A 1 year old child presents with massive elevation in ALP. (20X normal)Liver and bone disease must be ruled out. This child probably had transient hyperphosphataemia of infancy, which is a benign condition without sequalae. The ALP levels should return to normal within a few weeks.

A careful history, physical examination, and abbreviated laboratory evaluation are usually sufficient to rule out other causes of the elevated alkaline phosphatase (AP).

History — The clinician should inquire about bone disease (unexplained fractures, family history of bone disease, or complaints of bone pain); symptoms suggestive of liver disease (right upper quadrant pain, pruritus, steatorrhea, or dark-colored urine); drugs; renal disease; and nonspecific symptoms including anorexia, weight loss, fever, and lethargy.

Risk factors for nutritional rickets should be assessed, including exclusive breast feeding or intake of less than one litre of vitamin D-fortified formula or milk daily, dark skin pigmentation, low exposure to sunlight, or prematurity. These infants and children are at risk for rickets unless given vitamin D supplements of at least 400 IU daily.

Physical examination — The patient should be examined for deformities, tenderness, or other abnormalities of bone, including skeletal abnormalities associated with rickets (beading at the costochondral junction or bowing of long bones) and bone tenderness. The examination should also include assessment for hepatomegaly, splenomegaly, liver tenderness, scleral icterus, jaundice, and stigmata of chronic liver disease (palmar erythema, spider telangiectasia, clubbing, caput medusae).

Laboratory testing — Initial laboratory testing should include serum aspartate aminotransferase, alanine aminotransferase, total and direct bilirubin, gamma-glutamyl transpeptidase (GGT), calcium, phosphorus, 25-hydroxyvitamin D (calcidiol), parathyroid hormone (PTH), blood urea nitrogen, and creatinine.

A normal result for each of these tests is adequate to establish a provisional diagnosis of TH in an otherwise healthy infant or young child. Of note, the serum GGT activity is six to seven times the upper limit of the adult reference range in normal full-term neonates; levels decline and reach adult levels by five to seven months of age.

Measurement of alkaline phosphatase isoenzymes by electrophoresis has been documented in the literature but is usually not needed. The presence of excessive bone and liver fractions supports the diagnosis of TH and argues against primary hepatic or bone disease.

Transient hyperphosphatasemia (TH) of infancy and early childhood is characterized by a marked elevation of serum alkaline phosphatase (AP) in the absence of detectable liver or bone disease. Almost all cases occur in infants and children younger than five years of age.

• In TH, the serum AP is typically elevated four to five times the upper limit of the pediatric reference range, and gradually returns to normal within two to three months.
• Serum AP activities are higher in children than in adults because of physiological osteoblastic activity. The upper limit of the pediatric reference range is up to three times higher than in adults, peaking in late infancy and again during puberty.
• TH is characterized by elevations in both bone and liver alkaline phosphatase isoenzymes. The pathogenesis has not been fully established, but is thought to include reduced clearance of AP due to increased sialic acid content, perhaps caused by or compounded by a transient surge in alkaline phosphatase production.
• The evaluation should include a history and physical examination to assess for evidence of primary liver or bone disease. Laboratory testing should include measurement of serum aspartate aminotransferase, total and direct bilirubin, gamma-glutamyl transpeptidase calcium, phosphorus, 25-hydroxyvitamin D, parathyroid hormone, blood urea nitrogen, and creatinine.
• The possibility of rickets should be raised by low serum levels of 25-hydroxyvitamin D, calcium or phosphorus, elevated serum parathyroid hormone, a history of risk factors for vitamin D deficiency such as exclusive breast feeding without vitamin D supplementation, or typical skeletal abnormalities. Any of these findings should prompt further evaluation, including radiographs of long bones.
• Even if rickets is excluded, all children should be evaluated to ensure adequate intake of vitamin D and supplemented with at least 400 IU daily if needed. Steps should also be taken to ensure adequate intake of calcium.
• If there is no evidence of liver or bone disease in an infant or young child, then the provisional diagnosis of TH can be made. Repeat measurement of serum AP should be performed at intervals until normal values are attained.

INTRODUCTION — Transient hyperphosphatasemia (TH) of infancy and early childhood is characterized by a marked elevation of serum alkaline phosphatase in the absence of detectable liver or bone disease, and a return to normal levels within weeks or months. The condition is thought to be benign; thus, this disorder is also called benign transient hyperphosphatasemia. Recognition of this phenomenon permits avoidance of unnecessary procedures and concerns, provided that underlying liver and bone disease are appropriately excluded.

CLINICAL PRESENTATION — TH occurs most commonly in infants and children younger than five years of age. A few adults with similar patterns have been reported. The serum alkaline phosphatase (AP) is typically elevated four to five times the upper limit of normal, but elevations up to 20 times the pediatric upper reference limit (or 50 times the adult upper reference limit) have been described]. In most cases there are elevations in both liver and bone isoenzymes, and (rarely) in intestinal isoenzymes.

Serum AP levels gradually return to normal within two to three months but have persisted as long as six months in a few cases. In a systematic review, the duration of the AP elevation was more than four months in 20 percent of cases. The half-life of AP ranges from 5 to 25 days, depending upon coexisting morbidities. In series reporting the results of long-term follow-up, no clinical sequelae were noted up to four years after the episode of TH.

Most children with TH are healthy, although TH has occurred in association with a variety of clinical conditions, including gastroenteritis, respiratory infection, failure to thrive, and asthma. TH has also been reported with viral infections such as respiratory syncytial virus , enteroviruses, and HIV; following liver; or kidney transplant; and in children receiving chemotherapy for leukemia and lymphoma. Some of these apparent disease associations may reflect more frequent laboratory testing to monitor the underlying disease. Indeed, in the largest study that prospectively evaluated a healthy population of infants and toddlers, no association with growth parameters was found. A seasonal distribution of cases has been noted in some series, with more cases identified in late summer and early fal.

NORMAL RANGES FOR SERUM AP — Serum alkaline phosphatase (AP) 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. A second peak occurs in early puberty for girls (around 12 years) and mid-puberty for boys (around 14 years), coinciding with maximum height velocity. The timing of height velocity and AP peak varies with the timing of pubertal maturation

 PATHOGENESIS — The pathogenesis of TH is not well understood, as both liver and bone isoenzymes are usually increased. Several investigators have demonstrated that a fraction of both isoenzymes has a characteristic increase in electrophoretic mobility, due to increased content of sialic acid. This observation has led to the hypothesis that the hyperphosphatasemia is caused by excessive sialylation of alkaline phosphatase (AP), which slows clearance of the isoenzymes.

The cause of the increased sialylation remains uncertain. By definition, TH is not caused by vitamin D deficiency. However, one hypothesis is that TH develops because there is increased production of AP during a period of catch-up growth after weight loss or vitamin D insufficiency, at a rate that overwhelms the mechanisms that normally desialylate the enzyme. If so, children with TH might display subclinical vitamin D insufficiency at the time of diagnosis. However, this was not the case in one series of healthy infants and children, in which there was no difference in serum levels of vitamin D, parathyroid hormone, calcium, or phosphorus among subjects with TH as compared to those with normal AP levels.

EVALUATION AND MANAGEMENT — Awareness of the entity of TH can avoid unnecessary tests in infants and children with this disorder.

The possibility of rickets should be raised by low serum levels of 25-hydroxyvitamin D with low serum calcium and/or phosphorus, elevated levels of PTH, a history of risk factors for vitamin D deficiency (exclusive breast feeding without vitamin D supplementation), or typical skeletal abnormalities. Any of these findings should prompt further evaluation for rickets, with radiographs of long bones.

Bone pain or other bone abnormalities should be evaluated radiographically for evidence of tumor, fracture, or juvenile Paget disease (a rare autosomal recessive disorder of bone turnover associated with bone deformities and susceptibility to fracture). Limb pain also can be caused by a variety of orthopedic, infectious, rheumatic, and neoplastic disorders, as discussed separately

Monitoring — Children with vitamin D deficient rickets should be treated with replacement doses of vitamin D (ergocalciferol). All other children should be evaluated to ensure adequate intake of vitamin D and supplemented with at least 400 IU daily if needed; steps should also be taken to ensure adequate intake of calcium

Follow-up to document return of serum alkaline phosphatase (AP) levels to normal is critical for confirmation of the diagnosis of TH. In our practice, we repeat serum AP measurement in a child with the provisional diagnosis of TH within six to eight weeks until a downward trend is noted and normal values are attained. Sustained serum AP elevation beyond three to four months should prompt reconsideration of other causes of hyperphosphatasemia, including the bone disorders mentioned in the preceding section.

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