What causes low Parathyroid Hormone (PTH) and hypercalcemia?

Causes of Low PTH and High Calcium

The most common causes of low parathyroid hormone (PTH) with hypercalcemia include malignancy, vitamin D disorders, granulomatous diseases, and medication effects, with malignancy being the leading non-parathyroid cause of hypercalcemia.

Primary Causes of Low PTH with Hypercalcemia

1. Malignancy-Related Hypercalcemia

• Humoral hypercalcemia of malignancy: Caused by tumor secretion of PTH-related peptide (PTHrP) 1
  • Common in squamous cell tumors and some hematologic malignancies
  • PTHrP shares amino acid sequence homology with PTH in the amino-terminal domain
  • Acts on the same receptor (PTHR1) with similar effects on calcium metabolism
• Osteolytic metastases: Direct bone destruction by metastatic tumors 1
• 1,25(OH)2D production: Some lymphomas produce active vitamin D 1

2. Vitamin D Disorders

• Vitamin D intoxication: Excessive supplementation or treatment 2, 1
• CYP24A1 mutations: Impaired vitamin D metabolism leading to elevated 1,25(OH)2D 3
  • Presents with hypercalcemia, hypercalciuria, elevated 1,25(OH)2D and suppressed PTH
  • May cause nephrocalcinosis or nephrolithiasis

3. Granulomatous Disorders

• Sarcoidosis, tuberculosis, other granulomatous diseases: Produce 1,25(OH)2D independently of PTH regulation 1

4. Medication-Induced

• Thiazide diuretics: Can cause hypercalcemia, especially in patients with underlying calcium metabolism disorders 2
• Vitamin A excess: Excessive vitamin A intake can lead to hypercalcemia 1
• Lithium and foscarnet: Associated with hypercalcemia 1

5. Endocrine Disorders

• Hyperthyroidism: Can cause increased bone turnover and hypercalcemia 1
• Adrenal insufficiency: May present with hypercalcemia 1
• Acromegaly: Associated with hypercalcemia in some cases 1

6. Other Causes

• Milk-alkali syndrome: Excessive calcium intake with absorbable alkali 1
• Immobilization: Especially in patients with high bone turnover 1
• Jansen's metaphyseal chondrodysplasia: Rare genetic disorder with gain-of-function mutation in PTHR1 1

Clinical Implications and Management

Evaluation

• Measure serum calcium, phosphorus, PTH, 25(OH)D, and 1,25(OH)2D levels
• Screen for malignancy (most common cause of non-parathyroid hypercalcemia)
• Review medication list for potential causes
• Consider genetic testing for suspected hereditary disorders (CYP24A1, SLC34A3) 3

Management Principles

• Treat the underlying cause
• For severe hypercalcemia:
  • Intravenous hydration
  • Consider calcitonin, bisphosphonates, or denosumab for rapid calcium lowering
• For vitamin D-related disorders:
  • Restrict calcium and vitamin D intake
  • Consider low calcium dialysate (1.5 to 2.0 mEq/L) in dialysis patients with hypercalcemia 4

Special Considerations in CKD

• In CKD patients with low PTH and high calcium:
  • Consider adynamic bone disease 4
  • Lower calcium dialysate concentration (1.5 to 2.0 mEq/L) might be appropriate 4
  • Reduce or eliminate calcium-based phosphate binders 4
  • Reduce or eliminate vitamin D therapy 4

Important Caveats

• Rare cases of primary hyperparathyroidism can present with hypercalcemia and undetectable PTH due to genetic mutations affecting PTH assay detection 5
• Persistent hypercalcemia with suppressed PTH can lead to nephrocalcinosis, nephrolithiasis, and renal function impairment 3
• Long-term follow-up is essential, as some conditions (like CYP24A1 mutations) may show improvement in hypercalcemia but persistent hypercalciuria and renal complications 3
• In CKD patients, adynamic bone disease with low PTH can lead to increased fracture risk and vascular calcification 4

Remember that while malignancy is the most common cause of non-parathyroid hypercalcemia in adults, the full differential diagnosis should be considered based on clinical presentation and laboratory findings.