A patient has an alkaline phosphatase of 24 U/L; could this low level be caused by hypothyroidism and what is the appropriate evaluation and management?

Low Alkaline Phosphatase in Hypothyroidism: Evaluation and Management

Direct Answer

A serum alkaline phosphatase of 24 U/L is markedly low and is NOT caused by hypothyroidism; instead, hypothyroidism typically presents with elevated ALP levels, and this patient requires immediate evaluation for hypophosphatasia or other causes of persistently low ALP. 1, 2

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Why Hypothyroidism Does Not Cause Low ALP

• Hypothyroidism is associated with elevated alkaline phosphatase, not low levels, because reduced thyroid hormone decreases bone turnover and can cause cholestatic patterns. 1
• The biochemical hallmark of hypothyroidism includes elevated TSH with low free T4, but ALP levels are typically normal or mildly elevated, never this profoundly suppressed. 3
• This patient's low ALP of 24 U/L points to a completely different pathophysiologic process unrelated to thyroid dysfunction. 2

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Differential Diagnosis for ALP 24 U/L

Primary Consideration: Hypophosphatasia

Hypophosphatasia (HPP) is the most common genetic cause of persistently low serum ALP and must be ruled out first. 2

• HPP results from pathogenic variants in the ALPL gene encoding tissue non-specific alkaline phosphatase. 2
• Adult-onset HPP typically presents with skeletal pain, chondrocalcinosis, calcific periarthritis, dental problems (tooth loss, "gray gums"), stress fractures, and pseudofractures. 2, 4
• Approximately 50% of adults with unexplained low ALP carry an ALPL mutation, most commonly heterozygous missense mutations. 4

Secondary Causes to Exclude

• Malnutrition and vitamin/mineral deficiencies (zinc, magnesium, vitamin C deficiency). 2
• Medications: Antiresorptive therapy (bisphosphonates, denosumab) can suppress bone turnover and lower ALP. 2
• Endocrine disorders: Severe hypothyroidism paradoxically can lower bone turnover in rare cases, but this would present with markedly elevated TSH. 2
• Acute severe illness: Low ALP can be an epiphenomenon of critical illness, but this is transient. 2

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Diagnostic Workup Algorithm

Step 1: Confirm Persistent Hypophosphatasemia

• Repeat serum total ALP to confirm the low value is persistent (at least two measurements). 5
• If total ALP remains low, proceed to bone-specific ALP measurement, as total ALP can occasionally be normal while bone-specific ALP is suppressed in HPP. 6

Step 2: Measure ALP Substrates

Measuring ALP substrates helps establish enzyme deficiency and supports the diagnosis of HPP: 2

• Serum pyridoxal 5'-phosphate (PLP, vitamin B6): Elevated PLP (above reference range) is highly specific for HPP and correlates inversely with ALP levels. 4
• Urine phosphoethanolamine (PEA): Elevated PEA correlates with low ALP and supports HPP diagnosis. 4
• Serum inorganic pyrophosphate: Elevated in HPP due to impaired ALP-mediated hydrolysis. 2

Step 3: Assess for Clinical Manifestations of HPP

Perform a targeted history and physical examination focusing on: 2, 4

• Dental history: Early tooth loss (especially primary teeth before age 5), recurrent dental abscesses, "gray gums" in childhood. 2
• Musculoskeletal symptoms: Chronic bone/joint pain, history of stress fractures or pseudofractures, chondrocalcinosis, calcific periarthritis. 2, 4
• Family history: First-degree relatives with similar symptoms, early tooth loss, or fractures. 4

Step 4: Biochemical Panel

• Serum calcium and phosphate: Mild hypercalcemia or hyperphosphatemia may be present in HPP. 4
• Serum creatinine and estimated GFR: To assess renal function. 2
• Thyroid function tests (TSH, free T4): To confirm hypothyroidism diagnosis and ensure it is adequately treated. 3, 7

Step 5: Genetic Testing

• Sequence the ALPL gene if clinical suspicion is high, substrates are elevated, or no secondary cause is identified. 2, 4
• Genetic confirmation of a pathogenic ALPL variant establishes the diagnosis of HPP. 2
• Important caveat: Approximately 50% of patients with persistently low ALP and clinical features do not have identifiable ALPL mutations on exon sequencing; these may harbor mutations in regulatory regions, epigenetic changes, or other unidentified genes. 2

Step 6: Imaging if Indicated

• Radiographs of symptomatic areas: Look for pseudofractures, osteomalacia, chondrocalcinosis, or enthesopathy. 2
• Bone densitometry (DXA scan): May show low bone mineral density in some HPP patients. 2

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Management Considerations

If HPP is Confirmed

• Asfotase alfa (enzyme replacement therapy) is FDA-approved for pediatric-onset HPP and may be considered in adults with significant symptoms (recurrent fractures, disabling pain, impaired mobility). 6
• Refer to a metabolic bone disease specialist or endocrinologist with expertise in HPP. 2

If Secondary Causes are Identified

• Correct nutritional deficiencies (zinc, magnesium, vitamin C). 2
• Review and adjust medications if antiresorptives are contributing. 2
• Optimize thyroid hormone replacement if hypothyroidism is inadequately treated, though this will not directly raise ALP. 3, 7

Thyroid Management in This Patient

• Ensure adequate levothyroxine dosing by checking TSH and free T4 every 6-8 weeks after dose adjustments, targeting TSH 0.45-4.5 mIU/L. 3, 7
• In adults with primary hypothyroidism, monitor TSH every 6-12 months once stable. 7
• The low ALP is unrelated to thyroid status and requires separate evaluation. 1, 2

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Critical Pitfalls to Avoid

• Do not assume low ALP is benign or related to hypothyroidism—it signals a distinct pathologic process. 2
• Do not rely solely on total ALP—bone-specific ALP may be low even when total ALP is normal. 6
• Do not overlook substrate measurement (PLP, PEA)—these are key diagnostic clues for HPP. 2, 4
• Do not dismiss mild symptoms—adult HPP often presents subtly with chronic pain, dental issues, or stress fractures that may be attributed to other causes. 2, 4
• Do not delay genetic testing if clinical suspicion is high, as approximately 50% of adults with unexplained low ALP carry ALPL mutations. 4

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Summary of Recommended Approach

1. Confirm persistent low ALP with repeat testing and consider bone-specific ALP. 5, 6
2. Measure ALP substrates (PLP, PEA) to establish enzyme deficiency. 2, 4
3. Perform targeted clinical assessment for dental, skeletal, and family history of HPP. 2, 4
4. Check serum calcium, phosphate, and renal function. 4
5. Optimize thyroid management independently, as hypothyroidism does not cause low ALP. 3, 7
6. Pursue genetic testing (ALPL sequencing) if HPP is suspected. 2, 4
7. Refer to a metabolic bone specialist if HPP is confirmed or strongly suspected. 2