What causes elevation of Alkaline Phosphatase (Alk Phos) levels?

Causes of Alkaline Phosphatase (ALP) Elevation

Elevated alkaline phosphatase (ALP) levels are most commonly caused by biliary obstruction, infiltrative liver diseases, bone disorders, sepsis, and malignancies, with the specific etiology requiring systematic evaluation through laboratory and imaging studies. 1

Common Causes of ALP Elevation

Hepatobiliary Causes

• Biliary obstruction:

  • Malignant obstruction (cholangiocarcinoma, pancreatic cancer)
  • Benign obstruction (gallstones, strictures)
  • Primary sclerosing cholangitis (PSC)
  • Primary biliary cholangitis (PBC)

• Infiltrative liver diseases:

  • Metastatic liver disease (most common cause of isolated elevated ALP in adults) 2
  • Hepatic granulomatous diseases (sarcoidosis)
  • Drug-induced cholestasis
  • Non-alcoholic fatty liver disease (NAFLD)
  • Alcoholic liver disease

Bone Disorders

• Paget's disease
• Bone metastases
• Osteomalacia
• Fracture healing
• Hyperparathyroidism
• Rickets (in children)

Infectious Causes

• Sepsis (can cause extremely high ALP even with normal bilirubin) 3
• Mycobacterium avium intracellulare (MAI)
• Cytomegalovirus infection

Other Causes

• Malignancy (both hepatic and bone involvement)
• Pregnancy (placental production)
• Benign familial hyperphosphatasemia (genetic condition) 4
• Transient hyperphosphatasemia of infancy and childhood
• Medication-induced elevations

Diagnostic Approach

Step 1: Confirm Elevation and Pattern

• Determine if ALP elevation is isolated or part of a pattern:
  • Cholestatic pattern: R ≤2 [(ALT/ULN)/(ALP/ULN)] 5
  • Mixed pattern: R >2 and <5
  • Hepatocellular pattern: R ≥5

Step 2: Initial Laboratory Evaluation

• Complete liver panel (AST, ALT, GGT, total/direct bilirubin, albumin, PT/INR)
• Important: Confirm hepatic origin with GGT (elevated in liver disease but not bone disease) 1
• Rule out non-hepatic causes (muscle injury with CK, cardiac troponins if indicated)

Step 3: Targeted Evaluation Based on Clinical Suspicion

• For suspected bone origin:

  • Calcium, phosphate, PTH, 25(OH) vitamin D levels
  • Bone-specific ALP isoenzyme testing
  • Bone imaging if indicated

• For suspected hepatobiliary origin:

  • Abdominal ultrasound (first-line imaging)
  • MRCP for detailed biliary evaluation
  • Viral hepatitis screening
  • Autoimmune markers (ANA, ASMA, immunoglobulins)

• For suspected malignancy:

  • Age-appropriate cancer screening
  • CT scan or MRI for detailed assessment
  • Consider tumor markers based on clinical suspicion

Special Considerations

Extremely High ALP Levels (>1000 IU/L)

Studies have shown that extremely high ALP levels (>1000 IU/L) are most commonly associated with:

• Sepsis (including in patients with normal bilirubin) 3
• Malignant biliary obstruction
• Infiltrative liver disease from metastatic cancer 2
• Bone metastases

Isolated ALP Elevation

When ALP is the only abnormal liver test:

• Metastatic malignancy is the most common cause (57% of cases) 2
• Bone disease accounts for approximately 29% of cases
• Unsuspected parenchymal liver disease accounts for only 7% of cases

Clinical Pitfalls to Avoid

1. Failure to distinguish bone from liver source: Always check GGT when ALP is elevated
2. Missing malignancy: Isolated ALP elevation has high association with malignancy and poor prognosis (47% mortality within 58 months) 2
3. Overlooking sepsis: Can cause extremely high ALP even with normal bilirubin 3
4. Ignoring benign causes: Conditions like benign familial hyperphosphatasemia can cause persistent ALP elevation without pathology 4
5. Incomplete evaluation: Follow a systematic approach rather than focusing on a single suspected diagnosis

Management Approach

1. Determine the source of ALP elevation (liver vs. bone vs. other)
2. Identify the specific underlying cause through targeted testing
3. Treat the underlying condition:
   • Biliary obstruction: Endoscopic or surgical intervention
   • PBC/PSC: Ursodeoxycholic acid
   • Bone disease: Specific treatment based on etiology
   • Sepsis: Appropriate antimicrobial therapy
4. Monitor ALP levels every 3-6 months during treatment 1
5. Consider referral to hepatology if:
   • Persistent unexplained elevation
   • Evidence of advanced fibrosis
   • Suspected autoimmune or biliary tract disease 1