What are the causes of elevated alkaline phosphatase (ALP) levels?

Causes of Elevated Alkaline Phosphatase (ALP) Levels

Elevated alkaline phosphatase (ALP) levels are most commonly caused by cholestatic liver diseases, bone disorders, and malignancies, with the specific etiology determining the appropriate diagnostic approach and treatment. 1, 2

Hepatic Causes

• Cholestatic liver diseases are major causes of ALP elevation, including:

  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
  • Drug-induced cholestasis
  • Partial bile duct obstruction 2

• Extrahepatic biliary obstruction can lead to significant ALP elevation:

  • Choledocholithiasis (gallstones)
  • Malignant obstruction (e.g., pancreatic cancer, cholangiocarcinoma)
  • Biliary strictures
  • Biliary infections 2, 1

• Infiltrative liver diseases frequently present with elevated ALP:

  • Hepatic metastases (most common in recent studies)
  • Amyloidosis
  • Sarcoidosis
  • Granulomatous hepatitis 2, 3

• Other hepatic conditions associated with ALP elevation:

  • Cirrhosis
  • Chronic hepatitis
  • Viral hepatitis
  • Congestive heart failure with hepatic congestion 2

Non-Hepatic Causes

• Bone disorders are significant sources of ALP elevation:

  • Paget's disease
  • Bony metastases
  • Fractures
  • High bone turnover in postmenopausal women 2, 4

• Physiologic causes can lead to elevated ALP levels:

  • Childhood (due to bone growth)
  • Pregnancy (placental production)
  • Adolescent growth spurts 2

• Systemic conditions associated with ALP elevation:

  • Sepsis (can cause extremely high ALP levels even with normal bilirubin)
  • AIDS and related infections (MAI, CMV)
  • Hyperthyroidism 5, 6

• Genetic and benign conditions:

  • Benign familial hyperphosphatasemia (rare genetic condition)
  • Transient hyperphosphatasemia of infancy and childhood 7

Clinical Significance of ALP Elevation

• In a recent observational study, the most common cause of isolated ALP elevation was underlying malignancy (57%), with 47% of patients dying within an average of 58 months after identification of elevated ALP 3

• Extremely high ALP levels (>1000 IU/L) are most frequently associated with:

  • Sepsis
  • Malignant biliary obstruction
  • AIDS-related conditions 5, 6

Diagnostic Approach to ALP Elevation

• Determine the source of ALP elevation:

  • Measure gamma-glutamyl transferase (GGT)
    • Elevated GGT suggests hepatic origin
    • Normal GGT suggests bone origin 2

• For suspected hepatic origin:

  • Review patient history and medications
  • Consider imaging of the biliary tree
    • Abdominal ultrasound is typically first-line
    • MRI with MRCP useful for persistent elevation with negative ultrasound 2, 1

• For suspected bone origin:

  • Consider bone-specific alkaline phosphatase (B-ALP) measurement
  • B-ALP is a sensitive marker for bone turnover and bone metastases 2, 4

• For isolated, unexplained ALP elevation:

  • Consider evaluation for occult malignancy, particularly with very high levels
  • Investigate for infiltrative liver disease
  • Rule out sepsis, especially in hospitalized patients 3, 5

Important Clinical Considerations

• ALP elevation pattern can help differentiate causes:

  • Isolated ALP elevation suggests cholestatic disease 1
  • ALP elevation with aminotransferase elevation suggests mixed pattern 1

• In patients receiving immune checkpoint inhibitors, an increase of ALP to ≥2x ULN should trigger evaluation for possible immune-mediated liver injury 1

• Failure of ALP to normalize after addressing the suspected cause should prompt reconsideration of the diagnosis and possibly liver biopsy 1