What causes low sodium (hyponatremia) with high calcium (hypercalcemia) and high vitamin D (hypervitaminosis D)?

Hypercalcemia with Hypervitaminosis D as the Primary Cause

The combination of hyponatremia, hypercalcemia, and elevated vitamin D levels is most commonly caused by vitamin D intoxication (hypervitaminosis D), which induces hypercalcemia through increased bone resorption and enhanced intestinal calcium absorption. 1, 2

Pathophysiology of Vitamin D-Induced Hypercalcemia

Vitamin D toxicity causes hypercalcemia primarily through increased bone resorption rather than enhanced intestinal absorption alone. 1 This mechanism explains why the hypercalcemia can be severe and persistent:

• Grossly elevated 25-hydroxyvitamin D [25(OH)D] levels (typically >150 ng/mL) with modestly elevated 1,25-dihydroxyvitamin D drive the hypercalcemia 1
• The increased bone resorption is the major determinant of the elevated calcium, not just gut absorption 1
• Hypercalcemia then causes hyponatremia through multiple mechanisms: nephrogenic diabetes insipidus from hypercalcemia-induced renal tubular dysfunction, volume depletion from polyuria, and direct effects on renal sodium handling 2, 3

Clinical Presentation and Diagnosis

Patients present with symptoms of hypercalcemia including anorexia, weakness, constipation, polyuria, and neurological impairment ranging from lethargy to severe hypotonia. 3 Key diagnostic features include:

• Serum calcium >10.5 mg/dL (often much higher, >4.0 mmol/L in severe cases) 2, 3
• Suppressed or low-normal PTH (PTH-independent hypercalcemia) 2, 4
• Markedly elevated 25(OH)D levels (>150 ng/mL, often >300 ng/mL) 1, 5
• Hypercalciuria and risk of nephrocalcinosis 3, 4
• EKG showing shortened QTc interval 3

The diagnosis requires confirming hypercalcemia with albumin-adjusted or ionized calcium, then measuring PTH to distinguish between PTH-dependent and PTH-independent causes. 2 When PTH is low or suppressed, vitamin D intoxication should be strongly considered after excluding malignancy 2

Common Causes of Vitamin D Intoxication

Excessive vitamin D supplementation is the most common iatrogenic cause, often from well-intentioned but misguided attempts to prevent rickets or from purchasing high-dose formulations online. 3, 5 Specific scenarios include:

• Daily doses exceeding 10,000 IU for prolonged periods 5
• Single massive doses (>300,000 IU) which should be avoided 5
• Accidental overdosing in infants and children from parental administration errors 3
• Rare genetic causes: CYP24A1 loss-of-function mutations impair vitamin D catabolism, causing hypervitaminosis D even with normal supplementation 4

Treatment Algorithm for Vitamin D-Induced Hypercalcemia

Immediate Management (Severe Hypercalcemia >14 mg/dL or Symptomatic)

Aggressive intravenous hydration with normal saline (200-300 mL/hour initially) is the first-line treatment to promote renal calcium excretion. 2, 3

• Add loop diuretics (furosemide) only after adequate rehydration to enhance calciuresis 3
• Monitor for volume overload and electrolyte disturbances 3

For severe or refractory hypercalcemia, bisphosphonates are highly effective because they directly inhibit the increased bone resorption driving the hypercalcemia. 1, 3

• Pamidronate 60-90 mg IV over 2-4 hours produces brisk reduction in calcium within days 1
• Bisphosphonates are more effective than corticosteroids for vitamin D toxicity 1
• However, bisphosphonates should be avoided in acute kidney injury; in this setting, denosumab 60 mg subcutaneously is the preferred antiresorptive agent 6

Corticosteroids (prednisone 40-60 mg daily) can be used but produce slower calcium reduction compared to bisphosphonates. 1, 3 They work by reducing intestinal calcium absorption and vitamin D metabolism 1

Hemodialysis is reserved for life-threatening hypercalcemia (>18 mg/dL) with neurological impairment or severe acute kidney injury unresponsive to medical therapy. 3

Maintenance Management

• Discontinue all vitamin D supplementation immediately 5, 4
• Avoid excessive sun exposure 4
• Maintain adequate hydration 4
• Monitor serum calcium, phosphorus, and renal function every 3 months initially 5

Special Consideration: CYP24A1 Mutations

In patients with recurrent PTH-independent hypercalcemia despite stopping vitamin D, or with family history of hypercalcemia and nephrolithiasis, consider CYP24A1 genetic testing. 4

• These patients have 1,25(OH)2D in the upper normal or elevated range with low-normal PTH 4
• Calculate the 25(OH)D:24,25(OH)2D ratio if available (elevated ratio suggests CYP24A1 deficiency) 4
• Long-term management includes strict avoidance of vitamin D supplementation and consideration of ketoconazole, fluconazole, or rifampicin to inhibit vitamin D activation 4

Critical Pitfalls to Avoid

Never use active vitamin D analogs (calcitriol, alfacalcidol) to treat nutritional vitamin D deficiency, as these bypass normal regulatory mechanisms and dramatically increase hypercalcemia risk. 5, 7

Do not assume hyperparathyroidism is the cause without checking PTH; vitamin D toxicity presents with suppressed PTH. 2, 4

Avoid single ultra-high loading doses of vitamin D (>300,000 IU) as these are inefficient and potentially harmful. 5

In patients with acute kidney injury from hypercalcemia, use denosumab rather than bisphosphonates to avoid further renal toxicity. 6