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A Man with Recurrent Fractures and Foot Pain.

CASE

A primary care physician telephoned to inquire about the clinical significance of low alkaline phosphatase (ALP) [4] in a 54-year-old man, which led to an investigation for the cause of the low ALP, a biochemical abnormality that is known to be underappreciated (1). The man was a military veteran currently working as a fireman. His records showed that he had a history of multiple fractures throughout his life, including the right clavicle at age 12 years, the left tibia with inflammation of the patellar ligament at the tibial tuberosity (Osgood--Schlatter disease) at 13 years, and the right ring finger when he was 15 years old. He reported severe foot pain starting in 2006 at age 44 years. At age 50 years, 2 separate radiographic examinations of the foot showed osteonecrosis of the second metatarsal (Freiberg disease) and loss of bone density. Around this time, he also reported a 2-week history of severe pain under the heel of his right foot. All these were observed despite no reported external injury or trauma. His current medications include corticosteroid nasal spray (mometasone furoate), dihydrocodeine, baclofen, cocodamol, quinine sulfate, propranolol, gabapentin, and diazepam.

As shown in Table 1, the man's records revealed that his ALP had been low on 5 separate occasions in the past 8 years. There was no biochemical evidence to suggest metabolic bone disease, hypothyroidism, or any other electrolyte disturbance, and he was vitamin D replete. Magnesium and vitamin B12 levels were marginally low, whereas zinc was within reference limits. Ferritin was raised, likely because of the acute phase response owing to fractures. Microalbuminuria was reported on 2 occasions. There was no evidence of diabetes mellitus. Given his history of fractures, we sent a plasma sample to a specialist laboratory for a vitamin B6 profile. The pyridoxal 5;-phosphate (PLP) concentration was strikingly increased for a non-vitamin B6-supplemented patient, giving a raised PLP-topyridoxic acid (PA) ratio (reference, <5 using SI units) (2).
QUESTIONS TO CONSIDER

1. What are potential causes of low ALP activity in blood
(hypophosphatasemia)?

2. How should hypophosphatasemia be investigated?

3. Which clinical condition is associated with hypophosphatasemia
and raised PLP concentration?


DISCUSSION

CAUSES OF HYPOPHOSPHATASEMIA

The causes of hypophosphatasemia are listed in Table 2. A systematic approach to the investigation is necessary, starting with causes for which laboratory tests are widely available. Reference intervals for ALP are assay-dependent, age- and sex-related, and must be taken into consideration (3). ALP is higher in neonates, increases even further during growth and puberty, and decreases to reach adult concentrations after growth has completed (3). Many clinical laboratories may report only an adult reference interval, and, correspondingly, some conditions in younger people may go undiagnosed if their concentrations are within the adult reference interval but are inappropriately low for their age. Zinc and magnesium deficiency, which are both cofactors of the enzyme ALP, are known causes and always should be excluded (4). Contamination with the anticoagulant EDTA, which can chelate both magnesium and zinc, reduces the activity of ALP in serum (5). Medications such as bone antiresorptives can result in hypophosphatasemia (4). Patients undergoing cardiac surgery have been reported to have low ALP activity (4). The cause is not well defined but has been speculated to be because of hemodilution or removal of cofactors by the cardiopulmonary bypass pump. Malnutrition has resulted in low serum ALP in 26% of 1 cohort of adult male patients (4) and is likely attributable to decreased cofactor supply. Wilson disease has been reported to cause hypophosphatasemia because copper competes with zinc, leading to incorporation of copper instead of zinc in the ALP active sites and yielding an enzyme with reduced activity (6). In addition, oxidative damage by hydroxyl free radicals generated during copper-catalyzed ascorbate oxidation has been reported to degrade ALP (7). Other conditions listed in Table 2 that have been associated with hypophosphatasemia were clinically excluded in this patient. The marginally low magnesium and vitamin B12 were unlikely to account for the hypophosphatasemia. In this case, the raised PLP, together with hypophosphatasemia and a history of recurrent fractures, was consistent with a diagnosis of hypophosphatasia (HPP).

HYPOPHOSPHATASIA (HPP)

Incidence and prevalence. HPP is an inherited metabolic bone disease arising from loss-of-function mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) (8--10). More than 300 TNSALP mutations have been identified and known to cause broad-ranging symptoms of varying severity (10). Autosomal-dominant and -recessive transmission may lead to mild and lethal perinatal HPP, respectively (8). The severe form affects 1 in 100000 to 300000 people, depending on the population, whereas the moderate form has been estimated to affect 1 in 6370 Europeans (10). The mild forms may be more common (9).

Clinical presentation. HPP can present at all ages, and 6 distinct forms are recognized (8--10). Odontohypophos-phatasia is the mildest and most prevalent, affecting both children and adults, presenting with dental features, notably loss of deciduous teeth usually before 5 years. Adult HPP typically presents in middle age with foot pain owing to stress fractures of the metatarsals or thigh pain because of pseudofractures of the femur. Patient history may reveal premature tooth loss or rickets in childhood. Childhood HPP has variable presentation, ranging from premature tooth loss, rickets, or skull deformities and short stature to gait abnormalities. Infantile HPP appears during the first 6 months of life with failure to thrive, respiratory complications owing to rachitic ribs, craniosynostosis resulting in increased intracranial pressure, hypercalcemia, and seizures. Perinatal HPP is almost always fatal, reflecting profound skeletal hypomineralization. A benign prenatal form has also been reported.

Pathogenesis. The hallmark of HPP is defective bone and tooth mineralization, leading to skeletal and dental abnormalities (8--10). Total serum ALP concentration is decreased in those with HPP, and the lower the concentration, the more severe the symptoms (9). Deficiency of TNSALP leads to the extracellular accumulation of several substrates, including inorganic pyrophosphate (PPi), which is a potent inhibitor of bone mineralization by blocking hydroxyapatite crystal formation (9). Another TNSALP substrate that accumulates is PLP, the principal circulating form of vitamin B6. TNSALP normally hydrolyzes PLP to pyridoxal, enabling it to cross the blood-brain barrier where it is regenerated to PLP, which acts as a coenzyme for several enzymes required for neurotransmitter synthesis (8--10). The accumulation of PLP in systemic circulation may lead to a deficiency of vitamin B6 in the central nervous system and is the basis for pyridoxine-dependent seizures in severe cases (8). Phosphoethanolamine, the degradation product of the phosphatidylinositol glycan, which anchors ALP to cell surfaces, also accumulates in those with HPP (8--10).

Diagnosis and biochemical features. The accumulation of these substrates in systemic circulation enables the diagnosis of HPP. PLP is reported to be a sensitive and specific marker for HPP, but false-positive results may be seen with vitamin B6 supplementation (8). It is recommended that this is stopped for at least 1 week before measuring PLP (10). In addition to PLP, some laboratories report PA, the metabolite of pyridoxal, and the PLPto-PA ratio (2). Phosphoethanolamine has been reported to be increased in blood and urine in patients with HPP; however, it is affected by diet, increases with age, has a circadian rhythm, and is increased with other metabolic bone diseases (8--10). Mutation detection is not deemed necessary for diagnosis but can provide information regarding inheritance patterns and recurrence risk and supports genetic counseling (8).

The absence of incorporation of minerals into the skeleton may result in hypercalcemia and hyperphosphatemia (8). Hypercalcemia results in hypercalciuria and sometimes nephrocalcinosis, especially in the infantile form (8). In addition, accumulation of PPi may lead to chondrocalcinosis, PPi arthropathy (pseudogout), and tissue calcification (10). In contrast, in rickets and osteomalacia, the prominent features are hypocalcemia, commonly hypophosphatemia, and vitamin D deficiency.

Treatment and management. Until recently there was no approved medical therapy for HPP. The main therapeutic strategies were pain management and surgical support (10). In 2015, asfotase alfa (recombinant TNSALP) was approved in the US for perinatal-, infantile-, and juvenile-onset disease, and in 2016 it was approved in the UK for only perinatal- and infantile-onset disease with a cost cap. Treatment with bisphosphonates, which are analogs of PPi and often considered for patients with recurrent fractures, can increase fracture risk and is contraindicated in those with HPP (8, 10). Pharmacological doses of vitamin D and/or calcium supplementation may induce or aggravate hypercalcemia and hyperphosphatemia (8) and should be avoided.
POINTS TO REMEMBER

* Low serum ALP is underappreciated and mostly overlooked.
Assay-dependent and age- and sex-specific reference
intervals should be used.

* Exclude causes such as malnutrition, magnesium and zinc
deficiency, hypothyroidism, celiac disease, and pernicious anemia,
and correlate biochemical findings with clinical features.

* A rare cause of hypophosphatasemia is HPP, a diagnosis that
is known to be easily missed. HPP presents at any age, but in
the adult-onset form it usually presents in middle age.

* The first-line test for HPP is low serum ALP. To confirm
HPP, measure the vitamin B6 profile--raised PLP level is
a sensitive and specific marker of HPP (PLP-to-PA ratio
reported by some laboratories).

* In those with HPP, treatment with bisphosphonates
increases fracture risk and is contraindicated. Vitamin D
at pharmacological doses and/or calcium supplementation
may induce or aggravate hypercalcemia.


CASE RESOLUTION

This man's condition was diagnosed in midlife, which is consistent with adult HPP. However, his history revealed fractures in childhood, suggesting that the diagnosis of childhood HPP may have been missed. His fractures have had a profound impact on his career, and he has had multiple referrals to the orthopedic department for treatment, which has been conservative. We did not consider genetic studies in this case owing to cost considerations and because the diagnosis was clear. His two children and extended family remain to be followed-up. His current treatment goals involve pain management and support. Unfortunately, asfotase alfa is not available in the UK National Health Service for adult-onset HPP. This raises important questions for health policymakers, physicians, and society as a whole to consider the opportunities and challenges of new therapies (10).

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References

(1.) Maman E, Borderie D, Roux C, Briot K. Absence of recognition of low alkaline phosphatase level in a tertiary care hospital. Osteoporos Int 2016;27:1251-4.

(2.) Talwar D, QuasimT, McMillan DC, KinsellaJ, Williamson C, O'Reilly DS. Optimisation and validation of a sensitive high-performance liquid chromatography assay for routine measurementofpyridoxal 5-phosphate in human plasma and red cells using pre column semi-carbazide derivatisation. J Chromat B Analyt Technol Biomed Life Sci 2003;792:333-43.

(3.) Adeli K, Ceriotti F, Nieuwesteeg M. Reference information forthe clinical laboratory. In: Nader R, Horwarth AR, Wittwer CT, editors. Tietz textbook of clinical chemistry and moleculardiagnostics. 6th Ed.St. Louis (MO): Elsevier; 2018. p. 1778.

(4.) Lum G. Significance of low serum alkaline phosphatase activity in a predominantly adult male population. Clin Chem 1995;41:515-8.

(5.) Davidson DF. Effects of contamination of blood specimens with liquid potassium-EDTA anticoagulant. Ann Clin Biochem 2002;39:273-80.

(6.) Oosthuizen N. Undetectable serum alkaline phosphatase activity in a patient with fulminant hepaticfailure and hemolyticanemia. Clin Chem 2011;57:382-7.

(7.) HoshinoT, Kumasaka K, Kawano K, Yamagishi F, Koyama I, Fujimori-Arai Y, et al. Low serum alkaline phosphatase activity associated with severe Wilson's disease. Is the breakdown of alkaline phosphatase molecules caused by reactive oxygen species? Clin Chim Acta 1995;238:91-100.

(8.) Whyte MP. Hypophosphatasia--aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2016;12:233-46.

(9.) Mornet E. Hypophosphatasia. Best Prac Res Clin Rheumatol 2008;22:113-27.

(10.) Whyte MP. Hypophosphatasia: enzyme replacementtherapy brings new opportunities and new challenges. J Bone Miner Res 2017;32:667-75.

Ravinder Sodi [1,2] * and David Hall [3]

[1] Department of Biochemistry, Blood Sciences, Royal Lancaster Infirmary & Furness General Hospital, University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, UK; [2] Lancaster Medical School, University of Lancaster, Lancaster, UK; [3] Medwyn Medical Practice, Carnwath, Lanarkshire, UK.

* Address correspondence to this author at: Department of Biochemistry, Blood Sciences, Royal Lancaster Infirmary & Furness General Hospital, University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, LA1 4RP, UK. Fax +44-01524-519703; e-mail Ravinder.Sodi@mbht.nhs.ukor ravsodi@yahoo.com.

Received April 24,2017; accepted August 11,2017.

DOI: 10.1373/clinchem.2017.275628

[4] Nonstandard abbreviations: ALP, alkaline phosphatase; PLP, pyridoxal 5'-phosphate; PA, pyridoxic acid; HPP, hypophosphatasia; TNSALP, tissue-nonspecific isoenzyme of alkaline phosphatase; PPi, inorganic pyrophosphate.
Table 1. Selected biochemical and hematological results. (a)

Analyte               Reference intervals    November 17,   July 31,
                                                 2008         2012

ALP                   30-130 (U/L)                12           15
ALT                   5-55 (U/L)                               22
Total bilirubin       <1.22 mg/dL                             0.58
                      (<21 pmol/L)                            (10)
Albumin               3.5-5.0 (g/dL)                          4.9
Phosphate             2.2-4.3 mg/dL
                      (0.7-1.4 mmol/L)
Calcium, adjusted/    8.8-10.4
  corrected            (2.2-2.6 mmol/L)
Vitamin D             10-68 ng/mL
                      (25-170 nmol/L)
Magnesium             1.70-2.43 mg/dL
                      (0.70-1.00 mmol/L)
Zinc                  71.9-117.7 mg/dL
                      (11-18 pmol/L)
Vitamin B12           197-771 ng/L
Folate                9-40 ng/mL
Ferritin              28-285 ng/mL
Hemoglobin            13.5-18.0 g/dL
Glucose               63-108 mg/dL
                      (3.5-6.0 mmol/L)
Microalbumin/         <2.5 mg/mmol (males)
  creatinine
Vitamin B6 profile
PLP                   4.9-34.6 ng/mL
                      (20-140 nmol/L)
PA                    1.65-11.0 ng/mL
                      (9-60 nmol/L)
PLP/PA ratio          <5 (using SI units)

Analyte               Reference intervals    April26,    March 13,
                                               2013        2014

ALP                   30-130 (U/L)              15          15
ALT                   5-55 (U/L)                28          19
Total bilirubin       <1.22 mg/dL               0.7         0.7
                      (<21 pmol/L)             (12)        (12)
Albumin               3.5-5.0 (g/dL)            5.3          5
Phosphate             2.2-4.3 mg/dL
                      (0.7-1.4 mmol/L)
Calcium, adjusted/    8.8-10.4
  corrected            (2.2-2.6 mmol/L)
Vitamin D             10-68 ng/mL
                      (25-170 nmol/L)
Magnesium             1.70-2.43 mg/dL
                      (0.70-1.00 mmol/L)
Zinc                  71.9-117.7 mg/dL
                      (11-18 pmol/L)
Vitamin B12           197-771 ng/L
Folate                9-40 ng/mL
Ferritin              28-285 ng/mL
Hemoglobin            13.5-18.0 g/dL           16.5
Glucose               63-108 mg/dL
                      (3.5-6.0 mmol/L)
Microalbumin/         <2.5 mg/mmol (males)
  creatinine
Vitamin B6 profile
PLP                   4.9-34.6 ng/mL
                      (20-140 nmol/L)
PA                    1.65-11.0 ng/mL
                      (9-60 nmol/L)
PLP/PA ratio          <5 (using SI units)

Analyte               Reference intervals    April 21,     June 6,
                                                2016         2016

ALP                   30-130 (U/L)               7
ALT                   5-55 (U/L)                 51
Total bilirubin       <1.22 mg/dL               0.70
                      (<21 pmol/L)              (12)
Albumin               3.5-5.0 (g/dL)            4.9           4.9
Phosphate             2.2-4.3 mg/dL                           3.3
                      (0.7-1.4 mmol/L)                      (1.05)
Calcium, adjusted/    8.8-10.4                            10.0 (2.51)
  corrected            (2.2-2.6 mmol/L)
Vitamin D             10-68 ng/mL                            28.4
                      (25-170 nmol/L)                        (71)
Magnesium             1.70-2.43 mg/dL                        1.67
                      (0.70-1.00 mmol/L)                    (0.69)
Zinc                  71.9-117.7 mg/dL                        100
                      (11-18 pmol/L)                        (15.3)
Vitamin B12           197-771 ng/L
Folate                9-40 ng/mL
Ferritin              28-285 ng/mL
Hemoglobin            13.5-18.0 g/dL                         16.6
Glucose               63-108 mg/dL              97.2
                      (3.5-6.0 mmol/L)         (5.4)
Microalbumin/         <2.5 mg/mmol (males)      12.7          7.3
  creatinine
Vitamin B6 profile
PLP                   4.9-34.6 ng/mL
                      (20-140 nmol/L)
PA                    1.65-11.0 ng/mL
                      (9-60 nmol/L)
PLP/PA ratio          <5 (using SI units)

Analyte               Reference intervals    September 5,
                                                 2016

ALP                   30-130 (U/L)
ALT                   5-55 (U/L)
Total bilirubin       <1.22 mg/dL
                      (<21 pmol/L)
Albumin               3.5-5.0 (g/dL)              4.8
Phosphate             2.2-4.3 mg/dL
                      (0.7-1.4 mmol/L)
Calcium, adjusted/    8.8-10.4                9.9 (2.48)
  corrected            (2.2-2.6 mmol/L)
Vitamin D             10-68 ng/mL                 38
                      (25-170 nmol/L)            (95)
Magnesium             1.70-2.43 mg/dL
                      (0.70-1.00 mmol/L)
Zinc                  71.9-117.7 mg/dL
                      (11-18 pmol/L)
Vitamin B12           197-771 ng/L               196.7
Folate                9-40 ng/mL                 9.40
Ferritin              28-285 ng/mL               309.9
Hemoglobin            13.5-18.0 g/dL             15.4
Glucose               63-108 mg/dL
                      (3.5-6.0 mmol/L)
Microalbumin/         <2.5 mg/mmol (males)
  creatinine
Vitamin B6 profile
PLP                   4.9-34.6 ng/mL              522
                      (20-140 nmol/L)           (2112)
PA                    1.65-11.0 ng/mL             2.2
                      (9-60 nmol/L)              (12)
PLP/PA ratio          <5 (using SI units)         176

(a) Conventional units (SI unitswhere applicable). ALT, alanine
aminotransferase.

Table 2. Causes of hypophosphatasemia (mechanism of
cause, where known).

General causes

Improperly collected blood-EDTA contamination
(cofactor chelation)

Inappropriate reference interval (assay-dependent,
age- and sex-based)

Medications: clofibrate, chemotherapy,
glucocorticoids, bone antiresorptives, antacids
(milk-alkali syndrome)

Massive blood transfusion (hemodilution)

Biochemical causes

Malnutrition (reduced cofactor supply)

Magnesium deficiency (cofactor)

Zinc deficiency (cofactor)

Hypothyroidism

Vitamin D intoxication

Vitamin C deficiency

Hypophosphatasia (mutation in TNSALP gene)

Disease associations

Bone diseases: osteogenesis imperfecta,
achondroplasia

Cardiac bypass surgery (massive blood transfusion)
Pernicious or severe anemia

Wilson disease ([Cu.sup.2+] competes with [Zn.sup.2+]; free-radical
damage generated by [Cu.sup.2+])

Cushing syndrome

Multiple myeloma

Celiac disease

Radioactive heavy metal poisoning


Commentary

Matthew B. Greenblatt *

Diagnosis and management of hypophosphatasia (HPP) entail a series of challenging clinical laboratory issues. The extensive differences in serum alkaline phosphatase (ALP) observed throughout normal growth during childhood and adolescence require provision of either locally determined or literature-derived age- and sex-adjusted pediatric reference intervals (1). Although HPP is an important cause of decreased ALP, workup of HPP in cases with isolated ALP reduction is not typically indicated because of the low pretest probability of HPP. Illustrative of this, retrospective examination of low ALP results gathered across years of testing at 1 site failed to identify any cases of HPP (2). Thus, workup for HPP is unlikely to be productive in the absence of a compatible clinical presentation. However, as the presentation of HPP runs a gamut of severity, from neonatal lethal forms all the way to subtle skeletal pain and fragility, it can be challenging to fully exclude HPP on clinical grounds alone when presented with a request for further workup of low ALP.

Enzyme replacement therapy can be achieved by administration of asfotase alfa, a fusion of the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme to Fc domains that is targeted to bone by a polyaspartic acid tail. Although treatment with asfotase alfa can substantially impact the course of HPP, it poses a series of challenges for laboratories (3). Asfotase alfa may interfere with measurements of other TNSALP substrates, such as the active form of vitamin B6, pyridoxal-5;-phosphate, owing to postphlebotomy hydrolysis. As asfotase alfa itself has alkaline phosphatase enzymatic activity, it may also interfere with ELISA assays that utilize ALP as the detection enzyme. Similarly, asfotase alfa is expected to increase ALP results. Although this effect may have utility in the monitoring of treatment, it may also complicate measurement of endogenous ALP activity in scenarios for which this is clinically indicated.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contribution to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References

(1.) Colantonio DA, Kyriakopoulou L, Chan MK, Daly CH, Brinc D, Venner AA, 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;58:854-68.

(2.) Lum G. Significance of low serum alkaline phosphatase activity in a predominantly adult male population. Clin Chem 1995;41:515-8.

(3.) Kishnani PS, Rush ET, Arundel P, Bishop N, Dahir K, Fraser W, et al. Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Mol Genet Metab 2017;122:4-17.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY.

* Address correspondence to the author at: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Ave., LC929a, New York, NY 10065. Fax 617- 277-9015; e-mail mag3003@med.cornell.edu.

Received September 14, 2017; accepted September 22, 2017.

DOI: 10.1373/clinchem.2017.280776

Commentary

Michael P. Whyte *

Alkaline phosphatase (ALP) is the most frequently assayed enzyme in all of medicine (1). The importance of an increased value in serum is appreciated by every clinician, yet it is remarkable how often subnormal values go unnoticed or ignored. Physicians look for hyperphosphatasemia to detect and follow skeletal or hepatobiliary disease, but hypophosphatasemia, although it is a consequence of many disorders, frequently remains uninvestigated (2). Fortunately, this man's substantial and persistent hypophosphatasemia seemed paradoxical for his history of skeletal problems. Subsequently, his marked increase in serum of the ALP substrate pyridoxal 5'-phosphate implicated hypophosphatasia (HPP) (2).

Importantly, any bisphosphonate therapy might now be avoided because bisphosphonates are analogs of inorganic pyrophosphate (2), the ALP substrate that accumulates and impairs bone mineralization in those with HPP (2). A search for a mutation causing HPP seemed unnecessary. However, a key question is whether he represents perhaps the 1 in 500 individuals who are heterozygous for this type of mutation and manifest these biochemical hallmarks of HPP yet are healthy "carriers" (3). In fact, his fracture history seems unimpressive with the broken tibia occurring in childhood, and why he has heel pain is unclear. Classically, adult HPP presents in middle age with recurrent metatarsal stress fractures that eventually fail to heal and subsequently pseudofractures elsewhere (2). His metatarsal disease is considered avascular necrosis. Nevertheless, I am concerned that the patient's markedly low ALP and substantially increased PLP indicate that overt HPP bone disease, if not already present, will eventually manifest. Histological examination of an undecalcified specimen of iliac crest, to assess for osteomalacia characteristic of adult HPP, would be a key further test. A recent bone-targeted enzyme-replacement therapy (asfotase alfa) is bringing more notoriety to HPP (3) and improved recognition and appreciation for the many causes and significance of hypophosphatasemia. However, some clinical laboratories lag behind this progress by not providing age- and sex-matched reference intervals for ALP and, remarkably, several academic medical centers fail to report a lower reference limit.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References

(1.) Siller AF, Whyte MP. Alkaline phosphatase: discovery and naming of our favorite enzyme.J Bone Miner Res 2018;33:362-64.

(2.) Whyte MP. Hypophosphatasia and how alkaline phosphatase promotes mineralization. In: Thakker RV, Whyte MP, Eisman J, Igarashi T, editors. Genetics of bone biology and skeletal disease. 2nd Ed. San Diego (CA): Elsevier (Academic Press); 2018. p.481-504.

(3.) Whyte MP. Hypophosphatasia: enzyme replacement therapy brings new opportunities and new challenges. J Bone Miner Res 2017;32:667-75.

Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine and Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO.

* Address correspondence to the author at: Shriners Hospitals for Children, 4400 Clayton Avenue, St. Louis, MO 63110. Fax 314-872-7844; e-mail mwhyte@shrinenet.org. Received November 27, 2017; accepted December 8, 2017.

DOI: 10.1373/clinchem.2017.280784
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Title Annotation:Clinical Case Study
Author:Sodi, Ravinder; Hall, David
Publication:Clinical Chemistry
Date:Apr 1, 2018
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