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Table. Suggested Management Guidelines for Patients With Primary Hyperparathyroidism*
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1.
Weber CJ, Sewell CW, McGarity WC. Persistent and recurrent sporadic primary hyperparathyroidism: histopathology, complications, and results of reoperation.  Surgery.1994;116:991-998.Google Scholar
2.
van Heerden JA, Grant CS. Surgical treatment of primary hyperparathyroidism: an institutional perspective.  World J Surg.1991;15:688-692.Google Scholar
3.
Uden P, Chan A, Duh QY, Siperstein A, Clark O. Primary hyperparathyroidism in younger and older patients: symptoms and outcome of surgery.  World J Surg.1992;16:791-798.Google Scholar
4.
Nussbaum SR, Zahrachnik RJ, Lavigne JR.  et al.  Highly sensitive two-site immunoradiometric assay of parathyrin and its clinical utility in evaluating patients with hypercalcemia.  Clin Chem.1987;33:1364-1367.Google Scholar
5.
Malmaeus J, Granberg PO, Halvorsen J, Akerstrom G, Johansson H. Parathyroid surgery in Scandinavia.  Acta Chir Scand.1988;154:409-413.Google Scholar
6.
Norman J, Chheda H. Minimally invasive parathyroidectomy facilitated by intraoperative nuclear mapping.  Surgery.1997;122:998-1004.Google Scholar
7.
Pattou F, Torres G, Mondragon-Sanchez A.  et al.  Correlation of parathyroid scanning and anatomy in 261 unselected patients with sporadic primary hyperparathyroidism.  Surgery.1999;126:1123-1131.Google Scholar
8.
Irvin GL, Carneiro DM. Rapid parathyroid hormone assay guided exploration.  Operative Tech Gen Surg.1999;1:18-27.Google Scholar
9.
Molinari AS, Irvin GL, Deriso GT, Bott L. Incidence of multiglandular disease in primary hyperparathyroidism determined by parathyroid hormone secretion.  Surgery.1996;120:934-937.Google Scholar
10.
Tezelman S, Shen W, Shaver JK.  et al.  Double parathyroid adenoma: clinical and biochemical characteristics before and after parathyroidectomy.  Ann Surg.1993;218:300-309.Google Scholar
11.
Gordon LL, Snyder WH, Wians Jr F, Nwariaku F, Kim LT. The validity of quick intraoperative parathyroid hormone assay: an evaluation in seventy-two patients based on gross morphology criteria.  Surgery.1999;126:1030-1035.Google Scholar
12.
Proye CA, Carnaille B, Bizard JP, Quievneux JL, Lecomte-Houcke M. Multiglandular disease in seemingly sporadic primary hyperparathyroidism revisited: where are we in the early 1990's? a plea against unilateral parathyroid exploration.  Surgery.1992;112:1118-1122.Google Scholar
13.
Irvin GL, Molinari AS, Figueroa C, Carneiro DM. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay.  Ann Surg.1999;229:874-879.Google Scholar
14.
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;126:1016-1022.Google Scholar
15.
Boggs JE, Irvin III GL, Carneiro DM, Molinari AS. The evolution of parathyroidectomy failure.  Surgery.1999;126:998-1003.Google Scholar
16.
Garner SC, Leight Jr GS. Initial experience with intraoperative PTH determinations in the surgical management of 130 consecutive cases of primary hyperparathyroidism.  Surgery.1999;126:1132-1138.Google Scholar
17.
Udelsman R, Donovan PI, Sokoll L. 100 consecutive minimally invasive parathyroid explorations.  Ann Surg.In press.Google Scholar
18.
 NIH Conference: diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus Development Conference statement  Ann Intern Med.1991;114:593-597.Google Scholar
19.
Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or with out parathyroid surgery.  N Engl J Med.1999;341:1249-1255.Google Scholar
20.
Scholz DA, Purnell DC. Asymptomatic primary hyperparathyroidism: 10-year prospective study.  Mayo Clin Proc.1981;56:473-478.Google Scholar
Contempo Updates
August 23/30, 2000

Management Changes in Primary Hyperparathyroidism

Author Affiliations

Author Affiliations: Department of Surgery, Jackson Memorial Hospital, University of Miami and Department of Veterans Affairs Medical Center, Miami, Fla.

 

Contempo Updates Section Editor: Stephen J. Lurie, MD, PhD, Contributing Editor.

JAMA. 2000;284(8):934-936. doi:10.1001/jama.284.8.934

With few exceptions, patients with hypercalcemia, normal renal function, and an elevated intact parathyroid hormone level have primary hyperparathyroidism. Currently, definitive treatment of this disease involves parathyroidectomy, which is the surgical removal of hypersecreting parathyroid gland(s), a procedure that involves surgical exploration of the neck, usually under general anesthesia. Patients with overt symptoms associated with this disease (eg, urinary tract stones, bone pain, cognitive symptoms) and marked hypercalcemia (calcium level >1.0 mg/dL [0.25 mmol/L] above normal range) are usually referred for parathyroidectomy. This procedure results in normocalcemia in 95% to 98% of patients and symptomatic improvement in 82%.1-3 A more difficult management dilemma occurs in the 80% of patients with hyperparathyroidism presenting with mild hypercalcemia and minimal or no symptoms.

In the last 10 years, several technological advances have influenced the diagnosis and treatment of patients with primary hyperparathyroidism. Perhaps the most important of these has been the widespread availability of laboratory assays for measuring intact parathyroid hormone (1-84). First described in 1987,4 this 2-site antibody assay has proven to be much more sensitive than previous assays, which measured only parts of the parathyroid hormone molecule. This specific assay has allowed more precise diagnosis of primary hyperparathyroidism in patients presenting with hypercalcemia. The management of less common etiologies, such as familial, secondary, or tertiary hyperparathyroidism, and multiple endocrine neoplasia, however, remains more complex and will not be discussed in this article.

Guided Approaches to Parathyroidectomy

Historically, the standard surgical approach in patients with primary hyperparathyroidism has consisted of general endotracheal anesthesia followed by bilateral neck exploration. Surgeons typically visualize all 4 glands and excise the grossly enlarged parathyroid glands, while leaving sufficient parathyroid tissue for normal function. At the time of surgery, however, it can be difficult to determine whether all the hypersecreting tissue has been removed. Some surgeons have used gland excision based on biopsy of parathyroid tissue with frozen section histopathology, but its diagnostic accuracy in determining adenoma vs hyperplasia is inconsistent and has not proven helpful in the operative decision of single or multiple gland involvement. Thus, the success of this operative approach historically has depended largely on the experience and judgment of the surgeon. Due to individual preference or insurance constraints, many patients undergo parathyroidectomy in hospitals where this procedure is only performed occasionally and the surgeon has limited experience. Failure to achieve postoperative normocalcemia occurred in 30% of patients in Scandinavian hospitals in which fewer than 10 parathyroidectomies were performed per year.5 Comparable studies have not been published in United States, but these findings have stimulated the development of several new surgical adjuncts to improve success rates and decrease operative morbidity.

Preoperative localization of the hypersecreting parathyroid gland(s) has been attempted by many techniques. The most sensitive appear to be ultrasonography (which is operator-dependent) and technetium-99-m sestamibi tomographic reprojection nuclear scanning (DuPont Merck Pharmaceutical, Billerica, Mass). The advantage of the computerized nuclear scan is the ability to print a 3-dimensional image, which can be taken to the operating room for visual reference by the surgeon. This radioisotope, which demonstrates good affinity for hypersecreting parathyroid glands, has led some surgeons to use a radio-guided probe to assist in finding the abnormal tissue.6 This method has some distinct advantages, but many surgeons find that a probe is not helpful or needed when the sestamibi scan clearly identifies the anatomical location of an overactive gland. With a sensitivity of 69% and specificity of 98%,7 the data from the sestamibi scan alone are limited in guiding the extent of resection. It can, however, direct the dissection to sites suspected of harboring hyperfunctioning glands.

Another innovative surgical adjunct in parathyroidectomy is the use of intraoperative, rapid parathyroid hormone assay. Because the half-life of parathyroid hormone is 3 to 4 minutes, successful excision of all hyperfunctioning parathyroid tissue can be rapidly confirmed in the operating room. This method, which has been commercially available since 1996 (Nichols Institute Diagnostics, San Juan Capistrano, Calif), provides a 10-minute assay of the plasma parathyroid hormone level that can be used during parathyroidectomy to determine quantitatively when all hyperfunctioning parathyroid tissue has been excised. Specifically, a decrease of 50% from the preoperative or preexcision parathyroid hormone level in peripheral blood plasma measured 10 minutes after gland excision predicts a postoperative return to normal or low serum calcium levels with an overall accuracy of 97%.8 On the other hand, an insufficient decrease in the hormone level after excision of a suspected parathyroid gland signals that more hypersecreting tissue is present, thus leading the surgeon to further exploration until all hyperfunctioning parathyroid tissue is excised.

Multiglandular disease, as identified by this quantitative biochemical frozen section, is present in 5% of patients with primary hyperparathyroidism and must be recognized and treated at the time of operation to ensure operative success.9 In contrast, a 14% to 24% incidence rate of multiglandular disease has been reported previously in patients with sporadic primary hyperparathyroidism when resection is based on a surgeon's judgment of gland size during traditional bilateral neck exploration.10-12

Intraoperative measurement of parathyroid hormone can also help the surgeon find and excise obscure or previously overlooked glands. The rapid parathyroid hormone assay is useful in patients with inaccurate or negative scans. For these difficult-to-find glands, rapid parathyroid hormone assay can be extremely beneficial by facilitating their localization with differential venous sampling, measuring the increase in hormone secretion after massage of specific areas, and correctly identifying the excision of abnormal parathyroid tissue when it is not easily recognized.13

With this operative approach, frozen section histopathology is rarely needed, operating time is shortened, and with a limited dissection, the patient can safely go home 2 to 3 hours after surgery. A serum calcium level can be obtained the next day in an outpatient setting and, in case of advanced osteoporosis, anticipated hypocalcemia can be treated prophylactically with oral calcium supplementation. This combination of surgical adjunctive techniques offers a real advance in the surgical approach to hyperparathyroidism.

Several recent reports indicate that these new techniques can not only improve the success rate of parathyroidectomy as measured by a return to normocalcemia in 98% of patients,8 but it can also substantially simplify the operation, from a bilateral neck exploration under general anesthesia with the accompanying morbidity, to a simpler outpatient procedure.14 Most patients would be eligible for parathyroidectomy (under local anesthesia) through a small (3-cm) incision, with limited, target-specific dissection. Excision of the hyperfunctioning gland(s) could be confirmed in the operating room by a quantitative decrease in the plasma parathyroid hormone level, which would assure the surgeon that all hypersecreting tissue has been removed, without the need for further dissection or visualization of the remaining glands. The failure rate of this minimally invasive procedure is 1.3% to 1.5%.15,16 Furthermore, surgeons who are qualified to perform a bilateral neck exploration for primary hyperparathyroidism should be capable of performing a minimally invasive procedure if the described surgical adjuncts are available. Any hospital can have these commercially available adjuncts and the costs appear to vary with surgical volume.14,17

Suggested Management

In 1990, the National Institutes of Health Consensus provided guidelines for the management and treatment of patients with primary hyperparathyroidism. These guidelines recommended parathyroidectomy for patients with symptoms, marked hypercalcemia of 1.0-1.6 mg/dL (0.25-0.40 mmol/L) above normal range, urinary stones, urinary calcium excretion of more than 400 mg/24 h (10 mmol/d), bone mass of 2 SDs or more below those of persons matched by age, sex, and race (z score), age younger than 50 years, and decreasing renal function.18 Because cases today are frequently diagnosed at a much milder or earlier stage of this disease, the decision of nonoperative observation vs parathyroidectomy has become more complex. Many patients tolerate mild hyperparathyroidism well without operative treatment. A recent study has shown that 73% of asymptomatic patients presenting with mild hypercalcemia (10.3-10.5 mg/dL [2.47-2.63 mmol/L]) did well over a 10-year period, without loss of cortical bone, progressive hypercalcemia, or excessive urinary calcium excretion. On the other hand, 27% of patients in this study had progressive disease, which led to parathyroidectomy.19 Unfortunately, there are currently no factors that can predict which patients will experience progressive disease.

Patients with osteoporosis will have a prompt and sustained increase in their bone mineral density (BMD) after successful parathyroidectomy. Although there are no studies relating the incidence of fractures to hyperparathyroidism, there was an average 6% increase in BMD of the femoral neck 1 year after parathyroidectomy, and 14% after 10 years.19 In patients with osteoporosis associated with hyperparathyroidism, this improvement is a well-defined benefit of parathyroidectomy. It should be pointed out, however, that patients with primary hyperparathyroidism have a higher incidence of cortical than trabecular bone loss. Because of its high cortical bone composition, the distal one third of the radius should be studied with BMD in these patients. This site is more specific for evaluation of bone loss caused by hyperparathyroidism than the lumbar spine or hip, since these are also affected by other causes of bone loss such as age and estrogen deficiency.

How do these new findings influence the management of patients with primary hyperparathyroidism? With less traumatic, limited parathyroidectomy available, the benefit of surgical treatment with minimal risks needs to be reevaluated. For instance, symptomatic elderly patients with comorbid disease, who are frequently denied operation due to risks related to anesthesia and bilateral neck dissection, might now be candidates for safe, minimally invasive parathyroidectomy resulting in marked relief of symptoms. On the other hand, we suggest that patients with mild hypercalcemic hyperparathyroidism (<0.4 mg/dL [0.1 mmol/L] above range) be followed up for 1 year to confirm the diagnosis in that some will return to normocalcemia20 and 73% will show no progressive disease.19 Parathyroidectomy is indicated in patients with progressive disease as described in Table 1.

In centers in which limited parathyroidectomy is available, asymptomatic patients with moderate hypercalcemia (0.4-0.9 mg/dL [0.1-0.23 mmol/L] above normal range) can be considered for earlier parathyroidectomy before severe bone loss or kidney damage occurs. We recommend consideration for parathyroidectomy if the BMD z score is lower than −1.0 in the forearm, or if urinary calcium excretion is greater than 300 mg/24 h (7.5 mmol/d). If only minimal bone density loss and normal urinary calcium excretion is shown by these quantitative tests, serial examinations are indicated to diagnose progressive disease. Hypercalcemia at the level of 1.0 mg/dL (0.25 mmol/L) or more above normal range should itself be considered an indication for intervention.

Based on the current data referenced in this review, we suggest a management scheme for patients with primary hyperparathyroidism as shown in Table 1. With a highly successful and less traumatic parathyroidectomy available today, our present guidelines differ from the National Institutes of Health Consensus report.18 We suggest operative treatment in patients with less bone loss in the forearm, mild elevation of urinary calcium excretion, and in asymptomatic patients older than 50 years to prevent continuing bone loss and/or renal involvement.

Armed with a secure diagnosis, good quantitative measurements of BMD, and a more thorough understanding of the clinical course of patients with mild hyperparathyroidism, the therapeutic options are more clearly defined. By monitoring these patients to detect stable or progressive disease and providing better results using a minimally invasive outpatient parathyroidectomy, real progress in the management of patients with primary hyperparathyroidism can be achieved.

References
1.
Weber CJ, Sewell CW, McGarity WC. Persistent and recurrent sporadic primary hyperparathyroidism: histopathology, complications, and results of reoperation.  Surgery.1994;116:991-998.Google Scholar
2.
van Heerden JA, Grant CS. Surgical treatment of primary hyperparathyroidism: an institutional perspective.  World J Surg.1991;15:688-692.Google Scholar
3.
Uden P, Chan A, Duh QY, Siperstein A, Clark O. Primary hyperparathyroidism in younger and older patients: symptoms and outcome of surgery.  World J Surg.1992;16:791-798.Google Scholar
4.
Nussbaum SR, Zahrachnik RJ, Lavigne JR.  et al.  Highly sensitive two-site immunoradiometric assay of parathyrin and its clinical utility in evaluating patients with hypercalcemia.  Clin Chem.1987;33:1364-1367.Google Scholar
5.
Malmaeus J, Granberg PO, Halvorsen J, Akerstrom G, Johansson H. Parathyroid surgery in Scandinavia.  Acta Chir Scand.1988;154:409-413.Google Scholar
6.
Norman J, Chheda H. Minimally invasive parathyroidectomy facilitated by intraoperative nuclear mapping.  Surgery.1997;122:998-1004.Google Scholar
7.
Pattou F, Torres G, Mondragon-Sanchez A.  et al.  Correlation of parathyroid scanning and anatomy in 261 unselected patients with sporadic primary hyperparathyroidism.  Surgery.1999;126:1123-1131.Google Scholar
8.
Irvin GL, Carneiro DM. Rapid parathyroid hormone assay guided exploration.  Operative Tech Gen Surg.1999;1:18-27.Google Scholar
9.
Molinari AS, Irvin GL, Deriso GT, Bott L. Incidence of multiglandular disease in primary hyperparathyroidism determined by parathyroid hormone secretion.  Surgery.1996;120:934-937.Google Scholar
10.
Tezelman S, Shen W, Shaver JK.  et al.  Double parathyroid adenoma: clinical and biochemical characteristics before and after parathyroidectomy.  Ann Surg.1993;218:300-309.Google Scholar
11.
Gordon LL, Snyder WH, Wians Jr F, Nwariaku F, Kim LT. The validity of quick intraoperative parathyroid hormone assay: an evaluation in seventy-two patients based on gross morphology criteria.  Surgery.1999;126:1030-1035.Google Scholar
12.
Proye CA, Carnaille B, Bizard JP, Quievneux JL, Lecomte-Houcke M. Multiglandular disease in seemingly sporadic primary hyperparathyroidism revisited: where are we in the early 1990's? a plea against unilateral parathyroid exploration.  Surgery.1992;112:1118-1122.Google Scholar
13.
Irvin GL, Molinari AS, Figueroa C, Carneiro DM. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay.  Ann Surg.1999;229:874-879.Google Scholar
14.
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;126:1016-1022.Google Scholar
15.
Boggs JE, Irvin III GL, Carneiro DM, Molinari AS. The evolution of parathyroidectomy failure.  Surgery.1999;126:998-1003.Google Scholar
16.
Garner SC, Leight Jr GS. Initial experience with intraoperative PTH determinations in the surgical management of 130 consecutive cases of primary hyperparathyroidism.  Surgery.1999;126:1132-1138.Google Scholar
17.
Udelsman R, Donovan PI, Sokoll L. 100 consecutive minimally invasive parathyroid explorations.  Ann Surg.In press.Google Scholar
18.
 NIH Conference: diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus Development Conference statement  Ann Intern Med.1991;114:593-597.Google Scholar
19.
Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or with out parathyroid surgery.  N Engl J Med.1999;341:1249-1255.Google Scholar
20.
Scholz DA, Purnell DC. Asymptomatic primary hyperparathyroidism: 10-year prospective study.  Mayo Clin Proc.1981;56:473-478.Google Scholar
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