What does it mean to have low alkaline phosphatase levels?

Low Alkaline Phosphatase: Diagnosis and Clinical Significance

Low alkaline phosphatase levels (32-34 IU/L) may indicate hypophosphatasia or be a diagnostic clue for Wilson disease, and warrant further investigation to determine the underlying cause.

Causes of Low Alkaline Phosphatase

Primary Genetic Causes

• Hypophosphatasia: The most common genetic cause, resulting from mutations in the ALPL gene that encodes tissue non-specific alkaline phosphatase 1
  • Affects approximately 3% of patients with low ALP in osteoporosis clinics 2
  • 50% of adults with unexplained low ALP have ALPL gene mutations 3

Secondary Causes

• Wilson disease: Low ALP is a characteristic finding in Wilson disease with acute liver failure, especially when the ratio of alkaline phosphatase (IU/L) to total bilirubin (mg/dL) is less than 2 4
• Other causes:
  • Malnutrition
  • Vitamin and mineral deficiencies
  • Endocrine disorders
  • Medication effects (including antiresorptives)
  • Severe acute illnesses 1
  • Blood transfusions and chemotherapy 5

Clinical Evaluation

History and Physical Examination

• Assess for:
  • Musculoskeletal pain
  • Dental problems (tooth loss occurs in 48% of those with ALPL mutations vs 12% without) 3
  • Stress fractures or atypical femoral fractures
  • Chondrocalcinosis
  • Calcific periarthritis
  • Liver disease symptoms (if Wilson disease is suspected)
  • Medication history (particularly antiresorptives)

Laboratory Workup

• Initial tests:

  • Confirm persistently low ALP with repeat testing
  • Serum calcium and phosphate (hyperphosphatemia may be present) 3
  • Liver function tests
  • Vitamin D levels

• Specialized tests if persistently low ALP is confirmed:

  • ALP substrate levels:
    • Pyridoxal phosphate (PLP)
    • Pyrophosphate
    • Phosphoethanolamine (PEA) 1
  • Elevated substrate levels strongly suggest enzyme deficiency

• Genetic testing:

  • ALPL gene sequencing if hypophosphatasia is suspected 1
  • ATP7B gene testing if Wilson disease is suspected 4

Clinical Implications

For Hypophosphatasia

• Avoid bisphosphonates and other antiresorptive therapies as they may worsen bone mineralization defects 2
• Monitor bone health regularly
• Consider alternative osteoporosis treatments if needed

For Wilson Disease

• In acute liver failure with low ALP, the ratio of alkaline phosphatase to total bilirubin < 2 is suggestive of Wilson disease 4
• Requires urgent diagnosis and treatment to prevent progression

Monitoring and Follow-up

• For persistently low ALP:
  • Regular monitoring of bone health
  • Periodic assessment of calcium and phosphate metabolism
  • Follow-up of any symptoms related to potential underlying causes

Important Considerations

• Low ALP alone without clinical manifestations may not require intervention
• The clinical significance of mildly low ALP (as in your case with values of 32-34) may be limited in some individuals 5
• The lower limit of the reference range for ALP may be somewhat arbitrary 5
• However, persistently low values warrant investigation, especially if there are any clinical symptoms or if considering treatments that could affect bone metabolism

When to Refer

• Consider referral to a specialist (endocrinologist, hepatologist, or geneticist) if:
  • ALP remains persistently low
  • There are symptoms suggestive of hypophosphatasia or Wilson disease
  • Genetic testing reveals pathogenic mutations
  • Substrate levels (PLP, PEA) are elevated