What causes decreased alkaline phosphatase (ALP) levels?

Causes of Decreased Alkaline Phosphatase

Decreased alkaline phosphatase (ALP) levels are most commonly caused by hypophosphatasia (a genetic disorder due to ALPL gene mutations), nutritional deficiencies (zinc, magnesium, malnutrition), antiresorptive medications (bisphosphonates, denosumab), and Wilson disease presenting as acute liver failure.

Primary Genetic Cause: Hypophosphatasia

Hypophosphatasia is 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 1.

• Approximately 50% of adults with unexplained low ALP carry an ALPL mutation, with missense mutations being most common (86% of cases) 2
• The prevalence of hypophosphatasia is 0.3% in osteoporosis clinic populations and 3% among patients with at least one low ALP measurement 3
• Clinical manifestations in adults include skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems (tooth loss, "gray gums"), stress fractures, and atypical femoral fractures 2, 3, 1
• Approximately 9.3% of patients diagnosed with fibromyalgia have consistently low ALP levels, suggesting potential undiagnosed hypophosphatasia 4

Biochemical Markers of Hypophosphatasia

• Elevated pyridoxal phosphate (vitamin B6) is a key diagnostic marker, with all patients having PLP above reference range carrying an ALPL mutation 2
• Elevated phosphoethanolamine in urine correlates inversely with ALP levels (r=-0.49, p=0.001) 2
• Mild hyperphosphatemia occurs in approximately 21% of cases and mild hypercalcemia in 7% 2
• Bone-specific ALP may be low even when total ALP is normal, warranting measurement when hypophosphatasia is suspected clinically 5

Wilson Disease

In acute liver failure presentations, markedly subnormal serum ALP (typically <40 IU/L) is characteristic of Wilson disease, occurring alongside Coombs-negative hemolytic anemia, coagulopathy, and relatively modest aminotransferase elevations (typically <2000 IU/L) 6.

• A ratio of alkaline phosphatase to total bilirubin of <2 strongly suggests Wilson disease in the acute liver failure setting 6

Medication-Induced Low ALP

Antiresorptive medications, including bisphosphonates and denosumab, can lower ALP levels and should be reviewed in medication history 6.

• These medications alter ALP levels despite underlying bone pathology 7
• This is particularly important when evaluating patients for hypophosphatasia, as antiresorptive therapy is relatively contraindicated in this condition 3

Nutritional and Metabolic Causes

Malnutrition and specific vitamin/mineral deficiencies are acquired causes of persistently low ALP 1.

• Zinc deficiency is a recognized cause of low ALP 1
• Magnesium deficiency can contribute to low ALP levels 1
• General malnutrition affects ALP production 1

Inflammatory and Acute Illness Contexts

Low serum ALP is an epiphenomenon of many severe acute injuries and diseases 1.

• In conditions with low albumin (such as inflammation), plasma ALP measurements may be unreliable, and red cell measurements are preferred 8
• Plasma albumin concentration and alkaline phosphatase activity influence pyridoxal phosphate concentration in plasma 8

Diagnostic Approach

Initial Evaluation

• Measure bone-specific ALP if total ALP is borderline or normal but clinical suspicion for hypophosphatasia exists (dental problems, skeletal pain, fractures, chondrocalcinosis) 5
• Check pyridoxal phosphate (vitamin B6) levels, as elevation strongly suggests hypophosphatasia 2, 4
• Measure serum calcium and phosphate, as mild elevations support hypophosphatasia 2
• Obtain urine phosphoethanolamine if available 2, 1

Confirmatory Testing

• Genetic testing for ALPL gene mutations confirms hypophosphatasia diagnosis 2, 5, 1
• Review medication history for antiresorptive agents 6
• Assess for nutritional deficiencies: zinc, magnesium, general malnutrition 1
• In acute liver failure with very low ALP (<40 IU/L), calculate ALP/total bilirubin ratio and evaluate for Wilson disease 6

Clinical Pitfalls

• Hypophosphatasia is frequently underdiagnosed or misdiagnosed as osteoporosis, leading to inappropriate antiresorptive therapy that can trigger atypical femoral fractures 3
• Normal total ALP does not exclude hypophosphatasia—bone-specific ALP may be low when total ALP is normal 5
• Vitamin B6 levels are rarely checked in patients with low ALP, missing a key diagnostic clue 4
• A substantial proportion of patients with clinical hypophosphatasia show normal results after sequencing ALPL exons, possibly due to unidentified mutations in regulatory regions, epigenetic changes, or abnormalities in other genes 1