Current Applications of the Intraoperative Parathyroid Hormone Assay in Parathyroid Surgery

July 1, 2007

By Richards, Melanie L Grant, Clive S

Parathyroid hormone measurement using a two-site immunochemiluminometric assay has allowed for a rapid and accurate technique that has found its way into the operative armamentarium of some parathyroid surgeons. It can be used to assess the completeness of parathyroid gland resection and allow for a minimally invasive parathyroidectomy. This operative approach has become a popular marketing tool, providing patients with confidence in their surgical outcome. The purpose of this review is to provide the surgeon with the practical points and pitfalls of the use of intraoperative parathyroid hormone in the treatment of parathyroid disease. THE CONCEPT OF intraoperative (IO) parathyroid hormone (PTH) monitoring was first described by Nussbaum in 1988.1 Four years later, a modified immunoradiometric assay to measure the whole molecule of PTH was introduced to the clinical setting.2 The main advantage at that time was confirmation of a biochemical cure in reoperative patients. The difficulty with this early assay was that it required at least 1 hour to obtain a result. This delay was not practical for use intraoperatively and was superseded by a faster technique using a two-site immunochemiluminometric assay to measure the active component of PTH (1-84 or intact-PTH). This new technique provided IOPTH levels in as little as 15 minutes and purportedly had a sensitivity of 94 per cent for predicting postoperative calcium levels.3 There have since been several modifications in the assay to reduce the detection of PTH fragments, resulting in improved sensitivity and specificity.4

It is critical in reviewing the literature on IOPTH to identify which factors and patient subpopulations were analyzed to predict success. For example, whether the studies included only patients who were candidates for a minimally invasive approach, whether patients found to have multiglandular disease were excluded, or whether all patients with hyperparathyroidism (HPT) were included. Strong proponents of the technique have reported remarkable success in predicting single-gland disease in 99 per cent of patients and multiple-gland disease in 91 per cent of patients with sporadic primary HPT (IHPT) treated with a limited exploration.5 At the Mayo Clinic, we have found IOPTH monitoring to have an overall accuracy of 97 per cent (Table 1), and it has in part enabled us to achieve cure rates for so-called “minimally invasive parathyroidectomy” that are comparable with the “gold standard” four-gland exploration.


Criteria for Success

The acceptable criteria for biochemical success after parathyroidectomy have been debated. The initial recommendation by Irvin1,6,7 was a 50 per cent reduction from the highest pre- excision IOPTH level when the sample is drawn 10 minutes after the abnormal parathyroid tissue is removed. The “highest preexcision IOPTH” level can be based on preincision or just before ligating the vascular pedicle of the offending parathyroid gland. This resulted in cure rates ranging from 97 to 100 per cent in patients with sporadic IHPT undergoing a directed parathyroidectomy based on the IOPTH criterion of >50 per cent decline from baseline.8-12

A number of surgeons have recommended that the postexcision IOPTH should drop a minimum of 50 per cent from the baseline and fall within the normal range.13-15 Similarly, we have determined that a curative operation is associated with at least a 50 per cent decline in the IOPTH, and that the levels be at or near normal. Of 2064 patients who underwent parathyroidectomy for IHPT at the Mayo Clinic from June 1998 through December 2005, we reviewed 1302 patients for whom IOPTH monitoring was used (Table 1). Primary operations were performed in 89 per cent of patients. In this group, IOPTH monitoring had a sensitivity of 98 per cent and a specificity of 91 per cent. The lowest sensitivity was in patients with multiglandular disease (95%), but it was very accurate (96-99%) in all patient groups. If the IOPTH levels meet the curative criteria, then the operation is successful in 99 per cent of patients.

TABLE 1. Results of Intraoperative PTH Monitoring in Patients with IHPT


The timing and location of baseline IOPTH levels have also been debated. All of the following have been recommended for obtaining a baseline PTH: before the incision, after massaging the adenoma, immediately before ligating the blood supply to the suspected parathyroid adenoma, and not at all. Surgeons have advocated drawing the blood peripherally, arterially, or from the internal jugular vein. Each method has its advantages and disadvantages. We generally obtain the baseline IOPTH level from the internal jugular vein, which is easily accessible and avoids the need for additional peripheral access. The internal jugular venous sample is also closer to the source of the offending parathyroid gland and the baseline IOPTH will be higher. It may take up to 15 minutes postexcision for the internal jugular IOPTH levels to normalize to a level comparable with a peripheral sample.15 This may lead to additional IOPTH sampling if a criterion of “normal” is used.

Role of IOPTH and Preoperative Imaging

There have been investigators that have proposed that adequate preoperative imaging alone makes the IOPTH assay unnecessary.16 Others have reported that a focused exploration performed with a localizing preoperative sestamibi scan in conjunction with intraoperative gamma probe localization results in a 96 per cent success rate.17 These results must be carefully interpreted when compared with the IOPTH. The variability of techniques, interpretation, and reported results of the imaging studies makes it extremely difficult to determine the best algorithm for one’s practice. Differing referral patterns also play a role. Some practices are referred patients primarily for focused exploration; others are treating patients with small tumors and questionable imaging studies. The results of IOPTH testing are accurate and consistently highly reliable from one institution to another. We have found the IOPTH assay to be a valuable adjunct to imaging studies, primarily as a critical final step to identify patients with multiglandular disease who were not appreciated on preoperative imaging studies.

Relying on sestamibi imaging alone will lead to failures in patients with multiglandular disease, as 39 to 75 per cent will have a solitary area of uptake on sestamibi imaging.5,18,19 In our practice, we have found sestamibi scintigraphy to have a sensitivity of 86 per cent. We define a false-positive result as one in which the offending parathyroid gland was not on the side identified on the imaging study or that the patient had additional hypercellular parathyroid glands not detected on imaging. False-positive results occur in 5.7 per cent of patients. Ultrasonographic localization at our institution has declined to a sensitivity of 61 per cent and has an 8.5 per cent incidence of false positives (a result of multiple rather than selected participating radiologists). These results do not compare with the high sensitivity (98%) and specificity (93%) of the IOPTH assay. Reliance on the imaging alone, even with the best of techniques, may lead to surgical failures and an increased need for reoperation. We recommend that the imaging be used to guide the initial extent of the operation and that IOPTH assay be used to confirm a curative single-gland excision or need to identify and excised additional abnormal parathyroid glands.

Familial HPT and Multiple-Gland Disease

Patients with familial disease will have isolated familial HPT or multiple endocrine neoplasia (MEN 1 or MEN 2). These distinct entities have historically been evaluated as one group. However, the patients with MEN 1 are at a higher risk for persistent or recurrent HPT compared with those with MEN 2 or familial isolated HPT.20 Although all of these groups are at risk for recurrent disease, limited parathyroidectomy has been advocated in familial HPT performed with IOPTH monitoring.21 This method has been shown to have an operative success rate of 93 per cent and a short-term (less than 6 months) recurrent HPT rate of 9 per cent.21 Only 80 per cent of this group of patients were cured with a unilateral neck exploration. Therefore, these investigators have recommended consideration of jugular venous sampling for PTH to determine which side of the neck to explore first. In our practice, we have continued to perform a bilateral exploration in patients with familial disease. We judge an 80 to 93 per cent short-term success rate inadequate compared with a 95+ per cent long-term success rate with a bilateral exploration.

The criterion of a 50 per cent decline from the highest pre- excision value appears to have its greatest success in settings where multiglandular disease is uncommon. Unfortunately, the reported incidence of multiglandular disease has ranged widely from 6 to 28 per cent in various reports from across the United States.22,23 The incidence of multiglandular disease in patients undergoing a focused exploration has been as low as 3 per cent.22 Our practice has maintained an approximate 13 per cent rate of multiglandular disease over several decades.14- 24 It is uncertain whether the variability in the incidence of multiglandular disease can be attributed to referral patterns, regionalization of familial HPT, or a confounding factor such as vitamin D deficiency. There also does not appear to be any ethnic or economic differences associated with the varying rates of multiglandular disease. It is this variability that has led to the recommendation a normal postexcision IOPTH value, as well as analysis of PTH decay kinetics. Groups with high rates of multiglandular disease have even proposed that a bilateral exploration be performed in all patients.25 Surgeons who see more patients with multiglandular disease have found that the 50 per cent rule may not always apply to these patients. There have been reports of a 50 per cent decline in the IOPTH level, suggesting a biochemical cure in the face of remaining grossly enlarged parathyroid glands that show histopathologic evidence of hypercellular parathyroid tissue when removed.26,27 It has also been noted that the decay kinetics show a steeper slope in solitary adenomas compared with multiglandular disease.28 Using a decay analysis can identify more patients with multiglandular disease than relying solely on a 50 per cent drop from the baseline values (54% vs 38%).28 However, this technique has not gained popularity, most likely because it is more time consuming and there is a known variability in individual PTH kinetics.

Reportedly, up to 75 per cent of patients with multiglandular disease will have false-positive decreases from their baseline IOPTH levels if relying on a 50 per cent decline.15 This discrepancy led to the concern of whether these pathologically confirmed hypercellular parathyroid glands were or were not hypersecreting PTH. Bench studies have shown that there are morphologically enlarged parathyroid glands that do not secrete excessive amounts of PTH.29 Is it possible that the patients have multiglandular disease and that they may not be hypersecreting PTH at the time of operation, but that they are prime candidates for developing recurrent disease. The key to whether “possibly” enlarged glands lead to recurrent HPT is based on follow-up data. We have found equivalent cure rates of 97 per cent for focused and bilateral explorations. These values have not changed in nearly a decade of using the IOPTH to measure success in parathyroid operations. This success is related not only to the monitoring of IOPTH levels, but also to the expertise in parathyroid imaging. Accurate imaging, in combination with an assessment of risk factors for familial disease, help guide the surgeon in selecting patients that would benefit from a focused or bilateral exploration.

In summary, the criteria of 50 per cent and nearnormal or PTH decay analysis will increase operative success in settings where there is an increased incidence of multiglandular disease. It is also likely that that there are patients who have enlarged parathyroid glands that are not hypersecreting. The use of the IOPTH analysis in combination with preoperative imaging and a thorough patient history are the keys to detecting and managing patients with multiglandular disease.


In experienced hands, an unsuccessful primary operation will occur in approximately 3 to 5 per cent of patients.14,30 With less experience, the frequency may be higher. Patients who are referred for possible reoperation will face increased morbidity rates and decreased success rates. A curative reoperation will often depend on the ability to identify the location of the offending parathyroid tissue before surgery. This search begins with a careful review of the previous operative and pathology reports. The endocrine surgeon will then use an armamentarium of localizing procedures to aid in planning the reoperative strategy. These studies may include technetium-99m sestamibi scintigraphy with or without single-photon emission CT, ultrasonography, CT scanning, magnetic resonance imaging, and selective venous sampling for PTH. The rapid PTH assay can also be used during selective venous sampling. This allows for immediate results and early re-exploration. This may reduce adhesion- related morbidity, as a reoperation was prospectively found to have a risk of recurrent laryngeal nerve injury six times higher compared with the primary operation.31 Jugular venous sampling for PTH can also be performed intraoperatively to regionalize the hypersecreting parathyroid tissue to one side of the neck.32,33

We have found the use of IOPTH monitoring extremely helpful in the reoperative setting. In a review of 2065 parathyroid operations at the Mayo Clinic in Rochester, we found that 259 (12.5%) were reoperations. Intraoperative PTH monitoring was used in 196 of 259 (75.7%) of these cases. The IOPTH sensitivity was 99 per cent and the specificity was 85 per cent for predicting cure. It was 97 per cent accurate.

Nearly one-third of patients will develop symptomatic hypocalcemia after a reoperation.34 This risk is highest in patients with multiple-gland disease. Unfortunately, imaging studies, laboratory tests, and a review of the medical records cannot assess the function or presence of the remaining normal parathyroid glands. A surgeon does not want the patient to leave the operating room with permanent hypoparathyroidism. The final IOPTH value is one of the best intraoperative tools available to assess the function of remaining parathyroid tissue and reduce the likelihood of permanent hypoparathyroidism. A low (below the reference range) or undetectable IOPTH level can guide the surgeon in a decision to proceed with autotransplantation. An early postoperative PTH level will be an indicator of native parathyroid function, as the autograft will generally take at least 2 to 4 weeks to produce PTH.

A low IOPTH level can also identify patients who will need supplementation with calcitriol. A postexcision IOPTH in reoperative surgery that has dropped 84 per cent or greater from baseline has a positive predictive value of 46 per cent for identifying patients with single-gland disease that will require calcium and vitamin D supplementation.34 In patients with multiple-gland disease, an 84 per cent reduction was associated with a 71 per cent chance of requiring calcium and vitamin D supplementation. The practicality of this use of IOPTH is limited because of the low predictive value in single-gland disease and the finding that most patients with multiglandular disease need the supplementation. For these reasons, we will routinely begin calcium supplementation in all patients undergoing parathyroidectomy. We reserve vitamin D supplementation for severe symptoms, vitamin D deficiency, osteoporosis, and in patients with multiglandular disease.

Secondary HPT (2HPT)

The use of IOPTH monitoring in 2HPT has been controversial because of variable PTH degradation kinetics in patients with renal disease. One study found that there was not a correlation between the IOPTH and the PTH obtained on postoperative Day I.35 Therefore, the authors concluded that there is no role for the IOPTH assay in surgery for 2HPT. However, other studies have found that the IOPTH levels in 2HPT have an average decline of 85 per cent from baseline and allows for the same criterion as in 1HPT.36,37 This was also confirmed when Chou et al.38 reported that the IOPTH at 10 minutes was as accurate as one obtained 30 minutes postexcision. It may take 15 or 20 minutes when using the criteria of near normal.

The use of IOPTH monitoring in 2HPT will depend on the operation performed. The operations commonly performed for 2HPT are a subtotal parathyroidectomy or a total parathyroidectomy with/without autotransplantation. A complete cervical exploration should be performed to identify all parathyroid glands and to evaluate for extranumerary glands. The primary use of the IOPTH will be to verify the adequacy of resection and to improve the detection of supernumerary glands. It is the surgeon’s responsibility to guarantee a viable remnant in a subtotal parathyroidectomy. The postexcision IOPTH level in patients undergoing a subtotal parathyroidectomy can be monitored in fashion similar to those patients with IHPT and multiglandular disease. It should decrease more than 50 per cent from the pre-excision levels and be as close to the normal range as possible. Theoretically, it should be a close to undetectable as possible after a total parathyroidectomy. The low IOPTH levels that we expect in treating patients with 2HPT makes it necessary to always provide postoperative calcium and vitamin D supplementation, often in large amounts.

Tertiary HPT (3HPT)

Parathyroidectomy for 3HPT is the least commonly performed, and the application of the IOPTH in this setting has not been defined. Patients with 3HPT will often have asymmetrical hyperplasia. On exploration, hyperplasia is found in 78 to 91 per cent of patients.39,40 Unlike their counterparts with multiglandular disease secondary to familial disease or 2HPT, these patients do not have a continued stimulus for developing hyperplasia unless they have vitamin D deficiency. These are optimal characteristics for undergoing parathyroidectomy with IOPTH monitoring.

The PTH degradation kinetics in 3HPT are comparable with those with IHPT with an average decreases from baseline of 77 to 89 per cent at 10 minutes.39,40 Using the criteria of a 50 per cent decline from baseline, anywhere from O to 50 per cent of the patients with 3HPT may have inappropriate elevations in PTH levels at 1 year of follow0 -up.39,40 Interesting, all of the patients were normocalcemic, which is the benchmark of a successful operation in 3HPT.39,40 The inclusion criteria of a “near-normal” IOPTH level may reduce the rate of persistent HPT. An isolated PTH elevation may also be attributable to an underlying total calcium or vitamin D deficiency. Patients with this biochemical profile have been shown to have reductions of the PTH levels when they are placed on calcium and vitamin D supplementation.41 Troubleshooting

Surgeons using IOPTH monitoring need to be familiar with the pharmokinetics and factors that may affect PTH. This will minimize unnecessary conversions to a bilateral exploration and decrease operative time spent waiting for repeat IOPTH levels. A curative operation will depend on biochemical results and surgical judgment.

The degradation of PTH appears to begin within the parathyroid glands and then the fragments are cleared by the liver and kidneys.42 Therefore, impairment in hepatic or renal function may prolong the breakdown of PTH. When assessing the drop in IOPTH levels it also important to recognize the variability of the PTH half-life. A kinetic analysis found that the PTH halflife ranged from 0.4 to 3.8 minutes (mean, 1.68 +- 0.94 minutes) in 45 patients with HPT.43 To account for this variability and the effects of renal impairment on IOPTH levels, it is time saving to incorporate a 15minute IOPTH level when treating patients with even mild elevations in serum creatinine. Otherwise, the surgeon may receive a persistently elevated 10-minute PTH. He or she will then be faced with a decision to be satisfied with the result, proceed with reexploration, or sample another IOPTH level and wait.

Vitamin D deficiency can stimulate PTH secretion and there may be a component of secondary HPT is association with 1 HPT. There are no reports showing that vitamin D deficiency can significantly affect the interpretation of IOPTH levels. It has primarily been associated with persistent elevations in PTH after parathyroidectomy in patients with normal or low calcium levels.

Propofol is a commonly used induction agent for general surgery. Its short half-life also makes it optimal for sedation when performing a parathyroidectomy under local anesthesia. A prospective randomized study in normal patients showed that propofol significantly increases baseline PTH levels after a bolus or continuous infusion at a rate greater than 25 meg/kg per minute.44 The percentage of PTH increase was dose dependent. The highest dose given was 200 meg/ kg per minute and this resulted in a 40 per cent increase in PTH levels. It also took 60 minutes for the PTH levels to normalize after a bolus of propofol. It is not known whether propofol increases PTH levels by stimulating secretion, delaying degradation, or whether it is actually interferes with the PTH assay. A second prospective randomized study found that there were no significant differences in PTH levels after propofol infusion in patients with 2HPT.45 The PTH levels in patients with 2HPT will generally be significantly higher than in patients with IHPT. There may not have been any difference in PTH levels in 2HPT with propofol because these patients were already maximally secreting PTH and that the breakdown of PTH was already impaired secondary to their renal failure. The clinical impact of propofol on the interpretation in IOPTH levels in IHPT is not known. A baseline PTH obtained before propofol or at least 15 minutes after its infusion will minimize any effect of propofol on the baseline PTH level. A persistently elevated PTH should also prompt an investigation into the timing and dosage of propofol.


The IOPTH assay has allowed for a focused parathyroidectomy with success rates equivalent to a fourgland exploration. The primary challenge of the IOPTH assay has been in the care of patients with multiglandular disease. With solid surgical judgment and an understanding of the IOPTH assay and its limitations, patients with all forms of HPTcan benefit from the use of IOPTH monitoring.


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From the Mayo Clinic, Rochester, Minnesota

Address correspondence and reprint requests to Melanie L. Richards, M.D., MHPE, Mayo Clinic, Department of Surgery, 200 First Street SW, Rochester, MN 55905.

Copyright Southeastern Surgical Congress Apr 2007

(c) 2007 American Surgeon, The. Provided by ProQuest Information and Learning. All rights Reserved.

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