What is the best course of action for an older adult, possibly a woman, with a history of radiation exposure or a family history of parathyroid disorders, presenting with a parathyroid nodule and potential primary hyperparathyroidism (PHPT)?

Management of Parathyroid Nodules

For an older adult with a parathyroid nodule and biochemically confirmed primary hyperparathyroidism (PHPT), surgical excision via parathyroidectomy is the definitive treatment, even when asymptomatic, given the potential negative effects of long-term hypercalcemia including persistent hypertension, bone demineralization, and nephrolithiasis. 1, 2

Initial Diagnostic Approach

Biochemical Confirmation

• Measure serum calcium (total calcium adjusted for albumin) and intact parathyroid hormone (PTH) to confirm PHPT 1
• If total calcium is normal but clinical suspicion remains high, measure ionized calcium, as occult PHPT can present with normal total calcium but elevated ionized calcium 3
• Check serum phosphorus and assess for target organ involvement (bone densitometry for osteoporosis, renal imaging for nephrolithiasis) 1, 4

Genetic and Syndromic Considerations

Given the patient's history of radiation exposure and potential family history:

• Radiation exposure history does NOT increase the likelihood of multigland disease (31% vs 28% in non-irradiated patients), contrary to common belief 5
• However, radiation-associated parathyroid adenomas tend to be smaller (511 mg vs 790 mg) with lower preoperative PTH levels 5
• Consider genetic testing for CDC73 (Hyperparathyroid-Jaw Tumor Syndrome) if the patient has ossifying jaw fibromas, parathyroid carcinoma, or family history, particularly if parafibromin immunohistochemistry shows loss of nuclear staining 1
• Consider MEN1 genetic testing if there is family history or clinical features of pancreatic neuroendocrine tumors or pituitary adenomas, as PHPT is the most common presenting feature (95% of MEN1 patients) 1

Preoperative Imaging Strategy

Imaging has no utility in confirming or excluding the diagnosis of PHPT but is essential for preoperative localization to facilitate minimally invasive parathyroidectomy (MIP). 1, 2

Recommended Imaging Modalities

• Parathyroid sestamibi scan (Tc-99m-Sestamibi scintigraphy) is recommended for preoperative localization 2, 4, 3
• Ultrasound of the neck to identify the parathyroid nodule and assess for thyroid nodules, which are frequently coexistent 3, 6
• 4-D parathyroid CT (multiphase CT without and with IV contrast) leverages unique perfusion characteristics to differentiate parathyroid adenomas from thyroid nodules and lymph nodes 1

Important Imaging Caveat

• Biopsy of suspicious neck lesions is discouraged in patients with potential CDC73-related syndrome due to risk of seeding carcinomatous cells through the biopsy track 1
• However, inadvertent fine-needle aspiration of a parathyroid adenoma can rarely cause hemorrhagic infarction leading to transient remission of PHPT, though recurrence typically occurs within months 7

Surgical Management

Minimally Invasive Parathyroidectomy (MIP)

• MIP is the preferred approach when preoperative imaging confidently localizes a single adenoma, offering shorter operating times, faster recovery, and decreased perioperative costs 1
• Requires intraoperative PTH monitoring to confirm removal of the hyperfunctioning gland 1
• Most patients with PHPT have a single adenoma (approximately 80% of cases), making MIP feasible in the majority 2

Bilateral Neck Exploration (BNE)

• Reserved for cases with discordant or nonlocalizing preoperative imaging, high suspicion for multigland disease, or familial syndromes (MEN1, CDC73) 1
• In MEN1, PHPT typically involves multigland disease requiring subtotal parathyroidectomy or total parathyroidectomy with autotransplantation 1

Surgical Referral

• Refer to a high-volume parathyroid surgeon, particularly for patients with suspected CDC73-related syndrome or familial PHPT 1

Medical Management (Non-Surgical Candidates Only)

Cinacalcet is FDA-approved for hypercalcemia in adult patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated based on serum calcium levels but who are unable to undergo surgery. 8

Cinacalcet Dosing for Primary HPT

• Starting dose: 30 mg orally twice daily with food 8
• Titrate every 2-4 weeks through sequential doses (30 mg twice daily → 60 mg twice daily → 90 mg twice daily → 90 mg 3-4 times daily) to normalize serum calcium 8
• Measure serum calcium within 1 week after initiation or dose adjustment 8
• Monitor serum calcium approximately every 2 months once maintenance dose established 8

Critical Monitoring for Hypocalcemia

• Common adverse reactions include nausea (30%), vomiting (27%), and hypocalcemia (11%) 8
• Severe or prolonged nausea/vomiting can lead to dehydration and worsening hypercalcemia, requiring careful electrolyte monitoring 8
• Seizures occurred in 0.7% of cinacalcet-treated patients in clinical studies 8

Special Considerations

Coexistent Thyroid Pathology

• In areas of iodine deficiency, thyroid nodules detected by preoperative ultrasound should be evaluated by thyroid scintigraphy even if TSH is normal 6
• If hot thyroid nodules are identified, consider combined parathyroid and partial thyroid resection 6

Postoperative Management

• Monitor for postoperative hypocalcemia, which may require temporary calcium and calcitriol supplementation 4
• PTH levels may be undetectable immediately postoperatively, necessitating supplementation for 1-4 months 4