what does it mean to have a low alkaline phosphatase?
J Clin Res Pediatr Endocrinol. 2018 Mar; 10(1): 19–24.
Could Alerting Physicians for Low Alkaline Phosphatase Levels Be Helpful in Early Diagnosis of Hypophosphatasia?
Asma Deeb
aneMafraq Hospital, Clinic of Paediatric Endocrinology, Abu Dhabi, United Arab Emirates
Abubaker Elfatih
2Shaikh Khalifa Medical City, Dispensary of Biochemistry, Abu Dhabi, United Arab Emirates
Received 2017 Feb 26; Accepted 2017 Jul 29.
Abstract
Objective:
Hypophosphatasia (HPP) is an inborn error of metabolism with significant morbidity and mortality. Its presentation is nonspecific leading to delayed or missed diagnosis. Low alkaline phosphatase (ALP) is a diagnostic test. Unlike loftier ALP, depression level is commonly not flagged by laboratories as abnormal. A new handling was shown to exist effective in HPP. In this study we aimed to constitute the frequency of low ALP levels requiring notification to physicians by the laboratory and also to describe the clinical manifestations of patients presenting with low ALP for a possible diagnosis of HPP.
Methods:
Patients under age eighteen years with low ALP levels were identified from biochemistry records over a period of 6 months. Reference ranges were used as per the Associated Regional and Academy Pathologists Reference Laboratory (Utah, Usa). Electronic results for patients with depression levels were checked for flagging as aberrant/low ALP results. Charts of identified patients were reviewed. Presenting features were categorized under groups of disorders.
Results:
ALP levels were tested in 2890 patients. 702 had values less than 160 U/L. Of these patients, 226 (32%) had age/gender specific low ALP. None of the low ALP results was flagged as low. Twenty-one had more than than one low reading and their charts were reviewed. Four patients in the neuromuscular and four in the miscellaneous group presented with features consistent with HPP despite these patients having no specific diagnoses.
Conclusion:
Laboratories do not alert physicians in cases with low ALP levels. A persistently low level in patients with unspecified diagnoses could be a key to diagnose HPP. Implementing lab-specific ranges and alerting for depression levels could prompt physicians to investigate for undiagnosed HPP.
Keywords: Alkaline phosphatase, hypophosphatasia, inborn error, laboratory, biochemistry
What is already known on this topic?
Hypophosphatasia is a rare disorder with significant morbidity and mortality. A loftier level of alkaline phosphatase is commonly highlighted past biochemistry labs. Asfotase alpha is a new and effective medication for hypophosphatasia handling.
What this study adds?
Unlike high element of group i phosphatase, low alkaline phosphatase is not e'er highlighted by biochemistry labs.
Identification of children presenting with not-specific clinical features and who accept more than i reading of low alkaline metal phosphatase could help diagnose children with hypophosphatasia. Devising lab specific reference ranges for element of group i phosphatase is important to avoid missing abnormally depression levels.
Introduction
Hypophosphatasia (HPP) is an inborn error of metabolism characterized past a low serum alkaline metal phosphatase (ALP) level due to a defect in the gene encoding the tissue-nonspecific isozyme of ALP (TNSALP) (1). Inheritance can be autosomal recessive or ascendant. As many equally 260 genetic mutations in the TNSALP factor have been associated with HPP (2). Penetrance is variable which results in a wide range of clinical features, with the spectrum ranging from stillbirth with no bone mineralization to early on loss of teeth without bone symptoms. Clinically, there are 6 forms of HPP based mainly on historic period at presentation: perinatal (lethal); perinatal (benign); infantile; childhood; adult and odontohypophosphatasia (1,3). Astringent forms of HPP (perinatal and infantile) are inherited equally autosomal recessive traits and in milder forms (adult and odontohypophosphatasia), autosomal recessive and autosomal dominant inheritance coexist (4). Genotype is known to exist associated with specific outcomes in the perinatal lethal blazon, whereas genotype/phenotype correlation is less pronounced in other, less astringent forms (5). HPP causes major morbidity in patients with substantial bone illness, myopathy and weakness. Hypercalcemia associated with nephrocalcinosis is a known characteristic of HPP (1). Craniosynostosis and skull dysmorphology occur in effectually 40% of infants (6). HPP is almost always fatal early in life when astringent skeletal disease is obvious at birth (1,7). Skeletal deterioration typically results in death from respiratory insufficiency (7). Bone fragility and recurrent fractures tin can be presenting features of HPP in childhood (8). The perinatal form might present with intractable seizures caused by secondary pyridoxine-deficiency encephalopathy. This is due to deficiency of ALP that is required for the metabolism of pyridoxal-5'-phosphate neurotransmitters (ix). Accordingly, HPP should be considered in neonates presenting with convulsions responding to pyridoxine. Although some of the in a higher place features might bespeak to the diagnosis of HPP, other presenting features of HPP can be less specific and include various symptoms and signs encountered in more common diseases (10). Appropriately, clinical diagnostic criteria for HPP are unspecific and confirming the diagnosis requires biochemical, radiological and perchance genetic testing. This fact has been a major reason for the disease to exist both underdiagnosed and misdiagnosed (11). A low ALP is a fundamental for differentiating the diagnosis of HPP from many other more common paediatric disorders (2). Alerts past biochemistry laboratories on abnormal levels of ALP are useful to draw attention to specific diagnoses. Although a loftier level of ALP is usually highlighted past biochemistry labs, low levels are non ordinarily flagged. Alerting for low ALP level could be an opportunity for the early diagnosis of HPP patients presenting with nonspecific manifestations. Early on detection of HPP will offer these patients the opportunity to benefit from a new enzyme replacement treatment that has recently been shown to be an effective modality to treat this potentially fatal affliction (12,13). This report was designed to check if biochemistry laboratories alarm physicians to depression ALP levels and too on the necessity of examining clinical features in those patients who accept persistently low ALP levels.
Methods
Using a cut-off level of 160 U/50, the electronic records of the Biochemistry Laboratory at Mafraq Infirmary, covering a report period of six months, from July 2014 to December 2014, were screened for patients aged 18 years or under who had low ALP readings (phase I). As the study was based on charts review, no consent was deemed necessary every bit per the local inquiry and ethics commission who approved the written report. The cutting-off value of 160 U/L was selected based on the Associated Regional and University Pathologists (ARUP) Reference Laboratory (Utah, The states) online test directory, being the highest level of the low range of ALP (14) (www.aruplab.com). The list of patients with depression ALP was filtered by age and gender in accord with the ARUP lab reference ranges (phase Two). The biochemistry laboratory records were also evaluated for highlighting abnormally. Patients who had at least two readings of ALP lower than normal value per age and gender together with no other normal values had their charts reviewed (phase 3).
Three groups of patients were excluded:
- Patients who had ii low values of ALP simply had one or more than normal value detected on subsequent testing.
- Those with a single low value of ALP with a normal value later or earlier.
- Only one borderline normal value at one presentation of astute illness with no further history of disease.
In the remaining records, a list of the main diagnoses of the patients was made and stratified into subcategories (phase IV). Details of the patients' presentations, working diagnoses and features suspicious of HPP were noted. The categories of diseases linked with a possible diagnosis of HPP included musculo-skeletal, rheumatological, neurological, renal, respiratory-related diseases and fractures. The guess number of patients with suspicion of HPP was estimated and their presenting features reported for each disease category was noted for utilise in further studies. The study was approved by the Enquiry and Ethics Committee at Mafraq Hospital (blessing number: MAF-REC-12/2015_06). The ALP level was measured on a fully automated Roche Cobas ® 8000 modular analyzer series c701 system (Roche Diagnostics GmbH, Mannheim, Germany, 2010). The assay is a basic, standardized, colorimetric assay traceable to the International Federation of Clinical Chemistry Reference Gen2 method as an optimized assay. ALP is measured in a reaction whereby ALP catalyzes the cleavage of phosphate from 4-nitrophenyl phosphate to form 4-nitrophenoxide (benzenoid grade), which undergoes spontaneous rearrangement at alkaline pH to the quinonoid grade (yellow color). The reaction is followed by measuring absorbance of the reactant color at 405 nm on the automated analyzer detection organization. The ALP assay performance specifications include an analytical measuring range of 5-1200 U/L, with a lower detection limit (analytical sensitivity ie the lowest measurable analyte level that can be distinguished from nix) of 5.00 U/L. The assay has a clinically reportable range of five.00-6000 U/L. The ALP analysis has a within-run precision coefficient of variation (CV%) of 0.vii% at an ALP hateful of 84.3 U/L and of 2.4% at a hateful of 92.8 U/L, while the analysis demonstrates a CV of 0.5% at an ALP mean of 222 U/50 and a CV% of 1.vii% at a hateful of 224 U/L. The inter-individual CV is 6.7%, with an intra-individual CV of 25.4% and a critical significant difference of 37%.
Results
During the vi-month report menstruation, there were 2890 tests for ALP performed in subjects 18 years of age or younger. In stage I of the report, this number was reduced to 702 patients who had readings below 160 U/L. None of the low levels of ALP was flagged equally abnormal by the biochemistry lab. Age stratification for normal reference values was performed, resulting in 349 patients being selected (stage Ii). Further filtering was done to this group to match reference range with gender. This reduced the number of patients to 226 at this stage (phase 3). Of those, 1 patient (male) was in the historic period bracket of xvi-eighteen years, 24 (20 males) between 14-15 years, 24 (xiv males) between 12-xiii, 19 between 10-11 years (NB from this age and younger, there is no gender divergence in the quoted lower normal value for ALP), 35 between vii-9 years, 74 between iv-6 years, 48 betwixt 1-3 years and ane betwixt 1-11 months (Table 1). Charts for all patients identified in stage III were reviewed. Two hundred and five patients were excluded equally per the exclusion criteria and 21 patients were studied further (Figure ane). The 21 patients were classified under disease categories based on presentation and working diagnoses. These were; rheumatologic disorders (five patients), fractures (five patients), neuromuscular diseases (four patients), immobility and repeated fractures (three patients) and a miscellaneous grouping (4 patients) (Table 2). The five patients in the rheumatology category had a confirmed diagnosis of systemic lupus erythematosus (3 patients) and juvenile rheumatoid arthritis (two patients). 5 patients had a single fracture of a long bone. Of those, one had a dislocated shoulder with a fracture of the humerus and another had orthodontic handling for teeth malposition and crowding. Three patients were diagnosed with cognitive palsy and were immobile with repeated fractures. The neuromuscular category included four children who did non have definite diagnoses. Two had arthrogryposis, i of whom also had repeated fractures. One presented with multiple skeletal deformities and the fourth patient had neuromuscular deformities with fractures. The miscellaneous group included a child with Down syndrome who was diagnosed with brusque limbs antenatally and admitted to the intensive intendance unit repeatedly with recurrent chest infections. I kid was diagnosed with nemaline myopathy and had kidney stones and some other was diagnosed with severe demyelinating sensory and motor neuropathy. The fourth patient had repeatedly low ALP readings and suffered from recurrent infections. The selected patients could potentially have HPP every bit their presentation is quite unspecific and their ALP is persistently low. Further diagnostic testing (particularly genetic testing) is recommended in these scenarios. This is mentioned below as a limitation of our study.
Table 1
Numbers of patients with depression element of group i phosphatase concentrations for age and gender (full 226)
Table 2
System interest in 21 patients with persistent low alkaline phosphatase and repeated medical presentations
Flow nautical chart showing of number subjects with depression alkaline metal phosphatase levels past age and gender
Discussion
HPP is a affliction that is associated with major co-morbidity and poor prognosis. The wide range of presenting features which are non-specific constitutes a complicating factor in its diagnosis (11). In the past, various treatment approaches accept been tried to treat the severe form of the affliction with poor results. Handling modalities included transplantation therapy using bone fragments and cultured osteoblasts (7), infusion of enriched plasma with ALP from patients with Paget disease (15), bone marrow transplant (16) and bourgeois treatment using low calcium milk and pamidronates (17). Calcitonin and chlorothiazide accept been used to reduce calcium level, which tin can reach very high levels (18). Bisphosphanates are pyrophosphate analogs and can precipitate the disease progression. Patients with undiagnosed HPP presenting with fractures and osteoporosis and treated with bisphosphanate are reported to progress into renal failure (xix) and using bisphosphanate to care for HPP is currently contraindicated. Asfotase Alfa is a recombinant, fusion protein comprising the TNSALP ectodomain and a terminal deca-aspartate motif for bone targeting (20). Information technology has been used in clinical trials and was shown to enhance healing of skeletal abnormalities and improve respiratory and motor dysfunction (12). Asfotase alfa has now been approved by the European Medicines Bureau for utilize in patients with HPP (13).
In our cohort, nosotros detected a grouping of patients who had low ALP levels, only no specific diagnosis (Table 2). Despite the depression ALP level in more than than ane occasion of testing, there was no alert by the biochemistry laboratory cartoon attending to the low value. In two groups of patients, those with rheumatic diseases and those with fractures causing immobility, the ALP abnormality could exist possibly attributed to the underlying illness. In a third group of patients, those with single fractures, the patients were healthy otherwise and unlikely to have an undiagnosed HPP. Still, some patients in the neuromuscular disorder group (four patients) and the miscellaneous group (four patients) are worth examining further to rule out the possibility of HPP. Two patients in particular in the miscellaneous grouping had repeated episodes of chest infection and intensive care unit admissions and one had a kidney rock. The four patients in the neuromuscular grouping had skeletal deformities and fractures and they did non have a specific diagnosis. They, too, authorize for further investigations to exclude HPP. Loftier levels of ALP can be encountered in a variety of os disorders, but low levels are not as often seen in clinical exercise. A high ALP level is routinely flagged up by the biochemistry lab but this is not the instance for low ALP levels. Biochemistry labs demand to accept reference ranges for ALP levels to highlight possible abnormalities particularly in case of associated hypercalcemia. The ALP analysis is widely available and is a fairly inexpensive test. It is a cardinal for diagnosing HPP and makes a skilful screening examination to diagnose HPP for which an effective treatment is now available.
Written report Limitations
The main limitation of the study is that nosotros did non confirm the diagnosis of HPP in those suspected cases where a definite cause for the ALP was not reached. Further plans for genetic testing on such suspected cases volition facilitate the diagnosis.
Conclusion
We conclude that persistent depression ALP levels in patients presenting with non-specific signs and symptoms tin exist used as a guide to farther investigate and exclude HPP. This is especially important because medication is at present available for HPP and has been shown to be effective in ameliorating morbidity and improving quality of life in this disease. Accordingly, the alerting of physicians to low levels of ALP by biochemistry labs tin can be very useful. We highlight the importance of having age and gender adjusted ALP reference ranges, specific for local laboratories or populations, to avoid missing the diagnosis of HPP. A clear plan of activeness needs to be fatigued on how to proceed with patients with low ALP levels and non-specific presentation.
Footnotes
Ideals
Ethics Commission Approval: The study was canonical past the Research and Ethics Committee of Mafraq Hospital (approving number: MAF-REC_12/2015_06).
Informed Consent: Every bit the study involved patients chart reviews rather patients interview or samples taking, information technology was deemed past the ethics committee that informed consent is not necessary to undertake the study.
Peer-review: Internally peer-reviewed.
Contributed past
Authorship Contributions
Surgical and Medical Practices: Asma Deeb, Concept: Asma Deeb, Abubaker Elfatih, Design: Asma Deeb, Abubaker Elfatih, Information Drove or Processing: Abubaker Elfatih, Analysis or Estimation: Asma Deeb, Abubaker Elfatih, Literature Search: Asma Deeb, Abubaker Elfatih, Writing: Asma Deeb.
Fiscal Disclosure: The authors declared that this study received no financial back up.
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Articles from Journal of Clinical Research in Pediatric Endocrinology are provided here courtesy of Galenos Yayinevi
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838368/
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