Tissue nonspecific and intestinal alkaline phosphatase crosstalk: a missing link in hypophosphatasia pathophysiology?

Tissue-nonspecific alkaline phosphatase (TNSALP) and intestinal alkaline phosphatase (IAP) are functionally similar enzymes, but their relationship in hypophosphatasia (HPP) remains unexplored. This study investigated the impact of HPP-a condition caused by ALPL gene mutations that impair TNSALP function-on serum and fecal IAP activity.

Total alkaline phosphatase (ALP) activity and isoenzyme-specific activities (using selective inhibitors: L-homoarginine for TNSALP, L-phenylalanine for IAP) were measured in serum and stool samples from 30 HPP patients and 30 matched healthy controls, alongside biochemical parameters correlations.

In serum, IAP activity showed a non-significant decrease in HPP patients compared to controls, while TNSALP and total ALP activity were reduced in HPP patients. In stools, both total ALP and IAP activities were significantly decreased compared to the control group. Multivariate linear regression revealed a strong positive association between TNSALP and IAP in both serum and feces, independent of age and sex. In serum, TNSALP and IAP were key predictors of total ALP activity (B = 0.876 and B = 0.745, respectively; p < 0.001; R² = 0.9396), with TNSALP also predicting serum IAP levels (B = 0.164; p < 0.001). In feces, IAP was the strongest predictor of total ALP activity (B = 0.921; p < 0.001), and fecal TNSALP strongly predicted IAP levels (B = 0.883; p < 0.001). Serum TNSALP activity correlated with bone metabolism markers, inflammation, underscoring its potential systemic role.

IAP does not seem to compensate for reduced TNSALP activity in HPP. Instead, their tight association suggests a coordinated regulation between the two isoenzymes, with diminished fecal IAP potentially contributing to gut inflammation in HPP. These findings clarify the interplay between TNSALP and IAP and their clinical implications.