What is alkaline phosphatase (ALP)?

Alkaline Phosphatase (ALP)

Alkaline phosphatase (ALP) is an evolutionary conserved enzyme that catalyzes the hydrolysis of phosphate monoesters at basic pH values, serving as an important biomarker for bone and liver disorders, with distinct isoenzymes originating from different tissues including bone, liver, intestine, and placenta. 1, 2

Types and Structure

Alkaline phosphatase exists in four main isozymes based on tissue expression:

• Tissue-nonspecific alkaline phosphatase (TNALP): Found in liver, bone, and kidney
• Intestinal ALP
• Placental ALP
• Germ cell ALP

The TNALP gene is located on chromosome 1, while intestinal and placental ALP genes are on chromosome 2 2.

Physiological Functions

• Bone mineralization: Critical role in skeletal development and bone formation
• Phosphate metabolism: Involved in transport of phosphate in intestinal epithelial cells
• Biomineralization: Essential for proper mineral deposition in bones and teeth
• Vitamin B6 metabolism: Contributes to vitamin B6 (pyridoxal phosphate) metabolism 1, 3

Clinical Significance

Diagnostic Value

ALP is likely the most frequently assayed enzyme in medicine 3. Elevated serum ALP activity serves as a marker for:

1. Bone disorders:

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

2. Liver disorders:

   • Cholestatic liver diseases
   • Biliary obstruction
   • Primary biliary cholangitis (PBC)
   • Primary sclerosing cholangitis (PSC)
   • Drug-induced liver injury

3. Other conditions:

   • Pregnancy (placental origin)
   • Growing children (bone origin)
   • Certain malignancies
   • Kidney disorders in CKD patients 1, 4, 5

Bone-Specific Alkaline Phosphatase (B-ALP)

B-ALP isoforms (B/I, B1, B1x, and B2) serve as specific markers for:

• Bone turnover assessment
• Monitoring metabolic bone diseases
• Predicting fracture risk
• Evaluating response to bone-targeted therapies 6, 4

In cancer patients with bone metastases, B-ALP can predict skeletal-related events (SREs) and overall survival 6.

Diagnostic Approach

When evaluating elevated ALP levels:

1. Determine the source:

   • Check gamma-glutamyl transferase (GGT) to distinguish between bone and liver origin
   • If GGT is normal, bone origin is likely
   • If GGT is elevated, liver origin is likely 1

2. For bone origin elevation:

   • Assess bone turnover markers
   • Check PTH and vitamin D levels
   • Consider phosphate levels (low phosphate with high ALP suggests certain bone disorders) 1

3. For liver origin elevation:

   • Calculate R ratio = (ALT/ULN)/(ALP/ULN) to classify liver injury pattern:
     • R ≥5: Hepatocellular pattern
     • R ≤2: Cholestatic pattern
     • R >2 and <5: Mixed pattern
   • Complete liver panel (AST, ALT, GGT, bilirubin, albumin, PT/INR)
   • Consider imaging (ultrasound, MRCP) 1

Clinical Pearls

• Serial ALP measurements are more valuable than a single reading; obtain two consecutive measurements at least 2 weeks apart
• ALP levels below 120 U/L are associated with improved survival in CKD patients 4
• ALP is membrane-bound and widely distributed in mammalian cells, though its exact physiological function remains incompletely understood 7
• Nonhepatic increases in ALP can occur in young animals, pregnant/lactating females, and with high-fat diets 7
• Certain medications can induce ALP elevation, including glucocorticoids and anticonvulsants 7

Monitoring Recommendations

• Regular monitoring of ALP every 3-6 months is recommended in patients with known liver or bone disorders
• More frequent monitoring is advised for severe elevation or rapid progression 1
• In CKD patients, monitoring ALP alongside other CKD-MBD markers helps guide treatment decisions 4

Treatment Considerations

Treatment depends on the underlying cause:

• Bone-related ALP elevation:

  • Vitamin D supplementation (2,000-4,000 IU daily) for vitamin D deficiency
  • Phosphate supplementation and calcitriol for hypophosphatemic conditions 1

• Liver-related ALP elevation:

  • Discontinue potentially hepatotoxic medications
  • Lifestyle modifications (weight loss, exercise, alcohol cessation)
  • Disease-specific treatments (e.g., ursodeoxycholic acid for PBC and PSC) 1