This Article Abstract Full Text (PDF) CME: Take the course for this article: Primary Hyperparathyroidism eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link 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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Suliburk, J. W. Articles by Perrier, N. D. Search for Related Content PubMed PubMed Citation Articles by Suliburk, J. W. Articles by Perrier, N. D.

Endocrinology

Primary Hyperparathyroidism

^aUniversity of Texas Medical School at Houston, Department of General Surgery, Houston, Texas, USA; ^bThe University of Texas M.D. Anderson Cancer Center, Department of Surgical Oncology, Houston, Texas, USA

Key Words. Primary hyperparathyroidism • Hypercalcemia • Parathyroidectomy • Asymptomatic hyperparathyroidism

Correspondence: Correspondence: Nancy D. Perrier, M.D., F.A.C.S., P. O. Box 301402, Unit 444, Houston, Texas 77230-1402, USA. Telephone: 713-794-1345; Fax: 713-745-1462; e-mail: nperrier{at}mdanderson.org

Received October 27, 2006; accepted for publication March 14, 2007.

	Learning Objectives

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
After completing this course, the reader will be able to:

1. Discuss the pathophysiology of primary hyperparathyroidism.
   
2. Discuss the clinical presentation, diagnosis, and treatment options for primary hyperparathyroidism.
   
3. Discuss cure of disease and recurrent or persistent disease.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
Primary hyperparathyroidism (PHPT) is classically thought of as the somatic manifestation of hypercalcemia in which patients suffer from a variety of complaints including abdominal pain, nephrolithiasis, osteopenia, and mental status changes. Contemporary PHPT patients are generally free of somatic manifestations and are most often diagnosed when routine biochemical testing shows an elevated serum calcium level. The modern day patient may present with much more subtle neurocognitive symptoms including fatigue, lethargy, muscle weakness, depression, and cognitive impairment. Advances in imaging technology, intraoperative parathyroid hormone measurement, and surgical technique now allow parathyroidectomy to be performed using a focused approach without the absolute need of a four-gland exploration. Minimally invasive techniques allow the procedure to be accomplished under local anesthesia on an outpatient basis. This brief review summarizes the presentation, biochemical evaluation, operative intervention, and follow-up care of the modern day PHPT patient.

Disclosure of potential conflicts of interest is found at the end of this article.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
Primary hyperparathyroidism (PHPT) is a generalized disorder of calcium metabolism resulting from abnormally high levels of serum calcium and an increased level of parathyroid hormone (PTH). PHPT is the most common cause of hypercalcemia in outpatients and has an incidence of approximately 25 cases per 100,000 persons in the general population [1]. The incidence increases with age, and PHPT is four times more common in women than men.

Traditionally, symptomatic PHPT patients presented with a variety of disorders including recurrent kidney stones, osteopenia, hypertension, peptic ulcer disease, mental status changes, and fatigue. However, the modern patient is often termed "asymptomatic, " having no somatic manifestations of disease. Such patients may in fact have vague neurocognitive symptoms or altered quality of life (pain, fatigue, depression, etc.) that may not be recognized as being associated with PHPT.

Most cases of PHPT are caused by a single enlarged parathyroid gland (80%–89%). Multiglandular involvement is less common and may be associated with the multiple endocrine neoplasia syndromes MEN I (hyperparathyroidism, pituitary adenomas, and pancreatic neuroendocrine tumors) and MEN IIa (medullary thyroid cancer, hyperparathyroidism, and pheochromocytomas). The purpose of this article is to briefly review the presentation and workup of PHPT.

	BACKGROUND

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
The first parathyroidectomy was performed by Mandl in 1925 in Vienna; he removed an enlarged parathyroid gland to cure a street car driver who had osteitis fibrosa cystica [2]. In the U.S., the first parathyroidectomy was performed in 1926 on sea captain Charles Martell, who was cured after a sixth operation finally removed an adenoma from beneath his sternum [3].

Thorough knowledge of the anatomy and embryology of the parathyroid glands is essential for successful parathyroid gland surgery. The descent of the inferior glands from the third branchial pouch and the superior glands from the fourth branchial pouch during fetal development results in variability in the locations of the parathyroid glands (Fig. 1). The normal superior glands are generally found on the posterior surface of the thyroid approximately 1 cm above the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. Enlarged glands may fall posteriorly into the tracheoesophageal groove. The normal inferior glands are more variable in location but are most commonly found on the posterolateral aspect of the inferior pole of the thyroid gland. When enlarged, the inferior glands may be located in the thymus or within the thyroid. Glands that do not drop in a usual fashion during development may lodge near the bifurcation of the carotid artery.

View larger version (49K): [in this window] [in a new window]   Figure 1. Usual locations of parathyroid adenomata. These positions apply to left- or right-sided glands. (A): Superior gland on the posterior surface of the thyroid capsule; may be confined within the thyroid capsule. (B): Superior gland in the tracheoesophageal groove lying between the cranial and caudal boundaries of the thyroid gland. (C): Superior gland in the tracheoesophageal groove caudal and inferior to the thyroid gland and with no contact with the thyroid gland. (D): Superior or inferior gland near the junction of the recurrent laryngeal nerve and the inferior thyroid artery. (E): Inferior gland that lies anterior to the trachea and just inferior to the thyroid parenchyma. (F): Inferior gland descended into the thyrothymic ligament. (G): superior or inferior parathyroid gland located within the thyroid gland.

Asymptomatic Hyperparathyroidism
The advent of automated laboratory serum analyzers in the 1960s allowed for the detection of what was then considered asymptomatic hypercalcemia, and the incidence of PHPT increased by fivefold during the next two decades. In fact, today the first sign of PHPT is frequently an elevated serum calcium value on a routine biochemical evaluation. A detailed history may reveal a variety of vague neurocognitive complaints including depression, easy fatigability, proximal muscle weakness, lethargy, and an overall feeling of dullness (Table 1). The nature of these unquantifiable complaints makes the disease presentation difficult to assess, yet these are now the most common presenting symptoms of PHPT. This group of modern PHPT patients has been termed "asymptomatic."

	DIAGNOSIS

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
It is important to note that the severity of hypercalcemia is not directly correlated with the severity of symptoms in PHPT [7]. When evaluating a patient with possible PHPT, the differential diagnosis includes all disorders that can cause hypercalcemia. Aside from PHPT, malignancy is the second most common cause of hypercalcemia in the general population. Other causes of hypercalcemia include sarcoidosis, lithium intake, diuretic use, tamoxifen, milk alkali syndrome, vitamin D deficiency, increased calcium intake, adrenal insufficiency, and thyrotoxicosis [15].

The diagnosis of PHPT can be made most simply by the presence of an increased serum calcium level in conjunction with an inappropriately elevated intact PTH (iPTH) level. This assay, known as a "two site test," recognizes the complete 84-amino-acid PTH molecule and incorporates two different antibodies that bind to unique sites on the complete PTH molecule, forming a sandwich that discriminates the intact PTH molecule from PTH-related protein. The assay possesses excellent specificity and sensitivity, rarely giving false positives. Nonparathyroid tumors that produce iPTH are extremely rare, but examples may include ovarian tumors, thymomas, and small cell lung cancers.

The clinician must also take a careful history to ensure that the patient is not taking lithium or thiazide diuretics as these can confound biochemical testing. The combined criteria of increased calcium and inappropriately increased PTH without confounding factors have a sensitivity and specificity approaching >95% for diagnosing classic PHPT.

	INDICATIONS FOR SURGICAL REFERRAL

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
Parathyroidectomy is the only curative therapy for PHPT. Any patient with a known complication of PHPT such as nephrocalcinosis, osteoporosis (T score less than –2.5 standard deviations [SD] at the lumbar spine, hip, or wrist), peptic ulcer disease, pancreatitis, or severe neuromuscular symptoms should be referred for surgical intervention. However, most patients with PHPT will be "asymptomatic" and may only have vague neurocognitive symptoms as discussed above.

To address the management of these asymptomatic patients, the National Institutes of Health (NIH) Consensus Development Panel convened in 1990 and again in 2002. The panel recommended parathyroidectomy for the following asymptomatic patients: (a) patients <50 years old, (b) patients who cannot participate in appropriate follow-up, (c) patients with a serum calcium level >1.0 mg/dl above the normal reference range, (d) patients with a urinary calcium level >400 mg/24 hours, and (e) patients with a 30% decrease in renal function (Table 2) [16].

It is important to note that there are no data to support the long-term efficacy of medical therapy or observation. In fact, a 51-year-old woman with asymptomatic PHPT that does not meet NIH criteria for surgery could need more than 20 years of follow-up and monitoring over the course of her life if observation is elected. Additionally, anywhere between 25% and 62% of patients who are observed will have disease progression [17]. Furthermore, studies indicate that both patients who do and do not meet the 2002 NIH criteria have substantial improvements in neurocognitive symptoms following parathyroidectomy [18, 19]. Because of this, the American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons issued a joint statement indicating that any asymptomatic PHPT patient with a reasonable life expectancy and minimal operative risk should be referred for surgical consultation [20]. The risk–benefit ratio should be discussed by the surgeon and the patient, taking into consideration the expertise and experience of the individual surgeon.

	PREOPERATIVE WORKUP

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
As part of the evaluation of PHPT, there are several baseline tests that all patients should undergo.

Bone Mineral Density Measurement
Bone mineral density should be evaluated by a dual-energy x-ray absorptiometry (DEXA) scan. Assessment of the lumbar spine, hip, and distal radius is necessary. A T score less than –2.5 SD is an indication for surgical intervention. Studies indicate that following successful parathyroidectomy, patients will have improved bone mineral density as early as 1 year after surgery [12, 21, 22].

24-Hour Urine Collection
A 24-hour urine collection for measurement of calcium and creatinine should be obtained to distinguish patients who have the uncommon, benign disorder known as familial hypercalcemic hypocalciuria (FHH). A 24-hour urine calcium level <100 mg/l is consistent with FHH. Generally, FHH patients have mild hypercalcemia in combination with high-normal or slightly above normal iPTH levels and a calcium-to-creatinine clearance ratio <0.01. These patients do not benefit from parathyroidectomy. A 24-hour urine collection for calcium also is beneficial in asymptomatic PHPT patients as calcium excretion levels >400 mg/24 hours may predict future complications of PHPT [17]. A urinary calcium level >400 mg/24 hours is also an indication for surgical intervention.

Serum Vitamin D and Alkaline Phosphatase
Vitamin D deficiency is becoming increasingly common and may mimic PHPT on laboratory evaluation. The same population that is most likely to develop PHPT is also likely to develop vitamin D deficiency as a result of lifestyle changes that minimize outdoor exposure to sunlight. Patients with vitamin D deficiency have low 25-hydroxyvitamin D levels, and this can stimulate PTH production, resulting in secondary hyperparathyroidism. Thus, patients found to have low levels of vitamin D should first undergo vitamin D replacement and then have serum calcium and PTH levels re-evaluated to distinguish those with PHPT from those with secondary hyperparathyroidism resulting from vitamin D deficiency. Our preferred treatment of this vitamin D deficiency is ergocalciferol, 50,000 U given orally twice weekly for 4–6 weeks. The goal is to bring the vitamin D level to at least 30 ng/dl. The patient is then placed on a maintenance ergocalciferol regimen of 2,600 IU daily for at least 1 month and biochemical testing for PHPT is repeated. If the PTH level significantly decreased while vitamin D increased, the diagnosis of secondary hyperparathyroidism is suspected.

Another important biochemical marker to assess preoperatively is serum alkaline phosphatase. Patients with elevated serum alkaline phosphatase but normal liver transaminase levels are likely to have high-turnover bone disease and are susceptible to postparathyroidectomy hypocalcemia. An elevated preoperative alkaline phosphatase level alerts the physician to possible "bone hunger" following surgical cure of PHPT. These patients may be at higher risk for needing postoperative treatment with oral and sometimes i.v. calcium as well as magnesium to avoid complications of severe hypocalcemia such as tetany and cardiac arrhythmias.

Imaging
Imaging techniques have no role in the diagnosis of PHPT but are helpful for preoperative localization of solitary enlarged parathyroid glands (adenomas). Useful modalities include sestamibi scanning, ultrasonography, magnetic resonance imaging (MRI), and, most recently, high-resolution four-dimensional computed tomography (4D CT). If a minimally invasive operative approach is being considered, preoperative localization is essential to determine where to actually begin the operation. Preoperative imaging is unnecessary if a four-gland exploration is to be performed.

Technetium 99m sestamibi scintigraphy (Fig. 2A) was first used to study cardiac function. Its role in parathyroid localization is based on the greater uptake of the isotope by the mitochondria of the parathyroid cells in hyperactive glands relative to the uptake by the neighboring thyroid tissue or suppressed parathyroid glands. The sensitivity of sestamibi scanning for detection of adenoma varies from 60% to 85%. A common source of false-positive results is the coexistence of thyroid nodules. False-negative results may be caused by the small size of a parathyroid gland. Sestamibi scanning is not accurate in patients with multiglandular disease and may give the false impression that only one gland is involved because it may uptake more isotope than the other glands. Sestamibi results should be correlated with ultrasound or another anatomic study.

View larger version (47K): [in this window] [in a new window]   Figure 2. Parathyroid adenoma imaging. (A): Sestamibi scan showing an enhancing left inferior parathyroid gland. (B): Single-photon emission computed tomography reconstruction showing contrast enhancement as a surrogate of the adenoma's hyperfunction. (C): Four-dimensional computed tomography reconstruction demonstrating a left inferior parathyroid adenoma.

MRI can be an especially useful test for identifying ectopic parathyroid glands. The test can be done instead of CT in patients allergic to i.v. contrast materials, but it is more expensive and thus less cost-effective than other imaging modalities. MRI may be confounded by adenomas being situated close to a thyroid goiter or thyroid nodules as well as by lymphadenopathy [24].

Traditional CT has had limited utility in imaging parathyroid adenomas. However, recent advances in the resolution of CT have allowed it to visualize structures in fine detail. We have recently begun imaging the neck using a technique known as 4D CT (Fig. 2C). 4D CT involves CT angiography of the neck using 1-mm slices with blood perfusion to the parathyroid gland calculated as perfusion over time. This calculation is extrapolated and used as a surrogate indicator of gland function. Thus, detailed information regarding both the function of the glands and anatomic location is obtained with one test [25].

	TECHNIQUES OF PARATHYROIDECTOMY

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
Parathyroidectomy may be performed via several different techniques. Traditionally, the operation has been a standard exploration to identify all four parathyroid glands via a transverse incision on the neck. Today, advances in surgical technique as well as preoperative localization permit "focused parathyroidectomy" to be performed either through a small unilateral incision that allows direct visualization (minimally invasive parathyroidectomy) or through subcentimeter incisions on the anterior or lateral neck that enable insertion of a videoscope and surgical instruments (endoscopic parathyroidectomy).

Minimally Invasive Parathyroidectomy
Minimally invasive parathyroidectomy allows patients to undergo parathyroidectomy on an outpatient basis via a modest (2 cm) incision on one side of the neck (Fig. 3). With the availability of adequate preoperative imaging, minimally invasive parathyroidectomy is becoming the most common way to perform parathyroidectomy, surpassing the traditional four-gland exploration. Patients must be carefully selected for minimally invasive parathyroidectomy to ensure that only a single adenoma exists. Prior neck surgery is not a contraindication, and in fact a minimally invasive approach may be preferred in this setting as it will allow a direct approach to the adenoma in the scarred neck tissue.

View larger version (98K): [in this window] [in a new window]   Figure 3. Incision used for a minimally invasive parathyroidectomy.

View larger version (10K): [in this window] [in a new window]   Figure 4. Intraoperative parathyroid hormone (IOPTH) measurements showing an appropriate decrease in PTH levels 5 minutes and 10 minutes after excision of an adenoma.

Four-Gland Exploration
The traditional and gold standard procedure for PHPT is a bilateral neck exploration to identify all four parathyroid glands and remove the adenoma or adenomas. In patients who have parathyroid hyperplasia (i.e., all glands are found to be enlarged at the time of operation), subtotal parathyroidectomy with removal of three and one half glands is usually performed. Total parathyroidectomy with autotransplantation of parathyroid tissue at a distant site is usually reserved for reoperative cases or patients with known MEN I or MEN IIa.

Four-gland exploration is best performed using a general anesthetic. The incision is made approximately 2 cm above the sternal notch and follows the skin lines transversely across the anterior neck. Identification of the recurrent laryngeal nerves and all four parathyroid glands is essential. When performed by an experienced endocrine surgeon, this procedure has a cure rate exceeding 95% [27].

When a gland is not found in a normal location, systematic exploration for the gland is undertaken based on knowledge of embryologic migration and anatomy. This includes exploration of the tracheoesophageal groove, the paraesophageal area, the carotid sheath, and the thymus. While a cervical thymectomy may be performed, exploration of the mediastinum is never done at the first operation. The mediastinum is explored only in patients who have a gland clearly localized to the mediastinum after careful evaluation and a proper cervical operation.

Endoscopic Parathyroidectomy
Endoscopic parathyroidectomy, also termed videoscopic parathyroidectomy, allows for detailed visualization of the delicate nerves and blood vessels surrounding the parathyroid glands. Like minimally invasive parathyroidectomy, endoscopic parathyroidectomy is best performed with the aid of preoperative localization studies as well as IOPTH monitoring.

Several different approaches are used for this technique. The first is an "anterior" approach, which uses a 10- to 15-mm incision just above the sternal notch for the entrance of the camera and endoscopic instruments. The anterior approach permits bilateral exploration if needed and, as described by Miccoli et al. [28, 29], no gas insufflation is used.

The second approach, the "lateral" approach advocated by Henry et al. [30, 31], uses one 5-mm and two 2-mm incisions adjacent to the sternocleidomastoid to facilitate the introduction of a camera and instruments. This approach does not allow the parathyroid glands on the contralateral side to be explored. The lateral approach is best for glands that are positioned posteriorly in the tracheoesophageal groove. Gas insufflation of the neck is employed to assist with exposure, and pressures are kept low to avoid significant s.c. emphysema. The procedure is most often performed using a general anesthetic and requires an overnight stay for observation.

The transaxillary approach has also been described for endoscopic parathyroidectomy [32]. This procedure avoids any scars on the neck. However, the operation is technically challenging, and its use should be restricted to centers that have surgeons with extensive experience with this approach.

	POSTOPERATIVE MANAGEMENT

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
The immediate postoperative management of the postparathyroidectomy patient focuses particular attention on the airway. The patient must be observed to ensure that there is no expanding hematoma in the surgical wound that may lead to venous congestion and glottic closure with resultant airway compromise. Antiemetics should be used liberally to limit nausea and vomiting, which could also lead to inadvertent wretching and suture dislodgement. With minimally invasive parathyroidectomy, patients may be discharged after a 4- to 6-hour observation period because minimal dissection has taken place (i.e., no violation of contralateral fascial planes). Patients who undergo a four-gland exploration or endoscopic exploration are generally observed overnight following surgery and may be discharged within 12–36 hours after surgery. Analgesics are used to control pain, which is usually minimal. Rarely is narcotic pain medication necessary to manage discomfort from the surgical incision.

Approximately 2% of patients who undergo minimally invasive parathyroidectomy will develop mildly symptomatic, transient hypocalcemia secondary to hungry bone syndrome. This is particularly true for patients who have an elevated serum alkaline phosphatase level preoperatively. Given that hypoparathyroidism is unlikely after minimally invasive parathyroidectomy because the normal glands have not been manipulated or devascularized, it is safe to discharge patients with only mild hypocalcemia with a plan for clinical monitoring of PTH and calcium levels. Appropriate patient education about the symptoms of hypocalcemia and the liberal use of calcium replacement therapy is necessary prior to discharge.

In contrast, patients undergoing four-gland exploration do need to be monitored postoperatively for the development of hypocalcemia resulting from aparathyroidism. Because of the possibility of devascularization of the pedicles of the normal parathyroid glands during four-gland exploration, these patients are at highest risk to develop hypocalcemia after parathyroidectomy and may need calcitriol (0.25–1 µg orally) to maintain normal serum levels of calcium postoperatively [33, 34]. Generally, the hypocalcemia will resolve spontaneously as the remaining previously suppressed parathyroid tissue begins to function again. Postoperative assessment of the PTH levels is useful to follow residual parathyroid gland function.

Regardless of the surgical technique used, patients return for postoperative evaluation 1–2 weeks after discharge. At this time, the surgical site is checked, and the patient is asked about possible symptoms of hypocalcemia. Serum levels of calcium, PTH, alkaline phosphatase, and vitamin D are also evaluated. Normalization of the calcium level suggests cure. An elevated PTH level in the postoperative setting should not be confused with persistent disease if the serum calcium level is normal. Such an elevation can be caused by an appropriate rise as a result of hungry bone syndrome. Assuming a normal postoperative evaluation, the patient is seen again in 6 months to reassess serum calcium levels and ensure cure.

	CURE AND RECURRENT OR PERSISTENT DISEASE

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
Cure of PHPT can be defined as normocalcemia 6 months after surgery irrespective of the level of PTH. Confirmed documentation of hypercalcemia within 6 months following parathyroidectomy is defined as persistent disease. Hypercalcemia documented 6 months or longer following parathyroidectomy is defined as recurrent disease [35].

Persistent or recurrent disease may be caused by several factors. Surgeon inexperience and an incomplete exploration are major contributors to initial treatment failure. Surgical success requires the ability to discern an abnormal gland among the anatomic structures in the neck. Supernumerary glands may also contribute to failure of the initial operation in up to 39% of cases of recurrent and or persistent disease [36]. Double adenomas occur in approximately 4% of cases; failure to identify double adenomas can be a result of false localization studies, because such studies are less sensitive in multiglandular disease, as well as a result of the use of minimally invasive parathyroidectomy in which contralateral exploration is not performed. Hyperplasia of all four glands occurs in approximately 15% of cases of primary hyperparathyroidism and is a cause of failure in almost 40% of reoperative cases [35]. Hyperplasia may reflect either an incomplete resection during the initial operation (persistent disease) or ongoing growth of remaining tissue.

Treatment of persistent or recurrent disease must be undertaken by a surgeon with extensive experience in reoperative parathyroid surgery with the assistance of localization imaging. If noninvasive studies fail to identify abnormal gland(s), then invasive testing such as selective venous sampling and/or selective cervical angiography may be employed [37, 38]. We feel that, in the operating room, IOPTH can also be used as a very useful adjunct.

For any reoperative neck surgery, the benefits and risks of the surgical procedure must be re-evaluated as the potential for morbidity, including recurrent laryngeal nerve injury, is significantly increased. Patients with persistent or recurrent disease who are not fit to undergo surgical intervention or who refuse surgery may be offered medical therapy, alcohol ablation, etc. [39, 40]. However, surgical therapy remains the only cure for PHPT and is the most cost-effective treatment for the disease.

	CASE STUDY

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
The following case study is representative of what a clinician may encounter when treating a patient for primary hyperparathyroidism.

A 72-year-old woman presents for her annual checkup. She has no focused complaints but indicates that she doesn't seem to have energy anymore. She has not been sleeping well and can't seem to get her daily tasks done efficiently. She has a slightly flat affect, which she blames on being "tired." She weighs 11.3 kg more than at last year's wellness checkup and indicates that she doesn't do as much as she used to. The patient has a long history of hypertension, hypercholesterolemia, and adult-onset diabetes, and has been evaluated in the past for an incidental finding of thyroid nodules. She has undergone a hysterectomy and an excisional breast biopsy. Her current medications include metoprolol, 50 mg twice daily (BID); quinapril, 20 mg daily; metformin, 500 mg BID; simvastatin, 20 mg daily; gabapentin, 300 mg BID; and levothyroxine, 175 µg daily. The physical examination is unremarkable. The results of a routine electrolyte panel are within normal limits except for a calcium level of 11.2 mg/dl (high reference, 10.2 mg/dl). She is evaluated for hypercalcemia and found to have an iPTH level of 170 pg/dl (high reference, 71 pg/dl). Follow-up testing shows her 24-hour urinary calcium level to be 453 mg, her bone mineral density (T score) to be –2.2, and her vitamin D level to be 31 pg/nl. To evaluate her cognitive proficiency she is asked to recite serial sevens backwards from 100, and she falters on multiple attempts. She is diagnosed with PHPT and referred for surgical evaluation.

After discussion with an endocrine surgeon, she elects to have a minimally invasive parathyroidectomy, and localization studies are obtained including sestamibi scanning (Fig. 2A) and 4D CT (Fig. 2C). Both demonstrate a left inferior parathyroid adenoma. The patient requires minimal preoperative clearance for the procedure because it is performed using local anesthesia with light sedation (Fig. 3). The adenoma is removed and IOPTH confirms an appropriate reduction in PTH levels (Figs. 4 and 5). The operative procedure takes 55 minutes, and the patient is discharged later the same day.

View larger version (20K): [in this window] [in a new window]   Figure 5. Photograph of an excised adenoma.

	CONCLUSION

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
PHPT is a disease that can be cured by an experienced endocrine surgeon in >95% of cases. Parathyroidectomy alleviates both the classic symptoms of the disease as well as a variety of nonclassic, subjective symptoms that can affect quality of life [41]. Advances in surgical techniques now permit parathyroidectomy to be performed using local anesthesia and on an outpatient basis with excellent cosmetic results. Recurrent or persistent disease is uncommon but presents challenges and remains a small but complicated problem. Further refinement in imaging techniques and advances in the surgical treatment of PHPT will focus on improvements in the preoperative identification of all hyperfunctioning glands. Determining which patients will benefit from surgical intervention to improve the nonclassic, neurocognitive symptoms of "asymptomatic" PHPT is also warranted.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
The authors indicate no potential conflicts of interest.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 
This work was partially funded by the Jahnigan Grant from the American Geriatric Society.

	REFERENCES

Top Learning Objectives Abstract Introduction Background Diagnosis Indications for Surgical... Preoperative Workup Techniques of Parathyroidectomy Postoperative Management Cure and Recurrent or... Case Study Conclusion Disclosure of Potential... Acknowledgment References

 

1. Bilezikian JP, Silverberg SJ. Clinical practice. Asymptomatic primary hyperparathyroidism. N Engl J Med 2004;350:1746–1751.[Free Full Text]
2. Mandl F. Therapeutischer versuch ber ostitis fibrosa generalisata mittels extirpation eine epithelkorpercher-tumors. Wien Klin Wochenschr 1925;38:1343.
3. Bauer W, Albright F, Aub JC. A case of osteitis fibrosa cystica (osteomalacia?) with evidence of hyperactivity of the para-thyroid bodies. Metabolic study II. J Clin Invest 1930;8:229–248.[Medline]
4. Eigelberger MS, Clark OH. Surgical approaches to primary hyperparathyroidism. Endocrinol Metab Clin North Am 2000;29:479–502.[CrossRef][Medline]
5. Silverberg SJ, Bilezikian JP, Bone HG et al. Therapeutic controversies in primary hyperparathyroidism. J Clin Endocrinol Metab 1999;84:2275–2285.[Free Full Text]
6. Pasieka JL, Parsons LL, Demeure MJ et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg 2002;26:942–949.[CrossRef][Medline]
7. Perrier ND. Asymptomatic hyperparathyroidism: A medical misnomer? Surgery 2005;137:127–131.[CrossRef][Medline]
8. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med 1994;96:101–106.[CrossRef][Medline]
9. Larsson K, Ljunghall S, Krusemo UB et al. The risk of hip fractures in patients with primary hyperparathyroidism: A population-based cohort study with a follow-up of 19 years. J Intern Med 1993;234:585–593.[Medline]
10. Lundgren E, Lind L, Palmer M et al. Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years. Surgery 2001;130:978–985.[CrossRef][Medline]
11. Piovesan A, Molineri N, Casasso F et al. Left ventricular hypertrophy in primary hyperparathyroidism. Effects of successful parathyroidectomy. Clin Endocrinol (Oxf) 1999;50:321–328.[CrossRef][Medline]
12. Silverberg SJ, Locker FG, Bilezikian JP. Vertebral osteopenia: A new indication for surgery in primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:4007–4012.[Abstract/Free Full Text]
13. Vestergaard P, Mollerup CL, Frokjaer VG et al. Cardiovascular events before and after surgery for primary hyperparathyroidism. World J Surg 2003;27:216–222.[Medline]
14. Roman SA, Sosa JA, Mayes L et al. Parathyroidectomy improves neurocognitive deficits in patients with primary hyperparathyroidism. Surgery 2005;138:1121–1128; discussion 1128–1129.[CrossRef][Medline]
15. Jacobs TP, Bilezikian JP. Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab 2005;90:6316–6322.[Abstract/Free Full Text]
16. Bilezikian JP, Potts JT Jr, Fuleihan Gel-H et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: A perspective for the 21st century. J Bone Miner Res 2002;17(suppl 2):N2–N11.[Medline]
17. Silverberg SJ, Shane E, Jacobs TP et al. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249–1255.[Abstract/Free Full Text]
18. Eigelberger MS, Cheah WK, Ituarte PH et al. The NIH criteria for parathyroidectomy in asymptomatic primary hyperparathyroidism: Are they too limited? Ann Surg 2004;239:528–535.[CrossRef][Medline]
19. Sywak MS, Knowlton ST, Pasieka JL et al. Do the National Institutes of Health consensus guidelines for parathyroidectomy predict symptom severity and surgical outcome in patients with primary hyperparathyroidism? Surgery 2002;132:1013–1019; discussion 1019–1020.[CrossRef][Medline]
20. AACE/AAES Task Force on Primary Hyperparathyroidism. The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract 2005;11:49–54.[Medline]
21. Abdelhadi M, Nordenstrom J. Bone mineral recovery after parathyroidectomy in patients with primary and renal hyperparathyroidism. J Clin Endocrinol Metab 1998;83:3845–3851.[Abstract/Free Full Text]
22. Neer RM, Arnaud CD, Zanchetta JR et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434–1441.[Abstract/Free Full Text]
23. Gilat H, Cohen M, Feinmesser R et al. Minimally invasive procedure for resection of a parathyroid adenoma: The role of preoperative high-resolution ultrasonography. J Clin Ultrasound 2005;33:283–287.[CrossRef][Medline]
24. Ishibashi M, Nishida H, Hiromatsu Y et al. Comparison of technetium-99m-MIBI, technetium-99m-tetrofosmin, ultrasound and MRI for localization of abnormal parathyroid glands. J Nucl Med 1998;39:320–324.[Abstract/Free Full Text]
25. Rodgers SE, Hunter GJ, Hamberg LM et al. Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. Surgery 2006;140:932–940; discussion 940–941.[CrossRef][Medline]
26. Chen H, Sokoll LJ, Udelsman R. Outpatient minimally invasive parathyroidectomy: A combination of sestamibi-SPECT localization, cervical block anesthesia, and intraoperative parathyroid hormone assay. Surgery 1999;126:1016–1021; discussion 1021–1022.[CrossRef][Medline]
27. Kouvaraki MA, Greer M, Sharma S et al. Indications for operative intervention in patients with asymptomatic primary hyperparathyroidism: Practice patterns of endocrine surgery. Surgery 2006;139:527–534.[CrossRef][Medline]
28. Miccoli P, Bendinelli C, Conte M et al. Endoscopic parathyroidectomy by a gasless approach. J Laparoendosc Adv Surg Tech A 1998;8:189–194.[Medline]
29. Miccoli P, Bendinelli C, Vignali E et al. Endoscopic parathyroidectomy: Report of an initial experience. Surgery 1998;124:1077–1079; discussion 1079–1080.[CrossRef][Medline]
30. Henry JF, Iacobone M, Mirallie E et al. Indications and results of video-assisted parathyroidectomy by a lateral approach in patients with primary hyperparathyroidism. Surgery 2001;130:999–1004.[CrossRef][Medline]
31. Henry JF, Raffaelli M, Iacobone M et al. Video-assisted parathyroidectomy via the lateral approach vs conventional surgery in the treatment of sporadic primary hyperparathyroidism: Results of a case-control study. Surg Endosc 2001;15:1116–1119.[CrossRef][Medline]
32. Ikeda Y, Takami H, Sasaki Y et al. Endoscopic neck surgery by the axillary approach. J Am Coll Surg 2000;191:336–340.[CrossRef][Medline]
33. Westerdahl J, Lindblom P, Valdemarsson S et al. Risk factors for postoperative hypocalcemia after surgery for primary hyperparathyroidism. Arch Surg 2000;135:142–147.[Abstract/Free Full Text]
34. Westerdahl J, Valdemarsson S, Lindblom P et al. Postoperative elevated serum levels of intact parathyroid hormone after surgery for parathyroid adenoma: Sign of bone remineralization and decreased calcium absorption. World J Surg 2000;24:1323–1329.[CrossRef][Medline]
35. Caron NR, Sturgeon C, Clark OH. Persistent and recurrent hyperparathyroidism. Curr Treat Options Oncol 2004;5:335–345.[Medline]
36. Mariette C, Pellissier L, Combemale F et al. Reoperation for persistent or recurrent primary hyperparathyroidism. Langenbecks Arch Surg 1998;383:174–179.[Medline]
37. Jones JJ, Brunaud L, Dowd CF et al. Accuracy of selective venous sampling for intact parathyroid hormone in difficult patients with recurrent or persistent hyperparathyroidism. Surgery 2002;132:944–950; discussion 950–941.[CrossRef][Medline]
38. Mundschenk J, Klose S, Lorenz K et al. Diagnostic strategies and surgical procedures in persistent or recurrent primary hyperparathyroidism. Exp Clin Endocrinol Diabetes 1999;107:331–336.[Medline]
39. Shoback DM, Bilezikian JP, Turner SA et al. The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 2003;88:5644–5649.[Abstract/Free Full Text]
40. Strewler GJ. Medical approaches to primary hyperparathyroidism. Endocrinol Metab Clin North Am 2000;29:523–539, vi.[CrossRef][Medline]
41. Edwards ME, Rotramel A, Beyer T et al. Improvement in the health-related quality-of-life symptoms of hyperparathyroidism is durable on long-term follow-up. Surgery 2006;140:655–664.[CrossRef][Medline]

This Article Abstract Full Text (PDF) CME: Take the course for this article: Primary Hyperparathyroidism eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link 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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Suliburk, J. W. Articles by Perrier, N. D. Search for Related Content