Causes of Low Alkaline Phosphatase
Low alkaline phosphatase (ALP) can result from genetic disorders (primarily hypophosphatasia), acute liver failure from Wilson disease, medication effects (especially bisphosphonates), or nutritional deficiencies, with hypophosphatasia being the most important genetic cause to identify given its specific treatment implications and risk of complications with antiresorptive therapy.
Primary Genetic Cause: Hypophosphatasia
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, 2.
Clinical Presentation
- Adult forms typically present with skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems (tooth loss, "gray gums" in childhood), and stress or atypical fractures 1, 3, 2
- Approximately 50% of adults with unexplained low ALP carry an ALPL mutation 1
- HPP affects 0.3% of osteoporosis clinic patients and 3% of those with documented low ALP 4
- The condition may be misdiagnosed as fibromyalgia, with 9.3% of FM patients having consistently low ALP levels 5
Diagnostic Approach for HPP
- Persistently low total ALP (typically <30 IU/L) is the primary screening marker 4, 2
- Bone-specific ALP should be measured when total ALP is borderline or normal, as cases exist with normal total ALP but low bone-specific ALP 3
- Elevated pyridoxal phosphate (PLP) is highly suggestive: all patients with PLP above reference range in one study carried an ALPL mutation 1
- Elevated phosphoethanolamine (PEA) in urine correlates inversely with ALP levels (r=-0.49) 1
- Genetic testing of ALPL confirms diagnosis, though some patients have mutations in regulatory regions not detected by standard exon sequencing 2
Wilson Disease (Acute Liver Failure Presentation)
In acute liver failure, markedly low serum ALP (<40 IU/L) with an alkaline phosphatase-to-total bilirubin ratio <2 strongly suggests Wilson disease 6, 7.
Key Diagnostic Features
- Coombs-negative hemolytic anemia with jaundice 6
- Modest aminotransferase elevations (typically <2000 IU/L, often AST>ALT) 6
- Total bilirubin typically ≥20 mg/dL with elevated indirect fraction 6
- Kayser-Fleischer rings present in only 50% of acute presentations 6
- Serum copper usually >200 μg/dL (>31.5 μmol/L) with greatly elevated 24-hour urinary copper 6
- Low ceruloplasmin (though may be normal in 15% of cases) 6
Medication-Induced Low ALP
Antiresorptive medications, particularly bisphosphonates, lower ALP levels and represent a critical iatrogenic cause 7, 4.
Clinical Significance
- This is especially important because antiresorptive therapy is relatively contraindicated in hypophosphatasia and may trigger atypical femoral fractures 4, 5
- Medication history review is essential before diagnosing primary bone disorders 7
- The reduction in ALP may cause PLP levels to appear relatively elevated due to reduced enzymatic degradation 7
Other Acquired Causes
Nutritional and Metabolic
- Malnutrition, vitamin deficiencies (particularly vitamin B6, zinc, magnesium), and mineral deficiencies 2
- Endocrine disorders 2
Laboratory Considerations
- In conditions with low albumin (inflammation), plasma ALP measurements may be unreliable, and red cell measurements are preferred 7
- The relationship between plasma PLP and ALP is quantitatively inverse and logarithmic 7
Clinical Pitfalls to Avoid
Do not assume low ALP is clinically insignificant: 9% of osteoporosis clinic patients have at least one low ALP measurement 4
Do not start bisphosphonates without excluding hypophosphatasia: this can precipitate atypical fractures in undiagnosed HPP patients 4, 5
Do not rely solely on total ALP: bone-specific ALP may be low when total ALP appears normal 3
Do not overlook Wilson disease in young patients with acute liver failure: the combination of low ALP, hemolysis, and modest transaminase elevation is pathognomonic 6
Check vitamin B6 (PLP) levels in patients with persistently low ALP: elevated PLP strongly suggests enzyme deficiency even before genetic testing 1, 2