Evaluation of Low Alkaline Phosphatase (Hypophosphatasia)
A low alkaline phosphatase level of 24 IU/L without other liver function abnormalities should be evaluated for hypophosphatasia, with consideration of Wilson's disease in the differential diagnosis, particularly if there are any neurological or hepatic symptoms.
Initial Diagnostic Approach
Step 1: Confirm the Finding
- Verify that the low ALP is persistent (not a lab error)
- Repeat the test to confirm the finding
- Check for potential pre-analytical causes of low ALP
Step 2: Clinical Assessment
- Evaluate for symptoms associated with hypophosphatasia:
- Skeletal pain
- Dental problems (premature loss of teeth)
- Recurrent fractures or stress fractures
- Chondrocalcinosis
- Calcific periarthritis
- Assess for symptoms of Wilson's disease:
- Neurological symptoms (tremor, dysarthria)
- Psychiatric symptoms
- Kayser-Fleischer rings
- Liver disease manifestations
Diagnostic Testing Algorithm
Laboratory Tests
Measure ALP substrates:
- Pyridoxal-5'-phosphate (PLP) - elevated in hypophosphatasia 1
- Phosphoethanolamine
- Pyrophosphate
Genetic testing:
- ALPL gene sequencing for hypophosphatasia 2
- ATP7B gene testing if Wilson's disease is suspected
Wilson's disease workup (if clinically indicated):
- Serum ceruloplasmin
- 24-hour urinary copper excretion
- Calculate ratio of alkaline phosphatase to total bilirubin (ratio <2 suggests Wilson's disease) 3
Additional tests:
- Vitamin B6 levels
- Calcium and phosphate levels
- Vitamin D status
- Parathyroid hormone
Imaging
- Skeletal X-rays if bone symptoms are present
- Abdominal ultrasound to evaluate liver morphology
Interpretation of Results
Hypophosphatasia
- Confirmed by:
- Persistently low ALP
- Elevated PLP levels
- Pathogenic variants in ALPL gene
- There is a significant negative linear relationship between log PLP and log ALP (log PLP = 5.99-2.76 log ALP) 1
Wilson's Disease
- Consider in differential diagnosis, especially if:
- Patient has neurological symptoms
- Low ALP with ratio of alkaline phosphatase to bilirubin <2 3
- Kayser-Fleischer rings present
- Elevated 24-hour urinary copper
Clinical Implications
- Low ALP in chronic liver disease patients (0.25% prevalence) has been associated with less biochemical evidence of active disease 4
- In acute liver failure, low ALP may be a marker of Wilson's disease 3
- Hypophosphatasia severity correlates with degree of ALP reduction 5
Important Caveats
- Low ALP can be an epiphenomenon of many severe acute injuries and diseases 5
- Secondary causes of low ALP should be ruled out:
- Malnutrition
- Vitamin and mineral deficiencies
- Endocrine disorders
- Medication effects (including antiresorptives)
- A substantial proportion of patients with clinical hypophosphatasia show normal results after sequencing ALPL exons 5
- Low ALP might not always be a determinant of bile duct pathology in patients with acute on chronic liver failure with autoimmune hemolytic anemia 6
Remember that while hypophosphatasia is the most common genetic cause of low serum ALP, Wilson's disease should be considered in the differential diagnosis, particularly in patients with liver or neurological manifestations.