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Proceedings of the National Academy of... Apr 2018The pathogenesis of parathyroid gland hyperplasia is poorly understood, and a better understanding is essential if there is to be improvement over the current strategies...
The pathogenesis of parathyroid gland hyperplasia is poorly understood, and a better understanding is essential if there is to be improvement over the current strategies for prevention and treatment of secondary hyperparathyroidism. Here we investigate the specific role of Klotho expressed in the parathyroid glands (PTGs) in mediating parathyroid hormone (PTH) and serum calcium homeostasis, as well as the potential interaction between calcium-sensing receptor (CaSR) and Klotho. We generated mouse strains with PTG-specific deletion of Klotho and CaSR and dual deletion of both genes. We show that ablating CaSR in the PTGs increases PTH synthesis, that Klotho has a pivotal role in suppressing PTH in the absence of CaSR, and that CaSR together with Klotho regulates PTH biosynthesis and PTG growth. We utilized the tdTomato gene in our mice to visualize and collect PTGs to reveal an inhibitory function of Klotho on PTG cell proliferation. Chronic hypocalcemia and ex vivo PTG culture demonstrated an independent role for Klotho in mediating PTH secretion. Moreover, we identify an interaction between PTG-expressed CaSR and Klotho. These findings reveal essential and interrelated functions for CaSR and Klotho during parathyroid hyperplasia.
Topics: Animals; Bone and Bones; Calcium; Calcium, Dietary; Female; Fibroblast Growth Factor-23; Glucuronidase; Homeostasis; Hypercalcemia; Hyperparathyroidism; Hyperplasia; Hypocalcemia; Hypophosphatemia; Immunoprecipitation; Kidney; Klotho Proteins; Male; Mice; Parathyroid Glands; Parathyroid Hormone; Protein Interaction Mapping; RNA, Messenger; Receptors, Calcium-Sensing; Receptors, G-Protein-Coupled
PubMed: 29618612
DOI: 10.1073/pnas.1717754115 -
Kidney International. Supplement Dec 1999Despite three decades of intensive research on the derangements of calcium phosphate metabolism of renal failure, several unresolved issues are still with us at the turn... (Review)
Review
Despite three decades of intensive research on the derangements of calcium phosphate metabolism of renal failure, several unresolved issues are still with us at the turn of the millennium: poor control of hyperphosphatemia, relative inefficacy of active vitamin D to prevent progressive parathyroid hyperplasia, and persistence of bone disease despite lowering of parathyroid hormone (PTH) and administration of active vitamin D. Although predictions are problematic, it is not unreasonable to hope that, barring unforeseen side effects, calcimimetics will prove to be valuable for suppressing or even preventing hyperparathyroidism, thus potentially replacing, at least in part, active vitamin D. There is also reason to hope that more effective phosphate binders with fewer side effects will become available and that controlled studies will provide a rationale for the administration of estrogens to dialyzed women. As regards understanding the pathological mechanisms, one can anticipate that the disturbances leading to autonomous growth of parathyroid cells will be elucidated and the signals involved in osteoclast/osteoblast differentiation pathways and osteoclast/osteoblast coupling will be clarified, with obvious impact on patient management.
Topics: Animals; Bone and Bones; Chronic Kidney Disease-Mineral and Bone Disorder; Estrogens; Female; Humans; Parathyroid Glands; Phosphates; Vitamin D
PubMed: 10633473
DOI: 10.1046/j.1523-1755.1999.07314.x -
Medicine Nov 2022Secondary parathyroid hyperplasia canceration is very rare and thus easily be overlooked during parathyroid ultrasound examination. However, secondary parathyroid...
INTRODUCTION
Secondary parathyroid hyperplasia canceration is very rare and thus easily be overlooked during parathyroid ultrasound examination. However, secondary parathyroid hyperplasia still has the possibility of canceration, and it is still important to be alert to its occurrence when performing ultrasound examinations and clinical treatment.
PATIENT CONCERNS
A 49-years-old man visited our outpatient department with generalized weakness and pain in both lower extremities a month ago.
DIAGNOSIS
Hyperparathyroidism secondary to chronic renal failure.
INTERVENTIONS
The patient underwent ultrasound and other preoperative examinations. The preoperative ultrasound showed 3 parathyroid enlargements, 2 on the left and 1 on the right. The patient then underwent surgical treatment.
OUTCOMES
Ultrasonography suggested the presence of 3 parathyroid hyperplasias, and ectopic right inferior parathyroid gland was visible during intraoperative examination. 10 days after surgery, the patient's Parathyroid Hormone returned to the normal range.
CONCLUSION
Secondary parathyroid hyperplasia has the potential to become cancerous, so doctors should be alert to its occurrence when conducting ultrasound examinations. Ultrasound examination is the key to its diagnosis and subsequent treatment.
Topics: Humans; Male; Middle Aged; Hyperplasia; Parathyroid Neoplasms; Parathyroid Glands; Hyperparathyroidism, Primary; Carcinoma
PubMed: 36401397
DOI: 10.1097/MD.0000000000031362 -
The Israel Medical Association Journal... Dec 2017Direct aspiration from suspected pathological tissue and rapid parathyroid hormone analysis may offer a reliable, cost effective alternative to currently used "gold...
BACKGROUND
Direct aspiration from suspected pathological tissue and rapid parathyroid hormone analysis may offer a reliable, cost effective alternative to currently used "gold standard" tests.
OBJECTIVES
To validate the accuracy of intraoperative measurements of parathyroid hormone levels in parathyroid adenomas.
METHODS
A prospective study included 22 patients diagnosed with primary hyperparathyroidism who underwent parathyroidectomy due to an adenoma or hyperplasia. Aspirations of tissues extracted from three adjacent areas (the pathological parathyroid, thyroid, and muscle tissues) were sent for rapid parathyroid hormone analysis. The assay values of these tissue aspirates were compared to the results of the pathology report based on frozen section analysis and the final pathology report.
RESULTS
All assay results were significantly higher for parathyroid tissue 16,800 to 1,097,986 pmol/L (median 26,600), than for either thyroid 1.7 to 415 pmol/L (median 6.5), P < 0.001, or muscle tissue 1.1 to 1230 pmol/L, (median 11.3), P < 0.001. All tissues showing high parathyroid assay values were also verified by pathology examinations: 7 had adenomas and 15 had a differential diagnosis of adenoma or hyperplasia. The frozen section identified all but one (false negative). Rapid intraoperative parathyroid levels > 1500 predicted parathyroid tissue with a 99% level of confidence, while levels between 1000 and 1500 predicted it with 95% confidence. The intraoperative parathyroid hormone assay showed > 70% decrease in 15/21 cases.
CONCLUSIONS
Rapid intraoperative parathyroid hormone analysis is a reliable and precise technique, equally accurate for frozen section analysis in predicting with high certainty intraoperative parathyroid tissue.
Topics: Biopsy, Needle; Clinical Chemistry Tests; Diagnosis, Differential; Female; Frozen Sections; Humans; Hyperparathyroidism, Primary; Hyperplasia; Intraoperative Care; Male; Middle Aged; Parathyroid Glands; Parathyroid Hormone; Parathyroid Neoplasms; Parathyroidectomy; Predictive Value of Tests; Reproducibility of Results
PubMed: 29235733
DOI: No ID Found -
Kidney International Aug 2008The identification of the calcium-sensing receptor (CaSR) and the clarification of its role as the major regulator of parathyroid gland function have important... (Review)
Review
The identification of the calcium-sensing receptor (CaSR) and the clarification of its role as the major regulator of parathyroid gland function have important implications for understanding the pathogenesis and evolution of secondary hyperthyroidism in chronic kidney disease (CKD). Signaling through the CaSR has direct effects on three discrete components of parathyroid gland function, which include parathyroid hormone (PTH) secretion, PTH synthesis, and parathyroid gland hyperplasia. Disturbances in calcium and vitamin D metabolism that arise owing to CKD diminish the level of activation of the CaSR, leading to increases in PTH secretion, PTH synthesis, and parathyroid gland hyperplasia. Each represents a physiological adaptive response by the parathyroid glands to maintain plasma calcium homeostasis. Studies of genetically modified mice indicate that signal transduction via the CaSR is a key determinant of parathyroid cell proliferation and parathyroid gland hyperplasia. Because enlargement of the parathyroid glands has important implications for disease progression and disease severity, it is possible that clinical management strategies that maintain adequate calcium-dependent signaling through the CaSR will ultimately prove useful in diminishing parathyroid gland hyperplasia and in modifying disease progression.
Topics: Animals; Disease Progression; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Mice; Parathyroid Glands; Parathyroid Hormone; Receptors, Calcium-Sensing; Signal Transduction
PubMed: 17568787
DOI: 10.1038/sj.ki.5002287 -
BMC Endocrine Disorders Nov 2012Thyroid hemiagenesis is a rare anomaly, more commonly seen on the left side (ratio 4:1) and in females (ratio 3:1). The first to describe this anomaly was Handfield...
BACKGROUND
Thyroid hemiagenesis is a rare anomaly, more commonly seen on the left side (ratio 4:1) and in females (ratio 3:1). The first to describe this anomaly was Handfield Jones in 1852.
CASE PRESENTATION
We present a 66 year old female patient with right thyroid hemiagenesis, parathyroid adenoma on the side of hemiagenesis and parathyroid hyperplasia on the contralateral side. The patient had neck pain and was diagnosed as Hashimto thyroiditis with hyperparathyroidism. Parathyroid hormone, thyroglobulin antibodies (Tg-Ab) and thyroid peroxidase antibodies (TPO-Ab) were elevated. Neck ultrasound and technetium 99mTc-methoxyisobutyl isonitrile (MIBI) scintigraphy confirmed the right thyroid hemiagenesis, but not adenoma of parathyroid glands. Intraoperatively, right thyroid hemiagenesis was confirmed and left loboistmectomy was performed with removal of left inferior hyperplastic parathyroid gland. Postoperative PTH (parathyroid hormone) levels were within normal range. Five months after the operation PTH level was elevated again with calcium values at the upper limit. MIBI scintigraphy was performed again which showed increased accumulation of MIBI in the projection of the right parathyroid gland. Surgical reexploration of the neck and excision of the right upper parathyroid adenoma was performed which was located behind cricoid laryngeal cartilage. After surgery a normalization of calcium and PTH occured.
CONCLUSION
From available literature we have not found the case that described parathyroid adenoma on the side of thyroid hemiagenesis,with parathyroid hyperplasia on the contralateral side.
PubMed: 23148717
DOI: 10.1186/1472-6823-12-29 -
The Journal of International Medical... Feb 2013This retrospective study investigated the characteristics of secondary hyperparathyroidism (SHPT) by examining the presence of the calcium-sensing receptor (CaSR) and...
OBJECTIVE
This retrospective study investigated the characteristics of secondary hyperparathyroidism (SHPT) by examining the presence of the calcium-sensing receptor (CaSR) and the rate of cell proliferation and apoptosis in parathyroid glands.
METHODS
Eighteen diffuse and 57 nodular hyperplastic parathyroid glands from 24 patients with SHPT were compared with 14 primary adenomas and 33 normal parathyroid glands using immunohistochemical staining of CaSR and a marker of proliferative activity (Ki67 antigen). Apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling assay.
RESULTS
The mean ± SE labelling index (LI) of CaSR (12.8% ± 1.5%) in nodular hyperplasia was significantly lower than that in normal parathyroid glands (26.8% ± 0.8%), whereas the mean ± SE LI of CaSR in diffuse hyperplasia was similar to that in normal parathyroid glands (23.3% ± 1.8%). The mean ± SE LI of Ki67 antigen was significantly higher in primary adenoma and nodular hyperplasia than in normal parathyroid glands.
CONCLUSION
These results indicate that downregulation of CaSR, and a higher rate of proliferation over apoptosis, could contribute to the pathological progression of SHPT.
Topics: Adenoma; Adult; Apoptosis; Demography; Humans; Hyperparathyroidism, Secondary; Hyperplasia; Immunohistochemistry; In Situ Nick-End Labeling; Middle Aged; Parathyroid Glands; Receptors, Calcium-Sensing
PubMed: 23569134
DOI: 10.1177/0300060513476600 -
Bioscience Reports Apr 2019The aim of the present study was to elucidate the diagnostic and prognostic implications of parafibromin immunohistochemistry (IHC) in parathyroid carcinoma (PC). We... (Meta-Analysis)
Meta-Analysis
The aim of the present study was to elucidate the diagnostic and prognostic implications of parafibromin immunohistochemistry (IHC) in parathyroid carcinoma (PC). We performed a meta-analysis to examine the rate of loss of parafibromin expression from 18 eligible studies. In addition, a diagnostic test accuracy review was conducted to investigate the diagnostic role of parafibromin in PC. The rates of loss of parafibromin expression were 0.522 (95% CI: 0.444-0.599), 0.291 (95% CI: 0.207-0.391), 0.027 (95% CI: 0.011-0.064), and 0.032 (95% CI: 0.008-0.119) in PC, atypical parathyroid adenoma (APA), parathyroid adenoma (PA), and parathyroid hyperplasia, respectively. In the diagnostic test accuracy review for diagnosis of PC, the pooled sensitivity and specificity of parafibromin IHC was 0.53 (95% CI: 0.46-0.59) and 0.96 (95% CI: 0.95-0.97), respectively. The diagnostic odds ratio and the area under curve on summary receiver operating characteristic curve was 25.31 (95% CI: 8.91-71.87) and 0.7954, respectively. In addition, the meta-analysis demonstrated that loss of parafibromin expression was significantly correlated with worse disease-free survival (hazard ratio: 2.832; 95% CI: 1.081-7.421). Loss of parafibromin IHC expression was significantly higher in PC than in APA, PA, and parathyroid hyperplasia. Parafibromin IHC could be useful for diagnosis and prediction of prognosis of PC in daily practice.
Topics: Biomarkers, Tumor; Disease-Free Survival; Humans; Hyperplasia; Immunohistochemistry; Parathyroid Glands; Parathyroid Neoplasms; Prognosis; ROC Curve; Tumor Suppressor Proteins
PubMed: 30926677
DOI: 10.1042/BSR20181778 -
Nephrology, Dialysis, Transplantation :... Mar 2015In chronic kidney disease (CKD), parathyroid hyperplasia contributes to high serum parathyroid hormone (PTH) and also to an impaired suppression of secondary...
BACKGROUND
In chronic kidney disease (CKD), parathyroid hyperplasia contributes to high serum parathyroid hormone (PTH) and also to an impaired suppression of secondary hyperparathyroidism by calcium, vitamin D and fibroblast growth factor 23 (FGF23). In rats, systemic inhibition of epidermal growth factor receptor (EGFR) activation markedly attenuated uremia-induced parathyroid hyperplasia and vitamin D receptor (VDR) loss, hence restoring the response to vitamin D. Therefore, we propose that parathyroid-specific EGFR inactivation should prevent CKD-induced parathyroid hyperplasia.
METHODS
A dominant-negative human EGFR mutant, which forms non-functional heterodimers with full-length endogenous EGFR, was successfully targeted to the parathyroid glands (PTGs) of FVB/N mice, using the 5' regulatory sequence of the PTH promoter. The parathyroid phenotype and serum chemistries of wild-type (WT) and transgenic mice were examined after 14 weeks of either sham operation or 75% renal mass reduction (NX).
RESULTS
Both genotypes had similar morphology and body weight, and NX-induction enhanced similarly serum blood urea nitrogen compared with sham-operated controls. However, despite similar serum calcium, phosphate and FGF23 levels in NX mice of both genotypes, parathyroid EGFR inactivation sufficed to completely prevent the marked increases in PTG enlargement, serum PTH and in parathyroid levels of transforming growth factor-α, a powerful EGFR-activator, and the VDR reductions observed in WT mice.
CONCLUSION
In CKD, parathyroid EGFR activation is essential for parathyroid hyperplasia and VDR loss, rendering this transgenic mouse a unique tool to scrutinize the pathogenesis of parathyroid and multiple organ dysfunction of CKD progression unrelated to parathyroid hyperplasia.
Topics: Animals; ErbB Receptors; Fibroblast Growth Factor-23; Humans; Hyperparathyroidism, Secondary; Hyperplasia; In Situ Hybridization; Male; Mice; Mice, Transgenic; Mutation; Parathyroid Glands; Parathyroid Hormone; Promoter Regions, Genetic; Rats; Receptors, Calcitriol; Renal Insufficiency, Chronic; Uremia
PubMed: 25324357
DOI: 10.1093/ndt/gfu318 -
British Medical Journal Jul 1971Twenty-eight members of a family over three generations were studied; six of them had hyperparathyroidism. Four of the six were siblings and one of these had suffered...
Twenty-eight members of a family over three generations were studied; six of them had hyperparathyroidism. Four of the six were siblings and one of these had suffered from recurrent hyperparathyroidism. No member of the family showed any other significant endocrine disturbance or active peptic ulceration.Attention is drawn to the prominent lack of symptoms despite dangerous levels of hypercalcaemia and advanced disease with the consequent need for estimation of serum calcium levels in all close relatives. Multiple gland involvement is common in familial hyperparathyroidism and is often coupled with a tendency to recurrence, necessitating long-term follow-up. Histological appearances vary considerably, and the risk of recurrence is not limited to cases showing primary chief cell hyperplasia, with the implication that resection of three parathyroid glands and part of the remaining gland may be the treatment of choice in all cases of familial hyperparathyroidism when multiple gland involvement is found.
Topics: Adenoma; Adolescent; Adult; Alkaline Phosphatase; Bone and Bones; Calcium; Female; Humans; Hyperparathyroidism; Hyperplasia; Male; Parathyroid Neoplasms; Pedigree; Phosphates; Recurrence
PubMed: 5090827
DOI: 10.1136/bmj.3.5766.87