What causes elevated alkaline phosphatase (alk phos) levels?

Causes of Elevated Alkaline Phosphatase (ALP)

Elevated alkaline phosphatase most commonly results from liver disorders (especially cholestatic conditions), bone disease, or malignancy, with sepsis and infiltrative diseases also being significant causes. 1, 2

Primary Causes by Organ System

Hepatobiliary Causes

• Cholestatic disorders:

  • Biliary obstruction (malignant or benign) 2
  • Primary biliary cholangitis (PBC) 3
  • Primary sclerosing cholangitis (PSC) 3, 1
  • Drug-induced cholestasis 2

• Infiltrative liver diseases:

  • Liver metastases (most common malignant cause) 2
  • Non-malignant infiltrative conditions (e.g., sarcoidosis) 2
  • Hepatic hemangiomas 4

• Other liver conditions:

  • Alcoholic liver disease (may show elevated ALP with AST/ALT ratio >2) 1
  • Parenchymal liver disease 2

Bone Causes

• Metastatic bone disease 2
• Paget's disease 4
• Rickets (with low phosphate, elevated PTH, low vitamin D) 1
• Primary bone disorders 5

Infectious/Inflammatory Causes

• Sepsis (can present with extremely high ALP even with normal bilirubin) 4
• AIDS-related conditions:
  • Mycobacterium avium intracellulare (MAI) infection
  • Cytomegalovirus infection 4

Other Causes

• Physiologic:
  • Pregnancy 5
  • Growth (in children and young adults) 5
  • High-fat diet 5
• Drug-induced:
  • Anticonvulsants 5
  • Glucocorticoids 5
• Rare genetic conditions:
  • Benign familial hyperphosphatasemia 6

Diagnostic Approach

Step 1: Determine if ALP is of Hepatic Origin

• Check concurrent GGT elevation (confirms hepatic source) 1
• Calculate R value: [(ALT/ULN)/(ALP/ULN)]
  • R ≥5: Hepatocellular pattern
  • R ≤2: Cholestatic pattern
  • R >2 and <5: Mixed pattern 1

Step 2: Evaluate for Liver Disease

• For cholestatic pattern:
  • Abdominal ultrasound (first-line imaging) 1
  • Consider MRCP for biliary tract evaluation, especially for PSC 1
  • Consider liver biopsy in PBC patients with persistent transaminases >100 U/L to evaluate for overlap syndrome 3

Step 3: Evaluate for Bone Disease

• If hepatic origin is not confirmed, consider:
  • Bone-specific ALP testing
  • Appropriate imaging studies for suspected bone pathology

Step 4: Consider Rare and Systemic Causes

• Evaluate for sepsis, especially with extremely high ALP levels 4
• Consider malignancy workup (most common cause of isolated elevated ALP of unclear etiology) 2
• Check for medication effects

Important Clinical Pearls

1. Extremely high ALP levels (>1000 U/L) are most commonly associated with:

   • Sepsis (can occur with normal bilirubin)
   • Malignant biliary obstruction
   • AIDS-related conditions 4

2. Isolated elevated ALP of unclear etiology:

   • 57% due to malignancy (hepatic, bone, or both)
   • 29% due to bone disease
   • Associated with poor prognosis (47% mortality within ~5 years) 2

3. Overlap syndromes should be considered when:

   • ALP remains elevated in autoimmune hepatitis
   • Transaminases persistently exceed 100 U/L in PBC 3

4. Diagnostic pitfalls:

   • Liver disease can mask hypophosphatasemia (normally characterized by low ALP) 7
   • Normal AST/ALT does not exclude significant liver disease 1
   • Isolated GGT elevation is a poor indicator of liver injury 1

5. Management considerations:

   • Disease-specific treatments (e.g., ursodeoxycholic acid for PBC and PSC)
   • For alcoholic liver disease: abstinence and nutritional support
   • Referral to specialists if GGT remains >3× ULN despite lifestyle modifications 1