Can hypercalcemia be caused by low vitamin D (Vitamin D) levels?

No, Low Vitamin D Does Not Cause Hypercalcemia

Low vitamin D levels do not cause hypercalcemia; in fact, the relationship is typically the opposite—vitamin D deficiency usually leads to hypocalcemia, not hypercalcemia. However, there is one critical exception: in granulomatous diseases like sarcoidosis, patients paradoxically present with both low 25-OH vitamin D AND hypercalcemia due to ectopic production of active vitamin D.

Understanding the Normal Relationship

In typical circumstances, low vitamin D causes LOW calcium, not high calcium:

• Vitamin D deficiency reduces intestinal calcium absorption in the duodenum and jejunum, leading to hypocalcemia and secondary hyperparathyroidism 1
• Chronic low calcium levels from vitamin D deficiency have adverse effects on bone mineralization and may be associated with increased mortality 1
• Patients with chronic kidney disease and low vitamin D levels typically show decreased blood levels of total and free calcium 1

The Critical Exception: Granulomatous Disease

The one scenario where you see BOTH low vitamin D AND hypercalcemia together is sarcoidosis and other granulomatous diseases:

Mechanism

• Granulomatous macrophages produce excessive 1α-hydroxylase enzyme, converting 25-OH vitamin D to active 1,25-(OH)₂ vitamin D independent of normal physiologic regulation 2, 3
• This results in the paradoxical pattern: low 25-OH vitamin D but elevated 1,25-(OH)₂ vitamin D 3
• Approximately 84% of sarcoidosis patients have low 25-OH vitamin D levels, yet 11% have high 1,25-(OH)₂ vitamin D levels 3
• Hypercalcemia occurs in approximately 6% of sarcoidosis patients 3, 4
• If untreated, this hypercalcemia leads to renal failure in 42% of affected patients 2, 3

Additional Contributing Factors

• Increased expression of parathyroid hormone-related protein (PTHrP) in sarcoidosis macrophages further contributes to hypercalcemia 3
• Various cytokines and growth factors produced by granulomas influence calcium metabolism 3

Diagnostic Algorithm When You See Low Vitamin D

When encountering a patient with abnormal calcium levels and low vitamin D, follow this approach:

1. Measure BOTH vitamin D metabolites simultaneously:

   • 25-OH vitamin D (storage form)
   • 1,25-(OH)₂ vitamin D (active form)
   • This distinguishes between true deficiency and granulomatous disease 5, 2

2. Check PTH level:

   • Elevated or normal PTH with hypercalcemia = primary hyperparathyroidism 4
   • Suppressed PTH (<20 pg/mL) with hypercalcemia = PTH-independent cause 4

3. Interpret the pattern:

   • Low 25-OH vitamin D + low 1,25-(OH)₂ vitamin D = true vitamin D deficiency (expect hypocalcemia)
   • Low 25-OH vitamin D + elevated 1,25-(OH)₂ vitamin D = granulomatous disease causing hypercalcemia 3

Critical Pitfalls to Avoid

Never supplement vitamin D without measuring both metabolites in patients with hypercalcemia:

• Supplementing vitamin D in sarcoidosis patients who already have elevated 1,25-(OH)₂ vitamin D will worsen hypercalcemia 5, 2
• Measuring only 25-OH vitamin D misses granulomatous disease where the active form drives the hypercalcemia 2

Baseline serum calcium testing is strongly recommended for all sarcoidosis patients, even without symptoms 3

When Vitamin D Actually CAUSES Hypercalcemia

Hypercalcemia from vitamin D occurs through excessive supplementation or treatment, not from deficiency:

• Vitamin D toxicity causes hypercalcemia primarily through increased intestinal calcium absorption and enhanced bone resorption 2, 6
• Vitamin D toxicity was the second most common cause of hypercalcemia (24.8% of cases) after primary hyperparathyroidism in one tertiary care series 7
• In chronic kidney disease patients treated with vitamin D metabolites or calcium supplementation, hypercalcemia is a frequent complication, especially in those with low-turnover bone disease 1, 2
• The combination of calcium-based phosphate binders, vitamin D sterols, and high calcium dialysate creates additive hypercalcemic effects 2

Special Consideration: Primary Hyperparathyroidism with Coexisting Vitamin D Deficiency

In patients with primary hyperparathyroidism AND vitamin D deficiency, vitamin D replacement is safe and does not worsen hypercalcemia:

• Vitamin D repletion in patients with mild asymptomatic primary hyperparathyroidism and vitamin D deficiency does not aggravate hypercalcemia and may limit disease progression 8
• In hypercalcemic primary hyperparathyroidism patients given vitamin D replacement, adjusted calcium concentrations actually fell significantly 8