The Oncologist, Vol. 12, No. 6, 644-653, June 2007; doi:10.1634/theoncologist.12-6-644 © 2007 AlphaMed Press
Primary HyperparathyroidismaUniversity 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: 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.
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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.
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.
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.
Symptomatic Hyperparathyroidism Classically, PHPT was diagnosed only after patients presented with advanced symptoms. The classic dictum of "stones, bones, moans, and groans" still applies to a small percentage of PHPT patients (<20%). Patients with PHPT may present with multiple somatic signs and symptoms including nephrolithiasis (usually calcium oxalate or calcium phosphate stones), peptic ulcer disease, extensive bone resorption (cortical bone density reduction with preservation of cancellous bone density), pancreatitis, proximal muscle weakness, and mental status changes. Hypercalcemic crisis is now rare.
Asymptomatic Hyperparathyroidism
More than 80% of contemporary PHPT patients are considered "asymptomatic" at diagnosis [4, 5]. Since PHPT has its highest incidence in the sixth and seventh decades of life, the patients' complaints may be easily dismissed as part of the normal aging process, menopause, or even fibromyalgia. However, multiple studies have verified significant improvement in asymptomatic PHPT patients' quality of life following parathyroidectomy [68]. In addition to increased survival, numerous studies demonstrate improvement in cardiovascular risk, arrest of ongoing renal impairment, and increased bone density, even in patients with overt osteoporosis [5, 913]. Furthermore, cognition often improves, which can have a profound impact on quality of life [14].
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.
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
However, a large number of PHPT patients do not meet any of these criteria. These patients require re-evaluation of serum calcium every 6 months, annual bone density scans, and continued monitoring for the development of more severe neuromuscular and cognitive symptoms. 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 riskbenefit ratio should be discussed by the surgeon and the patient, taking into consideration the expertise and experience of the individual surgeon.
As part of the evaluation of PHPT, there are several baseline tests that all patients should undergo.
Bone Mineral Density Measurement
24-Hour Urine Collection
Serum Vitamin D and Alkaline Phosphatase 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 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.
Ultrasonography is efficient, noninvasive, inexpensive, and does not require the injection of a contrast agent. However, the sensitivity of ultrasonography varies greatly, from 22% to 80%, and is dependent on the experience of the individual sonographer [23]. Furthermore, it can be difficult to locate retroesophageal, retrotracheal, retrosternal, and deep cervical glands using ultrasonography, and the examination may be confounded by thyroid nodules, cervical lymphadenopathy, or body habitus. Ultrasonography is best used to identify any thyroid pathology that may coexist with a 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].
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 takes advantage of the combination of preoperative localization and intraoperative iPTH monitoring (IOPTH) [26]. A small incision is made on the side of the neck that the adenoma has been localized to during preoperative evaluation. The procedure can be conducted using attended conscious sedation with local anesthesia. An iPTH level is drawn before (baseline) and after the adenoma is removed. A decrease of >50% from baseline at 5 or 10 minutes following resection suggests that the patient will be cured (Fig 4). If this drop does not occur, then multiglandular disease or hyperplasia should be suspected, and the patient should undergo further exploration (a traditional four-gland exploration).
The fact that minimally invasive parathyroidectomy can be performed using attended local anesthesia is especially important given that PHPT usually occurs in the elderly population, who may have multiple other medical problems that make them undesirable candidates for general anesthesia. Using a minimally invasive approach, these patients can now be cured of their disease without the need for extensive preoperative cardiopulmonary optimization or overnight hospitalization.
Four-Gland Exploration 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 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.
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 1236 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 (0.251 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 12 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 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.
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.
The patient is evaluated 2 weeks later, at which time she has no complaints and denies having any symptoms of hypocalcemia. At a 6-month follow-up visit, she is found to have a normal serum calcium level and states that she is sleeping well, has more energy, and is able to concentrate much better. At 1 year after surgery, she has improved bone mineral density as measured by DEXA scan and believes her quality of life has been significantly better since her parathyroidectomy.
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.
The authors indicate no potential conflicts of interest.
This work was partially funded by the Jahnigan Grant from the American Geriatric Society.
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