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Nephrology, Dialysis, Transplantation :... Jun 2012Secondary hyperparathyroidism (sHPT) represents an adaptive response to progressively impaired control of calcium, phosphorus and vitamin D in chronic kidney disease...
BACKGROUND
Secondary hyperparathyroidism (sHPT) represents an adaptive response to progressively impaired control of calcium, phosphorus and vitamin D in chronic kidney disease (CKD). It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone (PTH). Parathyroid hyperplasia in uremic rats can be prevented by calcium-sensing receptor (CaSR) activation with the calcimimetic cinacalcet (Sensipar®/Mimpara®); however, it is unknown, how long the effects of cinacalcet persist after withdrawal of treatment or if cinacalcet is efficacious in uremic rats with established sHPT.
METHODS
We sought to determine the effect of cinacalcet discontinuation in uremic rats and whether cinacalcet was capable of influencing parathyroid hyperplasia in animals with established sHPT.
RESULTS
Discontinuation of cinacalcet resulted in reversal of the beneficial effects on serum PTH and parathyroid hyperplasia. In rats with established sHPT, cinacalcet decreased serum PTH and mediated regression of parathyroid hyperplasia. The cinacalcet-mediated decrease in parathyroid gland size was accompanied by increased expression of the cyclin-dependent kinase inhibitor p21. Prevention of cellular proliferation with cinacalcet occurred despite increased serum phosphorus and decreased serum calcium.
CONCLUSIONS
The animal data provided suggest established parathyroid hyperplasia can be reversed by modulating CaSR activity with cinacalcet and that continued treatment may be necessary to maintain reductions in PTH.
Topics: Animals; Calcium; Cell Proliferation; Cinacalcet; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Hyperparathyroidism, Secondary; Hyperplasia; Kidney Failure, Chronic; Male; Naphthalenes; Parathyroid Glands; Parathyroid Hormone; Phosphorus; Rats; Rats, Sprague-Dawley; Uremia
PubMed: 22036941
DOI: 10.1093/ndt/gfr589 -
Hellenic Journal of Nuclear Medicine 2020The purpose of this study was to evaluate the diagnostic value of clinical parameters and parathyroid scintigraphy for asymptomatic primary hyperparathyroidism (aPHPT),...
OBJECTIVE
The purpose of this study was to evaluate the diagnostic value of clinical parameters and parathyroid scintigraphy for asymptomatic primary hyperparathyroidism (aPHPT), including quantitative parameter of laboratory and semiquantitative parameters derived from technetium-99m- metoxyisobutylisonitrile (Tc-MIBI) single photon emission computed tomography/computed tomography (SPECT/CT).
SUBJECTS AND METHODS
Two hundred and fourteen patients who had been diagnosed as PHPT and underwent surgical treatment were enrolled in this study. All patients were divided into two groups: aPHPT and symptomatic PHPT (sPHPT). Dual tracer Tc pertechnetate/Tc-MIBI, dual time point and tomography scintigraphy with Tc-MIBI SPECT/CT were performed. Clinical parameters included basic information, serum calcium (Ca), phosphorus (P), parathyroid hormone (PTH) and alkaline phosphatase (ALP) levels. Semiquantitative parameters of parathyroid scintigraphy included the average counts of early parathyroid (PT), late parathyroid (PT), early thyroid (T) and late thyroid (T), the ratio of PT/ T (R), the ratio of PT/ T (R), parathyroid washout (PTW=(PT-PT)/PT) and retention index (RI=(R-R)/R). P<0.05 was considered as statistically significant.
RESULTS
A total of 167 aPHPT patients (46 males, 121 females) were studied. One hundred and seventy four One hundred and seventy four174 parathyroid glands were removed after operation: 146 (87.4%) lesions were adenoma, 12 (7.2%) lesions were hyperplasia and 1 (0.6%) lesion was adenocarcinoma. There were significant differences in previous history (P=0.000), echo of parathyroid (P=0.004), thyroid function (P=0.029), clinical course (Z=-3.422, P=0.001), Tc-pertechnetat thyroid uptake (TcTU) (Z=-2.126, P=0.033), serum Ca level (t=-2.926, P=0.004) and serum PTH level (Z=-3.028, P=0.002) between aPHPT and sPHPT. For patients with aPHPT, there were significant differences for serum Ca level (t=2.832, P=0.005), R2 (Z=-2.597, P= 0.009) and RI (Z=-2.100, P=0.036) between adenoma and hyperplasia, and serum Ca level in aPHPT patients with adenoma was significantly higher compared with patients with hyperplasia. The areas under the curve (AUC) of clinical course, TcTU, serum Ca and PTH levels were 0.662, 0.399, 0.642 and 0.645 respectively for differential diagnosis of aPHPT and sPHPT. The AUC of R2 and RI were 0.737 and 0.692 respectively for differential diagnosis of adenoma and hyperplasia in patients with aPHPT. The sensitivity, negative predictive value (NPV) and accuracy for diagnosing aPHPT combined Tc-MIBI SPECT/CT with ultrasound (US) were significantly higher than dual tracer, dual time point, Tc-MIBI SPECT/CT and US, which were 97.5%, 95.2% and 55.6% respectively.
CONCLUSION
Laboratory inspection and semi-quantitative parameters of parathyroid scintigraphy had higher value for differential diagnoses of aPHPT and sPHPT, the same for adenoma and hyperplasia in patients with aPHPT. When combined Tc-MIBI SPECT/CT with US, the diagnostic efficiency would be significantly improved.
Topics: Adenoma; Asymptomatic Diseases; Female; Humans; Hyperparathyroidism, Primary; Hyperplasia; Male; Middle Aged; Parathyroid Glands; ROC Curve; Retrospective Studies; Single Photon Emission Computed Tomography Computed Tomography; Technetium Tc 99m Sestamibi; Thyroid Neoplasms
PubMed: 32716406
DOI: 10.1967/s002449912104 -
Nephrology, Dialysis, Transplantation :... Mar 2015In secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-α (TGFα) increase EGF receptor (EGFR) activation causing parathyroid...
BACKGROUND
In secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-α (TGFα) increase EGF receptor (EGFR) activation causing parathyroid hyperplasia, high parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress parathyroid hyperplasia because ADAM17 is required to release mature TGFα, the most potent EGFR-activating ligand.
METHODS
Computer analysis of the ADAM17 promoter identified TGFα and C/EBPβ as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGFα/EGFR-driven growth and parathyroid gland (PTG) enlargement were assessed in promoter-reporter assays in A431 cells and corroborated in rat and human SHPT, using erlotinib as anti-EGFR therapy to suppress TGFα signals, active vitamin D to induce C/EBPβ or the combination.
RESULTS
While TGFα induced ADAM17-promoter activity by 2.2-fold exacerbating TGFα/EGFR-driven growth, ectopic C/EBPβ expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, parathyroid ADAM17 levels correlated directly with TGFα and inversely with C/EBPβ. Furthermore, combined erlotinib + calcitriol treatment suppressed TGFα/EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBPβ to inhibit ADAM17-promoter activity, mRNA and protein. Importantly, in rat SHPT, the correction of vitamin D deficiency effectively reversed the resistance to paricalcitol induction of C/EBPβ to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%.
CONCLUSION
In SHPT, correction of vitamin D and calcitriol deficiency induces parathyroid C/EBPβ to efficaciously attenuate the severe ADAM17/TGFα synergy, which drives PTG enlargement and high PTH.
Topics: ADAM Proteins; ADAM17 Protein; Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; CCAAT-Enhancer-Binding Protein-beta; Calcitriol; Cell Proliferation; Cells, Cultured; ErbB Receptors; Erlotinib Hydrochloride; Gene Expression Regulation; Humans; Hyperparathyroidism, Secondary; Hyperplasia; Immunoenzyme Techniques; Kidney Diseases; Parathyroid Glands; Parathyroid Hormone; RNA, Messenger; Rats; Real-Time Polymerase Chain Reaction; Receptors, Calcitriol; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor alpha; Vitamin D; Vitamins
PubMed: 25294851
DOI: 10.1093/ndt/gfu311 -
Cureus Oct 2022Solitary parathyroid adenoma is the most common cause of primary hyperparathyroidism; however, multiple parathyroid adenomas are an uncommon phenomenon. In this case...
Solitary parathyroid adenoma is the most common cause of primary hyperparathyroidism; however, multiple parathyroid adenomas are an uncommon phenomenon. In this case report, we discuss a patient presenting with two concurrent ipsilateral parathyroid adenomas, and we review the literature. A 61-year-old African American female with a history of hypertension and kidney stones presented for the evaluation of hypercalcemia. Elevated serum calcium of 11 mg/dL was found on routine laboratory tests and low25 hydroxyvitamin-D level. Parathyroid hormone (PTH) was elevated at 172.5 pg/mL and increased to 443 pg/mL after correction of vitamin D deficiency. Renal function tests and thyroid function tests revealed normal findings. Imaging studies with 99mTc-Sestamibi scintigraphy raised concern for the possibility of either a parathyroid adenoma or hyperplasia. Minimally invasive parathyroidectomy with intraoperative PTH monitoring was planned. During surgery, the right superior parathyroid gland was found to be enlarged and was excised. However, intraoperative PTH monitoring showed an initial decrease to 203 pg/mL from a baseline of 443 pg/mL and a subsequent increase to 293 pg/mL suggesting the persistence of hyperparathyroidism. Further exploration of the neck revealed an enlarged right inferior parathyroid gland and two normal left parathyroid glands. Intraoperative PTH monitoring then revealed an appropriate decrease in PTH level to 56 pg/mL 10 minutes after excision of the right inferior parathyroid gland. More than a 50% decrease in PTH was achieved, and further exploration of the opposite side revealed no evidence of four-gland hyperplasia. Pathology reported two concurrent right superior and inferior parathyroid adenomas. Successful and curative parathyroidectomy for primary hyperparathyroidism was achieved. Although rare, multiple parathyroid adenomas occur in a significant minority of cases. Intraoperative PTH monitoring along with preoperative imaging provides guidance for curative parathyroidectomy. Additionally, more sensitive imaging such as four-dimensional computed tomography scans could lead to better localization, visualization, and identification of the second parathyroid adenoma.
PubMed: 36457632
DOI: 10.7759/cureus.30854 -
Experimental and Clinical... Sep 2022Tissue-specific immunogenicity can be characterized by the determination of human leukocyte antigens (HLA). Parathyroid hyperplasia tissue cells are presumed to have the...
OBJECTIVES
Tissue-specific immunogenicity can be characterized by the determination of human leukocyte antigens (HLA). Parathyroid hyperplasia tissue cells are presumed to have the ability to lose HLA class I expression profile during cultivation, whereas healthy parathyroid cells are presumed to already express HLA class I molecules at low levels. However, there are conflicting results about the expression of HLA class I antigens. In this study, our aim was to evaluate different patterns of HLA class I expression in different parathyroid tissue cells.
MATERIALS AND METHODS
Parathyroid tissue cells were isolated enzymatically and cultured in vitro. Expression of HLA class I (HLA-A, HLA-B, HLA-C) mRNA and protein levels were studied in 7 parathyroid adenomas and 9 parathyroid hyperplasia tissue samples by reverse transcriptase-polymerase chain reaction and Western blot analyses.
RESULTS
HLA-A protein expression remained stable in parathyroid adenoma and hyperplasia tissue, but HLA-A mRNA expression decreased in adenoma tissue. In parathyroid hyperplasia tissue, HLA-B protein expression remained stable, although mRNA expres-sion levels decreased during cultivation. HLA-C mRNA expression was steady in parathyroid adenoma yet significantly decreased in hyperplasia tissue samples. HLA-C protein expression levels were below 30 pg for both types of parathyroid tissue during cultivation.
CONCLUSIONS
HLA class I expression levels of para-thyroid hyperplasia and adenoma tissue were not found to be similar. Parathyroid hyperplasia tissue is the donor tissue for the treatment of permanent hypoparathyroidism. Therefore, expression patterns of HLA class I are directly relevant to the transplant process. In particular, the HLA region is highly polymorphic, and, as a consequence of this, heterogeneous correlations among HLA-A, HLA-B, and HLA-C expression patterns of parathyroid tissue should be evaluated in detail before transplant for future studies.
Topics: Adenoma; HLA Antigens; HLA-C Antigens; Humans; Hyperplasia; Parathyroid Glands; Parathyroid Neoplasms; RNA, Messenger; RNA-Directed DNA Polymerase; Treatment Outcome
PubMed: 30995898
DOI: 10.6002/ect.2018.0388 -
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 -
PloS One 2017Nodular hyperplasia of parathyroid glands (PG) is the most probable cause of medical treatment failure in secondary hyperparathyroidism (sHPT). This prospective cohort...
INTRODUCTION
Nodular hyperplasia of parathyroid glands (PG) is the most probable cause of medical treatment failure in secondary hyperparathyroidism (sHPT). This prospective cohort study is located at the interface of medical and surgical consideration of sHPT treatment options and identifies risk-factors for nodular hyperplasia of PG.
MATERIAL AND METHODS
One-hundred-eight resected PG of 27 patients with a broad spectrum of sHPT severity were classified according to the degree of hyperplasia by histopathology. Twenty routinely gathered parameters from medical history, ultrasound findings of PG and laboratory results were analyzed for their influence on nodular hyperplasia of PG by risk-adjusted multivariable binary regression. A prognostic model for non-invasive assessment of PG was developed and used to weight the individual impact of identified risk-factors on the probability of nodular hyperplasia of single PG.
RESULTS
Independent risk-factors for nodular hyperplasia of single PG were duration of dialysis in years, PG volume in mm3 determined by ultrasound and serum level of parathyroid hormone in pg/mL. Multivariable analyses computed a model with an Area Under the Receiver Operative Curve of 0.857 (95%-CI:0.773-0.941) when predicting nodular hyperplasia of PG. Theoretical assessment of risk-factor interaction revealed that the duration of dialysis had the strongest influence on the probability of nodular hyperplasia of single PG.
CONCLUSIONS
The three identified risk-factors (duration of dialysis, PG volume determined by ultrasound and serum level of parathyroid hormone) can be easily gathered in daily routine and could be used to non-invasively assess the probability of nodular hyperplasia of PG. This assessment would benefit from periodically collected data sets of PG changes during the course of sHPT, so that the choice of medical or surgical sHPT treatment could be adjusted more to the naturally changing type of histological PG lesion on an individually adopted basis in the future.
Topics: Adult; Aged; Biomarkers; Female; Humans; Hyperparathyroidism, Secondary; Hyperplasia; Middle Aged; Organ Size; Parathyroid Glands; Parathyroid Hormone; Parathyroidectomy; Prognosis; Prospective Studies; ROC Curve; Renal Dialysis; Risk Factors; Time Factors; Ultrasonography, Doppler
PubMed: 29040300
DOI: 10.1371/journal.pone.0186093 -
Cureus Jun 2023Multiple endocrine neoplasia type 2A (MEN2A) is a rare hereditary condition characterized by medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism....
Multiple endocrine neoplasia type 2A (MEN2A) is a rare hereditary condition characterized by medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism. The current standard of treatment of hyperparathyroidism involves surgical removal of visibly enlarged glands, and auto-transplantation of remnant tissue is often considered to minimize the risk of iatrogenic post-surgical hypocalcemia if multiple glands are enlarged. Rarely, hyperparathyroidism may recur due to hyperplasia or adenoma formation in the auto-transplanted tissue. The following case portrays a 51-year-old male, with a history of MEN2A status post total parathyroidectomy with cryopreservation and subsequent auto-transplantation of remnant parathyroid tissue to the left arm 18 years prior, who presented to establish care due to the insidious development of asymptomatic hypercalcemia. Workup included a laboratory examination showing elevated intact parathyroid hormone (PTH) and left arm ultrasound revealing three areas of enlarged parathyroid tissue at the transplant site, raising suspicion for the development of recurrent primary hyperparathyroidism in auto-transplanted tissue. The patient ultimately underwent a re-do subtotal parathyroidectomy of auto-transplanted tissue with surgical pathology confirming hyperplastic parathyroid tissue. This case highlights the significance of indefinite vigilant surveillance in this patient population, as a recurrence of hyperparathyroidism may occur even after decades of remission.
PubMed: 37485129
DOI: 10.7759/cureus.40715 -
Kidney International. Supplement Jul 2006Parathyroid hyperplasia is the cause of parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical...
Parathyroid hyperplasia is the cause of parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical contributors to the worsening of the hyperplastic parathyroid growth induced by KD. Reproduction of the features of human KD in the 5/6 nephrectomized rat model has shown that 80% of the mitogenic signals induced by KD in parathyroid cells that are aggravated by either high phosphate (P) or low calcium (Ca) diets occurred within 5 days after the onset of KD. Enhanced parathyroid expression of the potent growth promoter transforming growth factor alpha (TGFalpha) and its receptor, the epidermal growth factor receptor (EGFR), was identified as the main cause of parathyroid hyperplasia in experimental KD. Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGFalpha-activated EGFR, completely prevented high P- and low Ca-induced parathyroid hyperplasia in early KD, as well as the severe progression of high P-induced parathyroid growth in established secondary hyperparathyroidism, the latter characterized by marked TGFalpha and EGFR overexpression in the parathyroid glands. More importantly, the suppression of signals downstream from TGFalpha binding to EGFR with EGFR-TKI treatment also revealed that TGFalpha self-upregulation in the parathyroid glands is the main determinant of the severity of the hyperplastic growth, and that enhanced TGFalpha activation of EGFR mediates the reduction in parathyroid vitamin D receptor levels thereby causing resistance to both the antiproliferative and parathyroid hormone-suppressive properties of calcitriol therapy.
Topics: Animals; Calcitriol; Calcium, Dietary; Disease Models, Animal; Drug Resistance; Gene Expression Regulation; Humans; Hyperplasia; Hypocalcemia; Kidney Diseases; Parathyroid Glands; Phosphorus, Dietary; Rats; Signal Transduction; Vitamins
PubMed: 16810310
DOI: 10.1038/sj.ki.5001595 -
Diseases (Basel, Switzerland) Aug 2022Parathyroid proliferative disorder encompasses a wide spectrum of diseases, including parathyroid adenoma (PTA), parathyroid hyperplasia, and parathyroid carcinoma....
BACKGROUND
Parathyroid proliferative disorder encompasses a wide spectrum of diseases, including parathyroid adenoma (PTA), parathyroid hyperplasia, and parathyroid carcinoma. Imaging modalities that deliver their results preoperatively help in the localisation of parathyroid glands (PGs) and assist in surgery. Artificial intelligence and, more specifically, image detection methods, can assist medical experts and reduce the workload in their everyday routine.
METHODS
The present study employs an innovative CNN topology called ParaNet, to analyse early MIBI, late MIBI, and TcO4 thyroid scan images simultaneously to perform first-level discrimination between patients with abnormal PGs (aPG) and patients with normal PGs (nPG). The study includes 632 parathyroid scans.
RESULTS
ParaNet exhibits a top performance, reaching an accuracy of 96.56% in distinguishing between aPG and nPG scans. Its sensitivity and specificity are 96.38% and 97.02%, respectively. PPV and NPV values are 98.76% and 91.57%, respectively.
CONCLUSIONS
The proposed network is the first to introduce the automatic discrimination of PG and nPG scans acquired by scintigraphy with Tc-sestamibi (MIBI). This methodology could be applied to the everyday routine of medics for real-time evaluation or educational purposes.
PubMed: 36135211
DOI: 10.3390/diseases10030056