What is the additional workup for a patient with low alkaline phosphatase (ALP) levels?

Workup for Low Alkaline Phosphatase Levels

Low alkaline phosphatase (ALP) levels should be thoroughly evaluated for hypophosphatasia (HPP), the most common genetic cause of persistently low ALP, as this condition can be misdiagnosed as other disorders and may be worsened by certain treatments like antiresorptive therapy. 1

Initial Evaluation

• Confirm persistent low ALP:

  • Repeat ALP measurement to confirm persistently low levels
  • Check bone-specific ALP isoenzyme (may be low even when total ALP appears normal) 2

• Laboratory studies:

  • Measure ALP substrates:
    • Pyridoxal 5'-phosphate (vitamin B6) - typically elevated in HPP 2, 3
    • Pyrophosphate
    • Phosphoethanolamine in urine or serum
  • Calcium and phosphate levels
  • Parathyroid hormone (PTH)
  • 25(OH) vitamin D levels
  • Liver function tests (to rule out liver disease)
  • Check for zinc and magnesium deficiency (can cause low ALP)

Imaging Studies

• Skeletal radiographs to evaluate for:

  • Stress fractures
  • Pseudofractures
  • Chondrocalcinosis
  • Calcific periarthritis
  • Premature fusion of cranial sutures (in pediatric cases)

• Bone density scan (DXA) to assess for osteopenia/osteoporosis

Genetic Testing

• ALPL gene sequencing to identify pathogenic variants associated with HPP 1
  • Note that some patients with clinical HPP may have normal results after exon sequencing, suggesting mutations in regulatory regions or other genes 1

Clinical Assessment

• Detailed history focusing on:

  • Skeletal pain and weakness
  • History of fractures, especially stress fractures or atypical femoral fractures
  • Dental problems (early tooth loss, "gray gums") 2
  • Joint pain and arthritis
  • Family history of similar symptoms

• Physical examination focusing on:

  • Musculoskeletal system
  • Dental status
  • Neurological assessment

Differential Diagnosis

Low ALP can be seen in:

1. Genetic causes:

   • Hypophosphatasia (most common genetic cause)
   • Wilson's disease

2. Acquired causes:

   • Malnutrition
   • Vitamin and mineral deficiencies (zinc, magnesium)
   • Endocrine disorders (hypothyroidism, hypoparathyroidism)
   • Severe acute illness
   • Medication effects (antiresorptives, glucocorticoids)

Special Considerations

• Low ALP is often not flagged by laboratories as abnormal, leading to missed diagnoses 4
• Consider HPP in patients diagnosed with fibromyalgia who have low ALP levels (9.3% of fibromyalgia patients may have consistently low ALP) 3
• HPP should be considered in osteoporosis clinic patients with low ALP (found in 9% of such patients) 5
• Patients with HPP should avoid antiresorptive therapy as it may worsen their condition and increase risk of atypical femoral fractures 5

Management Implications

• Diagnosis of HPP may lead to enzyme replacement therapy with asfotase alfa 2
• Proper diagnosis prevents inappropriate treatment with antiresorptives, which are contraindicated in HPP 5
• Genetic counseling should be offered to affected individuals and families

Early diagnosis is crucial as treatment options are now available for HPP, and avoiding inappropriate treatments can prevent complications.