What is the diagnosis for a patient with hypercalcemia, a history of vitamin D deficiency, and recent vitamin D supplementation?

Diagnosis: Vitamin D Supplementation-Induced Hypercalcemia

The most likely diagnosis is iatrogenic hypercalcemia caused by recent vitamin D supplementation in the setting of pre-existing vitamin D deficiency, which should be confirmed by measuring both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels and immediately discontinuing all vitamin D therapy. 1, 2

Immediate Diagnostic Workup Required

Measure both 25(OH)D and 1,25(OH)2D simultaneously to distinguish between vitamin D toxicity from supplementation versus ectopic production (as in granulomatous disease). 1, 3 This distinction is critical because:

• Supplementation-induced hypercalcemia presents with elevated 25(OH)D (typically >160 nmol/L or >64 ng/mL) and suppressed PTH 2, 4
• Granulomatous disease (sarcoidosis, tuberculosis) presents with LOW 25(OH)D but ELEVATED 1,25(OH)2D due to ectopic 1α-hydroxylase activity in granulomas 1, 3, 5

Obtain PTH level to differentiate PTH-dependent from PTH-independent causes—in vitamin D-induced hypercalcemia, PTH should be suppressed or inappropriately normal. 1, 2

Most Likely Mechanism in This Patient

Given the history of vitamin D deficiency followed by recent supplementation, this represents vitamin D supplement-induced hypercalcemia through two mechanisms: 3, 6

• Increased intestinal calcium absorption from excessive vitamin D 3, 6
• Enhanced bone resorption stimulated by vitamin D metabolites 3, 6

The paradox of hypercalcemia occurring after treating vitamin D deficiency suggests either:

• Excessive supplementation dose (>4,000 IU daily increases toxicity risk) 3
• Individual susceptibility with impaired calcium regulation 7
• Concurrent calcium supplementation creating additive hypercalcemic effects 7

Critical Pitfall to Avoid

Never assume vitamin D deficiency requires aggressive supplementation in patients with hypercalcemia. 1 The American Thoracic Society explicitly warns against supplementing vitamin D without measuring both 25(OH)D and 1,25(OH)2D levels first, as this can worsen hypercalcemia in conditions like sarcoidosis where 1,25(OH)2D is already elevated despite low 25(OH)D. 1, 3

Alternative Diagnoses to Exclude

Primary Hyperparathyroidism

• Would show elevated or inappropriately normal PTH with hypercalcemia 2
• Typically presents with low-normal phosphorus 2
• Requires vitamin D deficiency to be corrected first, as deficiency causes secondary hyperparathyroidism that can mask the diagnosis 2

Granulomatous Disease (Sarcoidosis)

• Presents with low 25(OH)D but elevated 1,25(OH)2D 1, 3, 5
• Occurs in 11% of sarcoidosis patients, with hypercalcemia in 6% 3
• Untreated, leads to renal failure in 42% of affected patients 3
• Responds to glucocorticoids, which suppress ectopic 1α-hydroxylase activity 2, 6

CYP24A1 Mutations

• Rare cause of impaired 1,25(OH)2D degradation 5
• Presents with elevated 1,25(OH)2D, suppressed PTH, hypercalciuria, nephrocalcinosis 5
• Consider in patients with recurrent nephrolithiasis and elevated 1,25(OH)2D 5

Malignancy-Associated Hypercalcemia

• Would show elevated PTHrP with suppressed PTH 2
• Poor prognosis with median survival ~1 month in lung cancer 2
• Decreased 25(OH)D expected as hypercalcemia suppresses PTH-driven conversion to 1,25(OH)2D 2

Immediate Management Steps

1. Discontinue ALL vitamin D therapy immediately if serum calcium exceeds 10.2 mg/dL, including ergocalciferol, cholecalciferol, calcitriol, and alfacalcidol 1, 2

2. Stop calcium supplements and review all medications including thiazide diuretics 2

3. Ensure adequate hydration with IV crystalloid fluids not containing calcium if moderate-to-severe hypercalcemia 2

4. Measure serum calcium in 2-4 weeks after discontinuing vitamin D to confirm resolution 2

5. Monitor 24-hour urinary calcium to ensure normalization (<300 mg/24hr) before considering any future supplementation 2

Timeline for Resolution

• If 1α(OH)D3 or 1,25(OH)2D3 caused toxicity: Hypercalcemia resolves within 1 week 6
• If D2 or D3 caused toxicity: Hypercalcemia persists for several months due to fat storage 6
• Normalization of 25(OH)D levels: Takes approximately 1 year, but patients become normocalcemic once 25(OH)D drops below 400 ng/mL 8

When to Resume Vitamin D (If Needed)

Vitamin D supplementation should NOT be resumed until: 2

• Serum calcium consistently below 9.5 mg/dL
• Underlying cause identified and treated
• 24-hour urinary calcium normalizes

If restarted, use low doses (400-800 IU daily) with monthly calcium monitoring for 3 months. 1, 2