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

Causes of Elevated Alkaline Phosphatase (ALP) Levels

Elevated alkaline phosphatase (ALP) levels are most commonly caused by hepatobiliary disorders, bone diseases, and malignancies, with cholestatic liver diseases and bone disorders being the predominant etiologies. 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 1

• Extrahepatic biliary obstruction can lead to significant ALP elevation:

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

• Infiltrative liver diseases commonly cause ALP elevation:

  • Hepatic metastases (most common cause of isolated ALP elevation in one study)
  • Amyloidosis
  • Sarcoidosis 1, 2

• Other hepatic conditions associated with ALP elevation:

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

Bone-Related Causes

• Metabolic bone disorders:

  • Paget's disease of bone
  • Osteomalacia (including X-linked hypophosphatemia)
  • Rickets 3, 1

• Malignant bone involvement:

  • Bony metastases (second most common cause of isolated ALP elevation)
  • Primary bone tumors 1, 2

• Other bone conditions:

  • Fractures (healing process)
  • Hyperparathyroidism 1

Physiologic and Other Causes

• Normal physiologic states:

  • Childhood and adolescence (due to bone growth)
  • Pregnancy (placental production) 1

• Systemic conditions:

  • Sepsis (can cause extremely high ALP levels, sometimes with normal bilirubin) 4, 5
  • AIDS and associated opportunistic infections 4

• Rare causes:

  • Benign familial hyperphosphatasemia (genetic condition) 6
  • Drug toxicity (e.g., Dilantin) 4
  • Parenteral nutrition (reported in up to 65% of home parenteral nutrition patients) 1

Diagnostic Approach to Elevated ALP

• Source determination:

  • 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 medication history for potential drug-induced causes
  • Abdominal ultrasound as first-line imaging
  • If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP 1

• Severity classification to guide diagnostic approach:

  • Mild: <5 times upper limit of normal
  • Moderate: 5-10 times upper limit of normal
  • Severe: >10 times upper limit of normal 1

Clinical Significance and Prognosis

• Isolated elevated ALP of unclear etiology is frequently associated with underlying malignancy (57% in one study) 2
• An ALP level >160 U/L was found to be 12 times more likely to be associated with liver metastases in colorectal cancer patients 7
• In one study, 47% of patients with isolated elevated ALP of unclear etiology died within an average of 58 months, highlighting its potential prognostic significance 2

Important Considerations

• X-linked hypophosphatemia presents with increased ALP levels along with hypophosphatemia and renal phosphate wasting 3
• ALP levels are physiologically higher in children due to bone growth 3, 1
• Treatments like bisphosphonates can alter ALP levels despite underlying pathology 1
• In patients with extremely high ALP (>1000 IU/L), common causes include sepsis, malignant biliary obstruction, and infiltrative diseases 4, 5