Background/Purpose: Studies show a long diagnostic delay in Hypophosphatasia (HPP) and the accessibility for the genetic testing is not always possible. Our previous cross-sectional study (Tornero et al. OJRD (2020) 15:51) revealed alkaline phosphatase (ALP) levels < 25 IU/L seemed to be useful to identify individuals with ALPL variants among subjects with persistent hypophosphatasaemia. These data highlight the importance of establishing a specific biochemical profile and the value of including TNSALP substrates is a matter of interest. First, to confirm our previous results in a one-year follow-up of a longitudinal study. Second, to determine the value of including TNSALP substrates (serum pyridoxal phosphate-PLP-and urinary phosphoetanolamine-PEA) in a specific biochemical profile to detect variants in ALPL in individuals with persistent low ALP levels.

Methods: Biochemical parameters of subjects included in a prospective longitudinal study conducted at La Paz Hospital were employed. Subjects were divided into two groups according to their genetics (+ GT or -GTgroup). Substrates were determined at baseline and at one-year visit and ALP levels also at six-months. To confirm the threshold, diagnostic utility measures were calculated at the 3 visits. ROC curves were employed to determine PLP and PEA best cut-off levels. Hierarchical binary logistic regression analysis was used to determine how well the different models fit (Nagelkerke R²). Finally, diagnostic utility measures for each model were calculated.

Results: Using ALP data from the three visits, Specificity (E) ranged between 84-91%; positive predictive value (PPV), 76-87% and +LR 3-6.1%. The ROC curves revealed cut-off PLP levels with the best combination of S and E for PLP were 180 nmol/L (S: 72%, E:86%) and for PEA, 35 (S:58%, E89%) umol/g creat. The regression model showed an OR (95% IC) for ALP< 25 IU/L, PLP >180 and PEA >35 of 6.52 (1.07-39.6), 8.06 (2.2-29.9) and 4.4 (1.03-18.9). Compared to the model just including ALP, R² improved (0.161 to 0.526) when substrates were added (E and PPV:100% and S:22%), especially when PLP was included (Table 1).

Conclusion: This study confirms that ALP levels < 25 IU/L could be useful to identify individuals displaying ALPL variants. Additionally, the combination of this threshold with the proposed cut-off levels of its substrates, especially PLP, have shown a very high specificity to detect the disease and could help vigorously in the diagnostic work-up of HPP.

Table 1

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/biochemical-algorithm-to-identify-individuals-with-alpl-variants-between-subjects-with-persistent-hypophosphatasaemia/