doi:10.2967/jnmt.107.044040
Journal of Nuclear Medicine Technology Volume 36, Number 1, 2008 30-35
© 2008 by Society of Nuclear Medicine
Differences in Accuracy of 99mTc-Sestamibi Scanning Between Severe and Mild Forms of Primary Hyperparathyroidism
Francisco A.F. Bandeira1,
Raíssa I.R.B. Oliveira1,
Luiz H.M. Griz2,
Gustavo Caldas3 and
Cristina Bandeira3
1 Division of Endocrinology and Diabetes, Agamenon Magalhães Hospital, University of Pernambuco Medical School, Recife, Brazil; 2 Division of Endocrinology, University of Pernambuco Medical School, Recife, Brazil; and 3 Division of Endocrinology and Diabetes, Agamenon Magalhães Hospital, Dilab Laboratories, Recife, Brazil
Correspondence: For correspondence or reprints contact: Raíssa Oliveira, MD, Endocrine Unit, Department of Medicine, Agamenon Magalhães Hospital, Estrada do Arraial, 2723, Casa Amarela, 52051-380, Recife, PE, Brazil. E-mail: raissainojosa{at}hotmail.com
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ABSTRACT
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Preoperative localization of the parathyroids using 99mTc-sestamibi scanning has not yet been established as a routine diagnostic procedure for primary hyperparathyroidism. Several studies have demonstrated a variable degree of accuracy (70%–98%) in asymptomatic patients. Methods: We evaluated the accuracy of this technique in 64 patients who underwent scanning between January 2000 and January 2005 according to the clinical manifestations of the disease. Results: The study included 25 asymptomatic patients (group I), 18 nephrolithiasis patients without overt bone disease (group II), and 21 patients with severe bone involvement and osteitis fibrosa cystica (group III). Mean serum calcium in groups I, II, and III was 10.98 ± 0.02, 11.32 ± 0.17, and 13.35 ± 0.35 mg/dL, respectively. Mean serum parathyroid hormone in groups I, II, and III was 135.45 ± 13.50, 165.85 ± 15.06, and 579.6 ± 628.4 pg/mL, respectively. The 99mTc-sestamibi scan results were positive in 64% of the patients in group I, in 83% of those in group II, and in 100% of those in group III. Of the patients with severe bone disease, 70% showed increased uptake on the initial images, whereas in the other groups, increased uptake was seen only on the delayed images, as expected. Conclusion: Our data show a high degree of accuracy for the use of 99mTc-sestamibi scanning as a localizing procedure in severe primary hyperparathyroidism.
Key Words: 99mTc-sestamibi; parathyroid; accuracy; hyperparathyroidism
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INTRODUCTION
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Primary hyperparathyroidism (PHPT) is a relatively common disease characterized by an increase in the synthesis and secretion of parathyroid hormone (PTH) by one or more of the parathyroid glands, with a resultant increase in the serum concentration of calcium. The literature suggests that PHPT occurs in approximately 1 of 500 women and 1 of 2,000 men per year in their fifth to seventh decades of life. Excessive secretion of PTH is most frequently caused by a parathyroid adenoma (80%–85% of cases), hyperplasia involving more than 1 gland and usually all 4 glands (10%–15% of cases), or, rarely, parathyroid carcinoma (0.5%–1% of cases) (1).
Patients with PHPT may clinically present with nephrolithiasis, bone involvement, or neuropsychiatric disease or may be asymptomatic. Many aspects distinguish mild from severe PHPT. PHPT with severe skeletal involvement is characterized as osteitis fibrosa cystica (which is observed as demineralization on radiographs), bone mineral density (BMD) is extremely low, and bone turnover extremely high (2). In Brazil, PHPT is perceived as an asymptomatic ailment in about half the patients, whose PHPT is diagnosed during a routine laboratory assessment (3). In other series, asymptomatic patients account for 80% of those diagnosed with the condition (4). In patients from Western industrialized societies, milder forms of these classic features will be present in only 30%–40% of patients diagnosed with PHPT (4).
In laboratory tests, patients with PHPT reveal increased PTH, calcium, and alkaline phosphatase levels; decreased phosphorus levels; and usually increased urinary calcium excretion. In these patients, low serum levels of vitamin D have been reported to be related to the severity of the disease in terms of biochemical indices, bone turnover, and bone density measurements (5). Markers of bone resorption such as CTx (carboxyterminal cross-linking telopeptide of bone collagen, or serum C-telopeptide) and NTx (aminoterminal cross-linking telopeptide of bone collagen, or urinary N-telopeptide) are degradation products of collagen and are useful in monitoring bone loss. Measurement of CTx and NTx is convenient and specific for bone resorption, which reflects the rate of bone turnover.
The treatment of choice for adenoma is surgical excision. Postsurgical normalization of PTH and calcium levels and improvement of renal, musculoskeletal, and circulatory function could be achieved in 95% of patients when the surgery was performed by an experienced surgeon (6). Surgical failure may result from ectopic glands, involvement of multiple glands, supernumerary glands, a small tumor, or the surgeon's failure to recognize the gland involved (7).
Ultrasonography, CT, MRI, and scintigraphy have been widely used in the preoperative localization of abnormal parathyroid glands. 201Tl- or 99mTc-scintigraphy has been used since the early 1980s, but its use declined after the advent of novel technetium agents, mainly 99mTc-sestamibi and 99mTc-tetrofosmin, which offer lower radiation exposure and higher detection efficacy (8). The advent of the 99mTc-sestamibi scan in the early 1990s changed the management of PHPT. Although 99mTc-sestamibi has been used extensively for parathyroid imaging, the mechanism for its uptake by parathyroid cells remains unclear. It has been suggested that the electrical potential of the plasma and mitochondrial membrane regulates uptake of 99mTc-sestamibi and that tissues rich in mitochondria are avid for it. An increased blood flow is implicated in the uptake of 99mTc-sestamibi and may account for uptake by parathyroid and thyroid neoplasms (9).
A parathyroid 99mTc-sestamibi scan or other localizing methods are normally ordered for patients with PHPT recurrence after parathyroidectomy with the aim of detecting ectopic or residual glands to guide the surgeon in a second operation. A routine parathyroid scan before the first operation has been used to localize involved glands, which may improve the surgical success rate and reduce complications, leading to a less invasive procedure (7). Several studies have demonstrated a high degree of accuracy for 99mTc-sestamibi scanning in detecting the parathyroids preoperatively, with a better result than is obtained with ultrasound, CT, or MRI (10). However, few studies have clarified a possible association between the clinical forms of PHPT and the accuracy of 99mTc-sestamibi scanning of the parathyroid.
The aim of this study was to assess the accuracy of 99mTc-sestamibi scanning of the parathyroid for the various presentations of PHPT: asymptomatic patients, patients with nephrolithiasis, and patients with severe bone disease and osteitis fibrosa cystica.
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MATERIALS AND METHODS
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Patients
We studied 64 consecutive patients with PHPT diagnosed at our institution between January 2000 and January 2005, who underwent 99mTc-sestamibi parathyroid imaging and had no thyroid nodule on ultrasound in the area of 99mTc-sestamibi uptake. The diagnostic criteria for HPTP were based on hypercalcemia (total calcium levels
10.3 mg/dL) associated with high or inappropriately normal intact PTH levels.
The patients were divided into 3 groups. Group I comprised asymptomatic patients, characterized as those with PHPT without evidence of nephrolithiasis, bone disease, classic neuromuscular symptoms (proximal muscle weakness, atrophy, hyperreflexia, or gait disturbances), or the typical neuropsychiatric syndrome (mental confusion, depression, or symptoms of acute hypercalcemia). Given the elevated incidence of symptomatic PHPT in Brazil (2,3), we divided the symptomatic group into patients with renal disease and patients with bone disease (osteitis fibrosa cystica). Group II comprised patients with renal disease, always presenting with episodes of renal colic with evidence of solitary calculi or showing features of nephrocalcinosis without overt bone disease. In PHPT, the severity of disease in patients with nephrolithiasis is intermediate between that in asymptomatic patients and that in patients with severe bone disease. Group III comprised patients with severe bone disease causing bone pain and pathologic fractures and having typical features of osteitis fibrosa cystica. Patients with osteitis fibrosa cystica are characterized by severe skeletal involvement, demineralization on radiography, extremely low BMD, and extremely high bone turnover.
Serum calcium and phosphorus were measured using an autoanalyzer (Cobas-Mira Plus; Roche). Serum PTH was measured by automated immunochemiluminometric assay (Diagnostic Products Corp.). According to these tests, the reference range for serum calcium is 8.6–10.3 mg/dL, serum phosphorus is 2.5–4.5 mg/dL, and serum PTH is 10–65 pg/mL. In addition, we evaluated levels of 25-hydroxyvitamin D and their correlation with the levels of PTH hormone and biochemical markers of bone remodeling. Serum 25-hydroxyvitamin D was measured by radioimmunoassay after extraction of vitamin D metabolites (DiaSorin, Inc.). The reference range for serum 25-hydroxyvitamin D according to this test is 12–68 ng/mL. NTx excretion was determined by enzyme-linked immunosorbent assay. Assay values were corrected for creatinine. The reference range for urine NTx according to this test is 50–60 nmol/mmol of creatinine in premenopausal women, 15–120 nmol/mmol of creatinine in postmenopausal women, and 6–65 nmol/mmol of creatinine in men. CTx was assayed using an autoanalyzer immunoassay CrossLaps kit (Elecsys; Roche) according to the manufacturer's instructions. The reference range for serum CTx according to this test is 50–450 pg/mL in premenopausal women, 90–680 pg/mL in postmenopausal women, and 70–480 pg/mL in men. All markers were measured on fasting patients, and for the NTx test second-void morning urine samples were used, as is standard practice for the resorption markers.
To further evaluate patients with PHPT and its bone and renal complications, we measured renal function and daily urinary calcium excretion and performed renal ultrasonography and bone densitometry. The BMD was determined at the lumbar spine (L2, L3, and L4), femoral neck, and distal third of the nondominant radius, with use of dual-energy x-ray absorptiometry (Lunar Corp.). The precision error in vivo as a percentage coefficient of variation was 0.9% for the lumbar spine, 1.2% for the femoral neck, and 2% for the distal radius. The data on bone density are reported as t scores.
All tests were performed at Dilab Laboratories.
Image Acquisition
Before scintigraphy, all patients underwent a careful clinical examination to verify the presence of palpable thyroid nodules and underwent neck ultrasonography to evaluate the thyroid and parathyroid glands. Patients who had a nodular thyroid lesion in the area of the 99mTc-sestamibi uptake were excluded from the study.
After a 740-MBq (20-mCi) intravenous injection of 99mTc-sestamibi, anterior planar images of the neck and upper chest were acquired with a 256 x 256 matrix at 5 min (early phase) and 2 h (delayed phase), using a large-field-of-view dual-head
-camera (Siemens) equipped with a low-energy, high-resolution, parallel-hole collimator. The energy windows were set to 140 keV ± 5%. The zoom factor was 1.45. All interpretations were performed by 2 experienced nuclear medicine physicians. The scan findings were considered positive for parathyroid disease when an area of increased uptake that persisted on late imaging was found.
Statistical Analysis
Results were expressed as percentages or mean ± SD. The
2 test and Fisher exact test were used to compare percentages of positive scans among the groups. The Wilcoxon test was used to compare means. Probability values below 0.05 were defined as significant.
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RESULTS
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Group I accounted for 39.04% of the sample, 80% of the group being female. The mean age was 66.75 ± 0.63 y, serum calcium 10.98 ± 0.02 mg/dL, serum phosphorus 2.79 ± 0.29 mg/dL, PTH 135.45 ± 13.50 pg/mL, serum 25-hydroxyvitamin D 26.97 ± 4.13 ng/mL, urinary calcium 213.21 ± 42.7 mg, t score for lumbar spine BMD –2.02 ± 0.15, t score for femoral neck BMD –2.03 ± 0.28, and t score for distal third radius BMD –2.23 ± 0.74.
Group II accounted for 28.12% of the sample, 77.7% of the group being female. The mean age was 55.8 ± 5.09 y, serum calcium 11.32 ± 0.17 mg/dL, serum phosphorus 2.56 ± 0.47 mg/dL, PTH 165.85 ± 15.06 pg/mL, serum 25-hydroxyvitamin D 20.02 ± 0.56 ng/mL, urinary calcium 303.45 ± 58.9 mg, t score for lumbar spine BMD –1.83 ± 0.85, t score for femoral neck BMD –1.81 ± 0.38, and t score for distal third radius BMD –1.79 ± 0.04.
Group III accounted for 32.81% of the sample, 47.6% of the group being female. Mean age was 38.7 ± 4.38 y, serum calcium 13.35 ± 0.35 mg/dL, serum phosphorus 1.99 ± 0.29 mg/dL, PTH 579.6 ± 628.4 pg/mL, serum 25-hydroxyvitamin D 15.91 ± 1.11 ng/mL, urinary calcium 285.5 ± 67.1 mg, t score for lumbar spine BMD –4.25 ± 0.24, t score for femoral neck BMD –5.44 ± 1.37, and t score for distal third radius BMD –5.33 ± 0.69.
The mean NTx in groups I, II, and III was 51.3 ± 6.4 nmol/mmol of creatinine (9 patients), 154.1 ± 62.9 nmol/mmol of creatinine (10 patients), and 501.5 ± 201 nmol/mmol of creatinine (16 patients), respectively. The mean CTx in groups I, II, and III was 752.6 ± 496.3 pg/mL (16 patients), 727.3 ± 220.4 pg/mL (8 patients), and 2,210.2 ± 375.4 pg/mL (5 patients), respectively.
The baseline characteristics of the study groups are summarized in Table 1.