Certain symptoms and signs are useful predictors of different types of parathyroid pathology. Parathyroid adenoma is seldom if ever palpable, but parathyroid carcinoma is usually palpable.⁷ Exceptionally high concentrations of PTH or calcium in serum also may suggest parathyroid cancer.⁷ The diagnosis of familial multiple endocrine neoplasia type 1 (MEN1) or MEN2a predicts parathyroid hyperplasia^7–9; however, there is wide variation in the size of the abnormal parathyroid glands in patients with MEN1, so there might be a failure of the surgeon to recognize hyperplasia.¹⁰ The presence of multiple lipomas can occur in MEN1. Studies have identified the genetic defect in patients with MEN1 to be a MENIN mutation on chromosome 11q13¹¹ and in patients with MEN2, a RET proto-oncogene mutation on chromosome 10.¹² MEN2 must be distinguished from familial MEN2b, because hyperparathyroidism is not part of the latter. Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant trait usually manifested as asymptomatic hypercalcemia and relative hypocalciuria.^9,13 Mutations in the calcium-sensing receptor gene on chromosome 3 have been identified in a heterozygous form in benign FHH⁹ but not in sporadic adenomas. In patients with FHH, the hypercalcemia is PTH dependent and associated with mild parathyroid hyperplasia; however, subtotal parathyroidectomy is not effective and contraindicated. In such cases, measurement of urinary calcium excretion and detection of relative hypocalciuria (<100 mg/24 hours) should lead to cancellation of surgery and testing for hypercalcemia and hypocalciuria in relatives.¹³

Parathyroid Crisis

Parathyroid crisis is an unusual state of progressive, marked hyperparathyroidism producing anorexia, vomiting, dehydration, decrease in renal function, progressive hypercalcemia, deterioration of mental status, confusion, coma, and if untreated, death.14,15 Fatigue, muscle weakness, polyuria, and polydipsia are also frequent. Hypercalcemia may have been noted in the past but left untreated or inadequately treated. Often, no apparent reason can be found for the sudden worsening of hyperparathyroidism. Some cases are apparently precipitated by bacterial or viral infection, trauma, or recent surgery. Serum calcium should not be the only defining criterion for a hypercalcemic crisis, because asymptomatic patients with serum calcium of 20 mg/dL and patients in hypercalcemic crisis with serum calcium less than 14 mg/dL have been reported.¹⁶ Severe hyperparathyroidism may also be a manifestation of parathyroid carcinoma, which should be considered in the differential diagnosis.⁷

Parathyroid crisis is a potentially life-threatening disorder that requires vigorous medical management in preparation for definitive surgery. Attention must first be directed toward hydration, reduction of the hypercalcemia, and stabilization of the clinical state. Large amounts of intravenous saline are administered to ensure rehydration. This is followed by furosemide, which further reduces the hypercalcemia. At the same time, the diagnosis of hyperparathyroidism is established by measuring serum levels of calcium and intact PTH. If hydration and treatment with furosemide intravenously are not effective in reducing the hypercalcemia, treatment with bisphosphonates, calcitonin, or cinacalcet might be necessary, but surgery is indicated as quickly as the patient can be stabilized, because the crisis can worsen rapidly.¹⁴

Minimally Invasive Parathyroidectomy: Procedures for Preoperative and Intraoperative Localization of Abnormal Parathyroid Glands

Parathyroid Localization Before Initial Surgery

The overall trend in surgery over the past 10 years is towards minimally invasive techniques. The objective is to minimize length of incisions and the associated increased pain, higher rate of infection, and longer duration of hospital stay. With the ability to now reliably localize abnormal parathyroid glands and confirm their removal intraoperatively, minimally invasive parathyroidectomy (MIP) has become the procedure of choice for pHPT.17–23

There is general consensus that the best localization procedures for initial parathyroid operations are the combination of ultrasound (US) and sestamibi scanning (Fig. 9-1). The single best preoperative localization study is sestamibi, which has a specificity of 98%, but there has been reported variation in localization sensitivity for pHPT from 43% to 91%.^24,25 It has been recently reported that sestamibi optimization of acquisition and processing parameters may improve scan sensitivity in pHPT.²⁶ Sestamibi is a monovalent lipophilic cation that diffuses passively across the cell membrane and concentrates in mitochondria. It is preferentially concentrated in abnormal parathyroid tissue because of increased blood supply, higher metabolic activity, and an absence of p-glycoprotein on the cell membrane. Sestamibi scans can be done preoperatively to plan a MIP (Fig. 9-2).^20,27–34 High-resolution ultrasound is also a useful study for preoperative parathyroid localization.^35–37 It images the abnormal parathyroid gland as a hypoechoic (sonolucent) mass compared to the more echo-dense thyroid tissue (Fig. 9-3). It is specific, but it is not as sensitive as sestamibi. Its specificity is 98% and sensitivity is 66%.³⁸ Further, if both sestamibi and ultrasound are positive in the same location, the patient is virtually assured that an abnormal parathyroid gland will be found and removed.

FIGURE 9-1 Flow diagram for localization strategy in previously unoperated patients. US, Ultrasound.

FIGURE 9-2 A, Sestamibi scan showing uptake in thyroid as well as parathyroid tissue. B, Thyroid uptake of I-123. C, Subtracted image of sestamibi without I-123.

FIGURE 9-3 Hypoechoic mass (P) is an intrathyroidal parathyroid adenoma, with the more echogenic right superior thyroid lobe (T).

Parathyroid Localization Before Repeat Surgery

In patients with persistent or recurrent (normocalcemia for 6 months or longer, then recurrent hypercalcemia) hyperparathyroidism, the chance of successful surgery is reduced,39,40 and the incidence of complications is greater.^41–43 Therefore, maximum effort at parathyroid gland localization is made, commencing with the noninvasive procedures (US, computed tomography [CT], magnetic resonance imaging [MRI], and sestamibi scanning) and proceeding, if necessary, to the more invasive studies (Fig. 9-4). Currently, noninvasive techniques localize an abnormal gland in about 75% to 80% of patients requiring repeat surgery,⁴⁴ whereas invasive studies, such as venous sampling, selective angiography, or percutaneous ultrasound/CT-guided fine-needle aspiration, help with the remainder.^45,46

FIGURE 9-4 Flow diagram for localization strategy in previously operated patients.

Ultrasound

US, using a 10-MHz probe, is readily available, noninvasive, and the least expensive technique to preoperatively image abnormal parathyroid glands. It is particularly effective for localizing enlarged parathyroid glands in the neck and can be used to identify 60% of the abnormal glands in patients requiring reoperation.⁴⁴ US identifies juxtathyroidal parathyroid glands (see Fig. 9-3).

US has some disadvantages. It is operator-dependent, making the accuracy variable.35,37,38,47 It may fail to image posterior glands in the tracheoesophageal groove and glands in the anterior mediastinum. In multiple-gland hyperplasia, it generally demonstrates only the dominant gland.

Sestamibi Scintigraphy

Technetium 99m–labeled sestamibi scanning has superior resolution and sensitivity (80% to 90%) in detecting hypercellular parathyroid glands prior to reoperations.⁴⁸ Both the thyroid and parathyroid will take up sestamibi, but the uptake will be stronger and the signal will persist longer in parathyroid adenomas or hyperplasia (see Fig. 9-2). The combination of single-photon emission CT (SPECT) with sestamibi has improved the sensitivity to about 85%, especially for deep cervical and mediastinal parathyroid tumors.²⁵ Sestamibi has been combined with the gamma probe for hand-held intraoperative localization of abnormal parathyroid glands.^27,29–34 Advocates suggest that this approach is less invasive and can be done under local anesthesia as an outpatient procedure through a smaller incision. Sestamibi scans facilitate the dissection and make the surgery easier, but they have not been shown to affect the outcome in previously unoperated patients. One study demonstrated that there was no significant difference in cure rate between patients who had preoperative sestamibi scan and those who did not. The cure rate was 97.5% and 99%, respectively. However, there was a significant difference in cure rate between the negative sestamibi scan group (92.7%) and both the no-scan group (99.3%) and the positive-scan group (100%). Thus sestamibi scan can be used to identify those patients who are less likely to have successful surgery.⁴⁹

Computed Tomography

CT is particularly effective for identifying ectopic glands in the anterior mediastinum and enlarged glands in the tracheoesophageal groove. Ectopic glands in the anterior mediastinum often lie within the fat-replaced thymus, and even small adenomas are readily visualized (Fig. 9-5A). Ectopic glands in the tracheoesophageal groove are detected as a solid mass adjacent to the esophagus (Fig. 9-5B). Undescended glands near the carotid bifurcation are also identified by CT, provided that the examination is carried up to the level of the hyoid bone. On the other hand, CT is poor at detecting intrathyroid or juxtathyroid tumors and exposes the patient to risks associated with contrast media and radiation.

FIGURE 9-5 CT is the most useful imaging modality for identifying parathyroid adenomas located in the mediastinum (A) or in the tracheoesophageal groove (B).

Magnetic Resonance Imaging

Initial experience with MRI of abnormal parathyroid glands has been successful for large parathyroid adenomas, which on T2-weighted or stir-pulse sequences produce a bright signal.⁵⁰ In the mediastinum, this signal may be confused with fat, and a T1-weighted image is required to specifically identify the pathology. With gadolinium-enhanced MRI and T1- and T2-weighted images, MRI can now provide higher sensitivity than CT for identifying ectopic parathyroid tumors. It can be a useful study, and it may have more sensitivity than CT.

Summary of Radiographic Localization

We suggest that sestamibi and US be used in patients undergoing initial exploration for pHPT. Accurate preoperative localization studies allow a minimally invasive parathyroidectomy that shortens hospital stay, minimizes scar, and provides a successful outcome. Furthermore, in patients undergoing reoperations, preoperative radiologic localization studies are necessary and helpful to plan the operative approach (see Fig. 9-4). We recommend liberal use of each of the noninvasive imaging studies (US, CT, ^99mTc-sestamibi, and MRI) as an initial imaging cluster. If two studies identify the abnormal parathyroid gland in the same location, we proceed with surgery. Our institution is currently establishing 4D-CT technology, but it is not yet available. As such, if the noninvasive studies are equivocal, we then perform arteriography. If that study is positive, we perform surgery; if negative, we recommend selective venous sampling for rapid PTH measurements (as discussed above).⁵¹

Intraoperative Determination of Parathyroid Hormone

Intraoperative determination of PTH allows rapid monitoring of parathyroid status during parathyroid surgery.⁵⁴ Generally, after successful removal of a single parathyroid adenoma or adequate resection of hyperplastic glands, serum PTH levels begin to fall immediately and reach a 50% drop from the baseline level or normal range within 10 to 15 minutes.⁵⁵ Studies demonstrate that serum levels of intact PTH decline rapidly, only 5 minutes after resection of a parathyroid adenoma (Fig. 9-6).^56,57 Furthermore, the rate of decline is less in patients with hyperplasia and may provide an additional intraoperative means of diagnosing hyperplasia (Fig. 9-7).⁵⁸ A serum sample for PTH should be obtained just after the induction of anesthesia. Repeated serum samples are obtained intraoperatively immediately following resection of an enlarged gland, and then 10 minutes following removal. This protocol has been designed to take into account the half-life of PTH, which is 1 to 4 minutes, and avoid misleading results from a spike in concentration that may occur during handling and removal of the adenoma.⁵⁷ A 50% reduction in the PTH level from the median baseline level indicates a successful outcome (see Fig. 9-6).⁵⁶ Some also recommend a second criterion of a normal serum level of PTH. The operation can be terminated on this result without identification of other parathyroid glands. Furthermore, the assay can be used to diagnose an abnormal parathyroid gland by performing fine needle aspiration (FNA) of a mass lesion and then diluting the sample with heparinized saline and measuring PTH levels—which will be very high if the mass is parathyroid tissue.⁵⁸