- Email: [email protected]
Intraoperative rapid parathyroid hormone monitoring in parathyroid surgery
Otolaryngol Clin N Am 37 (2004) 779–787
Intraoperative rapid parathyroid hormone monitoring in parathyroid surgery Maisie Shindo, MD, FACS Department of Surgery, Division of Otolaryngology, State University of New York at Stony Brook, Stony Brook, HSC, T-19090, NY 11794, USA
The traditional approach for years in parathyroid surgery has been to perform bilateral exploration and examine all four parathyroid glands. With the ability to localize an adenoma preoperatively with imaging modalities (eg, sestamibi scan, ultrasound), unilateral exploration became popular and acceptable, with low rates of complication and recurrence. With unilateral exploration, identification of a normal gland on the same side is required to make sure that the patient does not have four-gland hyperplasia. Nevertheless, a second adenoma (double adenoma) on the contralateral side can be missed with this approach. With bilateral exploration, multiglandular disease is not likely to be missed, but bilateral exploration increases the risk for hypocalcemia and recurrent laryngeal nerve injury. Multiglandular disease is a facet of parathyroid surgery that continues to plague parathyroid surgeons. In recent years, however, modern adjunctive technology, including the ability to measure the parathyroid hormone rapidly and intraoperatively, has decreased the risk of missing multiglandular disease. The intact parathyroid hormone (iPTH) has a very short half-life of approximately 3 minutes. Therefore, measurement of iPTH level in the patient after removal of an identified adenoma would theoretically predict the success of surgery. In 1991 Irvin and colleagues [1] first introduced the intraoperative measurement of PTH level to predict postoperative calcium level. Since then many authors have demonstrated its accuracy and utility [3–19], and it has become an important tool in parathyroid surgery.
Intraoperative rapid parathyroid hormone assay systems The parathyroid hormone is an 84–amino acid peptide, which is metabolized rapidly to yield the biologically active N-terminal (amino acids E-mail address: [email protected] 0030-6665/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.otc.2004.02.009
780
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
1–34), the inactive mid-chain (amino acids 44–49), and the C-terminal (amino acids 34–84) molecules. PTH levels were first measured using radioimmunoassays to the C-terminal, the mid-molecule, or the N-terminal. Measurement of the C-terminal or the mid-molecule may not accurately reflect true hyperparathyroidism, because they are inactive. The N-terminal assay is very specific for hyperparathyroidism but is very insensitive because of its short half-life. A two-site immunoradiometric assay that detects both the N-terminal and a second site, known as the iPTH assay, is both very sensitive and specific for the diagnosis of hyperparathyroidism. This radioisotopic technique takes hours to perform. Therefore, to obtain the iPTH level rapidly for practical intraoperative use, this two-site antibody assay was modified by using chemiluminometric detection using acridinium ester instead of isotopes as an antibody label [2]. A second modification that decreased the centrifugation and incubation time shortened the turnaround time to approximately 15 minutes [3]. The values of iPTH obtained by this modified immunochemiluminometric assay correlate well with those obtained from the standard immunoradiometric assay. Currently, two systems are commonly used for intraoperative quick PTH (qPTH) measurement, the Nichols system (Nichols Institute Diagnostics, San Juan Capistrano, CA) and the Immulite system (Diagnostic Products Corporation, Los Angeles, CA). The Nichols system is generally a portable chemiluminometer workstation that can be placed in or just outside the operating room. Trained personnel normally process the blood and run the test; results are available in approximately 15 minutes. A hospital immunology laboratory generally uses the Immulite system for various radioimmunoassays, including routine iPTH assays. The system can also be adapted (Immulite Turbo) to run the intact PTH level rapidly. The specimen is transported from the operating room to the laboratory where it is centrifuged and processed. The entire process takes approximately 25 to 30 minutes, including transport time. One significant advantage of the Immulite system is the cost to the institution. If the hospital already has the Immulite system for processing various tests, the expense to the institution is the cost of the assay kits. The author’s hospital charges $150 for each assay ordered. On the other hand, with the Nichols system, the institution must purchase both the assay kits and the analyzer, the cost of which is rather substantial. Therefore, institutional charges for each assay using the Nichols system range from $500 to $650; most likely, the cost of the analyzer is amortized into the charges.
Interpretation and validity of quick parathyroid hormone assay Because of its very short half-life, the iPTH level should fall rapidly following successful removal of a single functioning parathyroid adenoma. Various criteria have been published for qPTH levels that predict successful
781
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
parathyroidectomy, as shown in Table 1 [4–13]. As the table indicates, there seem to be differences in the times when the baseline levels are drawn. Most parathyroid surgeons draw the level after anesthetic induction and before skin incision, but others compare the postexcision level to the level just before excising the adenoma. The most commonly used criterion for predicting success is that first described by Irvin and Deriso [1], that is, that the qPTH level falls below 50% of the highest pre-excision level within 5 minutes of excising the adenoma. Some use the qPTH level at 10 minutes after excision rather than the level 5 minutes after excision. Others also use much more stringent criteria that require the qPTH level to fall to at least 50% of baseline and be below the upper limit of normal.
Results of parathyroidectomy using quick parathyroid hormone assay In 1994, Irwin and colleagues [3,4] published their early experience with a small number of patients demonstrating the feasibility of using qPTH. They used a focused approach to excise an adenoma based on preoperative localization studies and using the intraoperative qPTH to determine if the procedure was successful or needed to be converted to bilateral exploration. They showed that the sensitivity of qPTH was 94% and that the operative times were significantly shorter. Subsequent to Irvin and colleagues’ reports, several authors evaluated the validity of qPTH by measuring iPTH levels before and after excision of abnormal glands during conventional bilateral exploration (Table 2) [9–12]. These studies evaluated the following parameters: (1) accuracy in predicting uniglandular versus multiglandular
Table 1 Interpretation of qPTH values
Baseline Level One level drawn after anesthetia induction and another before excision of gland–use the higher the two values Before excision of gland At induction Before induction Before incision One level drawn after anesthesia induction and another before excision of gland–use the higher the two values After separation of straps
Criteria for Successful Parathyroidectomy (postexcision level compared to baseline)
Reference #
50% of baseline at 5 minutes
4
50% of baseline at 5 minutes 50% of baseline at 7 minutes 50% of baseline at 10 minutes 50% at 10 minutes Two criteria evaluated 50% of baseline at 10 minutes 50% of baseline at 10 minutes and below upper limit of normal 50% of baseline at 15 minutes and below upper limit of normal
6 8 11 9,10,12 12
7
782
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
disease, (2) false-positive results, defined as the qPTH falling below 50% of baseline when one or more enlarged glands still remain, (3) false-negative results, defined as qPTH failing to fall below 50% when no additional enlarged glands remain. The accuracy rates in these studies ranged from 84% to 89%, with long-term chemical cure rates of 98% to 100%. The overall false-positive rates were 2% to 13%. Twelve percent to 60% of patients with multiglandular disease exhibit at least a 50% drop in the qPTH following excision of only one enlarged gland (false-positive result). The overall false negative rates were 3% to 8%. Subsequent to these initial validation studies, parathyroid surgeons began to use a focused, minimally invasive approach. With this focused approach, a small incision is made in the area of a suspected adenoma based on the results of preoperative localization studies (sestamibi parathyroid scan or ultrasound). Identification and removal of an adenoma is accomplished through standard open dissection or endoscopically. Some also use a radioguided gamma probe to aid in the initial search and to confirm an adenoma. After excision of the adenoma, intraoperative qPTH is used to determine if the patient is biochemically cured or needs further exploration for multiglandular disease. A number of series have reported cure rates of at least 98% using this approach [5–8,13–19]. The author’s approach to minimally invasive parathyroidectomy is to make a small incision over the location of the abnormal gland (determined by sestamibi scan with single photon emission CT) and using the qPTH levels to confirm success of the surgery. A frozen section is generally used only when the parathyroid gland does not have the typical appearance of an adenoma or when hyperplastic glands are excised and reimplanted. The baseline qPTH level is drawn just before or immediately after anesthetic induction. At 5 minutes and 10 minutes after excision of the adenoma, qPTH levels are drawn. The 5-minute level is sent to the laboratory, and the incision is closed. If the 5-minute qPTH level is 50% of the baseline level or
Table 2 Intraoperative PTH measurement during conventional bilateral parathyroid exploration
# of Patients Accuracy rate SA MGD Success rate False positive SA MGD False negative
Reference # 9
Reference # 10
Reference # 11
Reference # 12
72 89% 93% 76% 100% 6% 0 24% 7%
136 96%
112 84% 98.5% 58% 98% 13% 6% 37% 3%
115 80% 87% 58%
40% 98% 2% 0 60% 2%
3% 0 12% 17%
Abbreviations: MGD, multiglandular disease (includes double adenomas and hyperplasia); SA, single adenoma.
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
783
lower, and 65 pg/mL (the upper limit of normal) or lower, the procedure is terminated. If the 5-minute level is higher than 50% of baseline or higher than 65 pg/mL, the previously drawn 10-minute postexcision level is sent. If that level is still higher than 50% of baseline or higher than 65 pg/mL, the incision is reopened, and bilateral exploration is performed. In the author’s experience using this focused approach with preoperative sestamibi scan and intraoperative PTH monitoring, 98% of the patients have had successful biochemical cure with postoperative calcium or PTH levels returning to normal levels. Several studies have compared the outcome of parathyroid surgery using a focused approach with intraoperative qPTH to that of conventional bilateral exploration. The results of these studies indicate that the success rates of the focused approach operation are similar to or better than those of bilateral exploration, and complication rates tend to be lower. Carneiro and Irvin [16] reported that in patients undergoing parathyroidectomy, the longterm postoperative calcium and iPTH levels were normal in 98% (n = 144) of those who had a focused approach versus 85% (n = 176) of those who underwent conventional bilateral exploration. Burkey et al [17] compared the outcome of parathyroidectomy using three different approaches: gamma probe (n = 50), intraoperative qPTH (n = 50), and bilateral exploration (n = 50). The cure rates were 98%, 100%, and 96%, respectively; the complication rate was higher in the bilateral exploration group than in the other two. Similarly, Boggs and colleagues [15] reported a failure rate of 1.5% when sestamibi and qPTH were used versus 5% when bilateral exploration was performed without qPTH. In a study to evaluate whether qPTH improves the results of parathyroidectomy, Miura et al [12] showed that by adding qPTH to the operation, the accuracy of sestamibi scan improved from 83% to 92% and the accuracy of ultrasound improved from 71% to 86%.
Cost analyses Many authors have shown that the use of qPTH with sestamibi scan for parathyroid surgery reduces the length of stay [5,6,22]. Many centers now perform parathyroidectomy as an ambulatory surgical procedure. Some studies have shown that the perioperative cost for parathyroidectomy using a focused approach with sestamibi scan and qPTH is considerably (40%– 50%) less than bilateral exploration [5,6,22]. In these studies, the patients were discharged the same day. Others [7,17], however, have reported no appreciable reduction in cost because they did not perform these procedures in the ambulatory setting. If one compares sestamibi scan with qPTH to sestamibi alone for focused parathyroidectomy, the average cost for the former is higher by approximately $500 [22]. The improvement in cure rates seems to justify this added cost, however.
784
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
Limitations and pitfalls of quick parathyroid hormone Although qPTH significantly reduces the complications and length of hospital stay, it can potentially miss multiple-gland pathology, which may result in need for re-operation. In earlier reports where the criterion of reduction by more than 50% from baseline value at 5 minutes was used, multiple adenomas were missed. Hallfeldt et al [18] reported that in 2 of 36 patients, in whom they used these criteria but in whom the absolute qPTH value remained above normal range, the iPTH levels began to elevate again postoperatively [18]. One of these patients was re-explored and found to have hyperplasia. Gauger et al [20] reported on the changes in PTH values in 20 patients who were found to have double adenomas during bilateral exploration [20]. In 11 of the 20 patients, the qPTH levels were 50% of baseline or lower following excision of the first adenoma. In these 11 patients, a second adenoma was found during the planned bilateral exploration. Thus, the false-positive rate of qPTH was 55% in this group of patients. In the remaining 9 patients the qPTH values remained higher than 50% of baseline after excision of the first adenoma, giving a truenegative rate of 45%. Similarly, Jaskowiak et al [13] reported 50% falsepositive and 50% true-negative rates for qPTH when double adenomas are present. To explain this false-positive phenomenon with double adenomas, some hypothesize that the second adenoma, which is usually the smaller, may be suppressed or may not be hypersecretory. Therefore, if the second gland is not biochemically significant, the qPTH value will actually drop below 50% of baseline after excision of the active adenoma [20]. Even with four-gland hyperplasia, qPTH may exhibit kinetics similar to that of single adenomas. For example, one study reported that in 2 of 16 patients (12.5% false-positive rate) with hyperplasia from multiple endocrine neoplasia type 1 syndrome, the kinetics of qPTH was similar to that seen with a single adenoma (ie, 50% of baseline after excision of the first enlarged gland) [21]. The false-positive rates seem to be lower for hyperplasia than for double adenomas. Gordon and colleagues [9] reported that in their patients with multiglandular disease, qPTH had a false-positive rate of 24%. Furthermore, all of their false positives were double adenomas, and the first removed adenoma was generally larger than the second. In a retrospective analysis of sequential changes in qPTH during conventional bilateral exploration, Weber and Richie [11] reported a false-positive rate of 37% when multiglandular disease was present; within this group the false-positive rate was 67% for double adenomas and 31% for hyperplasia. In a small percentage of patients, the postexcision intraoperative qPTH may remain above 50% of baseline, but the subsequent postoperative calcium and iPTH levels return to normal (ie, false-negative qPTH). The significance of a false-negative value is that it results in unnecessary further exploration. One possible mechanism for such false-negative values is that circulating PTH can rise suddenly during manipulation of the adenoma;
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
785
therefore, if the postexcision value is compared with a baseline drawn before manipulation, it may not be significantly lower than baseline and sometimes can actually be higher than the baseline. Therefore, some surgeons draw two baseline levels, one either before or after incision and one just before excision of the adenoma, and use the higher of the two for the true baseline level [4,12]. Another option is to repeat the qPTH at either 10 minutes or 15 minutes after excision, at which time the values may be close to 50% of baseline. Alternatively, the surgeon can choose to perform bilateral exploration, which may or may not be necessary. There have been cases of false-negative qPTH. In one patient, the 5-minute qPTH level was 90% of the baseline, which was drawn at the time of anesthetic induction. It was repeated at 10 minutes and was 51% of baseline; it subsequently was below 40% of baseline and was within normal range at 20 minutes. The patient did undergo bilateral exploration, and two additional normal glands were identified (the fourth was not identified). The patient’s postoperative iPTH levels at 2 weeks and 2 months have remained normal. The serum calcium levels have remained around 10.6; this elevation is probably secondary to thiazide diuretic. In the second patient, the 5-minute postexcision level after excision of a slightly enlarged gland was 87% of baseline. The patient then underwent bilateral exploration, and the remaining glands were only minimally enlarged. He underwent excision of an additional two and one half glands. Following the three and one half gland excision, the qPTH was 49 pg/mL, 31% of baseline. Postoperatively, however, the iPTH levels began to rise above the preoperative levels. The patient is suspected of having a rare condition known as PTH-resistance syndrome, and is currently undergoing a work-up for this condition. Studies have shown that postoperative parathyroid levels can fluctuate considerably after successful parathyroidectomy. Carneiro and Irvin [16] reported that in 144 patients who underwent focused parathyroidectomy, postoperative iPTH levels varied considerably in 8% of the patients but returned to normal range at the most recent follow-up visit (average length of follow-up, 2.3 years). In the report by Chen et al [6], the mean postoperative iPTH level was 58 11 pg/mL with normal calcium levels. Inabet and colleagues [19] also reported that the 6-month postoperative iPTH level was 78.2 60 pg/mL with normal calcium levels in their patients who successfully underwent targeted parathyroidectomy.
Summary Intraoperative qPTH assay has become an important adjunct in modern parathyroid surgery. The use of preoperative sestamibi scan in combination with intraoperative qPTH in minimally invasive focused parathyroidectomy yields a success rate of at least 98%. This approach can decrease the length of hospital stay, and in many instances the procedure can be performed as
786
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
outpatient surgery. Adding qPTH to sestamibi scan improves the success of parathyroidectomy. The small additional cost of qPTH seems to justify adding this assay to the armamentarium to obviate the need for reoperation, which significantly increases cost and risks of complications.
References [1] Irvin GL, Dembrow VD, Prudhomme DL. Operative monitoring of parathyroid gland function. Am J Surg 1991;162:299–302. [2] Brown RC, Aston JP, Weeks I, Woodhead JS. Circulating intact parathyroid hormone measured by a two-site immunochemiluminometric assay. J Clin Endocrinol Metab 1987; 65:407–14. [3] Irvin GL, Deriso GT. A new practical intraoperative parathyroid hormone assay. Am J Surg 1994;168:466–8. [4] Irvin GL, Prudhomme DL, Deriso GT, Stakianakis G, Chandarlapathy SK. A new approach to parathyroidectomy. Ann Surg 1994;219:574–81. [5] Irvin GL, Sfakianakis G, Yeung L, et al. Ambulatory parathyroidectomy for hyperparathyroidism. Arch Surg 1996;131:1074–7. [6] Chen H, Sokoll LJ, Udelsman R. Outpatient minimally invasive parathyroidectomy: a combination of sestamibi SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126:1016–22. [7] Carty SE, Worsey J, Virji M, Brown M, Watson C. Concise parathyroidectomy: the impact of preoperative SPECT 99mTc sestamibi scanning and intraoperative quick parathormone assay. Surgery 1997;122:1107–16. [8] Patel PC, Pellitteri P, Patel N, Fleetwood M. Use of a rapid intraoperative parathyroid hormone assay in the surgical management of parathyroid disease. Arch Otolaryngol Head Neck Surg 1998;124:559–62. [9] Gordon LL, Snyder WH, Wians F Jr, Nwariaku F, Kim L. The validity of quick intraoperative parathyroid hormone assay: an evaluation in 72 patients based on gross morphologic criteria. Surgery 1999;126:1030–5. [10] Garner SC, Leight GS Jr. Initial experience with intraoperative PTH determinations in the surgical management of 130 consecutive cases of primary hyperparathyroidism. Surgery 1999;126:1032–8. [11] Weber CJ, Ritchie JC. Retrospective analysis of sequential changes in serum intact parathyroid hormone levels during conventional parathyroid exploration. Surgery 1999; 126:1139–43. [12] Miura D, Wada N, Arici C. Morita, Duh QY, Clark OH. Does intraoperative quick parathyroid hormone assay improve the results of parathyroidectomy? World J Surg 2002; 26:926–30. [13] Jaskowiak NT, Sugg SL, Helke J, Koka MR, Kaplan EL. Pitfalls of intraoperative quick parathyroid hormone. Arch Surg 2002;137:659–69. [14] Aggarwal G, Barakate MS, Robinson B, et al. Intraoperative quick parathyroid hormone versus same-day parathyroid hormone testing for minimally invasive parathyroidectomy: a cost effectiveness study. Surgery 2001;130:963–70. [15] Boggs JE, Irvin GL, Carneiro DM, Molinari AS. The evolution of parathyroidectomy failures. Surgery 1999;126:998–1002. [16] Carneiro DM, Irvin GL. Late parathyroid function after successful parathyroidectomy guided by intraoperative hormone assay (QPTH) compared with the standard bilateral neck exploration. Surgery 2000;128:925–9. [17] Burkey SH, Heerden JA, Farley DR, Thompson GB, Grant CS, Curlee KJ. Will directed parathyroidectomy utilizing the gamma probe or intraoperative parathyroid hormone
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
[18]
[19] [20]
[21]
[22]
787
assay replace bilateral cervical exploration as the preferred operation for primary hyperparathyroidism? World J Surg 2002;26:914–20. Hallfeldt KKJ, Trupka A, Gallwas J, Schmidbauer S. Minimally invasive video-assisted parathyroidectomy and intraoperative parathyroid hormone monitoring. Surg Endosc 2002;16:1759–63. Inebet WB, Dakin GF, Haber RS, et al. Targeted parathyroidectomy in the era of intraoperative parathormone monitoring. World J Surg 2002;26:921–5. Gauger PG, Agarwal G, England BG, et al. Intraoperative parathyroid hormone monitoring fails to detect double parathyroid adenomas: a 2-institution experience. Surgery 2001;130:1005–10. Tonelli F, Spini S, Tommasi M, et al. Intraoperative parathormone measurement in patients with multiple endocrine neoplasia type I syndrome and hyperparathyroidism. World J Surg 2000;24:556–62. Fahy BN, Bold RJ, Beckett L, Schneider PD. Modern parathyroid surgery: a cost-benefit analysis of localizing strategies. Arch Surg 2002;137:917–23.
Intraoperative rapid parathyroid hormone monitoring in parathyroid surgery Maisie Shindo, MD, FACS Department of Surgery, Division of Otolaryngology, State University of New York at Stony Brook, Stony Brook, HSC, T-19090, NY 11794, USA
The traditional approach for years in parathyroid surgery has been to perform bilateral exploration and examine all four parathyroid glands. With the ability to localize an adenoma preoperatively with imaging modalities (eg, sestamibi scan, ultrasound), unilateral exploration became popular and acceptable, with low rates of complication and recurrence. With unilateral exploration, identification of a normal gland on the same side is required to make sure that the patient does not have four-gland hyperplasia. Nevertheless, a second adenoma (double adenoma) on the contralateral side can be missed with this approach. With bilateral exploration, multiglandular disease is not likely to be missed, but bilateral exploration increases the risk for hypocalcemia and recurrent laryngeal nerve injury. Multiglandular disease is a facet of parathyroid surgery that continues to plague parathyroid surgeons. In recent years, however, modern adjunctive technology, including the ability to measure the parathyroid hormone rapidly and intraoperatively, has decreased the risk of missing multiglandular disease. The intact parathyroid hormone (iPTH) has a very short half-life of approximately 3 minutes. Therefore, measurement of iPTH level in the patient after removal of an identified adenoma would theoretically predict the success of surgery. In 1991 Irvin and colleagues [1] first introduced the intraoperative measurement of PTH level to predict postoperative calcium level. Since then many authors have demonstrated its accuracy and utility [3–19], and it has become an important tool in parathyroid surgery.
Intraoperative rapid parathyroid hormone assay systems The parathyroid hormone is an 84–amino acid peptide, which is metabolized rapidly to yield the biologically active N-terminal (amino acids E-mail address: [email protected] 0030-6665/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.otc.2004.02.009
780
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
1–34), the inactive mid-chain (amino acids 44–49), and the C-terminal (amino acids 34–84) molecules. PTH levels were first measured using radioimmunoassays to the C-terminal, the mid-molecule, or the N-terminal. Measurement of the C-terminal or the mid-molecule may not accurately reflect true hyperparathyroidism, because they are inactive. The N-terminal assay is very specific for hyperparathyroidism but is very insensitive because of its short half-life. A two-site immunoradiometric assay that detects both the N-terminal and a second site, known as the iPTH assay, is both very sensitive and specific for the diagnosis of hyperparathyroidism. This radioisotopic technique takes hours to perform. Therefore, to obtain the iPTH level rapidly for practical intraoperative use, this two-site antibody assay was modified by using chemiluminometric detection using acridinium ester instead of isotopes as an antibody label [2]. A second modification that decreased the centrifugation and incubation time shortened the turnaround time to approximately 15 minutes [3]. The values of iPTH obtained by this modified immunochemiluminometric assay correlate well with those obtained from the standard immunoradiometric assay. Currently, two systems are commonly used for intraoperative quick PTH (qPTH) measurement, the Nichols system (Nichols Institute Diagnostics, San Juan Capistrano, CA) and the Immulite system (Diagnostic Products Corporation, Los Angeles, CA). The Nichols system is generally a portable chemiluminometer workstation that can be placed in or just outside the operating room. Trained personnel normally process the blood and run the test; results are available in approximately 15 minutes. A hospital immunology laboratory generally uses the Immulite system for various radioimmunoassays, including routine iPTH assays. The system can also be adapted (Immulite Turbo) to run the intact PTH level rapidly. The specimen is transported from the operating room to the laboratory where it is centrifuged and processed. The entire process takes approximately 25 to 30 minutes, including transport time. One significant advantage of the Immulite system is the cost to the institution. If the hospital already has the Immulite system for processing various tests, the expense to the institution is the cost of the assay kits. The author’s hospital charges $150 for each assay ordered. On the other hand, with the Nichols system, the institution must purchase both the assay kits and the analyzer, the cost of which is rather substantial. Therefore, institutional charges for each assay using the Nichols system range from $500 to $650; most likely, the cost of the analyzer is amortized into the charges.
Interpretation and validity of quick parathyroid hormone assay Because of its very short half-life, the iPTH level should fall rapidly following successful removal of a single functioning parathyroid adenoma. Various criteria have been published for qPTH levels that predict successful
781
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
parathyroidectomy, as shown in Table 1 [4–13]. As the table indicates, there seem to be differences in the times when the baseline levels are drawn. Most parathyroid surgeons draw the level after anesthetic induction and before skin incision, but others compare the postexcision level to the level just before excising the adenoma. The most commonly used criterion for predicting success is that first described by Irvin and Deriso [1], that is, that the qPTH level falls below 50% of the highest pre-excision level within 5 minutes of excising the adenoma. Some use the qPTH level at 10 minutes after excision rather than the level 5 minutes after excision. Others also use much more stringent criteria that require the qPTH level to fall to at least 50% of baseline and be below the upper limit of normal.
Results of parathyroidectomy using quick parathyroid hormone assay In 1994, Irwin and colleagues [3,4] published their early experience with a small number of patients demonstrating the feasibility of using qPTH. They used a focused approach to excise an adenoma based on preoperative localization studies and using the intraoperative qPTH to determine if the procedure was successful or needed to be converted to bilateral exploration. They showed that the sensitivity of qPTH was 94% and that the operative times were significantly shorter. Subsequent to Irvin and colleagues’ reports, several authors evaluated the validity of qPTH by measuring iPTH levels before and after excision of abnormal glands during conventional bilateral exploration (Table 2) [9–12]. These studies evaluated the following parameters: (1) accuracy in predicting uniglandular versus multiglandular
Table 1 Interpretation of qPTH values
Baseline Level One level drawn after anesthetia induction and another before excision of gland–use the higher the two values Before excision of gland At induction Before induction Before incision One level drawn after anesthesia induction and another before excision of gland–use the higher the two values After separation of straps
Criteria for Successful Parathyroidectomy (postexcision level compared to baseline)
Reference #
50% of baseline at 5 minutes
4
50% of baseline at 5 minutes 50% of baseline at 7 minutes 50% of baseline at 10 minutes 50% at 10 minutes Two criteria evaluated 50% of baseline at 10 minutes 50% of baseline at 10 minutes and below upper limit of normal 50% of baseline at 15 minutes and below upper limit of normal
6 8 11 9,10,12 12
7
782
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
disease, (2) false-positive results, defined as the qPTH falling below 50% of baseline when one or more enlarged glands still remain, (3) false-negative results, defined as qPTH failing to fall below 50% when no additional enlarged glands remain. The accuracy rates in these studies ranged from 84% to 89%, with long-term chemical cure rates of 98% to 100%. The overall false-positive rates were 2% to 13%. Twelve percent to 60% of patients with multiglandular disease exhibit at least a 50% drop in the qPTH following excision of only one enlarged gland (false-positive result). The overall false negative rates were 3% to 8%. Subsequent to these initial validation studies, parathyroid surgeons began to use a focused, minimally invasive approach. With this focused approach, a small incision is made in the area of a suspected adenoma based on the results of preoperative localization studies (sestamibi parathyroid scan or ultrasound). Identification and removal of an adenoma is accomplished through standard open dissection or endoscopically. Some also use a radioguided gamma probe to aid in the initial search and to confirm an adenoma. After excision of the adenoma, intraoperative qPTH is used to determine if the patient is biochemically cured or needs further exploration for multiglandular disease. A number of series have reported cure rates of at least 98% using this approach [5–8,13–19]. The author’s approach to minimally invasive parathyroidectomy is to make a small incision over the location of the abnormal gland (determined by sestamibi scan with single photon emission CT) and using the qPTH levels to confirm success of the surgery. A frozen section is generally used only when the parathyroid gland does not have the typical appearance of an adenoma or when hyperplastic glands are excised and reimplanted. The baseline qPTH level is drawn just before or immediately after anesthetic induction. At 5 minutes and 10 minutes after excision of the adenoma, qPTH levels are drawn. The 5-minute level is sent to the laboratory, and the incision is closed. If the 5-minute qPTH level is 50% of the baseline level or
Table 2 Intraoperative PTH measurement during conventional bilateral parathyroid exploration
# of Patients Accuracy rate SA MGD Success rate False positive SA MGD False negative
Reference # 9
Reference # 10
Reference # 11
Reference # 12
72 89% 93% 76% 100% 6% 0 24% 7%
136 96%
112 84% 98.5% 58% 98% 13% 6% 37% 3%
115 80% 87% 58%
40% 98% 2% 0 60% 2%
3% 0 12% 17%
Abbreviations: MGD, multiglandular disease (includes double adenomas and hyperplasia); SA, single adenoma.
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
783
lower, and 65 pg/mL (the upper limit of normal) or lower, the procedure is terminated. If the 5-minute level is higher than 50% of baseline or higher than 65 pg/mL, the previously drawn 10-minute postexcision level is sent. If that level is still higher than 50% of baseline or higher than 65 pg/mL, the incision is reopened, and bilateral exploration is performed. In the author’s experience using this focused approach with preoperative sestamibi scan and intraoperative PTH monitoring, 98% of the patients have had successful biochemical cure with postoperative calcium or PTH levels returning to normal levels. Several studies have compared the outcome of parathyroid surgery using a focused approach with intraoperative qPTH to that of conventional bilateral exploration. The results of these studies indicate that the success rates of the focused approach operation are similar to or better than those of bilateral exploration, and complication rates tend to be lower. Carneiro and Irvin [16] reported that in patients undergoing parathyroidectomy, the longterm postoperative calcium and iPTH levels were normal in 98% (n = 144) of those who had a focused approach versus 85% (n = 176) of those who underwent conventional bilateral exploration. Burkey et al [17] compared the outcome of parathyroidectomy using three different approaches: gamma probe (n = 50), intraoperative qPTH (n = 50), and bilateral exploration (n = 50). The cure rates were 98%, 100%, and 96%, respectively; the complication rate was higher in the bilateral exploration group than in the other two. Similarly, Boggs and colleagues [15] reported a failure rate of 1.5% when sestamibi and qPTH were used versus 5% when bilateral exploration was performed without qPTH. In a study to evaluate whether qPTH improves the results of parathyroidectomy, Miura et al [12] showed that by adding qPTH to the operation, the accuracy of sestamibi scan improved from 83% to 92% and the accuracy of ultrasound improved from 71% to 86%.
Cost analyses Many authors have shown that the use of qPTH with sestamibi scan for parathyroid surgery reduces the length of stay [5,6,22]. Many centers now perform parathyroidectomy as an ambulatory surgical procedure. Some studies have shown that the perioperative cost for parathyroidectomy using a focused approach with sestamibi scan and qPTH is considerably (40%– 50%) less than bilateral exploration [5,6,22]. In these studies, the patients were discharged the same day. Others [7,17], however, have reported no appreciable reduction in cost because they did not perform these procedures in the ambulatory setting. If one compares sestamibi scan with qPTH to sestamibi alone for focused parathyroidectomy, the average cost for the former is higher by approximately $500 [22]. The improvement in cure rates seems to justify this added cost, however.
784
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
Limitations and pitfalls of quick parathyroid hormone Although qPTH significantly reduces the complications and length of hospital stay, it can potentially miss multiple-gland pathology, which may result in need for re-operation. In earlier reports where the criterion of reduction by more than 50% from baseline value at 5 minutes was used, multiple adenomas were missed. Hallfeldt et al [18] reported that in 2 of 36 patients, in whom they used these criteria but in whom the absolute qPTH value remained above normal range, the iPTH levels began to elevate again postoperatively [18]. One of these patients was re-explored and found to have hyperplasia. Gauger et al [20] reported on the changes in PTH values in 20 patients who were found to have double adenomas during bilateral exploration [20]. In 11 of the 20 patients, the qPTH levels were 50% of baseline or lower following excision of the first adenoma. In these 11 patients, a second adenoma was found during the planned bilateral exploration. Thus, the false-positive rate of qPTH was 55% in this group of patients. In the remaining 9 patients the qPTH values remained higher than 50% of baseline after excision of the first adenoma, giving a truenegative rate of 45%. Similarly, Jaskowiak et al [13] reported 50% falsepositive and 50% true-negative rates for qPTH when double adenomas are present. To explain this false-positive phenomenon with double adenomas, some hypothesize that the second adenoma, which is usually the smaller, may be suppressed or may not be hypersecretory. Therefore, if the second gland is not biochemically significant, the qPTH value will actually drop below 50% of baseline after excision of the active adenoma [20]. Even with four-gland hyperplasia, qPTH may exhibit kinetics similar to that of single adenomas. For example, one study reported that in 2 of 16 patients (12.5% false-positive rate) with hyperplasia from multiple endocrine neoplasia type 1 syndrome, the kinetics of qPTH was similar to that seen with a single adenoma (ie, 50% of baseline after excision of the first enlarged gland) [21]. The false-positive rates seem to be lower for hyperplasia than for double adenomas. Gordon and colleagues [9] reported that in their patients with multiglandular disease, qPTH had a false-positive rate of 24%. Furthermore, all of their false positives were double adenomas, and the first removed adenoma was generally larger than the second. In a retrospective analysis of sequential changes in qPTH during conventional bilateral exploration, Weber and Richie [11] reported a false-positive rate of 37% when multiglandular disease was present; within this group the false-positive rate was 67% for double adenomas and 31% for hyperplasia. In a small percentage of patients, the postexcision intraoperative qPTH may remain above 50% of baseline, but the subsequent postoperative calcium and iPTH levels return to normal (ie, false-negative qPTH). The significance of a false-negative value is that it results in unnecessary further exploration. One possible mechanism for such false-negative values is that circulating PTH can rise suddenly during manipulation of the adenoma;
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
785
therefore, if the postexcision value is compared with a baseline drawn before manipulation, it may not be significantly lower than baseline and sometimes can actually be higher than the baseline. Therefore, some surgeons draw two baseline levels, one either before or after incision and one just before excision of the adenoma, and use the higher of the two for the true baseline level [4,12]. Another option is to repeat the qPTH at either 10 minutes or 15 minutes after excision, at which time the values may be close to 50% of baseline. Alternatively, the surgeon can choose to perform bilateral exploration, which may or may not be necessary. There have been cases of false-negative qPTH. In one patient, the 5-minute qPTH level was 90% of the baseline, which was drawn at the time of anesthetic induction. It was repeated at 10 minutes and was 51% of baseline; it subsequently was below 40% of baseline and was within normal range at 20 minutes. The patient did undergo bilateral exploration, and two additional normal glands were identified (the fourth was not identified). The patient’s postoperative iPTH levels at 2 weeks and 2 months have remained normal. The serum calcium levels have remained around 10.6; this elevation is probably secondary to thiazide diuretic. In the second patient, the 5-minute postexcision level after excision of a slightly enlarged gland was 87% of baseline. The patient then underwent bilateral exploration, and the remaining glands were only minimally enlarged. He underwent excision of an additional two and one half glands. Following the three and one half gland excision, the qPTH was 49 pg/mL, 31% of baseline. Postoperatively, however, the iPTH levels began to rise above the preoperative levels. The patient is suspected of having a rare condition known as PTH-resistance syndrome, and is currently undergoing a work-up for this condition. Studies have shown that postoperative parathyroid levels can fluctuate considerably after successful parathyroidectomy. Carneiro and Irvin [16] reported that in 144 patients who underwent focused parathyroidectomy, postoperative iPTH levels varied considerably in 8% of the patients but returned to normal range at the most recent follow-up visit (average length of follow-up, 2.3 years). In the report by Chen et al [6], the mean postoperative iPTH level was 58 11 pg/mL with normal calcium levels. Inabet and colleagues [19] also reported that the 6-month postoperative iPTH level was 78.2 60 pg/mL with normal calcium levels in their patients who successfully underwent targeted parathyroidectomy.
Summary Intraoperative qPTH assay has become an important adjunct in modern parathyroid surgery. The use of preoperative sestamibi scan in combination with intraoperative qPTH in minimally invasive focused parathyroidectomy yields a success rate of at least 98%. This approach can decrease the length of hospital stay, and in many instances the procedure can be performed as
786
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
outpatient surgery. Adding qPTH to sestamibi scan improves the success of parathyroidectomy. The small additional cost of qPTH seems to justify adding this assay to the armamentarium to obviate the need for reoperation, which significantly increases cost and risks of complications.
References [1] Irvin GL, Dembrow VD, Prudhomme DL. Operative monitoring of parathyroid gland function. Am J Surg 1991;162:299–302. [2] Brown RC, Aston JP, Weeks I, Woodhead JS. Circulating intact parathyroid hormone measured by a two-site immunochemiluminometric assay. J Clin Endocrinol Metab 1987; 65:407–14. [3] Irvin GL, Deriso GT. A new practical intraoperative parathyroid hormone assay. Am J Surg 1994;168:466–8. [4] Irvin GL, Prudhomme DL, Deriso GT, Stakianakis G, Chandarlapathy SK. A new approach to parathyroidectomy. Ann Surg 1994;219:574–81. [5] Irvin GL, Sfakianakis G, Yeung L, et al. Ambulatory parathyroidectomy for hyperparathyroidism. Arch Surg 1996;131:1074–7. [6] Chen H, Sokoll LJ, Udelsman R. Outpatient minimally invasive parathyroidectomy: a combination of sestamibi SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126:1016–22. [7] Carty SE, Worsey J, Virji M, Brown M, Watson C. Concise parathyroidectomy: the impact of preoperative SPECT 99mTc sestamibi scanning and intraoperative quick parathormone assay. Surgery 1997;122:1107–16. [8] Patel PC, Pellitteri P, Patel N, Fleetwood M. Use of a rapid intraoperative parathyroid hormone assay in the surgical management of parathyroid disease. Arch Otolaryngol Head Neck Surg 1998;124:559–62. [9] Gordon LL, Snyder WH, Wians F Jr, Nwariaku F, Kim L. The validity of quick intraoperative parathyroid hormone assay: an evaluation in 72 patients based on gross morphologic criteria. Surgery 1999;126:1030–5. [10] Garner SC, Leight GS Jr. Initial experience with intraoperative PTH determinations in the surgical management of 130 consecutive cases of primary hyperparathyroidism. Surgery 1999;126:1032–8. [11] Weber CJ, Ritchie JC. Retrospective analysis of sequential changes in serum intact parathyroid hormone levels during conventional parathyroid exploration. Surgery 1999; 126:1139–43. [12] Miura D, Wada N, Arici C. Morita, Duh QY, Clark OH. Does intraoperative quick parathyroid hormone assay improve the results of parathyroidectomy? World J Surg 2002; 26:926–30. [13] Jaskowiak NT, Sugg SL, Helke J, Koka MR, Kaplan EL. Pitfalls of intraoperative quick parathyroid hormone. Arch Surg 2002;137:659–69. [14] Aggarwal G, Barakate MS, Robinson B, et al. Intraoperative quick parathyroid hormone versus same-day parathyroid hormone testing for minimally invasive parathyroidectomy: a cost effectiveness study. Surgery 2001;130:963–70. [15] Boggs JE, Irvin GL, Carneiro DM, Molinari AS. The evolution of parathyroidectomy failures. Surgery 1999;126:998–1002. [16] Carneiro DM, Irvin GL. Late parathyroid function after successful parathyroidectomy guided by intraoperative hormone assay (QPTH) compared with the standard bilateral neck exploration. Surgery 2000;128:925–9. [17] Burkey SH, Heerden JA, Farley DR, Thompson GB, Grant CS, Curlee KJ. Will directed parathyroidectomy utilizing the gamma probe or intraoperative parathyroid hormone
M. Shindo / Otolaryngol Clin N Am 37 (2004) 779–787
[18]
[19] [20]
[21]
[22]
787
assay replace bilateral cervical exploration as the preferred operation for primary hyperparathyroidism? World J Surg 2002;26:914–20. Hallfeldt KKJ, Trupka A, Gallwas J, Schmidbauer S. Minimally invasive video-assisted parathyroidectomy and intraoperative parathyroid hormone monitoring. Surg Endosc 2002;16:1759–63. Inebet WB, Dakin GF, Haber RS, et al. Targeted parathyroidectomy in the era of intraoperative parathormone monitoring. World J Surg 2002;26:921–5. Gauger PG, Agarwal G, England BG, et al. Intraoperative parathyroid hormone monitoring fails to detect double parathyroid adenomas: a 2-institution experience. Surgery 2001;130:1005–10. Tonelli F, Spini S, Tommasi M, et al. Intraoperative parathormone measurement in patients with multiple endocrine neoplasia type I syndrome and hyperparathyroidism. World J Surg 2000;24:556–62. Fahy BN, Bold RJ, Beckett L, Schneider PD. Modern parathyroid surgery: a cost-benefit analysis of localizing strategies. Arch Surg 2002;137:917–23.