What is the most likely cause of a 25‑hydroxyvitamin D level of approximately 218 ng/mL in a 47‑year‑old woman with an estimated glomerular filtration rate of 64 mL/min and a serum chloride of 109 mmol/L?

Vitamin D Level of 218 ng/mL in a 47-Year-Old Woman: Cause and Management

Most Likely Cause

The most likely cause of a vitamin D level of 218 ng/mL is excessive vitamin D supplementation (iatrogenic vitamin D toxicity), either through inadvertent overdosing, taking extremely high doses of pharmacological preparations, or prolonged use of doses exceeding 10,000 IU daily. 1

Understanding the Clinical Context

Defining Vitamin D Toxicity

• A serum 25-hydroxyvitamin D concentration of 218 ng/mL represents severe vitamin D toxicity, more than double the upper safety limit of 100 ng/mL. 2, 1
• Vitamin D toxicity typically manifests when serum 25(OH)D exceeds 150 ng/mL (375 nmol/L), which is the hallmark of overdosing. 1
• The optimal therapeutic range for vitamin D is 30–44 ng/mL; concentrations above 50 ng/mL provide no additional clinical benefit. 2

Renal Function Context

• The patient's GFR of 64 mL/min/1.73 m² indicates Stage 2 chronic kidney disease (mild reduction in kidney function). 3
• While CKD patients are at higher risk for vitamin D deficiency due to reduced synthesis, the extremely elevated level of 218 ng/mL cannot be explained by kidney dysfunction alone—this level requires exogenous intake. 3, 4
• Serum 25(OH)D levels begin to decline when eGFR falls below approximately 55–60 mL/min/1.73 m², but this patient's GFR of 64 is above that threshold. 4

Chloride Level

• The serum chloride of 109 mmol/L is at the upper limit of normal (typically 98–107 mmol/L) and may reflect mild dehydration, which can occur with vitamin D toxicity due to hypercalcemia-induced polyuria. 1

Differential Diagnosis of Vitamin D Toxicity

Exogenous (Iatrogenic) Causes – Most Likely

• Inadvertent or improper intake of extremely high doses of vitamin D supplements is the most common cause of vitamin D toxicity in adults. 1
• This includes:
  • Taking weekly doses (e.g., 50,000 IU) on a daily basis instead of weekly
  • Self-administration of doses higher than recommended due to misunderstanding of dosing instructions
  • Use of multiple vitamin D-containing supplements simultaneously
  • Prolonged daily doses exceeding 10,000 IU 1

Endogenous Causes – Less Likely but Must Be Excluded

• Granulomatous disorders (sarcoidosis, tuberculosis) can cause excessive production of 1,25(OH)₂D through unregulated extrarenal 1α-hydroxylase activity, but typically present with elevated 1,25(OH)₂D rather than markedly elevated 25(OH)D. 1
• Lymphomas may produce active vitamin D metabolites locally. 1
• Dysregulated vitamin D metabolism (hypersensitivity to vitamin D) can cause hypercalcemia even with recommended doses, reflecting increased 1α-hydroxylase activity or decreased 24-hydroxylase activity. 1

Mechanisms of Toxicity

• Vitamin D toxicity develops through:
  • Saturation of vitamin D binding protein capacity, leading to increased free (bioactive) vitamin D 1
  • Elevated 1,25(OH)₂D production overwhelming normal regulatory mechanisms 1
  • Increased intestinal calcium absorption and bone resorption causing hypercalcemia 1

Immediate Diagnostic Workup

Essential Laboratory Tests

• Serum corrected total calcium – to assess for hypercalcemia (the primary manifestation of vitamin D toxicity). 3, 1
• Serum phosphorus – often elevated in vitamin D toxicity. 3, 1
• Intact parathyroid hormone (PTH) – typically suppressed in vitamin D toxicity due to hypercalcemia. 2, 1
• Serum creatinine and eGFR – to monitor for worsening renal function from hypercalcemia. 3
• Urinalysis – to check for hypercalciuria and assess for nephrocalcinosis risk. 1

Additional Tests if Endogenous Cause Suspected

• Serum 1,25-dihydroxyvitamin D – if granulomatous disease or lymphoma is suspected (will be disproportionately elevated relative to 25(OH)D). 1
• Chest X-ray or CT – if sarcoidosis is suspected. 1
• Serum angiotensin-converting enzyme (ACE) – elevated in sarcoidosis. 1

Clinical Manifestations to Assess

Symptoms of Vitamin D Toxicity

• Confusion, apathy – neurological manifestations of hypercalcemia 1
• Recurrent vomiting, abdominal pain – gastrointestinal symptoms 1
• Polyuria, polydipsia, dehydration – nephrogenic diabetes insipidus from hypercalcemia 1
• Weakness, fatigue – from hypercalcemia and electrolyte disturbances 1

Immediate Management

Discontinuation of Vitamin D

• Immediately discontinue all vitamin D supplementation and calcium-containing supplements. 2, 1
• This includes over-the-counter multivitamins, prescription vitamin D, and any calcium/vitamin D combination products. 2

Management of Hypercalcemia (If Present)

• If serum calcium exceeds 10.2 mg/dL (2.54 mmol/L), hold all vitamin D therapy immediately. 3, 2
• Initiate aggressive oral hydration (or IV normal saline if symptomatic) to promote calciuresis. 2
• Monitor serum calcium weekly until normalization. 2
• Consider loop diuretics (furosemide) after adequate hydration to enhance calcium excretion. 1
• In severe cases (calcium >14 mg/dL or symptomatic), consider bisphosphonates or calcitonin. 1

Monitoring Protocol

• Check serum calcium and phosphorus every 2 weeks for the first month, then monthly until vitamin D levels normalize. 2
• Monitor renal function (creatinine, eGFR) every 2 weeks initially. 2
• Repeat 25(OH)D measurement in 3 months to assess rate of decline. 2

Expected Timeline for Resolution

• Vitamin D has a long half-life (approximately 2–3 weeks for 25(OH)D), so levels will decline slowly. 2
• Serum 25(OH)D should fall below 100 ng/mL within 3–6 months after discontinuation, depending on the degree of toxicity. 2
• Hypercalcemia typically resolves within 4–8 weeks after stopping vitamin D, but may persist longer with severe toxicity. 1

When to Resume Vitamin D (If Needed)

• Do not restart vitamin D therapy until:

  • Serum 25(OH)D falls below 100 ng/mL 2
  • Serum calcium returns to normal (<9.5 mg/dL) and remains stable for at least 4 weeks 2
  • PTH rises back into the normal range 2

• If supplementation is eventually warranted (e.g., level drops below 30 ng/mL and risk factors for deficiency exist):

  • Initiate a maintenance dose of 800–1,000 IU daily (not high-dose therapy) 2
  • Re-check serum 25(OH)D 3 months after restarting to verify achievement of target range (30–44 ng/mL) without overshoot 2

Critical Pitfalls to Avoid

• Never use active vitamin D analogs (calcitriol, alfacalcidol, doxercalciferol, paricalcitol) to treat nutritional vitamin D deficiency, as they bypass normal regulatory mechanisms and dramatically increase hypercalcemia risk. 3, 2
• Do not assume the patient is "just taking too much vitamin D" without excluding endogenous causes (granulomatous disease, lymphoma), especially if the patient denies excessive supplementation. 1
• Do not restart vitamin D supplementation prematurely before levels fall below 100 ng/mL and calcium normalizes, as this will perpetuate toxicity. 2
• Do not overlook the risk of nephrocalcinosis and irreversible renal damage from prolonged hypercalcemia; aggressive management is essential. 1

Special Considerations for CKD Stage 2

• For CKD patients with GFR 20–60 mL/min/1.73 m², standard nutritional vitamin D replacement with cholecalciferol or ergocalciferol is appropriate when deficiency is documented, but active vitamin D analogs should be avoided. 3, 2
• CKD patients are at higher risk for vitamin D deficiency due to reduced sun exposure, dietary restrictions, and urinary losses, but this patient's level of 218 ng/mL is clearly iatrogenic. 3
• Monitor calcium and phosphorus more frequently (every 2 weeks initially) in CKD patients during vitamin D toxicity management. 2