What is the initial workup for a patient with elevated all phosphatases (alkaline phosphatase)?

Initial Workup for Elevated Alkaline Phosphatase

The initial workup for elevated alkaline phosphatase should first determine the source of the elevation by measuring gamma-glutamyl transferase (GGT) and/or performing alkaline phosphatase isoenzyme fractionation to confirm if the elevation is of hepatobiliary origin. 1

Step 1: Confirm Source of Elevation

• Measure GGT: Elevated GGT with elevated ALP confirms hepatobiliary origin 1
• ALP isoenzyme fractionation: Determines if elevation is from liver, bone, intestine, or other tissue 1
• Consider patient demographics: ALP is physiologically higher in childhood (bone growth) and pregnancy (placental production) 1

Step 2: Hepatobiliary Source Evaluation

If GGT is elevated, confirming hepatobiliary source:

1. Imaging of biliary tree:

   • Ultrasound as first-line imaging 1
   • Consider CT or MRI based on clinical scenario 1

2. Laboratory testing:

   • Complete liver panel (AST, ALT, bilirubin, albumin, PT/INR) 1
   • Viral hepatitis serologies (HAV-IgM, HBsAg, HBcIgM, HCV antibody) 1
   • Consider autoimmune markers:
     • Antimitochondrial antibody (for primary biliary cholangitis) 1
     • Antinuclear antibody and anti-smooth muscle antibody 1
     • IgG levels (for autoimmune hepatitis or overlap syndromes) 1

3. Evaluate for common causes:

   • Choledocholithiasis (most common cause of extrahepatic obstruction) 1
   • Malignant obstruction 1, 2
   • Biliary strictures 1
   • Primary biliary cholangitis or primary sclerosing cholangitis 1
   • Drug-induced cholestasis 1
   • Infiltrative liver diseases (sarcoidosis, amyloidosis, metastases) 1, 2

Step 3: Bone Source Evaluation

If GGT is normal but ALP remains elevated (suggesting bone origin):

1. Imaging:

   • Consider bone scan if clinical symptoms of bone pain are present 1
   • Plain radiographs of symptomatic areas

2. Laboratory testing:

   • Calcium, phosphorus, parathyroid hormone 3
   • 25-OH vitamin D and 1,25-(OH)₂ vitamin D 1
   • Consider osteocalcin (marker of bone turnover) 3

3. Evaluate for common causes:

   • Bone metastases (common cause of extremely high ALP) 4, 2
   • Paget's disease 4
   • Osteomalacia
   • Hyperparathyroidism
   • Fracture healing

Step 4: Other Sources

If neither hepatobiliary nor bone source is confirmed:

1. Consider rare causes:
   • Benign familial hyperphosphatasemia 5
   • Intestinal source (intestinal ALP can be elevated in some conditions) 5
   • Sepsis (can cause extremely high ALP even with normal bilirubin) 4
   • Malignancy (particularly metastatic disease) 2
   • Sarcoidosis 1
   • HIV/AIDS-related conditions 4

Important Clinical Considerations

• Recent research shows that isolated elevated ALP of unclear etiology is most commonly associated with underlying malignancy (57%), with 47% mortality within 58 months of identification 2
• Extremely high ALP levels (>1000 U/L) are most frequently seen in patients with sepsis, malignant obstruction, and AIDS 4
• Persistent elevation for ≥6 months warrants more extensive evaluation including possible liver biopsy 1
• In patients with known malignancy and elevated ALP, consider evaluation for bone and liver metastases 1, 2

Pitfalls to Avoid

• Failing to determine the source tissue of ALP elevation before pursuing extensive workup
• Overlooking malignancy as a common cause of isolated ALP elevation
• Assuming hepatic origin without confirming with GGT or isoenzyme fractionation
• Neglecting to consider benign familial hyperphosphatasemia, which can prevent unnecessary diagnostic tests 5
• Focusing only on liver causes when bone pathology may be the source

By following this systematic approach, clinicians can efficiently identify the source and cause of elevated alkaline phosphatase, leading to appropriate management decisions that impact morbidity and mortality.