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Revista chilena de pediatría

versión impresa ISSN 0370-4106

Rev. chil. pediatr. vol.88 no.1 Santiago  2017 

Clinical Case


Benign transient hyperphosphatasemia in infants, clinical series



Luisa Schonhaut B., Ana Rocha R.

Department of pediatrics, Clínica Alemana de Santiago, School of Medicine, Universidad del Desarrollo, Santiago, Chile

Correspondencia a:

Introduction: Alkaline Phosphatase (ALP) is a group of 4 isoenzymes produced in different tissues. Elevated levels of ALP can be developed under physiological conditions, and can indicate the presence of bone or hepatobiliary diseases. In children, one of its most common harmless causes is benign transient hyperphosphatasemia (BTH), a little known condition. The objective is to report BTH cases and propose a monitoring plan. Case reports: The cases of 5 children aged between 11 and 50 months are presented, 4 of them female, with the incidental finding of a sudden and severe ALP elevation (> 1,000 U/l), in tests ordered due to either abnormal growth and development, or intercurrent infections. Bone and liver disease were ruled out using the patient history, physical examination and basic laboratory results. Isoenzymes levels were determined in 2 patients. A return to normal ALP levels was observed over a period of 1-6 months, with no evidence of further complications. Conclusion: BTH is a benign self-limiting biochemical disorder, which should be considered in children under 5 years old with severe ALP elevation in the absence of clinical or laboratory abnormalities suggestive of bone or liver disease.

Keywords: Alkaline phosphatase; Isoenzymes; Benign transient hyperphosphatasaemia.



Alkaline Phosphatase (ALP) is a group of 4 isoenzymes produced in different tissues such as bones, liver, kidney, placenta and bowel; in children approximately 85% of these are produced in the bones and the rest are primarily hepatic. Serum ALP activity varies throughout life, greater in children than in adults, especially during puberty, with an increment of 3 to 4 times above the reference value due to an elevated osteoblastic activity in the bone during pubertal growth1.

Hyperphosphatasemia is characterized by elevated serum levels of ALP and can be developed under physiological conditions, during pregnancy or puberty, under clearly pathological circumstances, in response to bone or hepatobiliary diseases, due to benign family history, Paget’s disease and under idiopathic conditions; one of the most frequent and harmless causes in infants and preschoolers is benign transient hyperphosphatemia in infancy (BTH).

In 1985 Kraut defined the diagnostic criteria for BTH that are still valid nowadays. Based on these references, BTH is presented in children under 5 years of age with a severe (greater than 1,000 IU/ l), isolated and transient elevation of ALP levels in the absence of signs and symptoms of bone or liver disease, returning to normal values ​​over a period of 4 months (table 1).

Table 1. Diagnostic Criteria for Benign Transient Hyperphosphatasemia (BTH), (Kraut, 1985)

The prevalence of BTH is difficult to estimate because it is usually an incidental finding in laboratory tests requested by different causes3,4. In healthy children, between 6 months and 5 years old, rates of severe ALP elevation from 2% to 6% have been reported5–7, condition not common in older children or adults8.

The aim of this paper is to report a case series of BTH, a differential diagnosis to be considered in the event of elevated ALP, and to propose management guidelines to avoid costly tests and unnecessary distress among parents and pediatricians.

Clinical Cases

A retrospective series on 5 children diagnosed with BTH between 2011 and 2015 is presented.

Patient 1

8 month-old infant, female, with a history of recurrent respiratory distress associated with abnormal growth and development since 6 months of age, progressive decrease in growth rate (H/A: 0.5 to -0.4 Standard deviation [SD]) and drop in weight/height ratio (W/H: -0.8 to -2DS), with normal physical examination. Blood count, VHS, biochemical profile, sweat test, liver profile and urine test were requested, all of which were normal. Blood count, VHS, biochemical profile, sweat test, liver profile and urine test were requested, all of which were normal. One finding that attracted attention was a plasma ALP elevation (1512 IU/l) (tables 2 and 3); to complete the study, after a month, repeated examinations were carried out to rule out bone and liver disease, with return of plasma ALP to normal levels of 343 IU/l. During the first year of follow-up, the patient presented a favorable clinical course with recovery of the development curve and decrease of the respiratory episodes.

Table 2. Clinical characteristics of the patients studied

Table 3. Laboratory characteristics of the patients studied

Patient 2

11-month old female, with a history of allergy to cow’s milk, diagnosed by a compatible medical history and positive counter-evidence, breastfed and use of a hypoallergenic formula. She presented a stable growth and development until 9 months (W/H -0.2 DS and H/A -0.5 DS), but evolved as steady weight and drop in weight/height curve (W/H -0.4 DS and H/A -0.8). Intercurrent high fever required general examinations and urine tests, compatible with urinary tract infection. Blood count showed leukocytosis with left shift and severe ALP elevation (4,552 IU / l), meanwhile calcium, phosphorus, and liver enzymes were within the normal range. Isoenzymes revealed predominance of bone over liver from 96.3% to 3.7% respectively (tables 2 and 3). It evolved with return of ALP to normal levels of 269 IU/l 3 months after follow-up and recovery of the development curve.

Patient 3

One year and 7 month-old female infant, previously healthy with good development and growth (W/H -0.4 DS and H/A 0.5 DS), whose tests showed a severe ALP elevation (5,553 IU / l) after prolonged fever with loss of appetite and vomiting (table 2). Isoenzyme measurements showed a predominance of the 75% bone over 24% hepatic. The rest of the study did not show hepatic or bone alteration through blood count, VHS, transaminases, calcium, phosphorus, parathyroid hormone (PTH); normal 25-OH vit D3 and bone scintigraphy levels (table 3). The follow-up of ALP levels after a month showed a slight increase over the previous value (5,857 IU / l), with good clinical recovery of intercurrent fever. At 3 months, values ​​decreased to 631 IU/l, returning to normal levels at 6 months, to a value of 297 U/l.

Patient 4

4 years 2 month-old female infant with Down syndrome and without a relevant medical history, with W/H > +2 DS; normal blood count, biochemical profile, transaminases, transglutaminase and urine antibodies after episodes of diarrhea and abdominal pain, but with an increase in ALP plasma values, 2,950 IU/l; a new ALP measurement was requested confirming high values ​​(2,212 Ul/l), and with normal calcium, phosphorus and PTH levels, but low levels of 25-OH vit D3 (17.5 mg / ml), initiating an intake of 800 IU/day of 25-OH vit D3 (tables 2 and 3). At 5 months of follow-up, the ALP levels were normalized to 373 IU/l, but with low levels of 25-OH vit D3, 22.3 mg/ml, increasing the intake of 25-OH vit D3 to 1,000 UI daily. The clinical evolution of the patient was favorable.

Patient 5

2 years 2 month-old premature male patient, 31 weeks of gestational age, birth weight of 1,400 g (25th percentile), birth size 39 cm (25th percentile), with a history of osteopenia, which recovered at 3 months of age after treatment with calcium and phosphorus. No other complications related to prematurity. Repeated studies of ALP, calcium and phosphorus were within a normal range. Due to a history of regular weight gain (W/H-0.3 DS and H/A -1.7 DS), at 2 years of age a complete new study was requested, which was normal (blood count, VHS, biochemical profile, liver profile, urine test, serology for celiac disease, 25-OH vit. D3 and thyroid study), except for a severe ALP elevation (1,583 IU/l) (tables 2 and 3). Monthly follow-up showed decreasing values, reaching normal levels after 3 months (222 IU/l).


A retrospective series of 5 children with incidentally detected severe (> 1,000 IU/l) and transient increase in ALP levels during 2011 and 2015 are presented. This finding was performed in laboratory tests requested by short height or intercurrent infectious disease. Four of the 5 patients were female, all younger than 5 years, coincident with what is reported5,7, as this condition has been described in children older than this age and/or in adults8, with a similar incidence in both genders9.

The etiology of BTH is still unknown, but the finding of respiratory and gastrointestinal viral infections, and the temporal coincidence with antibodies against different enteroviruses, leads to a probable infectious etiology 10; seasonality, another cause that would support this hypothesis, has not been consistent in all case reports, and it was not found in our series either 9,11. Other authors associate the transient ALP increase to an abnormal growth and development, which has not been demonstrated yet 5. These associations can be due to an individual selection bias, since in healthy infants, laboratory parameters are usually evaluated in relation to specific nutritional or infectious conditions. According to the evidence gathered in Gualco review, 35% of BTH is diagnosed in a routine evaluation9.

Liver or bone alterations were ruled out in all our patients by anamnesis, physical examination and basic laboratory tests, which measured levels of transaminases, calcium and phosphorus; in 4 children, 25-OH vit D3 and PTH levels, and in 2 others, isoenzymes levels were requested. The exception was patient number 4, whose levels of 25-OH vit D3 were in a low range, but in the absence of other signs suggesting rickets, it was concluded that this insufficiency would not explain the ALP increase. Patient 5 had a history of prematurity and osteopenia, he recovered during the first 3 months of corrected age, with normal ALP values ​​prior to the finding of BTH. Authors have reported a non-association of BTH with other laboratory parameters, such as vit 25-OH D3, PTH, calcium, magnesium and phosphorus levels5,7.

It is important to mention that because children were referred to the specialist by different pediatricians, there was no common criteria for the study or follow-up. This is why the isoenzymes test was only performed in 2 of 5 patients, in which, according to expectations, bone predominated over liver elevation. Although this is another criteria defined by Kraut, recent articles argue its value to confirm the diagnosis 11; Teitelbaum et al., in a prospective cohort study of 20 children with severe ALP increase and without evident disease, performed clinical follow-up and retest of ALP within 2 to 3 months without additional tests, demonstrating that the increase and subsequent regression of ALP (meeting Kraut’s other criteria) are enough elements12.

Kraut described that the return of ALP to normal levels occur within a period not exceeding 4 months, however, only in 81% of the published cases this criterion is met9. In the follow-up of our patients, we observed a return of ALP to normal levels in a slightly higher than expected period in 2 of the 5 patients.

It is important to keep in mind that when ALP increases as a response to skeletal diseases, as rickets, bone predominates (hyperphosphatase) and it is usually associated with abnormalities in calcium, 25-OH vit D3 and phosphorus levels, plus evident skeletal alterations. Polyostotic fibrous dysplasia, osteogenesis imperfecta, hereditary osteolysis and cystic fibrosis, as well as bone neoplasias and metastases may also produce an increase in ALP levels, but in these cases, elevation is accompanied by other clinical elements such as deafness, premature loss of teeth, hyperostosis enlargement of the long bones and pain in the phalanges of the hands, with accelerated bone remodeling and hypercalcemias.

Idiopathic hyperphosphatasia is a rare bone disorder and corresponds to the autosomal recessive form of Paget’s disease, which is characterized by bone turnover. The affected children are normal at birth and then have progressive diffuse bone malformations, such as collapse of the spinal bone, lengthening of the skull and deafness. Benign familial hyperphosphatemia is another type of non-pathological hyperphosphatemia with autosomal dominant inheritance, with ALP increase in the bone, liver and bowel, and values ​​generally range from 500 to 700 IU/l, plus one of the parents must be affected; bone scintigraphy is normal and bone or hepatobiliary diseases should be ruled out13. Table 4 shows the differential diagnosis of hyperphosphatasia.

Table 4. Differential diagnosis of severe hyperphosphatemia

Based on published evidence, we recommend that, in the absence of other altered clinical and biochemical parameters, in those patients younger than 5 years of age who present an incidental elevation of ALP above 1000 IU/l, BTH should be suspected and ALP measurement should be repeated within 2 to 3 months12,14,15. If ALP persists elevated, the quantification should be repeated at 4 months of follow-up and complemented with: calcium, phosphorus, PTH, 25-OH vit. D3, quantification of isoenzymes, carpal radiography and liver profile measurements. If the complementary examinations were normal and ALP levels remained high, a family group study is also recommended to rule out benign familial hyperphosphatemia. However, if there are no affected relatives, a larger study and a subsequent follow-up should be carried out to establish the differential diagnosis between sporadic benign persistent hyperphosphatemia and secondary hyperphosphatasemia. Clinical follow-up should continue until the return of ALP to normal levels (figure 1)3.

Figure 1. Suggested algorithm for the study and follow-up of children under 5 years of age with an incidental finding of severe hyperphosphatasemia.

ALP: Alkaline Phosphatase; Ca: Calcium, P: phosphorus; PTH: Parathyroid Hormone; 25OHD3: 25 OH Vitamin D3; LDH: lactate dehydrogenase; TA: transaminases; BTH: Benign Transient Hyperphosphatemia of Childhood. Clinical signs of bone disease: skeletal deformities, short stature, pathological fractures or bone pain. Clinical signs of liver disease: Jaundice, choluria, fecal acholia, and hepatosplenomegaly. Biochemical signs of bone disease: altered levels of calcium, phosphorus, 25OH Vitamin D3 and parathyroid hormone. Biochemical signs of liver disease: elevation of liver enzymes.


Nowadays BTH is accepted as a benign biochemical disorder rather than a clinical problem, with a self-limiting evolution and no following consequences, something important to keep in mind when confronting a case of a child with severe ALP increase in the absence of other clinical or laboratory disorders, so that unnecessary concerns and further examinations can be avoided.




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Ethical Responsabilities

Protection of people and animals: The authors state that the procedures followed ethical standards of the responsible human experimentation committee and in agreement with the World Medical Association and the declaration of Helsinki.

Confidentiality of data: The authors state that they have followed the protocols of their work center on the publication of patient data.

Privacy rights and informed consent: The authors state that they have obtained the informed consent from patients and subjects included in the study. These documents are in the possession of the corresponding author.

Conflict of interests

This work complies with the requirements of informed consent, ethics committee, funding, studies on animals and the absence of conflict of interest as required.

Received: 30-12-2015; Accepted: 28-4-2016

Correspondencia a:

Ana Rocha R.

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