Optimizing intraoperative parathyroid hormone monitoring in primary hyperparathyroidism

The short- and long-term outcomes of minimally invasive parathyroidectomy guided by intraoperative parathyroid hormone (PTH) monitoring (IPM) have been extensively published and remain excellent regardless of the intraoperative protocol used. Unfortunately, the logistics of implementing IPM as a true point-of-care adjunct and the increased number of patients with mild hyperparathyroidism (normocalcemic and normohormonal hyperparathyroidism) have limited the usefulness of IPM in some centers. We all know that IPM is an accurate tool in guiding parathyroidectomy in sporadic primary hyperparathyroidism. What remains controversial is which intraoperative PTH protocol is the most accurate. In reality, any protocol is adequate if it guides the surgeon to about 98% operative success rate and allows minimally invasive parathyroidectomy in most patients. As most of us use different criteria and intraoperative protocols, I can only share my experience and describe what I have learned in the past 25 years of studying IPM in patients with sporadic primary hyperparathyroidism. Around 2007, just before I left the University of Miami for my current institution at the Medical University of South Carolina, Dr George Irvin and I looked at the short- and long-term outcomes of his patients who were operated on using the Miami criterion. This criterion requires a ≥50% PTH drop from the highest, either preincision or 0’, 10 minutes after removal of the suspicious gland to predict postoperative normocalcemia with a 97% accuracy. The reason for re-evaluating the operative outcomes of parathyroidectomy guided by the Miami criterion was to adjust the intraoperative PTH criteria to decrease operative failures by preventing false positive rates (approximately 1%) while keeping false negative results and unnecessary further explorations to a minimum. The reevaluation of these patients’ outcomes resulted in the Charleston criteria, which I have used since 2007. The same protocol for blood drawing is used with peripheral samples collected before neck incision (preincision), 0’ which is collected at the time the last vessel to the parathyroid gland is ligated, 5’ sample, which is collected to expedite the procedure in case the criteria is met at this time, and a 10’ sample. Part 1 of the criteria requires either a ≥65% PTH drop from the highest level, preincision or 0’, 10 minutes after excision of a suspicious gland, or ≥50% PTH drop and a return to normal range for the intraoperative PTH assay. Most patients will meet the intraoperative PTH criteria with this requirement. About 3% of the patients will need part 2 of the criteria, which requires a ≥50% PTH drop and a return to the normal range 20 minutes after excision of the suspicious gland. Over 15 years, 1,115 patients with classic sporadic hyperparathyroidism (hypercalcemia and elevated PTH levels) were operated on using this protocol with the Charleston criteria guidance. Nine hundred and eighty-eight (89%) patients were followed for >6 months with an average of 3.5 years (0.5–15 years). As a result of this protocol, operative success (eucalcemia for at least 6 months postoperatively) was achieved in 98% of the patients with an incidence of multiglandular disease of 16%, which is slightly higher than before likely because of these more stringent criteria. This adjustment of the intraoperative PTH criteria decreased the false positive results to 0.5% from 1% with the Miami criterion. Notably, false negative rates remained low at about 3%. The long-term outcome of this protocol is acceptable, with a 2% recurrence rate (hypercalcemia and elevated PTH following a period of eucalcemia of 6 months). It is important to mention that during these 15 years, 3 different rapid intraoperative PTH assays were used at the Medical University of South Carolina. Siemens Immulite turbo PTH assay was used in 49% of these procedures, and 41% of the cases were performed with The Future Diagnostics (FD) STAT-IntraOperative-Intact-PTH, and recently with Roche Cobas e411in 10% of the cases. The described protocol has performed similarly with all 3 assays with similar rates of false positive and false negative results; however, these assays are not equal. The different assays could affect operative outcome depending on the criteria used to guide parathyroidectomy. For example, when the data of 914 out of 1,115 successfully treated patients operated with this protocol followed over an average of 3.5 years (0.5–15 years) was evaluated, the final peripheral PTH level at 10 minutes was above the normal PTH range in 24% of the patients. When the Siemens assay was used, 10% of the patients had a PTH above the normal range in 10 minutes, while 37% of the patients operated on with FD assay and 16% with Roche had 10’ PTH above normal range at the end of the procedure. In addition, the normal range for each assay is not always clearly defined; therefore, it is important to determine the normal range in your own institution if the PTH normal range is part of the intraoperative PTH criteria. This information is important when the surgeon interprets the data from studies using different assays and protocols. Surgeons should be aware of these nuances when implementing these results in their practice, as the protocol with one assay might have different results with another assay. Furthermore, recently it has been described that final PTH below 40 pg/mL is the best predictor of long-term postoperative normocalcemia. In this group of successfully treated patients guided by this protocol, 52% of the cured patients had a peripheral PTH level >40 pg/mL at the final 10 minutes sample. The incidence of PTH above 40 pg/mL 10 minutes after gland excision with these assays was also different (Siemens 35%, FD 69%, and Roche 55%). On the other hand, it is important to mention that although all operative failures and 50% of the recurrences would have been predicted by a PTH level >40 pg/mL in 10’ after gland excision, about half of cured patients would have been further explored unnecessarily. One could choose to be very aggressive to decrease the operative failures to a minimum and maybe prevent some recurrences; however, one also would need to decide if unnecessary bilateral exploration in about half of the patients is worthwhile. It is important to remember that reoperating on a patient following minimally invasive parathyroidectomy is usually quite simple and feasible with low morbidity. Therefore, it is the surgeon’s choice to be more or less aggressive to achieve the desired outcome. Personally, there are significant benefits to being conservative and choosing a less stringent criteria (less postoperative hypocalcemia, less scar tissue in case a reoperation for thyroid and parathyroid disease is needed, shorter operations, and potentially fewer complications) in exchange for operating on a handful of patients that might have failed or recurred. This decision can also be tailored to the patient's input during surgical evaluation. Some have wisely recommended to follow these patients with final PTH >40 pg/mL closely as they have a higher chance of short- and long-term postoperative hypercalcemia. ^{,  ,}