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

Causes of Decreased Alkaline Phosphatase (ALP) Levels

Decreased alkaline phosphatase levels are most commonly associated with hypophosphatasia, a rare genetic disorder caused by mutations in the ALPL gene, but can also occur in various acquired conditions including malnutrition, vitamin deficiencies, and certain medications. 1

Primary Causes of Low ALP

Genetic Causes

• Hypophosphatasia (HPP): The most common genetic cause of low ALP
  • Results from pathogenic variants in the ALPL gene encoding tissue non-specific ALP 1
  • Prevalence: Found in approximately 0.3% of osteoporosis clinic patients and 3% of patients with at least one low ALP measurement 2
  • Clinical presentation varies widely:
    • Severe pediatric-onset cases with bone hypomineralization
    • Adult forms with milder manifestations including:
      • Skeletal pain
      • Chondrocalcinosis
      • Calcific periarthritis
      • Dental problems (loose teeth, "gray gums")
      • Stress fractures 1, 3

Acquired Causes

• Nutritional and Metabolic Factors:

  • Malnutrition
  • Vitamin and mineral deficiencies
  • Zinc deficiency
  • Magnesium deficiency

• Endocrine Disorders:

  • Hypothyroidism
  • Hypoparathyroidism

• Medications:

  • Antiresorptive therapies
  • Certain chemotherapeutic agents
  • High-dose vitamin D

• Other Medical Conditions:

  • Chronic liver disease (found in 0.25% of CLD patients) 4
  • Severe acute injuries and diseases (transient decrease)
  • Wilson's disease

Diagnostic Approach to Low ALP

Laboratory Evaluation

1. Confirm persistently low ALP levels (< 40 IU/L)

   • Distinguish between transient, intermittent, and persistent low ALP 4

2. Measure bone-specific ALP

   • May be low even when total ALP is normal 5
   • Critical for diagnosis in cases with normal total ALP

3. Test for ALP substrates

   • Pyrophosphate
   • Pyridoxal phosphate (vitamin B6) - often elevated in HPP
   • Phosphoethanolamine 1

4. Additional laboratory tests

   • Calcium and phosphate levels
   • Vitamin D status
   • Liver function tests
   • Parathyroid hormone (PTH)

Genetic Testing

• ALPL gene sequencing for suspected hypophosphatasia
  • Identification of pathogenic variants confirms diagnosis
  • Note: Some patients with clinical HPP may have normal results after exon sequencing 1

Clinical Evaluation

• Bone health assessment:

  • Bone mineral density testing
  • Evaluation for fractures (especially stress and atypical fractures)

• Dental examination:

  • Assessment for premature tooth loss
  • Dental abnormalities

Clinical Significance and Management

Importance of Recognition

• Low ALP in chronic liver disease patients is associated with less biochemical evidence of active disease 4
• Misdiagnosis of HPP as osteoporosis can lead to inappropriate treatment with antiresorptives, which are contraindicated in HPP 2

Management Considerations

• For hypophosphatasia:

  • Enzyme replacement therapy (asfotase alfa) for severe forms 3
  • Multidisciplinary care including:
    • Nutritional support
    • Calcium and phosphate intake adjustment
    • Vitamin D monitoring
    • Personalized physical therapy
    • Regular dental care 3

• For acquired causes:

  • Address underlying condition (nutritional deficiencies, medication effects)
  • Monitor for complications, particularly fracture risk

Pitfalls and Caveats

• Low ALP is often overlooked in clinical practice
• Normal total ALP does not rule out hypophosphatasia - bone-specific ALP may still be low 5
• Persistently low ALP in osteoporosis patients should raise suspicion for HPP, which requires different treatment approaches 2
• Genetic testing may not identify all cases of HPP, as mutations may exist in regulatory regions or other genes 1