What if alkaline phosphatase (alk phos) is elevated?

Evaluation and Management of Elevated Alkaline Phosphatase

When alkaline phosphatase (ALP) is elevated, a systematic diagnostic approach is essential as it most commonly indicates hepatobiliary disease, bone disorders, or underlying malignancy. 1, 2

Step 1: Determine the Source of Elevation

• Measure gamma-glutamyl transferase (GGT) to confirm hepatobiliary origin - elevated GGT suggests liver source while normal GGT suggests bone origin 1, 2
• Consider alkaline phosphatase isoenzyme fractionation if available to definitively identify the tissue source 2
• Review medication history for potential drug-induced causes, particularly in older adults who are more prone to cholestatic drug-induced liver injury 1

Step 2: For Suspected Hepatobiliary Origin

• Obtain additional liver function tests including aminotransferases (ALT, AST), bilirubin (total and direct), albumin, and prothrombin time 2

• Perform abdominal ultrasound as first-line imaging to evaluate for:

  • Biliary obstruction (choledocholithiasis, strictures, malignancy) 1, 2
  • Parenchymal liver disease 2
  • Infiltrative liver diseases (metastases, amyloidosis) 1

• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP (magnetic resonance cholangiopancreatography) 1, 2

Step 3: For Suspected Bone Origin

• Consider bone-specific alkaline phosphatase (B-ALP) measurement 1
• Evaluate for common bone disorders:
  • Paget's disease 1
  • Bone metastases 1, 3
  • Fractures 1

Common Causes of Elevated ALP

Hepatobiliary Causes:

• Cholestatic liver diseases (primary biliary cholangitis, primary sclerosing cholangitis) 1
• Extrahepatic biliary obstruction (choledocholithiasis, malignant obstruction) 1
• Infiltrative liver diseases (metastases, amyloidosis) 1, 3
• Cirrhosis and chronic hepatitis 1

Non-Hepatic Causes:

• Bone disorders (Paget's disease, bone metastases, fractures) 1, 3
• Malignancy (both hepatic infiltration and bony metastases) 3
• Sepsis (can present with extremely high ALP and normal bilirubin) 4
• Physiologic causes (childhood growth, pregnancy) 1, 5
• Benign familial hyperphosphatasemia (rare genetic condition) 6

Special Considerations

• For patients with localized bone pain or elevated ALP, a bone scan is indicated 7
• In patients with early-stage breast cancer (stage I-II), routine systemic imaging is not recommended in the absence of symptoms 7
• For patients with locally advanced breast cancer or symptoms suspicious for metastatic disease, abdominal imaging using diagnostic CT or MRI is indicated if ALP is elevated 7
• Recent research shows that isolated elevated ALP of unclear etiology is most commonly associated with underlying malignancy (57%), particularly metastatic disease, and carries a poor prognosis 3

Follow-up Recommendations

• If initial evaluation is unrevealing, repeat ALP measurement in 1-3 months 1
• Monitor closely if ALP continues to rise, as this may indicate progression of underlying disease 1
• For persistently elevated ALP without clear cause, especially with other abnormal liver tests, consider liver biopsy 2

Important Pitfalls to Avoid

• Don't attribute isolated ALP elevation to non-alcoholic steatohepatitis (NASH) as elevation of ALP ≥2× ULN is atypical in NASH 1
• Don't overlook sepsis as a cause of extremely high ALP, which can occur with normal bilirubin 4
• Remember that ALP can be induced by certain medications, including glucocorticoids and anticonvulsants 5
• Be aware that an isolated, elevated ALP of unclear etiology is associated with several serious disorders and should prompt thorough investigation 3