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

Workup of Elevated Alkaline Phosphatase

The appropriate workup for elevated alkaline phosphatase (ALP) should begin with a complete liver panel, including bilirubin, albumin, ALT, AST, ALP, and GGT, along with a full blood count to determine the source and severity of elevation. 1

Initial Evaluation

Step 1: Determine if ALP is isolated or part of broader abnormalities

• Check if other liver enzymes are elevated (AST, ALT, GGT)
• Calculate AST:ALT ratio (>2 suggests alcoholic liver disease, >3 has high probability) 1
• Review complete blood count for signs of systemic disease

Step 2: Assess for common causes based on clinical context

• Liver origin: Biliary obstruction, infiltrative liver disease, hepatic metastases
• Bone origin: Paget's disease, bone metastases, metabolic bone disorders
• Other sources: Pregnancy, sepsis, medication effects

Diagnostic Algorithm

For suspected liver origin ALP elevation:

1. First-line imaging: Abdominal ultrasound (superior for evaluating biliary tract abnormalities and parenchymal liver changes) 1
2. Additional imaging based on ultrasound results:
   • If biliary obstruction suspected: MRCP
   • If parenchymal disease or focal lesions: CT scan or MRI
   • If fibrosis assessment needed: Transient elastography (FibroScan)

For suspected bone origin ALP elevation:

1. Bone-specific ALP isoenzyme testing
2. Skeletal survey or bone scan if metastatic disease suspected
3. Evaluation of calcium, phosphate, PTH, and vitamin D levels

For unclear etiology:

Recent evidence shows that isolated elevated ALP of unclear etiology is most commonly associated with:

• Underlying malignancy (57%) - either infiltrative intrahepatic malignancy or bony metastasis 2
• Bone disease (29%)
• Unsuspected parenchymal liver disease (7%)
• Non-malignant infiltrative liver disease (2%) 2

Important Clinical Considerations

• Normal AST and ALT do not exclude significant liver disease, as both can be normal even in cirrhosis 1
• Isolated GGT elevation is a poor indicator of liver injury 1
• In children, consider transient hyperphosphatasemia (THP), which is benign and self-limiting 3
• Extremely high ALP levels (>1000 U/L) are most frequently seen in patients with sepsis, malignant obstruction, and AIDS 4

Monitoring and Follow-up

• Repeat liver enzymes (including GGT) every 3-6 months 1
• Follow-up imaging based on clinical course
• Consider referral to a specialist if:
  • GGT remains elevated >3× upper limit of normal despite lifestyle modifications
  • Evidence of advanced fibrosis is present 1

Pitfalls to Avoid

• Don't assume all ALP elevations indicate liver disease - ALP is found in multiple tissues and can be elevated due to bone disorders, pregnancy, or other conditions 5
• Don't overlook malignancy - An isolated, elevated ALP of unclear etiology is strongly associated with metastatic disease and carries significant mortality (47% mortality within an average of 58 months) 2
• Don't miss biliary obstruction - Ultrasound is superior to CT for evaluating biliary tract abnormalities 1
• Don't ignore normal liver transaminases - Normal AST/ALT doesn't exclude significant liver disease 1