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Background: Primary hyperparathyroidism (PHPT) caused by double adenoma may carry a higher risk of failure to cure. We compared outcomes in single adenoma (SA), double adenoma (DA) and four-gland hyperplasia (HP)., Methods: Patients undergoing initial parathyroidectomy for PHPT were categorized by diagnosis. The primary outcome was persistent/recurrent disease postoperatively., Results: Of 3408 patients, 81.3% had SA, 9.5% had DA, and 9.3% had HP. Rates of persistence/recurrence were 2.9%, 5.3%, and 4.5% in SA, DA, and HP, respectively (p = 0.281). Patients with persistence/recurrence had higher preoperative calcium (11.0 vs 10.7 mg/dl, p = 0.028) and PTH (96 vs 77 pg/ml, p = 0.015), and lower rates of IOPTH normalization (77% vs 96%, p < 0.001). On multivariable analysis, DA was associated with increased risk of persistent/recurrent disease (OR 3.0, p = 0.017)., Conclusions: Most patients with DA are cured with removal of two glands, but approximately 5% experience disease persistence/recurrence. Low-normal final IOPTH was associated with lower risk of persistent/recurrent disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The incidence of primary hyperparathyroidism has increased 300% in the United States in the past 30 years, and secondary hyperparathyroidism is almost universal in patients with end-stage renal disease. We assessed the presence of environmental chemicals in human hyperplastic parathyroid tumors as possible contributing factors to this increase., Methods: Cryopreserved hyperplastic parathyroid tumors and normal human parathyroids were analyzed by gas chromatography and liquid chromatography coupled to ultra-high-resolution mass spectrometry, bioinformatics, and biostatistics., Results: Detected environmental chemicals included polychlorinated biphenyls, polybrominated diphenyl ethers, dichloro-diphenyl-trichloroethane derivatives, and other insecticides. A total of 99% had p,p'-dichlorodiphenyldichloroethylene. More than 50% contained other environmental chemicals, and many classified as endocrine disruptors. Polychlorinated biphenyl-28 and polychlorinated biphenyl-49 levels correlated positively with parathyroid tumor mass. Polybrominated diphenyl ether-47 concentrations in tumors were inversely correlated with patients' serum calcium levels. Cellular metabolites in pathways of purine and pyrimidine synthesis and mitochondrial energy production were associated with tumor growth and with p,p'-dichlorodiphenyldichloroethylene in primary hyperparathyroidism tumors. In normal parathyroids, p,p'-dichlorodiphenyldichloroethylene , polychlorinated biphenyl-28, polychlorinated biphenyl-74, and polychlorinated biphenyl-153, but not p,p'-dichlorodiphenyldichloroethylene or polychlorinated biphenyl-49, were detected., Conclusion: Environmental chemicals are present in human parathyroid tumors and warrant detailed epidemiologic and mechanistic studies to test for causal links to the growth of human parathyroid tumors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Parathyroid gland disorders are rare conditions with an incidence that displays great variability among populations. Its direct influence in calcium homeostasis originates variable symptoms that affect bone remodelling among other processes. This study aimed to provide data on the epidemiology and characteristics of patients admitted with these disorders in Spain between 2003 and 2017, and to analyse disease management and direct medical costs. Medical records in which a disorder of the parathyroid gland was registered as the admission motive were extracted from a nationwide hospital-discharge database via the Spanish Ministry of Health. Records from 12,903 patients were obtained, with predominance of female patients (74.70%) and of admissions due to hyperparathyroidism (90.23%). The number of patients admitted per year increased over the study period along the incidence of these disorders. The year 2017 incidence of hyperparathyroidism was 2.95 per 10,000, 4.03 per 10,000 in females and 1.37 in males; the same year, the incidence of hypoparathyroidism was 0.17 per 10,000. Length of hospital stay was significantly extended in patients with hypoparathyroidism (7.16 days), admitted mostly due to emergencies. Heart failure was diagnosed in more than 20% of admissions in patients with secondary and tertiary hyperparathyroidism and hypoparathyroidism, while this last group displayed the highest levels of mineral metabolism disruption. Parathyroidectomy was performed in 78.95% of all admissions for primary hyperparathyroidism. The total annual direct medical cost parathyroid gland disorders has increased over the study period, due to the increase of the costs associated to hyperparathyroidism, whereas the cost per patient remained relatively stable, with an average of €3,748, €3,430 and €3,737 for patients with hyperparathyroidism, hypoparathyroidism and other disorders of the parathyroid gland, respectively. This study provides novel data to extend the scarce available knowledge on parathyroid gland disorders' epidemiology and management in Spain., Competing Interests: The authors declare no competing interests. AM employment at BCN Health does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Persistent/recurrent hyperparathyroidism occurs in 2%-5% of patients with sporadic primary hyperparathyroidism (PHPT). In this study, the incidence and time to recurrence in patients with single-gland disease (SGD), double adenomas (DAs), or four-gland hyperplasia (FGH) at initial parathyroidectomy were compared., Methods: This retrospective review included adult patients with sporadic PHPT who underwent initial parathyroidectomy with intraoperative parathyroid hormone monitoring (IOPTH) from 1/2000 to 12/2016 with ≥6 mo follow-up. An abnormal parathyroid was defined by a gland weight of ≥50 mg. A concurrent serum calcium >10.2 mg/dL and parathyroid hormone >40 pg/mL was defined as persistent PHPT if present <6 mo and recurrent PHPT if present ≥6 mo postoperatively after initial normocalcemia., Results: Of 1486 patients, 1203 (81%) had SGD, 159 (11%) DA, and 124 (8%) FGH. Among the 3 groups, there was no difference in the percent decrease from the baseline or time of excision to final postexcision IOPTH levels between groups (79% versus 80% versus 80%, respectively; P = 0.954) or in the proportion of patients with a final IOPTH ≥40 (22% versus 18% versus 14%; P = 0.059). Overall, 22 (1.5%) had persistent PHPT and 26 (1.7%) had recurrent PHPT. Persistent PHPT was more frequent with DAs (6; 3.8%) than other groups (SGD: 16, 1.3%; FGH: 0; P = 0.02). At median follow-up of 33 mo (IQR, 18-60), there was no difference in recurrence rate (1.6% versus 2.5% versus 2.4%; P = 0.57) or median time (mo) to recurrence (SGD: 59 [IQR, 21-86], DAs: 36 [IQR, 29-58], FGH: 23 [IQR, 17-40]; P = 0.46)., Conclusions: Recurrent PHPT occurred in 1.7% of patients who underwent curative initial parathyroidectomy, with no difference in incidence or time to recurrence between groups based on the number of glands removed. Patients with DA more commonly had persistent PHPT, raising the possibility of unrecognized FGH., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Patients with primary hyperparathyroidism (PHPT) may be asymptomatic, and some may present with normocalcemic PHPT (NPHPT). Patients with vitamin D deficiency may also be asymptomatic, with normal calcium and elevated PTH concentrations. These latter patients are usually diagnosed with vitamin D deficiency-induced secondary hyperparathyroidism (VD-SHPT). Therefore, it is very difficult to distinguish PHPT and NPHPT from VD-SHPT based on calcium or PTH concentrations in clinical settings. In this case-control study, we aimed to verify the diagnostic power of a new parathyroid function index (PFindex = Ca*PTH/P)., Methods: This study enrolled 128 patients with surgically and pathologically confirmed PHPT, including 36 with NPHPT, at a hospital in West China between January 2009 and September 2017. Thirty-seven patients with VD-SHPT and 45 healthy controls were selected from the population of a cross-sectional epidemiological study as the SHPT and healthy groups, respectively. We used the PFindex to describe the characteristics of PHPT, NPHPT, and VD-SHPT.. Differences between the four groups were compared, and a receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic power of PFindex., Results: The PHPT group had the highest PFindex (454 ± 430), compared to the other three groups (NPHPT: 101 ± 111; SHPT: 21.7 ± 6.38; healthy: 12.2 ± 2.98, all p < 0.001). A PFindex cut-off value of 34 yielded sensitivity and specificity rates of 96.9 and 97.6% and of 94.4 and 94.6% for the diagnoses of PHPT and NPHPT, respectively. The use of a PFindex > 34 to differentiate NPHPT from VD-SHPT yielded the highest positive likelihood ratio and lowest negative likelihood ratio., Conclusion: The PFindex provided excellent diagnostic power for the differentiation of NPHPT from VD-SHPT. This simple tool may be useful for guiding timely decision-making processes regarding the initiation of vitamin D treatment or surgery for PHPT.

Primary hyperparathyroidism (PHPT) is a common endocrinopathy characterized by hypercalcemia and elevated levels of parathyroid hormone. The primary cause of PHPT is a benign overgrowth of parathyroid tissue causing excessive secretion of parathyroid hormone. However, the molecular etiology of PHPT is incompletely defined. Here, we demonstrate that semaphorin3d (Sema3d), a secreted glycoprotein, is expressed in the developing parathyroid gland in mice. We also observed that genetic deletion of Sema3d leads to parathyroid hyperplasia, causing PHPT. In vivo and in vitro experiments using histology, immunohistochemistry, biochemical, RT-qPCR, and immunoblotting assays revealed that Sema3d inhibits parathyroid cell proliferation by decreasing the epidermal growth factor receptor (EGFR)/Erb-B2 receptor tyrosine kinase (ERBB) signaling pathway. We further demonstrate that EGFR signaling is elevated in Sema3d parathyroid glands and that pharmacological inhibition of EGFR signaling can partially rescue the parathyroid hyperplasia phenotype. We propose that because Sema3d is a secreted protein, it may be possible to use recombinant Sema3d or derived peptides to inhibit parathyroid cell proliferation causing hyperplasia and hyperparathyroidism. Collectively, these findings identify Sema3d as a negative regulator of parathyroid growth.-/- parathyroid glands and that pharmacological inhibition of EGFR signaling can partially rescue the parathyroid hyperplasia phenotype. We propose that because Sema3d is a secreted protein, it may be possible to use recombinant Sema3d or derived peptides to inhibit parathyroid cell proliferation causing hyperplasia and hyperparathyroidism. Collectively, these findings identify Sema3d as a negative regulator of parathyroid growth., (© 2019 Singh et al.)

OBJECTIVE The study aimed to evaluate the total effective and organ absorbed radiation doses associated with three- and four-phase parathyroid computed tomography (CT) and sestamibi scans used for the preoperative localisation of parathyroid adenomas in a cohort of patients with primary hyperparathyroidism at a single institution. We aimed to assess the risk of cancer incidence for the organs demonstrating the highest absorbed doses for the different imaging techniques, and more specifically determine the risk for our cohort of patients. METHODS Fifty patients with primary hyperparathyroidism had both multiphase CT and sestamibi scans. The Imaging Performance Assessment of CT Scanners (ImPACT) calculator was used to estimate the patient-effective and organ-absorbed radiations doses for all the CT examinations. For sestamibi scans, the US Nuclear Regulatory Commission NUREG/CR-6345 publication was used to estimate the dose for each patient. The attributable risks of cancer were calculated using the Health Protection Agency HPA-CRCE-028 publication. RESULTS The mean patient total effective doses were 15.9% ± 2.8 mSv, 20.2% ± 2.8  mSv and 5.6 ± 0.24 mSv for three-phase CT, four-phase CT and sestamibi examinations, respectively. In our cohort, the highest attributable lifetime risk was for lung cancer (0.03%) after multiphase CT. This compared with a tenfold lower risk for thyroid cancer (0.003%). After sestamibi, the highest risk was for colon cancer (0.06%). CONCLUSIONS Multiphase CT is associated with a higher radiation dose and thus a higher potential risk of cancer, but this risk is low in the older population that constituted the majority of our cohort.

Context: Hypercalciuria is frequently found in primary hyperparathyroidism (1HPT) and, although it generally normalizes after successful parathyroidectomy, may persist in some patients. The factors associated with persistent calcium renal leak (cRL) have not been clarified., Objective: The purpose of this study was to determine the prevalence of cRL in our 1HPT population and investigate cRL-related factors., Design: This was a retrospective longitudinal study., Setting: The study was conducted in an outpatient setting., Patients/intervention: The participants were 95 patients with 1HPT successfully operated on who had a normal estimated glomerular filtration rate., Main Outcome Measures: The biochemical parameters of calcium metabolism and bone mineral density (BMD) measured by dual-X-ray absorptiometry before and 24 months after surgery were assessed. All histological findings were recorded., Results: The prevalence of hypercalciuria before and after surgery was 74% and 32%, respectively. Before, surgery patients with cRL showed lower calcium and higher phosphate levels than those without cRL (10.9 ± 0.6 vs 11.4 ± 0.8 mg/dL [2.7 ± 0.2 vs 2.8 ± 0.2 mmol/L], P = .01 and 2.6 ± 0.5 vs 2.4 ± 0.4 mg/dL [0.84 ± 0.2 vs 0.77 ± 0.1 mmol/L], P = .04, respectively), whereas 24-h calciuria levels and the prevalence of 1HPT complications (osteoporosis, renal stones, and hypertension) were comparable. After surgery, serum calcium, phosphate, and PTH levels were comparable between patients with and without cRL. The prevalence of the histological finding of parathyroid hyperplasia was higher in patients with cRL (50%) than in patients without cRL (22%) (P = .01). The presence of cRL was independently associated with presurgery hypercalciuria (odds ratio, 4.71; 95% confidence interval, 1.18-18.8; P = .03) and parathyroid hyperplasia (odds ratio, 3.52; 95% confidence interval, 1.31-9.43; P = .01). Only patients without cRL had improved BMD at the spine (P = .04), total femur (P = .01), and femoral neck (P = .01)., Conclusions: cRL is present in 30% of patients with 1HPT after successful surgery, and it is associated with parathyroid hyperplasia before surgery and the lack of improvement in BMD after surgery.