27.1 Introduction

Over the past few decades the surgical management of primary hyperparathyroidism has evolved dramatically. Historically, all patients underwent a bilateral neck exploration to assess all four parathyroid glands, and any grossly diseased glands were resected. Today, with the advent of improved localization studies combined with intraoperative parathyroid hormone (IOPTH) monitoring, minimally invasive parathyroidectomy has gained widespread acceptance, particularly among experienced endocrine surgeons. This chapter discusses the development of the IOPTH assay as well as the current recommendations and techniques for its usage.

27.2 History of the Intraoperative Parathyroid Hormone Assay

In the 1970s, physicians at the University of Miami first began using a radioimmunoassay to measure parathyroid hormone (PTH) levels for patients undergoing parathyroidectomy. However, this early assay measured fragments of the molecule, rather than the intact molecule, which often led to inconsistent results. In 1987, Samuel Nussbaum at the Massachusetts General Hospital reported a highly sensitive two-site antibody immunoradiometric assay to measure intact PTH. The surgeons at Massachusetts General Hospital subsequently reported their results at the American Association of Endocrine Surgeons (AAES) annual meeting and proposed that their assay could be used as an intraoperative tool, because it had a short, 15-minute turnaround time. However, their report was received with skepticism as being an unnecessary test in the hands of an experienced endocrine surgeon. Shortly thereafter, surgeons at the University of Miami started to perform their own intraoperative assay with a similar turnaround time of 15 minutes. Their “quick” PTH (QPTH) assay had similar results to the standard assay. Using their assay, these surgeons studied samples measured at various operative intervals. They also learned that manipulating the gland raised intraoperative measurements. Through their various lab value comparisons, they discovered that the half-life of PTH was 3.5 to 4 minutes. ¹

Around this time, surgeons in France published reports of using a new, limited approach to parathyroidectomy performed with ultrasound localization, local anesthesia, and confirmation of excision of an adenoma with PTH assays and cyclic adenosine monophosphate (cAMP) levels. However, their assays took more than 45 minutes to run, and they often did not confirm removal of disease until long after the operation was concluded. If there was evidence of multigland disease based on the IOPTH assay values, the patient had to undergo a second operation. ^{1 , 2 , 3}

Nichols Institute Diagnostics finally brought a major advancement to IOPTH monitoring in the United States with an immunochemiluminometric assay (ICMA) in 1993. This method did not use radioisotopes, thus making it portable. The assay was rapid, stable, and showed no cross-reactivity with PTH fragments like previous assays did. ¹

In 1992, surgeons at the University of Miami began using sestamibi scans for preoperative localization of parathyroid adenomas. Combining preoperative localization with intraoperative PTH assays, they shortened their operative times for parathyroidectomy. At around the same time, Boggs et al showed that ICMA had a sensitivity of 97%, specificity of 100%, and overall accuracy of 97% for predicting postoperative calcium levels. ^{1 , 4} These results were presented at the AAES in 1996, after which a sudden interest was spurred in the focused parathyroidectomy method now widely performed. ¹

However, the cost of using this new intraoperative PTH assay technology was initially high, slowing adoption by surgeons. The University of Miami evaluated the decreased costs associated not only with shorter operative times, but their ability to perform the surgery as an outpatient. They showed that same-day parathyroid surgery versus an overnight stay cost 39% less. ¹ Thus cost-effectiveness was another driving factor in support of using IOPTH monitoring to help perform more focused parathyroidectomies.

27.3 Differences in the Molecular Structure of PTH and Its Effect on the Assay

The molecular pathway and structure of PTH have a significant effect on how the assay is measured. PTH is first translated in the endoplasmic reticulum of the parathyroid chief cell as a 115-amino-acid-sequence molecule called preproPTH. Subsequently, two amino acid sequence cleavages occur, first to create proPTH and then to create the final 84-amino-acid-length intact PTH molecule termed (1–84) PTH. Less than 1% of (1–84) PTH reaches the PTH receptors in target organs after being released from the parathyroid glands. When PTH is metabolized, only the inactive C-terminal portions (cPTH) are rereleased into the circulation. The N-terminal products (nPTH) have biological activity but make up a much smaller portion of circulating hormone. In contrast, cPTH has a longer half-life and is secreted primarily by the kidneys. Thus cPTH fragments are elevated in patients with renal dysfunction, which may adversely affect the results of assays measured in patients with renal failure. Fig. 27.1 depicts the production and degradation pathway of PTH. ⁵

“Intact PTH” assays are two-site sandwich assays in which the nPTH and cPTH ends are bound by separate antibodies. Ideally, a PTH assay will selectively bind and measure (1–84) PTH. However, (1–84) PTH circulates in much smaller numbers than the various PTH fragments, making its measurement challenging. In fact, most of the early assays reacted with the more abundant, smaller cleavage products and fragments of PTH (which are devoid of bioactivity) more than with the active (1–84) PTH molecule. Additionally, the ratio of (1–84) PTH to its fragments can vary significantly in patients with renal dysfunction and varying parathyroid gland activity. These challenges associated with the accuracy of IOPTH assays and which molecules were actually being measured have been studied and evaluated extensively. Fortunately, newer generations of IOPTH assays have improved rates for detecting the actual (1–84) PTH molecules, rather than the inactive fragments. ^{5 , 6}

27.4 Intraoperative PTH Monitoring Improves the Success of Minimally Invasive Parathyroidectomy

With the increased accuracy of preoperative localization studies, many surgeons have shifted toward minimally invasive parathyroidectomy rather than routine four-gland exploration. Minimally invasive parathyroidectomy techniques use focused, unilateral, and often endoscopic methods. ⁷ However, during minimally invasive parathyroidectomy, because all four glands are not directly visualized, the surgeon does not necessarily know whether or not all of the diseased parathyroid tissue has been removed. By incorporating IOPTH assessment, surgeons can excise the image-localized adenoma and immediately assess for biochemical resolution of the hyperparathyroidism to determine if the operation has been successful. If intraoperative PTH levels fail to decline appropriately, the surgeon can immediately convert to a bilateral neck exploration, thus potentially avoiding a second operation for the patient.

When ultrasound identifies a single adenoma, the addition of IOPTH measurements increases the operative success from 71 to 86%. ⁷ Likewise, when sestamibi scan localizes a single adenoma, use of IOPTH improves the operative success from 83 to 92%. ⁷ When both ultrasound and sestamibi scan are used and have concordant results, their combined accuracy in localization is 95%. ⁷ When IOPTH assessment is added to ultrasound and sestamibi in this setting, the operative success increases to 97%. ⁷ Some argue that this gain of 2% does not justify the use of IOPTH monitoring in this setting and increases the length of operation and costs. ⁷

IOPTH assessment is especially helpful in the setting of discordant findings on preoperative imaging studies. About half to two-thirds of patients with hyperparathyroidism will have discordant imaging findings. ⁷ The use of IOPTH monitoring in this setting has been shown to guide the operative management in 74% of these patients, leading to an operative success rate of 93%. Sixty-six percent of these patients were able to have successful unilateral exploration. ⁷

Cayo et al prospectively studied more than 755 patients with primary hyperparathyroidism and found that IOPTH monitoring accurately predicted success of parathyroidectomy in 97.5% of patients with multigland disease. ⁸ However, other studies report that IOPTH is not as successful with multigland disease. ^{9 , 10} Siperstein et al reported that, when a bilateral neck exploration is routinely performed, even when preoperative localization studies identified a single adenoma, unsuspected additional morphologically abnormal parathyroid glands are identified in 20 to 22% of patients. Adding IOPTH only reduced the rate of identifying unsuspected multigland disease to 16 to 17%. However, one criticism of this study is that, although the additional glands were morphologically abnormal, they may not have been functionally abnormal. Overall, IOPTH assessment correctly predicts multigland disease in only 22% of patients who have it. ¹¹