MON-746 - Keep It in the Dark: Importance of Proper B6 Tubing for Hypophosphatasia Diagnosis

Introduction
Hypophosphatasia (HPP) is a rare bone disease caused by an ALPL gene mutation leading to defective production of alkaline phosphatase (ALP). ALP is essential for bone mineralization and dephosphorylation of pyridoxal 5’-phosphate (PLP), the active form of vitamin B6. Biochemical markers of HPP are low ALP and high serum PLP as measured by the plasma vitamin B6 level. However, pre-analytical factors can confound PLP to mask the expected findings of HPP with the potential to delay diagnosis.
Case descriptions
Case 1: A 32-year-old female with endometriosis and postural orthostatic tachycardia syndrome (POTS) presented with chronic lower extremity polyarthralgia, lifelong dental issues (fillings in all teeth), brain fog, and significant fatigue. She had chronically low ALP of 23-28 (reference range 35-135 IU/L) and a plasma B6 of 69.9 (reference range 20-125 nmol/L). Given a persistent clinical suspicion for HPP, despite the normal B6, genetic testing was pursued and revealed a heterozygous pathogenic variant in ALPL, confirming HPP and prompting initiation of asfotase alfa.
Case 2: A 66-year-old male with poorly healing metatarsal fracture presented with wrist and elbow arthralgia. He endorsed fatigue, brain fog, anxiety, premature loss of deciduous teeth, and deep bone pain. Adult dental records showed mild to moderate alveolar bone loss. Labs showed chronically low ALP ranging 28-30 IU/L. Initial plasma B6 levels were 130.7 and 86.8 nmol/L. Proper collection technique one month later revealed a true B6 level of 410.4 nmol/L. He was diagnosed with HPP and started on asfotase alfa with symptom improvement.
Discussion
The normal B6 result in both cases was attributed to improper sample handling, as PLP is highly photosensitive and degrades on light exposure. HPP is challenging to recognize with a median diagnostic delay of nearly six years, particularly in milder phenotypes with nonspecific symptoms such as chronic pain, dental abnormalities, and fatigue. Accurate laboratory assessment is critical, yet ALP and PLP can yield misleading results under certain conditions. ALP may rise into normal range in the context of acute fracture, pregnancy, nicotine use, dietary deficiencies, hyperparathyroidism, hyperthyroidism, acromegaly, menopause, malignancy, certain medications, Alzheimer’s disease, and cardiovascular disease. Conversely, PLP is highly susceptible to photolytic degradation, a phenomenon recognized since 1958, even under artificial indoor lighting. This case underscores the necessity of strict adherence to PLP sample handling protocols. In patients with high clinical suspicion for HPP, a normal PLP result should prompt repeat testing with confirmation of light protection through collection and processing, or consideration of genetic testing. For clinicians, awareness of this pre-analytical issue is essential to avoid a missed or delayed HPP diagnosis.

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