Low Alkaline Phosphatase in a Young Child
In a young child with low alkaline phosphatase, you must first determine if this is transient or persistent through repeat testing, then systematically evaluate for hypophosphatasia by measuring ALP substrates (pyridoxal-5'-phosphate and phosphoethanolamine) if the low ALP persists. 1
Initial Assessment and Repeat Testing
- Most cases of low ALP in children are transient and resolve on repeat measurement, often associated with acute illnesses like upper respiratory tract infections or anemia 2, 1
- Obtain a repeat ALP measurement after 2-4 weeks to distinguish transient from persistent hypophosphatasemia 1
- If the child has a previous ALP measurement that was normal (>100 U/L), this strongly suggests transient hypophosphatasemia and typically requires no further workup 1
Evaluation for Persistent Low ALP
When ALP remains persistently low on repeat testing, proceed with the following systematic approach:
Comprehensive Metabolic Assessment
- Measure serum calcium, phosphate, creatinine, liver transaminases, and bilirubin to exclude secondary causes 3, 4
- Check PTH and 25(OH) vitamin D levels to rule out metabolic bone disorders 4
- Low ALP with hypercalcemia or hyperphosphatemia may suggest hypophosphatasia 5
ALP Substrate Measurement (Critical Step)
- Measure plasma pyridoxal-5'-phosphate (PLP) and urinary phosphoethanolamine (PEA) in all children with persistent low ALP 2, 1
- Elevated PLP and/or PEA indicate tissue non-specific alkaline phosphatase deficiency and strongly suggest hypophosphatasia 6, 1
- The degree of substrate elevation correlates inversely with ALP levels (r=-0.51 for PLP, r=-0.49 for PEA) 5
Genetic Testing
- Proceed with ALPL gene sequencing if PLP and/or PEA are elevated 2, 1
- Approximately 13.5% of children with persistent hypophosphatasemia and 50% of those requiring substrate measurement will have ALPL mutations 2
- Both heterozygous and homozygous mutations can cause clinically significant disease 2, 5
Clinical Features to Assess
Look specifically for these manifestations of hypophosphatasia:
Skeletal Manifestations
- Bone pain, skeletal deformities, or growth impairment 4, 7
- Rib cage malformations that may cause respiratory insufficiency 7
- Radiographic evidence of rickets or osteomalacia 7
Dental Abnormalities
- Premature tooth loss (particularly primary teeth before age 5) 5, 7
- Dental abscesses or poor dental health 7
Neurological Symptoms
- Seizures (due to elevated pyridoxal-5'-phosphate, which is a vitamin B6 antagonist) 7
- This is a potentially lethal complication requiring urgent recognition 7
Common Pitfalls to Avoid
- Do not dismiss low ALP as physiologic without repeat testing - transient hypophosphatasemia is common but persistent cases require full evaluation 1
- Do not skip substrate measurement (PLP and PEA) even in asymptomatic children with persistent low ALP, as hypophosphatasia can be clinically silent initially 1
- Do not assume normal ALPL gene sequencing excludes hypophosphatasia - mutations in regulatory regions or epigenetic changes may not be detected by standard exon sequencing 6
- Be aware that ALP levels show significant overlap between affected and unaffected individuals, making substrate measurement essential for diagnosis 1
Monitoring if Hypophosphatasia Confirmed
- Measure height, weight, BMI, blood pressure, ALP, calcium, phosphate, creatinine, PTH, and 25(OH) vitamin D every 3-6 months 4
- Assess growth velocity and bone deformities annually 4
- Arrange dental visits twice yearly after tooth eruption 4
- Monitor for respiratory complications in severe cases 7
Treatment Considerations
- Enzyme replacement therapy (asfotase alfa) is available for severe forms of hypophosphatasia with life-threatening complications 7
- Supportive care includes management of pain, orthopedic interventions for deformities, and dental care 7
- Avoid bisphosphonates, as these can worsen hypophosphatasia by further inhibiting bone mineralization 6