What Causes Low Alkaline Phosphatase (ALP) Levels?
Low alkaline phosphatase levels can result from hypophosphatasia (a genetic disorder), acute severe illnesses, malnutrition, vitamin/mineral deficiencies, endocrine disorders, or antiresorptive medications like bisphosphonates. 1
Primary Genetic Cause
- Hypophosphatasia (HPP) is the most common genetic cause of persistently low serum ALP, resulting from pathogenic variants in the ALPL gene that encodes tissue non-specific alkaline phosphatase 1
- HPP affects approximately 0.3% of osteoporosis clinic patients and 3% of patients with at least one documented low ALP level 2
- Adult-onset HPP typically presents with milder manifestations including skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems (loose teeth, "gray gums"), and stress fractures 1
- Approximately 50% of adults with unexplained low serum ALP carry an ALPL mutation, with missense mutations being most common (86% of cases) 3
Acute and Secondary Causes
- Low serum ALP can be an epiphenomenon of many severe acute injuries and diseases, though the specific mechanisms are not fully elucidated 1
- Malnutrition and vitamin/mineral deficiencies can cause persistently low ALP levels 1
- Endocrine disorders may contribute to low ALP 1
- Antiresorptive medications, including bisphosphonates and denosumab, can lower ALP levels and should be reviewed in medication history 4, 1
Special Clinical Context: Wilson Disease
- In acute liver failure presentations, markedly subnormal serum alkaline phosphatase (typically <40 IU/L) is characteristic of Wilson disease 5
- A ratio of alkaline phosphatase to total bilirubin of <2 strongly suggests Wilson disease in the acute liver failure setting 5
- This pattern occurs alongside Coombs-negative hemolytic anemia, coagulopathy, and relatively modest aminotransferase elevations (typically <2000 IU/L) 5
Diagnostic Approach
When evaluating low ALP, the key distinction is between transient versus persistent low levels:
- Persistently low ALP (defined as <30 IU/L on multiple occasions) warrants investigation for hypophosphatasia 2
- Measure ALP substrates including pyridoxal phosphate (PLP), phosphoethanolamine (PEA), and pyrophosphate to establish enzyme deficiency 1
- Bone-specific ALP should be measured when total ALP is borderline or normal but clinical suspicion for HPP remains high, as cases exist with normal total ALP but low bone-specific ALP 6
- Elevated vitamin B6 (pyridoxal phosphate) levels above the reference range strongly suggest HPP, with all such patients in one study carrying a mutated ALPL allele 3
- Genetic testing for ALPL gene variants confirms the diagnosis, though approximately 50% of patients with clinical HPP may have normal exon sequencing, suggesting unidentified regulatory mutations or epigenetic changes 1
Clinical Significance and Monitoring
- ALP levels inversely correlate with serum calcium, pyridoxal phosphate, and urine phosphoethanolamine 3
- The presence of ALPL mutations is associated with tooth loss (48% versus 12% in non-carriers), lower ALP levels, higher PLP and PEA levels, and mildly increased serum phosphate 3
- Low ALP in osteoporosis clinic patients is critical to identify because HPP may be misdiagnosed as osteoporosis and incorrectly treated with antiresorptive therapy, which is relatively contraindicated in HPP 2
- Persistently low ALP occurs in 0.4% of osteoporosis clinic attendees and 0.6% of all hospital patients 2
Key Clinical Pitfalls
- Do not assume all low ALP is benign or transient—persistent low levels require systematic evaluation for HPP 2
- Total ALP may be normal in some HPP cases—measure bone-specific ALP when clinical features suggest HPP despite normal total ALP 6
- Avoid prescribing bisphosphonates or other antiresorptives without first excluding HPP in patients with low or low-normal ALP and fragility fractures 2
- In acute liver failure with low ALP, urgently consider Wilson disease as this requires immediate liver transplantation evaluation 5