What causes a low serum alkaline phosphatase level?

Causes of Decreased Serum Alkaline Phosphatase

Low serum alkaline phosphatase (ALP) is most commonly caused by hypophosphatasia—a genetic disorder due to loss-of-function mutations in the ALPL gene—but secondary causes including malnutrition, micronutrient deficiencies, endocrine disorders, antiresorptive medications (especially bisphosphonates), and Wilson disease presenting with acute liver failure must be systematically excluded. 1

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Primary Genetic Cause: Hypophosphatasia

Hypophosphatasia is the leading genetic etiology of persistently low ALP and results from pathogenic variants in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase. 1, 2

Clinical Manifestations in Adults

• Adults typically present with mild musculoskeletal complaints: skeletal pain, chondrocalcinosis, calcific periarthritis, stress fractures, and pseudofractures. 1
• Premature loss of primary teeth (often before the usual eruption age) is a hallmark feature. 1
• Approximately 50% of adults with unexplained low ALP carry an ALPL mutation, most commonly heterozygous missense variants predicted to impair enzyme activity. 3
• Even when total ALP appears normal, bone-specific ALP may be low (<5.3 μg/L), and genetic testing can confirm hypophosphatasia. 4

Diagnostic Thresholds

• Persistent low ALP in adults is defined as serum ALP < 40 IU/L; some osteoporosis guideline societies use a stricter cutoff of < 30 IU/L when screening for hypophosphatasia. 1

Biochemical Markers Supporting Enzyme Deficiency

• Elevated pyridoxal phosphate (PLP) and elevated urinary phosphoethanolamine (PEA) are ALP substrates that accumulate when enzyme activity is deficient; approximately 24% of individuals with low ALP have PLP above the reference range, and all carry a mutated ALPL allele. 3
• ALP levels are inversely correlated with serum calcium (r = –0.38), PLP (r = –0.51), and urinary PEA (r = –0.49). 3
• In conditions with low albumin (e.g., inflammation), plasma ALP measurements may be unreliable; red cell PLP measurements are more reliable than plasma measurements for differentiating true from apparent vitamin B6 status. 1

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Wilson Disease: A Critical Differential in Acute Liver Failure

In acute liver failure, markedly subnormal serum ALP (typically < 40 IU/L) is characteristic of Wilson disease and occurs alongside Coombs-negative hemolytic anemia, coagulopathy unresponsive to parenteral vitamin K, and relatively modest aminotransferase elevations (typically < 2000 IU/L). 5, 1

Diagnostic Clues

• An alkaline phosphatase-to-total bilirubin ratio < 2 is highly specific for Wilson disease in this setting and should trigger urgent evaluation for liver transplantation. 5, 1
• The low-ALP pattern reflects massive hepatocyte necrosis with copper-mediated inhibition of ALP activity. 1
• Serum copper is usually ≥ 200 μg/dL (31.5 μmol/L), and 24-hour urinary copper excretion is greatly elevated. 5
• Kayser-Fleischer rings may be absent in 50% of patients with acute liver failure due to Wilson disease. 5, 1
• Low values for serum ALP were observed in 11 of 12 patients with Wilson disease presenting with hemolytic anemia; in eight, ALP was below the lower limit of normal. 6

Clinical Urgency

• Failure to recognize Wilson disease in young adults with acute liver failure and an ALP-to-bilirubin ratio < 2 can delay life-saving transplantation. 1
• Expeditious diagnosis is critically important because these patients require urgent liver transplantation to survive. 5

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Medication-Induced Low ALP

Antiresorptive medications, particularly bisphosphonates and denosumab, can lower ALP levels by reducing bone turnover and should be reviewed in the medication history of any patient with low ALP. 1, 7

• Bisphosphonates may cause PLP levels to appear relatively elevated due to reduced enzymatic degradation. 1
• A thorough medication review is essential before diagnosing primary bone disorders. 8

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Secondary Causes of Low ALP

Malnutrition and Micronutrient Deficiencies

• Malnutrition, vitamin deficiencies (especially vitamin C, vitamin D, zinc), and mineral deficiencies can all reduce serum ALP. 1, 2

Endocrine Disorders

• Hypothyroidism, hypoparathyroidism, and other endocrine abnormalities may present with low ALP. 1, 2

Acute Illness and Iatrogenic Causes

• Low serum ALP is an epiphenomenon of many severe acute injuries and diseases, including neonates undergoing exchange transfusions with plasma, patients (particularly children) receiving chemotherapy, and during cardiopulmonary bypass. 9, 2

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Diagnostic Approach to Persistently Low ALP

Step 1: Confirm Persistence and Exclude Laboratory Error

• Repeat ALP measurement to confirm that the low value is reproducible and not a laboratory artifact. 1

Step 2: Comprehensive Medication and Clinical History

• Review all prescribed, over-the-counter, and supplement medications, with particular attention to bisphosphonates, denosumab, and other antiresorptives. 1, 8
• Assess for symptoms of hypophosphatasia: skeletal pain, chondrocalcinosis, calcific periarthritis, stress fractures, pseudofractures, and premature tooth loss. 1
• In young patients (especially < 40 years) with ALP < 40 IU/L, consider Wilson disease and assess for signs of acute liver failure, hemolytic anemia, and neurologic symptoms. 5, 1

Step 3: Measure ALP Substrates

• Pyridoxal phosphate (PLP) and urinary phosphoethanolamine (PEA) should be measured; elevations suggest enzyme deficiency and support a diagnosis of hypophosphatasia. 3, 2
• If total ALP is borderline or normal but clinical suspicion is high, measure bone-specific ALP (normal range 5.3–19.5 μg/L); values < 5.3 μg/L warrant genetic testing. 4

Step 4: Genetic Testing

• Whole-gene sequencing of ALPL should be performed when clinical and biochemical findings suggest hypophosphatasia. 5, 2
• Approximately 50% of adults with unexplained low ALP carry an ALPL mutation; however, a substantial proportion show normal results after sequencing ALPL exons, and it remains unknown if these patients carry unidentified mutations in regulatory regions, epigenetic changes, or abnormalities in other genes. 3, 2

Step 5: Evaluate for Wilson Disease (if age < 40 years and ALP < 40 IU/L)

• Immediate work-up should include:
  • Ceruloplasmin level (typically low in Wilson disease)
  • 24-hour urinary copper (markedly elevated)
  • Serum copper (often > 200 μg/dL)
  • Complete blood count to detect hemolytic anemia
  • Slit-lamp examination for Kayser-Fleischer rings 5, 8
• If acute liver failure is present, calculate the alkaline phosphatase-to-total bilirubin ratio; a ratio < 2 strongly suggests Wilson disease and mandates urgent transplant evaluation. 5, 1

Step 6: Assess for Secondary Causes

• Evaluate nutritional status, vitamin and mineral levels (especially vitamin C, vitamin D, zinc), and thyroid and parathyroid function. 1, 2
• Consider recent acute illness, chemotherapy, or cardiopulmonary bypass as transient causes. 9, 2

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Critical Pitfalls to Avoid

• Do not dismiss low ALP as benign or a laboratory artifact without confirming persistence and excluding secondary causes. 1
• Do not overlook Wilson disease in young adults with acute liver failure and an ALP-to-bilirubin ratio < 2; failure to recognize this pattern can delay life-saving transplantation. 1
• Do not assume that a normal total ALP excludes hypophosphatasia; bone-specific ALP may be low even when total ALP is within the reference range. 4
• Do not underestimate the importance of medication review, particularly for bisphosphonates and other antiresorptives, which are common iatrogenic causes of low ALP. 1, 8