This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Udelsman, R. Articles by Clark, O. H. Search for Related Content PubMed PubMed Citation Articles by Udelsman, R. Articles by Clark, O. H. Related Collections Calcium and Bone Metabolism Endocrine Oncology

Surgery for Asymptomatic Primary Hyperparathyroidism: Proceedings of the Third International Workshop

Carmalt Professor of Surgery and Oncology (R.U.), Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06510; Clinical Professor of Surgery and Oncology (J.L.P.), Department of Surgery, University of Calgary, Calgary, Alberta, Canada AB T2N 1N4; Director of Endocrine Surgery (C.S.), Northwestern University, Department of Surgery, Chicago, Illinois 60611; Head of Surgical Oncology (J.E.M.Y.), St. Joseph’s Healthcare Clinical Professor of Surgery, McMaster University, Hamilton, Ontario, Canada L8S 4L8; and UCSF/Mt. Zion Medical Center (O.H.C.), Department of Surgery, University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Robert Udelsman, M.D., M.B.A., Carmalt Professor of Surgery and Oncology, Chairman, Department of Surgery, Yale University School of Medicine, P.O. Box 208062, New Haven, Connecticut 06520-8062. E-mail: Robert.Udelsman{at}yale.edu.

	Abstract

Top Abstract Introduction Question 1. What are... Question 2. Who should... Question 3. What is... Question 4. What is... Question 5. What operative... Question 6. Is parathyroid... Summary and Conclusions References

 
Context: An international workshop on primary hyperparathyroidism (PHPT) was convened on May 13, 2008, to review and update the previous summary statement on the management of asymptomatic PHPT published in 2002.

Evidence Acquisition: Electronic literature sources were systematically reviewed, addressing critical aspects of the surgical issues pertaining to the indications, imaging, surgical treatment, and cost-effective management of patients with PHPT.

Evidence Synthesis: The surgical group concluded that many patients with "asymptomatic" PHPT have neurocognitive symptoms that may be unmasked after successful parathyroidectomy. Furthermore, reduced bone density and increased fracture risk can be improved with parathyroidectomy. When PHPT is symptomatic, it may be associated with nephrolithiasis, increased cardiovascular disease, and decreased survival. Preoperative imaging studies should only be performed to help plan the operation, and negative imaging should never preclude surgical referral. Noninvasive localization studies including ultrasound and sestamibi scans are often employed, especially in anticipation of focused explorations. Invasive localization studies should be reserved for remedial explorations where noninvasive imaging has been unsuccessful.

Conclusions: When performed by expert parathyroid surgeons, parathyroid surgery is safe, cost-effective, and associated with very low perioperative morbidity. Minimally invasive approaches to parathyroid surgery appear to be as effective as the classic bilateral cervical exploration approach.

	Introduction

Top Abstract Introduction Question 1. What are... Question 2. Who should... Question 3. What is... Question 4. What is... Question 5. What operative... Question 6. Is parathyroid... Summary and Conclusions References

 
An international workshop on primary hyperparathyroidism (PHPT) was convened on May 13, 2008, in Orlando, Florida. The workshop was supported by 10 national and international scientific societies including the American Association of Endocrine Surgeons (AAES) and the International Association of Endocrine Surgeons (IAES). The focus of the workshop was to review and update the recommendations of the summary statement published after the 2002 workshop on asymptomatic PHPT (1). The current overall findings and updated summary statement are also published in this issue of the Journal of Clinical Endocrinology & Metabolism. This manuscript is focused on issues that pertain to the surgical management of patients with "asymptomatic" PHPT. Levels of evidence for references cited in this manuscript are tabulated in Table 1.

	Question 1. What are the indications for surgery in patients with PHPT?

Top Abstract Introduction Question 1. What are... Question 2. Who should... Question 3. What is... Question 4. What is... Question 5. What operative... Question 6. Is parathyroid... Summary and Conclusions References

Neuropsychiatric symptoms and quality of life (QOL)

In this issue of the Journal, Silverberg et al. reviewed the literature with regard to neurocognitive function in PHPT. They confirmed that patients with PHPT often complain of vague, nonspecific symptoms (6, 7, 8, 9, 10, 11, 12, 13, 14). These symptoms include fatigue, lassitude, mood swings, irritability, anxiety, depression, difficulty concentrating, memory loss, and increased sleep requirements (5, 6, 7, 8, 9, 12, 14, 15, 16, 17, 18, 19, 20).

In a population-based Swedish study, patients with PHPT had more complaints of lassitude, fatigue, irritability, and lack of sexual interest than aged-matched controls (18). In a cohort study using the Comprehensive Psychological Rating Scale, Joborn et al. (17) found that the majority of patients with PHPT had considerably more psychiatric symptoms compared with healthy controls and showed improvement of these symptoms after parathyroidectomy. Similarly, Chan et al. (7) observed that the majority of PHPT patients had subjective improvement after parathyroidectomy as determined by questionnaire. In a recent systematic review of all prospective studies in which cognitive function was measured with formal neuropsychological tests, Coker et al. (19) found six small studies characterized by inconsistent findings illustrating the need for prospective investigations with long-term follow-up.

The review of Coker points out the inherent weaknesses in neurocognitive instruments such as the SF-36 QOL scale. A patient-based outcome tool, which quantifies 13 disease-specific symptoms of PHPT has been developed and validated at the University of Calgary (11, 14, 16, 17, 18, 19, 20, 21). Using this tool, patients with PHPT were found to have more symptoms relative to a comparison group of nontoxic thyroidectomy patients and to show improvement within 7–10 d after parathyroidectomy.

There are two randomized controlled trials assessing QOL after parathyroidectomy vs. medical management in patients with mild PHPT. A randomized controlled study of 53 patients by Talpos et al. (22) demonstrated improved QOL in two of nine domains of the SF-36 in patients undergoing operation compared with ongoing medical surveillance. In contrast, Bollerslev et al. (23) found no significant difference after surgical treatment vs. medical observation in regard to their overall QOL at 2 yr. These investigators did, however, find that the overall QOL in the PHPT was significantly lower than normal population-based controls. They also found that the medically observed group had a significant decrease in physical domains over 2 yr, whereas no change was seen in the surgical group.

In summary, there is now a considerable body of literature that supports the possibility that many patients with PHPT have neurocognitive features that, in some cases, show improvement after successful parathyroid surgery. However, to resolve this ongoing debate, well-controlled randomized prospective trials are clearly indicated.

Bone density and fracture risk

The majority of studies document that both men and women with PHPT are more likely to have low bone density and increased fracture risk in comparison to controls (24, 25). Patients with PHPT and normal bone density also experience more fractures (24, 25, 26). In cohort studies, fracture risk declines after parathyroidectomy. This effect is independent of age, gender, and the initial serum calcium or PTH levels. It is also independent of the weight of the removed parathyroid tissue and the underlying histopathological diagnosis. Although these data are suggestive, we still do not have randomized controlled trial data evaluating the effects of parathyroidectomy on fracture risk in PHPT.

Nephrolithiasis

The frequency of developing new kidney stones among those with a history of nephrolithiasis declines after surgery. Renal concentrating capacity may show improvement after successful parathyroidectomy (27, 28). Mitlak et al. (29) reported that about one third of the 85 patients they followed with minimal or mild PHPT developed impaired renal function or premature osteopenia when followed for 10 yr. The prospective study by Silverberg et al. (30) also documented that about 25% of their asymptomatic patients developed problems within 10 yr, included among which was nephrolithiasis.

Cardiovascular disease

The subject of cardiovascular disease in PHPT has been reviewed by Silverberg et al., in this issue of the Journal. Other investigators have demonstrated an increased incidence of hypertension (31, 32, 33, 34), left ventricular hypertrophy (35), vascular calcification and stiffness (36), and myocardial events (37, 38). Although more studies are required, prevention of these cardiovascular events, when possible, by earlier parathyroidectomy rather than treatment of cardiac complications might be prudent in patients who can be defined to be at risk (37, 38).

Survival

Large population-based cohort studies demonstrate that patients with PHPT appear to be at risk for premature death (39, 40, 41, 42). Although these data were not specifically derived from asymptomatic patients, those described by Palmer et al. (39) had a median blood calcium level of 10.4 mg/dl (2.6 mmol/liter) and would not have qualified for surgical intervention based on previous consensus guidelines. Most of the deaths were due to cardiovascular disease or cancer (39). Data from Wermers et al. (42) suggest that overall survival was not affected in their cohort with mild PHPT. Increasing serum calcium levels were associated with poorer survival in multivariate analysis. A potential increase in mortality, however, was not seen with conservative treatment of mild PHPT (42).

	Question 2. Who should perform parathyroid surgery?

Top Abstract Introduction Question 1. What are... Question 2. Who should... Question 3. What is... Question 4. What is... Question 5. What operative... Question 6. Is parathyroid... Summary and Conclusions References

 
Surgeon experience is considered by virtually all experts to be the single most important variable that has a direct effect upon cure and complication rates for parathyroidectomy. Despite this well-accepted tenet, there are few published data that directly test this hypothesis. Due to ethical and selective bias in reporting, a true comparison study is highly unlikely to be performed. Indirect data can be extrapolated from the thyroid literature in which a large retrospective administrative database demonstrated that surgical experience as measured by volume of cases per year was the single most important predictor of clinical and economic outcomes (43). Recent data confirm a linear relationship between surgical volume and optimization of outcomes in endocrine surgery (44). It is also clear that the vast majority of surgical residents completing training programs have insufficient experience in endocrine surgery to be considered experts (45). In recognition of this issue, the AAES has endorsed endocrine surgery fellowship programs throughout the United States and Canada.

Patients and their referring endocrinologists should seek out surgeons and institutions that have devoted the time and resources required to optimize operative outcomes. Due to electronic media sources, there is an overwhelming amount of information available to patients, and unfortunately the quality and accuracy of the data are at times compromised. Although there are no clear minimal standards that can be recommended, it is important that patients and their referring physicians seek information from reliable sources.

	Question 3. What is the role of preoperative imaging?

Top Abstract Introduction Question 1. What are... Question 2. Who should... Question 3. What is... Question 4. What is... Question 5. What operative... Question 6. Is parathyroid... Summary and Conclusions References

 
Preoperative imaging in the setting of PHPT is designed to assist the surgeon in identifying the anatomic localization of abnormally functioning or enlarged parathyroid glands. Positive imaging studies are not useful for the confirmation of a diagnosis of PHPT. Moreover, negative imaging studies do not exclude the diagnosis of PHPT. Furthermore, all imaging studies demonstrate both false-positive and false-negative findings that can be misleading. Therefore, all patients subjected to preoperative parathyroid imaging studies should have a confirmed biochemical diagnosis of PHPT.

The selection of one or more imaging studies is affected by the anticipated approach (focused vs. bilateral exploration) and whether or not the operation will be a remedial procedure in a scarred operative field. The most commonly employed imaging studies are sestamibi scans and cervical ultrasound. The quality of sestamibi scans, however, varies widely between institutions, and sonography is highly dependent on the skill and interest level of the individual performing the study (46, 47). Computed tomography (CT) and magnetic resonance imaging (MRI) scans are also sometimes used, especially in patients with persistent or recurrent hyperparathyroidism. In patients requiring remedial cervical exploration, PTH assay of the aspirate from an ultrasound-guided fine-needle aspiration (FNA) of a perceived adenoma can confirm the location of parathyroid tissue. Angiography and selective venous sampling for PTH are occasionally employed for remedial cases when noninvasive studies are negative or conflicting.

Noninvasive imaging

Sestamibi scan Sestamibi scanning is the most popular and sensitive noninvasive parathyroid localization procedure. It can localize abnormal parathyroid glands in both eutopic and ectopic locations. The quality of sestamibi scanning varies widely among institutions (46). Some series report an accuracy rate of over 90%, but most centers achieve only 50 to 70% accuracy. In a prospective study of 387 patients by Civelek et al. (48), the sensitivity for single adenomas was 90%, but 27% of double adenomas and 55% of hyperplastic glands were missed. The major factors contributing to a nonlocalizing sestamibi study are multigland disease, small parathyroid glands, or coexistent thyroid disease. The main advantage of sestamibi scans is the ability to localize parathyroid glands in ectopic sites including the mediastinum.

Ultrasound In many centers all patients having parathyroid surgery undergo routine preoperative ultrasound, and some endocrinologists and surgeons believe that this is the most cost-effective procedure. Ultrasonography is painless, noninvasive, and inexpensive; does not expose the patient to radiation; and can be duplicated in the operative theater. Ultrasound can identify coexistent thyroid pathology and be used to locate intrathyroidal parathyroid adenomas. The accuracy of ultrasound is highly operator dependent. Abnormalities identified as possible parathyroid tissue not infrequently prove to be a thyroid nodule or lymph node. One recent study showed that surgeon-performed ultrasound had a sensitivity of 82% with a specificity of 90%, compared with radiology-performed ultrasound, which had a sensitivity of 42% and a specificity of 92% (47). Despite these possible advantages, ultrasonography neither evaluates the mediastinum nor offers functional information.

CT scan Rapid spiral thin-slice CT scanning of the neck and mediastinum, with evaluation of axial, coronal, and sagittal views, provides impressive delineation of anatomy and vascular flow. The sensitivity is improving and ranges from 50–75%. Recent data suggest that four-dimensional CT scans employing multiple sequences with iv contrast and fine-cut imaging have improved sensitivity and may be particularly helpful in anticipation of remedial cervical exploration (49).

MRI scan Contrast-enhanced MRI can identify abnormal parathyroid tissue. In comparison to other modalities, it is time-consuming, expensive, less sensitive, and more difficult to interpret. It can be useful for mediastinal lesions but it is not superior to CT, and a significant number of patients are excluded because of indwelling pacemakers and other metallic implants (50). It can nonetheless be useful when performing localization in anticipation of remedial exploration.

Positron emission tomography (PET) scan PET with or without simultaneous CT scan (PET/CT) can occasionally identify parathyroid adenomas in patients with persistent or recurrent PHPT when other localization studies are negative or equivocal. But because (F-18) fluorodeoxyglucose also concentrates in the thyroid, this technique is somewhat limited.

Invasive imaging

Parathyroid FNA FNA of a presumed parathyroid gland can be performed and the aspirate can be analyzed for PTH. This technique is safe and relatively inexpensive, but is not recommended for routine de novo cases (51).

Arteriography and selective venous sampling for PTH

These techniques are costly and invasive and require an experienced and committed interventional radiologist. Highly selective venous localization is positive in up to 80% of patients with persistent or recurrent PHPT when other studies are negative or discordant. They should only be used for patients who have failed previous explorations and for whom other localization techniques are noninformative (52).

	Question 4. What is the appropriate operation, and what are the cure and completion rates?

Top Abstract Introduction Question 1. What are... Question 2. Who should... Question 3. What is... Question 4. What is... Question 5. What operative... Question 6. Is parathyroid... Summary and Conclusions References

 
The surgical treatment of PHPT has undergone substantive changes since the first successful parathyroidectomy was performed by Felix Mandl in 1925 (53). It is now the expectation that the vast majority of patients will be cured during initial surgical exploration with a low probability of morbidity. A variety of operative techniques can be employed. The conventional time-honored operation employing general endotracheal anesthesia and bilateral cervical exploration is safe and effective when performed by experienced surgeons. Recent technical innovations including improved preoperative localization, availability of rapid intraoperative PTH assays, endoscopic refinements, and intraoperative gamma detection probes have resulted in the broad application of focused or minimally invasive approaches with excellent outcomes.

Sporadic primary hyperparathyroidism is caused by a single enlarged parathyroid gland (parathyroid adenoma) in approximately 85% of cases, whereas multigland hyperplasia occurs in 15% and parathyroid carcinoma is found in less than 1% of patients. Unlike previous dogma that mandated surgical identification of both enlarged and normal parathyroid glands, the current paradigm in many centers is to identify and excise the incident enlarged gland and to confirm operative cure employing a rapid intraoperative PTH assay. Due to the relatively short half-life of PTH (4–5 min), a dramatic drop in circulating hormone can be detected once the abnormally secreting gland or glands have been removed. A curative drop in PTH allows the surgeon to terminate the operation and obviate additional exploration, whereas failure of the PTH levels to demonstrate an adequate decrement mandates additional exploration due to the presence of presumed additional hypersecreting gland(s). Because the majority of patients can be cured by removing a single enlarged gland, many surgeons perform this procedure employing local or regional anesthesia through small incisions on an outpatient basis (54, 55).

Minimally invasive parathyroidectomy procedures can be grouped into three major categories. The most commonly performed technique employs local or cervical block anesthesia, a 1- to 2-in. (2.5- to 5.0-cm) incision, focused exploration to remove the incident gland seen on preoperative imaging, and a rapid intraoperative PTH assay to confirm the adequacy of resection (54, 55). In Europe, two groups perform a similar operation employing an endoscopic camera. These groups suggest that the cosmetic results are superior because the port incisions are smaller than the minimally invasive open techniques (56, 57). The endoscopic technique often requires general anesthesia and, for the most part, has not been adopted in North America because it requires additional personnel and costs and do not improve outcomes or speed of recovery. Another technique employs preoperative administration of radioactive sestamibi and subsequent exploration with an intraoperative gamma probe to help locate enlarged parathyroid glands. Although the gamma probe concept is theoretically attractive, most groups have abandoned this technique because the incremental gamma probe-derived information adds little to the data obtained from preoperative localization.

There are few well-designed prospective studies comparing conventional parathyroid exploration with minimally invasive techniques. These studies demonstrate no differences in cure or complication rates when performed by experienced endocrine surgeons (58, 59). Two large retrospective studies of minimally invasive parathyroidectomy demonstrate cure rates of 95–98% and complication rates ranging from 1–3% in previously unexplored patients (54, 55). It is important to distinguish initial operative exploration from remedial cases where the failure and complication rates in the latter are higher. Nonetheless, even in challenging remedial exploration cases, experienced surgeons obtain cure and complication rates that approach those of the unexplored patient (52).

	Question 5. What operative adjuncts are available to assist the surgeon?

Top Abstract Introduction Question 1. What are... Question 2. Who should... Question 3. What is... Question 4. What is... Question 5. What operative... Question 6. Is parathyroid... Summary and Conclusions References

 
A variety of operative adjuncts are available in specialized centers, including rapid intraoperative PTH assays, employment of a gamma probe in conjunction with a preoperative sestamibi injection, intraoperative ultrasound, and the ability to perform intraoperative internal jugular vein sampling to measure PTH and determine the presence of an ipsilateral venous gradient. All of these techniques are highly institution specific. Most experts agree that the intraoperative PTH assay is the most useful of these techniques (60). Intraoperative venous sampling is reserved for cases where the surgeon is unable to locate the abnormal parathyroid gland and has immediate availability of an intraoperative PTH assay.

	Question 6. Is parathyroid surgery cost effective?

Top Abstract Introduction Question 1. What are... Question 2. Who should... Question 3. What is... Question 4. What is... Question 5. What operative... Question 6. Is parathyroid... Summary and Conclusions References

 
Cost analyses performed before the introduction of focused or outpatient parathyroidectomy probably do not reflect the current cost-effectiveness of surgical treatment. Before the last decade, parathyroidectomy commonly required a longer operation and an inpatient stay of several days. Despite this, surgery was found to be less costly than the medical treatment of PHPT when the time interval required for medical treatment exceeded 5.5 yr (61).

Guidelines for formal cost-effectiveness analysis (CEA) were outlined by the Panel on Cost-Effectiveness in Health and Medicine in 1996 (62). Many studies claiming to evaluate cost-effectiveness do not conform to these guidelines and are not considered formal CEA. Consequently, there are few formal CEAs on asymptomatic PHPT published in the English language literature. To our knowledge, only three formal studies are available to date that meet the methodological standards to be considered formal analyses (63, 64, 65).

Sejean et al. (63) compared bilateral neck exploration, unilateral neck exploration, video-assisted parathyroidectomy, and medical monitoring. The base case scenario was a 55-yr-old woman with asymptomatic sporadic PHPT, and the time horizon was the remaining life expectancy. The authors found that monitoring was less costly but less effective than surgery. Both minimally invasive strategies were more effective than bilateral neck exploration or monitoring, although slightly more costly due to the cost of localization studies. Sensitivity analysis found that surgery remained more effective than monitoring when the age used in the base-case scenario varied between 40 and 80 yr.

Zanocco et al. (64) compared monitoring, pharmacological therapy (i.e. calcimimetics, bisphosphonates, calcitonin, etc.), and parathyroidectomy for sporadic asymptomatic PHPT. The model’s reference case scenario was a 60-yr-old patient who did not meet the 2002 NIH criteria for parathyroidectomy, and the time horizon for the analysis was the patient’s remaining life expectancy. The authors found that monitoring was the least expensive but least effective option. Both inpatient and outpatient parathyroidectomy were cost-effective. Pharmacological therapy was not cost-effective unless the annual cost was less than $221 (2005 U.S. dollars). The incremental cost-effectiveness ratio for cinacalcet was greater than $20 million per quality adjusted life year.

Zanocco et al. (65) examined how age at diagnosis impacts treatment decisions in sporadic asymptomatic PHPT. They compared monitoring, pharmacological therapy, and parathyroidectomy for sporadic asymptomatic PHPT. In the base case scenario, the age at diagnosis was varied. Threshold analysis identified the optimal treatment strategy of life expectancies ranging from 6 months to 75 yr. The authors found that parathyroidectomy was cost effective for patients with a predicted life expectancy of 5 yr (outpatient parathyroidectomy) or 6.5 yr (inpatient parathyroidectomy). For patients with a shorter life expectancy, observation was the most cost-effective strategy. Pharmacological therapy was not found to be cost effective at any age modeled.

The competing strategies evaluated in these three studies were observation, parathyroidectomy, and pharmacological therapy for hypercalcemia. In each study, the strategy of medical monitoring was found to be less effective than surgery. Surgery was found to be less costly and more effective than pharmacological therapy. The conclusion from these formal studies is that parathyroidectomy is a cost-effective treatment strategy for asymptomatic PHPT.

	Summary and Conclusions

Top Abstract Introduction Question 1. What are... Question 2. Who should... Question 3. What is... Question 4. What is... Question 5. What operative... Question 6. Is parathyroid... Summary and Conclusions References

 
Patients who have overt signs and symptoms of PHPT are symptomatic and in almost all cases benefit from parathyroidectomy. Patients who appear to have asymptomatic PHPT frequently have significant neurocognitive compromise that is only appreciated after a successful parathyroidectomy has unmasked their symptoms. In addition, cohort studies suggest that patients with asymptomatic PHPT often have diminution in bone density and perhaps an increase in fracture rates that improve with parathyroidectomy.

Patients with biochemically confirmed PHPT should be referred to an experienced parathyroid surgeon for consultation. If surgery is to be performed, the surgeon should organize the imaging studies that are obtained to localize abnormal parathyroid glands. Imaging studies are not appropriate for confirming the diagnosis of PHPT or for screening patients for surgical referral. Negative imaging should not preclude surgical referral or intervention. The success rate of an experienced endocrine surgeon is consistently superior to the true positive rate of imaging.

The type of operative procedure and the employment of operative adjuncts is highly institution specific and should be based on the expertise and resource availability of the surgeon and institution. Parathyroid surgery when performed by an experienced surgeon is safe, cost-effective, and associated with a very high rate of cure and very low rate of perioperative morbidity. Although some patients may elect nonoperative management, they should do so only after being informed of the apparent risks of nonoperative treatment. The authors believe the surgeon is the ideal individual to explain the risks, benefits, and alternatives to operative intervention.

	Acknowledgments

 
Dotty Franco and Marzena Jasinski are thanked for their assistance with the preparation of the manuscript.

	Footnotes

 
Disclosure Summary: All authors have nothing to declare.

Abbreviations: CEA, Cost-effectiveness analysis; CT, computed tomography; FNA, fine-needle aspiration; MRI, magnetic resonance imaging; PHPT, primary hyperparathyroidism; QOL, quality of life.

Received August 11, 2008.

Accepted November 14, 2008.

	References

Top Abstract Introduction Question 1. What are... Question 2. Who should... Question 3. What is... Question 4. What is... Question 5. What operative... Question 6. Is parathyroid... Summary and Conclusions References

 

1. Bilezikian JP, Potts Jr JT, Fuleihan Gel H, Kleerekoper M, Neer R, Peacock M, Rastad J, Silverberg SJ, Udelsman R, Wells SA 2002 Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab 87:5353–5361[Free Full Text]
2. Clark OH, Wilkes W, Siperstein AE, Duh QY 1991 Diagnosis and management of asymptomatic hyperparathyroidism: safety, efficacy, and deficiencies in our knowledge. J Bone Miner Res 6(Suppl 2):S135–S142; discussion, 151–152
3. Clark OH 1994 "Asymptomatic" primary hyperparathyroidism: is parathyroidectomy indicated? Surgery 116:947–953[Medline]
4. Clark OH 2003 How should patients with primary hyperparathyroidism be treated? J Clin Endocrinol Metab 88:3011–3014[Free Full Text]
5. Perrier ND 2005 Asymptomatic hyperparathyroidism: a medical misnomer? Surgery 137:127–131[CrossRef][Medline]
6. Hasse C, Sitter H, Bachmann S, Zielke A, Koller M, Nies C, Lorenz W, Rothmund M 2000 How asymptomatic is asymptomatic primary hyperparathyroidism? Exp Clin Endocrinol Diabetes 108:265–274[CrossRef][Medline]
7. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH 1995 Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy. A case-control study. Ann Surg 222:402–412; discussion, 412–414
8. Prager G, Kalaschek A, Kaczirek K, Passler C, Scheuba C, Sonneck G, Niederle B 2002 Parathyroidectomy improves concentration and retentiveness in patients with primary hyperparathyroidism. Surgery 132:930–935; discussion, 935–936
9. Sywak MS, Knowlton ST, Pasieka JL, Parsons LL, Jones J 2002 Do the National Institutes of Health consensus guidelines for parathyroidectomy predict symptom severity and surgical outcome in patients with primary hyperparathyroidism? Surgery 132:1013–1019; discussion, 1019–1020
10. Solomon BL, Schaaf M, Smallridge RC 1994 Psychologic symptoms before and after parathyroid surgery. Am J Med 96:101–106[CrossRef][Medline]
11. Pasieka JL, Parsons LL, Demeure MJ, Wilson S, Malycha P, Jones J, Krzywda B 2002 Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 26:942–949[CrossRef][Medline]
12. Mittendorf EA, Wefel JS, Meyers CA, Doherty D, Shapiro SE, Lee JE, Evans DB, Perrier ND 2007 Improvement of sleep disturbance and neurocognitive function after parathyroidectomy in patients with primary hyperparathyroidism. Endocr Pract 13:338–344[Medline]
13. Perrier ND, Coker LH, Rorie KD, Burbank NS, Kirkland KA, Passmore LV, Tembreull T, Stump DA, Laurienti PJ 2006 Preliminary report: functional MRI of the brain may be the ideal tool for evaluating neuropsychologic and sleep complaints of patients with primary hyperparathyroidism. World J Surg 30:686–696[CrossRef][Medline]
14. Mihai R, Sadler GP 2008 Pasieka’s parathyroid symptoms scores correlate with SF-36 scores in patients undergoing surgery for primary hyperparathyroidism. World J Surg 32:807–814[CrossRef][Medline]
15. Scholz DA, Purnell DC 1981 Asymptomatic primary hyperparathyroidism. 10-year prospective study. Mayo Clin Proc 56:473–478[Medline]
16. Okamoto T, Gerstein HC, Obara T 1997 Psychiatric symptoms, bone density and non-specific symptoms in patients with mild hypercalcemia due to primary hyperparathyroidism: a systematic overview of the literature. Endocr J 44:367–374[Medline]
17. Joborn C, Hetta J, Johansson H, Rastad J, Agren H, Akerstrom G, Ljunghall S 1988 Psychiatric morbidity in primary hyperparathyroidism. World J Surg 12:476–481[CrossRef][Medline]
18. Lundgren E, Ljunghall S, Akerstrom G, Hetta J, Mallmin H, Rastad J 1998 Case-control study on symptoms and signs of "asymptomatic" primary hyperparathyroidism. Surgery 124:980–985; discussion, 985–986
19. Coker LH, Rorie K, Cantley L, Kirkland K, Stump D, Burbank N, Tembreull T, Williamson J, Perrier N 2005 Primary hyperparathyroidism, cognition, and health-related quality of life. Ann Surg 242:642–650[CrossRef][Medline]
20. Eigelberger MS, Cheah WK, Ituarte PH, Streja L, Duh QY, Clark OH 2004 The NIH criteria for parathyroidectomy in asymptomatic primary hyperparathyroidism; are they too limited? Ann Surg 239:1–8[Medline]
21. Pasieka JL, Parsons LL 1998 Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg 22:513–518; discussion, 518–519
22. Talpos GB, Bone 3rd HG, Kleerekoper M, Phillips ER, Alam M, Honasoge M, Divine GW, Rao DS 2000 Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey. Surgery 128:1013–1020; discussion, 1020–1021
23. Bollerslev J, Jansson S, Mollerup CL, Nordenstrom J, Lundgren E, Torring O, Varhaug JE, Baranowski M, Aanderud S, Franco C, Freyschuss B, Isaksen GA, Ueland T, Rosen T 2007 Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab 92:1687–1692[Abstract/Free Full Text]
24. Vander Walde LH, Liu IL, O'Connell TX, Haigh PI 2006 The effect of parathyroidectomy on bone fracture risk in patients with primary hyperparathyroidism. Arch Surg 141:885–889; discussion, 889–891
25. Vestergaard P, Mollerup CL, Frokjaer VG, Christiansen P, Blichert-Toft M, Mosekilde L 2000 Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 321:598–602[Abstract/Free Full Text]
26. Nomura R, Sugimoto T, Tsukamoto T, Yamauchi M, Sowa H, Chen Q, Yamaguchi T, Kobayashi A, Chihara K 2004 Marked and sustained increase in bone mineral density after parathyroidectomy in patients with primary hyperparathyroidism; a six-year longitudinal study with or without parathyroidectomy in a Japanese population. Clin Endocrinol (Oxf) 60:335–342[CrossRef][Medline]
27. Deaconson TF, Wilson SD, Lemann Jr J 1987 The effect of parathyroidectomy on the recurrence of nephrolithiasis. Surgery 102:910–913[Medline]
28. Hedback G, Abrahamsson K, Oden A 2001 The improvement of renal concentration capacity after surgery for primary hyperparathyroidism. Eur J Clin Invest 31:1048–1053[CrossRef][Medline]
29. Mitlak BH, Daly M, Potts Jr JT, Schoenfeld D, Neer RM 1991 Asymptomatic primary hyperparathyroidism. J Bone Miner Res 6(Suppl 2):S103–S110; discussion, S121–S124
30. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP 1999 A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 341:1249–1255[Abstract/Free Full Text]
31. Hellstrom J, Birke G, Edvall CA 1958 Hypertension in hyperparathyroidism. Br J Urol 30:13–24[Medline]
32. Heath 3rd H 1991 Clinical spectrum of primary hyperparathyroidism: evolution with changes in medical practice and technology. J Bone Miner Res 6(Suppl 2):S63–S70; discussion, S83—S84
33. Lafferty FW, Hubay CA 1989 Primary hyperparathyroidism. A review of the long-term surgical and nonsurgical morbidities as a basis for a rational approach to treatment. Arch Intern Med 149:789–796[Abstract/Free Full Text]
34. Uden P, Chan A, Duh QY, Siperstein A, Clark OH 1992 Primary hyperparathyroidism in younger and older patients: symptoms and outcome of surgery. World J Surg 16:791–797; discussion, 798
35. Piovesan A, Molineri N, Casasso F, Emmolo I, Ugliengo G, Cesario F, Borretta G 1999 Left ventricular hypertrophy in primary hyperparathyroidism. Effects of successful parathyroidectomy. Clin Endocrinol (Oxf) 50:321–328[CrossRef][Medline]
36. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, Shea S, Szklo M, Bluemke DA, O'Leary DH, Tracy R, Watson K, Wong ND, Kronmal RA 2008 Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 358:1336–1345[Abstract/Free Full Text]
37. Vestergaard P, Mollerup CL, Frokjaer VG, Christiansen P, Blichert-Toft M, Mosekilde L 2003 Cardiovascular events before and after surgery for primary hyperparathyroidism. World J Surg 27:216–222[Medline]
38. Stefenelli T, Abela C, Frank H, Koller-Strametz J, Globits S, Bergler-Klein J, Niederle B 1997 Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up. J Clin Endocrinol Metab 82:106–112[Abstract/Free Full Text]
39. Palmer M, Adami HO, Bergstrom R, Jakobsson S, Akerstrom G, Ljunghall S 1987 Survival and renal function in untreated hypercalcaemia. Population-based cohort study with 14 years of follow-up. Lancet 1:59–62[Medline]
40. Hedback G, Oden A 1998 Increased risk of death from primary hyperparathyroidism–an update. Eur J Clin Invest 28:271–276[CrossRef][Medline]
41. Leifsson BG, Ahren B 1996 Serum calcium and survival in a large health screening program. J Clin Endocrinol Metab 81:2149–2153[Abstract]
42. Wermers RA, Khosla S, Atkinson EJ, Grant CS, Hodgson SF, O'Fallon WM, Melton 3rd LJ 1998 Survival after the diagnosis of hyperparathyroidism: a population-based study. Am J Med 104:115–122[CrossRef][Medline]
43. Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA, Udelsman R 1998 The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg 228:320–330[CrossRef][Medline]
44. Stavrakis AI, Ituarte PH, Ko CY, Yeh MW 2007 Surgeon volume as a predictor of outcomes in inpatient and outpatient endocrine surgery. Surgery 142:887–899[CrossRef][Medline]
45. Harness JK, Organ Jr CH, Thompson NW 1995 Operative experience of U.S. general surgery residents in thyroid and parathyroid disease. Surgery 118:1063–1069; discussion, 1069–1070
46. Pappu S, Donovan P, Cheng D, Udelsman R 2005 Sestamibi scans are not all created equally. Arch Surg 140:383–386[Abstract/Free Full Text]
47. Van Husen R, Kim LT 2004 Accuracy of surgeon-performed ultrasound in parathyroid localization. World J Surg 28:1122–1126[CrossRef][Medline]
48. Civelek AC, Ozalp E, Donovan P, Udelsman R 2002 Prospective evaluation of delayed technetium-99m sestamibi SPECT scintigraphy for preoperative localization of primary hyperparathyroidism. Surgery 131:149–157[CrossRef][Medline]
49. Mortenson MM, Evans DB, Lee JE, Hunter GJ, Shellingerhout D, Vu T, Edeiken BS, Feng L, Perrier ND 2008 Parathyroid exploration in the reoperative neck: improved preoperative localization with 4D-computed tomography. J Am Coll Surg 206:888–895; discussion, 895–896
50. Johnson NA, Tublin ME, Ogilvie JB 2007 Parathyroid imaging: technique and role in the preoperative evaluation of primary hyperparathyroidism. AJR Am J Roentgenol 188:1706–1715[Abstract/Free Full Text]
51. Maser C, Donovan P, Santos F, Donabedian R, Rinder C, Scout L, Udelsman R 2006 Sonographically guided fine needle aspiration with rapid parathyroid hormone assay. Ann Surg Oncol 13:1690–1695[CrossRef][Medline]
52. Udelsman R, Donovan PI 2006 Remedial parathyroid surgery: changing trends in 130 consecutive cases. Ann Surg 244:471–479[Medline]
53. Mandl F 1926 Therapeutisher versuch bein falls von ostitis fibrosa generalisata mittles. Wien Klin Wochenshr Zentral 53:260–264
54. Udelsman R 2002 Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 235:665–670; discussion, 670–672
55. Irvin 3rd GL, Solorzano CC, Carneiro DM 2004 Quick intraoperative parathyroid hormone assay: surgical adjunct to allow limited parathyroidectomy, improve success rate, and predict outcome. World J Surg 28:1287–1292[CrossRef][Medline]
56. Miccoli P, Berti P, Materazzi G, Ambrosini CE, Fregoli L, Donatini G 2008 Endoscopic bilateral neck exploration versus quick intraoperative parathormone assay (qPTHa) during endoscopic parathyroidectomy: a prospective randomized trial. Surg Endosc 22:398–400[CrossRef][Medline]
57. Henry JF, Sebag F, Tamagnini P, Forman C, Silaghi H 2004 Endoscopic parathyroid surgery: results of 365 consecutive procedures. World J Surg 28:1219–1223[CrossRef][Medline]
58. Westerdahl J, Bergenfelz A 2007 Unilateral versus bilateral neck exploration for primary hyperparathyroidism: five-year follow-up of a randomized controlled trial. Ann Surg 246:976–980; discussion, 980–981
59. Russell CF, Dolan SJ, Laird JD 2006 Randomized clinical trial comparing scan-directed unilateral versus bilateral cervical exploration for primary hyperparathyroidism due to solitary adenoma. Br J Surg 93:418–421[CrossRef][Medline]
60. Chen H, Mack E, Starling JR 2005 A comprehensive evaluation of perioperative adjuncts during minimally invasive parathyroidectomy: which is most reliable? Ann Surg 242:375–380; discussion, 380–383
61. Heath 3rd H, Hodgson SF, Kennedy MA 1980 Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community. N Engl J Med 302:189–193[Abstract]
62. Gold MR 1996 Cost-effectiveness in health and medicine. New York: Oxford University Press
63. Sejean K, Calmus S, Durand-Zaleski I, Bonnichon P, Thomopoulos P, Cormier C, Legmann P, Richard B, Bertagna XY, Vidal-Trecan GM 2005 Surgery versus medical follow-up in patients with asymptomatic primary hyperparathyroidism: a decision analysis. Eur J Endocrinol 153:915–927[Abstract/Free Full Text]
64. Zanocco K, Angelos P, Sturgeon C 2006 Cost-effectiveness analysis of parathyroidectomy for asymptomatic primary hyperparathyroidism. Surgery 140:874–881; discussion, 881–882
65. Zanocco K, Sturgeon C 2008 How should age at diagnosis impact treatment strategy in asymptomatic primary hyperparathyroidism? A cost-effectiveness analysis. Surgery 144:290–298[CrossRef][Medline]

This article has been cited by other articles:

				J. P. Bilezikian, A. A. Khan, J. T. Potts Jr, and on behalf of the Third International Workshop on t Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Third International Workshop J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 335 - 339. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Udelsman, R. Articles by Clark, O. H. Search for Related Content PubMed PubMed Citation Articles by Udelsman, R. Articles by Clark, O. H. Related Collections Calcium and Bone Metabolism Endocrine Oncology