How should vitamin D toxicity presenting with hypercalcemia in an adult who has taken ≥10,000 IU daily for weeks to months be diagnosed and managed?

Vitamin D Toxicity: Diagnosis and Management

Immediate Discontinuation and Assessment

Stop all vitamin D supplementation immediately and measure serum calcium, 25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone (PTH), phosphorus, and creatinine to confirm toxicity and assess severity. 1, 2, 3

• Vitamin D toxicity is defined as serum 25(OH)D levels >150 ng/mL, with acute toxicity typically occurring at levels >200 ng/mL 1, 2, 3
• The upper safety limit for 25(OH)D is 100 ng/mL; levels above this threshold substantially increase toxicity risk 1, 2
• Toxicity in healthy adults generally requires daily intake >100,000 IU or serum 25(OH)D >100 ng/mL 1, 2
• Prolonged daily doses ≥10,000 IU for weeks to months can produce toxicity, particularly in susceptible individuals 1, 4

Diagnostic Laboratory Pattern

The characteristic biochemical profile includes:

• Hypercalcemia (often the presenting feature) 1, 2, 3
• Suppressed or low PTH (distinguishes this from primary hyperparathyroidism) 1, 3
• Normal or elevated phosphorus (unlike primary hyperparathyroidism) 3
• Elevated or normal alkaline phosphatase 3
• Hypercalciuria (elevated urine calcium-to-creatinine ratio) 2, 3
• Markedly elevated 25(OH)D (>150 ng/mL confirms toxicity) 1, 2, 3

Obtain a spot urine calcium-to-creatinine ratio to quantify hypercalciuria and assess renal calcium handling 2

Clinical Manifestations by Severity

Mild-to-Moderate Hypercalcemia (Calcium 11–14 mg/dL)

• Gastrointestinal: nausea, vomiting, constipation, abdominal pain 2, 3, 5, 4
• Neurological: fatigue, weakness, altered mental status, irritability, confusion 2, 3, 5, 4
• Renal: polyuria, polydipsia (nephrogenic diabetes insipidus), acute kidney injury 2, 3, 5, 4
• General: weight loss, dehydration 4

Severe Hypercalcemia (Calcium >14 mg/dL)

Emergency intervention is mandatory when calcium exceeds 14 mg/dL due to life-threatening cardiac, neurological, renal, and gastrointestinal complications. 2, 3

• Cardiovascular: bradycardia, hypotension, arrhythmias, vascular calcification 2
• Neurological: encephalopathy, coma 2
• Renal: acute kidney injury, nephrocalcinosis, kidney stones 2, 3, 5
• Gastrointestinal: pancreatitis (rare but serious) 4

Treatment Algorithm

Step 1: Discontinue All Vitamin D and Calcium Sources

• Stop all vitamin D supplements (cholecalciferol, ergocalciferol, and especially active analogs like calcitriol) 1, 2, 3, 4
• Discontinue all calcium-containing supplements and calcium-based phosphate binders 1
• Avoid sun exposure during recovery, as UV radiation can further increase vitamin D synthesis 2
• Implement a low-calcium diet (restrict dairy, fortified foods) 2, 3

Step 2: Manage Hypercalcemia Based on Severity

For Calcium 11–14 mg/dL (Moderate):

• Aggressive intravenous hydration with normal saline (200–300 mL/hour initially) to promote calciuresis 2, 3, 4
• Loop diuretics (furosemide 20–40 mg IV every 6–12 hours) after adequate hydration to enhance urinary calcium excretion 2, 3
• Increase oral fluid intake to maintain high urine output 1
• Monitor serum calcium weekly until normalization 1

For Calcium >14 mg/dL (Severe—Emergency):

Initiate all of the following therapies simultaneously: 2, 3

• Intravenous saline hydration (as above) 2, 3
• Loop diuretics (furosemide) 2, 3
• Glucocorticoids (prednisone 40–60 mg daily or equivalent) to reduce intestinal calcium absorption and enhance renal excretion 2, 3, 6
• Calcitonin (4–8 IU/kg subcutaneously or intramuscularly every 6–12 hours) for rapid but transient calcium reduction 2, 3
• Bisphosphonates (pamidronate 60–90 mg IV over 2–4 hours, or zoledronic acid 4 mg IV over 15 minutes) to inhibit bone resorption 2, 3, 6

Bisphosphonates are particularly effective in vitamin D toxicity because enhanced bone resorption is a prominent mechanism of hypercalcemia. 6

Step 3: Monitor for Complications

• Renal ultrasonography to screen for nephrocalcinosis and kidney stones if hypercalciuria is present 2
• Serial serum creatinine to monitor renal function 3, 5, 4
• Electrocardiogram if calcium >13 mg/dL to assess for arrhythmias 2
• Check serum calcium and phosphorus every 2 weeks for the first month, then monthly until 25(OH)D normalizes 1

Expected Timeline for Resolution

Vitamin D is stored in adipose tissue, so toxicity effects may persist for months despite discontinuation of the exogenous source. 3, 7

• Do not restart vitamin D until serum calcium has been normal for at least 4 weeks and 25(OH)D falls below 100 ng/mL 1
• Serum 25(OH)D may remain elevated for 3–6 months or longer due to slow release from fat stores 3, 7
• PTH should rise back into the normal range as calcium normalizes 1
• Continue monitoring serum calcium every 3 months and 25(OH)D levels periodically until both stabilize 1

Critical Pitfalls to Avoid

• Never use active vitamin D analogs (calcitriol, alfacalcidol, doxercalciferol, paricalcitol) to treat nutritional vitamin D deficiency, as they bypass normal regulation and dramatically increase hypercalcemia risk 1, 2
• Do not assume normal calcium excludes toxicity—tissue damage can occur from elevated 25(OH)D even before hypercalcemia develops 2
• Glucocorticoids are more effective than bisphosphonates alone in some cases of vitamin D toxicity, particularly when intestinal calcium absorption is the dominant mechanism 6
• Avoid single annual mega-doses (≥300,000–500,000 IU), which increase falls, fractures, and toxicity risk 1, 2
• Question patients about all supplements, not just labeled vitamin D products—manufacturing errors and contamination have caused toxicity from creatine, protein powders, and other supplements 5, 7

High-Risk Populations Requiring Extra Caution

• Chronic kidney disease (CKD) patients have impaired calcium and phosphorus regulation; monitor serum calcium and phosphorus at least every 3 months during any vitamin D supplementation 1, 2
• Elderly individuals are vulnerable due to age-related renal decline, polypharmacy, and altered calcium balance 2
• Patients with granulomatous diseases (sarcoidosis, tuberculosis) have unregulated extra-renal 1,25-dihydroxyvitamin D production and can develop hypercalcemia even without supplementation 2
• Immobilized patients require dose reduction to prevent hypercalciuria and hypercalcemia 2

When to Resume Vitamin D (If Needed)

• Confirm serum calcium is normal (<9.5 mg/dL) and stable for ≥4 weeks 1
• Verify 25(OH)D has declined to <100 ng/mL, ideally <50 ng/mL 1, 2
• Restart only if there is a documented indication (e.g., deficiency <20 ng/mL, osteoporosis, malabsorption) 1
• Use conservative maintenance dosing: 800–1,000 IU daily, targeting 25(OH)D of 30–44 ng/mL 1, 2
• Recheck 25(OH)D 3 months after restarting to ensure safe levels 1