What are the causes of persistent serum hypercalcemia in patients with or without a history of malignancy?

Causes of Persistent Serum Hypercalcemia

Primary hyperparathyroidism and malignancy account for over 90% of persistent hypercalcemia cases, with primary hyperparathyroidism being the most common cause in outpatients and malignancy-associated hypercalcemia predominating in hospitalized patients. 1, 2

Primary Hyperparathyroidism (PTH-Dependent)

Primary hyperparathyroidism is characterized by elevated or inappropriately normal PTH levels despite hypercalcemia, representing autonomous parathyroid hormone secretion. 3 This occurs when:

• Single parathyroid adenoma (most common presentation, accounting for majority of cases) causes excessive PTH secretion 4
• Persistent hyperparathyroidism is defined as failure to achieve normocalcemia within 6 months after initial parathyroidectomy 4
• Tertiary hyperparathyroidism develops in patients with long-standing chronic kidney disease, manifesting as hypercalcemic hyperparathyroidism where PTH secretion becomes autonomous despite rising calcium levels 4

Post-Transplant Hyperparathyroidism

Hypercalcemia following kidney transplantation occurs in 1-5% of recipients due to persistent hyperparathyroidism from the preceding chronic kidney disease period. 4 The mechanism involves:

• Restoration of kidney function partially reverses PTH resistance and restores calcitriol production 4
• Increased intestinal calcium absorption and enhanced PTH effects on renal calcium transport create hypercalcemia 4
• This hypercalcemia post-transplant has been associated with increased risk of graft failure and all-cause mortality 4

Malignancy-Associated Hypercalcemia (PTH-Independent)

Malignancy is the most frequent cause of hypercalcemia in hospitalized patients, occurring in 10-25% of patients with advanced cancers and carrying a poor prognosis with median survival of approximately 1 month. 3, 5, 2

Mechanisms of Malignancy-Related Hypercalcemia

PTHrP-mediated humoral hypercalcemia is the most common mechanism:

• Parathyroid hormone-related peptide (PTHrP) acts systemically to stimulate osteoclast-mediated bone resorption and increase renal calcium reabsorption 5, 6
• Most commonly occurs in squamous cell carcinomas of lung or head and neck, and genitourinary tumors like renal cell carcinoma 3, 6
• Skeletal metastases may be minimal or absent in these patients 3

Osteolytic metastases-related hypercalcemia:

• Extensive bone invasion by tumor cells produces local factors that stimulate osteoclastic bone resorption 3, 2
• Commonly associated with breast cancer and multiple myeloma 3, 7

1,25-dihydroxyvitamin D-mediated hypercalcemia:

• Occurs in lymphomas and certain hematologic malignancies that produce calcitriol 2, 7
• Results in increased intestinal calcium absorption 7

Vitamin D-Related Causes

Granulomatous diseases, particularly sarcoidosis, cause hypercalcemia through extrarenal production of 1,25-dihydroxyvitamin D by activated macrophages in granulomas. 3, 1 Key features include:

• Low 25-hydroxyvitamin D but elevated 1,25-dihydroxyvitamin D is the characteristic pattern 3
• Increased 1α-hydroxylase activity in granulomas converts 25-OH vitamin D to active 1,25-(OH)2 vitamin D 3
• Also occurs in other granulomatous conditions and some lymphomas 1, 7

Vitamin D intoxication from excessive supplementation:

• Causes increased intestinal calcium absorption 1
• Presents with elevated 25-hydroxyvitamin D levels 3

Medication-Induced Hypercalcemia

Thiazide diuretics cause hypercalcemia by:

• Increasing renal tubular calcium reabsorption 1
• Reducing urinary calcium excretion 3

Lithium therapy induces hypercalcemia through:

• Altering parathyroid gland calcium sensing 1
• Causing inappropriately elevated PTH secretion 1

Calcium-based phosphate binders and vitamin D analogs in chronic kidney disease:

• Calcitriol and vitamin D analogues cause hypercalcemia in 22.6-43.3% of patients in clinical trials 8
• Excessive calcium supplementation combined with vitamin D increases absorption 4, 3

Other Endocrine Causes

Thyrotoxicosis causes hypercalcemia through:

• Increased bone turnover and osteoclastic activity 1
• Direct thyroid hormone effects on bone resorption 1

Familial and Genetic Causes

Familial hypocalciuric hypercalcemia (FHH):

• Genetic disorder affecting calcium-sensing receptor 1
• Characterized by lifelong mild hypercalcemia with inappropriately low urinary calcium excretion 1

Williams syndrome in pediatric populations:

• Idiopathic infantile hypercalcemia most common in first 2 years 4
• Lifelong abnormalities of calcium and vitamin D metabolism may persist 4
• Increased calcium absorption from gut with unknown etiology 4

Immobilization

Prolonged immobilization causes hypercalcemia through:

• Increased osteoclastic bone resorption without compensatory bone formation 1
• Particularly problematic in patients with high bone turnover (adolescents, Paget's disease) 1

Milk-Alkali Syndrome

Excessive calcium and absorbable alkali intake creates:

• Hypercalcemia, metabolic alkalosis, and renal insufficiency 1
• Often from calcium carbonate supplements combined with dairy products 1

Critical Diagnostic Algorithm

Measure intact PTH first to categorize hypercalcemia:

• If PTH elevated or inappropriately normal: Primary hyperparathyroidism, tertiary hyperparathyroidism, lithium use, or familial hypocalciuric hypercalcemia 3, 1
• If PTH suppressed (<20 pg/mL): Measure PTHrP, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D 3, 7
  • Elevated PTHrP: Malignancy-associated hypercalcemia 3, 2
  • Elevated 1,25-dihydroxyvitamin D with low 25-hydroxyvitamin D: Granulomatous disease or lymphoma 3
  • Elevated 25-hydroxyvitamin D: Vitamin D intoxication 3

Always measure ionized calcium when possible, as total calcium corrected for albumin can be inaccurate and lead to misdiagnosis. 3, 1