What causes low alkaline phosphatase (ALP) levels, specifically a level of 30?

Low Alkaline Phosphatase (ALP 30 U/L): Causes and Diagnostic Approach

A low ALP of 30 U/L most commonly indicates hypophosphatasia (HPP), a genetic disorder caused by ALPL gene mutations, though medication effects (especially bisphosphonates), malnutrition, vitamin/mineral deficiencies, and Wilson disease must also be excluded. 1, 2

Primary Causes to Consider

Hypophosphatasia (Most Important Genetic Cause)

• HPP 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. 2
• Approximately 50% of adults with unexplained low ALP carry an ALPL mutation, with most being heterozygous missense mutations that have damaging effects on protein activity. 3
• Adult-onset HPP typically presents with milder manifestations including skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems (tooth loss, "gray gums" in childhood), and stress/atypical fractures rather than severe bone disease. 2, 4
• Critical pitfall: Total ALP can be normal in some HPP cases—bone-specific ALP may be low when total ALP appears normal, so bone-specific ALP testing is essential if clinical suspicion exists. 4
• The prevalence of HPP is approximately 3% among patients with at least one low ALP measurement and 0.3% in general osteoporosis clinic populations. 5

Medication-Induced (Second Most Common)

• Antiresorptive medications, particularly bisphosphonates and denosumab, can lower ALP levels by reducing bone turnover and enzymatic degradation. 1, 6
• This is especially important in older patients (>60 years) who are more likely to be on these medications. 6
• Medication review is crucial as the first step in evaluation. 1

Wilson Disease (Critical to Exclude in Acute Presentations)

• 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). 1
• A ratio of alkaline phosphatase to total bilirubin <2 strongly suggests Wilson disease. 1

Nutritional and Metabolic Causes

• Malnutrition, vitamin deficiencies (especially vitamin C, vitamin D), and mineral deficiencies (zinc, magnesium) can cause low ALP. 2
• Hypothyroidism and other endocrine disorders may contribute to low ALP levels. 2
• In conditions with low albumin (inflammation, nephrotic syndrome), plasma ALP measurements may be unreliable, and red cell measurements are preferred. 1

Diagnostic Algorithm

Step 1: Initial Laboratory Assessment

• Measure pyridoxal phosphate (vitamin B6)—elevated levels strongly suggest HPP as ALP normally degrades this substrate. 2, 4, 3
• Check serum calcium and phosphate (mild hypercalcemia or hyperphosphatemia may occur in HPP). 3
• Measure urine phosphoethanolamine (PEA)—elevated in HPP due to substrate accumulation. 2, 3
• Order bone-specific ALP if total ALP is borderline or normal but clinical suspicion for HPP exists. 4
• ALP levels inversely correlate with serum calcium (r=-0.38), pyridoxal phosphate (r=-0.51), and urine PEA (r=-0.49). 3

Step 2: Clinical History Focus

• Document history of dental problems (premature tooth loss, childhood dental issues). 2, 3
• Ask about stress fractures, atypical femoral fractures, or chronic musculoskeletal pain. 2, 5
• Review for chondrocalcinosis or calcific periarthritis symptoms. 2
• Review all medications, especially bisphosphonates, denosumab, and other antiresorptives. 1, 6
• Screen for symptoms of Wilson disease if liver dysfunction present (jaundice, confusion, hemolysis). 1

Step 3: Determine Persistence

• Persistently low ALP (low on majority of measurements over ≥2 months) has higher diagnostic significance than transiently low levels. 5
• In osteoporosis clinic populations, 9% have at least one low ALP, but only 0.4% have persistently low levels. 5

Step 4: Genetic Testing

• If pyridoxal phosphate is elevated (above reference range) or clinical features suggest HPP, proceed with ALPL gene sequencing. 4, 3
• All patients with elevated vitamin B6 in one study carried an ALPL mutation. 3
• Important limitation: A substantial proportion of patients show normal results after sequencing ALPL exons—they may carry unidentified mutations in regulatory regions, epigenetic changes, or abnormalities in other genes. 2

Step 5: Exclude Other Causes

• Check zinc and magnesium levels to exclude deficiency states. 7
• Consider Wilson disease workup (ceruloplasmin, 24-hour urine copper, slit-lamp examination) if liver abnormalities present. 1
• Assess nutritional status and vitamin D levels if malnutrition suspected. 2

Critical Clinical Pitfalls

• Do not assume low ALP is benign or ignore it—9.3% of fibromyalgia patients may have undiagnosed HPP with consistently low ALP levels. 7
• Never start or continue bisphosphonates in patients with suspected or confirmed HPP—antiresorptive therapy is relatively contraindicated and can trigger atypical femoral fractures. 5, 7
• Do not rely solely on total ALP—bone-specific ALP may reveal HPP when total ALP appears normal. 4
• Always check vitamin B6 levels—this simple test is frequently overlooked but highly informative for HPP diagnosis. 4, 7
• Low ALP occurs in only 0.6% of all hospital patients, making it a relatively specific finding that warrants investigation. 5

Treatment Implications

• If HPP is confirmed, enzyme replacement therapy with asfotase alfa is available to improve symptoms and prevent complications. 4, 7
• Misdiagnosis of HPP as osteoporosis and subsequent treatment with antiresorptives can worsen outcomes and increase fracture risk. 5