What does an elevated alkaline phosphatase (ALP) level indicate?

Elevated Alkaline Phosphatase: Causes and Evaluation

An elevated alkaline phosphatase (ALP) level most commonly indicates cholestatic liver disease, bone disorders, or malignancy, requiring systematic evaluation to determine the source and underlying cause. 1

Sources of Elevated ALP

• ALP is primarily produced in the liver (canalicular membrane of hepatocytes and biliary epithelium) and bone, with smaller amounts from intestines, kidneys, white blood cells, and placenta 1
• Determining the source is crucial for proper diagnosis and management 2

Determining the Source of Elevated ALP

• Measure gamma-glutamyl transferase (GGT) to differentiate between hepatic and non-hepatic origin:
  • Elevated GGT + elevated ALP = likely hepatic origin
  • Normal GGT + elevated ALP = likely bone origin 1, 2
• ALP isoenzyme fractionation can differentiate between liver, bone, and intestinal isoenzymes in complex cases 1

Hepatic Causes of Elevated ALP

• Cholestatic liver diseases:
  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
  • Drug-induced cholestasis
  • Partial bile duct obstruction 2
• Extrahepatic biliary obstruction:
  • Choledocholithiasis (gallstones)
  • Malignant obstruction (particularly cholangiocarcinoma)
  • Biliary strictures 2, 3
• Infiltrative liver diseases:
  • Amyloidosis
  • Hepatic metastases
  • Sarcoidosis 2, 4
• Other hepatic conditions:
  • Cirrhosis
  • Chronic hepatitis
  • Viral hepatitis
  • Congestive heart failure 2
• Sepsis (can cause extremely high ALP levels, sometimes with normal bilirubin) 5, 3

Non-Hepatic Causes of Elevated ALP

• Bone disorders:
  • Paget's disease
  • Bone metastases
  • Fractures
  • High bone turnover in postmenopausal women 2, 6
• Physiologic causes:
  • Childhood (due to bone growth)
  • Pregnancy (placental production) 2
• Rare causes:
  • Benign familial hyperphosphatasemia 7

Diagnostic Approach for Elevated ALP

1. Confirm elevated ALP and measure GGT to determine likely source 1
2. For suspected hepatic origin:
   • Review patient history and medications
   • Check other liver function tests (bilirubin, transaminases)
   • Perform abdominal ultrasound as first-line imaging 8, 2
   • If ultrasound is negative but ALP remains elevated, consider MRI with MRCP 8
3. For suspected bone origin:
   • Consider bone-specific alkaline phosphatase (B-ALP) measurement
   • Evaluate for bone disorders, metastases, or high bone turnover 2

Clinical Significance of ALP Elevation Level

• Extremely high ALP levels (>1000 IU/L) are most commonly associated with:
  • Malignant biliary obstruction
  • Infiltrative liver disease
  • Sepsis
  • Metastatic disease 5, 4, 3
• Moderately elevated ALP in postmenopausal women is often due to high bone turnover and may normalize with bisphosphonate therapy 6

Important Considerations and Pitfalls

• Don't assume all ALP elevations are liver-related; confirm source with GGT 1
• In patients with isolated elevated ALP of unclear etiology, metastatic malignancy is common (57% in one study) 4
• Extremely high ALP levels warrant thorough investigation, as they are associated with serious conditions and potentially poor prognosis 4
• For patients on home parenteral nutrition, chronic cholestasis with elevated ALP is common (reported in about 50% of patients) and may progress to severe liver disease 8