What causes low alkaline phosphatase levels?

Causes of Low Alkaline Phosphatase

Low alkaline phosphatase (ALP) levels are most commonly caused by hypophosphatasia (a genetic disorder of the ALPL gene), Wilson disease in acute liver failure presentations, medication effects (particularly bisphosphonates), and nutritional deficiencies, with hypophosphatasia being the primary genetic cause requiring systematic evaluation. 1, 2

Primary Genetic Cause: Hypophosphatasia

Hypophosphatasia represents 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. 2

• Approximately 50% of adults with unexplained low ALP carry an ALPL mutation, with missense mutations being most common (86% of cases) and typically heterozygous. 3
• The condition causes defective bone mineralization and presents heterogeneously in adults with skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems (tooth loss, "gray gums"), stress fractures, and atypical femur fractures. 3, 2, 4
• Substrate accumulation occurs when enzyme activity is sufficiently low, manifesting as elevated pyridoxal phosphate (PLP/vitamin B6), elevated phosphoethanolamine (PEA), and mild hyperphosphatemia. 3, 2

Wilson Disease Presentation

In acute liver failure, markedly low serum ALP (<40 IU/L) with an alkaline phosphatase-to-total bilirubin ratio <2 strongly suggests Wilson disease, particularly when accompanied by Coombs-negative hemolytic anemia, modest aminotransferase elevations, and total bilirubin ≥20 mg/dL with elevated indirect fraction. 1

• The American Association for the Study of Liver Diseases recommends considering Wilson disease in young patients with acute liver failure, as this combination is pathognomonic. 1
• Diagnostic features include Kayser-Fleischer rings (present in only 50% of acute cases), serum copper >200 μg/dL, greatly elevated 24-hour urinary copper, and low ceruloplasmin (though normal in 15% of cases). 1

Medication-Induced Low ALP

Antiresorptive medications, particularly bisphosphonates, represent a critical iatrogenic cause of low ALP levels and must be identified before diagnosing primary bone disorders. 1

• Medication history review is essential in the diagnostic workup, as these drugs can significantly lower ALP levels. 1
• This is particularly important because antiresorptive therapy can trigger atypical femur fractures in undiagnosed hypophosphatasia patients. 4

Nutritional and Metabolic Causes

Persistently low serum ALP may be secondary to:

• Malnutrition, vitamin and mineral deficiencies (particularly zinc and magnesium). 2
• Endocrine disorders affecting bone metabolism. 2
• Low albumin states, where plasma ALP measurements become unreliable and red cell measurements are preferred. 1

Chronic Liver Disease Association

In chronic liver disease (CLD), low ALP levels occur in approximately 0.25% of patients with consistently low levels, and these patients demonstrate significantly lower serum aminotransferase and bilirubin levels compared to those with normal or elevated ALP. 5

• This association suggests less biochemical evidence of active disease, though the clinical significance remains under investigation. 5

Diagnostic Approach Algorithm

Step 1: Confirm Persistent Low ALP

• Verify low total ALP with multiple measurements (<40 IU/L is markedly low; values below normal range warrant investigation). 1, 3
• Consider bone-specific ALP testing, as total ALP may be normal while bone-specific ALP is low in some hypophosphatasia cases. 6

Step 2: Evaluate for Acute Presentations

• In acute liver failure with low ALP, immediately assess for Wilson disease by checking ceruloplasmin, serum copper, 24-hour urinary copper, and examining for Kayser-Fleischer rings. 1
• Calculate alkaline phosphatase-to-total bilirubin ratio and assess for hemolytic anemia. 1

Step 3: Review Medication History

• Document all antiresorptive medications (bisphosphonates, denosumab) and other drugs that may lower ALP. 1

Step 4: Measure ALP Substrates

• Check pyridoxal phosphate (vitamin B6) - elevated levels (above reference range) strongly suggest enzyme deficiency and are present in all mutation carriers with substrate accumulation. 3, 2
• The relationship between plasma PLP and ALP is quantitatively inverse and logarithmic. 1
• Measure phosphoethanolamine in urine (elevated in hypophosphatasia). 3, 2
• Check serum phosphate (mild hyperphosphatemia occurs in ~21% of cases) and calcium (mild hypercalcemia in ~7%). 3

Step 5: Assess Clinical Manifestations

• Document dental history (early tooth loss, dental abscesses, "gray gums" in childhood). 3, 6
• Evaluate for skeletal manifestations: chronic musculoskeletal pain, history of stress fractures, atypical femur fractures, chondrocalcinosis. 3, 2, 4
• Screen for fibromyalgia-like symptoms, as 9.3% of fibromyalgia patients may have consistently low ALP. 4

Step 6: Genetic Testing

• Perform ALPL gene sequencing when clinical suspicion exists, particularly if vitamin B6 is elevated or clinical manifestations are present. 3, 6, 2
• 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. 2

Step 7: Nutritional Assessment

• Check zinc and magnesium levels, assess for malnutrition, and evaluate endocrine function if other causes are excluded. 2

Critical Pitfalls to Avoid

• Do not rely solely on total ALP - bone-specific ALP may be low when total ALP appears normal. 6
• Do not overlook vitamin B6 testing - this is frequently missed but provides crucial diagnostic information, with all patients having elevated B6 carrying ALPL mutations. 3, 4
• Do not dismiss mild symptoms - adult hypophosphatasia often presents with seemingly minor complaints like musculoskeletal pain that can be misdiagnosed as fibromyalgia. 3, 4
• Do not prescribe bisphosphonates without excluding hypophosphatasia - this can precipitate atypical femur fractures in affected patients. 4
• In low albumin states, plasma ALP measurements are unreliable - use red cell measurements instead. 1