What causes low alkaline phosphatase (ALP) levels?

Causes of Low Alkaline Phosphatase (ALP)

Low alkaline phosphatase levels are most commonly associated with Wilson disease, hypophosphatasia, and certain acute conditions, with Wilson disease being a critical diagnosis to consider in patients with acute liver failure and low ALP. 1

Primary Causes

1. Wilson Disease

• Characterized by abnormally low ALP levels, especially in acute liver failure presentation
• Typically shows ALP levels around 40 IU/L or lower 1
• Often presents with:
  • Coombs-negative hemolytic anemia
  • Coagulopathy unresponsive to vitamin K
  • Rapid progression to renal failure
  • Modest elevations in serum aminotransferases (typically 2000 IU/L)
  • Ratio of alkaline phosphatase to total bilirubin of <2 1

2. Hypophosphatasia (HPP)

• Inherited disorder caused by mutations in the ALPL gene which encodes tissue-nonspecific alkaline phosphatase (TNSALP) 2, 3
• May be more common than previously thought (estimated prevalence 1:194 to 1:508 for moderate forms) 4
• Clinical presentations:
  • Adult forms: skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems, stress fractures 3
  • Pediatric forms: severe bone hypomineralization 3
• Laboratory findings:
  • Persistently low ALP (<30 IU/L)
  • Elevated pyridoxal-5-phosphate (PLP) levels 4
  • Elevated phosphoethanolamine (PEA) in urine 2

Secondary Causes

1. Nutritional and Metabolic Factors

• Malnutrition 3
• Zinc deficiency (zinc is a cofactor for TNSALP) 5
• Vitamin D deficiency 5
• Vitamin B6 (pyridoxine) metabolism disorders 1

2. Medications

• Antiresorptive therapies 3
• Corticosteroids 1
• Anti-cancer drugs 1
• Anticonvulsants 1

3. Other Conditions

• Acute severe illness or injury 3
• Inflammation (can affect plasma PLP levels, related to ALP function) 1
• Endocrine disorders 3
• Low albumin states (albumin concentration influences PLP concentration in plasma) 1

Diagnostic Approach for Low ALP

1. Confirm persistently low ALP levels (multiple measurements <30 IU/L)

   • Transient low ALP is common (9% of osteoporosis clinic patients) 6
   • Persistent low ALP is less common (0.4% of osteoporosis clinic patients) 6

2. Screen for Wilson disease if liver abnormalities present:

   • Check ratio of alkaline phosphatase to total bilirubin (<2 suggests Wilson disease) 1
   • Assess for hemolytic anemia, elevated serum copper, and 24-hour urinary copper excretion
   • Look for Kayser-Fleischer rings (though may be absent in 50% of acute cases) 1

3. Screen for hypophosphatasia:

   • Measure ALP substrates: pyridoxal-5-phosphate (PLP), pyrophosphate, phosphoethanolamine 3
   • Consider genetic testing for ALPL mutations (found in 50% of adults with unexplained low ALP) 2
   • Assess for clinical manifestations: dental issues, bone pain, fractures 6, 2

4. Check for nutritional deficiencies:

   • Zinc levels (27.2% of HPP patients have zinc deficiency) 5
   • Vitamin D levels (73.5% of HPP patients have vitamin D deficiency) 5

Clinical Implications

• Low ALP in osteoporosis clinic patients warrants screening for hypophosphatasia (found in 3% of patients with low ALP) 6
• Antiresorptive therapy is relatively contraindicated in HPP but commonly used for osteoporosis 6
• Patients with Wilson disease and acute liver failure require urgent liver transplantation 1
• Zinc and vitamin D supplementation may be beneficial in HPP patients with deficiencies 5

Common Pitfalls

1. Overlooking low ALP as clinically significant (often considered "normal" or "good")
2. Misdiagnosing HPP as osteoporosis, leading to inappropriate antiresorptive therapy
3. Failing to recognize Wilson disease in acute liver failure due to relatively modest aminotransferase elevations
4. Not measuring PLP levels when low ALP is detected (recommended as automatic follow-up) 4
5. Missing ALPL mutations in genetic testing (some patients with clinical HPP show normal results after exon sequencing) 3