How Should Patients with Primary Hyperparathyroidism Be Treated?

Orlo H. Clark

Department of Surgery UCSF/Mount Zion Medical Center San Francisco, California 94143-1674

Address all correspondence and requests for reprints to: Orlo H. Clark, M.D., Department of Surgery, UCSF/Mount Zion Medical Center, 1600, Divisadero Street, Room C347, San Francisco, California 94143-1674.

Primary hyperparathyroidism (PHPT) has become a commonly recognized clinical problem since the advent of routine testing of blood calcium levels. Fortunately, most patients (99%) with PHPT have benign tumors (85% adenomas and 15% multiple abnormal parathyroid glands). When the serum calcium is elevated, symptoms that can occur in patients with PHPT include fatigue, weakness, exhaustion, depression, increased thirst, polyurea, nocturia, constipation, and musculoskeletal aches and pains (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). Associated conditions or complications of PHPT include hypertension, nephrolithiasis, osteopenia and osteoporosis, gout, peptic ulcer disease, and pancreatitis. However, because most patients with PHPT have only mild hypercalcemia, overt symptomatology is no longer common. Rather, some patients with PHPT will have only mild constitutional symptoms such as a sense of weakness and easy fatigability. Several studies document that in about 65–75% of these patients, the symptoms of PHPT and complications associated with PHPT do not appear to progress during a 10-yr period, although 25–35% of these patients do develop complications such as osteoporosis and kidney stones (13, 14, 15). Unfortunately, no investigation, to date, has been able to identify whether a particular patient with mild HPT will develop symptoms, complications, or progressive increases in blood calcium level.

Considerable controversy, therefore, remains concerning the most appropriate treatment for patients with mild or asymptomatic HPT. Some clinicians believe that patients over 50 yr of age with uncomplicated PHPT can be treated nonoperatively, consistent with the recently published new guidelines for medical or surgical management of this disease (16, 17). Others have a different view, believing that because surgery is virtually always an appropriate course, and given the fact that it is not possible to predict who among the asymptomatic will develop features of the disease over time, virtually all patients with PHPT should be treated by parathyroidectomy (5, 18, 19). The National Institutes of Health (NIH) consensus meeting in 1990 identified criteria for selecting patients with PHPT for parathyroidectomy, including 1) a blood calcium greater than 1–1.6 mg/dl above the upper limits of normal, 2) age under 50 yr, 3) osteoporosis (Z-score <-2.0 forearm), 4) decreased renal function (by more than 30%), 5) 24-h urine calcium greater than 400 mg/24 h, 6) nephrolithiasis, 7) severe psychoneurological problems, or 8) a history of life-threatening hypercalcemia (16). Numerous investigations document that these clinical and metabolic complications improve in most, but certainly not all, patients after parathyroidectomy (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). Many patients with these symptoms, however, are considered to be asymptomatic by the NIH consensus conference. More recent guidelines are similar, but the decision point regarding the serum calcium level is now reduced to 1 mg above the upper limit of normal and bone density now includes patients with a T-score less than -2.5 at any site (17). Although some clinicians would suggest that all patients with PHPT who are good surgical risks should be treated surgically, many others agree that the NIH recommendations are acceptable for determining whether surgical or medical treatment and observation are indicated (17, 18, 19). Debate also remains regarding how asymptomatic HPT should be defined, because many persons without PHPT have increased fatigue, depression, lethargy, and other possibly related symptoms (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). A recent randomized trial documented that patients with mild hypercalcemia have an improved quality of life after parathyroidectomy when compared with medically treated patients (8). Several investigations have documented that patients who fulfill or do not fulfill the NIH criteria for parathyroidectomy get the same psychoneurological benefits of parathyroidectomy (10, 11, 12). Recent investigations suggest that individuals with even mild HPT and minimal hypercalcemia are at increased risk of fracture and cardiovascular disease up to 10 yr before treatment for PHPT (20, 21). Patients with mild HPT have also been reported to have an increased risk of premature death from cardiovascular disease or cancer in some studies (22, 23, 24, 25, 26), but not all (27).

There has also been considerable controversy about the most appropriate operation for patients with sporadic PHPT. Bilateral neck exploration has been the traditional approach, without the use of preoperative localization tests, although Wang and Tibblin and colleagues have recommended a unilateral approach for patients with PHPT before the development of good localization procedures (1, 2, 28, 29, 30). The overall outcome of parathyroidectomy using a bilateral approach is excellent, with more than 95% being successfully treated, as reported by Allendorf et al. (31), in this issue of the JCEM, and recently also by Schell and Dudley (32) in a similar study. However, because about 85% of patients with PHPT without a family history of HPT have a solitary parathyroid gland, some surgeons have enthusiastically recommended a unilateral or focused exploration (33, 34, 35, 36, 37, 38). The improved accuracy rate of preoperative localization tests such as sestamibi scanning and ultrasonography have also supported a focal or lateral approach because these tests are quite accurate (about 80%) in the 85% of patients with solitary parathyroid tumors, when done by experienced radiologists and nuclear medicine physicians. Unfortunately, these localization tests are only about 35% accurate in patients with multiple abnormal parathyroid glands (39, 40). Some surgeons have also recommended using intraoperative sestamibi scanning to help identify the abnormal parathyroid gland at operation (36). Most investigations, however, document that radiofrequency-guided parathyroidectomy provides little or no more information than that provided by preoperative sestamibi scanning (39, 40, 41).

Intraoperative PTH (IOPTH) testing is also now available to help the surgeon know when all abnormal parathyroid glands have been removed (38, 42). In these patients, a successful operation is predicted when the IOPTH level falls by more than 50% from the highest pre-removal value 10 min after removal of an abnormal parathyroid tumor. IOPTH testing is quite accurate in the 85% of patients who have a solitary parathyroid tumor. Unfortunately, IOPTH testing is not as accurate in patients with multiple abnormal parathyroid glands and is correct in only about 50% of such patients (39, 43) (Haciyanli, M., G. Lal, G. Morita, Q. Y. Duh, G. Kebebew, and O. H. Clark, submitted for publication). Thus, the IOPTH level may fall more than 50% in some patients with multiple abnormal parathyroid glands when abnormal parathyroid glands remain in the neck. The reason for this decrease is not known but may be due to a different calcium or PTH receptor set point in these tumors.

Allendorf et al. (31) document that the surgical success rate of a bilateral approach by an experienced surgeon for patients with HPT is the same regardless of whether preoperative sestamibi scanning is done. This observation would confirm the comments of the late Dr. John Doppman, at the NIH consensus in 1990, who stated that the best localization test is to localize an experienced parathyroid surgeon (44). Overall, the success rate using a bilateral approach by Allendorf et al. (31) via a small (4 cm) incision was 99.3% without preoperative localization testing and 97.5% in those who had a positive preoperative sestamibi scan. Of interest and importance is the fact that the success rate in the 109 patients who had negative sestamibi scans was only 92.7%, which is significantly lower than in the scan positive or no scan groups.

Allendorf et al. (31) are to be congratulated on their excellent results that confirm other investigations documenting that a 95% or higher success rate of parathyroidectomy can be obtained in patients with PHPT (1, 2, 28, 32). In other reports, the success rate is highest in patients with sporadic HPT and benign parathyroid tumors, and is somewhat lower in patients with familial HPT, or parathyroid cancer or parathyromatosis (45, 46, 47). The retrospective investigation of Allendorf et al. (31) also confirms numerous previous and current reports that preoperative localization studies are not required before parathyroidectomy and that the bilateral approach remains the standard approach, especially when intraoperative PTH testing is not available. The authors also report that there was little to no difference in the operative time required in the various groups regardless of whether preoperative sestamibi scanning was done. Their operative times of under 45 min in a surgical training center are excellent. One might question whether the operative time was longer in the patients who were scan negative, for those with multiple abnormal parathyroid glands, and for those who had failed operations? Although I would agree with the conclusions of Allendorf et al. (31), the parathyroid operations in this study were all done by a senior experienced surgeon, whereas similar excellent results might not be accomplished by less experienced surgeons. Also, approximately 1% or 2% of patients with PHPT have parathyroid tumors situated in the middle mediastinum, intrathyroidal, undescended, or in other ectopic sites. When the position of these parathyroid tumors is suspected preoperatively, removal can usually be accomplished without much difficulty; when one is unaware of the ectopic location of the tumor, however, failure is more likely. It would, therefore, be interesting to know the reasons for the failed operations in the patients of Allendorf et al. (31).

There are several weaknesses of this important investigation. First, very few surgeons would accept normocalcemia at 1 month as curative. Most define recurrent PHPT as redevelopment of PHPT after 6 months of at least normocalcemia, and when it occurs earlier it is defined as persistent PHPT (48). This criticism is of less concern in patients having a thorough bilateral exploration rather than a focal operation. Second, why were 16 patients with hyperplasia and 7 other patients with other preoperative tests excluded from this investigation because a bilateral operation was to be performed? How was hyperplasia defined? Were patients with hyperplasia those with familial PHPT? If patients with hyperplasia were included, would it change the overall results? Third, how many normal parathyroid glands were identified in their patients, because it is often more difficult to identify all the normal parathyroid glands than to identify the tumor? Do the authors always see all of the normal parathyroid glands? Fourth, were there any complications in these patients? Fifth, did patients have their parathyroid tumors confirmed by frozen section or did they use IOPTH testing or other methods? Sixth, why do the authors suggest a possible error in diagnosis in the six patients when no tumor was identified, because the diagnosis of PHPT can be made today with nearly 100% accuracy?

To my knowledge, to date, only one prospective randomized investigation comparing a bilateral vs. unilateral parathyroid exploration with IOPTH assays has been done, and no major difference in outcome was noted in a relatively small number of patients (49). The current study documents that the vast majority of patients having bilateral neck explorations without localization testing can be successfully treated and the bilateral approach remains the standard operation. The authors also report that patients can be discharged within a few hours postoperatively. Thus, the duration of hospitalization is similar to some reports for patients having a focal approach (36, 37). Concern over bleeding postoperatively after a focal, lateral, or bilateral parathyroidectomy has made some surgeons, however, reluctant to send patients home from the recovery room. The rapid development of a neck hematoma can lead to respiratory failure and death (50, 51).

The current investigation and numerous previous reports document that superb results can be obtained using a bilateral approach by an experienced surgeon in patients with sporadic PHPT and that preoperative localization tests are not only not required, but do not seem to improve outcome. Although the results of this retrospective investigation support this observation, our responsibility as surgeons interested in this field is to continue to improve treatment of our patients. We and our patients would presumably prefer to have less invasive operations with fewer complications and an even better success rate, if this is possible. In our own investigations and those of others, it appears that the results obtained using a focused or a unilateral approach in scan-positive patients with IOPTH testing are comparable with those obtained using a bilateral approach (33, 34, 38, 39, 49, 52). The focused operation using IOPTH testing to help confirm that the outcome will be successful can be done via a 2.5-cm incision. Waiting for the IOPTH assay delays the operation by about 15 min. Patients having a focal approach are found to have fewer multiple abnormal parathyroid than when a bilateral approach is used (53, 54). Despite this observation, the short-term outcome is similar in these two groups (52). The question must, therefore, be raised as to whether recurrent HPT will become more common in patients who have been treated by a focused approach or do some histologically abnormal parathyroid fail to secret enough PTH to cause PHPT (52, 53, 54).

It should be noted that preoperative localization tests do not replace the need for an experienced surgeon. Localization tests will continue to improve with new equipment and more experience. Localization tests provide useful information and are essential when a focused or unilateral operation is to be done and before parathyroid reoperations. As shown by the authors, however, they are not essential for most patients with PHPT.

Currently, it appears that excellent results can be obtained by either a bilateral approach or the selective use of a focal or unilateral approach for patients with PHPT. The latter approaches require preoperative localization tests. When the tests localize a tumor, superb results can be obtained with minimal morbidity. When the tests are negative, the results are not quite as good, probably because more of these patients have hyperlasia. It appears that although we need standard approaches to clinical problems such as standard bilateral parathyroidectomy as recommended by Allendorf et al. (31), a selective approach can also be used to treat patients with PHPT surgically. As surgeons, we should not make our patient fit the operation, but rather the operation fit the patient! As technology and experience continues to improve, successful parathyroid operations should occur in nearly 100% of patients. Such advances include improved localization tests; improved surgical instruments such as lighted retractors and nerve monitors; safe general or local, regional anesthesia; and educating and training more general and head and neck surgeons in parathyroid surgery.

Footnotes

Abbreviations: HPT, Hyperparathyroidism; IOPTH, intraoperative PTH; PHPT, primary hyperparathyroidism.

Received April 4, 2003.

Accepted April 17, 2003.

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