Parathyroidectomy and Four-Gland Exploration for Hyperparathyroidism

Primary hyperparathyroidism is a common endocrinopathy. Surgery is the mainstay of treatment. Preoperative imaging is useful in localization of diseased glands and can allow for focal rather than four-gland exploration. Intraoperative adjuncts such as intraoperative parathyroid hormone (ioPTH) monitoring can be useful in select cases in determining the extent of parathyroid resection.

Hyperparathyroidism; primary hyperparathyroidism; parathyroidectomy.

Primary hyperparathyroidism is a common endocrinopathy with a prevalence of 23 cases per 10,000 women and 8.5 cases per 10,000 men.¹ The disorder is characterized by unregulated parathyroid gland function from an adenoma, hyperplasia, or rarely, malignancy which in turn causes hypercalcemia. In developed countries, only 15–20% of patients present with overt symptoms of hypercalcemia or obvious sequelae such as kidney stones.^2,3 Patients who are asymptomatic and found to have primary hyperparathyroidism on laboratory studies may have signs of end-organ manifestations such as decreased bone density or decreased renal function. Other patients that are asymptomatic may have non-specific symptoms such as fatigue, anxiety, and depression.²

Primary hyperparathyroidism is diagnosed by biochemical evaluation. Classic primary hyperparathyroidism is defined by elevation of both parathyroid hormone (PTH) and serum calcium, which physiologically should have an inverse relationship. Less common variants of the disease include normocalcemic hyperparathyroidism and normohormonal hyperparathyroidism, which are more difficult to definitively diagnose given more subtle laboratory findings. In the laboratory workup, it is important to send serum creatinine and 25-hydroxyvitamin D to assess for possible secondary hyperparathyroidism.

Once the diagnosis of primary hyperthyroidism is established, the following are the recommended criteria for definitive surgical management:⁴

• Age < 50 years.
• Serum calcium level > 1.0 mg/dL over the upper limit of normal.
• Renal involvement including nephrolithiasis, hypercalciuria (24-hour calcium level > 400 mg/dL), impaired renal function (glomerular filtration rate < 60 mL/min).
• Osteoporosis (t-score < -2.5 on DXA at lumbar spine, total hip, femoral neck or distal one-third radius) or vertebral fractures.
• Surveillance not feasible.

It is important to note that the above listed criteria are quite restrictive. Many, if not most, patients with primary HPT do not meet these criteria and yet may benefit from surgery. It is important that these patients are not excluded from surgical consideration, as corrective surgery could be protective of bone health and kidney function over time. It is our opinion that all patients with primary HPT should be considered for surgery. If a patient does not undergo surgery, they should undergo annual biochemical evaluation and DXA every one to two years.^2,4

The patient is an 81-year-old female with a history of many years of osteopenia treated with anti-resorptive therapy. On surveillance DXA scans, she progressed to osteoporosis with T -2.1, -2.0, -2.7, and -2.5 at the spine, total hip, femoral neck, and distal radius, respectively. Her biochemical evaluation revealed serum calcium 10.6 (normal range 8.5–10.5 mg/dL), PTH 84 (normal range 10–60 pg/mL), 24-hour urine calcium 360, and serum creatinine and 25-hydroxyvitamin D within normal range. Based on these findings, she was diagnosed with primary hyperparathyroidism and referred for surgical evaluation. 

While a complete physical exam is recommended during the workup for hyperparathyroidism, there are typically no pathognomonic exam findings. A neck exam should be performed to assess for concomitant thyroid disease but is unlikely to reveal a palpable parathyroid mass other than the rare case of a large parathyroid carcinoma. In cases of severe hypercalcemia, the physical exam may reveal dehydration, proximal muscle weakness, or bony tenderness.^5,6

Our patient’s physical exam was notable for a palpable right thyroid nodule and was otherwise unremarkable.

Imaging is not required to make a diagnosis of primary hyperparathyroidism nor to proceed to surgical management. Rather, preoperative imaging is useful in surgical planning and can allow for focal rather than four-gland exploration. All patients undergoing surgery for primary hyperparathyroidism should undergo preoperative ultrasound to assess for thyroid disease that may require concomitant surgery. High resolution ultrasound has 70–100% sensitivity for localizing abnormal parathyroid glands.⁷ However, ultrasounds are operator-dependent and frequently miss abnormal glands in particular locations such as posterior to the thyroid in the tracheoesophageal groove or substernal in the thymus.

Some patients with primary hyperparathyroidism undergo preoperative nuclear imaging with technetium-99 sestamibi scan. This technique relies on avid uptake and prolonged retention of the radiotracer by hyperfunctioning parathyroid glands. The sensitivity of sestamibi scan varies widely in the literature from 30–92%.⁷ While some studies have shown that sestamibi adds little to ultrasound evaluation,⁸ it can be useful in identifying abnormal glands in ectopic locations that are difficult to image with ultrasound. Sensitivity decreases with multigland disease and concomitant thyroid disease. 

In recent years, four-dimensional computed tomography (4D CT) scan has been used more frequently for preoperative parathyroid localization.⁹ The fourth dimension of time allows for additional information about the uptake and washout of contrast, which helps to distinguish parathyroid glands from thyroid tissue and lymph nodes. 4D CT has been shown to have superior localization in both single-gland and multigland disease compared to sestamibi and can be particularly useful in cases of recurrent disease.^10,11 We routinely obtain preoperative ultrasound and 4D CT scan at our institution. 

Our patient underwent neck ultrasound, which did not reveal evidence of a parathyroid adenoma. 4D CT demonstrated a candidate 0.8-cm left inferior parathyroid and a candidate 1.4-cm partially descended right superior parathyroid. No additional candidate lesions were identified. 

Upon its discovery in the early 1900s, classical primary hyperparathyroidism manifested as severe untreated disease characterized by osteitis fibrosis cystica, nephrolithiasis, and neuromuscular complications. This has changed substantially over time as most patients are asymptomatic and diagnosed with mild disease based on laboratory findings. Longitudinal studies have shown that most patients will have stability in serum and urinary biochemical analysis over time.¹¹ However, as mentioned above, patients that do not undergo surgery should have annual monitoring to assess for disease progression.

Patients who undergo surgery can undergo focused, unilateral, or bilateral four-gland exploration depending on preoperative localization studies and surgeon preference. Parathyroidectomy can achieve a cure rate of 97–99% for patients with or without preoperative localization. IoPTH monitoring should be used very selectively.⁴ The benefits of a more limited neck exploration include smaller incisions with better cosmesis, increased patient satisfaction, and less scar tissue in the case of contralateral recurrent disease.¹³ Some studies have demonstrated slightly higher disease persistence with focused exploration; however, long-term recurrence and overall cure rate is comparable between the two techniques.^14,15 Patients who have negative preoperative imaging studies or genetic conditions such as multiple endocrine neoplasia (MEN) 1 that predispose to multigland disease should undergo four-gland exploration.

Given that the patient’s preoperative localization studies demonstrated two small candidate lesions on contralateral sides, it was felt that her likelihood of multigland disease was high. Therefore, the decision was made to proceed with four-gland exploration. There exist two preoperative scoring systems, the CaPTHUS and the Wisconsin Index, that can be utilized to modify the pretest probability of single or multigland disease, although these are not routinely used in our practice. 

The core principles of four-gland parathyroid exploration include exonerating all possible anatomical locations and the ability to identify glands as visually abnormal. The superior parathyroid glands are typically more consistent in location and can be found in the perithyroidal fat posterior to the superior pole of the thyroid, as well as posterior to the recurrent laryngeal nerve. The inferior glands can be more variable in location, typically found around the lower pole of the thyroid, thyrothymic ligament, or pretracheal tissue. Possible ectopic locations include the thymus, the carotid sheath, the retroesophageal space, and within the thyroid.¹⁶ There is often symmetry between the right and left side, which can be useful if glands on one side have already been identified. Further, following branches of the inferior thyroid artery, which supplies blood to the parathyroids, can sometimes be useful to identify the glands.¹⁶ When abnormal, parathyroid glands tend to be larger and fuller, darker in color, and less compressible than normal glands. 

When there is high suspicion of multigland disease and a four-gland exploration is planned, it is prudent to identify all four glands prior to excising any specimens. If two or three glands are found to be abnormal, these are excised, and the normal glands are left in situ. If all four glands are found to be abnormal, all tissue should be excised other than a small remnant of one of the parathyroid glands. It is essential that this remnant appears well-vascularized at the end of the operation to reduce the risk of hypoparathyroidism.

There are several intraoperative adjuncts in parathyroid surgery. IoPTH monitoring can be useful in determining extent of resection. While surgeon practice is variable, guidelines recommend that if used, PTH be drawn at several timepoints: preincision, pre-excision of diseased gland(s), 5 minutes postexcision and 10 minutes postexcision. There are several ioPTH criteria used to determine cure with varying sensitivity and specificity. The most widely used and studied is the Miami Criterion, which requires ioPTH decrease by > 50% from the maximum pre-excision value at 10 minutes postexcision. Stricter criteria include the modified Miami Criterion, which in addition requires the ioPTH to approach the normal range, and the Rome Criterion, which requires a > 50% drop into the normal range at 20 minutes postexcision. IoPTH assay can also be used to determine laterality of diseased glands by drawing simultaneous bilateral internal jugular venous samples, and to confirm parathyroid tissue by needle aspiration of candidate tissue.¹⁷ Parathyroid tissue may also be confirmed by sending the specimen to pathology for frozen section, which is our practice for all excised glands.

Our patient underwent exploration with excision of the left inferior and right superior parathyroid glands. IoPTH sent 10 minutes after excision of the final diseased gland revealed an adequate decrease to 28 pg/mL from 133 pg/mL preoperatively. Final pathology of both glands demonstrated hypercellular parathyroid tissue. The patient was observed for several hours postoperatively and was discharged home the same day as surgery. She recovered appropriately from surgery without complications. At two months postoperative, her PTH was 49 pg/mL and calcium was 9.6 mg/dL. 

Nerveana nerve monitor.

The authors have no disclosures to report.

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