Screening for Hypophosphatasia in Adult Patients at a Maximum Care Provider-Retrospective Analyses over Fifteen Years

Abstract

Background/Objectives: Hypophosphatasemia (HPE) may be temporary (tHPE) in the context of severe diseases, such as sepsis or trauma, or it may persist (pHPE), indicating an adult form of hypophosphatasia (HPP; OMIM 171760), a rare metabolic bone disorder caused by pathogenic nucleotide variants (PNVs) in the ALPLgene. The aim of this study was to analyze the role of auxiliary general biomarkers in verifying low alkaline phosphatase (ALP) serum activity level as an alert parameter for PNVs in the ALPLgene, which are indicative of HPP. In this retrospective analysis, we examined adult patients with an ALP serum activity level below 21 U/L. The cohort comprised 88 patients with temporary HPE (tHPE group) and 20 patients with persistent HPE who underwent re-examination. Genetic analysis performed on 12 pHPE patients identified PNV in the ALPLgene in 11 cases (ALPL group). Hemoglobin [HB], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], calcium, phosphate, thyrotropin [TSH], albumin, total protein, and C-reactive protein [CRP] levels represented basic biomarkers. A comparative analysis between groups employed a Student's t-test, and a Student's t-test with bootstrap sampling (n = 10.000) was performed. Results: The mean HB, ALP, calcium, albumin, and total protein levels were lower in the tHPE group compared with the ALPL group (p < 0.01). AST and CRP were increased in the tHPE group (p < 0.01). The model showed an accuracy of 90% and an AUC of 0.94, which means that it can discern the two groups ~94% of the time. Conclusions: Basic biomarker evaluation effectively supports the interpretation of a decreased ALP serum activity level in the context of suspected HPP. In patients with laboratory HPE and biomarkers within reference, a PNV in the ALPLgene is highly suspected.

Keywords: ALPL gene; ALPL gene variant; alkaline phosphatase; hypophosphatasemia; hypophosphatasia; pathogenic nucleotide variants.

Figure 1

Flowchart of the assessment of the patients and the resulting study groups. UHL = University Hospital of Leipzig.

Figure 2

Overview of our recommended laboratory algorithm for the evaluation of a single low serum alkaline phosphatase (ALP) activity (hypophosphatasemia, HPE) result in the setting of a pathogenic nucleotide variant of the ALPL gene and possible differential diagnosis of temporary hypophosphatasemia (tHPE). ↓ = below the reference range; ↑ = above the reference range.