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Article CommentaryClinical Case Study

A Man with Recurrent Fractures and Foot Pain

Ravinder Sodi, David Hall
DOI: 10.1373/clinchem.2017.275628 Published March 2018
Ravinder Sodi
Department of Biochemistry, Blood Sciences, Royal Lancaster Infirmary & Furness General Hospital, University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, UK; Lancaster Medical School, University of Lancaster, Lancaster, UK;
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  • For correspondence: Ravinder.Sodi@mbht.nhs.ukravsodi@yahoo.com
David Hall
Medwyn Medical Practice, Carnwath, Lanarkshire, UK.
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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, co-codamol, 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-to-pyridoxic acid (PA) ratio (reference, <5 using SI units) (2).

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Table 1.

Selected biochemical and hematological results.a

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).

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Table 2.

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

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). Odontohypophosphatasia 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 PLP-to-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).

Footnotes

  • ↵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.

  • 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.

  • Received for publication April 24, 2017.
  • Accepted for publication August 11, 2017.
  • © 2017 American Association for Clinical Chemistry

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A Man with Recurrent Fractures and Foot Pain
Ravinder Sodi, David Hall
Clinical Chemistry Apr 2018, 64 (4) 639-642; DOI: 10.1373/clinchem.2017.275628
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A Man with Recurrent Fractures and Foot Pain
Ravinder Sodi, David Hall
Clinical Chemistry Apr 2018, 64 (4) 639-642; DOI: 10.1373/clinchem.2017.275628

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