What causes low alkaline phosphatase levels?

Causes of Low Alkaline Phosphatase

Low serum alkaline phosphatase levels are most commonly caused by hypophosphatasia, Wilson's disease, malnutrition, and certain medications, with hypophosphatasia being the most significant clinical concern requiring diagnosis and management. 1, 2

Primary Causes of Low Alkaline Phosphatase

Genetic Causes

• Hypophosphatasia (HPP)
  • Caused by pathogenic variants in the ALPL gene encoding tissue non-specific alkaline phosphatase
  • Prevalence of approximately 0.3% in osteoporosis clinic patients and 3% in patients with low ALP 1
  • Adult forms present with:
    • Skeletal pain
    • Chondrocalcinosis
    • Calcific periarthritis
    • Dental problems
    • Stress fractures and atypical femoral fractures
  • Diagnosis confirmed by:
    • Persistently low ALP levels
    • Elevated ALP substrates (pyrophosphate, pyridoxal phosphate)
    • ALPL gene analysis

Acquired Causes

• Wilson's disease

  • Particularly in acute presentations with liver failure
  • 8 of 12 patients with Wilson's disease presenting with hemolytic anemia had ALP below normal range 3
  • Characterized by:
    • Markedly subnormal serum alkaline phosphatase (typically 40 IU/L) 4
    • Ratio of alkaline phosphatase to total bilirubin of <2 4
    • Coombs-negative hemolytic anemia
    • Modest elevations in serum aminotransferases

• Nutritional and Metabolic Causes

  • Malnutrition
  • Zinc deficiency (zinc is a cofactor for alkaline phosphatase) 5
  • Vitamin D deficiency 5
  • Magnesium deficiency

• Medication-Related Causes

  • Antiresorptive therapies (bisphosphonates)
  • Certain antibiotics
  • Immunosuppressants

• Other Medical Conditions

  • Severe acute injuries
  • Critical illness
  • Endocrine disorders

Diagnostic Approach for Low Alkaline Phosphatase

1. Confirm persistent low ALP

   • Verify values below age and sex-specific reference ranges
   • Repeat measurement to confirm persistence (≥2 occasions)

2. Evaluate for Wilson's disease if liver disease present

   • Check AST/ALT ratio (>2 suggests alcoholic liver disease)
   • Measure serum copper and ceruloplasmin
   • 24-hour urinary copper excretion
   • Slit-lamp examination for Kayser-Fleischer rings

3. Screen for hypophosphatasia

   • Measure ALP substrates (pyridoxal-5-phosphate, phosphoethanolamine)
   • Consider ALPL gene analysis if clinical suspicion is high
   • Evaluate for fractures, particularly stress fractures or atypical femoral fractures

4. Assess nutritional status

   • Check serum zinc levels (27.2% of HPP patients are zinc deficient) 5
   • Check vitamin D levels (73.5% of HPP patients are vitamin D deficient) 5
   • Evaluate for malnutrition

5. Review medication history

   • Particularly antiresorptive therapies which are contraindicated in HPP

Clinical Implications

• Low ALP in patients with osteoporosis requires careful evaluation as HPP may be misdiagnosed as osteoporosis 1
• Antiresorptive therapy (first-line treatment for osteoporosis) is relatively contraindicated in HPP 1
• In patients with acute liver failure, low ALP combined with a ratio of alkaline phosphatase to total bilirubin of <2 strongly suggests Wilson's disease 4
• Zinc and vitamin D supplementation in deficient HPP patients can safely raise serum levels without exacerbating disease burden 5

Pitfalls and Caveats

• A substantial proportion of patients with clinical features of HPP show normal results after sequencing ALPL exons 2
• Transient low ALP can occur in many severe acute conditions and does not necessarily indicate HPP
• Low ALP in Wilson's disease is much more common in acute presentations with hemolytic anemia than in chronic forms 3
• Not all patients with persistently low ALP have a pathological condition; some may represent the lower end of the normal distribution

By understanding these causes and following a systematic diagnostic approach, clinicians can identify potentially serious underlying conditions in patients with low alkaline phosphatase levels.