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SUN-716 Addition Of The Liver Alkaline Phosphatase Isoform Improves Diagnostic Sensitivity In Adults With Hypophosphatasia

Year: 2025
Type: article
Abstract: Disclosure: B.E. Bertot: None. J. Samsel: None. J. Pallais: Alexion Pharmaceuticals, Inc., Research, UpToDate. Hypophosphatasia (HPP) is an underrecognized genetic disorder caused by loss-of-function mutations in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (TNAP), including the liver and bone isoforms. Current biochemical diagnostic strategies rely on persistently low total alkaline phosphatase (ALP) levels along with elevated ALP substrates such as pyridoxal 5’-phosphate (vitamin B6) and phosphoethanolamine (PEA). However, these tests demonstrate limited sensitivity, and many patients with genetically confirmed HPP are missed. We investigated whether measurement of the liver 1 isoform of ALP, using gel electrophoresis, enhances diagnostic sensitivity. Methods: We analyzed 22 adults with genetically or clinically confirmed HPP who underwent fractionated ALP testing by electrophoresis. To minimize diagnostic ambiguity, we calculated strict sensitivity—defined as all values for a given biomarker falling within the abnormal range expected in HPP—for total ALP, vitamin B6, urine PEA, bone-specific ALP (by immunoassay), and fractionated liver and bone ALP isoforms. We then assessed how the addition of liver 1 ALP isoform data affected sensitivity and tested differences using paired proportion comparisons. Results: The liver 1 ALP isoform had the highest strict sensitivity of any individual test (68.2%). Other tests showed lower sensitivities: total ALP (40.9%), vitamin B6 (36.4%), PEA (47.4%), bone-specific ALP (38.1%), and fractionated bone ALP (31.8%). Adding liver 1 ALP significantly improved sensitivity for each of these tests:•Vitamin B6 + liver 1 ALP: 90.9% (Δ +54.5%, p=0.001)•Fractionated bone + liver 1 ALP: 72.7% (Δ +40.9%, p=0.007)•Bone-specific ALP + liver 1 ALP: 76.2% (Δ +38.1%, p=0.013)•PEA + liver 1 ALP: 78.9% (Δ +31.6%, p=0.044)•Total ALP + liver 1 ALP: 68.2% (Δ +27.3%, p=0.069). Among patients missed by each individual test, liver 1 accurately identified 85.7% of those missed by B6, 60% by PEA and fractionated bone, and 46.2% by total ALP. Heat map analysis confirmed liver 1 ALP isoform as the most effective additive marker, consistently enhancing the performance of all standard tests. Conclusion: Measurement of the liver 1 ALP isoform by electrophoresis significantly improves the diagnostic sensitivity of standard biochemical tests for HPP. Its inclusion in clinical testing protocols may reduce underdiagnosis in adults suspected of having HPP. Presentation: Sunday, July 13, 2025
DOI: 10.1210/jendso/bvaf149.669
Authors: Brandon E Bertot, Joanna Samsel, J Carl Pallais
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $3,255
OpenAlex ID: W7093372196
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