Workup for Elevated Alkaline Phosphatase and ALT
The initial workup for elevated alkaline phosphatase (ALP) and alanine transaminase (ALT) should include ALP isoenzyme fractionation or gamma-glutamyl transferase (GGT) to determine the source of ALP elevation, followed by a complete liver panel, and appropriate imaging based on suspected etiology. 1, 2
Step 1: Determine Source of ALP Elevation
- Measure GGT and/or perform ALP isoenzyme fractionation to determine if ALP elevation is of hepatobiliary or bone origin 2
- Elevated GGT suggests hepatobiliary origin
- Normal GGT suggests bone origin
- ALP isoenzyme fractionation can definitively differentiate liver from bone or other tissue origin
Step 2: Complete Laboratory Evaluation
For suspected hepatobiliary origin:
- Complete liver panel:
- ALT, AST (already elevated)
- Total and direct bilirubin
- Albumin, prothrombin time/INR
- Viral hepatitis serologies (hepatitis B, C)
- Autoimmune markers:
- Antinuclear antibody (ANA)
- Anti-smooth muscle antibody (ASMA)
- Anti-mitochondrial antibody (AMA)
- Immunoglobulin G levels 1
- Other laboratory tests as clinically indicated:
- Complete blood count
- Lactate dehydrogenase (LDH)
- Calcium level 1
For suspected bone origin:
- Calcium, phosphorus
- Parathyroid hormone
- 25-hydroxyvitamin D
- Bone-specific markers
Step 3: Imaging Studies
For suspected hepatobiliary origin:
- Abdominal ultrasound as first-line imaging 2
- If ultrasound is inconclusive:
- MRI with MRCP (magnetic resonance cholangiopancreatography) for evaluation of biliary system 2
- CT abdomen if malignancy is suspected
For suspected bone origin:
- Bone scan if ALP is significantly elevated, or if there are clinical symptoms such as bone pain 1
- Skeletal survey or targeted bone radiographs based on symptoms
Common Etiologies to Consider
Hepatobiliary causes:
- Biliary obstruction
- Cholestatic liver diseases (PBC, PSC)
- Viral hepatitis
- Drug-induced liver injury
- Infiltrative liver diseases (malignancy, sarcoidosis, amyloidosis) 3
Bone causes:
- Fracture healing
- Paget's disease
- Osteomalacia
- Bone metastases 2
Important Considerations
In a recent observational study, the most common cause of isolated elevated ALP was underlying malignancy (57%), with infiltrative intrahepatic malignancy and bony metastasis being the predominant findings 3
Mild elevations of ALT with elevated ALP may be seen in celiac disease and typically normalize with a gluten-free diet 4
If ALT is >5× ULN with elevated ALP, consider more severe liver disease and evaluate accordingly 1
If ALT is >3× ULN with total bilirubin >2× ULN, this meets criteria for Hy's Law and requires urgent evaluation for potential severe drug-induced liver injury 1
Follow-up Recommendations
Repeat testing intervals should be based on severity of elevation:
- Mild elevations: repeat in 4-6 weeks
- Moderate elevations: repeat in 2-3 weeks
- Severe elevations: repeat in 1 week or sooner 2
Refer to nephrology if progressive renal insufficiency is detected 1
Consider liver biopsy if diagnosis remains unclear after non-invasive workup, especially if autoimmune markers are positive 1
Remember that an isolated elevated ALP of unclear etiology can be associated with significant underlying pathology, particularly metastatic malignancy, and warrants thorough investigation 3.