Can Hypophosphatasia Be Diagnosed with Normal B6 Levels?
Yes, hypophosphatasia can be diagnosed even when pyridoxal-5'-phosphate (vitamin B6) levels are normal, because up to 33% of patients with confirmed ALPL gene mutations have baseline PLP levels within the normal range. 1
Why Normal B6 Levels Don't Exclude Hypophosphatasia
The elevation of PLP in hypophosphatasia requires adequate vitamin B6 intake and stores. When a patient is vitamin B6 deficient, PLP levels can remain normal despite having hypophosphatasia, as demonstrated in a case of life-threatening perinatal hypophosphatasia where the exclusively breast-fed infant had normal plasma PLP levels due to concurrent B6 deficiency. 2 Once B6 supplementation was provided, the biochemical picture became more typical. 2
This finding is critical because:
- Elevated PLP levels in hypophosphatasia depend on B6 sufficiency—hypovitaminosis B6 can completely negate the expected PLP elevation. 2
- Even among mutation carriers with low serum alkaline phosphatase, baseline PLP levels fall within the normal range in approximately one-third of cases. 1
Diagnostic Approach When Suspecting Hypophosphatasia
Primary Diagnostic Markers
- Low serum alkaline phosphatase is the biochemical hallmark of hypophosphatasia and remains the primary screening test. 3, 4
- When total ALP appears normal, measure bone-specific ALP, as it can be low even when total ALP is within normal limits. 4 A case report documented hypophosphatasia confirmed by genetic testing in a patient with normal total ALP but low bone-specific ALP (4.4 μg/L; reference 5.3-19.5 μg/L). 4
Clinical Features to Assess
- Dental history is particularly revealing: premature loss of primary teeth, "gray gums," dental abscesses, or periodontal disease strongly suggest hypophosphatasia. 3
- Document history of fractures, chronic pain, fatigue, weakness, and joint pain—symptoms that can mimic fibromyalgia. 4, 5
- Assess growth patterns and any skeletal deformities. 3
Laboratory Workup
- Measure serum phosphate, calcium, and parathyroid hormone to distinguish hypophosphatasia from other metabolic bone diseases. 3
- Check 25-hydroxyvitamin D to exclude vitamin D deficiency. 3
- If PLP is normal but clinical suspicion remains high, consider a 2-day vitamin B6 challenge test (20 mg/day pyridoxine hydrochloride): after supplementation, all ALPL mutation carriers had PLP levels above 500 nmol/L (sensitivity 100%, specificity 96%). 1
Definitive Diagnosis
- Genetic testing for ALPL gene mutations is the gold standard for confirming hypophosphatasia. 3, 4 This is essential when bone-specific ALP is low or when clinical features are suggestive, regardless of PLP levels. 4
Critical Pitfalls to Avoid
- Do not rely solely on PLP levels to rule out hypophosphatasia—normal levels occur in one-third of mutation carriers and in all B6-deficient patients. 1, 2
- Do not assume normal total ALP excludes the diagnosis; always check bone-specific ALP when clinical suspicion exists. 4
- Avoid prescribing bisphosphonates in patients with hypophosphatasia, as they can cause atypical femur fractures. 3
- In patients with fibromyalgia and consistently low ALP (found in 9.3% of one cohort), screen for hypophosphatasia given the availability of enzyme replacement therapy. 5
Relationship Between ALP and PLP
- A significant inverse relationship exists between ALP and PLP levels: log PLP = 5.99 - 2.76 log ALP (r = -0.85, P < 0.001). 6
- PLP levels correlate with disease severity in hypophosphatasia. 6
- When interpreting PLP levels in any clinical context, always consider the prevailing serum ALP levels, as the metabolism of these compounds is closely interrelated. 6