Benign transient hyperphosphatasemia in infants and children: a retrospective database study

Abstract

Benign transient hyperphosphatasemia is a condition characterized by greatly increased serum alkaline phosphatase (ALP) without laboratory or clinical evidence of underlying bone or liver disease. It is usually identified incidentally during routine blood testing. We describe the demographic and clinical characteristics of benign transient hyperphosphatasemia in a cohort of healthy infants and children. We performed a retrospective review of electronic medical records on all children aged 1 day to 18 years with a diagnosis of benign transient hyperphosphatasemia, who were registered at 3 central districts in Israel from January 1, 2000, to December 31, 2020. The demographic and clinical characteristics were retrieved from the medical files. The study group comprised 382 infants and children aged from 2 months to 14 years who had serum ALP > 1000 U/L (mean 2557 U/L, range 1002–14,589 U/L). The majority of participants (87%) were aged up to 24 months (median age 14 months, IQR 10–18 months). Fifty-four percent of the study participants were male. In many patients, there was a history of recent fever, gastroenteritis or diarrhea, acute otitis media, and viral infection. A seasonal peak was observed in autumn-early winter, but this may be a detection bias.

Conclusion: Benign transient hyperphosphatasemia seems to be a disorder described among otherwise healthy infants and children, which resolves spontaneously. Other known causes of markedly elevated serum ALP should be excluded, especially bone and liver disease. Higher awareness and recognition of this benign condition are important in order to avoid unnecessary tests and parental anxiety.

What is Known: • Benign transient hyperphosphatasemia is a benign condition characterized by greatly increased serum alkaline phosphatase without laboratory or clinical evidence of underlying bone or liver disease, which usually resolves spontaneously, with no intervention.

What is New: • In the case of an incidental finding of high serum alkaline phosphatase in an otherwise healthy infant or child with no other clinical or laboratory suspicion of bone or liver disease, we recommend repeating the alkaline phosphatase level within a few months in order to confirm the resolution of this condition. • When benign transient hyperphosphatasemia is suspected, a “wait and see” approach is optimal in order to avoid unnecessary investigations and parental anxiety.

Introduction

Serum alkaline phosphatase (ALP) consists of a group of isoenzymes originating mainly from bone, liver, intestine, kidney, placenta, and white blood cells [1, 2]. In healthy children, the bone and liver fractions of ALP are predominant. The serum level of ALP changes with age: during the first 3 months of life, it is mildly elevated compared to adult levels, increases at puberty by 2- to threefold, and remains above the adult level for 1 or 2 years. The increase in ALP level during puberty is related to the bone growth spurt [2–4].

There is a wide differential diagnosis of elevated serum ALP: bone disorders (rickets, fractures, juvenile Paget’s disease, and bone malignancies), hepatic diseases (hepatitis, cholestasis, and malignancies), kidney diseases (chronic renal failure, renal tubular acidosis, and other tubulopathies), and certain drugs (antibiotics, anticonvulsants) [5]. A marked elevation of serum ALP values may be concerning to both pediatricians and parents.

Benign transient hyperphosphatasemia is a disorder of a temporary, markedly increased elevation of serum ALP in young children who have no evidence of liver or bone disease [6]. Benign transient hyperphosphatasemia is generally detected incidentally in laboratory tests requested for other purposes [7]. Kraut et al. [8] defined characteristic features of benign transient hyperphosphatasemia, including the age of presentation as less than 5 years, no evidence of bone or liver disease on physical examination or laboratory findings, elevation in both bone and liver ALP isoenzymes, and a return to normal serum ALP values within 4 months. Chu and Rothschild [9] incorporated Kraut’s original diagnostic criteria and updated them.

However, benign transient hyperphosphatasemia has also been reported in children older than 5 years, and rarely, in adults [10–13].

The aim of our study was to characterize the demographic and clinical characteristics of a cohort of infants and children diagnosed with benign transient hyperphosphatasemia.

Patients and methods

Clalit Health Services is the largest health provider in Israel. It is the largest of the four health insurer-provider health maintenance organizations (HMO) in Israel. According to the National Health Insurance law, all Israeli citizens resident in the country must be a member of one of the four health care providers. Clalit Health Services insures about 5 million (54%) of the Israeli population. The population of Clalit Health Services is generally counted as fairly representative of the entire population. While movement between HMOs is easy, actual transitions are less than 1% annually, and much lower among children, allowing full follow-up of cases. Each HMO supplies full virtually free medical coverage to its members.

The study includes three major districts in central Israel, Tel Aviv, and two adjacent districts covering a total of some 1.5 million members, almost all of whom are urban, and with a lower Arab proportion than the national population.

Clalit Health Services comprises a comprehensive computerized database, continuously updated with regard to subjects’ demographics, community and outpatient visits, laboratory tests, hospitalizations, medication prescriptions, and purchases. During each physician visit, a diagnosis is established according to the International Classification of Diseases, ninth revision (ICD-9).

Study population

The study population consisted of all subjects aged 1 day to 18 years who were registered in the central super-regions of Clalit Health Services during the study period (January 1, 2000, to December 31, 2020).

We performed a retrospective review of electronic medical records on all infants and children who had undergone at least two tests for serum ALP at community clinics. In our study, the diagnostic criteria for benign transient hyperphosphatasemia were ALP levels above 1000 IU/L among infants and children, with no evidence of liver or bone disease, and whose ALP values normalized within 7 months. We examined demographic variables (age, sex) as well as biochemical parameters, including serum ALP and other liver tests (AST, ALT, γGT, bilirubin), calcium, and phosphate levels, renal function test (urea and creatinine) in order to rule out bone or liver disease as an etiology for hyperphosphatasemia.

We excluded from our study patients with evidence of bone, liver, or renal disease, patients with vitamin D deficiency, or those receiving anti-epileptic drug therapy.

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Clalit Health Services (approval number 0050–21-COM).

Statistics

We extracted the study data into a central data table, which was anonymized for statistical analyses. Descriptive statistics were used to report the demographic and clinical variables of the study participants. The continuous variables were represented by mean, median, SD, and interquartile range (IQR). The categorical variables were represented in percentages.

Results

There were 382 infants and children diagnosed with benign transient hyperphosphatasemia. Their ages ranged from 2 months to 14 years. The median age was 1.2 years (IQR 0.93–1.52). The majority of participants (87%) were aged up to 24 months, and in this age group, most of the infants were aged 7 to 12 months. Fifty-four percent of the study participants were male. Characteristics of study participants are presented in Table 1.

Table 1.

Characteristics of 382 participants with benign transient hyperphosphatasemia

Characteristics	N (%)
Age range (years)
0–2	331 (87%)
3–6	47 (12%)
7–12	3 (0.8%)
13–18	1 (0.3%)
Age range (months)
0–6	8 (2.1%)
7–12	217 (56.8%)
13–24	106 (27.7%)
Sex
Male	208 (54%)
Female	176 (46%)
Duration of the benign transient hyperphosphatasemia (weeks)
4–8	160 (42%)
9–12	87 (23%)
13–16	57 (15%)
17–20	33 (8.6%)
21–24	33 (8.6%)
25–28	12 (3.1%)

All participants had serum ALP levels of > 1000 IU/L (range 1002–14,589 IU/L). The IQR 1368–2520 IU/L, median ALP level was 2014 IU/L. All study participants had a normal range of liver tests, calcium, phosphate and magnesium levels, and renal function test. The normalization period for serum ALP was between 4 and 28 weeks (median 9.1, IQR 6–14). In most participants (65%), serum ALP returned to the normal range within 4 to 12 weeks.

For all infants and children included in our study, the elevated serum ALP was an incidental finding during routine screening or screening for acute infection or other diseases, without a past (or known) diagnosis of bone disorders, hepatic disease, kidney disease, and drugs that can cause elevated level of ALP. Table 2 presents the underlying diagnoses at the determination of hyperphosphatasemia. The four leading diagnoses noted with hyperphosphatasemia included fever, gastroenteritis or diarrhea, acute otitis media, and viral infection in general. Three patients were diagnosed with failure-to-thrive. The majority of study participants with infectious diseases did not undergo serologic analyses or culture for infectious agents, and therefore, these data were not included in our study.

Table 2.

Underlying diagnosis in 382 infants and children at the determination of hyperphosphatasemia

Diagnosis	N (%)
Fever	106 (28%)
Gastroenteritis/diarrhea	94 (25%)
Acute otitis media	42 (11%)
Viral infection/disease	41 (11%)
Upper respiratory tract infection	33 (8.6%)
Pneumonia	30 (7.9%)
Tonsillitis/pharyngitis	17 (4.5%)
Urticaria/rash	9 (2.4%)
Bronchiolitis	4 (1.0%)
Urinary tract infection	3 (0.8%)
Failure to thrive	3 (0.8%)

The seasonal distribution of benign transient hyperphosphatasemia cases in our cohort is presented in Fig. 1.

Fig. 1.

Seasonal distribution of transient hyperphosphatasemia in infants and children

The incidence of benign transient hyperphosphatasemia in our study population was significantly higher in the autumn-early winter season (September–December) than in the rest of the calendar year (p < 0.0001, C² test). The lowest number of benign transient hyperphosphatasemia cases was in April.

Discussion

In this retrospective cohort study of healthy infants and children, we found that benign transient hyperphosphatasemia was more prevalent in toddlers aged younger than 2 years, but was also noted in older children and adolescents. According to the medical literature, the estimated prevalence of benign transient hyperphosphatasemia varies between 2.5 and 5.1%, depending on the different cut-off levels of serum ALP for defining hyperphosphatasemia [14].

Behúlová et al. [15] studied 194 cases of benign transient hyperphosphatasemia over 8 years. The peak ALP activity in their cohort was 2- to 20-fold higher than the pediatric upper reference limit. In that study, benign transient hyperphosphatasemia was detected in 49% of children in their second year of life, and in 96% of children younger than 5 years. Benign transient hyperphosphatasemia was associated with a variety of diseases, including gastrointestinal diseases, respiratory infections, congenital anomalies, and others [15].

Rasheed and Mayne reported 62 patients aged 0.2–14.6 years diagnosed with benign transient hyperphosphatasemia, with plasma ALP activity above 1000 IU/L. Of them, 15 (25%) were inappropriately investigated, and 5 (13%) were unnecessarily referred to tertiary care by their general physicians [16].

The exact etiology and pathogenesis of benign transient hyperphosphatasemia are unknown. The liver and/or bone isoenzyme levels of ALP appear to be increased in benign transient hyperphosphatasemia [8, 17]. Serum ALP elevation in benign transient hyperphosphatasemia might stem from a temporary increase in the release of ALP from the liver and bone, or an increase in sialylation of ALP, which results in a decreased hepatic clearance from the circulation [17, 18]. Several studies reported increased 25-OH vitamin D levels in benign transient hyperphosphatasemia [3, 4, 17]. Increased bone turnover or resorption was not found to be a causative factor for benign transient hyperphosphatasemia [9, 13].

Several studies showed that infectious agents, viral infections, in particular, are a possible etiology for the development of benign transient hyperphosphatasemia [4, 15, 17, 18, 20–23]. Suzuki et al. [20] reported 50 children younger than 8 years diagnosed with benign transient hyperphosphatasemia over a 3-year period. They found that the four most common infectious diagnoses observed in the benign transient hyperphosphatasemia cases were bronchitis, pneumonia, diarrhea, and fever. They detected antibodies for multiple enteroviruses [20]. Respiratory syncytial virus, Epstein–Barr virus, human bocavirus, rotavirus, HIV, and recently also the coronavirus — severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — were also found to be associated with benign transient hyperphosphatasemia [7, 24–29]. However, the co-occurrence of benign transient hyperphosphatasemia and infections might be incidental. Hue et al. investigated 316 children aged 8 to 24 months with benign transient hyperphosphatasemia and were unable to confirm the seasonal and viral infection predilection in this disorder [13].

A variety of acute infectious diseases leading to taking blood tests were reported at the time of diagnosis of our study cohort with benign transient hyperphosphatasemia. However, this association may most likely simply represent a detection bias, as there are more infections during the cold season, more children are examined by physicians, more blood tests are conducted and therefore more benign transient hyperphosphatasemia cases may be detected. The theory that the development of benign transient hyperphosphatasemia is associated with viral infection was considered to be supported by the clustering of benign transient hyperphosphatasemia cases during the autumn [15, 17] or winter [29]. Behúlová et al. found that 43% of 194 benign transient hyperphosphatasemia cases in Slovakia presented between September and November [15]. Crofton reported similar results among 35 children with benign transient hyperphosphatasemia in England [17]. Caroll and Coakley showed that among 21 children diagnosed with benign transient hyperphosphatasemia in Australia, a seasonal peak was noted in the winter [29], as demonstrated in our study. Australia and Israel enjoy a more temperate climate than Slovakia and England, where two other studies were conducted, and infections may be more prevalent during the cooler months of the year.

Three participants in our study (0.8%) were diagnosed with failure to thrive. Several previous retrospective studies reported the association between benign transient hyperphosphatasemia and failure to thrive [2, 19]. However, according to one group, comparison between studies is difficult, as most rely on not clearly defined clinical diagnoses, and the term “failure to thrive” is based on objective anthropometric criteria [13].

Otero et al. [30] suggested that if a thorough anamnesis and physical examination are normal in a child aged < 5 years who presents with elevated liver-ALP and bone-ALP isoenzymes, with normal levels of other liver enzymes and renal function tests then there is a high suspicion of benign transient hyperphosphatasemia and repeated ALP test can be withheld for 3 to 4 months [30].

The duration of abnormal serum ALP levels and the benign course and outcome of our study participants are similar to other studies published in the literature to date [3, 4, 8, 19, 29]. The majority of our study participants were aged up to 2 years, as previously published in other studies [6, 18]. Our study included 4 children aged > 6 years: all were boys, aged 6.1, 8.5, 11.1, and 14.4 years old. Two boys had routine blood tests, one had pneumonia and one had an upper respiratory tract infection. Serum ALP levels normalized in these four children within 1 to 2 months.

The main strengths of our study are threefold: the comprehensive demographic and clinical data retrieved from our computerized database; the relatively long study period; and the sizeable cohort. These factors may account for our ability to confirm a seasonal predilection at presentation. Our study did have some limitations. Firstly, its retrospective nature meant that data regarding serum levels of ALP isoenzymes, vitamin D, and PTH, as well as microbiologic tests (including blood serology, nose and throat viral cultures), were missing for most patients. Secondly, the selected serum ALP cut-off level might have reduced the number of participants. Thirdly, we did not collect clinical examination records (such as jaundice, spider angioma, rachitic rosary, craniotabes) but referred only to clinical diagnoses documented in the medical files. We believe that prospective studies will accurately estimate the incidence of benign transient hyperphosphatasemia and will elucidate its etiology and pathophysiology.

Conclusion

This study showed that benign transient hyperphosphatasemia is a condition described among healthy infants and children, which usually resolves spontaneously, with no intervention.

Therefore, in the case of an incidental finding of high serum ALP in an otherwise healthy infant or child with no other clinical or laboratory suspicion of bone or liver disease, we recommend repeating ALP level within a few months in order to confirm the resolution of this condition.

The identification of this benign condition is important in order to avoid unnecessary tests and parental anxiety.

Authors’ contributions

All the authors conceptualized and designed the study and drafted the initial manuscript. Dr. Moshe Hoshen performed the statistical analysis. All the authors wrote sections of the first draft of the manuscript and critically reviewed and revised the manuscript for important intellectual content. All the authors read and approved the final manuscript.

Availability of data and materials

No data sharing is available.

Declarations

Ethics approval and consent to participate

The study protocol was approved by Clalit Health Services Ethics Committee (Helsinki Institutional Review Board approval No. 0050–21-COM), which waived signed consent, as the study was not a clinical experiment and was based on an existing database.

Competing interests

The authors declare no competing interests.