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Nuclear Medicine and Biology 2021Parathyroid hyperplasia is a disease characterized by overactive parathyroid glands secreting increased levels of parathyroid hormone. Surgical removal of the...
INTRODUCTION
Parathyroid hyperplasia is a disease characterized by overactive parathyroid glands secreting increased levels of parathyroid hormone. Surgical removal of the parathyroid glands is the standard treatment but requires precise pre-operative localization of the glands. However, currently available imaging modalities show limited sensitivity. Since positron emission tomography (PET) is a molecular imaging technique with high accuracy and sensitivity, our aim was to develop a new PET tracer for overactive parathyroid glands imaging by radiolabelling cinacalcet, a drug binding to the calcium-sensing receptor of the parathyroid glands.
METHODS
[F]Cinacalcet was synthesized by copper-catalysed [F]trifluoromethylation of a boronic acid precursor using high molar activity [F]fluoroform. Ex vivo biodistribution and metabolism were evaluated in 12 healthy male Wistar rats at 5, 15, 45 and 90 min. PET scans were performed at baseline and after blocking with NPS R-568.
RESULTS
[F]Cinacalcet was obtained in an overall radiosynthesis time of 1 h with a radiochemical purity of 98 ± 1%, a radiochemical yield of 8 ± 4% (overall, n = 7, corrected for decay) and a molar activity of 40 ± 11 GBq/μmol (n = 7, at EOS). The ex vivo biodistribution showed uptake in the thyroid and parathyroid glands as well as in other glands such as adrenals, salivary glands and pancreas. The tracer was rapidly cleared from the blood via liver and kidneys and showed fast metabolism. PET images confirmed uptake in the target organ. However, in a blocking study with NPS R-568 specific binding of [F]cinacalcet to the CaSR could not be confirmed.
CONCLUSIONS
[F]Cinacalcet was successfully synthesized. First in vivo experiments in healthy rats showed uptake of the tracer in the target organ and fast metabolism, encouraging further in vivo evaluation of this tracer.
Topics: Cinacalcet
PubMed: 34743064
DOI: 10.1016/j.nucmedbio.2021.10.003 -
Metabolites Jan 2022Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that induces morbidity and mortality in patients. How CKD stimulates the... (Review)
Review
Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that induces morbidity and mortality in patients. How CKD stimulates the parathyroid to increase parathyroid hormone (PTH) secretion, gene expression and cell proliferation remains an open question. In experimental SHP, the increased gene expression is post-transcriptional and mediated by PTH mRNA-protein interactions that promote PTH mRNA stability. These interactions are orchestrated by the isomerase Pin1. Pin1 participates in conformational change-based regulation of target proteins, including mRNA-binding proteins. In SHP, Pin1 isomerase activity is decreased, and thus, the Pin1 target and PTH mRNA destabilizing protein KSRP fails to bind PTH mRNA, increasing PTH mRNA stability and levels. An additional level of post-transcriptional regulation is mediated by microRNA (miRNA). Mice with parathyroid-specific knockout of Dicer, which facilitates the final step in miRNA maturation, lack parathyroid miRNAs but have normal PTH and calcium levels. Surprisingly, these mice fail to increase serum PTH in response to hypocalcemia or uremia, indicating a role for miRNAs in parathyroid stimulation. SHP often leads to parathyroid hyperplasia. Reduced expressions of parathyroid regulating receptors, activation of transforming growth factor α-epidermal growth factor receptor, cyclooxygenase 2-prostaglandin E2 and mTOR signaling all contribute to the enhanced parathyroid cell proliferation. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. This review summarizes the current knowledge on the mechanisms that stimulate the parathyroid cell at multiple levels in SHP.
PubMed: 35208186
DOI: 10.3390/metabo12020111 -
Annales D'endocrinologie Aug 2022Lithium is an efficient treatment of bipolar disorder. Besides renal insufficiency, many endocrine side effects are described such as the occurrence of thyroid... (Review)
Review
Lithium is an efficient treatment of bipolar disorder. Besides renal insufficiency, many endocrine side effects are described such as the occurrence of thyroid disorders, hypercalcaemia and nephrogenic diabetes insipidus. Lithium inhibits the secretion of thyroid hormones. The prevalence of goiter is 4 times more common in Lithium-treated patients compared as to the general population. Hypothyroidism (8-20%) is more frequent in women and in case of pre-existing thyroid autoimmunity. Grave's disease and other hyperthyroidisms are sometimes reported. Lithium stimulates the proliferation of parathyroid cells by activating the Wnt pathway. An increase in serum calcium and PTH is described in patients treated with Lithium with a 4 to 6-fold higher risk of primary hyperparathyroidism than in the general population. Nevertheless, 24-hour urine calcium is not often increased, and the phenotype can mimic a hypercalcemia-hypocalciuria syndrome that may regress with Lithium discontinuation. Surgery should be cautious since parathyroid hyperplasia is more common than parathyroid adenoma. Nephrogenic diabetes insipidus is frequently reported and may be debilitating, sometimes intricated with severe dehydration, hypernatremia, and acute renal insufficiency. Nephrogenic diabetes insipidus is not generally reversible after Lithium discontinuation, especially in patients who have chronic kidney disease due to interstitial tubule nephritis. In conclusion, clinical assessment (goiter, diuresis) and biological monitoring of serum calcium, sodium creatinine, TSH and lithium are recommended in patients receiving Lithium therapy. The risk of Lithium discontinuation in case of side effects should be weighed against the psychological risk, and must be discussed with the psychiatrist.
Topics: Calcium; Diabetes Insipidus, Nephrogenic; Endocrinologists; Female; Goiter; Humans; Hypercalcemia; Hyperparathyroidism; Lithium; Lithium Compounds
PubMed: 35074396
DOI: 10.1016/j.ando.2022.01.001 -
Frontiers in Pharmacology 2022A common consequence of chronic renal disease is secondary hyperparathyroidism (SHPT) and is closely related to the mortality and morbidity of uremia patients. Secondary... (Review)
Review
A common consequence of chronic renal disease is secondary hyperparathyroidism (SHPT) and is closely related to the mortality and morbidity of uremia patients. Secondary hyperparathyroidism (SHPT) is caused by excessive PTH production and release, as well as parathyroid enlargement. At present, the mechanism of cell proliferation in secondary hyperparathyroidism (SHPT) is not completely clear. Decreased expression of the vitamin D receptor (VDR) and calcium-sensing receptor (CaSR), and 1,25(OH)2D3 insufficiency all lead to a decrease in cell proliferation suppression, and activation of multiple pathways is also involved in cell proliferation in renal hyperparathyroidism. The interaction between the parathormone (PTH) and parathyroid hyperplasia and 1,25(OH)2D3 has received considerable attention. 1,25(OH)2D3 is commonly applied in the therapy of renal hyperparathyroidism. It regulates the production of parathormone (PTH) and parathyroid cell proliferation through transcription and post-transcription mechanisms. This article reviews the role of 1,25(OH)2D3 in parathyroid cells in secondary hyperparathyroidism and its current understanding and potential molecular mechanism.
PubMed: 36267284
DOI: 10.3389/fphar.2022.1020858 -
Frontiers in Nephrology 2022Altered parathyroid gland biology is a major driver of chronic kidney disease-mineral bone disorder (CKD-MBD) in patients with chronic kidney disease. CKD-MBD is... (Review)
Review
Altered parathyroid gland biology is a major driver of chronic kidney disease-mineral bone disorder (CKD-MBD) in patients with chronic kidney disease. CKD-MBD is associated with a high risk of vascular calcification and cardiovascular events. A hallmark of CKD-MBD is secondary hyperparathyroidism with increased parathyroid hormone (PTH) synthesis and release and reduced expression of calcium-sensing receptors on the surface of parathyroid cells and eventually hyperplasia of parathyroid gland cells. The KDIGO guidelines strongly recommend the control of PTH in hemodialysis patients. Due to the complexity of parathyroid gland biology, mathematical models have been employed to study the interaction of PTH regulators and PTH plasma concentrations. Here, we present an overview of various model approaches and discuss the impact of different model structures and complexities on the clinical use of these models.
PubMed: 37674998
DOI: 10.3389/fneph.2022.893391 -
PloS One 2020Elevated parathyroid hormone (PTH) levels in secondary hyperparathyroidism (SHPT) lead to vascular calcification, which is associated with cardiovascular events and...
BACKGROUND
Elevated parathyroid hormone (PTH) levels in secondary hyperparathyroidism (SHPT) lead to vascular calcification, which is associated with cardiovascular events and mortality. Increased PTH production is caused by the excessive proliferation of parathyroid gland cells, which is accelerated by abnormal mineral homeostasis. Evocalcet, an oral calcimimetic agent, inhibits the secretion of PTH from parathyroid gland cells and has been used for the management of SHPT in dialysis patients. We observed the effects of evocalcet on ectopic calcification and parathyroid hyperplasia using chronic kidney disease (CKD) rats with SHPT.
METHODS
CKD rats with SHPT induced by adenine received evocalcet orally for 5 weeks. The calcium and inorganic phosphorus content in the aorta, heart and kidney was measured. Ectopic calcified tissues were also assessed histologically. To observe the effects on the proliferation of parathyroid gland cells, parathyroid glands were histologically assessed in CKD rats with SHPT induced by 5/6 nephrectomy (Nx) after receiving evocalcet orally for 4 weeks.
RESULTS
Evocalcet prevented the increase in calcium and inorganic phosphorus content in the ectopic tissues and suppressed calcification of the aorta, heart and kidney in CKD rats with SHPT by reducing the serum PTH and calcium levels. Evocalcet suppressed the parathyroid gland cell proliferation and reduced the sizes of parathyroid cells in CKD rats with SHPT.
CONCLUSIONS
These findings suggest that evocalcet would prevent ectopic calcification and suppress parathyroid hyperplasia in patients with SHPT.
Topics: Animals; Calcimimetic Agents; Hyperparathyroidism, Secondary; Hyperplasia; Male; Naphthalenes; Parathyroid Glands; Pyrrolidines; Rats; Rats, Sprague-Dawley; Vascular Calcification
PubMed: 32343734
DOI: 10.1371/journal.pone.0232428 -
Hemodialysis International.... Apr 2023Data on the incidence rates of hungry bone syndrome after parathyroidectomy in patients on dialysis are inconsistent, as the published rates vary from 15.8% to 92.9%.
INTRODUCTION
Data on the incidence rates of hungry bone syndrome after parathyroidectomy in patients on dialysis are inconsistent, as the published rates vary from 15.8% to 92.9%.
METHODS
Between 2009 and 2019, 120 hemodialysis patients underwent parathyroidectomy for secondary hyperparathyroidism at the Chang Gung Memorial Hospital. The patients were stratified into two groups based on the presence (n = 100) or absence (n = 20) of hungry bone syndrome after parathyroidectomy.
FINDINGS
Subtotal parathyroidectomy was the most common surgery performed (76.7%), followed by total parathyroidectomy with autoimplantation (23.3%). Pathological examination revealed parathyroid hyperplasia. Hungry bone syndrome developed within 0.3 ± 0.3 months and lasted for 11.1 ± 14.7 months. After surgery, compared with patients without hungry bone syndrome, patients with hungry bone syndrome had lower levels of nadir corrected calcium (P < 0.001), as well as lower nadir (P < 0.001) and peak (P < 0.001) intact parathyroid hormone levels. During 59.3 ± 44.0 months of follow-up, persistence and recurrence of hyperparathyroidism occurred in 25 (20.8%) and 30 (25.0%) patients, respectively. Furthermore, patients with hungry bone syndrome had a lower rate of persistent hyperparathyroidism than those without hungry bone syndrome (P < 0.001). Four patients (3.3%) underwent a second parathyroidectomy. Patients with hungry bone syndrome received fewer second parathyroidectomies than those without hungry bone syndrome (P < 0.001). Finally, a multivariate logistic regression model revealed that the preoperative blood ferritin level was a negative predictor of the development of hungry bone syndrome (P = 0.038).
DISCUSSION
Hungry bone syndrome is common (83.3%) after parathyroidectomy for secondary hyperparathyroidism in patients undergoing hemodialysis, and this complication should be monitored and managed appropriately.
Topics: Humans; Renal Dialysis; Hypocalcemia; Hyperparathyroidism, Secondary; Calcium; Parathyroidectomy; Parathyroid Hormone; Retrospective Studies
PubMed: 36719854
DOI: 10.1111/hdi.13067 -
Cell and Tissue Research Sep 2023Serum calcium homeostasis is mainly regulated by parathormone (PTH) secreted by the parathyroid gland. Besides PTH and Gcm2, a master gene for parathyroid... (Review)
Review
Serum calcium homeostasis is mainly regulated by parathormone (PTH) secreted by the parathyroid gland. Besides PTH and Gcm2, a master gene for parathyroid differentiation, many genes are expressed in the gland. Especially, calcium-sensing receptor (CaSR), vitamin D receptor (VDR), and Klotho function to prevent increased secretion of PTH and hyperplasia of the parathyroid gland under chronic hypocalcemia. Parathyroid-specific dual deletion of Klotho and CaSR induces a marked enlargement of the glandular size. The parathyroid develops from the third and fourth pharyngeal pouches except murine species in which the gland is derived from the third pouch only. The development of the murine parathyroid gland is categorized as follows: (1) formation and differentiation of the pharyngeal pouches, (2) appearance of parathyroid domain in the third pharyngeal pouch together with thymus domain, (3) migration of parathyroid primordium attached to the top of thymus, and (4) contact with the thyroid lobe and separation from the thymus. The transcription factors and signaling molecules involved in each of these developmental stages are elaborated. In addition, mesenchymal neural crest cells surrounding the pharyngeal pouches and parathyroid primordium and invading the parathyroid parenchyma participate in the development of the gland.
Topics: Mice; Animals; Parathyroid Glands; Transcription Factors; Organogenesis; Cell Differentiation; Embryonic Development; Thymus Gland; Mammals
PubMed: 37410127
DOI: 10.1007/s00441-023-03785-3 -
International Journal of Hyperthermia :... 2022Hyperparathyroidism (HPT) is classified into primary HPT (PHPT), secondary HPT (SHPT), tertiary HPT (THPT), and pseudohyperparathyroidism. Parathyroid surgery is... (Review)
Review
BACKGROUND
Hyperparathyroidism (HPT) is classified into primary HPT (PHPT), secondary HPT (SHPT), tertiary HPT (THPT), and pseudohyperparathyroidism. Parathyroid surgery is generally reserved for patients with symptomatic PHPT and asymptomatic patients who meet the surgical guideline criteria. However, the risk of complications and mortality after parathyroid gland surgery increases with increasing patient age.
AIM
This study aimed to review existing research on laser ablation, radiofrequency ablation, microwave ablation, and high-intensity focused ultrasound in the treatment of HPT and analyze its application prospects.
CONCLUSIONS
Thermal ablation is a good alternative treatment for patients with parathyroid hyperplasia who do not meet the criteria or decline surgery. Being a type of minimally invasive treatment, ultrasound-guided thermal ablation has the advantages of easy operation, rapid recovery, and reusability and is used widely.
Topics: Humans; Hyperparathyroidism, Primary; Hyperparathyroidism, Secondary; Parathyroid Glands; Ultrasonography; Ultrasonography, Interventional
PubMed: 35271788
DOI: 10.1080/02656736.2022.2028907