What causes elevated alkaline phosphatase (ALP) in a 5-year-old child?

Elevated Alkaline Phosphatase in a 5-Year-Old Child

In a 5-year-old with very high alkaline phosphatase, the most likely causes are physiologic bone growth, benign transient hyperphosphatasemia (which can reach levels >1000 U/L and resolves spontaneously), or pathologic conditions including rickets, X-linked hypophosphatemia, or cholestatic liver disease. 1, 2

Physiologic vs. Pathologic Elevation

Normal Physiologic Elevation

• ALP levels are physiologically higher throughout childhood due to active skeletal development, with bone-specific ALP representing 80-90% of total ALP in children's serum 1, 3
• Age-specific pediatric reference ranges must be used—never apply adult reference ranges to children 1, 3
• At age 5, children are still experiencing active bone growth, making moderately elevated ALP entirely normal 1

Benign Transient Hyperphosphatasemia (BTH)

• BTH is characterized by greatly increased serum ALP (often >1000 U/L, with reported ranges up to 14,589 U/L) without clinical or laboratory evidence of bone or liver disease 2
• The majority (87%) of BTH cases occur in children up to 24 months, but cases are documented through age 14 years 2
• BTH resolves spontaneously within 4 months without intervention 2, 4
• Often preceded by recent fever, gastroenteritis, diarrhea, acute otitis media, or viral infection 2
• Seasonal peak observed in autumn-early winter 2

Pathologic Causes Requiring Evaluation

Bone Disorders

• Rickets presents with elevated bone ALP, hypophosphatemia, low 25-hydroxyvitamin D, and elevated PTH 1, 5
• X-linked hypophosphatemia (XLH) shows elevated ALP, hypophosphatemia, and renal phosphate wasting 1
• Hypophosphatasia (paradoxically low ALP despite being a bone disorder) 5
• Healing fractures can elevate ALP 6, 3

Cholestatic Liver Disease

• Less common than bone-related causes in this age group but must be excluded 1
• Presents with elevated ALP and concomitantly elevated GGT 1
• May include genetic disorders like ABCB4 (MDR3) gene defects presenting as small duct PSC 1

Other Considerations

• In children with fractures suspicious for abuse, check calcium, phosphorus, and ALP, though ALP may be elevated with healing fractures 6
• Infiltrative liver diseases (sarcoidosis, amyloidosis) can cause intrahepatic cholestasis 1
• Rare: benign hyperphosphatasemia during chemotherapy (methotrexate, 6-mercaptopurine) 7

Diagnostic Algorithm

Step 1: Compare to Age-Specific Reference Ranges

• Determine if elevation is truly abnormal using pediatric reference ranges 1, 3
• Document the absolute ALP value and degree of elevation above normal 2

Step 2: Obtain GGT to Determine Source

• GGT is critical to distinguish hepatic from bone sources 1, 3
• If GGT is elevated: hepatic origin confirmed, indicating cholestasis—proceed with liver evaluation 1
• If GGT is normal: bone source suspected—proceed with bone metabolism evaluation 1, 3

Step 3A: If Bone Source (Normal GGT)

• Check serum phosphate, calcium, PTH, and 25-hydroxyvitamin D levels 1, 5
• Low phosphate with elevated ALP suggests rickets or XLH 1
• Obtain detailed history: recent illness, fever, gastroenteritis, viral infection 2
• Physical examination: look for skeletal deformities, bone pain, growth impairment, blue sclera (OI), abnormal dentition 6, 5
• Consider skeletal survey if fractures or bone abnormalities suspected 6

Step 3B: If Hepatic Source (Elevated GGT)

• Perform abdominal ultrasound as first-line imaging 3
• Check liver transaminases (ALT, AST), bilirubin, and direct bilirubin 3, 5
• Consider advanced imaging (CT or MRI/MRCP) if ultrasound inconclusive 3

Step 4: If All Initial Tests Normal (Suspected BTH)

• Adopt a "wait and see" approach—repeat ALP in 4-8 weeks 2, 4
• BTH should normalize within 4 months without intervention 2, 4
• No further testing needed if ALP normalizes 2, 4

Critical Pitfalls to Avoid

• Never assume all elevated ALP in children is physiologic without checking GGT 1
• Never use adult reference ranges—this is the most common error leading to unnecessary workups 1, 3
• Do not immediately pursue extensive imaging or subspecialty referral if clinical history suggests BTH and GGT is normal 2, 4
• In children with chronic cholestasis, monitor for fat-soluble vitamin deficiencies (A, D, E, K) and hepatic osteodystrophy 1
• When evaluating for child abuse with fractures, remember that ALP elevation may simply reflect healing fractures, not metabolic bone disease 6

When to Pursue Aggressive Workup vs. Observation

Pursue immediate workup if:

• GGT is elevated (hepatic source) 1
• Clinical signs of bone disease: skeletal deformities, bone pain, growth failure 5
• Abnormal calcium, phosphate, PTH, or vitamin D levels 1, 5
• Concern for child abuse with unexplained fractures 6

Observation appropriate if:

• GGT normal, recent viral illness or gastroenteritis, no clinical signs of disease 2, 4
• Calcium, phosphate, PTH, and vitamin D all normal 1
• Physical examination entirely normal 2, 4
• In these cases, repeat ALP in 4-8 weeks and expect normalization within 4 months 2, 4