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

Causes of Elevated Alkaline Phosphatase (ALP)

Elevated alkaline phosphatase levels are most commonly associated with cholestatic liver disease, bone disorders, or malignancy, requiring systematic evaluation to determine the underlying cause. 1

Hepatic Causes

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

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

• Extrahepatic biliary obstruction causes include:

  • Choledocholithiasis (gallstones)
  • Malignant obstruction (particularly cholangiocarcinoma)
  • Biliary strictures
  • Infections 2, 1

• Infiltrative liver diseases can lead to ALP elevation:

  • Amyloidosis
  • Hepatic metastases
  • Sarcoidosis 2, 3

• Other hepatic conditions associated with ALP elevation:

  • Cirrhosis
  • Chronic hepatitis
  • Viral hepatitis
  • Congestive heart failure 2, 1

Non-Hepatic Causes

• Bone disorders are significant sources of ALP elevation:

  • Paget's disease
  • Bony metastases
  • Fractures
  • High bone turnover in postmenopausal women 2, 1

• Infectious causes, particularly:

  • Sepsis (can cause extremely high ALP levels, sometimes with normal bilirubin)
  • Mycobacterium avium intracellulare infection
  • Cytomegalovirus infection 4, 5

• Physiologic causes:

  • Childhood (due to bone growth)
  • Pregnancy (due to placental production) 2, 6

• Other causes:

  • Malignancies (both with hepatic and bone involvement)
  • Parenteral nutrition (reported in up to 65% of home parenteral nutrition patients)
  • Benign familial hyperphosphatasemia (genetic condition) 3, 7

Diagnostic Approach

• Determine the source of elevated ALP:

  • Measure gamma-glutamyl transferase (GGT) - elevated GGT confirms hepatic origin, normal GGT suggests bone origin 1
  • Consider ALP isoenzyme fractionation to differentiate between liver, bone, and intestinal isoenzymes 1
  • Measure 5'-nucleotidase - elevations generally signal hepatobiliary disease 1

• For suspected hepatic origin:

  • Review patient history and medications
  • Check other liver function tests (bilirubin, transaminases)
  • Perform abdominal ultrasound as first-line imaging
  • If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP 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

Clinical Significance

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

  • Sepsis
  • Malignant biliary obstruction
  • Infiltrative liver disease
  • AIDS-related conditions 4, 5

• Severity classification of ALP elevation:

  • Mild: less than 5 times the upper limit of normal
  • Moderate: 5-10 times the upper limit of normal
  • Severe: more than 10 times the upper limit of normal 2

• Prognostic implications: An isolated, elevated ALP of unclear etiology is associated with poor prognosis, with studies showing 47% mortality within an average of 58 months after identification 3

Common Pitfalls to Avoid

• Assuming all ALP elevations are liver-related without confirming the source with GGT 1
• Overlooking malignancy as a cause, particularly metastatic disease 3
• Neglecting bone sources of ALP elevation 1
• Missing cholangiocarcinoma, which is a significant cause in certain geographic regions 5
• Failing to recognize benign familial hyperphosphatasemia, which can lead to unnecessary diagnostic tests 7