What are the causes of chronic alkaline phosphatase (ALP) elevation?

Causes of Chronic Alkaline Phosphatase (ALP) Elevation

Chronic ALP elevation is most commonly caused by cholestatic liver disease, bone disorders, or malignancy, with the specific source requiring differentiation through additional testing such as gamma-glutamyl transferase (GGT) measurement. 1

Hepatic Causes of Elevated ALP

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

  • Primary biliary cholangitis 1
  • Primary sclerosing cholangitis 1
  • Drug-induced cholestasis 1
  • Partial bile duct obstruction 1

• Extrahepatic biliary obstruction causes include:

  • Choledocholithiasis (most common cause of extrahepatic biliary obstruction) 1
  • Malignant obstruction 1, 2
  • Biliary strictures 1
  • Infections (e.g., AIDS cholangiopathy, liver flukes) 1

• Infiltrative liver diseases that can cause chronic ALP elevation:

  • Sarcoidosis 1, 2
  • Amyloidosis 1
  • Hepatic metastases 1, 3
  • Lead toxicity 2

• Other hepatic conditions associated with ALP elevation:

  • Cirrhosis 1
  • Chronic hepatitis 1
  • Viral hepatitis 1
  • Congestive heart failure (hepatic congestion) 1
  • Ischemic cholangiopathy 1

Non-Hepatic Causes of Elevated ALP

• Bone disorders are significant sources of ALP elevation:

  • Paget's disease 1
  • Bony metastases 1, 3
  • Fractures 1
  • High bone turnover in postmenopausal women 4
  • Osteoporosis with high bone turnover 4, 5

• Malignancy-related causes:

  • Infiltrative intrahepatic malignancy 3
  • Bony metastases 3
  • Combined hepatic and bone metastases 3

• Infectious causes:

  • Sepsis (can present with extremely high ALP and normal bilirubin) 2
  • Mycobacterium avium intracellulare (MAI) infection 2
  • Cytomegalovirus infection 2

• Physiologic causes:

  • Childhood (associated with bone growth) 1
  • Pregnancy (due to placental production) 1

Diagnostic Approach to Chronic ALP Elevation

• Determine the source of ALP elevation by measuring GGT:

  • Elevated GGT with elevated ALP confirms hepatic origin 1
  • Normal GGT with elevated ALP suggests bone origin 1

• For suspected hepatic origin:

  • Review patient's clinical history and medications 1
  • Consider imaging of the biliary tree to determine etiology 1
  • Abdominal ultrasound is typically the first-line imaging modality 1
  • MRI with MRCP may be useful for persistent elevation with negative ultrasound 1

• For suspected bone origin:

  • Consider bone-specific alkaline phosphatase (B-ALP) measurement 1
  • B-ALP is a sensitive marker for bone turnover and bone metastases 1
  • Consider bone scintigraphy for suspected metastatic disease 1

Clinical Significance and Prognosis

• An isolated, elevated ALP of unclear etiology is associated with several important disorders, particularly metastatic malignancy 3
• In a study of patients with isolated elevated ALP of unclear etiology, 47% died within an average of 58 months after identification 3
• Extremely high elevations of ALP (>1,000 U/L) are most frequently seen in patients with sepsis, malignant obstruction, and AIDS 2

Important Considerations

• ALP levels are physiologically higher in childhood due to bone growth 1
• ALP levels can be elevated in pregnancy due to placental production 1
• When measuring bone turnover markers like ALP, assessments should be performed at the same time of day due to circadian rhythm variations 1
• Treatments like bisphosphonates and denosumab can alter ALP levels despite the presence of underlying pathology 1, 4