Urine phosphoethanolamine is a specific biomarker for hypophosphatasia in adults

Shajani-Yi, Zahra<sup>1,2</sup>; Ayala-Lopez, Nadia<sup>1</sup>; Black, Margo<sup>3</sup>; Dahir, Kathryn McCrystal<sup>3</sup>

Affiliations

¹Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

²Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA

³Division of Endocrinology, Program for Metabolic Bone Disorders, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

Abstract and keywords

Objectives: We investigated the utility of urine phosphoethanolamine (PEA) as a marker to aid in diagnosing and/or confirming hypophosphatasia (HPP) in adults and for monitoring patients on enzyme replacement therapy (ERT).

Methods: Data was collected from seventy-eight adults who were referred to the Vanderbilt Program for Metabolic Bone Disease for evaluation of a possible or confirmatory HPP diagnosis between July 2014 through December 2019. Fifty-nine patients were diagnosed with HPP and nineteen were excluded from a diagnosis of HPP. The urine PEA results of those patients with a confirmed diagnosis of HPP and those patients with a diagnosis of HPP excluded were captured and compared to other laboratory and clinical parameters consistent with HPP, including alkaline phosphatase (ALP) activity, plasma pyridoxal 5′-phosphate (PLP), the presence of musculoskeletal abnormalities, and genetic testing for pathogenic mutations in ALPL.

Results: Initial urine PEA values in patients in our HPP cohort and not on ERT were significantly higher (median = 150.0 nmol/mg creatinine, IQR = 82.0–202.0) compared patients in our HPP negative group (median 18.0 nmol/mg creatinine, IQR = 14.0–30.0, p < 0.0001) and higher than patients on ERT (median 65.0 nmol/mg creatinine, IQR = 45.3–79.8). Patients who began ERT had a decline in urine PEA levels after treatment with a mean decrease of 68.1 %. Plasma ALP levels were significantly lower in the group of patients with HPP and not on ERT group (median = 24.0 U/L, IQR = 15.0–29.50) compared to the patients without HPP (median = 45.50 U/L, IQR = 34.0–62.0;) and plasma PLP levels were significantly higher in the HPP non-ERT group (median = 284.0 nmol/L, IQR = 141.0–469.4) compared to the patients without HPP (median = 97.5 nmol/L, IQR = 43.7–206.0;). The area under the curve (AUC) of urine PEA, ALP, and PLP to distinguish between HPP and non-HPP patients is 0.968, 0.927 and 0.781, respectively, in our cohort. Urine PEA had 100 % specificity (95 % CI of 83.2 % to 100.0 %) for diagnosing HPP at a value >53.50 nmol/mg creatinine with a sensitivity of 88.4 %; 95%CI 75.5 to 94.9 %. ALP had a 100 % specificity (95 % CI of 82.4 % to 100.0 %) for diagnosing HPP at a value <30.5 U/L with a sensitivity of 77.2 %; (95%CI 64.8 to 86.2 %). PLP had a 100 % specificity (95 % CI of 81.6 % to 100.0 %) for diagnosing HPP at a value >436 nmol/L with a sensitivity of 26.9 %; (95%CI 16.8 to 40.3 %). The most common pathogenic or likely pathogenic mutations in our cohort were c.1250A>G (p.Asn417Ser), c.1133A>T (p.Asp378Val), c.881A>C (p.Asp294Ala), c.1171C>T (p.Arg391Cys), and c.571G>A, (p.Glu191Lys).

Conclusions: Urine PEA is a promising diagnostic and confirmatory marker for HPP in patients undergoing investigation for HPP. Urine PEA also has potential use as a marker to monitor ERT compliance. Future studies are necessary to evaluate the association between PEA levels and clinical outcomes.

Keywords: Urine phosphoethanolamine (PEA); Hypophosphatasia; Alkaline phosphatase (ALP); Pyridoxal 5′-phosphate (PLP); Asfotase alfa; Enzyme replacement therapy

Links

DOI: 10.1016/j.bone.2022.116504

PubMed: 35878747

WoS: 000837142700003

History

Received: 2022-05-26

Revised: 2022-07-04

Accepted: 2022-07-19

Online: 2022-07-22

Cited Works (5)

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Cited By (1)

Year	Entry
2023	Seefried L, Genest F, Petryk A, Veith M. Effects of asfotase alfa in adults with pediatric-onset hypophosphatasia over 24 months of treatment. Bone. October 2023;175:116856.