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Autogenous parathyroid grafts for generalized primary parathyroid hyperplasia: contrasting outcome in sporadic hyperplasia versus multiple endocrine neoplasia type I.

Sixteen patients with generalized primary parathyroid hyperplasia were treated with attempted total parathyroidectomy and placement of an autogenous parathyroid graft in the forearm musculature; these patients have been followed for up to 79 months. We assessed completeness of parathyroidectomy on the basis of the background immunoreactive parathyroid hormone (iPTH) value 3 to 7 days after surgery, which predicted the chance of a graft-independent recurrence or persistence of hyperparathyroidism (0/8 if undetectable versus 4/5 if normal or high). Total parathyroidectomy was sometimes difficult to achieve because of the presence of supernumerary or ectopic parathyroid glands; to enhance the success rate of total parathyroidectomy, we suggest both the use of preoperative ultrasonography to locate intrathyroidal parathyroids and a routine search for supernumerary parathyroids that includes transcervical thymectomy. Graft function was monitored by measuring the secretory gradient for iPTH (the difference between the two antecubital fossae). Gradients on postoperative days 3 to 7 were barely detectable, but by 3 weeks, larger iPTH gradients were noted in every case. By 4 months, the graft could maintain normal serum calcium levels in all but one case. Autonomous graft function has evolved in four of six evaluable patients with type I multiple endocrine neoplasia (MEN I), but in none of the nine patients with sporadic hyperplasia (p = 0.043). A prospective study is needed to determine whether the use of a smaller number of parathyroid fragments for the autogenous graft in known MEN I patients might delay recurrence.

Adult↗

Concurrent primary parathyroid hyperplasia and parathyroid carcinoma.

We noted the association of parathyroid carcinoma and primary parathyroid hyperplasia in a 53-year-old woman who had a clinical and laboratory profile of primary hyperparathyroidism. At surgery, three hyperplastic parathyroid glands were excised, one of which also demonstrated parathyroid carcinoma. Postoperatively, she was treated for persistent hypercalcemia and died of congestive cardiac failure. At autopsy, there was evidence of metastatic parathyroid carcinoma, and a further hyperplastic parathyroid gland was identified. The association of parathyroid hyperplasia and carcinoma is rare.

Adenoma↗

Assessment of parathyroid autotransplantation for preservation of parathyroid function after total thyroidectomy.

BACKGROUND: Hypoparathyroidism with permanent hypocalcemia is a well-recognized complication after thyroid surgery. AIM: This study was conducted to assess the role of immediate parathyroid autotransplantation in the preservation of parathyroid function after total thyroidectomy. PATIENTS AND METHODS: Twenty-eight patients had autotransplantation of parathyroid glands resected or devascularized during total thyroidectomy. Data were collected prospectively regarding demographics, indication for surgery, operative procedure, pathologic diagnosis, number of glands transplanted, and subsequent course. Thyroid nodules were evaluated by ultrasonography, radionuclide scanning, and/or fine-needle aspiration cytology. All patients had serum ionized calcium, phosphorus, and intact parathyroid hormone (PTH) levels measured preoperatively and monitored regularly postoperatively for a period of 14 weeks and again at 6 months after operation. Patients were categorized into three groups according to the number of glands transplanted: one (group 1, n = 6), two (group 2, n = 14), or three glands (group 3, n = 8). In three other volunteers, one parathyroid gland was transplanted in the brachioradialis and subjected to electron microscopy 1, 2, and 4 weeks after transplantation. RESULTS: Total thyroidectomy was performed for malignant disease in 16 patients (57.1%) and for benign disease in 12 (42.9%) patients. All patients reverted to asymptomatic normocalcemia without the need for any medications within 4 to 14 weeks. Normal levels of serum markers were regained slower when one gland was transplanted compared with two or three glands (P <.01). Electron microscopic examination showed evidence of ischemic degeneration in the transplanted tissues 1 week postoperatively. Regeneration started by the second week and coincided with normalization of PTH levels. Optimum resting and nearly normal status of parathyroid tissue was achieved by the fourth week. CONCLUSIONS: This study showed that active PTH production coincides with regeneration of parathyroid cells and that autotransplantation of at least two resected or devascularized glands during total thyroidectomy nearly eliminates permanent postoperative hypoparathyroidism, thus improving the safety of total thyroidectomy performed for malignant or benign disease.

Adult↗

Ultrasound-guided parathyroid aspiration to diagnose parathyroid adenomas.

AIM: To ascertain the accuracy of ultrasound-guided fine needle aspiration and parathyroid hormone assay in the identification of parathyroid adenomas. DESIGN: Case study. SETTING: Tertiary referral clinic. PATIENTS: 12 subjects, consisting of 10 female and two male patients, with documented primary hyperaparathyroidism. INTERVENTION: Ultrasonography of the parathyroid glands was performed using an Acuson XP 128 machine with a linear array 7.5 MHz multihertz probe. Following accurate localization of the parathyroid lesion, fine needle aspiration was performed using a 23 gauge needle, and parathyroid hormone assay was performed on the aspirate. Preoperative localization was compared with intra-operative findings. RESULTS: Ultrasound examination detected 10 out of a possible 12 parathyroid adenomas (83% sensitivity), while ultrasound-guided fine needle aspiration only confirmed nine out of the 12 adenomas (75% sensitivity). CONCLUSIONS: While ultrasound-guided fine needle aspiration may be simple and with minimal morbidity, it does not appear to provide any advantage over ultrasound examination alone for the localization of parathyroid adenomas. It has a potential role in defining the nature of ultrasonically localized nodules.

Adenoma↗

The utility of a rapid parathyroid assay for uniglandular, multiglandular, and recurrent parathyroid disease.

The rapid parathyroid hormone assay (rPTH) is an effective tool in minimally invasive resections of parathyroid adenomas. However, there are relatively few reports examining its utility in the full spectrum of parathyroid disease. The purpose of this study was to examine the utility of the rapid parathyroid hormone assay in uniglandular, multiglandular, and recurrent hyperparathyroidism. A retrospective analysis of all patients undergoing parathyroid resection from June 2001 to March 2003 was undertaken. All patients underwent preoperative localization studies. Rapid parathyroid hormone (PTH) levels were drawn immediately prior to and 10 minutes following parathyroid resection. A decline of > or = 50 per cent rPTH qualified as a successful/complete resection. Additional intraoperative samples were drawn as needed for patients with multiglandular disease. Of 46 treated patients who were examined (average age, 54 years), 30 had single, 12 patients had multigland disease, and 4 had recurrent/persistent hyperparathyroidism. Thirty-seven patients had primary hyperparathyroidism (32 with single and 3 with double adenomas; 2 with hyperplasia), 4 patients had secondary hyperparathyroidism, and 5 tertiary hyperparathyroidism. All procedures were considered successful, as every patient exhibited a postresection decrement in rPTH exceeding 50 per cent (average decrement, 91%). Although 2 patients exhibited a postoperative PTH increase exceeding 50 per cent of the preoperative value, all remained asymptomatic and eucalcemic (median follow-up, 21.5 months). The rPTH assay is an effective tool in determining success of parathyroidectomy in patients with primary uni- and multiglandular as well as recurrent hyperparathyroidism. It can be used to achieve minimally invasive neck dissections or guide surgical decision-making in more complex cases.

Calcium↗

Transplantation of parathyroid tissue in experimental hypoparathyroidism: in vitro and in vivo function of parathyroid tissue microencapsulated with a novel amitogenic alginate.

Microencapsulation of tissues is an alternative to postoperative immunosuppression in transplantation. In 1994 iso-, allo- and xenotransplantation of microencapsulated parathyroid tissue was achieved in vivo. However, continued analysis of the coating substance (an alginate) determined mitogenic properties. Here, we report on the in vitro and in vivo function of parathyroid tissue microencapsulated with a novel amitogenic alginate suitable for use in humans. To assess in vitro function, parathyroid tissue encapsulated with mitogenic and amitogenic alginate was exposed to rising concentrations of calcium. For in vivo experiments, it was isotransplanted into parathyroidectomized rats. PTH release into medium and PTH serum levels as well as calcium levels of recipient rats were analyzed and compared to native (non-microencapsulated) tissue and empty capsules, respectively. In vivo, transplants were excised and subjected to histologic examination six months after trans-plantation. In vitro, parathyroid tissue encapsulated with amitogenic alginate releases approximately half of the PTH of the native tissue, not different from tissue encapsulated with the mitogenic alginate. In vivo, the novel alginate preserved parathyroid function similar to that of native tissue over the six month period resulting in complete reversal of hypoparathyroidism. Correspondingly, histologic examination revealed vital parathyroid tissue in intact microcapsules. By establishing in vitro function and successful long-term transplantation, we have documented the principle of microencapsulation of parathyroid tissue to be effective also with the novel amitogenic alginate, which is suitable for clinical use.

Alginates↗

Blood supply and parathyroid hormone secretion in pathological parathyroid glands.

The blood supply of pathologic parathyroid glands and the relation between parathyroid hormone secretion and parathyroid blood perfusion was studied during surgery for hyperparathyroidism. Blood flow in 39 single adenomas and 20 glands classified as primary or secondary hyperplasia were studied intraoperatively with laser Doppler flowmetry. The ipsilateral inferior thyroid artery was occluded during continuous flowmetry recording, which resulted in a 40% reduction of parathyroid blood flow in both groups. In 12 patients with single adenomas, intact parathormone (iPTH) was measured intraoperatively before and during occlusion of the ipsilateral inferior thyroid artery and after extirpation of the adenoma. During occlusion the iPTH levels were mainly unchanged despite blood flow reduction of up to 80%. After removal of the adenoma the iPTH normalized within 15 minutes. In a control group of eight single adenomas, iPTH was measured similarly without vascular occlusion, demonstrating comparable iPTH levels. This study demonstrates similar routes of vascularization for single adenomas and hyperplastic glands, as was earlier seen for normal parathyroid glands. The increased parathyroid hormone secretion from single adenomas appears to remain mainly unchanged during significant blood flow reduction.

Adenoma↗

Calcium-regulated secretion of tissue plasminogen activator and parathyroid hormone from human parathyroid cells.

The effects of Ca and other agents on secretion of plasminogen activator (PA) and PTH have been examined and compared, using parathyroid cells obtained from the glands of chronic renal patients. During 2 weeks culture at different [Ca], the secretory rates of PA activity and PTH were parallel; steady-state secretion over 24-h periods was maximal at 0.5-0.9 mM Ca, minimal at 1.5-2.5 mM Ca, and the [Ca] at 50% suppression was 1.1 mM. At 2.5 mM Ca, two inhibitors of cellular proteolysis, 3-methyladenine and chloroquine, stimulated secretion of both PA activity and PTH. The results indicated that secretion of PA from human parathyroid cells is regulated similarly to that of PTH. The characteristics of human parathyroid PA were also examined using human parathyroid adenoma tissue. In homogenates, the highest specific activity of PA was in microsomal fractions. The Mr of PA from tissue and from culture media was 70 kilodalton by sodium dodecyl sulfate gel electrophoresis followed by zymography, or by Western blotting using antisera to human tissue PA (tPA). Enzyme activity was inhibited by incubation with antisera to tPA but not to urokinase. In contrast to bovine parathyroid cells that secrete a urokinase, human parathyroids apparently contain and secrete tPA.

Adenine↗

Indian primary hyperparathyroidism patients with parathyroid carcinoma do not differ in clinicoinvestigative characteristics from those with benign parathyroid pathology.

INTRODUCTION: No foolproof preoperative diagnostic indicators of parathyroid carcinoma (PC) exist in absence of nonskeletal metastases. Palpable parathyroid tumor, advanced skeletal and renal manifestations, and very high serum calcium and parathyroid hormone levels are considered strong predictors. Most of these features are common in Indian primary hyperparathyroidism (PHPT) patients although only few have PC. The aim of this study was to identify dependable clinicoinvestigative predictors of PC in Indian PHPT patients. MATERIALS AND METHODS: Clinical, biochemical, radiological, and densitometric attributes of 100 PHPT patients who underwent successful parathyroidectomy (1990-2004) were studied. Various parameters of patient groups with parathyroid adenoma (n = 84), primary hyperplasia (n = 12), and carcinoma (n = 4) were compared using ANOVA, with P value < 0.05 considered significant. RESULTS: Mean age of patients was 37.4 years, with no difference in the 3 groups (P = 0.92). Patients in 3 groups had comparably severe bone disease; 36 had coexistent renal disease. Two patients with PC and 27 (32%) with adenoma had palpable parathyroid tumor. None of the biochemical parameters predicted malignant pathology. Mean tumor weight (milligram) in carcinoma patients (15,080 +/- 5,638.02) was significantly higher than those with adenoma (5,724 +/- 1,257.9) (P = 0.002). Postoperative course and recovery in carcinoma patients were similar to those with adenoma. In follow-up (mean: 33 months), none of the adenoma patients were found to have persistent/recurrent PHPT attributable to missed PC. CONCLUSION: Indian patients with parathyroid adenoma, hyperplasia, and carcinoma were not found to differ in their clinical, biochemical, and pathological characteristics except for significantly higher tumor weight in the carcinoma group.

Adenoma↗

Functional mediastinal parathyroid cyst. Dynamics of parathyroid hormone secretion during cyst aspirations and surgery.

A patient presented with a large neck mass, hypercalcemia, and elevated serum parathyroid hormone levels. Aspiration of the cystic mass yielded 100 ml of fluid that contained a low concentration of thyroxine, but large amounts of parathyroid hormone, as measured by bioassay or with three different radioimmunoassays. After each of four aspirations, the serum calcium level declined significantly. Serial measurements showed that serum amino-terminal and mid-region parathyroid hormone levels and urinary cyclic adenosine monophosphate values declined after aspiration. Surgical resection of the cervical-mediastinal cyst restored normal serum calcium and parathyroid hormone levels, and these have been maintained for nine months. Calculations suggest that parathyroid hormone traversing the cyst lumen might contribute significantly to the excess circulating parathyroid hormone.

Aged↗

Paraphysectomy-induced stimulation of parathyroid glands in mature frogs (Rana catesbeiana): evidence for telencephalic regulation of parathyroid gland function.

The relationship of the paraphyseal-choroid plexus complex to parathyroid gland function was investigated in adult frogs. Light microscopy and morphometric analysis indicated that total parathyroid gland volume, cell volume and vascular volume doubled by 7-28 days after surgical removal of the paraphyseal-choroid plexus complex (paraphysectomy). This increase correlated with the appearance of large Golgi-associated vesicles, an increase in the apparent number of cytoplasmic dense-core granules, and PTH within the parenchymal cells as monitored by immunofluorescence. Twelve months after paraphysectomy, parathyroid glands became cystic with a central fluid-filled cavity surrounded by a stratified cuboidal cell layer. The parenchymal cells of cystic glands contained numerous cytoplasmic dense-core granules and were also positive for PTH. Radioimmunoassay of cystic parathyroid fluid indicated a PTH concentration of 2 micrograms/microliter; however, analysis by SDS-PAGE indicated a wide range of proteins in cystic fluid. The results of this study indicate that paraphysectomy induces stimulation of the parathyroid glands and suggest a role for the paraphyseal-choroid plexus complex in the regulation of amphibian parathyroid gland function.

Animals↗

Retrospective analysis of sequential changes in serum intact parathyroid hormone levels during conventional parathyroid exploration.

BACKGROUND: The purpose of this study was to assess sequential changes in serum parathyroid hormone (PTH) levels during conventional parathyroidectomy. METHODS: Sera were collected before and 10 minutes after resection of each parathyroid tumor from 112 consecutive patients and assayed postoperatively within 48 hours for PTH. RESULTS: PTH reductions corroborated cures for 94 of 112 cases (84%), including 70 of 71 patients with solitary adenomas (SAs). However, there were 15 false positives (13%), in which PTH decreased more than 50% within 10 minutes of resection of 1 parathyroid tumor while additional parathyroid tumors remained in situ (1 of 71 SAs, 4 of 6 double adenomas, 7 of 15 primary hyperplasias, and 3 of 17 tertiary hyperplasias). There were 3 false negatives (3%), with PTH unchanged, even though postoperative PTH and calcium values confirmed cure (1 SA, 1 primary hyperplasia, and 1 tertiary hyperplasia). There were only 2 of 112 failed explorations (1.8%), which would not have been avoided by PTH monitoring because both subsequently were found to have mediastinal parathyroid adenomas. CONCLUSIONS: We conclude that intraoperative PTH changes corroborated outcome in SA but may under-estimate the extent of resection required in parathyroid hyperplasia.

Adenoma↗

Parathyroid hormone (PTH) assay of parathyroid cysts examined by fine-needle aspiration biopsy.

The authors report three cases of parathyroid cysts examined by the fine-needle aspiration biopsy technic. A presumptive diagnosis of parathyroid cyst was made when characteristic water-clear fluid was aspirated. The diagnosis was then confirmed by parathyroid hormone (PTH) assay. The authors believe that the C-terminal/midmolecule determination should be the assay of choice, because the N-terminal-specific assay gave normal or slightly elevated results in all the cases studied. If only an N-terminal-specific PTH assay is obtained, potential for a false negative diagnosis exists. With a correct PTH assay, a specific diagnosis of parathyroid cyst can be rendered, which enables appropriate treatment of total fluid aspiration, which thereby eliminates the need for thyroid hormone treatment or surgery in most cases. A discussion of PTH assays is presented along with speculations concerning the secretion of PTH by the parathyroid gland. The previous literature detailing cytologic findings and the PTH assays of parathyroid cysts diagnosed by the fine-needle aspiration biopsy are reviewed.

Adult↗

Intraoperative intact parathyroid hormone level monitoring as a guide to parathyroid reimplantation after thyroidectomy.

OBJECTIVE: The goal of this study was to determine whether intraoperative intact parathyroid hormone (IOiPTH) levels can predict the functional status of remaining parathyroids at the end of total thyroidectomy and thereby be a guide for parathyroid autotransplantation when glands are deemed not functional. STUDY DESIGN: Prospective study involving 23 patients undergoing either total thyroidectomy or completion thyroidectomy METHODS: During surgery, an attempt was made to identify all four parathyroid glands. Normal size vascular glands were preserved, whereas avascular glands were microdissected and reimplanted. Serial IOiPTH was measured preoperatively after each parathyroid was identified, manipulated, or removed and serum iPTH measurements were done postoperatively up to 56 days. RESULTS: The sensitivity of low IOiPTH in identifying a devascularized gland was 88.9%, and specificity was 92.9%. A normal IOiPTH level indicates at least two functioning glands. IOiPTH levels between 1.5 and 10 pg/mL indicate only one functional gland. Undetectable IOiPTH levels indicate no residual functioning gland. CONCLUSIONS: For patients undergoing total or completion thyroidectomy, IOiPTH should be routinely measured at the end of the procedure, and a level less than 10 pg/mL requires reassessment of remaining parathyroid glands. Vascularized glands should be preserved regardless of IOiPTH levels. Devascularized glands or glands of questionable vascularity should be considered for autotransplantation.

Humans↗

Parathyroid hormone and parathyroid hormone-related protein in the investigation of hypercalcaemia in two hospital populations.

BACKGROUND AND OBJECTIVE: Parathyroid hormone-related protein (PTHrP) produced by cancers has a central role as a humoral mediator of hypercalcaemia in patients with malignancy. Since the prevalences of hypercalcaemia of malignancy and parathyroid disease reflect the population studied, hypercalcaemic patients from a district general hospital (DGH) and an oncology centre (OC) were studied in order to assess the diagnostic role of assays for serum PTH and plasma PTHrP in different clinical settings. DESIGN: A prospective study of consecutive patients presenting with their first episode of hypercalcaemia during an 18-month period. PATIENTS: A total of 123 patients (DGH, n = 69; OC, n = 54) had corrected serum calcium concentrations > 2.65 mmol/l. MEASUREMENTS: PTH, PTHrP, calcium and albumin were measured together with urine calcium and creatinine, enabling fractional calcium excretion to be assessed. Urine cyclic adenosine monophosphate was also measured. RESULTS: Hypercalcaemia was attributed to malignancy alone in 72 patients (DGH, n = 20; OC, n = 52), benign causes in 42 (DGH, n = 42) and parathyroid disease coexisting with malignancy in 9 (DGH, n = 7; OC, n = 2). Plasma PTHrP levels were increased in 59/72 (82%) patients with hypercalcaemia due to malignancy. Measurements of both analytes contributed to a change in the final diagnosis in 12 patients (10%). Thus serum PTH was increased in seven patients with parathyroid disease coexisting with malignancy, and plasma PTHrP was increased in five patients with previous undiagnosed malignancy. Median survival for patients with parathyroid disease and coexisting malignancy was 13 months compared with 3 months for those with hypercalcaemia due to malignancy alone (P < 0.02). CONCLUSIONS: Since hypercalcaemia was attributable to parathyroid disease in 10% of all patients with malignancy we advise measurement of serum PTH at the initial presentation of hypercalcaemia in all patients, while plasma PTHrP may be useful to identify those patients in whom malignancy may not be clinically apparent, or coexist with primary hyperparathyroidism.

Calcium↗

Localization of abnormal parathyroid glands with jugular sampling for parathyroid hormone, and subtraction scanning with sestamibi or tetrofosmine.

BACKGROUND: Accurate pre-operative localization of abnormal parathyroid glands is an essential prerequisite for elective surgical approaches such as the unilateral approach for treatment of primary hyperparathyroidism. METHODS: In 175 patients undergoing a bilateral neck exploration for primary hyperparathyroidism, localization of abnormal parathyroid glands was performed with jugular venous sampling for parathyroid hormone (PTH, n = 75), subtraction scan with iodine 123 and technetium-99m-sestamibi (MIBI, n = 50), or tetrofosmine (TTF, n = 50). The results of these localization studies were compared with operative findings. RESULTS: The sensitivity of PTH, MIBI, and TTF was 41, 63, and 71%, respectively. The specificity was 90, 98, and 98% and the positive predictive value was 85%, 82%, and 87%, respectively. The smallest abnormal parathyroid that was correctly detected weighed 110 mg with PTH, 118 mg with MIBI, and 70 mg with TTF. Subtraction scan (MIBI and TTF) detected mediastinal glands in five cases out of six. In patients with multiglandular disease, the results of all three studies were severely impaired. CONCLUSIONS: Subtraction scanning with MIBI or TTF, but not jugular sampling for PTH, appeared to be useful for localization of abnormal parathyroid glands in patients with primary hyperparathyroidism. Nevertheless, an elective unilateral approach guided by the localization studies would not have allowed the excision of all abnormal parathyroid glands in patients with multiglandular disease.

Female↗

Intra-operative parathyroid hormone assay for simplified localization of parathyroid adenomas.

Lack of success in parathyroid surgery is usually due to failure to identify the abnormal parathyroid gland correctly at operation. The surgeon may be helped by rapid parathyroid hormone (PTH) assay in peripheral blood after removal of a suspected adenoma, and by frozen section histology, but these are not true localization techniques. We have adapted a non-isotopic immunoassay for rapid measurement of PTH in samples from the upper, middle and lower thyroid veins taken at operation, before exploration begins. Fifteen patients with primary hyperparathyroidism were operated on. In 10 the parathyroid adenoma was located easily, and was associated with high local venous PTH levels. In four patients the abnormal parathyroid was not immediately apparent but the assay indicated its location, which was confirmed after further exploration. In one patient there was no difference in PTH levels in the six venous samples. An ectopic adenomatous gland was successfully identified behind the thymus. The operation was successful in all patients as shown by a fall in the plasma calcium to the normal range. We conclude that intra-operative selective venous sampling and rapid PTH assay facilitates operative localization of parathyroid adenomas.

Adenoma↗

Lack of a direct effect of 1,25-dihydroxycholecalciferol on parathyroid hormone secretion by normal bovine parathyroid glands.

Because of differing reports of an effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on parathyroid hormone (PTH) secretion, the present studies were performed in vitro using bovine parathyroid gland slices and isolated parathyroid cells. Both COOH-terminal and NH2-terminal RIAs for PTH were employed. No effect of 1,25(OH)2D3 on PTH secretion was found during a 4-h incubation of parathyroid slices in variable external calcium concentrations. The results from dual RIA measurements also showed no effect of 1,25(OH)2D3 on PTH secretion by isolated parathyroid cells during 90- to 150-min incubations with variable calcium concentrations. In addition, extensive analysis by polyacrylamide gel electrophoresis showed no effect of 1,25(OH)2D3 on cAMP generation. Whereas calcium inhibited and isoproterenol stimulated the production of cAMP, 1,25(OH)2D3 had no effect. We conclude that 1,25(OH)2D3 does not affect parathyroid gland function acutely in vitro.

Animals↗