What is the workup for an adolescent with low alkaline phosphatase (alk phos)?

Workup for Adolescents with Low Alkaline Phosphatase

The primary diagnostic consideration for an adolescent with low alkaline phosphatase is hypophosphatasia, which requires measurement of ALP substrates, genetic testing, and evaluation of bone mineralization.

Initial Diagnostic Approach

• Low alkaline phosphatase (ALP) in adolescents should prompt consideration of hypophosphatasia (HPP), a genetic disorder characterized by dysfunctional tissue-non-specific isoenzyme of ALP that impacts bone metabolism 1
• Confirm persistent low ALP with repeat testing, as transient hypophosphatasemia is common and may not be clinically significant 2
• Interpret ALP levels in the context of age-specific reference ranges, as adolescents typically have higher values due to active bone growth 3

Clinical Evaluation

• Assess for history of:

  • Low-impact fractures or recurrent fractures 1
  • Dental issues including premature loss of teeth or "gray gums" 4
  • Skeletal pain, joint pain, or weakness 5
  • Family history of similar symptoms or confirmed HPP 6

• Physical examination should focus on:

  • Skeletal deformities 6
  • Dental abnormalities 6
  • Growth parameters (height, weight) 6

Laboratory Workup

First-line Tests

• Complete biochemical profile including:
  • Serum calcium, phosphate, and creatinine 6
  • Parathyroid hormone (PTH) 6
  • 25(OH) vitamin D and 1,25(OH)₂ vitamin D levels 6
  • Bone-specific ALP isoenzyme (especially important as total ALP may be normal while bone-specific ALP is low) 4

Second-line Tests (if low ALP is confirmed)

• Measure ALP substrates:

  • Pyridoxal-5'-phosphate (vitamin B6) - typically elevated in HPP 4, 7
  • Urinary phosphoethanolamine - typically elevated in HPP 7, 2
  • Pyrophosphate levels 7

• Calculate tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR) to assess renal phosphate handling 6

• Genetic testing for ALPL gene mutations to confirm diagnosis of HPP 5, 4

  • Over 260 genetic mutations have been associated with HPP 5

Imaging Studies

• Radiographic evaluation of:

  • Long bones to assess for rickets-like changes or osteomalacia 6
  • Spine for evidence of osteopenia or fractures 1
  • Skull if craniosynostosis is suspected 6

• Consider bone density testing (DXA scan) to evaluate bone mineralization 1

Differential Diagnosis

• Rule out other causes of low ALP:
  • Malnutrition or specific vitamin/mineral deficiencies 7
  • Endocrine disorders affecting bone metabolism 7
  • Medication effects, particularly antiresorptive therapies 7
  • X-linked hypophosphatemia (which typically presents with elevated, not low, ALP) 6

Clinical Pearls and Pitfalls

• Pitfall: Normal total ALP does not exclude HPP - bone-specific ALP may be low while total ALP remains within normal range 4
• Pitfall: Adult and adolescent forms of HPP often present with milder manifestations than infantile forms, leading to delayed diagnosis 1, 5
• Pearl: Low ALP is a distinguishing sign of HPP, contrasting with most metabolic bone diseases which present with elevated ALP 5
• Pearl: Even asymptomatic patients with persistently low ALP should be evaluated for HPP, as early detection can prevent complications 2

Follow-up Recommendations

• For confirmed HPP:

  • Regular monitoring of bone health and development 5
  • Dental follow-up for management of dental manifestations 5
  • Genetic counseling for family planning 6
  • Consider referral to specialists in metabolic bone disease 2

• For patients with transient or unexplained low ALP:

  • Periodic reassessment of ALP levels 2
  • Monitor for development of clinical symptoms 2