What causes elevated serum vitamin D (25-hydroxyvitamin D) levels?

Causes of Elevated Serum Vitamin D Levels

Elevated serum vitamin D (25-hydroxyvitamin D) levels are most commonly caused by excessive vitamin D supplementation, with toxicity typically occurring at levels above 150 ng/mL (375 nmol/L). 1

Common Causes of Elevated Vitamin D Levels

Exogenous (External) Causes

• Excessive supplementation: Most common cause
  • Inadvertent or improper intake of high-dose vitamin D supplements 1
  • Over-the-counter supplements with variable vitamin D content 2
  • Prescription vitamin D at doses exceeding recommendations
  • Cumulative effect of long-term supplementation 3

Endogenous (Internal) Causes

• Dysregulated vitamin D metabolism:
  • Reduced degradation of vitamin D metabolites
  • Elevated activity of 1α-hydroxylase enzyme 1
  • Inhibited activity of 24-hydroxylase enzyme 1
  • Genetic disorders affecting vitamin D metabolism

Specific Conditions

• Genetic disorders:
  • Mutations in CYP24A1 gene (reduced vitamin D catabolism) 2
  • Williams-Beuren syndrome (excessive production of 25(OH)D and 1,25(OH)2D) 1
• Granulomatous disorders:
  • Sarcoidosis (increased local production of active vitamin D) 1
  • Some lymphomas (increased production of 1,25(OH)2D) 1
• Idiopathic infantile hypercalcemia (reduced degradation of vitamin D metabolites) 1

Laboratory Findings in Vitamin D Toxicity

• Serum 25(OH)D concentrations >150 ng/mL (375 nmol/L) 1
• Hypercalcemia (often >10.2 mg/dL) 4
• Normal or high serum phosphorus levels 5
• Normal or low alkaline phosphatase (ALP) 5
• Low serum parathyroid hormone (PTH) (suppressed) 5
• High urine calcium/creatinine ratio 5

Clinical Manifestations of Vitamin D Toxicity

When vitamin D levels become toxic, patients may present with:

• Confusion and apathy
• Recurrent vomiting
• Abdominal pain
• Polyuria and polydipsia
• Dehydration
• Hypercalcemia-related symptoms 1

Risk Factors for Vitamin D Toxicity

• Self-administration of vitamin D in doses higher than recommended 1
• Improper dosing in infants and children 2
• Quality control issues with over-the-counter supplements 2
• Hypersensitivity to vitamin D (abnormal response to normal doses) 1
• Concurrent use of calcium supplements 6
• Pre-existing chronic kidney disease 6

Prevention and Monitoring

• The American Heart Association recommends daily vitamin D3 doses of 600 IU for adults up to age 70 and 800 IU for adults over 70 6
• Safe upper limit for most adults is 4,000 IU daily 6
• Measure serum calcium, phosphorus, and 25-hydroxyvitamin D levels after at least 3 months of supplementation 6
• Discontinue vitamin D therapy if serum calcium exceeds 10.2 mg/dL 4
• Discontinue vitamin D if serum phosphorus exceeds 4.6 mg/dL and hyperphosphatemia persists despite phosphate binder therapy 4

Laboratory Considerations

• Assay interference can occur in vitamin D toxicity
• High 25(OH)D levels can interfere with 1,25(OH)2D measurements in commonly used radioimmunoassays 7
• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is more accurate for measuring vitamin D metabolites in cases of suspected toxicity 7

Understanding these causes and mechanisms is crucial for proper diagnosis and management of elevated vitamin D levels, especially as public awareness of vitamin D benefits has led to increased self-supplementation and potential for toxicity.