What is the recommended workup for a low alkaline phosphatase (ALP) level?

Workup for Low Alkaline Phosphatase

In adults with persistently low alkaline phosphatase (ALP), the primary diagnostic goal is to distinguish between transient hypophosphatasemia due to acute illness and persistent hypophosphatasemia that may indicate hypophosphatasia or other chronic conditions.

Initial Confirmation and Basic Assessment

• Repeat ALP measurement within 7–10 days to confirm persistence, as many cases of low ALP are transient and associated with acute illness, sepsis, trauma, or critical care settings 1, 2.

• Obtain a complete metabolic panel including albumin, total protein, calcium, phosphate, AST, and CRP to differentiate transient hypophosphatasemia (which typically shows low albumin, low total protein, elevated AST, and elevated CRP) from persistent hypophosphatasemia (which shows normal or near-normal values for these markers) 1.

• Measure hemoglobin, as anemia is significantly more common in transient hypophosphatasemia associated with acute illness 1.

Distinguishing Transient from Persistent Low ALP

The pattern of auxiliary biomarkers is highly discriminatory:

• Transient hypophosphatasemia (tHPE) typically presents with:

  • Lower hemoglobin, albumin, total protein, and calcium 1
  • Elevated AST and CRP 1
  • ALP that normalizes once the underlying acute condition resolves 1, 2

• Persistent hypophosphatasemia (pHPE) typically presents with:

  • Normal hemoglobin, albumin, total protein, and inflammatory markers 1
  • ALP that remains low on repeat testing 1, 2
  • This pattern has 90% accuracy and an AUC of 0.94 for distinguishing persistent from transient causes 1

Workup for Persistent Low ALP

Step 1: Measure ALP Substrates

If ALP remains low after excluding transient causes, measure plasma pyridoxal-5'-phosphate (PLP) and urinary phosphoethanolamine (PEA) 3, 4, 2.

• Elevated PLP (above reference range) is present in approximately 24% of adults with unexplained low ALP and strongly suggests ALPL gene mutations 3.
• All individuals with PLP above the reference range in one cohort carried an ALPL mutation 3.
• ALP levels are inversely correlated with both PLP (r = -0.51, p = 0.001) and PEA (r = -0.49, p = 0.001) 3.
• A significant negative linear relationship exists: log PLP = 5.99 - 2.76 log ALP (r = -0.85, P < 0.001) 5.

Step 2: Nutritional and Micronutrient Assessment

• Measure serum zinc, magnesium, and copper, as zinc deficiency (a required cofactor for ALP) is a well-recognized cause of low ALP, particularly in malnutrition, chronic intestinal failure, or high stoma output 6.
• Obtain 25-hydroxyvitamin D and parathyroid hormone (PTH) to assess for vitamin D deficiency and secondary hyperparathyroidism 6.
• Check serum albumin and prealbumin to objectively assess protein-calorie malnutrition, which commonly produces low BUN (<10 mg/dL) due to reduced hepatic urea synthesis 6.

Step 3: Screen for Wilson Disease

• Calculate the total bilirubin-to-alkaline phosphatase ratio; a value > 2.0 is a strong indicator of Wilson disease, especially in the setting of acute liver failure 6.
• When the ratio is elevated or hepatic dysfunction is present, measure serum ceruloplasmin, 24-hour urinary copper, and serum copper 6.
• Perform slit-lamp examination for Kayser-Fleischer rings, which are present in approximately 50% of Wilson disease patients presenting with liver failure 6.
• Wilson disease typically manifests with markedly subnormal ALP (often < 40 IU/L), Coombs-negative hemolytic anemia, modest aminotransferase elevations (<2000 IU/L), and rapid progression to renal failure 6.

Step 4: Medication Review

• Conduct a thorough review of all medications, particularly antiresorptive agents (bisphosphonates, denosumab), which can lower ALP levels despite underlying pathology 7.
• Drug-induced cholestatic liver injury can also present with low ALP in certain contexts 7.

Step 5: Genetic Testing for Hypophosphatasia

If biochemical markers (elevated PLP and/or PEA) suggest hypophosphatasia or clinical features are compatible:

• Order ALPL gene sequencing 3, 4, 2.
• Approximately 50% of adults with unexplained persistent low ALP carry an ALPL mutation 3.
• Missense mutations are the most common (86% of cases) and the majority are predicted to have a damaging effect on protein activity 3.
• The presence of a mutated allele is associated with tooth loss (48% versus 12%; p = 0.04), slightly lower ALP levels (p = 0.002), higher PLP (p < 0.0001), higher PEA (p < 0.0001), and mildly increased serum phosphate (p = 0.03) 3.

Clinical Manifestations to Assess

Even in the absence of severe symptoms, inquire about:

• Dental problems and premature tooth loss, which are significantly more common in ALPL mutation carriers 3.
• Skeletal pain, chondrocalcinosis, calcific periarthritis, and stress fractures, which are typical of adult-onset hypophosphatasia 4.
• Mild hyperphosphatemia (present in 21% of cases) and mild hypercalcemia (present in 7% of cases) 3.
• Musculoskeletal pain, though many subjects experience only minor complaints without major health problems 3.

Important Caveats

• A substantial proportion of patients with persistent low ALP show normal results after sequencing ALPL exons 4. It remains unknown whether these patients carry unidentified mutations in regulatory regions of ALPL, epigenetic changes, or abnormalities in other genes 4.
• Patients with persistently low ALP require further clinical, biochemical, and radiological assessment for hypophosphatasia, even in the absence of clinical symptoms 2.
• There is significant overlap in ALP activities between study-positive patients and confirmed hypophosphatasia cases, so clinical context and substrate measurements are critical 2.
• Vitamin B6 (PLP) levels should be interpreted in conjunction with prevailing serum ALP levels, as the metabolism of these compounds is closely inter-related 5.