Low Alkaline Phosphatase at Age 28
In a 28-year-old with low alkaline phosphatase, the most likely diagnosis is hypophosphatasia (HPP), a genetic disorder caused by ALPL gene mutations that impairs bone mineralization and can present with chronic musculoskeletal pain, dental problems, stress fractures, and chondrocalcinosis. 1, 2
Primary Differential Diagnosis
Hypophosphatasia (Most Common Genetic Cause)
HPP is the most common genetic cause of persistently low serum ALP and should be the primary consideration in a 28-year-old. 2
Adult-onset HPP typically presents with milder manifestations including skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems (premature tooth loss, "gray gums"), and stress fractures rather than the severe bone hypomineralization seen in pediatric cases 1, 2
Approximately 50% of adults with unexplained low ALP carry an ALPL gene mutation, with missense mutations being most common (86% of cases) 1
Key clinical features to assess include history of premature tooth loss (present in 48% of mutation carriers vs 12% without mutations), chronic musculoskeletal pain, history of stress or atypical fractures, and joint pain 1, 3
Secondary Causes to Exclude
Before confirming HPP, rule out acquired causes of low ALP 2:
- Nutritional deficiencies: zinc, magnesium, vitamin C, or severe malnutrition 2
- Endocrine disorders: hypothyroidism, pernicious anemia 2
- Medications: particularly antiresorptive therapy (bisphosphonates, denosumab) which can lower ALP and potentially trigger atypical fractures in undiagnosed HPP 4, 2
- Acute severe illness: though this typically causes transient rather than persistent low ALP 2
Diagnostic Workup Algorithm
Step 1: Confirm Persistent Low ALP
- Obtain at least 2-3 measurements of total serum ALP to distinguish transient from persistent low levels 4
- Consider bone-specific ALP testing, as total ALP can occasionally be normal while bone-specific ALP is low in HPP 5
Step 2: Measure ALP Substrates
If ALP is persistently low, measure the following substrates that accumulate when ALP enzyme is deficient 1, 2:
- Pyridoxal 5'-phosphate (vitamin B6): elevated in HPP; all patients with vitamin B6 above reference range in one study carried an ALPL mutation 1
- Urine phosphoethanolamine (PEA): elevated in HPP and inversely correlated with ALP levels 1
- Serum pyrophosphate: elevated in HPP 2
Critical finding: The presence of elevated vitamin B6 (PLP) is highly suggestive of HPP, with 100% of patients having elevated PLP carrying a mutation in one study 1
Step 3: Additional Biochemical Testing
- Serum calcium: may be mildly elevated (inversely correlated with ALP levels) 1
- Serum phosphate: may be mildly elevated in HPP 1
- Zinc and magnesium levels: to exclude deficiency as a cause 2, 3
- Thyroid function tests: to exclude hypothyroidism 2
Step 4: Genetic Testing
If clinical suspicion is high and/or ALP substrates are elevated, proceed with ALPL gene sequencing 1, 2:
- Heterozygous mutations are most common in adults (present in nearly all mutation carriers in one study) 1
- Six novel mutations were identified in a single cohort, indicating ongoing discovery of pathogenic variants 1
- Important caveat: A substantial proportion of patients with clinical and biochemical features of HPP show normal ALPL exon sequencing, possibly due to unidentified mutations in regulatory regions, epigenetic changes, or abnormalities in other genes 2
Clinical Significance and Management Implications
Why Diagnosis Matters
Misdiagnosis of HPP as osteoporosis can lead to inappropriate treatment with antiresorptive therapy, which is relatively contraindicated in HPP and may trigger atypical femoral fractures 4, 2:
- In one study, 9% of osteoporosis clinic patients had low ALP, and 3% of those with low ALP were diagnosed with HPP 4
- Among patients with atypical femoral fractures, 2 out of 22 (9%) had low ALP 4
Treatment Considerations
- Enzyme replacement therapy with asfotase alfa is available for HPP and can improve symptoms 5
- Avoid bisphosphonates and denosumab in confirmed or suspected HPP 4, 2
Common Pitfalls to Avoid
Do not assume low ALP is clinically insignificant - persistently low ALP warrants investigation, particularly in young adults with musculoskeletal complaints 4, 2
Do not overlook bone-specific ALP testing - total ALP can be normal while bone-specific ALP is low in some HPP cases 5
Do not miss the fibromyalgia overlap - in one study, 9.3% of fibromyalgia patients had consistently low ALP, and none had been tested for HPP despite the availability of specific treatment 3
Do not forget to check vitamin B6 levels - this simple test is often overlooked but highly informative, with elevated levels strongly suggesting HPP 1, 3
Do not rule out HPP based on negative genetic testing alone - a normal ALPL gene sequence does not definitively exclude the diagnosis if clinical and biochemical features are present 2