What conditions cause hypercalcemia and hyperphosphatemia?

Conditions Causing Hypercalcemia and Hyperphosphatemia

The combination of hypercalcemia and hyperphosphatemia most commonly occurs in three specific clinical scenarios: tumor lysis syndrome, vitamin D intoxication, and primary hyperparathyroidism (though the latter typically causes hypophosphatemia, making it an important diagnostic pitfall).

Primary Causes

Tumor Lysis Syndrome

• Tumor lysis syndrome represents the classic acute scenario where massive cell lysis releases intracellular phosphate, causing hyperphosphatemia with concurrent hypercalcemia, hyperkalemia, and hyperuricemia 1
• This occurs when malignant cells rapidly break down, releasing their intracellular contents into the bloodstream 1

Vitamin D Intoxication

• Vitamin D intoxication causes hypercalcemia through overproduction of 25-hydroxyvitamin D, which increases intestinal calcium absorption 2
• Unlike typical vitamin D metabolism, this occurs apparently in the absence of conversion to 1,25(OH)₂D 2
• Hyperphosphatemia develops because elevated calcium-phosphate absorption overwhelms renal excretory capacity 1

Granulomatous Disorders (Including Tuberculosis)

• Lymphomas and benign granulomatous disorders produce 1,25-dihydroxyvitamin D [1,25(OH)₂D], which causes hypercalcemia 2
• Very high 1,25-dihydroxyvitamin D levels (>162 pg/mL) should prompt evaluation for tuberculosis, even when asymptomatic 3
• These conditions increase both calcium and phosphate absorption from the gastrointestinal tract 2

Critical Diagnostic Pitfall: Primary Hyperparathyroidism

Primary hyperparathyroidism typically causes hypercalcemia with hypophosphatemia (not hyperphosphatemia), making it a crucial diagnostic exclusion 4, 5

• PTH normally increases phosphate excretion in the kidneys, resulting in low serum phosphate 6
• If you encounter hypercalcemia and hyperphosphatemia together, primary hyperparathyroidism is unlikely unless there is concurrent renal failure 5
• One reported case showed simultaneous hypercalcemia and hypophosphatemia from primary hyperparathyroidism, which was corrected by hemodialysis using phosphorus-enriched dialysate 5

Secondary Hyperparathyroidism in Chronic Kidney Disease

In chronic kidney disease, the typical pattern is hypocalcemia with hyperphosphatemia, NOT hypercalcemia with hyperphosphatemia 7, 8

• Phosphate retention occurs early in CKD, triggering secondary hyperparathyroidism 7, 8
• Hyperphosphatemia directly lowers ionized calcium by forming calcium-phosphate complexes, reducing bioavailable calcium 7, 1
• This creates hypocalcemia (not hypercalcemia) with elevated PTH 7

Exception: Post-Kidney Transplant

• After successful kidney transplantation, persistent hyperparathyroidism can cause hypercalcemia (10-22% of recipients) due to restoration of renal function and reversal of PTH resistance 6
• However, these patients typically develop hypophosphatemia (50-80% in first 3 months), not hyperphosphatemia, due to persistent PTH-driven phosphate wasting 6

Malignancy-Related Hypercalcemia

Humoral Hypercalcemia of Malignancy

• Tumors secrete PTH-related peptide (PTHrP), which activates osteoclasts and causes bone resorption 9
• Common in squamous cell malignancies of lung/head/neck, renal cell carcinoma, and ovarian cancer 9
• Typically causes hypercalcemia with hypophosphatemia (similar to primary hyperparathyroidism) because PTHrP increases renal phosphate excretion 9

Local Osteolytic Hypercalcemia

• Extensive bone invasion by tumors (breast cancer, multiple myeloma) produces local factors stimulating osteoclast-mediated bone resorption 9
• This releases both calcium and phosphate from bone, potentially causing both hypercalcemia and hyperphosphatemia 9

Rare Genetic Cause

• Jansen's metaphyseal chondrodysplasia causes hypercalcemia due to gain-of-function mutation in PTHR1 (PTH/PTHrP receptor) 2
• This mimics increased PTHrP action and may present with both hypercalcemia and altered phosphate metabolism 2

Diagnostic Algorithm

When encountering hypercalcemia and hyperphosphatemia together:

1. First, assess acuity: Acute onset with other electrolyte abnormalities (hyperkalemia, hyperuricemia) suggests tumor lysis syndrome 1

2. Measure PTH: Suppressed PTH indicates non-parathyroid cause; elevated PTH with hyperphosphatemia suggests renal failure 7, 4

3. Check 1,25-dihydroxyvitamin D: Very high levels (>100 pg/mL) suggest granulomatous disease or lymphoma 3, 2

4. Evaluate for malignancy: Check PTHrP if cancer suspected; imaging for bone metastases if local osteolytic process suspected 9, 2

5. Assess renal function: Creatinine and GFR to exclude CKD as contributing factor 7

Management Considerations

The most dangerous error is aggressively treating hypocalcemia with calcium supplementation without first addressing hyperphosphatemia, as this worsens the calcium-phosphate product and dramatically increases the risk of metastatic calcification 1

• Monitor calcium-phosphate product (Ca × P); levels >55 mg²/dL² represent critical threshold for tissue precipitation 1
• In tumor lysis syndrome, severe cases may require dialytic procedures to remove excess phosphate 1
• Careful ECG monitoring is essential when multiple electrolyte derangements coexist, particularly with concurrent hyperkalemia 1