About HPP and low ALP
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Hypophosphatasia (HPP) is a rare, inherited metabolic disorder that may reveal itself at any age through a wide variety of symptoms.1,2 It has a high burden on patients, who often have long delays in diagnosis and treatment initiation.1,3–5

HPP is characterised by persistently low alkaline phosphatase (ALP) activity, and it is this key biochemical marker that is crucial to differentiating HPP from other conditions.6,7

Let’s connect persistently low ALP to the signs and symptoms of HPP and reduce time to diagnosis5,8
HPP is characterised by persistently low alkaline phosphatase (ALP) activity, impaired bone mineralisation, muscle weakness and other systemic manifestations.6

In healthy individuals, TNSALP hydrolyses inorganic pyrophosphate (PPi), a mineralisation inhibitor, to generate inorganic phosphate (Pi).4 Pi binds with calcium (Ca2+) to form hydroxyapatite crystals, the mineral matrix of bone.10

In HPP, deficient ALP leads to the accumulation of PPi and other substrates, leading to a range of skeletal defects and systemic complications.2,9

* Different isoforms of ALP exist; however, the majority is TNSALP,6,11 so throughout this webpage, it is referred to as ALP for simplicity.
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A low ALP level is not conclusive for an HPP diagnosis. Other more common causes of low ALP should be excluded before a definitive HPP diagnosis is made.8

* Limitations: an ALP level of <40 U/L is not conclusive for a diagnosis of HPP. The patient should be evaluated for other symptoms of HPP, and differential diagnoses should be ruled out. Check with your lab for their appropriate age- and sex-adjusted ALP reference range.8

† The connection between ALP and PEA has not been fully established. PPi is also a substrate associated with HPP, however, tests for PPi are not commercially available.2
Integral to the diagnostic evaluation are the considerations listed below, with the key diagnostic indicator being persistently low age- and sex-adjusted serum ALP activity levels:2,8,9
It is important to note that normal ranges for serum ALP activity are higher in infants, children and adolescents than in adults.7,13 Laboratories vary in their age- and sex-adjusted reference ranges; therefore, serum or plasma ALP activity must be interpreted based on laboratory-specific ranges.9

Limitations: check with your lab for their appropriate age- and sex-adjusted ALP reference range.
Note: graph adapted from Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) project (Colantonio DA, et al. 2012).19 CALIPER samples from 1,072 male and 1,116 female participants (newborn to 18 years) were used to calculate age- and sex-specific reference intervals.19 No variations in ALP based on ethnic differences were observed.
Table adapted from Bloch-Zupan A. 2016.14

ALP, alkaline phosphatase; Ca2+, calcium; HPP, hypophosphatasia; PTH, parathyroid hormone; PLP, pyridoxal 5’-phosphate; XLH, X-linked hypophosphataemia.
Persistently low ALP is the hallmark of HPP; however, it is crucial to use age- and sex-adjusted references ranges to detect low activity, especially in children2,9,11
AQP4, aquaporin–4; AQP4 Ab+, aquaporin–4 antibody positive; CNS, central nervous system;NMOSD, neuromyelitis optica spectrum disorder; QoL, quality of life.
Linglart A, Biosse-Duplan M. Hypophosphatasia. Curr Osteoporos Rep. 2016;14:95–105. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(Suppl 2):380–388. Rush ET, et al. Burden of disease in pediatric patients with hypophosphatasia: results from the HPP Impact Patient Survey and the HPP Outcomes Study Telephone interview. Orphanet J Rare Dis. 2019;14(1):201. Weber TJ, et al. Burden of disease in adult patients with hypophosphatasia: Results from two patient-reported surveys. Metabolism. 2016;65(10):1522–1530. Högler W, et al. iagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry. BMC Musculoskeletal Discord. 2019;20(1):80. Fenn JS, et al. Hypophosphatasia. J Clin Pathol. 2021;74(10)635–640. Bloch-Zupan A. Hypophosphatasia: diagnosis and clinical signs - a dental surgeon perspective. Int J Paediatr Dent. 2016;26:426–438. Bishop N. Transformative therapy in hypophosphatasia. Arch Dis Child. 2016;101(6):514–515. Whyte MP. Hypophosphatasia. Nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP, et al. eds. Principles of Bone Biology. San Diego, CA: Academic Press; 2008:1573–1598. Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch. 2010;77(1):4–12. Mckiernan FE, et al. Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res. 2014;29(7):1651–1660. ARUP. Alkaline phosphatase isozymes, Serum or Plasma. Available at: https://ltd.aruplab.com/Tests/Pub/0021020. Last accessed: February 2024. Adeli K. Biochemical Marker Reference Values across Pediatric, Adult, and Geriatric Ages: Establishment of Robust Pediatric and Adult Reference Intervals on the Basis of the Canadian Health Measures Survey. Clin Chem. 2015;61(8):1049–1062. Schumann G. IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 °C. Part 9: reference procedure for the measurement of catalytic concentration of alkaline phosphatase International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Scientific Division, Committee on Reference Systems of Enzymes (C-RSE) (1)). Clin Chem Lab Med. 2011;49(9):1439–1446. Quest Diagnostics. Alkaline phosphatase. Available at: https://testdirectory.questdiagnostics.com/test/test-detail/234/alkaline-phosphatase?cc=MASTER. Accessed February 2024. Labcorp. Alkaline phosphatase. Available at: https://www.labcorp.com/tests/001107/alkaline-phosphatase. Last accessed February 2024. Bangura A, et al. Hypophosphatasia: Current Literature for Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment. Cureus. 2020;12(6):e8594. Salles JP. Hypophosphatasia: Biological and Clinical Aspects, Avenues for Therapy. Clin Biochem Rev. 2020;41(1):13–27. Colantonio DA, et al. Closing the gaps in pediatric laboratory reference intervals: a CALIPER database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem. 2012;58:854–868.