What is alkaline phosphatase?

Alkaline Phosphatase (ALP): Clinical Significance and Interpretation

Alkaline phosphatase (ALP) is an enzyme found throughout the body, primarily concentrated in the liver, bones, intestines, and placenta, that plays a fundamental role in skeletal mineralization and serves as an important biomarker for various diseases affecting these tissues. 1

Types and Distribution

• Tissue-nonspecific alkaline phosphatase (TNALP): The predominant form expressed in:

  • Bone (bone-specific ALP or BALP)
  • Liver
  • Kidney

• Tissue-specific isoenzymes:

  • Intestinal
  • Placental

Clinical Significance

Bone Disorders

• Elevated BALP can help diagnose:

  • Metabolic bone diseases
  • Paget's disease
  • Osteomalacia
  • Bone metastases
  • Fracture healing

• High levels of bone-specific alkaline phosphatase can help diagnose osteomalacia in the setting of vitamin D deficiency, hypocalcemia, or hypophosphatemia 2

Liver and Biliary Disorders

• Cholestatic pattern: ALP elevation ≥2 times upper limit of normal (ULN), particularly when accompanied by elevated gamma-glutamyl transpeptidase (GGT) 2
• Used in calculating the R value to determine pattern of liver injury:
  • Hepatocellular pattern: R ≥5
  • Cholestatic pattern: R ≤2
  • Mixed pattern: R >2 and <5

Diagnostic Criteria for Liver Injury

According to EASL guidelines, liver injury can be defined by any of the following 2:

1. ALT level ≥5× ULN
2. ALP level ≥2× ULN (particularly with elevated GGT in the absence of bone disease)
3. ALT level ≥3× ULN with simultaneous total bilirubin level >2× ULN

Interpretation of Elevated ALP

Step 1: Confirm Source of Elevation

• Fractionation of ALP or measurement of other markers can help determine the source:
  • Liver origin: Elevated GGT
  • Bone origin: Normal GGT, elevated bone-specific ALP

Step 2: Evaluate Based on Pattern and Clinical Context

Liver/Biliary Origin

• Mild elevations (<2× ULN): May not warrant extensive workup 3
• Significant elevations (≥2× ULN): Warrant further evaluation 3
• Consider imaging:
  • Abdominal ultrasound as first-line imaging for biliary obstruction 3
  • MRCP for detailed biliary tract evaluation, especially for PSC diagnosis 3

Bone Origin

• Consider metabolic bone disorders, especially with:
  • Low serum phosphate
  • Elevated PTH
  • Low 25(OH) vitamin D
  • Radiographic signs of bone disease 3

Prognostic Value

• In chronic kidney disease (CKD), ALP is associated with:

  • Vascular calcification
  • Cardiovascular disease
  • Increased mortality risk 4
  • Target value below 120 U/L is associated with improved survival 4

• In patients on dialysis, elevated ALP is associated with increased fracture risk 2

Special Considerations

Physiologic Elevations

• Young growing individuals
• Pregnancy and lactation
• High-fat diets 5

Drug-Induced Elevations

• Glucocorticoids
• Anticonvulsants
• Various medications with hepatotoxic potential 5

Monitoring

• For drug-induced liver injury: Monitor liver tests at least weekly initially, then every 2-4 weeks 3
• For chronic conditions: Repeat liver enzymes every 3-6 months 3

When to Refer to a Specialist

Consider referral to hepatology if:

• ALP remains elevated >3× ULN despite lifestyle modifications
• Evidence of advanced fibrosis
• Presence of other significant liver abnormalities
• Suspected autoimmune or biliary tract disease 3

Pitfalls to Avoid

1. Isolated interpretation: Always interpret ALP in context with other liver enzymes and clinical findings
2. Ignoring bone sources: Elevated ALP without GGT elevation may indicate bone disease
3. Over-investigation: Mild elevations in ALP alone do not warrant extensive workup 3
4. Using ALP alone for diagnosis: In Charcot neuro-osteoarthropathy, ALP has insufficient accuracy for diagnosis or exclusion 2

Alkaline phosphatase remains one of the most frequently assayed enzymes in medicine 6, serving as a valuable biomarker for both skeletal and hepatobiliary diseases when interpreted in the appropriate clinical context.