What to do when alkaline phosphatase (alk phos) is elevated?

Evaluation and Management of Elevated Alkaline Phosphatase

When alkaline phosphatase (ALP) is elevated, first determine the source (hepatic vs. non-hepatic) with GGT or ALP isoenzyme fractionation, then pursue targeted diagnostic workup based on the likely origin to identify the underlying cause. 1

Step 1: Determine the Source of Elevated ALP

Alkaline phosphatase is present in multiple tissues, primarily:

• Liver/biliary tract
• Bone
• Intestine
• Placenta (during pregnancy)
• Kidneys

Initial Assessment:

• Measure gamma-glutamyl transferase (GGT) and/or perform ALP isoenzyme fractionation 1
  • Elevated GGT confirms hepatic origin of ALP
  • Normal GGT suggests bone or other non-hepatic source

Step 2: Diagnostic Approach Based on Source

A. If Hepatic Origin (Elevated GGT):

1. Evaluate for biliary obstruction:

   • Abdominal ultrasound (first-line imaging) 1
   • Consider MRCP if obstruction suspected but not seen on ultrasound

2. Check for cholestatic liver diseases:

   • Primary biliary cholangitis (PBC): Anti-mitochondrial antibody
   • Primary sclerosing cholangitis (PSC): MRCP, especially if inflammatory bowel disease present
   • Autoimmune hepatitis overlap: Check ANA, ASMA, IgG levels 1
   • Drug-induced cholestasis: Medication review

3. Consider other hepatic causes:

   • Infiltrative diseases: Sarcoidosis, amyloidosis, malignancy
   • Sepsis (can cause extremely high ALP even with normal bilirubin) 2
   • Metastatic disease to liver 3

B. If Bone Origin (Normal GGT, elevated bone ALP isoenzyme):

1. Evaluate for bone pathology:
   • Paget's disease: Check for bone pain, deformity, pathological fractures 4
   • Metastatic bone disease: Consider bone scan if clinical suspicion 1, 3
   • Osteomalacia/rickets: Check vitamin D, calcium, phosphate levels
   • Hyperparathyroidism: Check PTH, calcium levels
   • Fracture healing

C. If Other Non-Hepatic Origin:

1. Consider rare causes:
   • Benign familial hyperphosphatasemia 5
   • Pregnancy
   • Intestinal source (intestinal ALP isoenzyme)

Step 3: Management Based on Severity and Duration

For Mild Elevations (<2x ULN):

• If asymptomatic with no other abnormal liver tests, consider repeating in 1-3 months 6
• Many transient elevations normalize within 1-3 months

For Moderate Elevations (2-5x ULN):

• More urgent evaluation warranted
• Higher likelihood of significant underlying pathology

For Severe Elevations (>5x ULN):

• Expedited comprehensive evaluation
• Consider hospitalization if symptoms present
• Extremely high levels (>10x ULN) often associated with:
  • Sepsis
  • Malignant biliary obstruction
  • Advanced AIDS with opportunistic infections
  • Extensive bone or liver metastases 2

Special Considerations

For Persistent Elevations:

• If ALP remains elevated after initial workup, consider:
  • Liver biopsy if hepatic origin suspected
  • Bone biopsy if bone pathology suspected
  • Evaluation for occult malignancy (47% of patients with isolated elevated ALP of unclear etiology died within an average of 58 months) 3

For Cholestatic Liver Diseases:

• In primary biliary cholangitis or primary sclerosing cholangitis:
  • ALP >1.5x ULN is diagnostic criterion 1
  • ALP levels are used to monitor disease progression 7
  • ALP levels ≤2.0x ULN at 1 year after diagnosis associated with better 10-year survival (84% vs 62%) 7

For Suspected Overlap Syndromes:

• Consider overlap syndromes when ALP remains elevated despite immunosuppressive treatment 1
• MRCP should be considered in patients with AIH who have persistently elevated ALP 1

Common Pitfalls to Avoid

1. Failing to determine the source of elevated ALP - Always confirm hepatic vs. non-hepatic origin with GGT or isoenzyme fractionation

2. Overlooking non-hepatic causes - Remember that elevated ALP may be due to bone disease, pregnancy, or other conditions

3. Missing malignancy - Isolated elevated ALP is commonly associated with metastatic disease to liver or bone 3

4. Stopping at biliary imaging - If imaging is normal but ALP remains elevated, pursue additional testing for non-obstructive causes

5. Ignoring medications - Many drugs can cause cholestatic liver injury with elevated ALP

By following this systematic approach, you can efficiently identify the cause of elevated ALP and initiate appropriate management to address the underlying condition.