In an adolescent with isolated low ALP (alkaline phosphatase), a normal CMP (comprehensive metabolic panel), normal B12 (vitamin B12), and an intact PTH (parathyroid hormone), what is the next step in evaluation?

Evaluation of Low Alkaline Phosphatase in an Adolescent

Next Step: Measure Pyridoxal-5'-Phosphate (Vitamin B6) and Urinary Phosphoethanolamine

In an adolescent with persistently low ALP and normal CMP, B12, and intact PTH, the next step is to measure plasma pyridoxal-5'-phosphate (PLP, the active form of vitamin B6) and urinary phosphoethanolamine (PEA) to evaluate for hypophosphatasia (HPP). 1, 2

Why This Matters: Understanding Hypophosphatasia

• HPP is a rare inherited metabolic disorder caused by mutations in the ALPL gene that results in defective bone and teeth mineralization, with a phenotypic spectrum ranging from lethal perinatal forms to mild adult presentations that may remain undiagnosed despite persistently low ALP. 3

• Low serum ALP is the biochemical hallmark of HPP, but this finding is commonly not flagged by laboratories as abnormal (unlike elevated ALP), leading to delayed or missed diagnosis. 4

• Approximately 50% of adults with unexplained persistently low ALP carry an ALPL mutation, even when clinical manifestations are mild or absent. 2

Diagnostic Algorithm for Low ALP

Step 1: Confirm Persistent Hypophosphatasemia

• Repeat ALP measurement to confirm persistently low levels (typically <100 U/L in children, though age-specific reference ranges must be used). 1
• A single low value may represent transient hypophosphatasemia; most patients with one low reading will have normal values on repeat testing. 1

Step 2: Measure Substrate Accumulation Markers

• If ALP remains persistently low, measure plasma PLP and urinary PEA—these substrates accumulate when tissue-nonspecific alkaline phosphatase activity is deficient. 1, 2
• Elevated PLP (above reference range) is highly specific for HPP; in one study, all individuals with elevated PLP carried an ALPL mutation. 2
• ALP levels inversely correlate with both PLP (r=-0.51, p=0.001) and urinary PEA (r=-0.49, p=0.001). 2

Step 3: Consider Bone-Specific ALP

• If total ALP is borderline or normal but clinical suspicion for HPP remains high, measure bone-specific ALP, as rare cases of HPP present with normal total ALP but low bone-specific ALP. 5
• One case report documented HPP confirmed by genetic testing in a patient with normal total ALP but bone-specific ALP of 4.4 μg/L (reference 5.3-19.5 μg/L). 5

Step 4: Genetic Testing

• If PLP and/or PEA are elevated, proceed with ALPL gene sequencing to confirm the diagnosis and identify the specific mutation. 1, 3
• Heterozygous ALPL mutations are most common in mild cases; missense mutations predominate (86% in one series) and are typically predicted to have damaging effects on protein activity. 2

Clinical Features to Assess

Historical Red Flags for HPP

• Childhood history of premature tooth loss (especially primary teeth before age 5), "gray gums," or loose teeth. 5, 2
• Musculoskeletal complaints including bone pain, muscle weakness, joint pain, or progressive fatigue. 5, 2
• Fractures with minimal trauma or delayed fracture healing. 1

Physical Examination Findings

• Dental abnormalities including premature tooth loss or poor dentition. 2
• Skeletal deformities or signs of rickets (though less common in adolescents with mild HPP). 1
• Growth parameters should be documented, though growth is typically normal in mild HPP. 3

Laboratory Correlation Patterns

• Mild hyperphosphatemia (present in approximately 21% of adults with low ALP) and mild hypercalcemia (7%) may be seen. 2
• Serum calcium inversely correlates with ALP levels (r=-0.38, p=0.012). 2
• The presence of an ALPL mutation is associated with lower ALP levels, higher PLP and PEA, and mildly increased serum phosphate. 2

Critical Pitfalls to Avoid

• Do not dismiss persistently low ALP as clinically insignificant—even asymptomatic adolescents with low ALP may have HPP and require monitoring for future complications. 1, 2
• Do not rely solely on total ALP; bone-specific ALP should be measured if clinical suspicion is high despite borderline total ALP. 5
• Do not assume that absence of severe symptoms excludes HPP—mild forms may present only with dental problems or minor musculoskeletal complaints, or may be entirely asymptomatic. 2, 3
• Recognize that laboratory systems typically do not flag low ALP as abnormal, so clinicians must actively pursue the diagnosis when low values are identified. 4

Treatment Implications

• Early diagnosis is critical because enzyme replacement therapy (asfotase alfa) is now available and has been shown to be effective in HPP, potentially preventing years of undiagnosed morbidity. 5, 1
• Even in asymptomatic patients, genetic confirmation allows for appropriate monitoring and counseling regarding risk of future complications and inheritance patterns. 1, 3