Can thyroid cancer cause hypercalcemia?

Can Thyroid Cancer Cause Hypercalcemia?

Yes, thyroid cancer can cause hypercalcemia, but the mechanism and frequency differ significantly by cancer type. Medullary thyroid carcinoma (MTC) associated with Multiple Endocrine Neoplasia type 2A (MEN 2A) causes hypercalcemia through concurrent hyperparathyroidism rather than direct tumor effects, while hyperthyroidism from any thyroid pathology can independently cause hypercalcemia through increased bone turnover 1, 2.

Medullary Thyroid Carcinoma and MEN 2A

The most clinically relevant connection between thyroid cancer and hypercalcemia occurs in MEN 2A syndrome, where patients develop both MTC and primary hyperparathyroidism. 1

• In MEN 2A, serum intact parathyroid hormone levels and calcium levels should be measured when this syndrome is suspected, as hyperparathyroidism is a component of the syndrome 1
• Signs or symptoms of hyperparathyroidism rarely present before those of MTC in MEN 2A, even in the absence of screening 1
• The hypercalcemia in these cases results from the parathyroid component of MEN 2A, not from the medullary thyroid cancer itself 1

Paradoxical PTH Response in MTC

• Research demonstrates that some patients with medullary thyroid carcinoma show paradoxical increases in PTH during calcium infusions, particularly those with the greatest increases in calcitonin 3
• This suggests a functional relationship between calcitonin and PTH secretion in MTC patients, though this typically occurs in normocalcemic patients 3
• Most patients with elevated calcitonin levels from MTC remain normocalcemic with normal basal PTH levels 3

Hyperthyroidism-Associated Hypercalcemia

Thyrotoxicosis from any cause, including thyroid cancer, can produce hypercalcemia through increased bone turnover mediated by excess thyroid hormone. 2

• The mechanism involves thyroid hormone's direct effect on increasing bone resorption, leading to elevated serum calcium 2
• This form of hypercalcemia is characterized by suppressed PTH levels (distinguishing it from hyperparathyroidism) and elevated 1,25-dihydroxyvitamin D3 levels 2
• After thyroid ablation with radioactive iodine, serum calcium, free thyroxine, and 1,25-dihydroxyvitamin D3 levels normalize, while PTH levels return to normal range 2

Diagnostic Approach When Thyroid Cancer and Hypercalcemia Coexist

Always measure intact PTH first to distinguish PTH-dependent from PTH-independent hypercalcemia. 4, 5, 6

If PTH is Elevated or Inappropriately Normal:

• Consider MEN 2A syndrome if the patient has medullary thyroid carcinoma 1
• Evaluate for RET proto-oncogene mutations, which are found in at least 95% of MEN 2A kindreds 1
• Screen for pheochromocytoma, as this can also be part of MEN 2A 1
• Obtain 24-hour urine calcium and renal ultrasound to assess for nephrocalcinosis or kidney stones 4

If PTH is Suppressed (<20 pg/mL):

• Measure free T4 and TSH to evaluate for thyrotoxicosis 2
• Check 1,25-dihydroxyvitamin D3 levels, which are typically elevated in hyperthyroidism-associated hypercalcemia 2
• Consider thyroid uptake scan if hyperthyroidism is suspected 2
• Rule out other causes of PTH-independent hypercalcemia including malignancy-associated hypercalcemia from other cancers, vitamin D intoxication, and granulomatous diseases 4, 5, 6

Critical Clinical Pitfalls

• Do not assume hypercalcemia in a patient with thyroid cancer is due to bone metastases without checking PTH first—the most common causes are MEN 2A-associated hyperparathyroidism or thyrotoxicosis, not metastatic disease 1, 2
• Do not overlook family history—MEN 2A is inherited in an autosomal dominant fashion, and genetic testing for RET mutations can identify disease carriers before clinical symptoms develop 1
• Do not delay treatment of severe hypercalcemia (calcium ≥14 mg/dL) while pursuing diagnostic workup—initiate IV normal saline hydration immediately and consider bisphosphonates 4, 7, 5
• Do not confuse the paradoxical PTH response during calcium infusions in MTC patients with true hyperparathyroidism—most MTC patients without MEN 2A remain normocalcemic with normal basal PTH 3

Management Considerations

• For hypercalcemia associated with MEN 2A, parathyroidectomy is the definitive treatment for the hyperparathyroid component 4, 5
• For thyrotoxicosis-associated hypercalcemia, treating the underlying hyperthyroidism with radioactive iodine ablation or antithyroid medications normalizes calcium levels 2
• Genetic counseling and RET mutation testing should be offered to all patients with medullary thyroid carcinoma to identify familial cases and screen family members 1