Workup of Elevated Alkaline Phosphatase
Begin with determining the tissue source of ALP elevation by measuring gamma-glutamyl transferase (GGT) or performing ALP isoenzyme fractionation, followed by targeted imaging and laboratory evaluation based on whether the source is hepatobiliary or non-hepatic. 1
Initial Diagnostic Steps
Determine the Source of Elevation
- Measure GGT to establish hepatic origin: If GGT is elevated alongside ALP, the source is hepatobiliary; if GGT is normal, consider bone or other non-hepatic sources 1, 2
- Alternatively, perform ALP isoenzyme fractionation to definitively identify whether elevation is from liver (heat-stable), bone (heat-labile), or other tissues 2, 3
- Consider 5'-nucleotidase as an additional confirmatory test for hepatic origin 2
Critical pitfall: Do not assume hepatic origin without confirmation, as bone disease accounts for approximately 29% of isolated ALP elevations, and physiologic bone growth causes higher baseline ALP in younger patients 4, 2
If Hepatobiliary Origin Confirmed (Elevated GGT)
Imaging Evaluation
- Perform abdominal ultrasound as first-line imaging to assess for biliary ductal dilatation and gallstones 5, 1
- If ultrasound shows biliary ductal dilatation or is persistently elevated ALP with negative ultrasound, proceed to MRI abdomen with MRCP (with and without IV contrast) to evaluate for biliary obstruction etiology 5
- Patients with common bile duct stones on ultrasound should proceed directly to ERCP without additional imaging 5
Laboratory Workup
- Obtain complete liver panel: ALT, AST, total and direct bilirubin 1
- Check hepatitis serologies: HAV IgM, HBsAg, HBc IgM, HCV antibody 1
- Consider autoimmune markers (ANA, ASMA, AMA) if autoimmune liver disease suspected based on clinical context 1
Common Etiologies to Consider
Most concerning: Malignancy is the most common cause of isolated elevated ALP (57% of cases), with infiltrative intrahepatic malignancy and bony metastases being predominant 4. In hospitalized patients with extremely high ALP (>1000 U/L), the three major causes are:
- Biliary obstruction (particularly malignant obstruction and cholangiocarcinoma) 6, 7
- Sepsis (can present with extremely high ALP and normal bilirubin) 6, 7
- Infiltrative liver disease including metastases 6, 7
Important caveat: Approximately 47% of patients with isolated elevated ALP of unclear etiology died within an average of 58 months, underscoring the clinical significance of this finding 4
If Non-Hepatic Origin (Normal GGT)
Bone Disease Evaluation
- Measure calcium, phosphate, PTH, and vitamin D (25-OH and 1,25-OH) levels 1
- Assess bone-specific ALP if available 1, 2
- Consider imaging for bone lesions if metastatic disease or Paget's disease suspected 4
Specific Bone Disorders
- X-linked hypophosphatemia: Look for hypophosphatemia with renal phosphate wasting and elevated bone ALP; treat with phosphate supplements and active vitamin D (calcitriol or alfacalcidol), with burosumab for refractory cases 1, 2
- Paget's disease and osteomalacia: Bone-specific ALP is a reliable biomarker for disease activity 2
Management Based on Etiology
For Biliary Obstruction
For Drug-Induced Liver Injury
- Discontinue potential hepatotoxins if medically feasible 1
- If immune checkpoint inhibitor-related: hold therapy and consider corticosteroids for grade 2 or higher 1
For Primary Biliary Cholangitis
- Initiate ursodeoxycholic acid (UDCA) 1
Follow-Up Monitoring
- For chronic liver diseases: Monitor ALP and liver tests every 3-6 months 1
- For metabolic bone diseases: Monitor ALP, calcium, phosphate, and PTH every 6 months 1
- If no clear etiology identified and ALP remains elevated, maintain high suspicion for occult malignancy given the 57% prevalence in unexplained cases 4
Key consideration: An isolated elevated ALP with normal bilirubin does not exclude serious pathology—sepsis and infiltrative malignancy commonly present this way 6, 8