What are the clinical signs and symptoms of vitamin D toxicity (hypervitaminosis D)?

Clinical Signs and Symptoms of Vitamin D Toxicity

Vitamin D toxicity manifests primarily through hypercalcemia-related symptoms including fatigue, weakness, nausea, vomiting, constipation, altered mental status, polyuria, and polydipsia, typically occurring when serum 25-hydroxyvitamin D levels exceed 150 ng/mL. 1

Biochemical Thresholds

• Toxicity typically begins at 25(OH)D levels >150 ng/mL (>375 nmol/L), with acute toxicity more likely when levels exceed 200 ng/mL 1, 2
• The upper safety limit for serum 25(OH)D is 100 ng/mL, above which toxicity risk increases substantially 1, 3
• Hypercalcemia in healthy adults has been documented only when daily intake exceeds 100,000 IU or when 25(OH)D levels exceed 100 ng/mL 1, 2

Clinical Manifestations by System

Generalized Symptoms

• Fatigue and weakness are early manifestations resulting from elevated calcium impairing cellular function 1, 3
• These nonspecific symptoms may present before overt hypercalcemia develops 4

Gastrointestinal Symptoms

• Nausea, vomiting, and constipation commonly develop as hypercalcemia worsens 1, 3
• Anorexia and abdominal pain may accompany moderate hypercalcemia 1, 5

Neurological Symptoms

• Altered mental status, irritability, confusion, and encephalopathy emerge with progressive hypercalcemia 1, 3
• Severe cases can progress to lethargy, hypotonia (especially in infants), and even coma 1, 5

Renal/Endocrine Symptoms

• Polyuria and polydipsia result from hypercalcemia-induced nephrogenic diabetes insipidus 1, 2
• Renal injury and kidney stones may occur, with renal failure developing in up to 42% of untreated patients 3
• Nephrocalcinosis can develop, particularly with chronic administration 5

Cardiovascular Manifestations

• Bradycardia and hypotension may develop when serum calcium exceeds approximately 14 mg/dL 1, 2
• Complete heart block can occur through hypercalcemia-mediated cardiac conduction disturbances 2
• Vascular calcification and acceleration of atherosclerosis may occur as silent complications 1, 3
• EKG shows shortened QTc interval in vitamin D toxicity 5

Laboratory Findings

• Suppressed parathyroid hormone (PTH) is typical in vitamin D toxicity 1
• Elevated fasting urinary calcium excretion indicates enhanced bone resorption 6
• Hypercalcemia and hypercalciuria persist even after plasma calcium normalizes, emphasizing that enhanced bone resorption is a prominent feature 6

Critical Clinical Pitfalls

• Vitamin D toxicity can occur without overt hypercalcemia because tissues expressing 25-hydroxylase can be adversely affected directly; therefore, normal calcium levels do not exclude toxicity 1, 3
• Most cases of hypercalcemia due to vitamin D occur at serum concentrations <375 nmol/L (150 ng/mL), showing highly variable individual response 7
• Toxicity can result from manufacturing errors in supplements that do not claim to contain vitamin D, or from dispensing errors 8, 4

High-Risk Populations Requiring Extra Vigilance

Chronic Kidney Disease

• Patients with CKD require monitoring of serum calcium and phosphorus at least every 3 months during supplementation 9, 1
• Even standard vitamin D doses can precipitate hypercalcemia in CKD patients due to impaired calcium and phosphorus regulation 9, 1

Granulomatous Diseases (Sarcoidosis)

• Approximately 6% of individuals with sarcoidosis develop hypercalcemia independent of supplementation due to unregulated extra-renal production of active 1,25-dihydroxyvitamin D by activated macrophages 9, 1
• These patients require baseline serum calcium testing even without symptoms 9

Elderly Individuals

• Older adults are especially vulnerable due to age-related decline in renal function, polypharmacy, and altered calcium balance, requiring lower thresholds for monitoring 1

Safe Dosing Parameters

• Daily doses up to 4,000 IU are generally considered safe for most adults 1, 2, 3
• Doses up to 10,000 IU daily for several months have not produced adverse events in most studies, but toxicity risk exists 1
• Annual high-dose bolus regimens (500,000 IU) increase falls, injurious falls, and fractures; daily, weekly, or monthly dosing is preferred 1

Monitoring Recommendations

• Measure baseline 25(OH)D levels before initiating high-dose therapy 1
• Recheck 25(OH)D levels 3 months after starting supplementation to ensure safe concentrations 1
• When toxicity is suspected, obtain spot urine calcium-to-creatinine ratio together with serum calcium, 25(OH)D, and intact PTH 1
• Check serum calcium and phosphorus at least every 2 weeks during the first month, then monthly until normalization 1
• If hypercalciuria is present, schedule renal ultrasonography to screen for nephrocalcinosis and early kidney stone formation 1