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

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) is most commonly associated with malignancy, particularly metastatic disease, biliary obstruction, sepsis, and less commonly with primary parenchymal liver disease. 1

Major Causes of Elevated ALP

Hepatobiliary Causes

• Biliary obstruction
  • Malignant obstruction (e.g., cholangiocarcinoma) 1, 2
  • Benign obstruction (e.g., common bile duct stones) 3
• Infiltrative liver diseases
  • Malignant infiltration (e.g., metastatic cancer) 4
  • Non-malignant infiltration (e.g., sarcoidosis) 3, 4
• Parenchymal liver disease
  • Alcoholic liver disease (AST/ALT ratio >2 suggests this) 1
  • Autoimmune hepatitis 1
  • Primary biliary cholangitis (PBC) 1
  • Primary sclerosing cholangitis (PSC) 1
  • Drug-induced cholestasis 3
  • Toxin exposure (e.g., lead toxicity) 3

Bone-Related Causes

• Malignancy with bone involvement
  • Bony metastases 4
• Metabolic bone diseases
  • Paget's disease 1
  • X-linked hypophosphatemia 1
  • Vitamin D deficiency 1

Infectious Causes

• Sepsis (can present with extremely high ALP and normal bilirubin) 3
  • Gram-negative organisms 3
  • Gram-positive organisms 3
  • Fungal sepsis 3
• AIDS-related infections 3
  • Mycobacterium avium intracellulare (MAI) 3
  • Cytomegalovirus infection 3

Other Causes

• Benign familial hyperphosphatasemia (genetic condition) 5
• Pregnancy (placental source) 5, 6
• Hemangiomas of the liver 3
• Medication-induced (e.g., Dilantin toxicity) 3

Diagnostic Approach

When evaluating elevated ALP, consider:

1. Verify persistent elevation for more than 3-6 months 1
2. Consider age and sex-specific normal ranges (typically 20-200 nmol/L in adults) 1
3. Determine the source of elevated ALP through isoenzyme testing (liver, bone, or other) 1

First-line investigations:

• Complete liver panel (AST, ALT, ALP, bilirubin, albumin, PT) 1
• Calculate AST/ALT ratio (>2 suggests alcoholic liver disease) 1
• GGT (elevated in approximately 75% of habitual drinkers) 1
• Abdominal ultrasound (first-line imaging) 1

Additional tests based on clinical suspicion:

• MRCP for biliary tract evaluation (sensitivity 86%, specificity 94%) 1
• 25-OH vitamin D levels 1
• Hepatitis serology 1
• Autoimmune markers 1

Clinical Pearls and Pitfalls

• Extremely high ALP levels (>1,000 IU/L) are most commonly seen in sepsis, malignant obstruction, and AIDS 3, 2
• Patients with sepsis can have extremely high ALP with normal bilirubin 3
• The most common cause of isolated elevated ALP of unclear etiology is underlying malignancy (57%), particularly metastatic disease 4
• Failure of ALP to normalize within 4-6 weeks of appropriate treatment should prompt reevaluation 1
• Consider referral to hepatology if GGT remains elevated >3x ULN despite interventions 1
• An isolated elevated ALP is uncommonly associated with primary parenchymal liver disease and should raise suspicion for malignancy 4
• Benign familial hyperphosphatasemia is a rare genetic cause of elevated ALP that should be considered when other causes are excluded 5