Preoperative parathyroid gland localization with technetium-99m sestamibi in secondary hyperparathyroidism

Technetium-99m sestamibi scintigraphy has become a valuable tool in locating parathyroid glands in patients with primary hyperparathyroidism. The aim of this study was to evaluate its usefulness in secondary hyperparathyroidism. Twenty patients were injected intravenously with 740 MBq of 99mTc-sestamibi and images were obtained at 15 min and 2 h post injection. All patients underwent parathyroid ultrasonography (US) as well as bilateral surgical neck exploration and 64 parathyroid glands were removed. US revealed at least one enlarged gland in 15/20 patients (75%), while 99mTc-sestamibi scintigraphy showed focal areas of increased uptake in at least one gland in 17/20 patients (85%). When imaging results for all glands were evaluated according to surgical results, sensitivity was 54% for parathyroid scintigraphy and 41% for US, and specificity was 89% for both imaging techniques. There was a discrepancy between the two imaging modalities in 28 glands (35%). The mean surgical weight of US-positive glands (1492+/-1436 mg) was significantly higher than that of US-negative glands (775+/-703 mg) (P<0.05). However, there were no significant differences in weight between sestamibi-positive and sestamibi-negative glands. When only sestamibi-positive glands were considered, a positive correlation between uptake and weight was found (r=0.4, P<0.05). In conclusion, parathyroid US and 99mTc-sestamibi scintigraphy are complementary imaging techniques in the preoperative localization of abnormal parathyroid glands in patients with secondary hyperparathyroidism. The limited sensitivity of the techniques means that patients will still require bilateral neck exploration; therefore routine preoperative parathyroid scanning in renal patients is not justified.     

Vitamin D receptor gene polymorphism and parathyroid calcium sensor protein (CAS/gp330) expression in primary hyperparathyroidism

Calcitriol, via its receptor (VDR), inhibits parathyroid hormone (PTH) secretion and cell proliferation. Physically linked polymorphic VDR alleles denoted b,a, and T, comprise a novel risk factor for postmenopausal primary hyperparathyroidism (pHPT) by their presumed coupling to reduced VDR expression. This study examines VDR gene polymorphisms, parathyroid calcium-regulated cytoplasmic calcium concentrations ([Ca2+]i) and parathyroid expression of a calcium sensor protein (CAS/gp330). Genomic DNA was obtained from 66 postmenopausal women with pHPT and 66 age-matched female controls. Polymorphic VDR alleles were detected after polymerase chain reaction (PCR) and restriction digestion. Cryosections of pathologic parathyroid glands from 41 of the patients were immunostained with a monoclonal anti-CAS/gp330 antibody. Homozygosity for the VDR alleles b, a, and T was overrepresented in pHPT (p < 0.01-0.05) but did not couple to ED50 for calcium-regulated [Ca2+]i. The enlarged parathyroid glands possessed heterogeneous down-regulation of CAS/gp330. This down-regulation was the least conspicuous in the BBgenotype, and these few patients generally had larger parathyroid lesions (p < 0. 05). The VDR haplotype baTis a risk factor for pHPT possibly by hampering the regulatory actions of calcitriol. In contrast the BAt haplotype seems to be underrepresented in pHPT and to couple to larger parathyroid lesions as well as less deranged CAS/gp330 expression and parathyroid cell function. HPT in these individuals may relate to genetic events principally altering the regulation of cell proliferation, rather than calcium sensing of the parathyroid cells.     

Functional expression of the parathyroid cell calcium receptor in Xenopus oocytes

Various studies suggest the existence of a plasma membrane receptor on parathyroid cells that senses changes in the concentration of extracellular Ca2+. To test this hypothesis, Xenopus laevis oocytes were injected with poly(A)(+)-enriched mRNA from bovine parathyroid cells and examined for their ability to respond to increases in the concentration of extracellular Ca2+ or other polycations. Cytosolic Ca2+ concentrations were measured indirectly by recording Cl- currents through the endogenous, cytosolic Ca(2+)-activated Cl- channel. Increasing the concentration of extracellular Ca2+ (from 0.7 to 5 mM) or Mg2+ (from 0.8 to 10 mM) elicited oscillatory increases in the Cl- current. Responses to either divalent cation were not observed in oocytes injected with water or with mRNA prepared from HL-60 cells or rat liver. Responses elicited by extracellular Mg2+ persisted when extracellular Ca2+ was reduced to low micromolar levels. La3+, Gd3+, or neomycin B also evoked oscillatory increases in the Cl- current in oocytes under conditions of low extracellular Ca2+ levels. These extracellular polycations all cause the mobilization of intracellular Ca2+ in oocytes injected with parathyroid cell mRNA like they do in intact parathyroid cells. The injection of parathyroid cell mRNA thus confers on oocytes the ability to detect and respond to changes in the concentration of extracellular polycations. The data provide compelling evidence for the existence of a cell surface Ca2+ receptor protein(s) on parathyroid cells that regulates cellular function.     

In vitro parathyroid hormone release in patients with secondary hyperparathyroidism

BACKGROUND: The purpose of this study was to determine the precise endocrine characteristics of parathyroid function in secondary hyperparathyroidism (sHPT). METHODS: We examined the effects of extracellular ionized calcium (Ca2+) varying from 0.5 to 2.0 mM on parathyroid hormone (PTH) release in parathyroid cell suspensions using a mid-regional PTH assay. Cells were obtained from 26 patients with sHPT who were divided into two groups according to the type of hyperplasia they exhibited, either nodular (n = 16) or diffuse (n = 10). For comparison, we also analyzed data from nine patients with primary hyperparathyroidism (pHPT; adenomas). RESULTS: Significant in vitro suppression of PTH release by Ca2+ was observed in the majority of subjects, regardless of the histologic abnormality. The pHPT group exhibited no significant relationship between clinical and in vitro data. In contrast, in the sHPT group (taken as a whole), suppression of PTH release by Ca2+ exhibited a plateau at a total serum calcium concentration of 2.5 mmol/L, and a parathyroid gland weight of 2 g. CONCLUSIONS: These findings suggest that there is a curvilinear relationship in sHPT, but not pHPT, between the in vitro calcium sensitivity of parathyroid cells and total serum calcium, as well as gland weight. The in vitro calcium sensitivity in sHPT remains constant when the total serum calcium concentration exceeds 2.5 mmol/L, or when the gland weight exceeds 2 g.     

Primary hyperparathyroidism sustained by a giant adenoma of the parathyroid gland

A case of primary hyperparathyroidism sustained by an unusually large parathyroid adenoma is presented. The tumor affected a 45-year-old woman with a 15-year history of nephrolithiasis and presented as a palpable neck mass. On the basis of clinical findings and ultrasound examination, it was initially misdiagnosed as a thyroid nodule. CT scan and transesophageal endosonography gave a correct definition of the tumor, which was located behind the left thyroid lobe and expanded posterior to the pharynx and the esophagus in the prevertebral space. At surgery a parathyroid tumor measuring 8 x 7 x 3 cm and weighing 90 g was successfully removed. No signs of malignancy were observed by both morphological and cell kinetic analyses.     

Effects of parathyroid hormone and serum calcium on the phenotype and function of mononuclear cells in patients with primary hyperparathyroidism

The University of Pennsylvania Smell Identification Test (UPSIT) and a smell ability questionnaire were administered to 167 Japanese volunteers ranging in age from 20 to 59 years. Of these subjects, 80 also received the T&T olfactometer threshold test. Of the latter subjects, 36 were patients tested before endoscopic nasal surgery for sinusitis and polyposis. The patients exhibited decreased smell function, as measured by the T&T olfactometer, the UPSIT, and a 30-item version of the UPSIT in which the 10 least familiar items were removed (ps < 0.001). Spearman correlations ranging from 0.53 to 0.70 were found between (i) scores on the 30- and 40-item UPSITs and (ii) the T&T detection and recognition threshold values. Significant correlations were found between scores on the smell ability questionnaire and the olfactory test measures (UPSIT30 r = 0.56; UPSIT40 r = 0.58; T&T detection r = 0.56; T&T recognition r = 0.69, p < 0.001), indicating that subjects are relatively accurate in assessing their olfactory ability. This study suggests that the 30 and 40-item UPSITs correlate well with measures derived from the T&T olfactometer, and that all three tests are sensitive to the smell loss of Japanese sinusitis/polyposis patients.     

Population-based screening for primary hyperparathyroidism with serum calcium and parathyroid hormone values in menopausal women

BACKGROUND: Population-based screenings for primary hyperparathyroidism have failed to systematically use intact parathyroid hormone (PTH) values for diagnosis, to explore prevalence and diagnostic criteria of normocalcemic hyperparathyroidism, and to attempt surgical verification of the disorder. METHODS: A total of 5202 women (ages, 55 to 75 years) attending a population-based mammography screening were investigated for primary hyperparathyroidism. In women lacking a family history of hypercalcemia, significant renal impairment, or low urinary calcium excretion hyperparathyroidism was diagnosed on the basis of predetermined criteria encompassing lower intact serum PTH levels in hypercalcemia (serum PTH 25 ng/L or greater; reference range, 12 to 55 ng/L) than in two intervals of normocalcemia (serum PTH 35 or greater, greater than 55 ng/L). RESULTS: Prevalence of hyperparathyroidism was 2.1% (n = 109). At diagnosis total serum calcium and serum PTH levels were 2.32 to 3.19 mmol/L and 34 to 300 ng/L, respectively, and 66% of the women exhibited normocalcemia. Repeated examination showed persistent normocalcemia in 30 patients, and all but two of them had normal ionized plasma calcium levels. Significantly higher serum calcium, serum PTH, and urine calcium--but not serum creatinine--levels were found in patients with hyperparathyroidism compared with matched control subjects from the screened population. Within an ongoing stratified treatment program, 59 of 60 patients who underwent operation exhibited pathologic parathyroid tissue (mean weight, 591 mg). CONCLUSIONS: Substantial prevalence of sporadic primary hyperparathyroidism is demonstrated in a risk group. Although criteria for hyperparathyroidism recognition included patients with truly mild biochemical derangement, operative findings suggested underdiagnosis of the disorder.     

Vitamin D receptor polymorphisms correlate to parathyroid cell function in primary hyperparathyroidism

Calcitriol acts via its receptor (VDR) and inhibits PTH secretion and parathyroid cell proliferation. Increased prevalence of the polymorphic VDR alleles b, a, and T has been demonstrated in sporadic primary hyperparathyroidism. Sixty-two patients with primary hyperparathyroidism due to parathyroid adenoma (mean age, 69.5 +/- 1.4 yr) were genotyped for these VDR polymorphisms. Dispersed cells of the adenomas were exposed to increasing concentrations of extracellular Ca2+ and analyzed for PTH release and cytoplasmic Ca2+ concentrations. Ca2+-mediated PTH inhibition exhibited higher ED50 and less suppression in the cells of patients who were homozygous for the b, a, and T alleles (P < 0.05-0.10). When analyzing haplotypes, the patients with baT demonstrated a ED50 of 1.81 +/- 0.15 vs. 1.29 +/- 0.10 for BAt (P < 0.05). As VDR alleles were unrelated to parathyroid intracellular Ca2+, influences of polymorphic VDR alleles on PTH secretion seem to involve mechanisms other than the Ca2+-sensing protein of the parathyroid cell surface.     

Nonadenomatous thymic unencapsulated parathyroid tissue as a cause of persistent primary hyperparathyroidism

Primary hyperparathyroidism may be caused by ectopic intrathymic parathyroid adenomas or hyperplastic parathyroid glands. The association of the ectopic inferior parathyroid glands and the thymus is due to their common embryologic origin from the third pharyngeal pouch. We report a case of primary hyperparathyroidism due to an unusual pathologic parathyroid gland formation: nonadenomatous thymic unencapsulated parathyroid tissue. Two unsuccessful neck exploration revealed only two normal parathyroid glands within the cervical area. Radiologic imaging studies failed to localize an ectopic parathyroid adenoma. Mediastinal exploration and thymectomy showed one small focus of unencapsulated hypercellular parathyroid tissue expanding peripherally along the septa of thymic adipose tissue. The hyperparathyroidism resolved with the surgical procedure.     

Major histocompatibility complex class II expression and parathyroid autoantibodies in primary hyperparathyroidism

We evaluated whether kinins exert a protective action against the development of two-kidney, one clip (2K1C) hypertension, a model characterized by an activated renin-angiotensin system in the ischemic kidney and increased expression of the bradykinin (BK) B2 receptor in the contralateral kidney. BK B2-receptor knockout (B2-/-), wild-type (B2+/+), and heterozygous (B2+/-) mice underwent clipping of the left renal artery, with the other kidney remaining untouched. Basal systolic blood pressure (SBP, via tail-cuff plethysmography) was higher in B2-/- mice than in B2+/- or B2+/+ mice (121+/-2 versus 113+/-2 and 109+/-1 mm Hg; P<0.05 for both comparisons). SBP did not change from basal values after sham operation, but it increased in mice that underwent clipping. The increase in SBP was greater in 2K1C B2-/- mice than in B2+/- or B2+/+ mice (28+/-2 versus 14+/-2 and 14+/-2 mm Hg, respectively, at 2 weeks; P<0.05 for both comparisons). Blockade of the BK B2 receptor by Icatibant enhanced the pressure response to clipping in B2+/+ mice (29+/-2 mm Hg at 2 weeks). Intra-arterial mean blood pressure (MBP) was higher in 2K1C than in respective sham-operated mice, with the MBP difference being higher in B2-/- mice (32 and 38 mm Hg, at 2 and 4 weeks, respectively), and higher in B2+/+ mice given Icatibant (30 and 32 mm Hg) than in B2+/+ mice without Icatibant (17 and 18 mm Hg). At 4 weeks, acute injection of an angiotensin type 1 receptor antagonist normalized the MBP of 2K1C hypertensive mice. A tachycardic response was observed 1 week after clipping in B2-/- and B2+/- mice, but this effect was delayed in B2+/+ mice. However, the HR response to clipping in B2+/+ mice was enhanced by Icatibant. Within each strain, heart weight to body weight ratio was greater in 2K1C hypertensive mice than in sham-operated control animals (B2-/-: 5.7+/-0.1 versus 5.2+/-0.1; B2+/+: 5.1+/-0.1 versus 4.5+/-0.1; P<0.01 for both comparisons). The clipped kidney weight to nonclipped kidney weight ratio was consistently reduced in mice with 2K1C hypertension. Our results indicate that kinins acting on the BK B2 receptor exert a protective action against excessive blood pressure elevation during early phases of 2K1C hypertension.     

Suppressive effect of calcium on parathyroid hormone release in adynamic renal osteodystrophy and secondary hyperparathyroidism

Serum parathyroid hormone (PTH) levels are markedly lower in patients with the adynamic lesion (AD) of renal osteodystrophy than in those with secondary hyperparathyroidism (2 degrees HPT), but serum PTH values are often moderately elevated in AD when compared to subjects with normal renal and parathyroid gland function (NL). To study the inhibitory effect of calcium on PTH release in AD and in 2 degrees HPT, the response to two-hour intravenous calcium infusions was examined in 6 patients with AD, in 31 patients with 2 degrees HPT and in 20 NL. Basal serum PTH levels were 88 +/- 51, 536 +/- 395, and 26 +/- 6 pg/ml, respectively, in AD, 2 degrees HPT and NL, whereas basal ionized calcium levels did not differ. When expressed as a percentage of pre-infusion values, PTH levels at the end of two-hour calcium infusions were higher both in AD (23.2 +/- 5.6%) and in 2 degrees HPT (27.8 +/- 12.3%) than in NL, (11.9 +/- 5.8%, P < 0.001). Both the amplitude of suppression (%) and the rate of decline (min-1) in serum PTH were less in AD and 2 degrees HPT than in NL, P < 0.05 for each parameter; corresponding values for each group, with 95% confidence intervals, were 77% (73 to 82) and 0.039 min-1 (0.030 to 0.048) in AD, 72% (68 to 76) and 0.031 min-1 (0.025 to 0.036) in 2 degrees HPT and 87% (84 to 89) and 0.070 min-1 (0.058 to 0.089) in NL. Neither variable differed between AD and 2 degrees HPT. Basal and nadir serum PTH levels were highly correlated: r = 0.95 and P < 0.05 in AD; r = 0.90 and P < 0.01 in 2 degrees HPT; r = 0.75 and P < 0.01 in NL. The slope of this relationship was less, however, both in AD and in 2 degrees HPT than in NL, P < 0.05 by analysis of co-variance. Thus, serum PTH levels fell below 20% of pre-infusion values in fewer subjects with AD (1 of 6) or 2 degrees HPT (9 of 31) than in NL (17 of 20) (chi 2 = 17.81, P < 0.005). The results indicate that the inhibitory effect of calcium on PTH release in vivo does not differ in AD and 2 degrees HPT despite marked differences in basal serum PTH levels. Variations in functional parathyroid gland mass rather than disturbances in calcium-sensing by the parathyroids probably account not only for the lower basal serum PTH levels in patients with AD compared to those with 2 degrees HPT, but also for the moderately elevated serum PTH values commonly seen in patients with AD.     

Controlled trial of falecalcitriol versus alfacalcidol in suppression of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism

Since the first reports in the late 1950's, a large amount of data have been collected. The analysis of the main evidence from the major randomized trials will be analyzed in this paper according to preoperative, postoperative and chemoradiation approaches. Fifteen randomized preoperative trials were reported; they have been grouped according to the fractionation schedule. In the hypofractionation group (5 Gy for fraction), all five studies that delivered 3-5 doses in one week had a significant improvement in local control and one of them also showed improvement in survival. Operative mortality was higher in the radiotherapy arm if inadequate techniques had been applied. In 3 out of 8 studies with conventional fractionation there was a significant improvement in local control, but no impact in survival was detected. No studies with total dose lower than 34 Gy had an improvement in local control. None of the six randomized postoperative studies showed an improvement in local control or survival. In all trials the local control rate was uniform; ranging from 76% to 84%. Toxicity was higher in the radiotherapy arm. One preoperative and five postoperative randomized studies that used chemoradiation were analyzed. One postoperative chemoradiation study showed a significant improvement in survival in comparison to the surgery arm, and another showed the same advantage compared to the postoperative arm. Protracted infusional administration of 5FU concomitant to radiotherapy showed better survival than bolus administration. No advantages were shown in using MeCCNU or Levamisole in two studies. Toxicity was high and related to the dose and the modality of administration of the drugs in order to adequately treat the different stages of rectal cancer, patients must be carefully selected in order to prescribe the most effective and the least toxic treatment for the individual stage; organ preservation should be an essential goal for its impact on quality of life, and the cost estimates should be taken into account.     

Analysis of proliferative activity of the parathyroid glands using proliferating cell nuclear antigen in patients with hyperparathyroidism

To elucidate the cellular proliferative kinetics of the parathyroidal gland in patients with hyperparathyroidism, we investigated the expression of proliferating cell nuclear antigen (PCNA) in parathyroidal tissues using an immunohistochemical procedure. The PCNA labeling index (LI; maximum LI, maximal stained area; average LI, evenly distributed stained area) indicating cellular proliferative activity was defined as the number of PCNA-positive cells per 1000 parathyroid cells in the region of interest. We used these indexes to compare and investigate the proliferative activity of parathyroid cells under various conditions. The specimens used for the study were 42 parathyroid glands from 21 patients with primary hyperparathyroidism (19 cases of adenoma and 2 cases of primary hyperplasia due to multiple endocrine neoplasia type 1) and 129 parathyroid glands from 32 patients with secondary hyperparathyroidism. An additional 40 parathyroid glands resected during thyroid surgery of 30 normocalcemic patients were used as normal controls. In normally functioning parathyroids, a small number of cells in the growth phase were found. In primary hyperparathyroidism, proliferative activity was highest in the adenoma followed by primary hyperplasia. In contrast, the PCNA LIs showed a low value in the normal rim of the adenoma and normal glands resected as biopsy specimens from adenoma patients. We, therefore, assumed that proliferative activity was suppressed in these cells compared with that in normally functioning glands. In secondary hyperparathyroidism, when the cell component of the parathyroid tissues was divided into five types, PCNA immunoreactivity was lowest in the dark chief cells. Proliferative activity in cells of the oxyphil series was the same or higher than that in the clear chief cells or vacuolated chief cells. When classified according to the structure of the parathyroid glands, cell proliferation was significantly higher in the nodular type than in the diffuse type (maximum LI, 176 +/- 231 vs. 38.3 +/- 55.7; average LI, 120 +/- 188 vs. 24.8 +/- 43.5; mean +/- SD; P < 0.001). More PCNA-immunoreactive cells were found in autotransplanted glands with recurrence than in glands resected during the initial surgery. To summarize the PCNA expression classified according to the pathological types of hyperparathyroidism, the PCNA LIs were highest in secondary hyperplasia (maximum LI, 144 +/- 212; average LI, 96.0 +/- 169) and adenoma (maximum LI, 102 +/- 81.7; average LI, 67.5 +/- 67.7), followed by primary hyperplasia (maximum LI, 25.0 +/- 25.4; average LI, 19.2 +/- 22.2) and normal glands (maximum LI, 13.6 +/- 23.9; average LI, 4.40 +/- 8.90). These findings suggest that the cellular proliferative kinetics of the parathyroid gland differ depending on the type of hyperparathyroidism, glandular structure, and cell components. As the detection method of intranuclear expression of PCNA in cells is too sensitive, we should be careful not to overestimate the number of cells in the proliferative cycle. However, these results could not have been obtained using a conventional method such as DNA analysis by flow cytometry.     

Indications, technique, and efficacy of alcohol injection of enlarged parathyroid glands in patients with primary hyperparathyroidism

BACKGROUND: Percutaneous alcohol ablation of the parathyroid gland (PAAP) has been proposed as an alternative treatment for primary hyperparathyroidism in patients unsuitable for surgery. The current study aimed to determine the (1) selection criteria, (2) associated morbidity, and (3) efficacy of PAAP. METHODS: From 1987 to 1998, 36 patients with primary hyperparathyroidism (mean age 65 years) underwent PAAP. The indications for PAAP were (1) medical comorbidity, (2) technically unsafe reoperative surgery, (3) partial ablation of a single remaining gland, and (4) patient choice. RESULTS: There were no long-term complications. Two patients had temporary recurrent laryngeal nerve injury and 4 had temporary hypocalcemia. Over a median follow-up of 16 months, 12 (33%) of the patients remained eucalcemic. For analysis purposes patients were separated into 2 separate groups: 29 with attempted complete ablation and 7 with partial ablation of a single remaining gland only. Ten of the complete ablation group (34%) remained eucalcemic. In the partial ablation group only 2 remained eucalcemic, but all had adequately controlled serum calcium levels. CONCLUSION: PAAP should be considered for hyperparathyroid patients with excessive reoperative morbidity or prohibitive medical comorbidity or those in whom the intent is to partially ablate a single remaining enlarged gland. In these patients close follow-up of serum calcium is required, and repeat treatments may be necessary because recurrence of hypercalcemia is likely.     

Surgical significance of supernumerary parathyroid glands in renal hyperparathyroidism

In secondary hyperparathyroidism (2HPT) fundamentally all parathyroid glands, including supernumerary glands, become hyperplastic, and stimulation of parathyroid glands continues after parathyroidectomy (PTx). Therefore supernumerary glands have special significance during surgery for 2HPT, whether persistent or recurrent HPT. In the present study 570 patients underwent initial total PTx with a forearm autograft. The frequency, type, location, histopathology, and clinical significance of the supernumerary glands were evaluated. At the initial operation 90 supernumerary glands were removed from 82 to 570 patients (14.4%); 12 patients (2.1%) required extirpation of supernumerary glands for persistent/recurrent HPT. Altogether 104 supernumerary glands were identified at operation in 94 of the 570 patients (16.5%). Among these 104 glands, 25 (24.0%) were of the rudimentary, or split, type and 79 (76.0%) of the proper type. Supernumerary glands were most frequently identified in the thymic tongue (53/104, 51.0%); 32 (60.4%) of these 53 glands were identified only microscopically. In 6 of the 570 cases (1.1%), reoperation was required for persistent HPT due to supernumerary glands located in the mediastinum, and 6 patients underwent neck reexploration for recurrence. Histopathologically, 61 of 104 (58.7%) supernumerary glands, including 36 glands recognized only microscopically, showed diffuse hyperplasia, and 43 (41.3%) displayed nodular hyperplasia. Residual small supernumerary glands with diffuse hyperplasia have the potential to be transformed to nodular hyperplasia during long-term hemodialysis. Therefore all parathyroid glands including supernumerary glands should, if possible, be removed at the initial operation. Routine removal of the thymic tongue and careful examination of the regions surrounding the lower poles of the thyroid, especially on the left side, are important steps in the surgical treatment.     

Role of glycosylation in expression and function of the human parathyroid hormone/parathyroid hormone-related protein receptor

Parathyroid hormone (PTH) regulates calcium metabolism through a specific G protein-coupled, seven-transmembrane helix-containing receptor. This receptor also binds and is activated by PTH-related protein (PTHrP). The human (h) PTH/PTHrP receptor is a membrane glycoprotein with an apparent molecular weight of approximately 85000 which contains four putative N-glycosylation sites. To elucidate the functional role of receptor glycosylation, if any, we studied hormone binding and signal transduction in human embryonic kidney cells transfected with hPTH/PTHrP receptor (HEK-293/C-21). These cells stably express 300000-400000 receptors per cell. Inhibition of N-glycosylation with an optimized concentration of tunicamycin yielded completely nonglycosylated hPTH/PTHrP receptor (approximately 60 kDa). This receptor form is fully functional; it maintains nanomolar binding affinity for PTH- and PTHrP-derived agonists and antagonists. PTH and PTHrP agonists stimulate cyclic AMP accumulation and increases in cytosolic calcium levels. In addition, the highly potent benzophenone (pBz2)-containing PTH-derived radioligand [Nle8,18,Lys13(epsilon-pBz2),L-2-Nal23,Tyr34 3-125I)]bPTH(1-34)NH2 can photoaffinity cross-link specifically to the nonglycosylated receptor. The molecular weight (approximately 60000) of the band representing the photo-cross-linked, nonglycosylated receptor (obtained from the tunicamycin-treated HEK-293/C-21 cells) was similar to that of the deglycosylated photo-cross-linked receptor (obtained by enzymatic treatment with Endoglycosidase-F/N-glycosidase-F). Our findings indicate that glycosylation of the hPTH/PTHrP receptor is not essential for its effective expression on the plasma membrane or for the binding of ligands known to interact with the native receptor. The nonglycosylated hPTH/PTHrP receptor remains fully functional with regard to both of its known signal transduction pathways: cAMP-protein kinase A and phospholipase C-cytosolic calcium.     

Late outcome of 304 consecutive patients with multiple gland enlargement in primary hyperparathyroidism treated by conservative surgery

The aim of this study was to assess the late outcome of patients with primary hyperparathyroidism and multiple gland enlargement (MGE) treated by conservative surgery. MGE in primary hyperparathyroidism is the presence of two or more enlarged glands weighing more than 50 mg. Conservative surgery consists in resecting the grossly enlarged glands without biopsying the normal glands. Some authors have suggested that this approach overlooks minute hyperplasia, leading to late recurrences of hyperparathyroidism; conversely, it may result in the unnecessary resection of grossly enlarged, but not hyperfunctioning, glands. Altogether 1231 patients were operated on for primary hyperparathyroidism between 1966 and 1995. Of these patients, 304 (24.9%) had MGE, including 42 cases of multiple endocrine neoplasia (MEN), 12 familial cases, and 250 seemingly sporadic cases. Two, three, or four glands (or more) were involved in 61.8%, 21.4%, and 16.4% of cases, respectively. During the early postoperative period one patient died and ten were reoperated for persistent hypercalcemia. The pathologic diagnoses were double adenomas (13.5%), hyperplasia (35.8%), association of the two (39.8%), and a normal second gland (10.8%) on light microscopy findings. None of the 30 deaths that occurred during follow-up was related to hyperparathyroidism. Altogether 190 patients (79%) were available for follow-up (average 89.3 months): 90% were normocalcemic, 4.7% hypocalcemic, and 5.2% hypercalcemic. A late iPTH assay was done in 147. PTH was appropriate to the serum calcium level in 84.3% and appropriate to normal calcemia in 91.6% of 132 cases. Conservative surgery is thus an acceptable treatment for MGE in patients with hyperparathyroidism. Few late recurrences occur, for which there are no individual predictive criteria.     

99m-Tc-MIBI SPECT parathyroid gland scintigraphy for the preoperative localization of small parathyroid gland adenomas

AIM: It was the of this study to assess the value of the 99mTc-MIBI scintigraphy in SPECT technique in the preoperative lateral location of small parathyroid adenoma (PTA). METHODS: 25 consecutive patients (8 male, 17 female, mean age 63 +/- 13 years) with the established diagnosis of primary hyperparathyroidism and non-diagnostic ultrasonography were scanned preoperatively. After a thyroid examination to exclude radionuclide accumulating thyroid adenoma, planar and tomographic images were acquired 20 min. and 120 min. after i.v. injection of 740 MBq 99mTc-MIBI using a 3 head gamma camera (Picker Prism 3000). The first 10 patients underwent an additional 201Tl/99mTc subtraction scintigraphy in a 2 days protocol. RESULTS: All patients had small, solitary PTA (< 1 g). 201Tl/99mTc subtraction scintigraphy (n = 10) showed only a sensitivity of 50%. Using planar MIBI-scintigraphy lateral location of PTA was possible in 18 cases (sensitivity: 72%). There was an increase in sensitivity up to 96% using the SPECT technique and the 3D display (volume-rendered reprojection). CONCLUSION: In contrast to 201Tl/99mTc subtraction scintigraphy, which showed only a low sensitivity, a reliable lateral location of small PTA was obtained using the tomographic 99mTc-MIBI scintigraphy. This method offers e.g. the possibility for the surgeon to perform an unilateral parathyroidectomy.