What is the appropriate work-up for a patient with elevated alkaline phosphatase (alkphos)?

Workup of Elevated Alkaline Phosphatase

The appropriate workup for a patient with elevated alkaline phosphatase should first determine the tissue origin of the elevation (hepatobiliary vs. bone) through gamma-glutamyl transferase (GGT) and/or alkaline phosphatase isoenzyme fractionation before proceeding with targeted investigations. 1

Step 1: Confirm Hepatobiliary Origin

• Measure GGT and/or perform alkaline phosphatase isoenzyme fractionation to determine if the elevated ALP is of hepatobiliary origin 1
• 5'-nucleotidase can also be obtained, although it is less commonly used 1
• If GGT is normal, the elevated ALP is likely of bone origin; if GGT is elevated, hepatobiliary origin is likely but does not exclude a bone component 2

Step 2: Clinical Assessment and Basic Laboratory Testing

• Review medication history (including over-the-counter drugs) for potential drug-induced causes 1
• Assess risk factors for liver disease, alcohol consumption, and comorbid conditions 1
• Obtain additional liver function tests:
  • Aminotransferases (ALT, AST) 1
  • Bilirubin (total and direct) 1
  • Albumin and prothrombin time (to assess synthetic function) 1

Step 3: Targeted Workup Based on Suspected Origin

If Hepatobiliary Origin (Elevated GGT):

• Abdominal ultrasound to evaluate for:
  • Biliary obstruction (most common cause of extrahepatic cholestasis) 1
  • Parenchymal liver disease 1
  • Infiltrative liver disease 3
• Consider serologic testing for common hepatic diseases:
  • Viral hepatitis markers (HAV-IgM, HBsAg, HBc-IgM, HCV antibody) 1
  • Autoimmune markers (ANA, ASMA, immunoglobulin levels) if suspected 1
• If initial evaluation is unrevealing but ALP remains elevated:
  • Consider MR cholangiography or endoscopic retrograde cholangiography to evaluate for primary sclerosing cholangitis or dominant stricture 1
  • Consider CT or MRI abdomen if infiltrative disease or malignancy is suspected 1, 3

If Bone Origin (Normal GGT):

• Consider bone-specific causes:
  • Paget's disease 4
  • Osteomalacia 1
  • Bone metastases 3, 4
  • High bone turnover in postmenopausal women 5
• Obtain bone-specific tests if clinically indicated:
  • Bone-specific alkaline phosphatase (BAP) 1, 5
  • Calcium, phosphate, PTH, and vitamin D levels 1
• Consider bone scan if:
  • Clinical symptoms such as bone pain are present 1
  • Malignancy is suspected 1
  • Radiographic findings suggest bony neoplasm 1

Step 4: Advanced Testing Based on Initial Results

• If malignancy is suspected (based on recent research, malignancy accounts for 57% of cases of isolated elevated ALP of unclear etiology) 3:
  • Consider CT chest/abdomen/pelvis to evaluate for primary malignancy or metastatic disease 3
  • Consider bone scan if bone metastases are suspected 1
• If initial workup is unrevealing:
  • Consider liver biopsy for persistently elevated ALP without clear cause, especially if other liver tests are abnormal 1
  • Monitor ALP levels over time - persistent elevation warrants continued investigation 1

Common Pitfalls and Caveats

• Extremely high ALP levels (>1000 U/L) are most frequently seen in patients with sepsis, malignant biliary obstruction, and AIDS 4
• Patients with sepsis can have extremely high ALP with normal bilirubin 4
• An isolated elevated ALP of unclear etiology has significant prognostic implications - in one study, 47% of patients died within an average of 58 months 3
• Elevated ALP in postmenopausal women is often due to high bone turnover and may respond to bisphosphonate therapy 5
• Fluctuating ALP levels in primary sclerosing cholangitis may be due to intermittent blockage of strictured bile ducts by biliary sludge or small stones, which can mimic drug-induced liver injury 1