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Clinical manifestations and low alkaline phosphatase (ALP) activity can confirm a diagnosis of hypophosphatasia (HPP).1,2

Detection of low alkaline phosphatase activity in patients with clinical manifestations of hypophosphatasia can lead to an accurate diagnosis.1,2

Low alkaline phosphatase can be identified with a readily available, routine laboratory test1,2,28
Alkaline phosphatase activity should be age-adjusted and is laboratory-specific2

Early and accurate diagnosis is essential to avoid preventable morbidities and premature mortality.26,29,30

aSerum PLP (vitamin B6) is the most sensitive alkaline phosphatase substrate marker for hypophosphatasia, though it may not be elevated in all patients.2

Hypophosphatasia is inherited, so a diagnosis should raise suspicion of the disease in other family members.1,2

In family members with clinical signs and symptoms of hypophosphatasia, a routine test for low alkaline phosphatase activity can confirm a diagnosis.1

Family members of patients may have undiagnosed hypophosphatasia.2,21

The alkaline phosphatase lower limit of normal is significantly higher in children than in adults.31,32

Growth and development profoundly affect the normal range for alkaline phosphatase.31,33

Adapted from the Canadian Laboratory Initiative on Paediatric Reference Intervals (CALIPER) project (Colantonio et al, 2012). No variation in ALP based on ethnic differences was observed. Reference intervals shown were established on the Abbott ARCHITECT C8000 analyzer.31

bAdult interval provided by the Abbott ARCHITECT ALP product information sheet is for females >15 and males >20 years of age. For younger ages, Abbott does not provide lower limits of normal.32

Confirm that your laboratory is using age- and gender-adjusted alkaline phosphatase reference intervals.

Low alkaline phosphatase is the biological hallmark of hypophosphatasia.1,3 Growth and development profoundly affect the normal range for alkaline phosphatase.31,33

ALKALINE PHOSPHATASE CALCULATOR

To assess your patient's alkaline phosphatase level, select your patient's gender, and enter his or her age and alkaline phosphatase value.

{{testType}}
Reference intervals shown are relevant to the Abbott ARCHITECT c8000 analyzer and may vary across individual laboratories.
GENDER
Age
ALP (U/L)
You must indicate gender, age, and ALP value.
REFERENCES
References: 1. Colantonio DA, Kyriakopoulou L, Chan MK, 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(5):854-868. doi: 10.1373/clinchem.2011.177741. Epub 2012 Feb 27. 2. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388. 3. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190-200. 4. Shipman KE, Holt AD, Gama R. Interpreting an isolated raised serum alkaline phosphatase level in an asymptomatic patient. BMJ. 2013;346:f976 doi: 10.1136/bmj.f976. 5. Whyte MP. Hypophosphatasia. In: Glorieux FH, Pettifor JM, Juppner H, eds. Pediatric Bone: Biology & Diseases Rev. 2nd ed. San Diego, CA: Academic Press; 2012:771-794. 6. Whyte MP. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. Vol 1. 3rd ed. San Diego, CA: Academic Press; 2008:1573-1598. 7. Estey MP, Cohen AH, Colantonio DA, et al. CLSI-based transference of the CALIPER database of pediatric reference intervals from Abbott to Beckman, Ortho, Roche and Siemens Clinical Chemistry Assays: direct validation using reference samples from the CALIPER cohort. Clin Biochem. 2013;46(13-14):1197-1219. doi: 10.1016/j.clinbiochem.2013.04.001. Epub 2013 Apr 8. 8. Nield LS, Mahajan P, Joshi A, Kamat D. Rickets: not a disease of the past. Am Fam Physician. 2006;74(4):619-630. 9. Simmons JH. Best practices in: recognizing and diagnosing hypophosphatasia. Clinical Endocrinology News website. http://www.clinicalendocrinologynews.com/fileadmin/content_pdf/cen/Alexion_10_11_Final_Web.pdf. Published September 30, 2013. Accessed June 26, 2015. 10. Bhan A, Rao AD, Rao DS. Osteomalacia as a result of vitamin D deficiency. Endocrinol Metab Clin North Am. 2010;39(2):321-331. doi: 10.1016/j.ecl.2010.02.001. 11. Lab Tests Online. Liver panel. https://labtestsonline.org/understanding/analytes/liver-panel/tab/test. Published February 24, 2015. Accessed September 24, 2015. 12. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Bird TD, Dolan CR, Stephen K, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1150/. Published November 20, 2007. Updated August 5, 2010. Accessed June 26, 2015.

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References:
  1. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388.
  2. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1150/. Published November 20, 2007. Updated February 4, 2016. Accessed October 26, 2017.
  3. Whyte MP. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. Vol 2. 3rd ed. San Diego, CA: Academic Press; 2008:1573-1598.
  4. Whyte MP. Hypophosphatasia. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T, eds. Genetics of Bone Biology and Skeletal Disease. London, UK: Academic Press; 2013:337-360.
  5. Zankl A, Mornet E, Wong S. Specific ultrasonographic features of perinatal lethal hypophosphatasia. Am J Med Genet Part A. 2008;146A(9):1200-1204.
  6. Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007;40(6):1655-1661.
  7. Balasubramaniam S, Bowling F, Carpenter K, et al. Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5‘-phosphate availability. J Inherit Metab Dis. 2010;33(3):25-33.
  8. Silver MM, Vilos GA, Milne KJ. Pulmonary hypoplasia in neonatal hypophosphatasia. Pediatr Pathol. 1988;8(5):483-493.
  9. Fallon MD, Teitelbaum SL, Weinstein RS, Goldfischer S, Brown DM, Whyte MP. Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms. Medicine. 1984;63(1):12-24.
  10. Whyte MP, Greenberg CR, Salman NJ, et al. N Engl J Med. 2012;366(10):904-913.
  11. Beck C, Morbach H, Wirth C, Beer M, Girschick HJ. Whole-body MRI in the childhood form of hypophosphatasia. Rheumatol Int. 2011;31(10):1315-1320.
  12. Barvencik F, Beil FT, Gebauer M, et al. Skeletal mineralization defects in adult hypophosphatasia—a clinical and histological analysis. Osteoporos Int. 2011;22(10):2667-2675.
  13. Coe JD, Murphy WA, Whyte MP. Management of femoral fractures and pseudofractures in adult hypophosphatasia. J Bone Joint Surg Am. 1986;68(7):981-990.
  14. Gagnon C, Sims NA, Mumm S, et al. Lack of sustained response to teriparatide in a patient with adult hypophosphatasia. J Clin Endocrinol Metab. 2010;95(3):1007-1012.
  15. Schalin-Jäntti C, Mornet E, Lamminen A, Välimäki MJ. Parathyroid hormone treatment improves pain and fracture healing in adult hypophosphatasia. J Clin Endocrinol Metab. 2010;95(12):5174- 5179.
  16. Collmann H, Mornet E, Gattenlöhner S, Beck C, Girschick H. Neurosurgical aspects of childhood hypophosphatasia. Childs Nerv Syst. 2009;25(2):217-223.
  17. Seshia SS, Derbyshire G, Haworth JC, Hoogstraten J. Myopathy with hypophosphatasia. Arch Dis Child. 1990;65(1):130-131.
  18. Mornet E. Hypophosphatasia. Orphanet J Rare Dis. 2007;2:40.
  19. Data on File, Alexion Pharmaceuticals.
  20. Bianchi ML. Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int. 2015;26(12):2743-2757.
  21. Whyte MP, Murphy WA, Fallon MD. Adult hypophosphatasia with chondrocalcinosis and arthropathy. Variable penetrance of hypophosphatasemia in a large Oklahoma kindred. Am J Med. 1982;72(4):631-641.
  22. Reibel A, Maniére M-C, Clauss F, et al. Orodental phenotype and genotype findings in all subtypes of hypophosphatasia. Orphanet J Rare Dis. 2009;4:6.
  23. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190-200.
  24. van den Bos T, Handoko G, Niehof A, et al. Cementum and dentin in hypophosphatasia. J Dent Res. 2005;84(11):1021-1025.
  25. Eade AWT, Swannell AJ, Williamson N. Pyrophosphate arthropathy in hypophosphatasia. Ann Rheum Dis. 1981;40(2):164-170.
  26. Mohn A, De Leonibus C, de Giorgis T, Mornet E, Chiarelli F. Hypophosphatasia in a child with widened anterior fontanelle: lessons learned from late diagnosis and incorrect treatment. Acta Paediatr. 2011;100(7):e43-e46.
  27. Whyte MP, Mahuren JD, Vrabel LA, Coburn SP. Markedly increased circulating pyridoxal-5’- phosphate levels in hypophosphatasia. J Clin Invest. 1985;76(2):752-756.
  28. Lab Tests Online. ALP. Washington DC: American Association for Clinical Chemistry; 2001. https://labtestsonline.org/understanding/analytes/alp/tab/test/. Updated March 22, 2017. Accessed October 26, 2017.
  29. Sutton RAL, Mumm S, Coburn SP, Ericson KL, Whyte MP. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012;27(5):987-994.
  30. Cundy T, Michigami T, Tachikawa K, Dray M, Collins J. Phenotypic change in a patient with hypophosphatasia with the onset of renal failure. 40th Annual Congress of the European Calcified Tissue Society (ECTS); May 18-21, 2013; Lisbon, Portugal.
  31. Colantonio DA, Kyriakopoulou L, Chan MK, 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(5):854-868.
  32. Architect cSystems/Aeroset System alkaline phosphatase assay [package insert]. Abbott Park, IL: Abbott Laboratories; 2007.
  33. Turan S, Topcu B, Gökçe I, et al. Serum alkaline phosphatase levels in healthy children and evaluation of alkaline phosphatase z-scores in different types of rickets. J Clin Res Pediatr Endocrinol. 2011;3(1):7-11.