What does an elevated alkaline phosphatase (ALP) level indicate?

Elevated Alkaline Phosphatase: Clinical Significance and Diagnostic Approach

An elevated alkaline phosphatase (ALP) primarily indicates cholestatic liver disease, bone disorders, or malignancy, with the specific source requiring further diagnostic evaluation to determine appropriate management and assess potential impact on mortality and quality of life. 1

Sources of Elevated ALP

ALP is produced in multiple tissues, with key sources being:

• Liver: Present in the canalicular membrane of hepatocytes and biliary epithelium 1
• Bone: Associated with osteoblastic activity 1, 2
• Other tissues: Intestines, kidneys, placenta, and white blood cells (in smaller amounts) 1

Determining the Source of Elevated ALP

Step 1: Assess for Physiologic Elevations

• Growth-related: Higher in childhood due to bone growth 1
• Pregnancy: Due to placental production 1
• Elderly patients: May have higher bone turnover, especially postmenopausal women 2

Step 2: Measure Gamma-Glutamyl Transferase (GGT)

• GGT is found in liver, kidneys, intestine, prostate, and pancreas, but NOT in bone 1
• Concomitantly elevated GGT confirms liver as the source of elevated ALP 1
• If GGT is normal with elevated ALP, consider bone source 1

Step 3: Consider Additional Testing Based on Clinical Suspicion

• For suspected liver source:

  • Liver imaging (ultrasound as first-line) 1
  • Other liver function tests (bilirubin, transaminases)

• For suspected bone source:

  • Bone-specific alkaline phosphatase (BAP) 2
  • Bone imaging if clinically indicated

• For unclear source:

  • ALP isoenzyme fractionation can identify liver, bone, or intestinal origin 1, 3
  • 5'-nucleotidase levels (elevated in hepatobiliary disease) 1

Common Causes of Elevated ALP

Hepatobiliary Causes 1

• Extrahepatic biliary obstruction:

  • Choledocholithiasis (most common)
  • Malignant obstruction
  • Biliary strictures
  • Infections (AIDS cholangiopathy, liver flukes)

• Intrahepatic cholestasis:

  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
  • Drug-induced cholestasis
  • Infiltrative liver diseases (sarcoidosis, amyloidosis, hepatic metastases)

• Other liver conditions:

  • Cirrhosis
  • Chronic hepatitis
  • Viral hepatitis
  • Congestive heart failure (hepatic congestion)
  • Ischemic cholangiopathy

Bone Causes 1, 4, 2

• Paget's disease
• Bony metastases
• Fractures
• High bone turnover (especially in postmenopausal women)

Other Causes

• Malignancy: Most common cause of isolated, elevated ALP of unclear etiology (57%) 5

  • Infiltrative intrahepatic malignancy
  • Bony metastasis
  • Combined hepatic and bone metastases

• Sepsis: Can cause extremely high ALP levels, sometimes with normal bilirubin 6

• Rare causes:

  • Benign familial hyperphosphatasemia (genetic condition) 3
  • Drug-induced (glucocorticoids, anticonvulsants) 7

Clinical Significance and Prognosis

• An isolated elevated ALP of unclear etiology may be associated with poor prognosis, with 47% mortality within an average of 58 months in one study 5

• In patients on home parenteral nutrition, mild increases in ALP often indicate cholestasis and are reported in about 50% of patients 1

• In postmenopausal women, elevated ALP is often due to high bone turnover and responds to bisphosphonate therapy 2

Key Pitfalls to Avoid

1. Assuming all ALP elevations are liver-related: Always confirm the source using GGT or isoenzyme testing 1

2. Missing malignancy: In patients with isolated elevated ALP of unclear etiology, consider metastatic disease as a common cause 5

3. Overlooking drug effects: Many medications can cause elevated ALP, including glucocorticoids and anticonvulsants 7

4. Ignoring physiologic causes: Remember that pregnancy, childhood growth, and aging can all cause elevated ALP 1, 2

5. Failing to monitor: In chronic conditions like home parenteral nutrition, regular monitoring of ALP is essential to detect progression to severe liver disease 1