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Journal of Pediatric Endocrinology & Metabolism, 23, xxx-xxx (2010)
Benign Transient Hyperphosphatasemia of Infancy. A Common Benign Scenario, a Big Concern for a Pediatrician Alfredo Eymann1, Nicolás Cacchiarelli1, Guillermo Alonso2 and Julián Llera1 1
Clinical Pediatric Service and 2Pediatric Endocrinology Section, Department of Pediatrics at the Hospital Italiano de Buenos Aires, Argentina ABSTRACT
Benign transient hyperphosphatasemia of infancy (BTH) is a condition characterized by disproportionately high levels of SAP. We report 4 cases of healthy patients with an elevated serum alkaline phosphatase. The mean age of the patients was 33 (14-52) months, with three females and one male. All children had a normal physical exam and anthropometric measures. The maximum values of serum alkaline phosphatase recorded in the 4 patients were: 11900, 6500, 9700 and 7600 UI/L respectively, with the rest of the laboratory exams and diagnostic images being normal. The clinical course of all the patients was favourable and no patient presented signs of symptoms of illness. Blood was drawn on 6 occasions in patients 1 and 5 occasions in the rest. Benign transient hyperphosphatasemia of infancy was diagnosed. It is important to know the characteristics of this condition to order the necessary amount of complementary studies.
KEY WORDS
hyperphosphatasemia, benign transient hyperphosphatasemia of infancy, serum alkaline phosphatase, rational approach for diagnosis
INTRODUCTION
physical exam, it is sometimes necessary to order and interpret complementary studies (CS) to achieve a better understanding of the clinical situation. However, the ordering of these tests is not always adjusted to logically search for risk factors and pathologies according to epidemiological and pathophysiological criteria. One specific analysis that is often carried out in this context is a hepatogram that evaluates, among other values, the activity of serum alkaline phosphatase (SAP). This level is determined by the action of a diverse family of isoenzymes, the most quantitatively significant of which are found in the biliary surface of the hepatocyte and in the osteoblast. Benign transient hyperphosphatasemia of infancy (BTH) is a condition characterized by disproportionately high levels of SAP. It was first described by Bach in 19541, with diagnostic criteria defined in 1985 by Kraut et al.2. Although it has been the subject of various scientific studies since then, primary care physicians often lack sufficient knowledge of this condition and therefore frequently fail to recognize or even suspect it. We believe it is important to document the management of patients with BTH in order to help avoid the unnecessary ordering of further diagnostic exams in patients that present with an elevated SAP. Our objective is to describe 4 healthy patients that presented to the outpatient pediatric clinic with an elevated SAP as well as the other diagnostic criteria of BTH. In light of these cases, we will also conduct a review of the existing literature on this condition.
While the majority of clinical diagnoses can be made based on a detailed history and adequate PATIENT REPORTS Corresponding author: Alfredy Eymann
[email protected] VOLUME 23, NO. 6, 2010
We describe the case history of 4 patients who presented to the outpatient pediatric clinic during 1
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A. EYMANN ET AL
the year 2005. Data from the following studies were collected: complete blood count (CBC), erythrosedimentation rate, hepatogram, gammaglutamyltransferase, calcium, phosphate, isoenzymes of SAP, uremia, creatininemia, calciuria, creatininuria, 25- hydroxyvitamin D, X-ray of the hand and wrist, X-ray of the sella turcica and long bones, bone scan and abdominal ultrasound. The SAP was measured using a motionrelated method that utilized a 2-amino-2-methyl1-propanol plug with reactive alkaline phosphatase. The reference value for children up to 5 years old is 60-321 UI/L. The mean age of the patients was 33 (14-52) months, with three females and one male. All children had a normal physical exam and anthro-
pometric measures (Table 1). The maximum values of SAP recorded in the 4 patients were: 11900, 6500, 9700 and 7600 UI/L respectively, with the rest of the laboratory exams and diagnostic images being normal. The reasons for ordering CS were: fever, asthenia, low weight and preoperative inguinal hernia. An elevated family demand to order CS was recorded in the first 3 cases. The clinical course of the all the patients was favourable and no patient presented signs of symptoms of illness. Blood was drawn on 6 occasions in patients 1 and 5 occasions in the rest. Table 2 describes the number and type of complementary studies carried out.
TABLE 1
Clinical characteristics Patient number
Sex
Age (months)
Reason for ordering lab tests
Maximum SAP* value (UI/L)
Period of normalization (months)
Weight Z score
Height Z Score
1
F
39
Fever
11900
3
- 1,57
- 1,18
2
F
52
Asthenia
6500
8
+ 0,29
- 0,47
3
M
14
Low weight
9700
4
- 1,19
+ 0,16
4
F
27
Preoperative
7600
2
+ 0,93
+ 0,62
*SAP: serum alkaline phosphatase TABLE 2
Type and number of complementary studies ordered Patients
Laboratory studies
Diagnostic Imagery
1
CBC (6), hepatogram (6), erythrosedimentation (3), calcium (3), phosphate (3), gamma- glutamyltransferase (2), 5-nucleotidase (2), LDH (2), bony SAP, SAP isoenzymes, hydroxyvitamin D, complete urine, calcium and urinary creatine CBC (5), hepatogram (5), erythrosedimentation (2), calcium (2), phosphate (2), gamma- glutamyltransferase (2), 5-nucleotidase (2) and complete urine
Rx of hand and wrist, Rx of sella turcica and long bones, bone scan, abdominal ultrasound.
3
CBC (5), hepatogram (5), erythrosedimentation (2), calcium (2), phosphate (2) complete urine
Rx of hand and wrist
4
CBC (5), hepatogram (5), erythrosedimentation, calcium (2), phosphate (2), coagulogram and complete urine
Rx of hand and wrist
2
Rx of hand and wrist
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BENIGN TRANSIENT HYPERPHOSPHATASEMIA OF INFANCY
DISCUSSION
The ordering of SAP in all 4 patients was always circumstantial (preoperative studies or in order to evaluate hyperpyrexia, asthenia, and low weight). The value was normalized over the course of 4 months in all of the patients, with exception of one that normalized at 8 months. These findings are consistent with previous published case studies in which patients achieved normalization after 4 months. In light of these results, the diagnostic criteria of BTH are currently being revised3,4. The clinical course and the CS of the patients described in this study are similar to those reported in the published literature4-6. Serum alkaline phosphatase is a group of 4 isoenzymes that originate primarily from the bone, liver, placenta, intestine and kidney. The different SAP isozymes represent molecules encoded by different genes with similar activity and specific expression in different tissues. Under normal physiological conditions in pediatric patients, the bone isoenzyme contributes 85% to the SAP and the liver isosenzyme contributes 15%. SAP activities are generally higher in children than in adults because of physiologically higher rates of osteoblastic activity. In infants, activities are approximately three times the upper reference limit for adults, peaking between one and six months of age. By two years of age, serum AP levels fall to approximately twice the upper reference limit for adults. SAP increases again 2-3 times during puberty at the expense of the bone isoenzyme and maintains this high value for 1 or 2 years before reaching adult values5,6. BTH is characterized by a marked increase in SAP, which spontaneously returns to normal after 4 to 6 months. The elevated SAP value is generally found incidentally in routine laboratory studies or during the evaluation of other illnesses, as occurred in the patients presented in this study. It is a transient, benign and self-limited entity described by Bach. Kraut et al. determined the diagnostic criteria and delineated an increase in SAP of 3 to 50 times as normal value in addition to the following characteristics: 1) an age of less than 5 years; 2) variable seemingly unrelated symptoms ranging from normal control to severe VOLUME 23, NO. 6, 2010
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neurological or gastrointestinal syndromes; 3) no evidence for bone or liver disease on physical examination; 4) no biochemical or laboratory evidence for bone or liver disease except for the spectacular isolated rise in SAP activity; 5) an SAP isoenzymes analysis showing an elevation in both bone and liver activity; and 6) a return to normal SAP activity values within four months2. Finally, it is important to clarify that the SAP values found in this condition are significantly greater that those normally found in pathologies of bone and liver. These criteria are currently under revision and there have already been published cases with patients older than 5 years of age and normalization periods of greater than 4 months from the time of the diagnostic test. Most children with SAP elevations are healthy, although it has occurred in association with a variety of clinical conditions, including liver diseases, leukaemia and lymphoma, rickets and other metabolic osseous diseases7,8. SAP elevations have also been reported with viral infections such as gastroenteritis, upper respiratory infections, HIV infections or following liver or kidney transplant. Some of these apparent disease associations may reflect more frequent laboratory testing to monitor the underlying disease. A limitation of this study is that we only measured the isoenzymes of SAP in the first patient. In the remaining 3 patients in whom the isoenzymes were not measured, a diagnosis of BTH was based on SAP normalization and no subsequent development of illness in the following year. The pathogenesis of this condition is unknown. Different theories have attempted to explain the increase in SAP as an increase in intracellular synthesis, a rupture in the anchor of alkaline phosphatase from the cellular membrane, a decrease in plasma degradation, and activation of the circulating enzyme5. In other studies on BTH, there is no evidence of either bony or hepatic disease. It is important for the clinical pediatrician, when faced with an elevated SAP value, not to order unnecessary diagnostic studies. The diagnostic criteria of this condition include the absence of bony and hepatic disease, which is why studies must be ordered to
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rule them out when a patient presents with an elevated SAP level. As a primary diagnostic evaluation, we consider is necessary to carry out, at the very least, the following tests: calcium, phosphate, X-ray of the wrist, complete hepatogram including gamma-glutamyltransferase and the measuring of SAP isoensymes. The need to order a more complete set of studies depends on the unique clinical situation of the patient and the results of the studies previously described. When a patient presents with an elevated SAP, no diagnostic evidence of bony or hepatic disease, and the first four diagnostic criteria of BTH, It is recommended to continue with clinical surveillance and laboratory testing until the SAP level normalizes. BTH is a benign, transitory and self-limited entity. It is important to know the characteristics of this condition to be able to communicate its course and prognosis to the family as well as order the necessary amount of complementary studies. ACKNOWLEDGEMENT
translation of this article.
BIBLIOGRAPHY 1. Bach U; Das verhalten der alkalischen serumphosphatase bei Frughgerborenen. Rachitikern und Spasmophilen. Z Kinderheilk 1954; 74: 593-609. 2. Kraut JR, Metrick M, Maxwell NR, et al: Isoenzyme studies in transiente hyperphosphatasemia of infancy, in new cases and review of the literature. Am J Dis Child 1985; 139:736-740. 3- Griffiths J. Transient hyperphoaphatasemia of infancy and childhood. Arch Patol Lab Med 1995; 119: 784789. 4. Garrote de Marcos J. Hiperfosfatasemia transitoria benigna. Aporte de veinte nuevos casos. An Esp Pediatr 1996; 44: 112-116. 5. Tolaymat N, Nunes M: Benign transient hyperphoaphatasemia of infancy and childhood. Southern Medical Journal 2000. 93; 12: 1162-1164. 6. Pace A., Osinde M: Hiperfosfatasemia benigna de la infancia. Una aproximación diagnóstica racional. Arch Arg de pediatria. 1999; 97 (6):383-389. 7. Massey GV , Dunn NL, Heckel JL. Benign transient hyperphoaphatasemia in children with leukemia and lynphoma. Clin Pediatr 1996; 35 :501-504. 8. Koneru B Mrked transient alchaline phosphatemia following peditric liver transplantation. Ann J Dis Childhood 1989; 143: 569-670.
We would like to thank Samuel Funt for the
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