What are the causes of elevated Alkaline Phosphatase (ALP) levels?

Causes of Elevated Alkaline Phosphatase (ALP)

Elevated alkaline phosphatase is most commonly caused by cholestatic liver disease, bone disorders, or malignancy, with specific etiologies varying based on the source tissue and degree of elevation. 1, 2

Determining the Source of Elevated ALP

• ALP is primarily produced in the liver and bone, with smaller amounts from intestines, kidneys, white blood cells, and placenta 2
• Measuring gamma-glutamyl transferase (GGT) helps differentiate between hepatic and non-hepatic sources:
  • Elevated GGT with elevated ALP suggests hepatic origin
  • Normal GGT with elevated ALP suggests bone origin 2
• ALP isoenzyme fractionation can further differentiate between liver, bone, and intestinal isoenzymes 2

Hepatic Causes of Elevated ALP

• Cholestatic liver diseases:
  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
  • Drug-induced cholestasis
  • Partial bile duct obstruction 1
• Extrahepatic biliary obstruction:
  • Choledocholithiasis (gallstones)
  • Malignant obstruction (cholangiocarcinoma, pancreatic cancer)
  • Biliary strictures
  • Infections 1, 3
• Infiltrative liver diseases:
  • Amyloidosis
  • Hepatic metastases
  • Sarcoidosis 1, 4
• Other hepatic conditions:
  • Cirrhosis
  • Chronic hepatitis
  • Viral hepatitis
  • Congestive heart failure 1, 2

Non-Hepatic Causes of Elevated ALP

• Bone disorders:
  • Paget's disease
  • Bone metastases
  • Fractures
  • Primary hyperparathyroidism
  • High bone turnover in postmenopausal women 1, 5
• Physiologic causes:
  • Childhood (growth)
  • Pregnancy (placental production) 1
• Other causes:
  • Sepsis (can cause extremely high ALP with normal bilirubin)
  • AIDS-related infections (MAI, CMV)
  • Chronic renal failure 6, 5

Significance of ALP Elevation Magnitude

• Extremely high levels (>1,000 IU/L) are most commonly associated with:
  • Sepsis
  • Malignant biliary obstruction
  • Infiltrative liver disease
  • AIDS-related conditions 6, 3
• Moderate elevations are seen in:
  • Cholestatic liver diseases
  • Bone disorders
  • Parenchymal liver disease 7, 2

Clinical Approach to Elevated ALP

• Review patient history, including age, medications, and symptoms of underlying disease 2
• Check other liver function tests (bilirubin, transaminases) to determine pattern of liver injury 7
• For isolated ALP elevation:
  • Measure GGT to determine source (hepatic vs. non-hepatic)
  • Consider bone-specific alkaline phosphatase (B-ALP) measurement for suspected bone origin 2, 5
• For suspected hepatic origin:
  • Initial imaging with abdominal ultrasound
  • Consider MRI with MRCP for persistent elevation with negative ultrasound 1, 2
• For suspected bone origin:
  • Consider bone scan, vitamin D levels, PTH measurement 5

Important Considerations

• An isolated elevated ALP of unclear etiology is frequently associated with underlying malignancy (57% in one study) 4
• Bone-specific ALP increases linearly with age in both sexes and rises significantly after menopause 5
• Treatment with vitamin D (alphacalcidol) can reduce ALP levels in hyperparathyroidism and even euparathyroid individuals 8
• Treatments like bisphosphonates can alter ALP levels despite underlying pathology 5

Common Pitfalls to Avoid

• Assuming all ALP elevations are liver-related without confirming source with GGT 2
• Overlooking malignancy as a cause, particularly in cases of isolated ALP elevation 4
• Missing cholangiocarcinoma, which can present with ALP elevation in endemic areas 3
• Failing to recognize that sepsis can cause extremely high ALP levels with normal bilirubin 6