What causes elevated alkaline phosphatase (ALP) levels in toddlers?

Elevated Alkaline Phosphatase in Toddlers

In toddlers, elevated alkaline phosphatase (ALP) is most commonly physiologic due to active bone growth, but pathologic causes include bone disorders (rickets, X-linked hypophosphatemia), cholestatic liver disease, benign transient hyperphosphatasemia, and rarely infiltrative diseases.

Physiologic Causes

The single most important cause of elevated ALP in toddlers is normal bone growth. 1, 2

• Bone-specific ALP represents 80-90% of total ALP in children's serum, compared to only 50% in adults 2
• ALP levels are physiologically higher throughout childhood and adolescence due to active skeletal development 1
• Boys may have slightly higher ALP levels than girls at 12 months of age 3
• ALP concentrations typically decrease between 12 and 24 months as growth velocity slows 3

Pathologic Causes

Bone Disorders

Rickets and osteomalacia are critical diagnoses not to miss, as they cause significant morbidity if untreated. 1, 2

• Elevated heat-labile (bone) ALP is a reliable biomarker for rickets activity 2
• X-linked hypophosphatemia (XLH) presents with elevated ALP, hypophosphatemia, and renal phosphate wasting 1, 2
• In XLH, healing of rickets is evidenced by normalization of ALP levels and radiological signs 1
• Bone ALP levels help assess disease activity, severity, and treatment efficacy in metabolic bone diseases 2

Benign Transient Hyperphosphatasemia (BTH/THI)

Benign transient hyperphosphatasemia is a common, self-limited condition in toddlers that requires recognition to avoid unnecessary workup. 4, 5, 6

• Characterized by markedly elevated ALP (often >1000 U/L, sometimes 1,077-9,271 U/L) in otherwise healthy children 4, 5
• Typically occurs in children aged 11-25 months 5
• Prevalence of hyperphosphatasemia (ALP >1000 U/L) is approximately 5.3% at 12 months and decreases to 0.6% at 24 months 3
• ALP levels normalize or decrease significantly within 3-4 months without intervention 4, 5, 6
• May be associated with recent viral infections or gastroenteritis, though the exact pathophysiology remains unclear 4, 5, 6

Cholestatic Liver Disease

While less common in toddlers than bone-related causes, hepatobiliary disease must be excluded when ALP is elevated. 1

• Cholestatic conditions include primary sclerosing cholangitis, biliary obstruction, and autoimmune sclerosing cholangitis 1
• Measurement of gamma-glutamyl transpeptidase (GGT) is critical in toddlers to distinguish hepatic from bone sources, as ALP is elevated with bone growth 1, 2
• Concomitantly elevated GGT confirms hepatic origin and indicates cholestasis 1, 2
• In children with suspected liver disease, serum aminotransferase elevations may be more significantly elevated than in adults 1
• Autoimmune overlap syndrome (autoimmune hepatitis with sclerosing cholangitis) is significantly more common in children than adults 1

Other Causes

• Infiltrative liver diseases (sarcoidosis, amyloidosis) can cause intrahepatic cholestasis 1
• Genetic disorders such as ABCB4 (MDR3) gene defects may present as small duct PSC in children 1
• Intestinal, kidney, and white blood cell sources contribute minimally to total ALP 1

Diagnostic Approach

Initial Assessment

When evaluating elevated ALP in a toddler, first determine if the elevation is physiologic or pathologic by comparing to age-specific reference ranges. 2, 3

1. Obtain GGT to differentiate hepatic from non-hepatic sources 1, 2

   • GGT is not found in bone, so normal GGT with elevated ALP suggests bone origin 1
   • Elevated GGT indicates hepatic cholestasis 1, 2

2. If GGT is normal (bone source suspected):

   • Check serum phosphate, calcium, parathyroid hormone (PTH), and 25-hydroxyvitamin D levels 1, 2
   • Low phosphate with elevated ALP suggests rickets or XLH 1, 2
   • Obtain wrist/knee radiographs to assess for rickets 4
   • Consider benign transient hyperphosphatasemia if child is otherwise healthy and recently had viral illness 4, 5, 6

3. If GGT is elevated (hepatic source):

   • Perform abdominal ultrasound as first-line imaging to assess for biliary obstruction 1, 2
   • Check serum aminotransferases, direct bilirubin, and review medication history 1
   • Consider MRI with MRCP if ultrasound is inconclusive and cholestatic process persists 1, 2
   • Liver biopsy may be relevant in children for diagnosing small duct PSC or autoimmune features 1

Key Clinical Pitfalls

• Do not assume all elevated ALP in toddlers is physiologic without checking GGT 1, 2
• Avoid extensive workup for benign transient hyperphosphatasemia - if child is healthy with normal physical exam, normal GGT, calcium, phosphate, and no bone/liver symptoms, observe for 3-4 months 4, 5, 6
• Do not use adult reference ranges - age-specific pediatric ranges are essential 1, 2
• In children with chronic cholestasis, monitor for fat-soluble vitamin deficiencies (A, D, E) and hepatic osteodystrophy 1
• Infants with hyperphosphatasemia may be smaller than those with normal ALP, suggesting an association with growth parameters 3