Does the Final Intraoperative PTH Level Really Have to Fall into the Normal Range to Signify Cure?
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- Reiher, A.E., Schaefer, S., Chen, H. et al. Ann Surg Oncol (2012) 19: 1862. doi:10.1245/s10434-011-2192-3
Intraoperative parathyroid hormone (IOPTH) helps shorten the duration of surgery and increase the likelihood of surgical cure. Although general consensus agrees that the IOPTH should fall by 50%, there is much debate as to whether the IOPTH needs to fall into the normal range.
We retrospectively reviewed a prospective database of patients undergoing surgery for treatment of primary hyperparathyroidism. We included all patients with an IOPTH that fell by >50% by 10 or 15 min, but that did not fall into the normal range (parathyroid hormone remained ≥60 pg/ml). We excluded patients who had undergone prior neck surgery or had known multiple endocrine neoplasia 1 or 2.
A total of 1,231 patients underwent a parathyroidectomy, 155 of whom met the study’s inclusion/exclusion criteria (12.6%). A total of 117 patients had an IOPTH fall by 50% by 10 min, and 38 patients’ IOPTH fell by 50% by 15 min. Overall surgical cure rate was 98.7%. One patient from the 10-minute group and one patient from the 15-minute group had persistent disease on follow-up. One patient in the 15-minute group had recurrent disease. With a mean ± SEM 18.1 ± 2.1 months’ follow-up, the recurrence rate in this cohort was 0.6%. The average calcium at last follow-up was 9.4 ± 0.0 mg/dl.
Allowing the IOPTH to fall by 50% by 15 min, regardless of whether the IOPTH falls into the normal range, results in a high success rate when performed by experienced surgeons. This helps reduce intraoperative time used waiting for additional parathyroid hormone levels and the risks associated with unnecessary bilateral neck exploration.
Primary hyperparathyroidism can be definitively cured with surgery. Seventy percent to 95% of cases are due to a single adenoma, close to 4% are due to double adenomas, close to 15% are due to parathyroid hyperplasia, and very few cases are due to parathyroid carcinoma.1 The advent of intraoperative intact parathyroid hormone (IOPTH) monitoring, along with preoperative localization studies, has allowed surgeons to perform minimally invasive parathyroidectomies rather than the traditional bilateral neck exploration for the majority of patients who ultimately have single-gland disease. This has led to decreased hospital length of stay, increased surgical cure rate, and decreased rate of complications.2–6 IOPTH monitoring has also led to better detection of multiglandular disease, thus decreasing the need for multiple surgeries to achieve surgical cure.7
Multiple criteria for IOPTH monitoring are available. The Miami criteria recommends >50% decrease in IOPTH from the highest baseline IOPTH level at 10 min after excision.6,8 Other criteria recommend allowing the IOPTH to decrease by 50% and into the normal range.9–11 Also debated is whether to use the pre-excision parathyroid hormone (PTH) or initial IOPTH as the baseline to look for a 50% decrease for cure. A previous study at our institution revealed that if the 5 min postexcision IOPTH rises above the baseline but a subsequent decline is observed over the next 5–15 min, patients still have a high likelihood of surgical cure (100% cure rate in this series).12
In this study, we investigated the rate of surgical cure when the IOPTH fell by 50% at either 10 or 15 min after excision, but remained ≥60 pg/ml.
This study was a retrospective review of a prospectively maintained database collected between March 2001 and April 2010. During this time, 1,231 patients underwent surgical resection with IOPTH monitoring for primary hyperparathyroidism at the University of Wisconsin. Baseline PTH levels were drawn before skin incision and then at least 5, 10 and 15 min after excision of a suspicious parathyroid adenoma or after resection of multigland disease. Bilateral exploration was done if preoperative imaging suggested multiple abnormal glands, if the initially discovered parathyroid was only slightly enlarged (suggesting hyperplasia), or if the IOPTH did not decrease by 50%.
Our protocol for IOPTH testing has been previously described.13 Briefly, blood was collected before incision as well as 5, 10, and 15 min after resection of the parathyroid gland. If the 5 min post resection value was elevated above the preincision value, additional IOPTH samples were drawn at successive 5 min intervals, and our baseline was defined as the highest value either before incision or after excision. This is based on a previous study at our institution, which demonstrated that using the highest baseline PTH, either before excision of the adenoma or 5 min after excision, to determine a 50% decrease in IOPTH can ensure surgical cure.12 Curative parathyroidectomy was defined as normocalcemia (serum calcium ≤10.2 mg/dl) 6 months after the operation, while persistent disease was defined as patients with hypercalcemia (serum calcium >10.2 mg/dl) within 6 months of follow-up. Recurrent disease was defined as hypercalcemia (serum calcium >10.2 mg/dl) more than 6 months after surgery.
We included all patients whose IOPTH fell by >50% by 10 or 15 min, but did not fall into the normal range (IOPTH remained ≥60 pg/ml). At our institution, the Elecsys 2010 (Roche) assay is used for IOPTH, and the reference range is 14–72 pg/ml. Although our lab assay reference range for PTH is 14–72 pg/ml, we used a cutoff of 60 pg/ml to account for variations in reference ranges for different laboratory assays used during this time period at different institutions. We excluded patients who had undergone prior neck surgery or had known multiple endocrine neoplasia 1 or 2. Results are expressed as the mean ± SEM.
Statistical analysis was performed by Microsoft Excel (2003 for Microsoft Windows; Microsoft, Redmond WA). Throughout the statistical analysis, the significance level was set as P ≤ 0.05.
Comparison of patients with a final IOPTH <60 or ≥60 pg/mla
≥50% decrease by 15 min, final IOPTH <60 pg/ml (n = 784)
≥50% decrease by 15 min, final IOPTH ≥60 pg/ml (n = 155)
Average age at time of surgery (y)
59.7 ± 0.5
63.7 ± 1.2
Sex, male:female (% female)
Average serum calcium (mg/dl) preoperatively
11.1 ± 0.0
11.5 ± 0.1
Average serum PTH (pg/ml) preoperatively
112 ± 2
203 ± 12
Average IOPTH (pg/ml) at 50% decrease
31.2 ± 0.4
110.0 ± 7.1
Characteristics of patients with a final IOPTH ≥60 pg/ml after falling by ≥50% at 10 or 15 mina
50% decrease in IOPTH by 10 min (n = 117)
50% decrease in IOPTH by 15 min (n = 38)
Average age (y)
63.5 ± 1.4
64.2 ± 1.8
Sex, male:female (% female)
Preoperative average serum calcium (mg/dl)
11.6 ± 0.1
11.2 ± 0.1
Preoperative average serum PTH (pg/ml)
220 ± 15
155 ± 13
Average IOPTH at 50% decrease
101 ± 5
138 ± 25
Average IOPTH decrease
Postoperative average serum calcium (mg/dl) at last follow-up
9.4 ± 0.0
9.4 ± 0.1
Overall surgical cure rate for patients who had a final IOPTH decrease of ≥50% but whose final IOPTH remained ≥60 pg/ml was 98.7%. Two patients had persistent disease, one patient from the 10-minute group and one patient from the 15-minute group. The patient in the 10-minute group was a 79 year old woman who was found to have persistent disease 4 months after resection of a parathyroid adenoma. She ultimately was found to have a second adenoma during follow-up surgery, which was successfully resected. Last follow-up serum calcium, 25 months from the time of her second surgery, was normal. The patient in the 15-minute group with persistent disease was a 70 year old man who had a parathyroid adenoma resected, but postoperatively had persistently elevated calcium levels. A follow-up neck exploration performed 10 months after his initial surgery revealed a second adenoma, which was successfully resected. Last serum calcium, 15 months from the time of his second surgery, was normal.
With a mean of 18.1 ± 2.1 months’ and a median of 9 months’ follow-up, the recurrence rate was 0.6%. Although the recurrence rate is low, only 35% of patients had >12 months of follow-up, so we cannot comment on long-term recurrence rates in this cohort. Average calcium at last follow-up for patients whose final IOPTH decreased by 50% but was ≥60 pg/ml was 9.36 ± 0.04 mg/dl. One patient, from the 15-minute group, had recurrent disease. The patient was a 71 year old woman found to have a parathyroid adenoma during her initial surgery. Follow-up calcium 9 months after surgery was elevated, and imaging revealed a second adenoma, which was resected 11 months after her initial surgery. Because cure was defined by normocalcemia in this study, postoperative PTH levels were not available on all patients. Of those with available data, the average PTH at last follow-up was: PTH 60 ± 7 for patients whose final IOPTH fell by 50% but remained ≥60 pg/ml at 15 min, and PTH 65 ± 5 for patients whose final IOPTH fell by 50% but remained ≥60 pg/ml at 10 min. For patients with available follow-up PTH levels, 55% had follow-up PTH levels ≥60 pg/ml.
By using our criteria for surgical cure, a 50% decrease in the IOPTH at 10 or 15 min, regardless of whether or not the IOPTH fell into the normal range, helped to prevent unnecessary bilateral exploration. In our cohort of 1,231 patients, 10.6% of patients were spared additional, unnecessary neck exploration with a 10 min cutoff. By extending that up to 15 min we increased the percentage of patients spared additional surgical exploration to 14%. This means that 52 unnecessary bilateral neck explorations would need to be performed to prevent one operative failure.
Minimally invasive parathyroidectomy utilizing IOPTH monitoring has led to a decreased need for bilateral neck exploration. The short half-life of PTH (1–3 min) makes it ideal for intraoperative use in determining surgical cure.14 Multiple studies have demonstrated shorter hospital stays, lower hospital costs, and equal surgical cure rates using minimally invasive parathyroidectomy compared to traditional bilateral neck exploration. The use of IOPTH has eliminated the need for intraoperative frozen sections.1,3,13,15 Minimally invasive parathyroidectomy resulted in a 50% decrease in overall cost when compared to bilateral neck exploration.2
In our retrospective review using a prospective database, we found a high surgical cure rate for primary hyperparathyroidism when IOPTH decreased by 50% but did not fall into the normal range at 10 or 15 min. Baseline IOPTH used was initial IOPTH or 5 min after excision, whichever IOPTH was higher. We chose this because our previous data had shown that this is equally effective.12 Although the original Miami criterion recommend a 50% decrease at 10 min, we also included patients who decreased by 15 min in a separate analysis. We have found that after the IOPTH postexcision to 15 min can decrease the need for further neck exploration and ensure success when the IOPTH falls by >50%.13 Westerdahl et al.16 use a criteria of IOPTH falling by 60% after gland excision, whether or not the final IOPTH fell into the normal range, and also follow IOPTH for up to 15 min. By means of these criteria, they had 100% operative success. After 5 years, 95% of their patients remained normocalcemic.
Although our lab assay reference range for PTH is 14–72 pg/ml, we used a cutoff of 60 pg/ml to account for variations in reference ranges for different laboratory assays used at different institutions. The upper level of the PTH reference in the literature ranges from 56–72 pg/ml.17 Criteria that used a 50% decrease in IOPTH and into the normal range are based on the concern that multiglandular disease will be missed if the final IOPTH does not fall into the normal range. One study reported 29% of patients with a 50% decrease in IOPTH but not into the normal range were ultimately found to have additional pathology (8 double adenomas and one patient with parathyroid hyperplasia).1,9 However, other studies have demonstrated excellent cure rates despite final IOPTH levels not falling into the normal range. Of note, the majority of these studies have retrospectively applied different criteria to analyze outcomes, and therefore the outcomes are theoretical. Carneiro et al.5 applied the Miami criterion to patients who had undergone minimally invasive parathyroidectomy for nonfamilial primary hyperparathyroidism, and compared predictive outcomes by means of different criteria. By using the Miami criterion, their surgical success rate was 97%. When applying criteria using 50% decrease and into the normal range by 10 min, the false-negative rate was 24%, and the criteria would have incorrectly predicted insufficient resection in an additional 56 patients. A retrospective review by Chiu et al.11 applied 5 different criterion to 352 patients who had undergone parathyroidectomy for primary hyperparathyroidism. The criteria of >50% decrease from highest baseline IOPTH level at 10 min and final IOPTH level within the reference range resulted in a high operative success, but also additional unnecessary surgical exploration. By means of a criteria of >50% decrease from preincision IOPTH level at 10 min resulted in improved postoperative normocalcemia compared to the criteria requiring final IOPTH to fall into the normal range. A 2008 study by Carneiro-Pla et al.18 demonstrated excellent cure rates using criteria similar to that used at our institution, an IOPTH decrease of >50% from the highest preincision or pre-excision level at 10 min. Previous studies from our institution have demonstrated our criteria predicted success in 97.5% of patients with multiglandular disease (157 of 161).19 Our study is novel in that our data were collected prospectively, and our results are based on the criteria we have described. Our surgeons follow these guidelines (final IOPTH decrease by 50%, by 15 min, and does not have to fall into the normal range), and have had excellent outcomes.
There are many small differences in how surgeons apply IOPTH criteria, and most studies have demonstrated excellent cure rates regardless of the criteria used. In this study we did not want to validate our overall IOPTH approach, but instead wanted to answer the specific question of whether or not the IOPTH must fall into the normal range to ensure cure. Surgeons who use this added criteria will argue that the failure rate in this cohort is too high, based on the fact that when they continue further exploration they often identify additional enlarged glands. However, it is difficult to know whether or not their additional exploration/resection was truly necessary. If the additional exploration had not been performed, would that patient have been cured anyway? Because we prospectively have relied only on a 50% decrease in IOPTH, this has allowed us to identify a cohort of patients who fall into this intermediate group, who met a 50% decrease criteria, but did not fall into the normal range. This is the group that would be managed differently between centers, with some centers continuing exploration and others ending the surgery. Because this cohort represents only 14% of our patients, if the outcomes are different in this smaller cohort it could easily be diluted when examining the outcomes of the entire series of >1,000 patients. By focusing our analysis on this subset of patients we have increased our sensitivity to detect a difference in outcomes within this subgroup. We have shown, in the largest published series, that the cure rate in this “intermediate” group of patients is equal to that of all patients undergoing surgical treatment for cure of parathyroid disease.
By using our criteria, our surgical success rate among patients with primary hyperparathyroidism whose IOPTH decreased by 50% but not into the normal range was 98.7%. Success rates after parathyroidectomy for primary hyperparathyroidism when performed by an experienced surgeon usually exceeds 95%.20 Thus, by using our criteria, the standard expectations for surgical cure of primary hyperparathyroidism using minimally invasive parathyroidectomy were achieved, and an additional 14% of patients were spared additional neck exploration by waiting up to 15 min after excision to achieve a 50% decrease in IOPTH, and by allowing the final IOPTH to remain ≥60 pg/ml.
In conclusion, allowing the IOPTH to fall by 50% by 15 min, regardless of whether the PTH falls into the normal range, results in a high success rate when performed by experienced surgeons. Following this guideline resulted in a 98.7% cure rate at our institution in this series. Our results provide further evidence that surgical cure can be achieved in patients with primary hyperparathyroidism without reaching normal intraoperative PTH levels. This helps reduce intraoperative time by eliminating the time needed for additional IOPTH levels and the risks associated with unnecessary bilateral neck exploration. In the hands of experienced surgeons, our criteria meet or exceed the expected cure rates. By using our criteria, 14% of patients undergoing parathyroidectomy for primary hyperparathyroidism at our institution were spared an unnecessary bilateral neck exploration.