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

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) is most commonly caused by hepatobiliary disease, bone disorders, or malignancy, with specific etiologies requiring systematic evaluation through laboratory tests and imaging to determine the source. 1

Primary Sources of Elevated ALP

Alkaline phosphatase is a membrane-associated enzyme found in multiple tissues, primarily:

• Liver and biliary tract (hepatobiliary source)
• Bone (osteoblastic activity)
• Intestines
• Placenta
• Kidneys

Diagnostic Classification

Hepatobiliary Causes

• Cholestatic liver disease 2

  • Biliary obstruction (stones, strictures, malignancy)
  • Primary biliary cholangitis (PBC)
  • Primary sclerosing cholangitis (PSC)
  • Drug-induced cholestasis
  • Infiltrative liver diseases

• Hepatocellular diseases (often with concurrent elevation of aminotransferases)

  • Viral hepatitis
  • Alcoholic liver disease
  • Nonalcoholic fatty liver disease (NAFLD)
  • Drug-induced liver injury
  • Autoimmune hepatitis

Bone Causes

• Increased osteoblastic activity
  • Paget's disease
  • Osteomalacia
  • Healing fractures
  • Hyperparathyroidism
  • Bone metastases 2

Malignancy-Related Causes

• Infiltrative intrahepatic malignancy (most common cause of isolated elevated ALP) 3
• Bone metastases (especially from prostate, breast, and lung cancers) 2
• Combined hepatic and bone metastases 3

Infectious Causes

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

Other Causes

• Physiologic

  • Pregnancy (placental production)
  • Growth in children and adolescents

• Rare causes

  • Benign familial hyperphosphatasemia 5
  • Sarcoidosis
  • Lead toxicity
  • Hyperthyroidism
  • Chronic kidney disease

Diagnostic Approach

1. Determine if ALP elevation is isolated or part of a pattern:

   • Isolated ALP elevation suggests cholestatic or bone disease
   • ALP elevation with aminotransferases suggests hepatocellular disease
   • ALP elevation with hyperbilirubinemia suggests biliary obstruction

2. Confirm hepatic origin:

   • Measure gamma-glutamyl transpeptidase (GGT) - elevated GGT confirms hepatic source 1
   • Consider 5'-nucleotidase as another confirmatory test

3. Laboratory evaluation:

   • Complete liver panel (ALT, AST, total and direct bilirubin, albumin, PT/INR)
   • Consider ALP isoenzyme fractionation to determine tissue source
   • Viral hepatitis serologies and autoimmune markers if hepatic origin suspected

4. Imaging studies:

   • Abdominal ultrasound as first-line imaging 1
   • Consider CT or MRI for more detailed assessment
   • Bone scan if bone source suspected

Common Pitfalls and Caveats

• Extremely high ALP levels (>1000 IU/L) are most commonly associated with sepsis, malignant biliary obstruction, and infiltrative liver disease 4
• Isolated elevated ALP of unclear etiology is associated with poor prognosis, with nearly half of patients dying within 5 years in one study 3
• Time of day affects ALP levels - measurements should be performed consistently at the same time of day due to circadian variation 2
• Medications can induce ALP elevation (glucocorticoids, anticonvulsants, antibiotics)
• Bone-specific ALP may be elevated in patients with chronic kidney disease 1
• Pregnancy causes physiologic elevation of ALP, particularly in the third trimester

By systematically evaluating the pattern of ALP elevation and associated findings, clinicians can efficiently determine the underlying cause and direct appropriate management.