Why would serum alkaline phosphatase be low?

Low Alkaline Phosphatase: Causes and Clinical Approach

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, antiresorptive medications (especially bisphosphonates), and Wilson disease in 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, pseudofractures, and premature loss of primary teeth (often before the usual eruption age). 1, 2
• Many patients report only minor symptoms such as mild musculoskeletal pain, and none may have major health problems despite biochemical abnormalities. 3

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
• Approximately 50% of adults with unexplained low serum ALP carry an ALPL mutation, most commonly heterozygous missense mutations predicted to have a damaging effect on protein activity. 3

Biochemical Markers

• Elevated pyridoxal-5′-phosphate (PLP) is a key substrate marker; all patients with PLP above the reference range carried a mutated ALPL allele. 3
• Elevated phosphoethanolamine (PEA) in urine correlates inversely with ALP levels (r = -0.49, p = 0.001) and is more pronounced in mutation carriers. 3
• ALP levels are inversely correlated with serum calcium (r = -0.38, p = 0.012), PLP (r = -0.51, p = 0.001), and urine PEA (r = -0.49, p = 0.001). 3

Genetic Confirmation

• When clinical and biochemical findings suggest hypophosphatasia, whole-gene sequencing of ALPL should be performed to confirm pathogenic variants. 1
• Bone-specific ALP measurement may reveal deficiency even when total ALP is normal; one case report documented HPP with normal total ALP but low bone-specific ALP (4.4 μg/L; reference 5.3–19.5 μg/L), confirmed by genetic testing. 4

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Secondary Causes of Low ALP

Medication-Induced

• Antiresorptive medications—particularly bisphosphonates and denosumab—can lower ALP levels by reducing bone turnover and should be reviewed in the medication history. 1, 2
• These agents may cause PLP levels to appear relatively elevated due to reduced enzymatic degradation. 1

Nutritional and Metabolic Deficiencies

• Malnutrition, micronutrient deficiencies (especially zinc, magnesium, vitamin B6), and endocrine disorders (hypothyroidism, hypoparathyroidism) can all depress ALP activity. 2

Wilson Disease 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, vitamin K–resistant coagulopathy, and relatively modest aminotransferase elevations (typically < 2000 IU/L). 1, 5
• An ALP-to-total bilirubin ratio < 2 is highly specific for Wilson disease in this setting and should trigger urgent evaluation for liver transplantation. 1, 5
• Serum copper concentrations are usually ≥ 200 µg/dL (≈ 31.5 µmol/L), 24-hour urinary copper excretion is markedly elevated, and Kayser-Fleischer rings may be absent in approximately 50% of patients presenting with acute liver failure. 1, 5
• Failure to recognize Wilson disease in young adults (< 40 years) with acute liver failure and an ALP-to-bilirubin ratio < 2 can delay life-saving liver transplantation; rapid diagnosis is therefore critical. 1, 5

Chronic Liver Disease

• In a large outpatient liver disease database, only 0.25% of 19,037 patients had consistently low serum ALP levels (< 40 IU/L). 6
• Patients with consistently low ALP had significantly lower serum aminotransferase and bilirubin levels throughout follow-up (p < 0.05), suggesting less biochemical evidence of active disease, while Fib-4 levels and MELD scores were similar. 6

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Diagnostic Approach

Initial Evaluation

1. Confirm persistence: Repeat ALP measurement to ensure the finding is reproducible and not a laboratory artifact. 1
2. Medication review: Identify any antiresorptive agents (bisphosphonates, denosumab) or other drugs that may suppress ALP. 1, 2
3. Assess for secondary causes: Screen for malnutrition, vitamin/mineral deficiencies (zinc, magnesium, vitamin B6), hypothyroidism, and hypoparathyroidism. 2

Biochemical Testing

• Measure pyridoxal-5′-phosphate (PLP) and urine phosphoethanolamine (PEA): Elevated levels support hypophosphatasia. 1, 3
• Bone-specific ALP: Consider measurement if total ALP is borderline or normal but clinical suspicion for hypophosphatasia remains high. 4
• In conditions with low albumin (e.g., inflammation), plasma ALP measurements may be unreliable; red cell PLP measurements are more reliable for differentiating true from apparent vitamin B6 status. 1, 5

Genetic Testing

• If clinical (musculoskeletal pain, premature tooth loss) and biochemical (elevated PLP, low bone-specific ALP) findings suggest hypophosphatasia, perform whole-gene sequencing of ALPL to confirm pathogenic variants. 1

Urgent Evaluation for Wilson Disease

• In patients < 40 years with ALP < 40 IU/L and any signs of acute liver dysfunction, immediately check:
  • Ceruloplasmin level (typically low)
  • 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
• Do not dismiss markedly low ALP (< 40 IU/L) in younger patients as benign; it signals a potential Wilson disease emergency that mandates prompt transplant evaluation. 5

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Critical Pitfalls to Avoid

• Do not assume low ALP is benign or a laboratory artifact without confirming persistence and excluding secondary causes; 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
• Do not rely solely on total ALP when hypophosphatasia is suspected; bone-specific ALP and substrate markers (PLP, PEA) provide additional diagnostic clarity. 4, 3
• Recognize that ALP levels can transiently normalize or even elevate in hypophosphatasia patients with concurrent liver disease (e.g., alcohol-induced hepatitis), potentially masking the diagnosis. 7
• In plasma with low albumin (e.g., inflammation), plasma ALP activity influences PLP concentration measurements; red cell PLP measurements are more reliable. 1