What causes elevated alkaline phosphatase (ALP) levels?

Causes of Elevated Alkaline Phosphatase (ALP)

Elevated alkaline phosphatase (ALP) is most commonly caused by cholestatic liver disease, bone disorders, or underlying malignancy, with cholestatic conditions being the primary hepatic cause. 1

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 1

• Extrahepatic biliary obstruction can lead to significant ALP elevation:

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

• Infiltrative liver diseases commonly cause ALP elevation:

  • Hepatic metastases (particularly common in significantly elevated ALP)
  • Amyloidosis
  • Non-malignant infiltrative conditions 1, 3

• Other hepatic conditions:

  • Cirrhosis
  • Chronic hepatitis
  • Viral hepatitis
  • Congestive heart failure with hepatic congestion 1

Non-Hepatic Causes

• Bone disorders are a significant source of ALP elevation:

  • Paget's disease
  • Bony metastases (commonly seen in patients with markedly elevated ALP)
  • Fractures and healing bones
  • Primary bone tumors 1, 3

• Malignancy-related (most common cause of isolated elevated ALP in recent studies):

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

• Physiologic causes:

  • Childhood and adolescence (due to bone growth)
  • Pregnancy (placental production)
  • High-fat diet 1, 4

• Other causes:

  • Sepsis (can cause extremely high ALP even with normal bilirubin)
  • Certain infections (especially in immunocompromised patients)
  • Drug-induced (glucocorticoids, anticonvulsants)
  • Endocrine disorders 4, 5

Diagnostic Approach to ALP Elevation

• Determine source of elevation:

  • Measure gamma-glutamyl transferase (GGT) - elevated GGT suggests hepatic origin, normal GGT suggests bone origin 1
  • Consider bone-specific alkaline phosphatase (B-ALP) measurement for suspected bone origin 1

• For suspected hepatic origin:

  • Review patient history and medications
  • Abdominal ultrasound is typically first-line imaging
  • MRI with MRCP for persistent elevation with negative ultrasound 1

Important Clinical Considerations

• An isolated, elevated ALP of unclear etiology is frequently associated with underlying malignancy (57% in recent studies), particularly metastatic disease 3

• Extremely high ALP levels (>1000 IU/L) are most commonly seen in:

  • Sepsis
  • Malignant biliary obstruction
  • Advanced HIV/AIDS
  • Extensive metastatic disease 5

• ALP can be transiently elevated in patients with liver disease even in conditions that typically cause low ALP (like hypophosphatasia) 6

• Nearly half of patients with isolated elevated ALP of unclear etiology in one study died within an average of 58 months, highlighting its potential prognostic significance 3