Initial Workup for Elevated Alkaline Phosphatase
The first step is to confirm hepatobiliary origin by measuring gamma-glutamyl transferase (GGT) concurrently—if GGT is also elevated, the source is hepatobiliary; if GGT is normal, the source is likely bone or other non-hepatic tissue. 1, 2
Step 1: Determine the Source of ALP Elevation
- Measure GGT immediately to differentiate hepatobiliary from bone origin, as GGT is found in liver, kidneys, intestine, prostate, and pancreas but critically NOT in bone. 1
- If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone. 2
- Elevated GGT confirms hepatic origin; normal GGT suggests bone or other non-hepatic sources. 2, 3
Step 2: If Hepatobiliary Origin Confirmed (Elevated GGT)
Initial Laboratory Workup
- Obtain a complete liver panel: ALT, AST, total and direct bilirubin, albumin. 4, 2
- Calculate the R value [(ALT/ULN)/(ALP/ULN)] to classify injury pattern: cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5). 5
- Consider viral hepatitis serologies (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors are present. 5
- Check autoimmune markers (ANA, ASMA, AMA) if autoimmune liver disease is suspected. 4
Imaging Evaluation
- Abdominal ultrasound is first-line imaging to assess for biliary ductal dilatation, gallstones, liver masses, or infiltrative lesions. 1, 5
- If ultrasound shows common bile duct stones, proceed directly to ERCP without additional imaging. 1
- If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP to evaluate for intrahepatic biliary abnormalities, primary sclerosing cholangitis, or biliary strictures. 1, 5
Specific Diagnostic Considerations
- In patients with inflammatory bowel disease and elevated ALP, high-quality MRCP is recommended to evaluate for primary sclerosing cholangitis. 4
- If MRCP is normal in IBD patients with suspected PSC, consider liver biopsy to diagnose small-duct PSC. 5
- Review all medications thoroughly, especially in older patients, as cholestatic drug-induced liver injury comprises up to 61% of cases in patients ≥60 years. 5
- Consider infiltrative diseases (sarcoidosis, amyloidosis, hepatic metastases) in patients with unexplained elevation. 1, 5
Step 3: If Bone Origin Suspected (Normal GGT)
Laboratory Workup
- Measure calcium, phosphate, PTH, and vitamin D levels. 1
- Obtain bone-specific ALP if available, as it is a sensitive marker for bone turnover and metastases. 5
Imaging Evaluation
- Bone scan is indicated if there is localized bone pain or clinical suspicion for bone pathology (Paget's disease, metastases, fractures). 1, 5
- In patients with known malignancy history, elevated ALP should prompt evaluation for metastatic disease even if asymptomatic. 1
- Patients under 40 years with suspected bone pathology may require urgent referral to a bone sarcoma center. 5
Step 4: Severity-Based Approach
- Mild elevation (<5× ULN): Follow the standard workup above; if initial evaluation is unrevealing, repeat ALP in 1-3 months. 5
- Moderate elevation (5-10× ULN): Expedite workup with imaging and laboratory evaluation. 4
- Severe elevation (>10× ULN): Requires urgent expedited workup given high association with serious pathology such as biliary obstruction, cholangiocarcinoma, or metastatic disease. 2, 5
Important Clinical Pitfalls
- Do not attribute isolated ALP elevation to NASH, as elevation ≥2× ULN is atypical in NASH. 5
- Physiologic elevations occur in childhood (due to bone growth) and pregnancy (second/third trimester due to placental production). 1, 5
- In patients with PSC, abrupt ALP elevations may reflect transient obstruction from inflammation, bacterial cholangitis, or choledocholithiasis rather than disease progression. 5
- Normal ALP does not exclude PSC—some patients with PSC have normal ALP levels. 2
- Consider X-linked hypophosphatemia in patients with elevated ALP, hypophosphatemia, and elevated FGF23. 5