What is the etiology of hypercalcemia in an adult patient with normal vitamin D levels and no evidence of hyperparathyroidism?

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Etiology of Hypercalcemia When Hyperparathyroidism is Ruled Out

When hyperparathyroidism and vitamin D toxicity are excluded, the most common causes of hypercalcemia are malignancy (particularly through PTHrP secretion), granulomatous diseases like sarcoidosis, medications, and less commonly, genetic disorders affecting vitamin D metabolism or calcium sensing. 1

Initial Diagnostic Framework

The approach to non-PTH-mediated hypercalcemia requires measuring PTHrP, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D to distinguish between the major etiologic categories. 1 The relationship between these vitamin D metabolites provides critical diagnostic information that guides the differential diagnosis. 1, 2

Key Laboratory Pattern Recognition

  • Elevated PTHrP with suppressed PTH: This pattern indicates malignancy-associated hypercalcemia, occurring in 10-25% of patients with lung cancer (especially squamous cell carcinoma), and carries a poor prognosis with median survival of approximately 1 month. 1

  • Low 25-OH vitamin D but elevated 1,25-(OH)₂ vitamin D: This paradoxical pattern suggests granulomatous diseases such as sarcoidosis or tuberculosis, where increased 1α-hydroxylase activity in granulomas or macrophages produces excessive 1,25(OH)₂D despite low substrate levels. 1, 2, 3

  • Elevated 25-OH vitamin D with normal or elevated 1,25-(OH)₂ vitamin D: This suggests vitamin D intoxication, where supraphysiological amounts of 25(OH)D directly activate the vitamin D receptor. 3

Major Etiologic Categories

Malignancy-Associated Hypercalcemia

  • PTHrP-secreting tumors are the most common cause of non-parathyroid hypercalcemia, including squamous cell carcinomas, renal cell carcinoma, breast cancer, and various other solid tumors. 4 PTHrP shares amino acid sequence homology with PTH and activates the same PTHR1 receptor, producing similar skeletal and metabolic effects. 4

  • Hematologic malignancies (lymphomas, multiple myeloma) may produce 1,25(OH)₂D ectopically or release osteolytic cytokines and growth factors that cause bone resorption and hypercalcemia. 4, 3

  • Decreased 25-hydroxyvitamin D is expected in malignancy-associated hypercalcemia because the suppressed PTH cannot stimulate conversion to active 1,25-dihydroxyvitamin D. 1

Granulomatous and Lymphoproliferative Disorders

  • Sarcoidosis, tuberculosis, and other granulomatous diseases cause hypercalcemia through ectopic CYP27B1 (25(OH)D-1-hydroxylase) expression in activated macrophages within granulomas, producing excessive 1,25(OH)₂D. 3

  • The diagnostic hallmark is low 25-OH vitamin D with elevated or inappropriately normal 1,25-(OH)₂ vitamin D, reflecting autonomous extrarenal production. 1, 2

  • Glucocorticoids are effective treatment for vitamin D-mediated hypercalcemia in these conditions, as they suppress macrophage 1α-hydroxylase activity. 1

Medication-Induced Hypercalcemia

  • Thiazide diuretics reduce urinary calcium excretion and should be discontinued in patients with hypercalcemia. 1, 5

  • Lithium shifts the calcium set-point of the parathyroid glands, potentially causing hypercalcemia even with "normal" PTH levels. 4

  • Vitamin A intoxication, foscarnet, and calcium-based phosphate binders (particularly in CKD patients) can all cause hypercalcemia. 4, 1

  • Milk-alkali syndrome from excessive calcium carbonate ingestion (often with antacids) remains an important cause, particularly in patients taking calcium supplements. 4, 6

Genetic and Metabolic Disorders

  • CYP24A1 mutations impair degradation of 1,25(OH)₂D, causing elevated serum 1,25(OH)₂D with suppressed PTH, hypercalciuria, nephrocalcinosis, and nephrolithiasis. 3 This is increasingly recognized in first-time calcium stone formers. 3

  • Familial hypocalciuric hypercalcemia (FHH) due to calcium-sensing receptor mutations presents with moderate hypercalcemia, normal or mildly elevated PTH, and relative hypocalciuria (24-hour urine calcium <200 mg or calcium/creatinine clearance ratio <0.01). 7

  • Hypophosphatasia (ALPL mutations) presents with hypercalcemia and characteristically low alkaline phosphatase levels. 7

Endocrine Causes

  • Hyperthyroidism increases bone turnover and can cause mild hypercalcemia through increased osteoclastic activity. 4

  • Adrenal insufficiency causes hypercalcemia through volume depletion and increased calcium reabsorption. 4

  • Acromegaly may be associated with hypercalcemia through increased intestinal calcium absorption. 4

Immobilization

  • Prolonged immobilization causes hypercalcemia through increased bone resorption, particularly in patients with high bone turnover (adolescents, Paget's disease, malignancy). 4

Critical Diagnostic Algorithm

  1. Confirm true hypercalcemia by measuring ionized calcium if albumin is abnormal, as total calcium can be misleading. 1, 8

  2. Verify PTH is appropriately suppressed (<20 pg/mL) to confirm non-PTH-mediated hypercalcemia. 1

  3. Measure PTHrP to identify malignancy-associated hypercalcemia. 1

  4. Measure both 25-OH vitamin D and 1,25-(OH)₂ vitamin D simultaneously, as their relationship is diagnostically critical. 1, 2

  5. Obtain 24-hour urine calcium or spot urine calcium/creatinine ratio to distinguish FHH from other causes. 1, 5

  6. Review all medications including over-the-counter supplements, thiazides, lithium, and calcium-containing products. 1, 5

  7. Assess for malignancy with appropriate imaging (chest CT for lung cancer, age-appropriate cancer screening). 1

  8. Consider granulomatous disease if 1,25-(OH)₂D is elevated with low 25-OH vitamin D; obtain chest imaging and ACE levels. 2, 3

Common Pitfalls to Avoid

  • Do not supplement vitamin D in patients with hypercalcemia until the etiology is identified and calcium normalizes, as supplementation can worsen hypercalcemia in granulomatous diseases or CYP24A1 mutations. 2, 3

  • Do not assume "normal" vitamin D levels exclude vitamin D-mediated hypercalcemia—measure 1,25-(OH)₂D specifically, as it may be elevated despite normal or low 25-OH vitamin D in granulomatous diseases. 1, 2

  • Do not overlook occult malignancy—PTHrP-secreting tumors may be small and difficult to detect initially, requiring thorough evaluation and follow-up. 1, 4

  • Do not confuse FHH with primary hyperparathyroidism—FHH has relative hypocalciuria and does not require parathyroidectomy. 7

  • Measure ionized calcium rather than relying solely on corrected calcium, as correction formulas are often inaccurate. 8

References

1
Guideline

Hypercalcemia Diagnosis and Management

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

2
Guideline

Management of Hypercalcemia with Low Vitamin D Levels

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

4
Research

Nonparathyroid Hypercalcemia.

Frontiers of hormone research, 2019

5
Guideline

Diagnosis and Management of Mild Primary Hyperparathyroidism

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

6
Research

Clinical review: Rare causes of hypercalcemia.

The Journal of clinical endocrinology and metabolism, 2005

7
Research

Genetic hypercalcemia.

Joint bone spine, 2019

8
Research

Investigation of hypercalcemia.

Clinical biochemistry, 2012

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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