Workup of Low Alkaline Phosphatase
When a patient presents with low alkaline phosphatase (ALP) levels, the most important initial step is to rule out hypophosphatasia (HPP), as this genetic disorder can be misdiagnosed as osteoporosis and inappropriately treated with antiresorptive therapy, potentially leading to increased fracture risk. 1, 2
Prevalence and Significance
- Low ALP has been found in approximately 9% of patients attending osteoporosis clinics, 0.6% of general hospital patients, and 9.3% of patients diagnosed with fibromyalgia 1, 3
- Persistently low ALP is relatively rare, with only 0.4% of osteoporosis clinic patients showing consistently low levels 1
- In patients with chronic liver disease, only 0.25% have consistently low ALP levels 4
Diagnostic Algorithm for Low ALP
Step 1: Confirm Persistent Low ALP
- Repeat ALP measurement to confirm if the low level is persistent rather than transient 1
- Define low ALP as <40 IU/L in adults (or below the lower limit of normal for the laboratory) 4
- Check for pre-analytical errors that might affect ALP measurement 5
Step 2: Evaluate for Hypophosphatasia (HPP)
- Measure ALP substrates to establish enzyme deficiency 2:
- Pyridoxal phosphate (vitamin B6)
- Pyrophosphate
- Phosphoethanolamine
Step 3: Clinical Assessment for HPP Features
- Assess for key clinical manifestations of HPP 1, 2:
- History of fractures, especially stress fractures or atypical femoral fractures
- Skeletal pain
- Dental problems (early tooth loss, dental abscesses)
- Chondrocalcinosis
- Calcific periarthritis
Step 4: Genetic Testing
- Consider ALPL gene analysis to confirm HPP diagnosis 2
- Note that some patients with clinical HPP may have normal results after sequencing ALPL exons 2
Step 5: Rule Out Other Causes of Low ALP
Evaluate for Wilson Disease
- Calculate the ratio of total bilirubin (mg/dL) to alkaline phosphatase (IU/L)
- A ratio >2.0 is a reliable indicator of Wilson disease in acute liver failure 6
- Check for other Wilson disease features:
- Hemolytic anemia
- Kayser-Fleischer rings (present in ~50% of cases)
- Low serum ceruloplasmin
- Elevated serum and urinary copper levels 6
Assess for Other Conditions Associated with Low ALP
- Malnutrition and vitamin/mineral deficiencies 2
- Endocrine disorders 2
- Medication effects, particularly antiresorptive therapies 2
- Acute severe illness or injury 2
- Autoimmune hemolytic anemia 5
Special Considerations
Chronic Liver Disease
- Patients with chronic liver disease and consistently low ALP may have less biochemical evidence of active disease 4
- In acute liver failure, a low ALP combined with high bilirubin (bilirubin/ALP ratio >2.0) strongly suggests Wilson disease 6
Osteoporosis and Fracture Risk
- HPP prevalence is approximately 3% in osteoporosis clinic patients with low ALP 1
- Antiresorptive therapy (used for osteoporosis) is contraindicated in HPP as it may increase fracture risk 1, 3
- Consider HPP in patients with atypical femoral fractures and low ALP 1
Fibromyalgia-Like Symptoms
- Consider HPP in patients diagnosed with fibromyalgia who have persistently low ALP levels 3
- Up to 44% of fibromyalgia patients with consistently low ALP have a history of fractures 3
Follow-up Recommendations
- For patients diagnosed with HPP, avoid antiresorptive therapies 1, 3
- Consider referral to specialists based on the underlying cause:
- Endocrinologist or metabolic bone disease specialist for HPP
- Hepatologist for Wilson disease or other liver conditions
- Monitor for fracture risk in patients with confirmed HPP 1, 3
- Consider enzyme replacement therapy for HPP to prevent complications such as fractures 3