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Stem Cells and Development Nov 2023The parathyroid gland plays an essential role in mineral and bone metabolism. Cultivation of physiological human parathyroid cells has yet to be established and the...
The parathyroid gland plays an essential role in mineral and bone metabolism. Cultivation of physiological human parathyroid cells has yet to be established and the method by which parathyroid cells differentiate from pluripotent stem cells remains uncertain. Therefore, it has been hard to clarify the mechanisms underlying the onset of parathyroid disorders, such as hyperparathyroidism. In this study, we developed a new method of parathyroid cell differentiation from human induced pluripotent stem (iPS) cells. Parathyroid cell differentiation occurred in accordance with embryologic development. Differentiated cells, which expressed the parathyroid hormone, adopted unique cell aggregation similar to the parathyroid gland. In addition, these differentiated cells were identified as calcium-sensing receptor (CaSR)/epithelial cell adhesion molecule (EpCAM) double-positive cells. Interestingly, stimulation with transforming growth factor-α (TGF-α), which is considered a causative molecule of parathyroid hyperplasia, increased the CaSR/EpCAM double-positive cells, but this effect was suppressed by erlotinib, which is an epidermal growth factor receptor (EGFR) inhibitor. These results suggest that TGF-α/EGFR signaling promotes parathyroid cell differentiation from iPS cells in a similar manner to parathyroid hyperplasia.
Topics: Humans; Parathyroid Glands; Induced Pluripotent Stem Cells; Hyperplasia; Transforming Growth Factor alpha; Epithelial Cell Adhesion Molecule; ErbB Receptors; Cell Differentiation; Receptors, Calcium-Sensing
PubMed: 37639359
DOI: 10.1089/scd.2023.0130 -
EBioMedicine Apr 2024To date, because of the difficulty in obtaining normal parathyroid gland samples in human or in animal models, our understanding of this last-discovered organ remains...
BACKGROUND
To date, because of the difficulty in obtaining normal parathyroid gland samples in human or in animal models, our understanding of this last-discovered organ remains limited.
METHODS
In the present study, we performed a single-cell transcriptome analysis of six normal parathyroid and eight parathyroid adenoma samples using 10 × Genomics platform.
FINDINGS
We have provided a detailed expression atlas of parathyroid endocrine cells. Interestingly, we found an exceptional high expression levels of CD4 and CD226 in parathyroid endocrine cells, which were even higher than those in lymphocytes. This unusual expression of lymphocyte markers in parathyroid endocrine cells was associated with the depletion of CD4 T cells in normal parathyroid glands. Moreover, CD4 and CD226 expression in endocrine cells was significantly decreased in parathyroid adenomas, which was associated with a significant increase in Treg counts. Finally, along the developmental trajectory, we discovered the loss of POMC, ART5, and CES1 expression as the earliest signature of parathyroid hyperplasia.
INTERPRETATION
We propose that the loss of CD4 and CD226 expression in parathyroid endocrine cells, coupled with an elevated number of Treg cells, could be linked to the pathogenesis of parathyroid adenoma. Our data also offer valuable information for understanding the noncanonical function of CD4 molecule.
FUNDING
This work was supported by the National Key R&D Program of China (2022YFA0806100), National Natural Science Foundation of China (82130025, 82270922, 31970636, 32211530422), Shandong Provincial Natural Science Foundation of China (ZR2020ZD14), Innovation Team of Jinan (2021GXRC048) and the Outstanding University Driven by Talents Program and Academic Promotion Program of Shandong First Medical University (2019LJ007).
Topics: Humans; Parathyroid Glands; Parathyroid Neoplasms; Down-Regulation; Carcinogenesis; Cell Transformation, Neoplastic; Hyperplasia; Lymphocytes
PubMed: 38471398
DOI: 10.1016/j.ebiom.2024.105053 -
International Journal of Pediatric... Oct 2023Multiple endocrine neoplasia (MEN) syndromes are a group of hereditary cancer syndromes that can predispose children to endocrine neoplasms developing within the head...
INTRODUCTION
Multiple endocrine neoplasia (MEN) syndromes are a group of hereditary cancer syndromes that can predispose children to endocrine neoplasms developing within the head and neck.
OBJECTIVE
To examine the neoplastic manifestations of MEN type 1 (MEN1) and MEN type 2 (MEN2) in the pediatric head and neck.
METHODS
Single-institution, retrospective review of pediatric MEN between 2005 and 2022.
RESULTS
Fifty-three children were genetically confirmed with MEN (15 MEN1, 34 MEN2A, and 4 MEN2B), while three patients received clinical diagnoses of MEN1. The male to female ratio was essentially equal (1.15:1), and a documented family history of cancer was present in 89% (50/56). After multidisciplinary evaluation, a familial MEN diagnosis was confirmed in 91% (51/56). The mean ages of initial presentation and surgical intervention were 8.9 years (SD 5) and 9.8 years (SD 4.8), respectively. Although patients with MEN2 received surgery earlier than patients with MEN1 (8.7 vs 12.7 years), surgical patients with MEN2 in this cohort were older relative to current American Thyroid Association (ATA) guidelines primarily due to late presentation. Thyroid malignancies were identified in 36% (9/25) of thyroidectomy specimens (21 MEN2A, 4 MEN2B), with medullary thyroid carcinoma (MTC) present in five MEN2A patients and three MEN2B patients (89%), and papillary thyroid carcinoma (PTC) present in one MEN2A patient (11%). Nearly 90% (8/9) of thyroid malignancies were occult, with some occurring earlier than predicted by current guidelines (ATA-MOD and ATA-H). Central neck dissections were performed in 24% (2 MEN1, 2 MEN2A, and 4 MEN2B), with two MEN2B (50%) demonstrating cervical lymph node (LN) metastases. Additional histopathologic findings included C-cell hyperplasia in 57% (12/21) of MEN2A thyroidectomy patients. Of the eight MEN1 parathyroidectomy patients, four demonstrated parathyroid hyperplasia and four presented with parathyroid adenoma.
CONCLUSION
Nearly 60% required head and neck procedures. While MEN1 guidelines were appropriate for our cohort, we identified patients with MEN2 that developed MTC earlier than expected based on current ATA guidelines, including children in categories considered lower risk. In conjunction with a multidisciplinary approach, pediatric head and neck surgeons should be aware of the potential need for earlier surgical intervention in the pediatric MEN2 population.
Topics: Humans; Child; Female; Male; Multiple Endocrine Neoplasia Type 2a; Multiple Endocrine Neoplasia Type 2b; Hyperplasia; Multiple Endocrine Neoplasia; Thyroid Neoplasms
PubMed: 37604101
DOI: 10.1016/j.ijporl.2023.111703 -
Problemy Radiatsiinoi Medytsyny Ta... Dec 2023to assess the hormonal and metabolic disorders in the Chernobyl nuclear power plant (ChNPP) accident survivors (AS), having got secondary normocalcemic non-renal...
OBJECTIVE
to assess the hormonal and metabolic disorders in the Chernobyl nuclear power plant (ChNPP) accident survivors (AS), having got secondary normocalcemic non-renal hyperparathyroidism (HPT) in the late period upon exposure to ionizing radiation (IR).
MATERIALS AND METHODS
The routine clinical, anthropometric, instrumental (thyroid and parathyroid diagnosticultrasound), laboratory (biochemical, hormonal), statistical methods were applied. In both prospective (n = 48, control group n = 19) and retrospective studies the data of 2,234 subjects including 1,372 irradiated adults (862 non-irradiated persons in the control group) were evaluated. Clinical consequences of exposure to IR on the endocrine system were evaluated in ChNPP AS.
RESULTS
High prevalence of vitamin D lack or deficiency was established retrospectively in 81.8 % of the ChNPP AS and in 89.5 % of the control group subjects. In general, there was neither effect of exposure to IR on the vitamin D status in study subjects, nor any difference between the study groups. According to diagnostic ultrasound patterns the parathyroid hyperplasia was diagnosed in 629 cases (28.2 %). Among the ChNPP AS it was found in 32.7 % of cases (n = 450) vs. 20.7 % (p > 0.005) in the control group (a 1.6-fold difference). HPT diagnosed as serum parathyroid hormone content > 65 ng/ml was diagnosed in 123 cases (21.1 %) i.e. in almost every fifth person. Increased serum level of parathyroid hormone was found in the 94 ChNPP AS and in 25 persons of the comparison group. In other words, the frequency of HPT was 23.7 % among the AS being significantly more than in the comparison group (13.2 %, p < 0.005). Frequency of normocalcemic non-renal HPT was slightly different by years of observation with a trend to the year-by-year increase.
CONCLUSIONS
High prevalence of vitamin D lack or deficiency was established in the ChNPP AS, being however independent of exposure to IR. Frequency of parathyroid hyperplasia/adenoma was 1.6 times higher in the irradiated subjects than in persons of the control group. Annual increase in frequency of the non-renal normocalcemic HPT was also revealed reaching nowadays 23.7 % among the AS, which is significantly higher than in the comparison group.
Topics: Adult; Humans; Retrospective Studies; Radiation Exposure; Chernobyl Nuclear Accident; Hyperplasia; Prospective Studies; Case-Control Studies; Hyperparathyroidism, Primary; Parathyroid Hormone; Vitamin D; Survivors; Ukraine
PubMed: 38155131
DOI: 10.33145/2304-8336-2023-28-316-328 -
The Journal of Clinical Endocrinology... Jul 2023The contribution of [18F]F-fluorocholine (FCH)-positron emission tomography (PET)/computed tomography (CT) in normocalcemic primary hyperparathyroidism (nPHPT) remains...
CONTEXT
The contribution of [18F]F-fluorocholine (FCH)-positron emission tomography (PET)/computed tomography (CT) in normocalcemic primary hyperparathyroidism (nPHPT) remains unknown.
OBJECTIVE
To evaluate the sensitivity and specificity of FCH-PET/CT in a cohort of osteoporotic patients with nPHPT and discordant or negative [99mTc]Tc-sestamibi scintigraphy and ultrasonography who all underwent parathyroidectomy (PTX).
DESIGN
Longitudinal retrospective cohort study in patients referred for osteoporosis with mild biological primary hyperparathyroidism.
SETTING
Tertiary referral center with expertise in bone metabolism and surgical management of hyperparathyroidism.
PATIENTS
Among 109 patients with PHPT analyzed, 3 groups were individualized according to total serum calcium (tCa) and ionized calcium (iCa): 32 patients with hypercalcemia (HtCa group), 39 patients with normal tCa and elevated iCa (NtCa group), and 38 patients with both normal tCa and iCa (NiCa). All patients had biochemical follow-up confirming or not the success of PTX.
MAIN OUTCOME MEASURES
To evaluate the performance of FCH-PET/CT in terms of sensitivity and specificity, and to compare with first-line imaging procedures in the setting of nPHPT.
RESULTS
The sensitivity of FCH-PET/CT was 67% in the hypercalcemic group, 48% in the NtCa group (P = .05 vs HtCa), and 33% in the NiCa group (P = .004 vs HtCa). Specificity ranged from 97% to 99%. FCH-PET/CT was positive in 64.3% of patients with negative conventional imaging, with biochemical resolution after PTX in 77.8% of patients. Triple negative imaging was observed in 20 patients, with PHPT resolution in 85% of these patients.
CONCLUSION
This study highlights the contribution of FCH-PET/CT in a well-phenotyped cohort of normocalcemic patients with discordant or negative findings in [99mTc]Tc-sestamibi scintigraphy and ultrasonography. However, negative imaging in nPHPT does not rule out the possibility of surgical cure by an experienced surgeon.
Topics: Humans; Positron Emission Tomography Computed Tomography; Hyperparathyroidism, Primary; Parathyroid Glands; Retrospective Studies; Calcium; Technetium Tc 99m Sestamibi; Radionuclide Imaging; Ultrasonography; Choline; Radiopharmaceuticals; Organotechnetium Compounds
PubMed: 36750257
DOI: 10.1210/clinem/dgad073 -
International Urology and Nephrology Dec 2023Pretransplant osteoporosis and vascular calcification probably increase the risk of fractures and cardiovascular events after kidney transplantation. In the present...
INTRODUCTION
Pretransplant osteoporosis and vascular calcification probably increase the risk of fractures and cardiovascular events after kidney transplantation. In the present study, we investigated the related risk factors of osteoporosis and vascular calcification among end-stage renal disease (ESRD) patients awaiting kidney transplantation.
METHODS
A total of 221 ESRD patients (age, 43.4 ± 14.3 years; 125 males and 96 females; median dialysis duration, 61.0 m) awaiting kidney transplantation were enrolled in this cross-sectional study. Serum levels of bone turnover markers and intact parathyroid hormone (iPTH) were analyzed from fasting morning blood samples. Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD). Vascular calcification was evaluated by lateral abdominal radiography and plain radiographic films of the pelvis and hands.
RESULTS
The osteoporosis prevalence was 27.6% in this cohort of kidney transplantation candidates, and the prevalence of vascular calcification was 51.1%. The related factors for osteoporosis and vascular calcification were similar and included older age, longer dialysis duration, parathyroid hyperplasia, and higher levels of iPTH and bone turnover markers. In the multivariable regression model, age and iPTH were independent risk predictors of both vascular calcification and osteoporosis. There were strong, positive correlations between iPTH and all bone turnover markers. The moderate and severe hyperparathyroidism (iPTH 600-1499 pg/ml and iPTH 1500 pg/ml) were related to reduced serum albumin and hemoglobin levels.
CONCLUSION
The involvement of high iPTH levels in vascular calcification, osteoporosis, and malnutrition indicated the need of treating hyperparathyroidism early in patients awaiting kidney transplantation. Prospective studies are needed to further examine the utility of bone turnover markers.
Topics: Male; Female; Humans; Adult; Middle Aged; Kidney Transplantation; Cross-Sectional Studies; Kidney Failure, Chronic; Bone Density; Osteoporosis; Vascular Calcification; Parathyroid Hormone; Hyperparathyroidism
PubMed: 37093441
DOI: 10.1007/s11255-023-03606-0 -
Cureus Oct 2023Background Parathyroid hormone (PTH) and Dickkopf-related protein 1 (DKK-1) have been mentioned together at the intersection of autoimmune rheumatologic diseases (ARDs)...
Background Parathyroid hormone (PTH) and Dickkopf-related protein 1 (DKK-1) have been mentioned together at the intersection of autoimmune rheumatologic diseases (ARDs) and osteoimmunology. However, few studies have evaluated the association between primary hyperparathyroidism (PHPT) and ARDs. Methodology This retrospective study included 225 PHPT patients and 386 patients with thyroid nodules as a control group. The electronic hospital records of all patients were screened going back nine years for the presence of ARDs. Patients who were diagnosed at least three months ago, had complete serologic tests, and were continuing with rheumatologic follow-up were included. Results The prevalence of ARDs in the PHPT group was 9.77% (22/225), while the prevalence of ARDs in the CG was 1.04% (4/386, p < 0.001). The prevalence of rheumatoid arthritis in the PHPT group was 4.4% (10/225), ankylosing spondylitis 3.1% (7/225), systemic lupus erythematosus 0.88% (2/225), Behçet's disease 0.88% (2/225), and mixed connective tissue disease 0.44% (1/225). Of the 22 patients with ARDs, 21 (95.45%) were diagnosed before they were diagnosed with PHPT, and the median time from diagnosis with ARD to the onset of PHPT was 36 months (interquartile range = 61.5). Logistic regression analysis showed a positive correlation between the duration of PHPT and ARDs (odds ratio (OR) = 1.06; 95% confidence interval (CI) = 1.02-1.09, p < 0.001) and a negative correlation between ARDs and calcium levels (OR = 0.26; 95% CI = 0.09-0.79, p = 0.018). Conclusions The prevalence of ARDs increased in PHPT patients and PHPT accompanying ARDs developed after rheumatologic disease. ARDs with PHPT are cases with a prolonged duration of PHPT and mildly elevated calcium, probably preceded by parathyroid hyperplasia. Therefore, the factors that cause ARDs may trigger a process that leads to mild PHPT.
PubMed: 37841984
DOI: 10.7759/cureus.46906 -
Clinical Endocrinology Nov 2023Accurate demarcation between multiple endocrine neoplasia, type 1 (MEN1)- related primary hyperparathyroidism (MPHPT) and sporadic PHPT (SPHPT) is important to plan the...
OBJECTIVE
Accurate demarcation between multiple endocrine neoplasia, type 1 (MEN1)- related primary hyperparathyroidism (MPHPT) and sporadic PHPT (SPHPT) is important to plan the management of primary parathyroid disease and surveillance for other endocrine and nonendocrine tumours. The objective of this study is to compare the clinical, biochemical and radiological features and surgical outcomes in patients with MPHPT versus SPHPT and to identify the predictors of MEN1 syndrome in PHPT.
DESIGN, PATIENTS AND MEASUREMENTS
This was an ambispective observationalstudy involving 251 patients with SPHPT and 23 patients with MPHPT evaluated at the endocrine clinic of All India Institute of Medical Sciences, New Delhi, India between January 2015 and December 2021.
RESULTS
The prevalence of MEN1 syndrome among patients with PHPT was 8.2% and a genetic mutation was identified by Sanger sequencing in 26.1% of patients with MPHPT. Patients with MPHPT were younger (p < .001), had lower mean serum calcium (p = .01) and alkaline phosphatase (ALP; p = .03) levels and lower bone mineral density (BMD) Z score at lumbar spine (p < .001) and femoral neck (p = .007). The prevalence of renal stones (p = .03) and their complications (p = .006) was significantly higher in MPHPT group. On multivariable analysis, factors predictive of MPHPT were hyperplasia on histopathology [OR 40.1, p < .001], ALP levels within reference range [OR 5.6, p = .02] and lumbar spine BMD [OR 0.39 per unit increase in Z score, p < .001].
CONCLUSIONS
Patients with MPHPT have more severe, frequent and early onset of bone and renal involvement despite milder biochemical features. A normal serum ALP, low BMD for age and gender at lumbar spine and histopathology evidence of hyperplasia are predictive factors for MEN1 syndrome in PHPT.
Topics: Humans; Hyperparathyroidism, Primary; Hyperplasia; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia; Treatment Outcome; Bone Density
PubMed: 37393194
DOI: 10.1111/cen.14945 -
Clinical Nephrology. Case Studies 2023We present two atypical cases of calciphylaxis presenting with ocular ischemic pathology - both without the hallmark cutaneous manifestations - to raise awareness of...
PURPOSE
We present two atypical cases of calciphylaxis presenting with ocular ischemic pathology - both without the hallmark cutaneous manifestations - to raise awareness of this rare yet highly disabling condition.
OBSERVATIONS
We report two cases of ophthalmic calciphylaxis presenting as (1) anterior ischemic optic neuropathy (AION) and cilioretinal artery occlusion in a 76-year-old woman with pre-dialysis kidney failure, and (2) AION with contralateral central retinal artery occlusion (CRAO) in a 44-year-old man on hemodialysis.
CONCLUSION AND IMPORTANCE
These cases highlight the need for judicious clinical suspicion of calciphylaxis in patients with kidney failure, presenting with microvascular ischemic ophthalmic pathology such as AION or CRAO. Confirmation with temporal artery biopsy is essential to direct targeted individualized multi-disciplinary treatment of calciphylaxis and avoid unnecessary steroid exposure in cases masquerading as giant cell arteritis (GCA).
PubMed: 38169875
DOI: 10.5414/CNCS111088 -
Frontiers in Endocrinology 2023Until recently no major epidemiological research of primary hyperparathyroidism (PHPT) has been conducted in the Russian Federation, this led to the creation of the...
INTRODUCTION
Until recently no major epidemiological research of primary hyperparathyroidism (PHPT) has been conducted in the Russian Federation, this led to the creation of the Russian online registry. The objective of this study is to estimate the clinical and biochemical profile, classical and non-classical complications, surgical intervention and medical therapy of the patients with different forms of PHPT in the Russian Federation.
MATERIALS AND METHODS
The cross-sectional, observational, continuous study was conducted at the Endocrinology Research Centre (Moscow). The present study explored retrospective data from 6003 patients submitted to the Registry between 12.12.2016 and 25.10.2022 from 81 regions of the Russian Federation (http://pgpt.clin-reg.ru/).
RESULTS
The median age was 59 [60; 66] years with a female:male ratio of 11.7:1. Symptomatic PHPT was observed in 74.3% while asymptomatic form - only in 25.7% of cases. Bone pathology was the predominant clinical manifestation in 62.5% of cases (n=2293), mostly in combination with visceral complications 45.7% (n=1676). The majority of patients (63.3%) had combined visceral disorders including kidney damage in 51.8% and gastroduodenal erosions/ulcers in 32.3% of patients. Symptomatic patients were older (60 [53; 67] vs. 54 [45; 62] years, p<0.001) and had more severe biochemical alterations of calcium-phosphorus metabolism. Cardiovascular disease (СVD) was recorded in 48% of patients, among them the most frequent was arterial hypertension (up to 93.9%). A genetic test was conducted in 183 cases (suspicious for hereditary PHPT) revealing the mutations in , , genes in 107, 6 and 2 cases, respectively. Surgery was performed in 53.4% of patients with remission achievement in 87%, the relapse/persistence were recorded in 13% of cases. Histological examination revealed carcinoma in 4%, atypical adenoma in 2%, adenoma in 84% and hyperplasia in 11% of cases. Drug therapy was prescribed in 54.0% of cases, most often cholecalciferol.
CONCLUSION
The detection rate of PHPT has increased in the Russian Federation in recent years. This increase is associated with the start of online registration. However, the majority of patients remain symptomatic with significant alterations of phosphorus-calcium metabolism that indicates delayed diagnosis and requires further modifications of medical care.
Topics: Humans; Male; Female; Middle Aged; Calcium; Retrospective Studies; Hyperparathyroidism, Primary; Cross-Sectional Studies; Registries; Calcium, Dietary; Adenoma; Phosphorus
PubMed: 37465121
DOI: 10.3389/fendo.2023.1203437