SURGERY. American Association of Endocrine Surgeons. Presidential address: Chasin hormones DECEMBER 1999

Transcription

1 Volume 126 Number 6 SURGERY DECEMBER 1999 American Association of Endocrine Surgeons Presidential address: Chasin hormones George L. Irvin, III, MD, Miami, Fla From the University of Miami School of Medicine, Miami, Fla FIRST, I D LIKE TO SAY to the members of the American Association of Endocrine Surgeons that serving as your president for the past year has been the single highest honor I have experienced in my professional career. Our group has the special distinction of sharing a common interest in a surgical discipline that is not only fascinating but often challenging. Furthermore, our work is unique because much of our time is spent trying to manage the overproduction of hormones which, unless controlled, can cause severe dysfunction in the human body. Today, I am going to confine my remarks to the hormone made by the parathyroid glands and how management of this has influenced and changed the treatment of hyperparathyroidism. As two of our past presidents, Dr Colin Thomas and Dr Norman Thompson, have pointed out in their discussions of the history of hyperparathyroidism, 1,2 the hormone itself was first demonstrated in 1923 by a general surgeon, A. M. Hanson, in Fairibault, Minn. This extraordinary Presented at the 20th Annual Meeting of the American Association of Endocrine Surgeons, New Haven, Conn, May 2-4, Reprint requests: George L. Irvin, III, MD, Department of Surgery (M-875), University of Miami School of Medicine, PO Box , Miami, FL Surgery 1999;126: Copyright 1999 by Mosby, Inc /99/$ /6/ private practice surgeon extracted from bovine parathyroid glands, using hydrochloric acid, a substance that was successful in treating experimental tetany. A year later, Hanson reported that this extract could raise calcium levels in parathyroidectomized dogs, and, when given over a long period of time, caused osteoporosis. 3,4 About the same time, J. B. Collip, in Edmonton, extracted from parathyroid tissue a substance that corrected hypocalcemia in experimental parathyroidectomized animals. More important, Collip was instrumental in making this hormone commercially available to investigators and physicians who were called upon to treat patients with severe tetany. 2 Thirty-four years later, two groups of investigators were able to isolate and characterize this extract as parathyroid hormone. Howard Rasmussen and Lyman Craig, working at the Rockefeller Institute in New York, and, independently, G. D. Aurbach who at that time was an NIH-supported, post-doctoral research fellow at Tufts University in Boston were able to extract a stable homogeneous parathyroid polypeptide, using a strong phenol solution. 5-7 These investigators demonstrated that hypercalcemia and phosphaturic properties resided in a single hormonal substance. In 1963, Solomon Berson and Rosalyn Yalow, at the Bronx VA Hospital and collaborating with G. D. Aurbach and John Potts at the NIH in Bethesda, described a radioimmunoassay for parathyroid hor- SURGERY 993

2 994 Irvin Surgery December 1999 Fig 1. Intraoperative ipth assays from peripheral plasma. mone. They used the principle of competitive inhibition of the binding of highly purified parathyroid hormone labeled with iodine 131 to specific hormone antibodies produced in the guinea pig. 8 For the discovery of this assay method used for measuring insulin and other hormones, Yalow received the Nobel Prize in Once the ability to measure parathyroid hormone was available, the race was on to apply it clinically. The question that intrigued many groups at that time was how to raise an antibody that recognized human parathyroid hormone specifically. This was difficult, not only because of the relatively low molecular weight of parathyroid hormone, but also because it had many similarities to native hormone present in most of the laboratory animals used at that time for antibody production. In 1965, at the Michael Reese Hospital in Chicago, Dr Eric Reiss and Dr Janet Canterbury, a post-doctoral fellow, were working on this problem. From a slaughterhouse in Chicago, they harvested bovine parathyroid glands, which were injected into guinea pigs, rabbits, goats, and sharks in an attempt, unsuccessful, to raise specific antibodies. They thought about using chickens but found it very difficult to control these animals for repeated injections. Dr Canterbury has related to me that this problem was finally solved when one of the old animal caretakers, who came from a farm in Georgia, showed them the proper way to handle chickens. He took a large leghorn chicken, tucked its head underneath his arm, and rocked back and forth for a period of time. In doing this, the bird would become quite docile and allow researchers to inject extracted bovine parathyroid gland with Freund s adjuvant repeatedly into the footpad. Dr Canterbury tells me that the animal caretaker believed that the birds were hypnotized, but in reality the birds suffered severe vertigo, from which they subsequently recovered with no further damage other than very large footpads. Finally, after many attempts, an antibody to bovine parathyroid was obtained that had a high affinity for human PTH in 3 out of 21 chickens. These researchers published their findings in 1968 and, using this antibody, developed an assay with good identification of parathyroid hormone concentrations in man. 9 The radioimmunoassay became an important diagnostic tool, though it took 2 weeks to perform. In 1972, Reiss and Canterbury moved to the University of Miami, where I had the privilege of working with them. With their assay, the diagnosis of suspected primary hyperparathyroidism became much more secure. Like other assays available at that time, their assay measured the C-terminal, and later, the mid-molecule part of the hormone, rather than the intact molecule. These fragments had a variable half-life and therefore often yielded clinically confusing results. The next major breakthrough came in 1987, when Samuel Nussbaum and his group at the endocrine unit at the Massachusetts General Hospital in Boston described a highly sensitive twosite antibody immunoradiometric assay (IRMA) for measuring intact parathyroid hormone. 10 Their assay used two different antibodies, one against the segment of the hormone molecule, which was coated on a polystyrene bead, and another antibody against the 1-34 segment, which was labeled with iodine 125. When these were added together with the unknown amount of intact parathyroid hormone in a sample, very accurate measurements were possible. In that same year, Brown, Aston, Weeks, and Woodhead, from Cardiff, published their results measuring circulating intact parathyroid hormone using a two-site immunochemiluminometric assay (ICMA) with increased sensitivity and specificity. 11 Their method was rapid, stable, and, importantly, showed no cross reactivity with PTH fragments. At the eighth annual meeting of the AAES in Chicago that year, Curley and Wheeler, with their coworkers from Cardiff, showed that the ICMA for the intact (1-84) PTH could distinguish between normals, patients with hyperparathyroidism, and those with hypercalcemia of malignancy. 12 These workers also showed that the half-life of the intact hormone was about 5 minutes. The next year, in 1988, Nussbaum, Thompson, and Hutcheson, with two members of our organization, Randall Gaz and Chiu-an Wang, presented a report of 13 patients at the Ninth Annual Meeting of the AAES in Boston, suggesting that this intact PTH IRMA could be used as an intraoperative adjunct in the surgical treatment of primary hyperparathyroidism. 13 Their assay had a 15- minute turnaround time. With the half-life of the intact molecule now known to be about 5 minutes, they suggested that this assay could be used intraoperatively as a guide to the extent of neck explo-

3 Surgery Irvin 995 Volume 126, Number 6 Fig 2. Operative failure rates in parathyroidectomy. ration. Dr Wang, as past president of our organization, was a proponent of limited neck dissection in the treatment of primary hyperparathyroidism and was very enthusiastic about the possible advantages of such an assay. Most of the audience was interested, but did not share his enthusiasm for applying such a test to intraoperative use. A few of us thought there was not much need for such an assay, in that operative success rates in the treatment of primary hyperparathyroidism were running between 90% and 95%. It is amazing how good you think you are when most patients undergoing a surgical procedure have excellent results following their operation. This was the case in early 1990, when a member of our surgical family in Miami, R.M., who was the operating room supervisor at the University of Miami/Jackson Memorial Hospital, came to me with a serum calcium of 13 mg/dl and the diagnosis of primary hyperparathyroidism. At surgery, we excised one very large parathyroid gland but, with our usual bilateral neck and upper mediastinum exploration, we were able to find only one normal parathyroid gland in the contralateral neck. With the confidence of a 95% success rate, we ended the operation at that point. Imagine my embarrassment when this patient s calcium failed to fall over the next few days and remained around 12.5 mg/dl. This failure did not disappear into the community; everyone in the hospital knew what happened and who the patient s surgeon was. It became obvious to me that we needed some way to measure parathyroid gland hypersecretion intraoperatively, as suggested by the Boston group 2 years earlier. Without spending any money, we borrowed a small centrifuge, a gamma counter, and a vacuum pump with a few automatic pipets. With help from the Incstar Corp (Stillwater, Minn), which furnished us with some labeled antibodies used in its standard assays, we were ready to try Dr Nussbaum s technique for measuring PTH intraoperatively. Some engineers who were working at our university made a heated test-tube shaker, which was used for enhancement of the reaction time. Within 4 months, we had worked out many of the problems for intraoperative use and had an assay that could give us results within 15 minutes. Our initial patient, R.M., whom we failed to cure 4 months previously, was found to have a second large parathyroid gland hidden in the contralateral thyroid lobe, which we removed with a thyroid lobectomy. Within 10 minutes, her PTH level dropped significantly, and I am pleased to report that she has been normocalcemic for the past 8 years. If the intraoperative assay (QPTH) had been available at the initial operation, the hormone level would not have dropped after the excision of the one large parathyroid gland, and this would have alerted us to the fact that hypersecreting parathyroid tissue was still present and would have prevented this operative failure. This one case went a long way toward convincing us of the usefulness of the intraoperative PTH assay. The next piece of evidence was furnished by Bergenfelz, Nordén, and Ahrén in These investigators asked the question, Is intraoperative hormone measurement better than frozen section histopathology? Their data showed, quite convincingly, that the decline in the plasma level of ipth obtained after excision of suspected parathyroid tissue could distinguish between a single adenoma and multiglandular disease. 14 With the evolution of intraoperative parathyroid hormone measurement, the question remained as to whether it could really be helpful to the surgeon. As Dr Wang postulated 12 years ago, the primary benefit of intraoperative PTH assay would be its ability to quantitatively assure the surgeon that all hyperfunctioning tissue had been removed. All surgeons performing parathyroidectomies can relate to the saying, When you know you ve got it, you can stop looking, thus saving many sometimes exasperating hours searching for normal glands to be sure that multiglandular disease is not present. A secondary benefit of the intraoperative PTH assay is that it can help the surgeon identify and excise obscurely located or overlooked

4 996 Irvin Surgery December 1999 hyperfunctioning glands. Differential venous sampling from the internal jugular veins, either before the incision is made or early after retraction of the strap muscles, can often lateralize the position of an overactive parathyroid gland, thus directing the surgical dissection to the suspected area. This can be especially helpful in patients with multinodular goiters where ultrasonography and sestamibi scan parathyroid localization can be misleading. Stimulation by local massage of tissues that may harbor a hyperfunctioning parathyroid that is not obvious on dissection can be quite helpful, especially in the previously operated neck. Fig 1 shows the intraoperative PTH levels during exploration of a very difficult to find parathyroid adenoma. The previous surgery had been very thorough, including a thyroid lobectomy, partial thymectomy, and carotid sheath exploration, resulting in much scarring. Massage in the area of the esophagus, inferior to the subclavian artery, resulted in a marked increase in the peripheral PTH level. Although this abnormal parathyroid gland could not be palpated, increase in the hormone level directed surgical dissection to this ectopic location and led to successful excision of the abnormal tissue. Since 1993, our group has combined preoperative localization studies using a technetium-99msestamibi scan along with an intraoperative PTH assay. We now use the immunochemiluminescence method (Nichols Institute Diagnostics, San Juan Capistrano, Calif) for measuring intraoperative parathyroid hormone levels. This assay has a 10- minute turnaround time and several advantages over IRMA, as described previously. 12 When compared with patients undergoing surgery without these surgical adjuncts, the operative failure rates have improved. 15 In our institution, the operative failure rate of initial parathyroidectomy has significantly decreased from 6% to 1.5% (Fig 2). 16 The intraoperative use of the parathyroid hormone assay has also helped in reoperation of patients with failed initial parathyroidectomy or late recurrence. The success rate in reoperative parathyroidectomy has improved from 76% to 97% since the use of QPTH was initiated. 17 Slight improvement in the operative success rate alone, however, will not justify the cost of implementing these new technical modalities to insurance providers and hospital administrators. How, then, does the surgeon justify the use of intraoperative parathyroid hormone assay? Clear hospital costs savings result with the use of QPTH as a result of shorter operating room time, less use of frozen section histopathology, fewer failed operations, and fewer overnight hospital stays. It is difficult to put a figure on the hospital costs for such an operation, since such costs and charges for parathyroidectomy vary tremendously around the country. Our real cost savings were seen in decreased bed care. Our friendly local hospital administrators looked at their costs for patients undergoing parathyroidectomy with a same-day discharge and compared them with similar patients undergoing a 1-night hospital stay. Using these cost figures, they were able to come up with a bundled hospital charge for parathyroidectomy that was 39% less if done with a same-day discharge compared to an overnight admission. We thought that successful outpatient parathyroid surgery would be of great interest to internists, endocrinologists, and primary care physicians, as well as patients. To let referring physicians know about this new approach, a report of a consecutive series of 57 patients was submitted for publication. The article describing intraoperative parathyroid hormone assay and ambulatory parathyroidectomy was rejected by several prestigious journals, including The New England Journal of Medicine, Journal of the American Medical Association, Annals of Internal Medicine, and the American Journal of Medicine. Having no success in our attempt to reach this audience of referring physicians, we submitted this report to the American Surgical Association, where it was accepted on the program as an alternate presentation for the 1996 meeting. When no one died or withdrew an accepted paper for the association meeting, we again failed to find an audience. Next, we sent our manuscript to the Annals of Surgery for review. When the editorial board also turned it down, we were becoming discouraged. Finally, Dr Claude Organ encouraged us to resubmit this work to the Archives of Surgery, where it was finally published a year and a half after the first submission. 18 With that publication, the intraoperative parathyroid hormone assay has now achieved slow, but increasing, acceptance around the world. The concept remains valid: When chasing excessive hormone production, surgeons would like to have real-time, quantitative assurance that their operation is going to be successful. QPTH is now being performed in at least 26 cities in the United States and in 11 countries throughout the world. What about the future? New technical advances will soon allow easier, quicker, less expensive, and very accurate intraoperative hormone assays. Surgeons would like to have a dipstick or litmus paper method for looking at the hormone secretory levels at surgery. I foresee that intraoperative assays will be of benefit to surgeons in their quest to contain the hypersecretion not only of parathyroid hormone, but also of insulin, gastrin, calcitonin,

5 Surgery Irvin 997 Volume 126, Number 6 and ACTH. When surgeons have the ability to measure endocrine gland function intraoperatively, our dedication to chasing hormones will become a lot easier and much more fun. REFERENCES 1. Thomas CG. Presidential address: the glands of Owen a perspective on the history of hyperparathyroidism. Surgery 1990;108: Thompson NW. The history of hyperparathyroidism. Acta Chir Scand 1990;156: Hanson AM. An elementary chemical study of the parathyroid glands of cattle. Mil Surgeon 1923;52: Hanson AM. The hormone of the parathyroid gland. Mil Surgeon 1924;54: Rasmussen H, Craig LC. Purification of parathyroid hormone by use of countercurrent distribution. J Am Chem Soc 1959;81: Aurbach GD. Isolation of parathyroid hormone after extraction with phenol. J Biol Chem 1959;234: Rasmussen H, Craig LC. Isolation and characterization of bovine parathyroid hormone. J Biol Chem 1961;236: Berson SA, Yalow RS, Aurbach GD, Potts JT. Immunoassay of bovine and human parathyroid hormone. Proc Natl Acad Sci U S A 1963; 49: Reiss E, Canterbury JM. A radioimmunoassay for parathyroid hormone in man. Proc Soc Exp Biol Med 1968;128: Nussbaum SR, Zahrachnik RJ, Lavigne JR, Brennan GL, Nozawa-Ung K, Kim LY, et al. Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem 1987;33: 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: Curley IR, Wheeler MH, Aston JP, Brown RC, Weeks I, Woodhead JS. Studies in patients with hyperparathyroidism using a new two-site immunochemiluminometric assay for circulating intact (1-84) parathyroid hormone. Surgery 1987;102: Nussbaum SR, Thompson AR, Hutcheson KA, Gaz RD, Wang C. Intraoperative measurement of parathyroid hormone in the surgical management of hyperparathyroidism. Surgery 1988;104: Bergenfelz A, Nordén NE, Ahrén B. Intraoperative fall in plasma levels of intact parathyroid hormone after removal of one enlarged parathyroid gland in hyperparathyroid patients. Eur J Surg 1991;157: Carty SE, Worsey I, Virji MA, Brown ML, Watson CG. Concise parathyroidectomy: the impact of preoperative SPECT 99m-Tc-sestamibi scanning and intraoperative quick parathormone assay. Surgery 1997;122: Boggs JE, Carneiro DM, Irvin GL. The evolution of parathyroidectomy failures. Surgery 1999;126: Irvin GL, Molinari AS, Figueroa C, Carneiro DM. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 1999; 229: Irvin GL, Sfakianakis G, Yeung L, Deriso GT, Fishman LM, Molinari AS, et al. Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996; 131: Receive tables of contents by To receive the tables of contents by , sign up through our Web site at Choose Notification. Simply type your address in the box and click the Subscribe button. Alternatively, you may send an message to majordomo@mosby.com Leave the subject line blank and type the following as the body of your message: subscribe surgery_toc You will receive an to confirm that you have been added to the mailing list. Note that table of contents s will be sent out when a new issue is posted to the Web site.