What is the appropriate management for a patient with hypophosphatasia (low alkaline phosphatase level) and hyperpyridoxinemia (elevated plasma vitamin B6)?

Management of Hypophosphatasia with Elevated Plasma Vitamin B6

Diagnosis and Assessment

For patients with low alkaline phosphatase (ALP) levels and elevated plasma vitamin B6 (pyridoxal 5'-phosphate or PLP), enzyme replacement therapy with asfotase alfa is the recommended treatment to address the underlying hypophosphatasia (HPP). This approach directly targets the deficiency in tissue-nonspecific alkaline phosphatase (TNSALP) activity that characterizes HPP.

Key Diagnostic Findings:

• Low alkaline phosphatase (ALP) level
• Elevated plasma vitamin B6 (PLP) level of 75.9
• Pending urine phosphoethanolamine (PEA) test

Confirming the Diagnosis:

• The inverse relationship between ALP and PLP is well-established in HPP, with a significant negative correlation (log PLP = 5.99-2.76 log ALP) 1
• Consider testing bone-specific ALP, which may be low even when total ALP appears normal 2
• Genetic testing for ALPL gene mutations should be performed to confirm the diagnosis

Treatment Approach

First-line Treatment:

1. Enzyme Replacement Therapy (ERT)

   • Asfotase alfa (Strensiq) is the definitive treatment for HPP
   • Dosing should be determined based on disease severity
   • This therapy replaces the deficient TNSALP enzyme, allowing for proper metabolism of PLP to pyridoxal (PL) 3

2. Monitoring Parameters During Treatment:

   • Serum ALP levels
   • Plasma PLP and pyridoxal (PL) levels
   • Urinary calcium:creatinine ratio to monitor for nephrocalcinosis 4
   • Clinical symptoms (bone pain, muscle weakness, dental issues)

Special Considerations:

Vitamin B6 Status:

• Despite elevated PLP levels, patients with HPP may paradoxically experience functional vitamin B6 deficiency because PLP cannot cross the blood-brain barrier without being dephosphorylated to PL 5
• Monitor pyridoxal (PL) levels, which should increase with effective ERT 3
• Assess 4-pyridoxic acid (PA) levels to evaluate vitamin B6 sufficiency 6

Seizure Management:

• In severe cases, particularly in infants, pyridoxine-responsive seizures may occur due to inability to convert PLP to PL 3
• If seizures are present, administer pyridoxine hydrochloride while monitoring with EEG
• Pyridoxine supplementation can be gradually discontinued after ERT is established and PL levels normalize 3

Follow-up and Monitoring

Regular Assessment:

• Monitor ALP, calcium, phosphate, and PTH levels every 6 months 4
• Kidney ultrasonography every 2 years to check for nephrocalcinosis 4
• Dental examinations twice yearly to prevent and treat dental infections 4
• Orthopedic assessment for any musculoskeletal symptoms 4

Potential Complications:

• Secondary hyperparathyroidism may develop and should be managed by:
  • Increasing active vitamin D dosage
  • Adjusting phosphate supplements
  • In severe cases, calcimimetics might be considered 7

Important Considerations

• HPP can be misdiagnosed when only total ALP is measured; bone-specific ALP may be low even with normal total ALP 2
• The relationship between ALP and PLP is inversely proportional - as ALP decreases, PLP increases 1
• Enzyme replacement therapy not only improves bone mineralization but also normalizes vitamin B6 metabolism 3
• Adults with HPP may develop dietary vitamin B6 insufficiency despite elevated PLP levels 5

Remember that HPP is a rare disease with variable presentation, and treatment should be guided by disease severity, with enzyme replacement therapy being the cornerstone of management for symptomatic patients.