of isolated elevated ALP of unclear etiology 3.