Causes of Low Alkaline Phosphatase
Low alkaline phosphatase (ALP) levels can result from genetic disorders (primarily hypophosphatasia), medication effects (especially antiresorptive agents like bisphosphonates), nutritional deficiencies, and severe acute illnesses, with hypophosphatasia being the most important genetic cause to identify given its implications for treatment decisions.
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.
- Prevalence: Among patients with low ALP levels, approximately 50% carry an ALPL mutation, with most being heterozygous missense mutations 2
- In osteoporosis clinic populations, HPP is diagnosed in 3% of patients with low ALP and 0.3% of all attendees 3
- Clinical manifestations in adults include skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems (tooth loss), stress fractures, and atypical femoral fractures 1, 2
- Critical diagnostic consideration: HPP may be misdiagnosed as osteoporosis, and antiresorptive therapy is relatively contraindicated in HPP, making correct diagnosis essential 3
Medication-Induced Causes
Antiresorptive medications are an important iatrogenic cause of low ALP that must be identified in the medication history 4.
- Bisphosphonates and denosumab can lower ALP levels and may mask underlying bone pathology 5
- These medications should be reviewed carefully when evaluating any patient with low ALP 4
Acute Illness and Severe Disease States
Low serum ALP is an epiphenomenon of many severe acute injuries and diseases 1.
- In acute liver failure, markedly subnormal serum ALP (typically <40 IU/L) is characteristic of Wilson disease, occurring alongside Coombs-negative hemolytic anemia, coagulopathy, and relatively modest aminotransferase elevations (typically <2000 IU/L) 4
- A ratio of alkaline phosphatase to total bilirubin of <2 strongly suggests Wilson disease in this context 4
Nutritional and Metabolic Causes
Acquired disorders that can cause persistently low ALP include 1:
- Malnutrition
- Vitamin and mineral deficiencies (particularly zinc, magnesium, and vitamin C deficiencies)
- Endocrine disorders
Chronic Liver Disease
In patients with chronic liver disease, low serum ALP levels occur in approximately 0.25% of cases and are associated with less biochemical evidence of active disease 6.
- Patients with consistently low ALP levels have significantly lower serum aminotransferase and bilirubin levels compared to those with normal or elevated ALP 6
- This represents a hitherto unreported association between low ALP and less active hepatic inflammation 6
Important Diagnostic Considerations
Laboratory Measurement Issues
- In conditions with low albumin (such as inflammation), plasma ALP measurements may be unreliable, and red cell measurements are preferred 4
- Total ALP may be normal while bone-specific ALP is low in some HPP cases, warranting bone-specific ALP testing when clinical suspicion exists 7
Diagnostic Workup for Suspected HPP
When HPP is suspected based on persistently low ALP, the following approach is recommended 1, 2:
- Measure ALP substrates: Pyridoxal phosphate (PLP), pyrophosphate, and phosphoethanolamine (PEA) to establish enzyme deficiency
- ALP levels are inversely correlated with serum calcium, PLP, and urine PEA 2
- PLP levels above the reference range strongly suggest HPP; all patients with elevated PLP in one study carried an ALPL mutation 2
- Genetic testing: Sequencing of ALPL exons to identify pathogenic variants 1
- Note that a substantial proportion of patients show normal results after sequencing ALPL exons, possibly due to unidentified mutations in regulatory regions, epigenetic changes, or abnormalities in other genes 1
Clinical Patterns
Persistently low ALP (low on the majority of measurements) is more clinically significant than transiently low levels 3.