Workup for Elevated Alkaline Phosphatase
The appropriate workup for an elevated alkaline phosphatase (ALP) level should begin with determining the source of elevation through targeted laboratory testing and imaging, with specific attention to hepatobiliary and bone pathologies as the most common causes.
Initial Evaluation
Laboratory Tests
- Repeat ALP with fractionation to identify isoenzymes (bone, liver, intestinal)
- Complete liver panel:
- ALT, AST, GGT, total and direct bilirubin
- GGT is particularly useful to differentiate liver from bone source 1
- Complete blood count
- Calcium, phosphate, and creatinine
- 25(OH) vitamin D and PTH levels
- Estimated GFR 2
Imaging
- Abdominal ultrasound (first-line imaging for hepatobiliary evaluation)
- If hepatobiliary source suspected:
- CT or MRI of abdomen/pelvis if ultrasound is inconclusive
- If bone source suspected:
- Targeted bone radiographs of symptomatic areas
- Consider bone scan for suspected metastatic disease
Interpretation Based on Pattern
Hepatobiliary Source (Most Common)
- Suspect when GGT is also elevated
- Common causes:
- Biliary obstruction (malignant or benign)
- Infiltrative liver disease (primary or metastatic)
- Drug-induced liver injury
- Sepsis (can present with elevated ALP and normal bilirubin) 1
Bone Source
- Suspect when GGT is normal but ALP remains elevated
- Common causes:
- Metastatic bone disease
- Paget's disease
- Osteomalacia
- Hyperparathyroidism
- Fracture healing
Other Sources
- Intestinal (usually not clinically significant)
- Placental (in pregnancy)
- Malignancy (can cause elevation through both liver and bone involvement) 3
Special Considerations
Extremely High ALP (>1000 U/L)
When ALP is extremely elevated (>1000 U/L), the most common causes are:
- Sepsis (can occur with normal bilirubin)
- Malignant biliary obstruction
- Advanced metastatic disease (liver and/or bone)
- AIDS with opportunistic infections 1
In Children
Consider transient hyperphosphatasemia in children with isolated ALP elevation, especially following viral illness. This benign condition typically resolves within 4 months 4.
In Renal Failure
Patients on hemodialysis frequently have elevated ALP from bone disease. Measurement of bone-specific ALP and osteocalcin is recommended 5.
Follow-up Testing
If initial workup is inconclusive:
- Repeat ALP in 2-4 weeks to assess trend
- If persistently elevated without diagnosis:
- Consider liver biopsy for unexplained hepatic source
- Consider bone biopsy for unexplained bone source
- Evaluate for occult malignancy (especially in patients >50 years)
Important Pitfalls to Avoid
- Failing to fractionate ALP when the source is unclear
- Overlooking malignancy as a cause (accounts for 57% of unclear ALP elevations) 3
- Assuming liver disease when GGT is normal (likely bone source)
- Excessive workup for mild, isolated elevations in otherwise asymptomatic patients
- Missing drug-induced causes (review all medications)
Remember that an isolated elevated ALP of unclear etiology is associated with significant mortality (47% within 58 months) and often indicates serious underlying conditions, particularly metastatic malignancy 3.