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.
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: a low age and sex adjusted ALP level 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.2Integral to the diagnostic evaluation are the considerations listed below. To support diagnosis of HPP in children or adults two major criteria or one major and two minor criteria are required, with the key diagnostic indicator being persistently low age- and sex-adjusted serum ALP activity levels. Confirming that the reduction in ALP is not due to another condition or drug is critical in following the diagnostic pathway2,8,9
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.
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 Khan, A. 2023.20
ALP, alkaline phosphatase; Ca2+, calcium; HPP, hypophosphatasia; PTH, parathyroid hormone; PLP, pyridoxal 5’-phosphate; XLH, X-linked hypophosphataemia.
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.