What causes low alkaline phosphatase levels?

Causes of Low Alkaline Phosphatase

Low alkaline phosphatase (ALP) levels are most commonly associated with hypophosphatasia, a rare genetic disorder, but can also occur in several other conditions including Wilson's disease, malnutrition, vitamin deficiencies, and following cardiac surgery. 1

Primary Causes

Genetic Disorders

• Hypophosphatasia: The most common genetic cause of low ALP, resulting from pathogenic variants in the ALPL gene that encodes tissue non-specific alkaline phosphatase 1
  • Pediatric forms present with severe bone hypomineralization
  • Adult forms typically present with milder manifestations:
    • Skeletal pain
    • Chondrocalcinosis
    • Calcific periarthritis
    • Dental problems
    • Stress fractures

Acute Medical Conditions

• Wilson's disease: Low ALP is a characteristic finding in patients with acute liver failure presentation of Wilson's disease 2

  • Typically presents with:
    • Coombs-negative hemolytic anemia
    • Coagulopathy unresponsive to vitamin K
    • Rapid progression to renal failure
    • Modest rises in serum aminotransferases
    • Low serum alkaline phosphatase (typically 40 IU/L)
  • A ratio of alkaline phosphatase to total bilirubin of <2 is suggestive of Wilson's disease 2

• Cardiac surgery and cardiopulmonary bypass: Most frequent cause (26.5%) of low ALP in a predominantly male population 3

Secondary Causes

Nutritional and Metabolic Factors

• Malnutrition: Second most common cause (12%) of low ALP in adults 3
• Magnesium deficiency: Accounts for approximately 4.8% of cases 3
• Zinc deficiency: Zinc is a cofactor for tissue non-specific alkaline phosphatase 4
• Vitamin D deficiency: Can complicate hypophosphatasia and contribute to rickets despite normal calcium and phosphate levels 5

Endocrine Disorders

• Hypothyroidism: Accounts for approximately 2.4% of cases 3

Hematologic Conditions

• Severe anemia: Accounts for approximately 1.2% of cases 3

Medication-Related

• Antiresorptive therapy: Can further lower ALP levels in patients with underlying hypophosphatasia 6

Diagnostic Approach

1. Confirm persistently low ALP:

   • Repeat measurement to ensure it's not transient
   • Low ALP is defined as <30 IU/L 3

2. Evaluate for Wilson's disease if acute liver failure is present:

   • Check for Coombs-negative hemolytic anemia
   • Assess coagulation parameters
   • Measure serum copper and 24-hour urinary copper excretion
   • Look for Kayser-Fleischer rings 2

3. Screen for hypophosphatasia if persistent low ALP:

   • Measure ALP substrates: pyrophosphate, pyridoxal phosphate (vitamin B6), phosphoethanolamine 1
   • Consider genetic testing for ALPL gene mutations 1
   • Evaluate for clinical manifestations: bone pain, fractures, dental issues

4. Rule out nutritional deficiencies:

   • Check zinc levels (27.2% of hypophosphatasia patients have zinc deficiency) 4
   • Assess vitamin D status (73.5% of hypophosphatasia patients have vitamin D deficiency) 4
   • Evaluate magnesium levels

5. Consider other differential diagnoses:

   • Paget's disease (characterized by raised alkaline phosphatase) 2
   • Osteomalacia (typically has elevated alkaline phosphatase) 2
   • Recent cardiac surgery history

Clinical Implications

• Low ALP in osteoporosis clinic patients may signal hypophosphatasia (found in 3% of patients with low ALP) 6
• Antiresorptive therapy, commonly used for osteoporosis, is relatively contraindicated in hypophosphatasia 6
• Supplementation of zinc and vitamin D according to general guidelines can be safely applied to hypophosphatasia patients without exacerbating disease burden 4

Prevalence

• Low ALP occurs in approximately 0.19% of the general population 3
• In osteoporosis clinics, about 9% of patients have at least one low ALP measurement 6
• Persistent low ALP is found in 0.4% of osteoporosis clinic patients 6

Understanding the cause of low ALP is crucial for proper diagnosis and management, particularly to avoid misdiagnosis of conditions like hypophosphatasia as osteoporosis, which could lead to inappropriate treatment with antiresorptive therapy.