Elevated serum parathormone level after \"concise parathyroidectomy\" for primary sporadic hyperparathyroidism

Elevated serum parathormone level after “concise parathyroidectomy” for primary sporadic hyperparathyroidism Sally E. Carty, MD, Michelle M. Roberts, MD, Mohamed A. Virji, MD, Laura Haywood, RN, and John H. Yim, MD, Pittsburgh, Pa

Background. Cure after parathyroid exploration is traditionally assessed by serum calcium concentration 6 months postoperatively. Postoperative normocalcemic elevation of serum parathormone (PTH) level has been described but is of unclear significance. Methods. In a 6-year prospective study of outcomes in 380 patients undergoing initial parathyroidectomy for primary sporadic hyperparathyroidism, we measured intact serum PTH and calcium levels at more than 5 months. Those with normocalcemic high PTH levels were begun on oral calcium + vitamin supplements and monitored. Results. At more than 5 months postoperatively, normocalcemic elevation in serum PTH level occurred in 28% of patients, was more common after resection of double adenomas (P = .01), and predated the onset of recurrent hypercalcemia in 3 of 3 patients with unrecognized multiglandular disease. Although delayed treatment with calcium and vitamin supplements produced no clear benefit, patients who took such supplements from the date of surgery were much less likely to have an elevated serum PTH level more than 5 months later (P = .0005). Conclusions. After successful parathyroid surgery, compensatory normocalcemic elevation in serum PTH level is frequent and may arise from dietary deficiency. Monitored supplemental intake of calcium and vitamin D appears to prevent or to normalize the condition in most patients. Patients with normocalcemic elevation in serum PTH level should receive evaluation for dietary deficiencies as well as follow-up for possible residual disease. (Surgery 2002;132:1086-93.) From the Departments of Surgery, Endocrinology, and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa

ENDOCRINE SURGEONS CARE A GREAT DEAL about the success and safety of evolving techniques for parathyroid exploration in primary hyperparathyroidism. Toward this end, new techniques for rapid intraoperative serum parathormone (PTH) assay have recently gained wide acceptance.1-6 Cure after parathyroidectomy has traditionally been assessed by the measurement of serum level of calcium postoperatively. Cases of operative failure are often categorized into persistent versus recurrent hyperparathyroidism. In persistent hyperparathyroidism, hypercalcemia is uncorrected by the initial surgery or arises less than 6 months afterwards, usually signifying a missed adenoma. In recurrent hyperPresented at the 23rd Annual Meeting of the American Association of Endocrine Surgeons, Banff, Alberta, Canada, April 7-9, 2002. Reprint requests: Sally E. Carty, MD, FACS, Associate Professor of Surgery, 497 Scaife Hall, University of Pittsburgh, Pittsburgh, PA 15261. © 2002, Mosby, Inc. All rights reserved. 0039-6060/2002/$35.00 + 0 11/6/128479 doi:10.1067/msy.2002.128479

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parathyroidism, hypercalcemia arises more than 6 months after initial exploration and generally indicates multiglandular disease that was unrecognized, although recurrent hyperparathyroidism can also arise when an adenoma was devascularized or with regrowth of a parathyroid carcinoma. To usefully distinguish between recurrent and persistent hyperparathyroidism, the assessment of cure after parathyroid surgery thus obligates, in the modern era, a final determination of serum level of calcium at 6 months or more postoperatively. After apparently curative parathyroid surgery, normocalcemic elevation in the serum PTH level has been widely described and studied.4,7-18 The reported incidence of this phenomenon has ranged from 8% to 40%, but its etiology remains unclear, its significance uncertain, and its management controversial. METHODS Prospective clinical database. Clinical information about operations performed for hyperparathyroidism by members of the Section of

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Endocrine Surgery at the University of Pittsburgh is prospectively entered into a computerized database. In January 1995 we began systematically evaluating a new method of parathyroid exploration for which we coined the term concise parathyroidectomy. This method and its initial results were previously described in detail.3 In brief, patients are evaluated clinically, and when the diagnosis of primary sporadic hyperparathyroidism is biochemically verified, a preoperative single photon emission computed tomography (SPECT) 99mTc-sestamibi scan is performed. The results of SPECT sestamibi scanning are used to direct the initial side of exploration. Intraoperative rapid PTH monitoring is used to help distinguish adenoma from hyperplasia, at once facilitating selective unilateral exploration and thorough identification of multiglandular disease. Surgical technique for concise parathyroidectomy. Under general anesthesia the patient’s anterior neck extension and habitus are evaluated to site a mid-cervical incision made with bupivacaine preemptive local analgesia. If the results of preoperative sestamibi imaging are negative or are positive bilaterally, the right side of the neck is explored first by default. With the thyroid lobe rotated medially, a baseline rapid serum PTH level is drawn from the internal jugular vein before dissection of any parathyroid tissue. Normal and ectopic locations for enlarged parathyroid tissue are then dissected on the basis of preoperative SPECT sestamibi findings. We routinely use frozen section examination to confirm parathyroid tissue presence and weight. Whenever possible, identification and distal hemibiopsy of the ipsilateral normal parathyroid gland were performed at the time of adenoma resection. If hyperplasia is identified, a subtotal parathyroidectomy is performed with cryopreservation of excised parathyroid tissue. On excision of an adenoma or completion of a subtotal parathyroidectomy, the exact time is noted for subsequent determination of a postexcision rapid serum PTH level. Until January 1, 2000, we drew the postexcision rapid PTH level 15 minutes later; since then we have used a postexcision interval of 10 minutes. If the postexcision quick PTH level is not both less than 65 pg/mL and less than 50% of the preexcision level, the incision is reopened for contralateral or further exploration with subsequent intraoperative PTH level(s) as required. Intraoperative rapid PTH monitoring. Rapid intact PTH analysis is performed during parathyroid surgery on plasma samples (ethylenediaminetetraacetic acid as anticoagulant) by adaptation of a chemiluminescent immunometric

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method (Nichols Institute Diagnostics, San Juan Capistrano, Calif). The method was modified for rapid analysis such that the assay is completed in 10 minutes in a facility adjacent to the operating suite, and the results are available for intraoperative management within 15 minutes of sampling of blood, as described previously.2,3 The modified method has a linearity range from 35 to 2600 pg/mL and an intra-assay coefficient of variation of less than 10%. Postoperative management. Patients whose operative findings allowed a unilateral exploration were considered candidates for same day discharge from the hospital. Patients who required bilateral exploration remained in-house overnight because of longer operation and the theoretically higher potential for hypocalcemia, hematoma, and nerve injury.3 All patients were discharged on oral calcium supplementation for 5 days postoperatively (Oscal, 1 g twice a day). Patients were asked to return to the office at 7 to 10 days and at 6 months postoperatively. At the 6-month visit, fasting intact serum PTH and calcium levels were obtained, the healed incision length was measured, and any chronic medications or persisting complications were noted. Patients with elevated intact serum PTH levels at more than 5 months were asked to begin oral calcium supplementation (Oscal, 1 g twice a day) plus a multivitamin and whenever possible were monitored at 6-month intervals until the level of PTH normalized or recurrent hyperparathyroidism was diagnosed. Patient population and data analysis. To perform the current study, under an Institutional Review Board–approved protocol we reviewed the prospectively entered information associated with all consecutive initial operations performed for primary sporadic hyperparathyroidism from January 1, 1995 to September 1, 2001. There were 568 such operations. In 380 patients there was documented follow-up of more than 5 months including PTH level. Mean follow-up from date of surgery was 15.8 months, ranging from 5 to 81.2 months. Statistical analysis was done with Fisher exact test or Student 2-tailed t test, and P values less than .05 were considered significant. RESULTS Results of initial parathyroid exploration for primary sporadic hyperparathyroidism. Of the 380 patients, 302 (79%) were women and the mean age at operation was 60.2 years (range, 15.7 to 88 years). The mean preoperative serum PTH level, expressed as percent of the upper limit of normal for the assay used, was 248% (range, 46% to 1628%). Identified pathologic causes for primary sporadic hyper-

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Table I. Operative results N Mean operating time (min) Median length of stay Rate of same day discharge

All patients

Unilaterally explored

380 82.4 (range, 34-239; ± standard deviation 38.5) 1 day 27.2%

237 66.8 (34-156; ± 21.7) 1 day 38.5%

parathyroidism were adenoma (85.2%), double adenoma (3.8%), hyperplasia (10.2%), and carcinoma (0.8%). As may be seen, the observed 13.9% distribution of multiglandular disease is generally reflective of that already well-described in the literature. Among patients found to have a single parathyroid adenoma, the results of preoperative SPECT 99mTc sestamibi imaging correctly predicted the side of the adenoma (right or left) in 84.9%, wrongly prompted bilateral exploration in 10.4%, and were negative in 4.7%. In those patients found to have parathyroid hyperplasia, the results of SPECT sestamibi imaging identified that fact preoperatively in only 38.6% of patients. The use of intraoperative rapid serum PTH analysis allowed us to selectively perform a unilateral exploration for 237 of 380 patients (62.4%) (Table I). Use of rapid PTH monitoring even allowed curative unilateral exploration for double adenomas in 3 patients (0.8%), one of whose second adenoma was supernumerary (fifth gland) in origin. In this study, the number of quick PTH samples required per parathyroid exploration was 2 in 79% of patients and varied from 2 to 5. Mean operative time “skin-to-skin” overall was 82 minutes and was demonstrably shorter for patients able to undergo unilateral exploration (Table I). Mean (± standard deviation) incision length, directly measured at the conclusion of surgery just before the application of steri-strips, was 4.5 ± 1.1 cm (range, 3.3 to 9.8 cm), and healed incision length at 6 months was 3.8 ± 0.8 cm (range, 2.1 to 6.7 cm). Overall, the median length of hospital stay was 1 day (range, 0 to 13 days); however, for patients explored unilaterally, same day discharge from the hospital was possible in 39% of patients. Interestingly, although the high rate of unilateral exploration did not change during the 6 years of this study, for those patients able to undergo unilateral exploration the rate of same day discharge nearly doubled over time to a rate of 63% in 2000 to 2001; we believe this is reflective of changing pressures in the health care environment. Complications of surgery. Permanent hypoparathyroidism occurred in 1 patient (1 of 380, 0.3%) who had undergone subtotal resection for

hyperplasia. Permanent recurrent laryngeal nerve paralysis occurred in 3 patients (0.8%), 2 of whom had required en bloc resection of parathyroid carcinoma involving the nerve. There were no instances of hematoma or postoperative death. Error in preoperative diagnosis was documented in 2 patients who later proved to have familial hypocalciuric hypercalcemia and pseudohyperparathyroidism, respectively. Persistent hyperparathyroidism complicated operation in 6 of 380 patients (1.6%) (Table II) and was correctly predicted in each case by the results of intraoperative PTH monitoring. Two such patients had a failed unilateral exploration for multiglandular disease; in 1 patient a close-to-adequate drop in postexcision intraoperative PTH level from 151 to 73 pg/mL was incorrectly taken as evidence of adequate exploration for the missed contralateral second adenoma resected a year later at his curative reexploration. In the other patient, prior thyroid surgery had produced such dense scar tissue that contralateral exploration for hyperplasia was thought to be unwise and was not performed. Of the 4 unsuccessfully bilaterally explored patients, 1 awaits reexploration for a fifth gland adenoma and 1 woman was successfully reexplored for a fifth gland adenoma residing within the carotid sheath posterior to the carotid artery. Recurrent hyperparathyroidism has been diagnosed to date in 3 patients (Table II). In each, the etiology appears to be missed multiglandular disease. In 2 patients our strict criteria for an adequate drop in intraoperative PTH 15 minutes postexcision failed to identify the inadequate extent of parathyroidectomy. In the third patient the intraoperative PTH 15 minutes postexcision did not fall to within the normal range, but the surgeon chose to view the observed 97.4% drop in its level to be sufficient evidence of operative success. Importantly, in all 3 patients recurrent hyperparathyroidism was first predicted by a normocalcemic high PTH level at more than 5 months postoperatively, followed later by the onset of hypercalcemia (at 12, 27, and 38 months, respectively). Furthermore, in all 3 cases with residual disease, the diagnosis was facilitated or

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Surgery Volume 132, Number 6 Table II. Operative failures Serum PTH level (pg/mL) Exploration type

Operative findings

Postoperative serum calcium level (mg/dL) Preexcision Postexcision >6 mo

Bilateral Bilateral Bilateral Bilateral Unilateral Unilateral

Unsuccessful Unsuccessful Unsuccessful Unsuccessful Adenoma, 90 mg Adenoma, 496 mg

Unilateral Bilateral Unilateral

Adenoma, 178 mg Adenoma, 440 mg Adenoma, 966 mg

Persistent hyperparathyroidism High 327 173 High 147 82 High 118 132 High 102 159 High 352 163 High 151 73 Recurrent hyperparathyroidism Normal 763 34 Normal 43 10 Normal 3316 88

“uncovered” by the management of an elevated postoperative PTH level with chronic calcium supplementation. Elevated follow-up PTH levels at more than 5 months. Excluding the 6 patients with persistent hypercalcemia due to failed exploration, the observed rate of normocalcemic hyperparathormonemia at more than 5 months postoperatively was 105 of 374 (28.1%). The degree of normocalcemic PTH elevation, expressed as percent of the upper limit of normal for the PTH assay used, was 169% ± 128% and ranged from 103% to 1201%. Among those patients found to have hyperplasia at surgery, the rate of PTH elevation was similar at 26%. However, those patients treated at initial operation for double adenomas were more likely to manifest an elevated PTH level 6 months after surgery (66.7%). Other factors that were examined for correlation with PTH elevation more than 5 months postoperatively included patient age, degree of elevation in preoperative PTH level, and adenoma weight. Patient age and adenoma weight did not correlate, but a high degree of preoperative PTH elevation was found to predict a higher likelihood of postoperative PTH elevation (P = .0002). When an elevated follow-up serum PTH level was noted, patients were asked to begin a multivitamin plus an oral calcium supplement and to comply with further calcium and PTH determinations at 6-month intervals. To date, 58 patients (all at least a year out from their operation) have been able to receive further follow-up. Over time, the PTH level has normalized in 32 of 58 patients, dropped in 15 patients, and remained stable in 3 patients. In 8 of 58 patients the level of PTH has

Final diagnosis

257 89 94 96 381 245

Missed adenoma Missed adenoma Missed 5th gland, adenoma Missed 5th gland, adenoma Partially treated multiglandular Missed second adenoma

114 260 109

Unrecognized multiglandular Missed second adenoma Unrecognized multiglandular

risen over time. To date, in 3 of 8 such patients with rising PTH levels we have observed the onset of hypercalcemia, defining the presence of recurrent hyperparathyroidism (and described above). In the 32 patients whose PTH normalized in continuing long-term follow-up, the time to normalization of PTH was 484 ± 347 days in 18 patients started at more than 5 months on calcium supplements, compared to 781 ± 661 days in 9 of 32 patients who did not take supplemental calcium and 347 ± 206 days in 5 of 32 patients who chronically ingested calcium from the day of surgery. These differences were not significant. Regardless of our instructions, some patients independently chose to take oral calcium longterm from the day of surgery. Typical reasons given for this decision were “it’s to protect my bones,” “my family gets osteoporosis,” or “because my gynecologist/internist/endocrinologist told me to.” In evaluating the course of a patient’s postoperative PTH elevation, any history of long-term intake of specific calcium-containing supplements was considered positive. Normocalcemic elevation in PTH was present in 15.1% of 126 patients who reported the long-term use of calcium supplements from surgery onward, compared to 36.3% of patients who reported no use of such supplements (P = .0005). DISCUSSION In 1995 we embarked on a protocol-driven prospective examination of late postoperative serum PTH level after initial parathyroid exploration for primary hyperparathyroidism. We planned for thorough endocrinologic evaluation of those patients found to have an elevated serum

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PTH level. In spite of the clear recommendations already in the literature,11,16 we quickly found that we could control neither the willingness of patients to comply with recommended follow-up care nor the willingness of community caregivers to support further care or endocrinologic testing of such patients. In evaluating our present data from this large recent series, we are pleased to be able to draw the following conclusions: 1. SPECT sestamibi scanning was useful in directing initial parathyroid exploration but cannot be safely relied on to exclude parathyroid hyperplasia. Intraoperative rapid serum PTH monitoring reliably identifies hyperplasia, with an observed low failure rate of 0.5% (2 of 380) for the detection of multiglandular disease. 2. The concise parathyroidectomy technique allows selective unilateral exploration in two thirds of patients with primary sporadic hyperparathyroidism, minimizing operative time, limiting the degree of dissection, and producing a 98% cure rate and a 1% major morbidity rate. 3. Almost 30% (105 of 374) of apparently cured patients have normocalcemic elevation of PTH level more than 5 months postoperatively. Early long-term intake of calcium and vitamin supplements appears to greatly reduce the likelihood of this condition. However, in a small proportion of such patients (3%, 3 of 111), normocalcemic elevation in PTH 6 months after surgery may progress to recurrent hyperparathyroidism. In the group of 111 operated patients with an increased serum PTH level at more than 5 months, most (95%) patients likely do not have recurrent hyperparathyroidism, because their serum calcium concentrations have remained normal to date. We therefore must consider other possible reasons for the postoperative elevation in PTH. PTH is an intermittently secreted hormone, and a small percentage of patients may have had blood drawn during a transient “spike” of PTH secretion. More likely however, the serum PTH was elevated as a secondary response to calcium or vitamin D deficiency. A decrease in serum ionized calcium triggers the calcium sensor of parathyroid cells, resulting in increased secretion of PTH. Patients may have had a low calcium intake as a result of dietary insufficiency or prior restrictions imposed when they were hypercalcemic. A substantial proportion of patients may have had vitamin D deficiency as a result of lack of intake or inadequate sun exposure. Vitamin D deficiency is increasingly common in northern latitudes,19-21 having been reported in 57% of inpatients and 40% of outpatients (ages, 49 to 83 years) in one recent study.19 In patients with primary

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hyperparathyroidism, concurrent vitamin D deficiency is common and has been found to exacerbate the degree of preoperative serum PTH elevation, symptomatology, and bone disease.22 Moreover, in osteoporotic patients manifesting coexistent vitamin D insufficiency and unoperated primary hyperparathyroidism, vitamin D therapy was recently reported to result in substantial shortterm gain in bone mineral density.23 In our series a higher preoperative serum PTH level correlated to a higher likelihood of remote postoperative PTH elevation, and in this phenomenon vitamin D deficiency may well have played a role. Other factors contributing to a postoperative normocalcemic elevation in serum PTH level may have included mild degrees of inadequate calcium intake, renal insufficiency with impaired 1,25 dihydroxy vitamin D production, vitamin D end-organ resistance, or the use of loop diuretics such as furosemide that increase calcium excretion. Postmenopausal women can have elevations in serum PTH levels that correct with use of estrogen replacement therapy.24 Also, during the first month of treatment for osteoporosis with osteoclast inhibitors such as alendronate, calcitonin, or raloxifene, transient decreases in calcium of 1% to 3% with compensatory increases in serum PTH of 20% to 60% have been observed.21 Unfortunately, we were not able to examine these factors. Many groups have examined normocalcemic elevation in serum PTH after surgery for primary hyperparathyroidism. The reported rates for this phenomenon have ranged from 7.5% to 40%. Bone hunger, severity of preoperative hyperparathyroidism, older age, adenoma weight, preoperative bone density, and compromised renal function have been suggested as etiologies.7,9,11-14,16-18 Some have termed the phenomenon secondary hyperparathyroidism14 despite the vast potential confusion that may result from a new use for a term already well-established in another clinical context. We propose another name for the phenomenon, compensatory normocalcemic hyperparathormonemia (CHP). In one important study from Sweden, the observed 17% incidence of CHP correlated with lower preoperative and postoperative levels of vitamin D.11 In an even more recent report from France, an observed 31% incidence of CHP was again explained as an adaptive response reaction to renal dysfunction or vitamin D deficiency.16 Because concurrent vitamin D deficiency has been found to exacerbate the degree of preoperative serum PTH elevation in patients with primary hyperparathyroidism,22 we suspect that prior reports describing a correlation between pre-

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operative PTH elevation and the likelihood of postoperative CHP may thus have unknowingly been describing a subset of vitamin D–deficient patients. Although we were not able to systematically measure renal function or vitamin D levels, our data do strongly indicate that dietary deficiency in calcium or vitamin D is an important and correctable cause of CHP and suggest that CHP may also resolve more rapidly with such therapy. Moreover, our data may give rise to an intriguing explanation for CHP. We have shown that about a third of patients will have CHP after curative parathyroidectomy for primary hyperparathyroidism, apparently arising from a total body deficit of calcium or vitamin D. Whatever the etiology for the deficit, in some patients the remaining (and previously suppressed) normal parathyroid glands appear postoperatively to be vigorously hypersecreting to restore homeostasis. Before any surgery, could the initial development of sporadic primary hyperparathyroidism somehow be driven etiologically by dietary deficiency in the first place? In other words, could primary hyperparathyroidism arise initially as a compensatory phenomenon that then escapes feedback regulation? This concept could even be extended to the problem of recurrent hyperparathyroidism; rather than representing operative failure from missed hyperplasia, perhaps if a calcium- or vitamin D-deficient patient lives long enough, their remaining glands can react with compensatory metachronous hyperparathyroidism. In support of this hypothesis is the recent report that suboptimal vitamin D nutrition stimulates parathyroid adenoma weight in primary hyperparathyroidism.25 Those experts involved in the current lively controversy concerning the ability of rapid serum PTH assay to correctly identify all patients with multiglandular parathyroid disease4,19,26-28 will no doubt be interested in the 0.5% (2 of 380) observed incidence of multiglandular disease apparently missed by our rather strict criteria for a postexcision drop in serum PTH level. Although the present series using rapid PTH assay is to our knowledge the largest described to date, a comprehensive analysis of the rapid PTH methodology is beyond our scope here and awaits a further report. The most important point is to urge the surgeon to precisely follow the criteria for an adequate drop and not to give in to any temptation to ignore “nearly normal” results. We concur that any postexcision elevation in serum PTH level demands attention, whether that be simply repeating the postexcision level to uncover a “slow degrader” of PTH or formally proceeding to a contralateral

exploration to exclude hyperplasia.26 There is no doubt that with sufficient follow-up recurrent hyperparathyroidism can occur after apparently successful surgery with rapid PTH assay. Our data agree with those of Weber and Ritchie28 that intraoperative serum PTH changes may in fact underestimate the extent of resection required in parathyroid hyperplasia, especially among patients with apparent curative resection of double adenomas. There are some endocrine surgeons who vigorously deny the existence of double adenomas, preferring to term such situations nodular hyperplasia. The follow-up of our patients with double adenomas is ongoing. In conclusion, we recommend that all patients after apparently successful parathyroid surgery be not only specifically released from any previously imposed restriction of calcium intake but also maintained for at least 6 months on calcium and vitamin supplementation (Oscal 1 g twice a day or equivalent plus a multivitamin containing 400 to 800 IU vitamin D). All patients after apparently successful parathyroid exploration should be monitored for at least 6 months with fasting intact serum PTH and calcium levels at 6 months. Patients with normocalcemic elevation in PTH at 6 months, as well as their primary physicians, should be counseled about the possibility of continuing bone hunger versus recurrent hyperparathyroidism (which itself may be uncovered by long-term calcium therapy and therefore corrected sooner). Such patients should have vitamin D, creatinine clearance, albumin, and bone density testing. Patients found to have double adenomas must be followed with particular vigilance. We dedicate this study to the memory of Charles G. Watson, MD, beloved endocrine surgeon and colleague, whose gracious dedication on behalf of patients with hyperparathyroidism will make him long remembered. We are grateful to Frank S. Puchalski and Carol L. Bykowski for help and technical support. We are deeply grateful to Dr George L. Irvin, III, for his valuable and generous insight and support. REFERENCES 1. Irvin GL, Prudhomme DL, Deriso GT, Sfakianakis G, Chandarlapaty SKC. A new approach to parathyroidectomy. Ann Surg 1994;219:574-81. 2. Irwin GL, Deriso GT. A new, practical intraoperative PTH assay. Am J Surg 1994;168:466-8. 3. Carty SE, Worsey MJ, Virji MA, Brown ML, Watson CG. Concise parathyroidectomy: the impact of preoperative SPECT 99mTc sestamibi scanning and intraoperative quick parathormone assay. Surgery 1997;122:1107-16. 4. Carneiro DM, Irvin GL. Late parathyroid function after successful parathyroidectomy guided by intraoperative hor-

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DISCUSSION Dr Keith S. Heller (Long Island, New York). I congratulate you not only on what you have done but on emphasizing to all of us that it is not enough to just measure calcium at the first postoperative visit, congratulate ourselves and send the patients home. I have a comment and a question. We have been following a series of about 500 patients for as long as 3 years. We routinely put our patients on calcium postoperatively. Our incidence of persistent elevated PTH is also about 15%. We have been measuring vitamin D postoperatively. There is a correlation between persistently high PTH and low vitamin D. It is not perfect, but there is a correlation. At what point do you say to yourself, maybe this is recurrent disease, and when do you start another workup? After all, we are all referred symptomatic patients with high normal calcium levels and elevated PTH. We operate on them and we find an adenoma. After 1 or 2 years, do you reevaluate the patient if the PTH is high and do a sestamibi scan, a 24-hour urine, etc? Dr Carty. Excellent question. I personally use the strict criteria for reoperation: high serum level of calcium, kidney stones, urine calcium level greater than 400, positive dexascan, and/or drop in creatinine clearance by 30%. If those factors are absent, if the calcium is normal for example, then the patient doesn’t warrant the additional risk of reoperation in my opinion. I would just follow them closely. Dr Heller. What if the calcium is normal but some of those other things are present? Dr Carty. If one of those findings is present, then we would reoperate. But in the normocalcemic patient without those features, I would counsel them as to what I am worried about and follow them closely.

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Dr George L. Irvin, III (Miami, Florida). I was privileged to review this paper ahead of time, and you will find it very intriguing. However, I disagree with your protocol for measuring the intraoperative PTH. You draw the assay sample from the jugular vein rather than from a peripheral vein or artery. This is going to bias your results. If the tumor is near where you put your needle, the hormone level is going to be stepped up compared to a peripheral sample. Also, by comparing only 2 samples, a preoperative one and a 10-minute after excision one, you will have a higher false-positive, false-negative rate. These 2 technical differences will result in less accurate prediction of postoperative calcium levels when compared to other published criteria for measuring hormone changes using more frequent sampling at a distal site. Dr Carty. In this series of 380 patients, the PTH was misinterpreted by the surgeon twice. It also failed to identify multiglandular disease twice. That is not very often. So it is true, we do draw the PTH from the ipsilateral internal jugular vein before beginning the dissection, but if that is skewing our results, it is not skewing them very much. I don’t understand quite how any intraoperative manipulation would have made our results more predictive of multiglandular disease. Dr Irvin. The most important point in this whole paper is what a high PTH level in a normocalcemic patient means. Bergenfelz and others have called attention to this fairly frequent postoperative finding. You have shown that if you give these people calcium and vitamin D, hormone secretion is decreased. Therefore, this is not secondary or recurrent hyperparathyroidism as these glands are not autonomous. I like your words: the finding of this normocalcemic high PTH level is a compensatory mechanism for bringing calcium homestasis back to normal in the postparathyroidectomy period. Dr Christopher R. McHenry (Cleveland, Ohio). This is an important phenomenon to educate our endocrinologists about because it is frequently misconstrued as being indicative of persistent disease. Dr Carty. Or they think we are wasting the health care dollar to measure it in the first place?

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Dr McHenry. One of the things that has been observed by a number of surgeons from this organization is that if you measure a PTH level within 24 hours of surgery in this group of patients, it is normal and this is predictive of a curative parathyroidectomy. This phenomenon is thought to occur as a result of bone demineralization. The timing of resolution of the high PTH levels is consistent with bone remineralization. I wondered if you had any bone mineral studies or markers of bone turnover, such as alkaline phosphatase levels, in patients with this phenomenon. Dr Carty. No, this study is limited in that we were not able to measure vitamin D levels etc. and were not able to do postoperative dexascans. Dr McHenry. Despite treatment with calcium or vitamin D, the high PTH levels failed to normalize in about a third of your patients. If you thought that the high PTH levels were the result of vitamin D deficiency, don’t you think that after this prolonged period of treatment you would see resolution of the high PTH levels? Can you speculate on what you think the cause is for the persistent elevation in PTH levels? Dr Carty. I think that is the central question. It is not a third of patients, it is 15% of our patients who took calcium from the day of surgery who had normocalcemic hyperparathormonemia postoperatively. Dr Paul LoGerfo, who can’t be here this morning, had a very good idea so I wish to credit him. His idea was that perhaps these patients are somehow unable to properly convert ergocalciferol in the diet. Perhaps what they need is Rocaltrol in the active form of vitamin D. I am no expert on vitamin D insensitivity, but this is an explanation that we have considered now for the past 5 or 6 years as an etiology for the problem in the remaining subset of patients. Can I go back and answer your first question: Is initial intraoperative PTH level predictive? No, because each of these patients had an initial intraoperative PTH level that was normal. Dr Dennistoun K. Brown (Billings, Montana). Did you assess symptomatology? Dr Carty. We did prospectively follow symptomatology. We did not, however, look at those data for this paper.