Transient hyperphosphatasemia of infancy and early childhood

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, with a return to normal levels within weeks or months. Because the condition is thought to be benign, it is also called benign TH. Recognition of this phenomenon permits avoidance of unnecessary procedures and concerns, provided that underlying liver and bone disease are appropriately excluded.

The clinical presentation and evaluation of an infant or young child with marked elevation of serum alkaline phosphatase will be reviewed here. Evaluation of an older child or adult with elevated alkaline phosphatase, or of any individual with elevations of multiple liver enzymes, is discussed separately. (See "Enzymatic measures of hepatic cholestasis (alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)" and "Approach to the patient with abnormal liver biochemical and function tests".)

EPIDEMIOLOGY — TH is most common in young children, with a peak prevalence between 6 and 24 months of age. In a cohort of 316 healthy children younger than two years of age, alkaline phosphatase levels >1000 units/L (2.5 times the upper limit of normal) were found in 2.8 percent [1]. More moderate elevations of alkaline phosphatase (between 400 and 1000 units/L) were found in 5.1 percent of the subjects. A slightly higher prevalence rate was found in a Swedish study in healthy children aged 6 months to 18 years. Elevated serum alkaline phosphatase levels >1000 units/L were noted in 6 of 97 children, all of whom were between 7 and 22 months of age. Hence, the prevalence of TH in the age group from six months to two years was 6.2 percent. None of the children older than two years had serum alkaline phosphatase levels >1000 units/L [2].

Most children with TH are healthy. TH has also been reported in association with poor weight gain, asthma, viral infections (eg, respiratory syncytial virus [3-5], enteroviruses [6], Epstein-Barr virus [7], HIV [8] and severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] [9]), liver or kidney transplantation [10-12], treatment with cyclosporine [13], or chemotherapy for leukemia and lymphoma [14,15]. 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 poor weight gain or other growth parameters was found [1]. A seasonal distribution of cases has been noted in some series, with more cases identified in late summer and early fall [14,16].

A retrospective review over a 20-year period revealed similar findings. In this study cohort of 382 children <14 years of age with serum alkaline phosphatase >1000 units/L (mean 2557 units/L, range 1002 to 14,589 units/L), the median age was 14 months (interquartile range 10 to 18 months), 87 percent were <24 months, and only 1 percent were older than seven years of age [17]. In many cases, the laboratory testing was prompted by an intercurrent illness, such as fever, gastroenteritis, acute otitis media, or viral infection; a seasonal peak was observed in autumn to early winter.

CLINICAL PRESENTATION — TH is usually identified as an incidental finding when an isolated elevation in serum alkaline phosphatase is noted during laboratory testing for routine health care, or as part of an evaluation for a specific complaint. TH occurs most commonly in infants and children younger than five years of age. A few adults with similar patterns have been reported [18-23]. The serum alkaline phosphatase concentration is typically elevated four to five times the upper reference limit, but elevations up to 20 times the pediatric upper reference limit (or approximately 50 times the adult upper reference limit) have been described [16,23-25]. In most cases, there are elevations in both liver and bone alkaline phosphatase isoenzymes and (rarely) in intestinal alkaline phosphatase isoenzymes [16,26].

NORMAL RANGE FOR ALKALINE PHOSPHATASE — Serum alkaline phosphatase 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 [24]. By two years of age, serum alkaline phosphatase activity falls to approximately twice the upper reference limit for adults (figure 1). 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 alkaline phosphatase peak varies with the timing of pubertal maturation. (See "Measurement of growth in children", section on 'Height velocity'.)

PATHOGENESIS — The pathogenesis of TH is not well understood because both liver and bone alkaline phosphatase isoenzymes are usually increased. A fraction of both isoenzymes has a characteristic increase in electrophoretic mobility due to increased content of sialic acid [14,24]. The sialylation delays clearance of the isoenzyme from the circulation. This observation has led to the hypothesis that the hyperphosphatasemia seen in TH is caused by excessive sialylation of alkaline phosphatase, which slows clearance of the isoenzymes.

The cause of the increased sialylation remains uncertain. One hypothesis is that TH develops because there is increased production of alkaline phosphatase during a period of catch-up growth after weight loss or during recovery from vitamin D insufficiency, at a rate that overwhelms the mechanisms that normally desialylate the enzyme [14]. If so, children with TH might be expected to 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 compared with those with normal alkaline phosphatase activities [1].

The half-life of serum alkaline phosphatase varies depending upon coexisting morbidities that can affect its metabolism [14]. The typical time course of TH (several weeks to months) is consistent with a transient abnormality in alkaline phosphatase production or metabolism, followed by gradual clearance of the excess alkaline phosphatase.

EVALUATION — Awareness of the entity of TH can avoid unnecessary tests in infants and children with this finding. A careful history, physical examination, and abbreviated laboratory evaluation are usually sufficient to rule out other causes of the elevated alkaline phosphatase, which include many different liver and bone diseases. (See 'Differential diagnosis' below.)

History — The history should include:

●Assessment of risk factors for nutritional rickets, including exclusive breastfeeding without vitamin D supplementation, intake of less than one liter of vitamin D-fortified formula or milk daily, dark skin pigmentation, low exposure to sunlight, or prematurity. Infants are at risk for rickets unless given at least 400 international units daily of vitamin D. In children one year and older, the recommended vitamin D intake for children is 600 international units (15 micrograms) daily. (See "Overview of rickets in children" and "Vitamin D insufficiency and deficiency in children and adolescents".)

●Features suggesting bone disease, including unexplained fractures, family history of bone disease, or complaints of bone pain.

●Symptoms suggesting liver disease or cholestasis, including right upper quadrant pain, jaundice, scleral icterus, pruritus, steatorrhea, dark-colored urine, or easy bruising.

●Medication history to identify possible drug-induced liver injury. (See "Drug-induced liver injury".)

●History of kidney disease, or congenital malformations that may be associated with kidney disease, or suggestive symptoms (polyuria, poor growth). This is because chronic kidney disease may be complicated by renal osteodystrophy.

●Nonspecific symptoms including anorexia, poor growth, weight loss, fever, and lethargy. These symptoms suggest the possibility of systemic disease rather than TH, including primary liver and bone disorders, and call for further evaluation.

Physical examination — The physical examination should evaluate for:

●Bone deformities or tenderness and, particularly, skeletal abnormalities associated with rickets, including beading at the costochondral junction or bowing of long bones, and delayed closure of the fontanelles in infants. (See "Overview of rickets in children".)

●Signs suggesting liver disease, including 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 (AST), alanine aminotransferase (ALT), total and direct bilirubin, gamma-glutamyl transpeptidase (GGTP), calcium, phosphorus, 25-hydroxyvitamin D (calcidiol), parathyroid hormone, blood urea nitrogen, and creatinine. These tests serve to screen for primary liver disease, rickets, and renal osteodystrophy. (See 'Differential diagnosis' below.)

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 GGTP 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 [27].

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. (See "Enzymatic measures of hepatic cholestasis (alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)".)

DIAGNOSIS — TH should be suspected in a child younger than five years of age presenting with isolated elevations in serum alkaline phosphatase at least four times the upper limit of normal, using reference ranges appropriate to the child's age. (See 'Clinical presentation' above.)

●A provisional diagnosis of TH can be made if a focused history, physical examination, and laboratory testing reveal no evidence of underlying liver or bone disease. (See 'Evaluation' above.)

●The diagnosis of TH can be confirmed if serum alkaline phosphatase returns to the normal range within four months, as determined by serial testing. (See 'Management' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of an elevated serum alkaline phosphatase includes a wide spectrum of diseases affecting liver and bone. The history, physical examination, and initial laboratory testing usually are sufficient to categorize the disorder and guide further work-up. The primary considerations in children are outlined briefly below.

●Normal bone growth – Serum alkaline phosphatase activities are generally higher in children than in adults because of physiologically higher rates of osteoblastic activity, especially during periods of rapid growth such as infancy and puberty (figure 1). Age-specific reference ranges for serum alkaline phosphatase approximate these normal variations, but some children may well have mild elevations above these reference ranges due to normal variations in the timing of growth spurts. (See 'Normal range for alkaline phosphatase' above.)

●Liver disease – A wide spectrum of liver diseases are associated with elevated alkaline phosphatase activity. Most of these can be identified by elevations in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), conjugated bilirubin, gamma-glutamyl transpeptidase (GGTP), and/or serum bile acids. The results can be categorized hepatocellular, cholestatic, or both:

•Hepatocellular injury – Suggested by elevations in ALT and AST. Examples include viral hepatitis, metabolic disorders, and drug toxicity.

•Cholestatic injury – Suggested by elevations of serum alkaline phosphatase and GGTP, out of proportion to elevation of ALT and AST. Cholestasis develops due to diminished bile formation and/or excretion and can be classified as biliary (obstructive, large extrahepatic, or small intrahepatic bile ducts) or hepatocellular (defect in membrane transport, embryogenesis, or metabolic dysfunction) in origin. Conjugated bilirubin and serum bile acids are typically elevated. Examples include biliary atresia, gallstones, and several inherited disorders of cholestasis. (See "Causes of cholestasis in neonates and young infants".)

In some rare cholestatic disorders, GGTP is normal or low despite marked cholestasis and elevated liver enzymes; examples include bile acid synthesis defects or progressive familial intrahepatic cholestasis (except type 3). (See "Causes of cholestasis in neonates and young infants", section on 'Disorders of bile acid metabolism' and "Causes of cholestasis in neonates and young infants", section on 'Progressive familial intrahepatic cholestasis'.)

●Rickets – 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 parathyroid hormone, a history of risk factors for vitamin D deficiency (exclusive breastfeeding without vitamin D supplementation), or typical skeletal abnormalities. Any of these findings should prompt further evaluation for rickets with radiographs of long bones. (See "Overview of rickets in children".)

●Renal osteodystrophy – Laboratory evidence of renal dysfunction (elevated creatinine) suggests the possibility of renal osteodystrophy. This is an important cause of bone disease, which can include rickets. Bone disease occurs in children with renal insufficiency for many reasons, including reduced formation of 1,25-dihydroxyvitamin D, metabolic acidosis, and secondary hyperparathyroidism. (See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

●Other primary bone disorders – 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. (See "Clinical manifestations and diagnosis of Paget disease of bone" and "Overview of common presenting signs and symptoms of childhood cancer", section on 'Bone and joint pain' and "Overview of the causes of limp in children".)

MANAGEMENT — All children with suspected or confirmed TH should be evaluated to ensure adequate intake of vitamin D and supplemented if needed (at least 400 international units of vitamin D for infants and 600 international units daily for children). Steps should also be taken to ensure adequate intake of calcium. These steps are appropriate for any child but are particularly important for a child with suspected TH to avoid confounding from coincidental vitamin D insufficiency. (See "Vitamin D insufficiency and deficiency in children and adolescents".)

Follow-up to document return of serum alkaline phosphatase levels to normal is critical for confirmation of the diagnosis of TH [28]. In our practice, we repeat serum alkaline phosphatase measurement within six to eight weeks and continue to monitor periodically until normal values are attained. Sustained serum alkaline phosphatase elevation lasting more than four months should prompt reconsideration and evaluation for other causes of hyperphosphatasemia, particularly liver and bone disorders. (See 'Differential diagnosis' above.)

NATURAL HISTORY AND PROGNOSIS — In children with TH, serum alkaline phosphatase activity gradually returns to normal within two to three months, but in a few cases, the abnormality has persisted for as long as six months [29,30]. In a systematic review, the median duration of the alkaline phosphatase abnormality was 10 weeks and it lasted for longer than four months in 20 percent of cases [23].

In series reporting the results of long-term follow-up, no clinical sequelae were noted up to four years after the episode of TH [31,32].

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – 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. Almost all cases occur in infants and children younger than five years of age. (See 'Clinical presentation' above.)

In TH, the serum alkaline phosphatase is typically elevated four to five times the upper limit of the pediatric reference range and gradually returns to normal within four months. (See 'Clinical presentation' above and 'Natural history and prognosis' above.)

●Normal range for alkaline phosphatase – Serum alkaline phosphatase activities are higher in children than in adults because of physiologic osteoblastic activity. The upper limit of the pediatric reference range is up to three times higher than in adults, peaking during infancy and again during puberty (figure 1). (See 'Normal range for alkaline phosphatase' above.)

●Pathogenesis – 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 alkaline phosphatase due to increased sialic acid content, perhaps caused by or compounded by a transient surge in alkaline phosphatase production. (See 'Pathogenesis' above.)

●Evaluation – The history, physical examination, and laboratory testing are designed to rule out other causes of elevated alkaline phosphatase activity.

•Laboratory tests – Laboratory testing should include measurement of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and direct bilirubin, gamma-glutamyl transpeptidase (GGTP), calcium, phosphorus, 25-hydroxyvitamin D, parathyroid hormone, blood urea nitrogen, and creatinine. (See 'Evaluation' above.)

•Differential diagnosis – Other causes of elevated alkaline phosphatase activity include primary liver disease, bone disease, and renal osteodystrophy.

In particular, 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 breastfeeding without vitamin D supplementation; or typical skeletal abnormalities. Any of these findings should prompt further evaluation, including radiographs of long bones. (See 'Differential diagnosis' above and "Overview of rickets in children".)

●Diagnosis and management – 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. All children should be evaluated to ensure adequate intake of vitamin D and supplemented if needed (at least 400 international units of vitamin D for infants and 600 international units daily for children). Steps should also be taken to ensure adequate intake of calcium.

The diagnosis of TH can be confirmed if serum alkaline phosphatase activity returns to the normal range within four months, as determined by serial testing. Sustained serum alkaline phosphatase elevation lasting more than four months should prompt reconsideration and evaluation for other causes of hyperphosphatasemia. (See 'Diagnosis' above and 'Management' above.)